Derivatives of heteroarylcarbamoylbenzene

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

 

The present invention relates to activators of glucokinase, comprising as active ingredients derived heteroarylboronic. The invention further relates to new derivatives of heteroarylboronic.

Glucokinase (GK) (ATP:D-hexose 6-phosphotransferase, EC2.7.1.1) is one of the four types of hexokinase mammals (hexokinase IV). Hexokinase is an enzyme in the first stage pikolinos ways that catalyze the reaction from glucose to glucose-6-phosphate. Expression of glucokinase widely localized in the liver and pancreatic beta-cells, and it plays an important role in glucose metabolism throughout the body by regulating or controlling stage limits the extent of glucose metabolism in these cells. Types of glucokinase, expressed in liver and pancreatic beta-cells differ in the sequence of the 15 N-terminal amino acids due to differences in splicing, but their enzymatic properties are identical. Enzyme activity three hexokinase (I, II, III), other than glucokinase, become saturated with glucose concentrations below 1 mm, whereas the Km of glucokinase glucose is 8 mm, or close to the physiological level of glucose. So, mediated by glucokinase intracellular glucose metabolism is accelerated in response to changes in BROWNELLS by the increase occurring after a meal or ingestion of glucose (10-15 mm) from normal glucose (5 mm).

theory, according to which glucokinase acts as a glucose sensor of pancreatic beta cells and liver, defended for about 10 years (for example, Garfinkel D. Et al., Computer modeling identifies glucokinase as a glucose sensor of pancreatic beta cells, American Journal discrimination, Vol. 247 (3Pt2) 1984, pp. 527-536).

Recent results on managed glucokinase gene mice confirmed that glucokinase actually plays an important role in systemic glucose homeostasis. Mice that lack functional glucokinase gene die shortly after birth (e.g., Grupe A. Et al., Transgenic blows determines that there is substantial need in glucokinase in pancreatic beta-cells in the maintenance of glucose homeostasis, Cell Vol. 83, 1995, p.69-78), although healthy and diabetic mice, sverkhekspressiya glucokinase have lower levels of glucose in the blood (for example, Ferre, T. Et al., Correction of diabetic alterations by glucokinase, Proceedings of the National Academy of Sciences of the U.S.A., Vol. 93, 1996, str-7230). With the increase of the glucose response of pancreatic beta cells and liver, although differing, both act in the direction of lowering blood glucose. Pancreatic beta cells to secrete more insulin, the liver consumes glucose and stores it as glycogen, reducing the release of glucose.

This variation of enzyme activity is glucokinase is important for mediated liver and pancreatic beta cell glucose homeostasis in mammals. The mutant form of glucokinase gene is expressed in the case of a type of diabetes that occurs in adolescence, known as MODY2 (starting with the maturation onset diabetes of the young), and it was shown that reduced glucokinase activity is responsible for the increase in blood glucose (for example, Vionnet N. Et al., minor mutation glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus, Nature Genetics, Vol. 356, 1992, str-722).

On the other hand, were found in families with a mutation that increases the activity of glucokinase, and such individuals are hypoglycemic symptoms (e.g., Glaser C. et al., Familial hyperinsulinism caused by an activating glucokinase mutation (Family hyperinsulinism caused by activating mutations of the glucokinase), New England Journal Medicine, Vol. 338, 1998, str-230).

This suggests that people also glucokinase acts as a glucose sensor and thus plays an important role in glucose homeostasis. Use glucokinase sensor systems should be possible to achieve the regulation of glucose in patients with type II diabetes. As glucokinase activators must have effects of accelerating the secretion of insulin from pancreatic beta cells and promotion of uptake of glucose and inhibiting the release of glucose by the liver, they are potentially useful as terapeutiche the fir agents for patients with diabetes type II.

In recent years, it has been demonstrated that glucokinase pancreatic beta cells is expressed locally in the rat brain, especially in ventromedial hypothalamus (VMH). It is known approximately 20% of VMH neurons as "reacting glucose neurons", and for a long time it was believed that they play an important role in regulating body weight. The introduction of glucose into the brain of rats reduces feed intake and inhibition of glucose metabolism by vnutricerepnogo the introduction of similar glucose glucosamine causes hyperphagia. Electrophysiological experiments showed that responds to glucose neurons are activated in response to physiological changes in glucose levels (5-20 mm), but their activation is inhibited by inhibition of the metabolism of glucose, glucosamine, or similar. It is believed that the system, detecting the level of glucose in the VMH, based on indirect glucokinase mechanism similar to the mechanism of insulin secretion of pancreatic beta cells. Accordingly, substances that activate glucokinase in VMH in addition to pancreatic beta cells, not only showing the cleaning effect of glucose, but also have the potential to correct obesity, which is a problem for most patients with type II diabetes.

This indicates that the compounds exhibiting the effects of activated what I glucokinase, are useful as therapeutic and/or prophylactic agents against diabetes, a therapeutic and/or prophylactic agents against diabetes-related complications such as retinopathy, nephropathy, neuropathy, ischemic cardiopathy, arteriosclerosis and similar, and as therapeutic and/or prophylactic agents against obesity or obesity.

Described was the compound represented by the following formula (IV)having the substituents in the 3 - and 5-positions of the benzene ring, as well as derivatives heteroarylboronic (I) of the present invention.

This compound is tert-butylene group and at the 3 - and 5-positions heteroarylboronic ring, but does not have alkyl groups in the 3 - and 5-positions in contrast to the compounds of the invention. It has also imidazo-[1,2-a]pyridine associated with the nitrogen atom carbamoyl group, but the relative positional relationship between the nitrogen atom of the pyridine ring imidazo-[1,2-a]peredelnoj group and carbamoyl group differs from the relative positional relationship between carbamoyl group and the nitrogen atom of the heteroaryl group in the compounds of the invention (for example, Japanese laid out publication of the international application No. 11-505524).

The connection represented by the following f is rmulas (V), having two of the substituent in the benzene ring heteroarylboronic derivative, has also been described (for example, Japanese laid out publication of the international application No. 2001-526255).

Although the compound described in the above patent document 2, a partially corresponds to the structure of the compounds of the present invention in that one of the two substituents is triptoreline, triptoreline group included in the X1-(Ring A)-R1compounds of the present invention, and that it contains the pyridine ring in the form of groups associated with the nitrogen atom carbamoyl groups in the compounds of the present invention, the nitrogen atom of the pyridine ring, associated with the nitrogen atom carbamoyl group is adjacent to the carbon atom in the pyridine ring, which is connected with the nitrogen atom carbamoyl group, whereas the compound described in the above Patent document 2, characterized in that the nitrogen atom is connected through another carbon atom lying between it and the carbon atom in the pyridine ring, which is connected with the nitrogen atom carbamoyl group, as well as the fact that the position of communications metoxygroup differs from the position of connection of the compounds of the present invention.

The compound represented by the following formula (VI), has also been described (e.g. the R, in Japanese laid out publication of the international application No. 2002-509536).

Although the compound described in the above patent document 3, corresponds to the structure of the compounds of the present invention in that one of the two substituents in the benzene ring is 2-methyl-4-iodine-phenylamino, and that the nitrogen atom is adjacent to the carbon atom connected to the nitrogen atom carbamoyl group, however it differs in that the positional relationship between the 2-methyl-4-iodine-phenylamino group and carbamoyl group differs from positinos linkages in the compounds of the invention, and the fact that it has vorgruppe as another of two substituents in the benzene ring, while the compounds of the present invention do not contain any halogen atoms as the substituent of the benzene ring.

Through careful research aimed at developing new drugs against diabetes, manifesting new drug actions, which are also superior to the medicinal action of existing drugs against diabetes as a result of action different from the action of existing drugs, found that the compounds represented by formula (I)shown below, have the effects of activating glucokinase. In particular, this is th invention relates to the next.

(1) a Compound represented by the following formula (I):

[in which X1represents oxygen, sulfur or NH, X2represents oxygen, sulfur or CH2, R1represents 1 or 2 substituent, optionally present in the Ring And which are selected from the group consisting of alkylsulfonyl, alkanoyl, lower alkyl, hydroxyalkyl, hydroxy, allylcarbamate, alkylsulfonyl, dialkylamino, alkylthio, alkoxy, dialkylamino, alkoxycarbonyl, alkoxycarbonyl, halogen atoms, alkanolamine, alkoxycarbonylmethyl, alkylsulfonyl, cyano and trifloromethyl, R2represents a C3-7 cyclic alkyl group (in which one of the constituent carbon atoms of the ring (excluding the carbon atom among the components of the carbon atoms of the ring, which is associated with X2) optionally substituted by oxygen, NH, N-alkanoyl or CONH), the lower alkyl group with straight or branched chain or lower alkenylphenol group, optionally having a Deputy selected from the group consisting of halogen atoms, carboxyl, alkoxycarbonyl, hydroxy, amino (in which the amino may be optionally substituted 1 or 2 alkanolamine or lower alkyl groups), alkoxy and N-allylcarbamate, R3represents 1 or 2 Deputy who, not necessarily present in the Ring, which is selected from the group consisting of lower alkyl, alkoxy, alkylamino, lower dialkylamino, halogen atoms, trifloromethyl, hydroxyalkyl (in which the hydrogen of the hydroxy-group in the hydroxyalkyl group may be substituted by lower alkyl), aminoalkyl, alkanoyl, carboxyl, alkoxycarbonyl and cyano, the following formula (II):

represents a 6 - to 10-membered aryl group or 5 - to 7-membered heteroaryl group, optionally having in the ring 1 or 2 substituent represented by the group R1above and the following formula (III):

represents monocyclic or bicyclic heteroaryl group, optionally having in the ring 1 or 2 substituent represented by the group R3above, in which the carbon atom of Ring B, which is connected to the nitrogen atom of amide group in formula (I), forms a C=N bond with the nitrogen atom of the ring, and their pharmaceutically acceptable salts;

(2) Connection on p.(1), where X1represents O or S, and X2represents O or CH2;

(3) the Connection of p.(2), where the Ring a represents a phenyl group or 5 - to 6-membered heteroaryl group;

(4) the Connection of p.(2), where the Ring a represents a phenyl group;

(5) the Compound according to p.(2)where Ko is ICO And represents 5- - 6-membered heteroaryl group;

(6) the Compound according to any one of paragraphs.(4)-(5), in which R1is hydrogen, alkylsulfonyl, alkanoyl, hydroxyalkyl, allylcarbamate, alkylsulfonyl, dialkylamino, dialkylamino, alkoxycarbonyl, halogen atom, alkanolamines, alkylsulfonamides or alkoxycarbonylmethyl;

(7) the Compound according to p.(4), where R1represents alkylsulfonyl, alkanoyl, hydroxyalkyl, alkanolamines, alkylsulfonamides or alkoxycarbonylmethyl;

(8) the Compound according to p.(4), where R1represents alkylsulfonyl, alkanoyl or hydroxyalkyl;

(9) the Compound according to any one of paragraphs.(3)to(8), in which formula (III) represents monocyclic or bicyclic heteroaryl group (provided that the heteroaryl group is a 5-alkoxycarbonyl-pyridine-2-yl or 5-carboxyl-pyridine-2-yl), optionally having in the ring 1 or 2 substituent represented by the symbol R3above, in which the carbon atom of Ring b, which is connected to the nitrogen atom of amide group in formula (I), forms a C=N bond with the nitrogen atom of the Ring;

(10) Connection p.(7), where the Ring has at least one heteroatom in the ring selected from the group consisting of nitrogen atoms, sulfur and oxygen in addition to nitrogen atom, forms a C=N group together with the carbon atom at the Kohl is e, which is connected to the nitrogen atom of amide group in formula (I);

(11) the Compound according to any connection of PP.(1)to(10), in which R2represents a C3-7 cyclic alkyl group (in which one of the constituent carbon atoms of the ring are optionally replaced with oxygen, NH or N-alkanoyl), the lower alkyl group with straight or branched chain or lower alkenylphenol group optionally substituted by a halogen atom, carboxyla, alkoxycarbonyl, hydroxy, amino group (in which the amino group may optionally be substituted by 1 or 2 lower alkyl groups), alkoxy, N-allylcarbamate or alkanolamine;

(12) the Compound according to any one of paragraphs.(1)to(11), in which the ring is thiazolyl, imidazolyl, isothiazolin, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrimidinyl, peridotitic or benzothiazolyl;

(13) the Compound according to any one of paragraphs.(1)to(12), in which R3represents lower alkyl, alkoxy, halogen atom, hydroxyalkyl (in which the hydrogen atom of the hydroxy group in the hydroxyalkyl group may be substituted by lower alkyl), aminoalkyl or alkanoyl;

(14) the Compound according to any one of paragraphs.(1)to(12), in which R3represents lower alkyl or hydroxyalkyl (in which the hydrogen atom of the hydroxy group in the hydroxyalkyl group may be substituted by lower alkyl);

<> (15) the Compound represented by formula (I):

[in which the symbols have the same definitions specified above], which is

5-isopropoxy-3-(4-methysulfonylmethane)-N-(4-methylthiazole-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-ethoxy-3-(4-methysulfonylmethane)-N-(4-methoxymethyl-thiazol-2-yl)benzamid,

5-cyclopentyloxy-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide,

3-(2-fluoro-4-methysulfonylmethane)-5-isopropoxy-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)benzamid,

5-isopropoxy-3-(4-methysulfonylmethane)-N-pyrazole-3-yl-benzamide,

5-isopropoxy-3-(4-methysulfonylmethane)-N-pyrazin-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide,

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methysulfonylmethane)-N-pyrimidine-4-yl-benzamide,

5-isopropoxy-3-(4-methysulfonylmethane)-N-(pyrimidine-2-yl)benzamid,

<> N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide,

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazole-2-yl-benzamide,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide,

5-(2-amino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-dimethylamino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-propoxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamid,

3-(4-methysulfonylmethane)-5-(2-methoxy-propoxy)-N-(4-methyl-thiazol-2-yl)benzamid,

5-isopropoxy-3-(4-methysulfonylmethane)-N-(thiazolo[5,4-b]pyridine-2-yl)benzamid,

5-(2-hydroxymethyl-allyl)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-(3-hydroxy-2-methyl-propyl)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

Hydrochloride 3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)-5-(piperidine-4-yl-oxy)benzamide,

5-(1-acetyl-piperidine-4-yloxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamid,

2-[3-(4-methysulfonylmethane)-5-(4-methylthiazole-2-yl-carbarnoyl)phenoxy]propionic acid,

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(1-methylcarbamoylmethyl)-N-(4-methyl-thiazol-2-yl)benzamid,

5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-pyridin-2-yl-benzamide,

5-(2-hydroxy-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-cyclopentyloxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

N-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methyl-thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-([1,2,4]thiadiazole-5-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methoxycarbonyl-pyridine-2-yl)benzamid,

-[5-isopropoxy-3-(4-methysulfonylmethane)benzoylamine]nicotinic acid,

5-(2-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)benzamid,

N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(2-methylthiazole-4-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4-methoxymethyl-thiazol-2-yl)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide,

N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-isopropoxy-3-(4-methoxycarbonylaminophenyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methylcarbamoyl-phenoxy)-N-thiazol-2-yl-benzamide,

3-(4-dimethylcarbamoyl-phenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methylcarbamoylmethyl-phenoxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methanesulfonylaminoethyl-phenoxy)-N-thiazol-2-yl-benzamide,

3-[4-(1-hydroxy-propyl)phenoxy]--isopropoxy-N-thiazol-2-yl-benzamide,

methyl ester of 6-[3-isopropoxy-5-(thiazol-2-ylcarbonyl)phenoxy]nicotinic acid,

3-(5-hydroxymethyl-pyridine-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(methanesulfonamide-2-yl)-N-thiazol-2-yl-benzamide,

3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methoxycarbonyl-pyrazin-2-yl-oxy)-N-thiazol-2-yl-benzamide,

3-(5-cyano-pyridine-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-4-yl-oxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-3-yl-oxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-3-yl-oxy)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-isopropoxy-3-(4-methyl-[1,2,4]triazole-3-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-thiazol-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4H-[1,2,4]triazole-3-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methylsulfanyl-[1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(tetrahydrofuran-3-yl-oxy)-N-thiazol-2-yl-3-(4H-[1,2,4]triazole-3-ylsulphonyl)benzamid,

5-(2-hydroxy-1-methyl-this is XI)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazole-2-ylsulphonyl)benzamid,

5-(3-hydroxy-1-methyl-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazole-2-ylsulphonyl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylaminoethyl)-N-thiazol-2-yl-benzamide,

3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(pyridine-4-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridine-3-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamid,

N-[3-hydroxymethyl-1,2,4-thiadiazole-5-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

5-(3-hydroxy-1-methylethoxy)-3-(4-methysulfonylmethane)-N-[5-methyl-1,2,4-thiadiazole-3-yl]benzamide,

5-(hydroxy-1-methylethoxy)-3-(4-methysulfonylmethane)-N-(3-methoxy-1,2,4-thiadiazole-5-yl]benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1,2,5-thiadiazole-3-yl]benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4-trifluoromethyl-thiazol-2-yl]benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4,5,6,7-tetrahydroindazole-2-yl]benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(pyridazin-3-yl]benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]-triazole-5-yl)-3-(4-meth is sulfanilamide)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(3-methyl-[1,2,4]-oxadiazol-5-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)benzamid,

N-(4-cyano-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(pyridin-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methyl-isothiazol-3-yl)benzamid,

5-(3-hydroxy-cyclopentyloxy)-3-(4-methysulfonylmethane)-N-(thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methoxy-thiazol-2-yl)benzamid,

5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methysulfonylmethane)-N-(thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1H-[1,2,3]triazole-4-yl)benzamid,

N-(1-acetyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(pyrazole-3-yl)benzamid,

N-(5,6-dihydro-4H-cyclopentadiene-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-metasolv is Difenoxin)-N-(thieno[3,2-d]thiazole-2-yl)benzamid,

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(4-cyano-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-metilsulfonilmetane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-acanaloniidae)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-isopropylphenoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxy-4-methyl-4,5,6,6A-tetrahydro-an-cyclopentadiene-2-yl)-3-(4-methysulfonylmethane)benzamid,

3-(4-dimethylcarbamoyl-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-acetylphenol)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(1,3,4-thiadiazole-2-ylsulphonyl)benzamid,

N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-guide is hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminophenyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazole-5-yl)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-isopropoxy-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylaminoethyl)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-cyclopropylamino-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(6-acanaloniidae-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

tert-butyl ester 2-[3-(4-methysulfonylmethane)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid,

3-(6-acanaloniidae-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)-5-(tetrahydrofuran-yl)benzamid,

N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

2-[3-(4-methysulfonylmethane)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid,

3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyridin-2-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-chloro-1-methyl-ethoxy)-3-(6-acanaloniidae-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-N-(isoxazol-3-yl)-3-(6-methanesulfonamido-3-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(pyridin-2-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-means heilperin-3-yloxy)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamid,

3-(4-dimethylaminoethoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(3-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-isopropylacetanilide-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(3-chloro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-3-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-3-yloxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-4-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-4-yloxy)benzamide,

2-[3-(6-acanaloniidae-3-yloxy)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid, or

5-(2-fluoro-1-vermeil-ethoxy)-3-(3-fluoro-4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

or its pharmaceutically acceptable salt;

(16) the Connection

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-thiazol-2-yl-benzamide, or its pharmaceutically acceptable salt;

(17) the Connection

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethylethoxy)benzamide, or its pharmaceutically acceptable salt;

(18) the Connection

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-IU insulter-phenoxy)-N-pyridin-2-yl-benzamide, or its pharmaceutically acceptable salt;

(19) the Connection

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(2-methylthiazole-4-yl)benzamide, or its pharmaceutically acceptable salt;

(20) the Connection

5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide, or its pharmaceutically acceptable salt;

(21) the Connection

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamide, or its pharmaceutically acceptable salt;

(22) the Connection

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide, or its pharmaceutically acceptable salt;

(23) the Connection

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide, or its pharmaceutically acceptable salt;

(24) the Connection

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide, or its pharmaceutically acceptable salt;

(25) the Connection

3-(6-econsultancy-pyridine-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazole-3-yl)benzamide, or its pharmaceutically acceptable salt;

(26) the Connection

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonyl-pyridine-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide, or its pharmaceutically acceptable salt;

(27) the Connection

3-(6-econsultancy-pyridine-3-ILO is si)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamid, or its pharmaceutically acceptable salt;

(28) the Connection

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonyl-pyridine-3-yloxy)-N-(pyrazole-3-yl)benzamide, or its pharmaceutically acceptable salt;

(29) a Pharmaceutical composition suitable for the treatment, prophylaxis or prevention of attack of type II diabetes, comprising the following ingredients(1)-(3):

(1) the compound represented by formula (I),

(2) 1, 2 or more compounds selected from the group consisting of the following (a)to(g):

(a) other activators of glucokinase,

(b) biguanide,

(c) PPAR agonists

(d) insulin,

(e) somatostatin,

(f) inhibitors α-glucosidase and

(g) substances that promote insulin secretion, and

(3) a pharmaceutically acceptable carrier;

(30) a glucokinase Activator comprising a compound according to any one of items (1)to(28)above, as an active ingredient;

(31) drug for the treatment and/or prevention of diabetes, comprising a compound according to any one of items (1) to (28)above, as an active ingredient; and

(32) drug for the treatment and/or prevention of obesity and obesity comprising a compound according to any one of items (1) to (28)above, as the active ingredient.

The meaning of the terms used in the present description, will be explained, and compounds of the invention is Udut disclosed in detail below.

"Aryl" group is C6-14 aryl hydrocarbon group, examples of which include phenyl, naphthyl, biphenyl and antril.

"Lower alkyl group" is preferably C1-6 alkyl group with straight or branched chain, examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, isopentyl, 1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,2,2-trimethylpropyl and 1-ethyl-2-methylpropyl.

"Lower Alchemilla" group represents a C1-6 lower alkenylphenol group with a straight or branched chain, examples of which include vinyl, allyl, 1-butenyl, 2-butenyl and 1-pentenyl.

"Alkoxy group" represents a group in which the hydrogen of the hydroxyl group substituted by the above lower alkyl group, and examples of which include methoxy, ethoxy, propoxy, isopropoxy, butoxy,Deut-butoxy,tert-butoxy, pentyloxy, isopentylamine, hexyloxy, etexilate.

"Heteroaryl" group is a 5 - to 7-membered monocyclic group having a heteroaryl group 1-3 heteroatoms selected from the group consisting of atoms to which Sloboda, sulfur and nitrogen, or a bicyclic heteroaryl group, which includes such monocyclic heteroaryl group fused with a benzene ring or pyridine ring, and examples include furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrazinyl, hinely, ethanolic, hintline, hinolinol, honokalani, cinnoline, benzimidazolyl, imidazopyridine, benzofuranyl, naphthylidine, 1,2-benzisoxazole, benzoxazole, benzothiazole, oxazolopyridine, peridotites, isothiazolines and sensational.

"Halogen atom" is, for example, fluorine, chlorine, bromine, iodine or similar.

"Hydroxyalkyl group" is a group in which one hydrogen of the above-mentioned lower alkyl group is substituted by a hydroxy-group, and its examples include hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, 1-hydroxyethyl, 2-hydroxypropyl and 2-hydroxy-1-methyl-ethyl.

"Alkylcarboxylic" group is karbamoilnuyu group monosubstituted the above-mentioned lower alkyl group and its examples include methylcarbamoyl, ethylcarbitol, propellerblades, isopropylcarbamate, butylcarbamoyl,Deut-butylcarbamoyl andtert-butylcarbamoyl.

"Dialkylanilines" group submitted the karbamoilnuyu group, disubstituted by identical or different lower alkyl groups, and examples of "dialkylammonium" groups include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylamino, dipropylamino, methylpropylketone and diisopropylamino.

"Alkylamino" group represents an amino group, monosubstituted the above-mentioned lower alkyl group and its examples include methylamino, ethylamino, propylamino, isopropylamino, butylamino,Deut-butylamino andtert-butylamino.

"Dialkylamino" group represents an amino group, a disubstituted by identical or different lower alkyl groups, and examples include dimethylamino, diethylamino, dipropylamino, methylpropylamine, diisopropylamino.

"Aminoalkyl" group represents a group in which one hydrogen of the above-mentioned alkyl group is a substituted amino group, and its examples include aminomethyl, aminoethyl and aminopropyl.

"Alcoolica" group represents a group in which the above-mentioned alkyl group linked to a carbonyl group, and its examples include methylcarbamyl, ethylcarboxyl, propylmalonic and isopropylcarbonate.

"Alkanolamine" group represents a group in which the above-mentioned alcoolica group is linked to the amino group, and its examples include methylcobalamin, ethylcarbodiimide, isopropylene is ylamino.

"Alkanolamine" group represents a group in which one hydrogen of the above-mentioned alkyl group is substituted by the above-mentioned alkanolamine group, and its examples include acetamidomethyl, ethylcarbodiimide, methylcarbamoylmethyl and isopropylcarbodiimide.

"Alkylthio" group represents a group in which the above alkyl group is linked to the sulfur atom, and examples include the methylthio, ethylthio, propylthio, isopropylthio.

"Alkylsulfonyl" group represents a group in which the above alkyl group is associated with sulfonyloxy group, and its examples include methylsulphonyl, ethylsulfonyl, propylsulfonyl and isopropylphenyl.

"Alkylsulfonyl" group represents a group in which one hydrogen of the amino group is monosubstituted above alkylsulfonyl group, and its examples include methylsulfonylamino, ethylsulfonyl, propylsulfonyl, isopropylbenzylamine.

"Alkoxycarbonyl" group represents a group in which the hydrogen of the carboxyl group is substituted by the above alkyl group and its examples include methoxycarbonyl, etoxycarbonyl, propylmalonic and isopropylcarbonate.

"Alkoxycarbonyl" group represents a group in which one hydrogen of the amino group one is substituted by the above-mentioned alkoxycarbonyl group, and its examples include methoxycarbonylamino, ethoxycarbonylethyl, propylnitrosamine, isopropylcarbodiimide.

"Alkoxycarbonylmethyl" group represents a group in which one hydrogen of the above-mentioned alkyl group is substituted by the above-mentioned alkoxycarbonyl group, and its examples include methoxycarbonylaminophenyl, ethoxycarbonylmethyl and isopropylcarbodiimide.

"Alkylsulfonyl" group represents a group in which one hydrogen group NH2sulfamoyl group is substituted by the above lower alkyl group and its examples include methylsulfonyl, ethylsulfonyl and isopropylphenol.

"Dialkylaminoalkyl" group represents a group in which two hydrogen atoms of the group NH2sulfamoyl group substituted by identical or different lower alkyl groups, and examples include dimethylsulphamoyl, diethylcarbamoyl, ethylmethylamino and diisopropylphenol.

For a more detailed description of the compounds of the present invention represented by the formula (I), each of the symbols used in the formula (I) will be explained using specific examples.

Formula (II):

represents a 6 - to 10-membered aryl group or 5 - to 7-membered heteroaryl group, n is necessarily having on the ring 1 or 2 substituent, represented by the symbol R1defined above.

As examples of "6 - to 10-membered aryl groups represented by Ring A, may be mentioned phenyl and naphthyl, among which phenyl is preferred.

As examples of the "5 - to 7-membered heteroaryl groups represented by Ring A, may be mentioned "5 - to 7-membered heteroaryl" groups for "heteroaryl" groups defined above, and 5 - to 6-membered heteroaryl group are preferred.

As examples of the "5 - to 7-membered heteroaryl groups represented by Ring A, preferred are furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, among which triazolyl, thiazolyl, thiadiazolyl, pyridyl and pyrazinyl are more preferred, and triazolyl, thiadiazolyl and pyridyl are even more preferred.

Preferred as Ring And are thiadiazolyl, phenyl and pyridyl, and phenyl and pyridyl is preferred.

The ring And is optional on the ring 1 or 2 substituent represented by R1where R1represents a group selected from alkylsulfonyl, alkanoyl, alkyl, hydroxyalkyl, hydroxy, allylcarbamate, alkylsulfonyl, dialkylamino, alkylthio, al is hydroxy, dialkylamino, alkoxycarbonyl, atoms, halogen, cyano, alkoxycarbonyl, alkanolamine, alkylsulfonamides, alkoxycarbonylmethyl and trifloromethyl, and when Ring a has two such substituent, the substituents may be the same or different.

As R1are preferred alkylsulfonyl, alkanoyl, hydroxyalkyl, allylcarbamate, alkylsulfonyl, dialkylamino, dialkylamino, alkoxycarbonyl, halogen atoms, alkanolamines, alkylsulfonamides and alkoxycarbonylmethyl, and alkylsulfonyl, alkanoyl, hydroxyalkyl, halogen atoms, alkanolamines, alkylsulfonamides and alkoxycarbonylmethyl more preferred, and alkylsulfonyl, alkanoyl, halogen atoms and hydroxyalkyl even more preferred, and particularly preferred is alkylsulfonyl.

When the Ring a has R1on the ring, the position to which R1attached to the Ring And is not particularly limited and may be any position connection.

When Ring a is phenyl, the position of the join R1on the phenyl group is preferably a para-position with respect to the relationship between the X1and phenyl group.

X1represents O, S or NH, among which are O or S are pre is respectful, but more preferred.

Thus, as examples X1-Ring A-R1where X1is and Ring a is phenyl, can be mentioned 4-(1-hydroxyethyl)phenoxy, 4-(1-hydroxypropyl)phenoxy, 4-methanesulfonate, 4-methylcarbamyl-phenoxy,

4-methylcarbamoyl-phenoxy, 4-ethylcarboxyl-phenoxy,

4-dimethylcarbamoyl-phenoxy,

4-methylcarbamoylmethyl-phenoxy,

4-methanesulfonylaminoethyl-phenoxy,

4-methoxycarbonylaminophenyl-phenoxy, 2-fluoro-phenoxy,

4-methoxycarbonyl-phenoxy, 4-hydroxymethyl-phenoxy,

4-methanesulfonyl-2-fluoro-phenoxy, 4-cyano-phenoxy,

4-methyl-phenyloxy, 4-trifluoromethyl-phenyloxy,

3-fluoro-4-methysulfonylmethane,

4 dimethylaminoethoxy,

3-chloro-4-methanesulfonate and

3 methysulfonylmethane, among which

4-(1-hydroxyethyl)phenoxy, 4-(1-hydroxypropyl)phenoxy,

4 methanesulfonate, 4-methylcarbamyl-phenoxy,

4-methylcarbamoyl-phenoxy, 4-ethylcarboxyl-phenoxy,

4-dimethylcarbamoyl-phenoxy,

4-methylcarbamoylmethyl-phenoxy,

4-methanesulfonylaminoethyl-phenoxy,

4-methoxycarbonylaminophenyl-phenoxy,

4-hydroxymethyl-phenoxy, 4-methanesulfonyl-2-fluoro-phenoxy,

3-fluoro-4-methysulfonylmethane,

4 dimethylsulfoniopropionate and

3-chloro-4-methanesulfonate are prefer the elegance,

4-(1-hydroxyethyl)phenoxy, 4-(1-hydroxypropyl)phenoxy,

4 methanesulfonate, 4-methylcarbamyl-phenoxy,

4-ethylcarboxyl-phenoxy, 4-methylcarbamoylmethyl-phenoxy,

4-methanesulfonylaminoethyl-phenoxy,

4-methoxycarbonylaminophenyl-phenoxy,

4-hydroxymethyl-phenoxy, 3-fluoro-4-methysulfonylmethane,

4 dimethylsulfoniopropionate and

3-chloro-4-methanesulfonate are more preferred,

4-(1-hydroxyethyl)phenoxy, 4-(1-hydroxypropyl)phenoxy,

4 methanesulfonate, 4-methylcarbamyl-phenoxy,

4-ethylcarboxyl-phenoxy, 4-hydroxymethyl-phenoxy and

3-fluoro-4-methanesulfonate are even more preferred, and

4 methysulfonylmethane is especially preferred.

As examples X1-Ring A-R1where X1is S, and the Ring a represents phenyl, can be mentioned

4-fluoro-phenylsulfanyl,

4-methyl-phenylsulfanyl, 4-trifluoromethyl-phenylsulfanyl,

4-(1-hydroxyethyl)phenylsulfanyl,

4-methanesulfonylaminoethyl,

4-methylcarbamyl-phenylsulfanyl,

4-ethylcarboxyl-phenylsulfanyl,

4-methylcarbamoyl-phenylsulfanyl,

4-dimethylcarbamoyl-phenylsulfanyl,

4-methylcarbamoylmethyl-phenylsulfanyl,

4-methylsulfonylamino-phenylsulfanyl,

4-methoxycarbonyl-phenylsulphonyl,

4-meth is xianbei-aminomethyl-phenylsulfanyl,

4-hydroxymethyl-phenylsulfanyl and 4-cyano-phenylsulfanyl,

among which 4-fluoro-phenylsulfanyl,

4-(1-hydroxyethyl)phenylsulfanyl,

4-methanesulfonylaminoethyl,

4-methylcarbamyl-phenylsulfanyl,

4-ethylcarboxyl-phenylsulfanyl,

4-methylcarbamoyl-phenylsulfanyl,

4-dimethylcarbamoyl-phenylsulfanyl,

4-methylcarbamoylmethyl-phenylsulfanyl,

4-methylsulfonylamino-phenylsulfanyl,

4-methoxycarbonyl-aminomethyl-phenylsulfanyl and

4-hydroxymethyl-phenylsulfanyl are preferred,

4-(1-hydroxyethyl)phenylsulfanyl,

4-methanesulfonylaminoethyl,

4-methylcarbamyl-phenylsulfanyl,

4-ethylcarboxyl-phenylsulfanyl,

4-methylcarbamoylmethyl-phenylsulfanyl,

4-methylsulfonylamino-phenylsulfanyl,

4-methoxycarbonyl-aminomethyl-phenylsulfanyl and

4-hydroxymethyl-phenylsulfanyl are more preferred,

4-(1-hydroxyethyl)phenylsulfanyl,

4-methanesulfonylaminoethyl,

4-methylcarbamyl-phenylsulfanyl,

4-ethylcarboxyl-phenylsulfanyl and

4-hydroxymethyl-phenylsulfanyl are even more preferred, and

4-methanesulfonylaminoethyl is especially preferred.

As examples X1-Ring A-R1where X1is S, and the Ring a represents a 5 - to 7-members of the ing heteroaryl group, may be mentioned 5-cyano-pyridine-2-ylsulphonyl,

5-bromo-pyridine-2-ylsulphonyl,

5-methoxycarbonyl-pyridine-2-ylsulphonyl,

5-hydroxymethyl-pyridine-2-ylsulphonyl,

5-methanesulfonyl-pyridine-2-ylsulphonyl,

5-methyl-pyridine-2-ylsulphonyl,

5-trifluoromethyl-pyridine-2-ylsulphonyl, pyridine-2-ylsulphonyl,

pyridine-4-ylsulphonyl, 6-methyl-pyridine-3-ylsulphonyl,

[1,3,4]thiadiazole-2-ylsulphonyl,

5-methylthio-[1,3,4]thiadiazole-2-ylsulphonyl,

5-methanesulfonyl[1,3,4]thiadiazole-2-ylsulphonyl,

[1,2,4]-triazole-3-ylsulphonyl, furan-3-ylsulphonyl,

thiophene-3-ylsulphonyl, pyrrol-3-ylsulphonyl,

imidazol-2-ylsulphonyl, thiazol-2-ylsulphonyl,

oxazol-2-ylsulphonyl, isoxazol-3-ylsulphonyl,

pyrazin-2-ylsulphonyl, pyrimidine-2-ylsulphonyl,

pyridazin-3-ylsulphonyl, and 3H-pyrazole-3-ylsulphonyl, among which 5-bromo-pyridine-2-ylsulphonyl,

5-hydroxymethyl-pyridine-2-ylsulphonyl,

5-methanesulfonamido-2-ylsulphonyl, pyridine-2-ylsulphonyl,

pyridine-4-ylsulphonyl, [1,3,4]thiadiazole-2-ylsulphonyl,

5-methanesulfonyl[1,3,4]thiadiazole-2-ylsulphonyl,

[1,2,4]-triazole-3-ylsulphonyl, furan-3-ylsulphonyl,

thiophene-3-ylsulphonyl, pyrrol-3-ylsulphonyl,

imidazol-2-ylsulphonyl, thiazol-2-ylsulphonyl,

oxazol-2-ylsulphonyl, isoxazol-3-ylsulphonyl,

pyrazin-2-ylsulphonyl, pyrimidine-2-ylsulphonyl,

PI is idaten-3-ylsulphonyl and 3H-pyrazole-3-ylsulphonyl are preferred,

5-hydroxymethyl-pyridine-2-ylsulphonyl,

5-methanesulfonamido-2-ylsulphonyl, pyridine-2-ylsulphonyl,

pyridine-4-ylsulphonyl, [1,3,4]thiadiazole-2-ylsulphonyl,

5-methanesulfonyl[1,3,4]thiadiazole-2-ylsulphonyl,

[1,2,4]-triazole-3-ylsulphonyl, thiazol-2-ylsulphonyl and

pyrazin-2-ylsulphonyl are more preferred,

5-hydroxymethyl-pyridine-2-ylsulphonyl,

5-methanesulfonamido-2-ylsulphonyl, pyridine-2-ylsulphonyl,

pyridine-4-ylsulphonyl, [1,3,4]thiadiazole-2-ylsulphonyl,

5-methanesulfonyl[1,3,4]thiadiazole-2-ylsulphonyl,

[1,2,4]-triazole-3-ylsulphonyl and thiazole-2-ylsulphonyl are even more preferred, and

pyridine-2-ylsulphonyl, pyridine-4-ylsulphonyl,

[1,3,4]thiadiazole-2-ylsulphonyl, [1,2,4]-triazole-3-ylsulphonyl and

the thiazole-2-ylsulphonyl are particularly preferred.

As examples X1-Ring A-R1where X1is On and the Ring a represents a 5 - to 7-membered heteroaryl group can be mentioned pyrimidine-4-yloxy, pyridin-3-yloxy, pyrazin-2-yloxy, pyridine-2-yloxy, 2-hydroxy-pyridine-3-yloxy,

2-hydroxy-pyridine-4-yloxy, 5-hydroxymethyl-pyridine-2-yloxy,

5-methylcarbamyl-pyridine-2-yloxy,

5-(1-hydroxyethyl)-pyridine-2-yloxy,

5-methoxycarbonylaminophenyl-pyridine-2-yloxy,

5-methanesulfonamido-2-yloxy,

5-meloxicam the Nile-pyridine-2-yloxy, 5-cyano-pyridine-2-yloxy,

5-bromo-pyridine-2-yloxy, 5-dimethylcarbamoyl-pyridine-2-yloxy,

5-methoxycarbonyl-pyridine-2-yloxy,

5-methylcarbamoylmethyl-pyridine-2-yloxy,

5-trifluoromethyl-pyridine-2-yloxy,

5-methylcarbamyl-imidazol-2-yloxy,

6-hydroxymethyl-pyrimidine-2-yloxy,

6-methylcarbamyl-pyrimidine-2-yloxy,

6-methanesulfonamido-2-yloxy,

6-hydroxymethyl-pyridin-3-yloxy,

6-methylcarbamyl-pyridazin-3-yloxy,

6-methanesulfonamido-3-yloxy,

5-hydroxymethyl-pyrazin-2-yloxy,

5-methylcarbamyl-pyrazin-2-yloxy,

5-methanesulfonamide-2-yloxy,

6-acanaloniidae-3-yloxy,

6-methanesulfonamido-3-yloxy, pyridine-3-yloxy,

pyridine-4-yloxy and 6-isopropylacetanilide-3-yloxy,

among them pyrimidine-4-yloxy, pyridin-3-yloxy,

pyrazin-2-yloxy, pyridine-2-yloxy,

2-hydroxy-pyridine-3-yloxy,

2-hydroxy-pyridine-4-yloxy, 5-hydroxymethyl-pyridine-2-yloxy,

5-methylcarbamyl-pyridine-2-yloxy,

5-(1-hydroxyethyl)-pyridine-2-yloxy,

5-methoxycarbonylaminophenyl-pyridine-2-yloxy,

5-methanesulfonamido-2-yloxy, 5-bromo-pyridine-2-yloxy,

5-dimethylcarbamoyl-pyridine-2-yloxy,

5-methylcarbamoylmethyl-pyridine-2-yloxy,

5-methylcarbamyl-imidazol-2-yloxy,

6-hydroxymethyl-pyrimidine-2-yloxy,

6-metalcarbon the l-pyrimidine-2-yloxy,

6-methanesulfonamido-2-yloxy,

6-hydroxymethyl-pyridin-3-yloxy,

6-methylcarbamyl-pyridazin-3-yloxy,

6-methanesulfonyl-pyridin-3-yloxy,

5-hydroxymethyl-pyrazin-2-yloxy,

5-methylcarbamyl-pyrazin-2-yloxy,

5-methanesulfonamide-2-yloxy,

6-acanaloniidae-3-yloxy,

6-methanesulfonamido-3-yloxy, pyridine-3-yloxy and

pyridine-4-yloxy are preferred, pyrazin-2-yloxy,

pyridine-2-yloxy, 2-hydroxy-pyridine-3-yloxy,

2-hydroxy-pyridine-4-yloxy, 5-hydroxymethyl-pyridine-2-yloxy,

5-methylcarbamyl-pyridine-2-yloxy,

5-(1-hydroxyethyl)-pyridine-2-yloxy,

5-methoxycarbonylaminophenyl-pyridine-2-yloxy,

5-methanesulfonamido-2-yloxy,

5-methylcarbamoylmethyl-pyridine-2-yloxy,

5-hydroxymethyl-pyrazin-2-yloxy,

5-methylcarbamyl-pyrazin-2-yloxy,

5-methanesulfonamide-2-yloxy,

6-acanaloniidae-3-yloxy and

6-methanesulfonamido-3-yloxy are more preferred, and

2-hydroxy-pyridine-3-yloxy, 2-hydroxy-pyridine-4-yloxy,

5-hydroxymethyl-pyridine-2-yloxy,

5-methylcarbamyl-pyridine-2-yloxy,

5-(1-hydroxyethyl)-pyridine-2-yloxy,

5-methanesulfonamido-2-yloxy,

6-methanesulfonamido-3-yloxy and

6-acanaloniidae-3-yloxy are particularly preferred.

X2 represents O, S or CH2among which About and CH2are preferred, and is more preferred.

R2represents a C3-7 cyclic alkyl group, a lower alkyl group or lower alkenylphenol group with a straight or branched chain, optionally having 1 or 2 substituent selected from the group consisting of halogen atoms, carboxyl, alkoxycarbonyl, hydroxy, amino (in which the amino may be optionally substituted 1 or 2 alkanolamine or lower alkyl groups), alkoxy and N-allylcarbamate.

As examples of the "halogen atoms"represented by the symbol R2may be mentioned the same atoms mentioned above. Preferred are chlorine and fluorine.

"Alkoxycarbonyl" group, represented by the symbol R2is a carbonyl group having alkoxygroup defined above, and as examples may be mentioned methoxycarbonyl, etoxycarbonyl, propylenecarbonate, isopropoxycarbonyl and tert-butyloxycarbonyl.

As examples of the "C3-7 cyclic alkyl group"represented by the symbol R2may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, among which preferred are cyclopentyl or cyclohexyl, and is preferred cyclopentyl.

When R2PR is dstanley C3-7 cyclic alkyl group, any of the carbon atoms forming the ring, other than a carbon atom binding to the X2may be replaced by oxygen, NH, N-alkanoyl or CONH.

As the groups in which the carbon atom, forms a C3-7 cyclic alkyl group, (other than the carbon atom binding to the X2replaced with oxygen, NH, N-alkanoyl or CONH", preferred groups in which a carbon atom is replaced by oxygen, NH or N-alkanols, and more preferred are groups in which he replaced Colorado or N-alkanoyl. More specifically, R2preferably represents, for example, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl or N-acetylpiperidine, and, more preferably, tetrahydrofuranyl, tetrahydropyranyl or N-acetylpiperidine.

"Lower alkyl group with straight or branched chain"represented by the symbol R2is lower alkyl, with the same values as mentioned above. As the lower alkyl groups, preferred are ethyl, propyl, isopropyl, butyl, isobutyl and sec-butyl, and more preferred are propyl, isopropyl, isobutyl and sec-butyl.

As "lower alkenyl groups"represented by the symbol R2may be mentioned the same groups that are mentioned above, among which propenyl, Isopropenyl and from utensil are preferred, and more preferred is isopropanol.

R2is preferably C3-7 cyclic alkyl group, a lower alkyl group with straight or branched chain, or a group in which a carbon atom, forms a C3-7 cyclic alkyl group (other than a carbon atom binding to the X2)replaced by oxygen, NH, N-alkanoyl or CONH, and more preferably it represents a lower alkyl group with straight or branched chain, or a group in which a carbon atom, forms a C3-7 cyclic alkyl group (other than a carbon atom binding to the X2)replaced by oxygen, NH, N-alkanoyl or CONH.

Therefore, as examples X2-R2can be mentioned propyl, isobutyl, sec-butyl, 3-methoxy-2-methyl-propyl, 2-methoxymethyl-butyl, 4-hydroxy-2-methyl-butyl, 2-hydroxymethyl-butyl, 3-hydroxy-butyl, 3-methoxybutyl, 3-hydroxy-2-methyl-propyl, 3-hydroxy-butyl, 3-methylcarbamoyl-propyl, 3-acetylamino-2-methyl-propyl, 2-hydroxymethyl-3-propenyl, 2-methyl-2-propenyl ethoxy, isopropoxy, 2-methoxy-1-methyl-ethoxy,

1-methoxymethyl-propoxy, 3-hydroxy-1-methyl-propoxy,

1-hydroxymethyl-propoxy, 2-amino-1-ethoxy, 2-hydroxy-propoxy,

2 methoxypropane, 2-hydroxy-1-methyl-ethoxy, 2-hydroxy-ethoxy,

2-dimethylamino-1-methyl-ethoxy, 1-carboxy-ethoxy,

2-methylcarbamoyl-e is hydroxy, 2-acetylamino-1-methyl-ethoxy,

cyclopentyloxy, cyclohexyloxy, cycloheptylamine,

2-hydroxy-cyclopentyloxy, tetrahydrofuran-3-yloxy,

tetrahydrofuran-2-yloxy, tetrahydrofuran-4-yloxy,

piperidine-4-yloxy, piperidine-3-yloxy, pyrrolidin-3-yloxy,

pyrrolidin-2-yloxy, 1-acetyl-piperidine-4-yloxy,

1-acetyl-piperidine-3-yloxy, 3 allyloxy, 3 isopropanolate,

1-methyl-allyloxy, 2-fluoro-1-vermeil-ethoxy,

2-fluoro-1-methyl-ethoxy and 2-chloro-1-methyl-ethoxy among them

ethoxy, isopropoxy, 2-methoxy-1-methyl-ethoxy,

1-methoxymethyl-propoxy, 3-hydroxy-1-methyl-propoxy,

1-hydroxymethyl-propoxy, 2-hydroxy-propoxy,

2 methoxypropane,

2-hydroxy-1-methyl-ethoxy, 2-hydroxy-ethoxy,

2-methylcarbamoyl-ethoxy, 2-acetylamino-1-methyl-ethoxy,

cyclopentyloxy, cyclohexyloxy, 2-hydroxy-cyclopentyloxy,

tetrahydrofuran-3-yloxy, tetrahydrofuran-2-yloxy,

tetrahydropyran-3-yloxy, tetrahydrofuran-4-yloxy,

piperidine-4-yloxy, piperidine-3-yloxy, pyrrolidin-3-yloxy,

pyrrolidin-2-yloxy, 1-acetyl-piperidine-4-yloxy,

1-acetyl-piperidine-3-yloxy, 3 isopropanolate,

1-methyl-allyloxy, butyl, isobutyl, sec-butyl,

3-methoxy-2-methyl-propyl, 2-methoxymethyl-butyl,

4-hydroxy-2-methyl-butyl, 2-hydroxymethyl-butyl,

3-hydroxy-butyl, 3-methoxybutyl, 3-hydroxy-2-m is Teal-propyl,

3-hydroxy-butyl, 3-methylcarbamoyl-propyl,

3-acetylamino-2-methyl-propyl, 2-hydroxymethyl-3-propenyl,

2-methyl-2-propenyl, 2-fluoro-1-vermeil-ethoxy,

2-fluoro-1-methyl-ethoxy and 2-chloro-1-methyl-ethoxy are preferred,

2-methoxy-1-methyl-ethoxy, 1-methoxymethyl-propoxy,

3-hydroxy-1-methyl-propoxy, 1-hydroxymethyl-propoxy,

2-hydroxy-propoxy, 2-methoxypropene,

2-hydroxy-1-methyl-ethoxy, 2-hydroxy-ethoxy,

2-methylcarbamoyl-ethoxy, 2-acetylamino-1-methyl-ethoxy,

cyclopentyloxy, cyclohexyloxy, 2-hydroxy-cyclopentyloxy,

tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,

1-acetyl-piperidine-4-yloxy, 1-acetyl-piperidine-3-yloxy,

3 isopropanolate, 3-methoxy-2-methyl-propyl,

2-methoxymethyl-butyl, 4-hydroxy-2-methyl-butyl,

2-hydroxymethyl-butyl, 3-hydroxy-butyl, 3-methoxybutyl,

3-hydroxy-2-methyl-propyl, 3-hydroxy-butyl,

3-methylcarbamoyl-propyl, 3-acetylamino-2-methyl-propyl,

2-hydroxymethyl-3-propenyl, 2-methyl-2-propenyl,

2-fluoro-1-vermeil-ethoxy and 2-fluoro-1-methyl-ethoxy are more preferred, and

2-methoxy-1-methyl-ethoxy,

1-methoxymethyl-propoxy, 3-hydroxy-1-methyl-propoxy,

1-hydroxymethyl-propoxy, 2-hydroxy-1-methyl-ethoxy,

2-acetylamino-1-methyl-ethoxy, 2-hydroxy-cyclopentyloxy,

tetrahydrofuran-3-yloxy, 1-acetyl-piperidin the-4-yloxy,

3-methoxy-2-methyl-propyl, 2-methoxymethyl-butyl,

4-hydroxy-2-methyl-butyl, 2-hydroxymethyl-butyl,

3-hydroxy-2-methyl-propyl, 3-acetylamino-2-methyl-propyl,

2-hydroxymethyl-3-propenyl and 2-fluoro-1-vermeil-ethoxy are particularly preferred.

The ring represents a group represented by the above formula (III):

which is monocyclic or bicyclic heteroaryl group in which the carbon atom of Ring B, which is connected to the nitrogen atom of amide group in formula (I), forms a C=N bond with the nitrogen atom of the ring.

"Heteroaryl" group, represented by the ring B, is a "heteroaryl" group, represented by formula (III) defined above and in which the carbon atom of ring B, which is linked to the amide group in formula (I), forms a C=N bond with the nitrogen atom. Double bond group C=N ring is the only formal representation and it is sufficient if the ring is a heteroaryl group.

Preferred examples of rings are rings in which the heteroaryl group does not include 5-alkoxycarbonyl-pyridine-2-ilen, or 5-carboxyl-pyridine-2-ilen group, and more preferred are monocyclic or bicyclic heteroaryl group having at least one heteroatom in the ring, are selected is from the group consisting of nitrogen atoms, sulfur and oxygen in addition to nitrogen atom, forms a C=N group together with the carbon atom in the ring, which is linked to the nitrogen atom of the amide group in formula (I) above.

The ring is monocyclic or bicyclic heteroaryl group having at least one heteroatom in the ring selected from the group consisting of nitrogen atoms, sulfur and oxygen in addition to nitrogen atom, forms a C=N group together with the carbon atom in the ring, which is linked to the nitrogen atom of the amide group in formula (I) above, and when ring b is a thiazole group, the substituent in the 5-position of the thiazole group is most preferable is not isopropyl.

When ring b is a monocycle, the number of atoms forming the monocycle is preferably 5 or 6, and more preferably 5. When the ring is bicyclam, it preferably represents a 9 - to 10-membered Bicycle, which is a 5 - or 6-membered monocycle, condensed with benzene ring or pyridine ring, and more preferably it is a 9-membered Bicycle, which is a 5-membered monocycle, condensed with a pyridine ring.

As examples of the ring can be mentioned thiazolyl, imidazolyl, isothiazolin, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyrid is l, pyridazinyl, pyrazolyl, pyrimidinyl, peridotitic and benzothiazolyl, among which preferred are thiazolyl, thiadiazolyl, isoxazolyl, pyrazinyl, pyridyl, peridotitic and pyrazolyl, and more preferred are thiazolyl, thiadiazolyl, isoxazolyl, peridotitic or pyrazolyl.

The ring may have 1 or 2 substituent represented by the symbol R3. R3represents a group selected from lower alkyl, alkoxy, alkylamino, lower dialkylamino, halogen atoms, trifloromethyl, hydroxyalkyl (in which the hydrogen of the hydroxy group in hydroxyalkyloxy group may be substituted by lower alkyl), aminoalkyl, alkanoyl, carboxyl, alkoxycarbonyl and cyano.

When the ring has two substituent represented by the symbol R3in the ring, they may be identical or different.

The position of the communication group, R3the ring may be any capable of forming a communication situation, without any special restrictions, regardless of whether the Ring is a 5 - to 7-membered monocyclic heteroaryl group or a 9 - to 11-membered bicyclic heteroaryl group.

Among them, R3is preferably lower alkyl, alkoxy, halogen, hydroxyalkyl (where the hydrogen of the hydroxy group in hydroxyalkyloxy group may be substituted by lower alkyl), aminoalkyl is or alkanoyl, and more preferably is lower alkyl, hydroxyalkyl (where the hydrogen of the hydroxy group in hydroxyalkyloxy group may be substituted by lower alkyl) or alkanoyl.

As examples R3can be mentioned methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, chlorine, fluorine, bromine, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxyethyl, methoxyethyl, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, aminomethyl, aminoethyl, aminopropyl, methylcarbamyl, ethylcarboxyl and propylboronic, among which preferred are methyl, ethyl, chloro, fluoro, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxycarbonyl, etoxycarbonyl, aminomethyl, aminoethyl, methylcarbamyl and ethylcarboxyl, and more preferred are methyl, hydroxymethyl, methoxymethyl and methylcarbamyl.

Therefore, as examples of the group represented by the following formula (VII):

[in which the symbols have the same definitions specified above] are preferred thiazol-2-yl, 4-methyl-thiazol-2-yl, 4-hydroxymethyl-thiazol-2-yl, 4-ethoxycarbonyl-thiazol-2-yl, 4-methoxymethyl-thiazol-2-yl, 4-aminomethyl-thiazol-2-yl, 4-cyano-thiazol-2-yl, 4-fluoro-thiazol-2-yl, imidazol-2-yl, 4-methyl-imidazol-2-yl, 4-methoxycarbonyl-imidazol-2-yl, isothiazol-3-yl, 4-guide is oxymethyl-isothiazol-3-yl, [1,3,4]thiadiazole-2-yl, 5-acetyl-[1,3,4]thiadiazole-2-yl, [1,2,4]triazole-2-yl, 5-hydroxymethyl-[1,2,4]triazole-3-yl, pyrazin-2-yl, pyridin-2-yl, 4-methyl-pyridine-2-yl, 4-methoxymethyl-imidazol-2-yl, 4-acetyl-imidazol-2-yl, 5-hydroxymethyl-imidazol-2-yl, 5-methyl-[1,3,4]thiadiazole-2-yl, 5-fluoro-[1,3,4]thiadiazole-2-yl, 5-methyl-[1,2,4]triazole-2-yl, 5-acetyl-[1,2,4]triazole-3-yl, isoxazol-3-yl, 4-methoxymethyl-isoxazol-2-yl, 5-methyl-isoxazol-3-yl, 5-hydroxymethyl-isoxazol-3-yl, 5-methoxymethyl-isoxazol-3-yl, 5-methylcarbamoyl-isoxazol-3-yl, 5-chloro-isoxazol-3-yl, 5-aminomethyl-isoxazol-3-yl, pyrazole-3-yl, 4-methyl-1H-pyrazole-3-yl, 6-methyl-pyridazin-3-yl, thiazol-4-yl, 2-methyl-thiazol-4-yl, isoxazol-3-yl, thiazolo[5,4-b]pyridine-2-yl, 3-methyl-[1,2,4]thiadiazolyl-5-yl and 1-methyl-1H-pyrazole-3-yl.

Thus, as preferable examples of compounds represented by formula (I) according to the invention

[in which the symbols have the same definitions specified above] can be mentioned

5-isopropoxy-3-(4-methysulfonylmethane)-N-(4-methylthiazole-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-ethoxy-3-(4-methysulfonylmethane)-N-(4-methoxymethyl-thiazol-2-yl)benzamid,

5-cyclopentyloxy-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yloxy)-N-eazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide,

3-(2-fluoro-4-methysulfonylmethane)-5-isopropoxy-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)benzamid,

5-isopropoxy-3-(4-methysulfonylmethane)-N-pyrazole-3-yl-benzamide,

5-isopropoxy-3-(4-methysulfonylmethane)-N-pyrazin-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide,

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methysulfonylmethane)-N-pyrimidine-4-yl-benzamide,

5-isopropoxy-3-(4-methysulfonylmethane)-N-(pyrimidine-2-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide,

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazole-2-yl-benzamide,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide,

5-(2-amino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-dimethylamino-1-methyl-ethoxy)-3-(methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-propoxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamid,

3-(4-methysulfonylmethane)-5-(2-methoxy-propoxy)-N-(4-methyl-thiazol-2-yl)benzamid,

5-isopropoxy-3-(4-methysulfonylmethane)-N-(thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-(2-hydroxymethyl-allyl)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-(3-hydroxy-2-methyl-propyl)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

hydrochloride 3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)-5-(piperidine-4-yl-oxy)benzamide,

5-(1-acetyl-piperidine-4-yloxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamid,

2-[3-(4-methysulfonylmethane)-5-(4-methyl-thiazol-2-yl-carbarnoyl)phenoxy]propionic acid,

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(1-methylcarbamoyl-ethoxy)-N-(4-methyl-thiazol-2-yl)benzamid,

5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-pyridin-2-yl-benzamide,

5-(2-hydroxy-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-cyclopentyloxy)-3-(4-methanesulfonyl is noxy)-N-thiazol-2-yl-benzamide,

N-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methyl-thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-([1,2,4]thiadiazole-5-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methoxycarbonyl-pyridine-2-yl)benzamid,

6-[5-isopropoxy-3-(4-methysulfonylmethane)benzoylamine]nicotinic acid,

5-(2-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)benzamid,

N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methansulfonate the XI)-N-(2-methylthiazole-4-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4-methoxymethyl-thiazol-2-yl)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide,

N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-isopropoxy-3-(4-methoxycarbonylaminophenyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methylcarbamoyl-phenoxy)-N-thiazol-2-yl-benzamide,

3-(4-dimethylcarbamoyl-phenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methylcarbamoylmethyl-phenoxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methanesulfonylaminoethyl-phenoxy)-N-thiazol-2-yl-benzamide,

3-[4-(1-hydroxy-propyl)phenoxy]-5-isopropoxy-N-thiazol-2-yl-benzamide,

methyl ester of 6-[3-isopropoxy-5-(thiazol-2-ylcarbonyl)phenoxy]-nicotinic acid,

3-(5-hydroxymethyl-pyridine-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methanesulfonamido-2-yl)-N-thiazol-2-yl-benzamide,

3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methoxycarbonyl-pyrazin-2-yl-oxy)-N-thiazol-2-yl-benzamide,

3-(5-cyano-Piri is in-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-4-yl-oxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-3-yl-oxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-3-yl-oxy)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazolo[5,4-b]-pyridine-2-yl-benzamide,

5-isopropoxy-3-(4-methyl-[1,2,4]triazole-3-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-thiazol-2-ylsulphonyl-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4H-[1,2,4]triazole-3-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methylsulfanyl-[1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(tetrahydrofuran-3-yl-oxy)-N-thiazol-2-yl-3-(4H-[1,2,4]triazole-3-ylsulphonyl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazole-2-ylsulphonyl)benzamid,

5-(3-hydroxy-1-methyl-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazole-2-ylsulphonyl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylaminoethyl)-N-thiazol-2-yl-benzamide,

3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(pyridine-4-sulfonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridine-3-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamid,

N-[3-hydroxymethyl-1,2,4-thiadiazole-5-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

5-(3-hydroxy-1-methylethoxy)-3-(4-methysulfonylmethane)-N-[5-methyl-1,2,4-thiadiazole-3-yl]benzamide,

5-(hydroxy-1-methylethoxy)-3-(4-methysulfonylmethane)-N-(3-methoxy-1,2,4-thiadiazole-5-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1,2,5-thiadiazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4-trifluoromethyl-thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4,5,6,7-tetrahydroindazole-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(pyridazin-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]-triazole-5-yl)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(3-methyl-[1,2,4]-oxadiazol-5-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)benzamid,

N-(4-cyano-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

p> 5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(pyridin-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methyl-isothiazol-3-yl)benzamid,

5-(3-hydroxy-cyclopentyloxy)-3-(4-methysulfonylmethane)-N-(thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methoxy-thiazol-2-yl)benzamid,

5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methysulfonylmethane)-N-(thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1H-[1,2,3]triazole-4-yl)benzamid,

N-(1-acetyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(pyrazole-3-yl)benzamid,

N-(5,6-dihydro-4H-cyclopentadiene-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(thieno[3,2-d]thiazole-2-yl)benzamid,

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(4-cyano-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-metilsulfonilmetane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-and the)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-acanaloniidae)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-isopropylphenoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxy-4-methyl-4,5,6,6A-tetrahydro-an-cyclopentadiene-2-yl)-3-(4-methysulfonylmethane)benzamid,

3-(4-dimethylcarbamoyl-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-acetylphenol)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(1,3,4-thiadiazole-2-ylsulphonyl)benzamid,

N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl))benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminophenyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazole-5-yl)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl))benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazole-3-yl))benzamid,

5-isopropoxy-3-(6-methanesulfonamido-3-yloxy)N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylaminoethyl)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-cyclopropylamino-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(6-acanaloniidae-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

tert-butyl ester 2-[3-(4-methysulfonylmethane)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid,

3-(6-acanaloniidae-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)-5-(tetrahydrofuran-3-yl)benzamid,

N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-piraso the-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

2-[3-(4-methysulfonylmethane)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid,

3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyridin-2-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-chloro-1-methyl-ethoxy)-3-(6-acanaloniidae-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-N-(isoxazol-3-yl)-3-(6-methanesulfonamido-3-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(pyridin-2-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamid,

3-(4-dimethylaminoethoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(3-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-isopr philselfology-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(3-chloro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-3-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-3-yloxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-4-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-4-yloxy)benzamide,

2-[3-(6-acanaloniidae-3-yloxy)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid and

5-(2-fluoro-1-vermeil-ethoxy)-3-(3-fluoro-4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

among them, examples of preferred compounds include

5-isopropoxy-3-(4-methysulfonylmethane)-N-(4-methylthiazole-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-ethoxy-3-(4-methysulfonylmethane)-N-(4-methoxymethyl-thiazol-2-yl)benzamid,

5-cyclopentyloxy-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide,

3-(2-fluoro-4-methysulfonylmethane)-5-isopropoxy-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)benzamid,

3-(4-methysulfonylmethane)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide,

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide,

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazole-2-yl-benzamide,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide,

5-(2-amino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-propoxy)-3-(4-methysulfonylmethane)-N-4-methyl-thiazol-2-yl)benzamid,

3-(4-methysulfonylmethane)-5-(2-methoxy-propoxy)-N-(4-methyl-thiazol-2-yl)benzamid,

5-isopropoxy-3-(4-methysulfonylmethane)-N-(thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-(2-hydroxymethyl-allyl)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-(3-hydroxy-2-methyl-propyl)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(1-acetyl-piperidine-4-yloxy)-3-(4-methysulfonylmethane)-N(4-methyl-thiazol-2-yl)benzamid,

2-[3-(4-methysulfonylmethane)-5-(4-methyl-thiazol-2-yl-carbarnoyl)phenoxy]propionic acid,

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-pyridin-2-yl-benzamide,

5-(2-hydroxy-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-cyclopentyloxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

N-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methyl-thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-([1,2,4]thiadiazole-5-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methoxycarbonyl-pyridine-2-yl)Besame is,

6-[5-isopropoxy-3-(4-methysulfonylmethane)benzoylamine]nicotinic acid,

5-(2-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)benzamid,

N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(2-methylthiazole-4-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4-methoxymethyl-thiazol-2-yl)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide,

N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-isopropoxy-3-(4-methoxycarbonylaminophenyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methylcarbamoyl-phenoxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methylcarbamoylmethyl-phenoxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4-methanesulfonylaminoethyl-phenoxy)-N-thiazol-2-yl-benzamide,

3-[4-(1-hydroxy-propyl)phenoxy]-5-isopropoxy-N-thiazol-2-yl-benzamide,

methyl ester of 6-[3-isopropoxy-5-(thiazol-2-ilıca bemail)phenoxy]-nicotinic acid,

3-(5-hydroxymethyl-pyridine-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methanesulfonamido-2-yl)-N-thiazol-2-yl-benzamide,

3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methoxycarbonyl-pyrazin-2-yl-oxy)-N-thiazol-2-yl-benzamide,

3-(5-cyano-pyridine-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-4-yl-oxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-3-yl-oxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-3-yl-oxy)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-isopropoxy-3-(4-methyl-[1,2,4]triazole-3-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-thiazol-2-ylsulphonyl-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(4H-[1,2,4]triazole-3-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methylsulfanyl-[1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(tetrahydrofuran-3-yl-oxy)-N-thiazol-2-yl-3-(4H-[1,2,4]triazole-3-ylsulphonyl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazole-2-ylsulphonyl)benzamid,

5-(3-hydroxy-1-meth is l-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazole-2-ylsulphonyl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylaminoethyl)-N-thiazol-2-yl-benzamide,

3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(pyridine-4-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridine-3-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamid,

N-(3-hydroxymethyl-1,2,4-thiadiazole-5-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

5-(hydroxy-1-methylethoxy)-3-(4-methysulfonylmethane)-N-(3-methoxy-1,2,4-thiadiazole-5-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1,2,5-thiadiazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]triazole-5-yl)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)benzamid,

N-(4-cyano-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(pyridin-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methyl-isati the evil-3-yl)benzamid,

5-(3-hydroxy-cyclopentyloxy)-3-(4-methysulfonylmethane)-N-(thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methoxy-thiazol-2-yl)benzamid,

5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methysulfonylmethane)-N-(thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1H-[1,2,3]triazole-4-yl)benzamid,

N-(1-acetyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(pyrazole-3-yl)benzamid,

N-(5,6-dihydro-4H-cyclopentadiene-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(thieno[3,2-d]thiazole-2-yl)benzamid,

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(4-cyano-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-metilsulfonilmetane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-acanaloniidae)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-isopropylphenoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxy-4-methyl-4,5,6,6A-tetrahydro-an-cyclopentadiene-2-yl)-3-(4-methysulfonylmethane)benzamid,

3-(4-acetylphenol)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminophenyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazole-5-yl)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-isopropoxy-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1 is-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(6-acanaloniidae-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)-5-(tetrahydrofuran-3-yl)benzamid,

N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyridin-2-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-chloro-1-methyl-ethoxy)-3-(6-ethane is unforeseen-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-N-(isoxazol-3-yl)-3-(6-methanesulfonamido-3-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(pyridin-2-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamid,

3-(4-dimethylaminoethoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(3-chloro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-3-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-3-yloxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-4-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-4-yloxy)benzamide and

5-(2-fluoro-1-vermeil-ethoxy)-3-(3-fluoro-4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

examples of more preferred compounds include

5-isopropoxy-3-(4-methysulfonylmethane)-N-(4-methylthiazole-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(2-methox the-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide,

3-(2-fluoro-4-methysulfonylmethane)-5-isopropoxy-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)benzamid,

3-(4-methysulfonylmethane)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide,

N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide,

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazole-2-yl-benzamide,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide,

5-isopropoxy-3-(4-methysulfonylmethane)-N-(thiazolo[5,4-b]pyridine-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-(3-hydroxy-2-methyl-propyl)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-pyridin-2-yl-benzamide,

5-(2-hydroxy-ethoxy)-3-(4-methysulfonylmethane)-N-ti is evil-2-yl-benzamide,

5-(2-hydroxy-cyclopentyloxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

N-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-([1,2,4]thiadiazole-5-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

6-[5-isopropoxy-3-(4-methysulfonylmethane)benzoylamine]nicotinic acid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)benzamid,

N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(2-methylthiazole-4-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4-methoxymethyl-thiazol-2-yl)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methanesulfonamido the si)-5-(tetrahydrofuran-3-yl-oxy)benzamide,

N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-4-yl-oxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-3-yl-oxy)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-3-yl-oxy)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

5-isopropoxy-3-thiazol-2-ylsulphonyl-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazole-2-ylsulphonyl)benzamid,

5-(3-hydroxy-1-methyl-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazole-2-ylsulphonyl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylaminoethyl)-N-thiazol-2-yl-benzamide,

3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(pyridine-4-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridine-3-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methane is oliveirense)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamid,

5-(hydroxy-1-methylethoxy)-3-(4-methysulfonylmethane)-N-(3-methoxy-1,2,4-thiadiazole-5-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]-triazole-5-yl)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(pyridin-2-yl)benzamid,

5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methysulfonylmethane)-N-(thiazol-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(pyrazole-3-yl)benzamid,

N-(5,6-dihydro-4H-cyclopentadiene-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(4-metilsulfonilmetane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(4-acanaloniidae)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(isopropylphenoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxy-4-methyl-4,5,6,6A-tetrahydro-an-cyclopentadiene-2-yl)-3-(4-methysulfonylmethane)benzamid,

3-(4-acetylphenol)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminophenyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazole-5-yl)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-isopropoxy-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(6-acanaloniidae-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-etox is)-3-(6-methanesulfonamido-3-yloxy)benzamide,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(pyrazole-3-yl)benzamid,

3-(6-methanesulfonamido-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamid,

3-(4-dimethylaminoethoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide and

3-(3-chloro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

and examples of particularly preferred compounds include

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)benzamid,

N-(4-hydro is simetal-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide,

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazole-2-yl-benzamide,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide,

5-isopropoxy-3-(4-methysulfonylmethane)-N-(thiazolo[5,4-b]pyridine-2-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-isopropoxy-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-pyridin-2-yl-benzamide,

5-(2-hydroxy-cyclopentyloxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-([1,2,4]thiadiazole-5-yl)benzamid,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide,

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(Tetra drofuran-3-yl-oxy)benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(2-methylthiazole-4-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4-methoxymethyl-thiazol-2-yl)benzamid,

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide,

N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamid,

5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazolo[5,4-b]-pyridine-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamid,

5-(2-fluoro-1-FPO is methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(pyrazole-3-yl)benzamid,

3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazole-3-yl)benzamide.

Derivatives heteroarylboronic of the present invention can also be used in the form of pharmaceutically acceptable salts. Such salts can be acid additive salts or addition salts of the bases.

Depending on the type of substituents of the compounds of the invention may exist as stereoisomers or tautomers, optical isomers, diastereoisomers and geometric isomers. Needless to mention, that all such isomers are included in the scope of the compounds of the invention. There is no need to mention that any desired mixture of these isomers are also included in the compounds of the invention.

Because compounds of the invention showing the action of activating glucokinase, they are useful as therapeutic and/or prophylactic agents against diabetes, as well as therapeutic and/or prophylactic agents against complications associated with diabetes.

The term "complications associated with diabetes " refers to conditions that occur in diabetes, and examples of such diabetes-related complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy and diabetic arteriosclerosis.

Connection from which Britania can be applied or for the treatment of insulin-dependent diabetes mellitus (IDDM) or to treat ainsliezubaida diabetes mellitus (NIDDM).

It is believed that insulin-dependent diabetes mellitus (IDDM) is caused by reduced insulin secretion and resistance to insulin in skeletal muscle due to genetic factors, while it is believed that leisureservices diabetes mellitus (NIDDM) is predominantly a disease of adults, with an increase in the resistance to insulin that is associated with obesity. Diabetes, therefore, classified as (IDDM) type I, or (NIDDM) type II, depending on the reasons.

It is believed that the compounds of the invention are useful not only in relation to diabetes type I, and type II diabetes, in which case adequate reduction in blood glucose was not possible using conventional medicines for diabetes.

Diabetes type II degree of postprandial hyperglycemia lasts for a significantly longer period than in healthy individuals, and compounds of the invention are also suitable for the treatment of diabetes of type II.

[The preferred method of carrying out the invention]

Methods for obtaining compounds of the invention will be explained below.

The compound (I) of the present invention can be easily obtained using well-known reactions or through the implementation of well-known methods. The compound (I) this is about the invention can also be obtained by the method of synthesis in the liquid phase, as well as solid-phase method, such as, for example, methods of combinatorial synthesis or parallel synthesis, which has developed rapidly in recent years.

Compounds of the invention are preferably obtained according to the following scheme, for example,

[where R represents lower alkyl, X represents halogen atom, and other symbols have the same definitions specified above].

(Stage 1-1) At this stage of the introduced protective group, a carboxyl group, 3,5-dihydrobenzoic acid (1A) with connection (1).

The protective group R carboxyl group of the compound (1) functions as a protective group of carboxyl group during stages 1-3, and it can be any group which can easily be removed in stage 4. As examples can be mentioned alkyl group with straight or branched chain such as methyl, ethyl and tert-butyl, halogenated lower alkyl groups such as 2-ethyliodide and 2,2,2-trichlorethyl, lower alkeneamine groups such as allyl, 2-propenyl and 2-methyl-2-propenyl, or kalkilya groups such as benzyl and PMB.

The protective group R to the carboxyl group can be introduced and removed by the method described in the literature (for example, Protective Groups in Organic Synthesis, T.W. Green, 2-e edition, John iley & Sons, 1991), the appropriate method or by combining it with the conventional method.

The compound (1)thus obtained can be isolated and purified by known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 1) At this stage, the compound (1) and p-methyldiphenylamine acid (2) are subjected to reaction in the presence of copper acetate and grounds with obtaining ester 5-hydroxy-3-(4-methylthiophene)benzoic acid (3).

Used the number of p-methyldiphenylamine acid (2) is usually from 1 to 10 equivalents, and preferably from 1 to 2.5 equivalents, relative to 1 equivalent of the compound (1).

Instead of copper acetate can be used nitrate of copper, but preferred is copper acetate.

The amount of copper acetate or copper nitrate is usually from 0.1 to 5 equivalents, and preferably from 1 to 1.5 equivalents.

As examples of the used grounds can be mentioned triethylamine, diisopropylethylamine and similar, among which preferred is triethylamine.

The amount used of the base is usually from 0 is about 10 equivalents, and preferably from 4 to 6 equivalents.

The reaction temperature is usually from 0aboutC to the boiling temperature under reflux, the reaction solvent, and preferably from 15 to 30aboutC.

The reaction time at this stage is usually from 2 to 48 hours, preferably 12 hours.

The solvent used in the reaction at this stage, can be any solvent which does not inhibit the reaction, and as examples may be mentioned methylene chloride, acetonitrile, toluene and similar among which methylene chloride is preferred.

The compound (3)obtained in this way can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 2) At this stage, the compound (3)obtained in stage 1 above, and alkylhalogenide (4) subject to interaction in the presence of a base to obtain compound (5).

As the compound (4) can be any compound that does not inhibit the reaction of this stage, and allows to obtain the compound (5), and as examples may be mentioned ethyliodide, 2-propyl-bromide is d, cyclopentenone, 2-bromoethanol and similar, among which are preferred, for example, 2-propyl bromide and cyclopentylamine, and more preferred 2-propyl bromide.

The amount used of the compound (4) is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalents, relative to 1 equivalent of compound (3).

As examples of the used grounds can be mentioned potassium carbonate, Diisopropylamine and similar among which preferred potassium carbonate.

The amount used of the base is usually 1 to 10 equivalents, and preferably from 1.5 to 3 equivalents.

The reaction temperature is usually from 0aboutC to the boiling temperature under reflux, the reaction solvent, and preferably from 25 to 40aboutC.

The reaction time is usually from 1 to 12 hours, and preferably from 4 to 8 hours.

The solvent for the reaction used in this stage may be any solvent which does not inhibit the reaction, and preferred is N,N-dimethylformamide.

The compound (5)obtained in this way can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or x is omatography, or it can be supplied to the next stage without isolation and purification.

(Stage 3) At this stage, the compound (5)obtained in stage 2 above, is subjected to interaction with mCPBA, giving the compound (6). The oxidation reaction at this stage can be carried out in accordance with the method described in the literature (e.g., Brown. D. et al., Simple pyrimidines. X. The formation and reactivity of 2-, 4-, and 5-pyrimidinyl sulfones and suldoxides, Journal of the Chemical Society [Section}C: Organic, Vol.7, 1967, str-572), the appropriate method or by combining it with the conventional method.

The used amount of mCPBA is usually from 2 to 10 equivalents, and preferably 3 to 4 equivalents, relative to 1 equivalent of the compound (5).

The reaction time is usually from 10 minutes to 12 hours, and preferably from 3 minutes to 1 hour.

The reaction temperature is usually from -78 to 15aboutWith, and preferably from 0 to 10aboutC.

Used solvent for the reaction may be any solvent which does not inhibit the reaction, and as examples may be mentioned methylene chloride, chloroform and similar among which preferred chloroform.

The compound (6)obtained in this way can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallize the Oia, pereosazhdeniya, by solvent extraction or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 4) At this stage protective group R carboxyl group of compound (6)obtained in stage 3, is removed, giving the compound (7).

Method of removal of the protective group R to the carboxyl group may be the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

Compound (7), thus obtained, may be produced and purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 5) At this stage, the compound (7)obtained in stage 4 above, is subjected to reaction with aminoguanidinium, represented by the following formula (8):

[where the symbols have the same definitions specified above], giving the compound (I-1).

This reaction can be carried out by conducting the conventional amide formation reaction described in the literature (e.g., Peptide Gosei no Kiso t Jikken, Izumiya, N. et al., Maruzen Publ., 1983, Comprehensive Organic Synthesis, Vol. 6, Pergamon Press, 1991), the appropriate method or combination with the conventional method, using, in particular, of a condensing agent, which is well known to specialists in this field, or it may be carried out using the method of activation of ester, method, mixed acid anhydride, acid chloride method, the acid, carbodiimide method, etc. available to specialista in this area. As examples of such amide-forming reactants may be mentioned thionyl chloride, oxalicacid, N,N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridine, N,N'-carbonyldiimidazole, diphenylphosphoryl, diphenyl-phosphorylated, N,N'-disuccinimidyl, N,N'-disuccinimidyl, the hydrochloride of 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide, ethylchloride, isobutylparaben, benzotriazol-1-yl-oxy-Tris(dimethylamino)fosfodiesterasa and similar, among which are preferred, for example, thionyl chloride, hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N-dicyclohexylcarbodiimide, benzotriazol-1-yl-oxy-Tris(dimethylamino)fosfodiesterasa. For the formation of the amide can be used a base and an adjuvant condensation together with the above-mentioned amide-forming reagent.

As examples of the bases may be mentioned tertiary aliphatic amines, such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-azabicyclo[4.3.0]non-5-ene (DBN), and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline, among which are preferred, for example, tertiary aliphatic amines, and especially preferably, for example, triethylamine and N,N-diisopropylethylamine.

As examples of auxiliary means of condensation can be mentioned, hydrate, N-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide and 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazol, among which are preferred, for example, N-hydroxybenzotriazole.

The amount used of the compound (8) will vary depending on the type of compounds and solvent and other reaction conditions, but is usually from 0.1 to 10 equivalents, and preferably from 0.5 to 3 equivalents, per 1 equivalent of the carboxylic acid derivative (7) or its reactive derivative.

The used amount of the amide-forming reagent varies depending on the type of compounds and solvent and other reaction conditions, but is usually from 1 to 10 equivalents, and preferably from 1 d is 3 equivalents, on 1 equivalent of the compound carboxylic acid (7) or its reactive derivative.

The amount of the condensing agent also varies depending on the type of compounds and solvent and other reaction conditions, but is usually from 1 to 10 equivalents, and preferably 1 to 3 equivalents, per 1 equivalent of the compound carboxylic acid (7) or its reactive derivative.

The amount used of the base also varies depending on the types of compounds and solvent and other reaction conditions, but is usually from 1 to 10 equivalents, and preferably 1 to 5 equivalents.

The solvent for the reaction used in this stage may be, for example, inert solvent, and it is not particularly limited if only it does not interfere with the reaction, and as examples may be mentioned methylene chloride, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, ethyl ester acetic acid, methyl ester acetic acid, acetonitrile, benzene, xylene, toluene, 1,4-dioxane, tetrahydrofuran, dimethoxyethane or a mixture thereof, among which are preferred from the point of view of providing a suitable reaction temperature methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide and similar.

The reaction temperature for this is tadie is usually from -78 aboutC to the boiling temperature under reflux of the solvent, and preferably from 0 to 30aboutC.

The reaction time at this stage is usually from 0.5 to 96 hours, and preferably from 3 to 24 hours.

Base, amide-forming reagent and the condensing agent used for this stage, each may be one type or a combination of more than one type.

When R3in the Ring In the compound (I-1)obtained at this stage, has a protective group, the protective group, if necessary, can be removed. The removal of the protective group can be carried out using the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), the appropriate method or combination with the conventional method.

The compound (I-1) of the present invention, obtained at this stage, you may stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography.

The compound (5)obtained in stage 3 can also be obtained using the following method.

[where the symbols have the same definitions specified above].

(Stage 6) At this stage, the compound (3), received the Noah in stage 1, subjected to reaction with an alcohol compound (9), giving the compound (5).

This reaction is the reaction of Mitsunobu, which is carried out in the presence of phosphine compounds and azo compounds in accordance with the method described in the literature (for example, Mitsunobu, O., The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products, Synthesis, Vol. 1., 1981, p.1-28), the appropriate method or combination with the generally accepted method.

The amount of alcohol compound (9)used at this stage is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalents relative to 1 equivalent of compound (3).

As conventional examples of phosphine compounds used at this stage, there may be mentioned triphenylphosphine and triethylphosphine.

The amount of phosphine compounds is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalents relative to 1 equivalent of compound (3).

As examples of azo compounds can be mentioned diethylazodicarboxylate and diisopropylsalicylic.

The amount of azo compounds is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalents relative to 1 equivalent of compound (3).

The reaction time at this stage is about the commonly from 1 to 48 hours, and preferably from 4 to 12 hours.

The reaction temperature at this stage is usually from 0aboutC to the boiling temperature under reflux, the reaction solvent, and preferably from 15 to 30aboutC.

The solvent for the reaction at this stage is not particularly limited if only it does not interfere with the reaction, and as examples may be mentioned tetrahydrofuran and toluene.

The compound (I-1)obtained in this way can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, pereosazhdeniya, solvent extraction, crystallization or chromatography, or it may be supplied to the next stage without isolation and purification.

The compound (I-2) of the present invention can be obtained according to the following scheme.

[where the symbols have the same definitions specified above].

(Stage 7) At this stage, the compound (1)obtained in the previous phase, is subjected to reaction with compound (4), giving the compound (10).

This stage can be carried out using the same method as in stage 2 above.

The number of equivalents alkylhalogenide connection (4) with respect to the compound (1) and reaction conditions, such as temperaturregler, reaction time, etc. may correspond to the method of stage 2 above, the appropriate method or combination with the generally accepted method.

(Stage 8) At this stage, the compound (10)obtained in stage 7 above, is subjected to reaction with a derivative of boric acid, represented by the following formula (11):

[where the symbols have the same definitions specified above], giving the compound (12).

When R1requires a protective group, the necessary protective group may be introduced in accordance with the type R1. A protective group for R1can be any group that acts as a protective group for R1from stage 8 to stage 10 and which can be easily removed after that, giving the compound (I-2) of the present invention.

By way of introduction and removal of the protective group for R1may be the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

R11in the Ring And can turn in R1.

The transformation from R11in the Ring a to R1can be carried out according to the method described in the literature (e.g., Comprehensive Organic Synthesis, Vol. 6, Pergamon Press, 1991); Comprehensive Organic Transformations, Richard L. et al., VCH Publishers, 1988), a corresponding method, or it is Oceania with generally accepted method.

As examples of the group R11can be mentioned formyl, halogen atoms and alkoxycarbonyl.

When R11represents a formyl group, for example, formyl group can be restored by turning it into a hydroxymethyl. The reaction for the conversion of the formyl group in hydroxymethylene may be a reaction by which the compound having a formyl group, is subjected to interaction with sodium borohydride to obtain compounds having a hydroxymethyl as R1.

Alternative compound having hydroxymethyl as R1may be sideropenia with subsequent reduction to result in aminomethyl.

The reaction conversion from alkoxycarbonyl group to alkylcarboxylic group may be accomplished by hydrolysis of compounds having alkoxycarbonyl group, and then punish him for the formation of amide with alkylamino obtaining compounds having alkoxycarbonyl group as R1.

As examples of derivatives of boric acid, represented by formula (11) above can be mentioned 4-bromo-phenylboric acid, 4-fluoro-phenylboric acid, 4-methyl-phenylboric acid, 4-methoxy-phenylboric acid, 4-trifluoromethyl-phenylboric acid, 4-hydroxymethyl-phenylboric acid, 4-acetyl-is universa acid, 4-cyano-phenylboric acid, 4-methoxycarbonyl-phenylboric acid, 4-carboxy-phenylboric acid, 4-formyl-phenylboric acid, 4-aminomethyl-phenylboric acid and 4-carbarnoyl-phenylboric acid.

When derived phenylboric acid represented by the formula (11), has R11as the substituent in Ring A, R11may have a protective group.

By way of introducing the protective group may be the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

The compound obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 9) At this stage removes the protective group R to the carboxyl group of compound (12)obtained in stage 8 above. This stage can be carried out in the same reaction conditions as in stage 4, using the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or the combin who deposits it with the conventional method.

The compound (13)obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 10) At this stage, the compound (13)obtained in stage 9 above, is subjected to interaction with aminoguanidinium (8), to obtain compound (I-2) of the present invention. This stage can be carried out under the same reaction conditions as stage 5.

The compound (I-2) of the present invention obtained in this way can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography.

The compound (I-3) of the present invention can be obtained according to the following scheme.

[where Y represents a halogen atom, and other symbols have the same definitions specified above].

(Stage 11) At this stage, the compound (14) is subjected to reaction with compound (4), giving compound (14-1). The number of equivalents of compound (4) with respect to 1 equivalent of the phenolic product is aqueous (14) and reaction conditions, such as reaction temperature, reaction time, etc. at this stage may correspond to the method stage 7.

The compound (14-1)obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, pereosazhdeniya, crystallization or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 12) At this stage, the compound (14-1), obtained in stage 11, above, is subjected to interaction with compound (15), giving the compound (16).

This reaction can be carried out using the reaction of the compound (14-1) and mercaptopropanol (15) in the presence of a base, hydroquinone and copper bromide.

As the bases used at this stage, there may be mentioned potassium carbonate, cesium carbonate, sodium hydride and similar, among which preferred are potassium carbonate and sodium hydride.

The amount of base used at this stage is usually from 0.5 to 20 equivalents, and preferably from 3 to 10 equivalents relative to 1 equivalent of the compound (14-1).

The amount of hydroquinone used at this stage is usually from 0.1 to 10 equivalents, and preferably from 0.2 to 1.5 equivalents relative who s to 1 equivalent of the compound (14-1)).

The amount of copper bromide used at this stage is usually from 0.1 to 10 equivalents, and preferably from 0.2 to 2 equivalents relative to 1 equivalent of the compound (14-1).

The reaction temperature is usually from 25°C to the boiling temperature under reflux, the reaction solvent, and preferably from 50°C to the boiling temperature under reflux, the reaction solvent.

The reaction time is usually from 10 minutes to 24 hours, and preferably from 15 minutes to 3 hours.

The solvent for the reaction, is used at this stage is not particularly limited if only it does not interfere with the reaction, and specific preferred example is N,N-dimethylformamide.

Compound (16)obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 13) At this stage protective group for the carboxyl group of compound (16)obtained in stage 12, is removed, giving the compound (17).

This stage can be carried out in accordance with the same method as in stage 4 or 9, or SIP the override method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

The compound (17)obtained in this way can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 14) At this stage, the compound (17)obtained in stage 13, is subjected to interaction with compound (8), to obtain compound (I-3) of the present invention.

This reaction is a reaction for the formation of amide linkages, and the reaction conditions including the reaction temperature and the solvent for the reaction, can be the same as at stage 5 or stage 10 above.

The compound (I-3) of the present invention, which is obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography.

The compound (I-4) of the present invention can be obtained according to the following scheme.

[where the symbols have the same definitions specified above].

(Stage 15) At this stage protective group for the carboxyl group of compound (10)obtained in stage 7, is removed. This stage can be carried out under the same reaction conditions as in stage 4, or by using the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

The compound (18)obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 16) At this stage, the compound (18)obtained in stage 15, is subjected to interaction with compound (8), to obtain the compounds (19). This reaction is a reaction for the formation of amide linkages, and the reaction conditions including the reaction temperature and the solvent for the reaction, can be the same as at stage 5 or stage 10.

The compound (19) of the present invention, which is obtained by this method, can stand out and be purified by the known methods of separation and purification such to the to, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 17) At this stage, the compound (19)obtained in stage 16, is subjected to reaction with a halogen compound represented by the following formula (20):

[where the Ring a represents a pyridine ring, pyrazinone ring, pyrimidine ring or pyridazinone ring, and other symbols have the same definitions specified above],

in the presence of a base to obtain compound (I-4) of the present invention.

The number of halogen compounds (20)used at this stage is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalents relative to 1 equivalent of the compound (19).

As the bases used at this stage, there may be mentioned potassium carbonate, cesium carbonate, sodium hydride and similar, and, among them, preferred is potassium carbonate.

The amount of base used at this stage is usually from 0.5 to 20 equivalents, and preferably from 1 to 10 equivalents, relative to 1 equivalent of the compound (19).

The reaction temperature is usually from 25o C to the boiling temperature under reflux, the reaction solvent, and preferably from 50aboutC to the boiling temperature under reflux, the reaction solvent.

The reaction time is usually from 1 to 48 hours, and preferably from 1 to 24 hours.

The solvent for the reaction, is used at this stage is not particularly limited if only it does not interfere with the reaction, and specific preferred example is N,N-dimethylformamide.

When R1requires a protective group, the necessary protective group may be introduced in accordance with the type R1. A protective group for R1can be any group which acts as a protective group for R1from stage 17 and which can easily be removed afterwards.

By way of introduction and removal of the protective group for R1may be the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

R11in the Ring And can also be converted to R1.

The transformation of R11in the Ring And R1can be carried out according to the method described in the literature (e.g., Comprehensive Organic Synthesis, Vol. 6, Pergamon Press, 1991); Comprehensive Organic Transformations, Richard L. et al., VCH Publishers, 1988), a corresponding method, or op is a Kingdom with generally accepted method.

As examples of the group R11may be mentioned halogen atoms and alkoxycarbonyl.

When R11is, for example, alkoxycarbonyl, alkoxycarbonyl can recover to become a hydroxymethyl.

The reaction for the conversion of alkoxycarbonyl in hydroxymethyl may be the reaction between the compound having alkoxycarbonyl group, and sociallyengaged obtaining compounds having a hydroxymethyl as R1.

Alternative compound having hydroxymethyl as R1may be sideropenia with subsequent reduction to result in aminomethyl.

When the halogen compound (20)represented by the formula shown above, has an R11as the substituent in Ring A, R11may also have a protective group.

By way of introducing the protective group may be the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

The compound (I-4)obtained in this way can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, presidenial chromatography.

The compound (I-5) of the present invention can be obtained according to the following scheme.

[where R22is R2not necessarily with the Deputy, and the other symbols have the same definitions specified above].

(Stage 18) At this stage, the compound (21) is subjected to interaction with a halogen compound represented by the formula (20)below:

[in which R4represents a protective group for hydroxy, and the other symbols have the same definitions specified above],

in the presence of a base to obtain compound (23).

Way of introducing a protective group, R4for the hydroxy-group of the compound (21)used at this stage may be the method described in the above-mentioned literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

This stage can be carried out using the same way as in stage 17 of the corresponding method, or its combination with the generally accepted method.

As examples R4can be mentioned methoxymethyl, benzyl, 4-methoxy-benzyl, 2-(trimethylsilyl)ethoxymethyl, tert-butyldimethylsilyl and tert-butylcarbamoyl.

Used to the number of connections (20) varies depending on the types of compounds and solvents and other reaction conditions, but it usually ranges from 0.1 to 20 equivalents, and preferably from 0.5 to 5 equivalents, relative to 1 equivalent of the compound (21).

The amount used of the base varies depending on the types of compounds and solvents and other reaction conditions, but usually it ranges from 0.1 to 20 equivalents, and preferably from 0.5 to 5 equivalents.

Used by the base can be any base which gives the possibility of obtaining compounds (23) using the reaction between compound (20) and compound (21) at this stage, and as examples may be mentioned cesium carbonate, sodium carbonate, potassium carbonate, potassium phosphate, potassium acetate, tert-butyrate, potassium and triethylamine.

Used for the reaction solvent may be inert solvent, and it is not particularly limited, as long as it does not inhibit the reaction, and as examples may be mentioned pyridine, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and 1-methyl-2-pyrrolidinone.

In the reaction system for this stage can be the oxide of copper (I)oxide copper (II) or copper chloride(I).

In the reaction system for this stage can also be present salt of palladium, such as palladium (II) acetate or palladium (II) chloride and the ligand, such as 2-(di-tert-butylphosphino)bifani is or triphenylphosphine.

In addition to contained in the reaction system for this stage can also be present silver carbonate, silver acetate, silver oxide, triptorelin silver and similar.

The reaction temperature at this stage is usually from 0aboutC to the boiling temperature under reflux, the reaction solvent, and preferably from room temperature to 150aboutC.

The reaction time at this stage is usually from 0.1 to 72 hours, and preferably from 0.5 to 5 hours.

The compound (23)obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 19) At this stage protective group for the hydroxy-group of the compound (23)obtained in stage 18 above, is removed to obtain the compound (24).

Removing the protective group at this stage can be carried out using the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method, or, when R4represents the method of simetal, the removal of the protective group can be carried out using, for example, triperoxonane acid (TFA), hydrochloric acid or similar.

When removal R4used TFA, TFA number is usually from 0.5 to 1000 equivalents, preferably 1 to 100 equivalents.

When removal R4uses hydrochloric acid, the amount of hydrochloric acid is usually from 0.5 to 1000 equivalents, preferably 1 to 100 equivalents.

The solvent for the reaction, is used at this stage is not particularly limited if only it does not interfere with the reaction, and as examples may be mentioned methylene chloride, chloroform, methanol and 1,4-dioxane.

The reaction temperature is usually from 0aboutC to the boiling temperature under reflux, the reaction solvent, and preferably from room temperature to the boiling temperature under reflux, the reaction solvent.

The reaction time is usually from 0.1 to 72 hours, and preferably from 0.5 to 12 hours.

The compound (24)obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography, or it may post the transfer to the next stage without isolation and purification.

(Stage 20) At this stage, the compound (24)obtained in the previous phase, is subjected to reaction with compound (25-1) or (25-2) to obtain the compound (26).

The reaction between the compound (24) and compound (25-1) is the reaction of Mitsunobu, which is carried out in the presence of phosphine compounds and azo compounds in accordance with the method described in the literature (for example, Mitsunobu, O., The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products, Synthesis, Vol. 1., 1981, p.1-28), the appropriate method or combination in the conventional way.

The amount of alcohol compound (25-1)used at this stage is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (24).

As examples used traditional phosphine compounds may be mentioned triphenylphosphine and triethylphosphine.

The amount of phosphine compounds is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalents relative to 1 equivalent of the compound (24).

As examples of azo compounds can be mentioned diethylazodicarboxylate and diisopropylsalicylic.

The amount of azo compounds is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalent is allentow relative to 1 equivalent of the compound (24).

The reaction time at this stage is usually from 1 to 48 hours, and preferably from 4 to 12 hours.

The reaction temperature at this stage is usually from 0°C to the boiling temperature under reflux, the reaction solvent, and preferably from 15 to 30°C.

The solvent for the reaction, is used at this stage is not particularly limited if only it does not interfere with the reaction, and as examples may be mentioned tetrahydrofuran and toluene.

The reaction between the compound (24) and compound (25-2) can be carried out using the same method as in stage 2 above.

The number of equivalents of halogen compounds (25-2) with respect to the compound (24) and reaction conditions such as reaction temperature, reaction time, etc. may correspond to the method of stage 2, the appropriate method or combination with the generally accepted method.

The compound (26) can be obtained by the reaction between the compound (24) and a compound represented by the formula (25-3):

R22-X3(25-3)

[where R22is R2not necessarily with the Deputy, and X3represents a leaving group, such as mesilate or toilet].

The number of equivalents of compound (25-3) relative to the compound (24) and reaction conditions such as reaction temperature, reaction time, etc. can sootvetstvovala stage 2, the appropriate method or combination with the generally accepted method.

The compound (26)obtained in this way can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 21) At this stage protective group R carboxyl group of compound (26)obtained in the previous phase is removed, giving the compound (27).

This stage can be carried out under the same reaction conditions as in stage 4 above, or by using the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

Compound (27), thus obtained, may be produced and purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 22) At this stage, the compound (27)obtained in the previous phase, is subjected to reaction with the Ino compound (III), to obtain the compounds (28).

This stage is reaction formation of amide linkages, and the reaction conditions including the reaction temperature and the reaction solvent may be the same as on stages 5 and 10 above.

Connection (28) of the present invention, thus obtained, may be produced and purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, pereosazhdeniya or chromatography.

When R22in the compound (28) has no protective group, compound (28) will correspond to the compound of the present invention.

Also, when R22and/or R3compound (28) protective group is present, the protective group can be removed, giving the compound (I-5) of the present invention. The removal of the protective group can be carried out using the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

Example, when the necessary protective group, is a case in which a Deputy in R2is hydroxy, and as examples of protective groups for hydroxy may be mentioned tert-butyldimethylsilyl, which can UDA is taken with the use of hydrochloric acid, triperoxonane acid, sodium hydroxide, tetrabutylammonium fluoride or similar.

As an example, one set of connections for the connection (20), used at the stage of 18, may be mentioned compounds represented by the following formula (22):

[in which the symbols have the same definitions specified above], and these compounds may be obtained according to the scheme illustrated below.

[where the symbols have the same definitions specified above].

(Stage 18-1) At this stage dihalogenide compound (22-1) is subjected to interaction with toolboxitem sodium obtaining derived alkylsulfonamides (22-2).

As examples of dihalogenide used at this stage, can be mentioned 2,5-dibromopyridine, 2.5-dichloropyridine, 2.5-diacerein, 5-bromo-2-chloropyridine, 2-chloro-5-yodellin and 5-bromo-2-herperidin.

The number of dialkoxy sodium used at this stage is usually from 0.1 to 3 equivalents, and preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (22-1).

As examples used toolboxitem sodium can be mentioned thiamethoxam sodium, titoxd sodium and similar.

The solvent used at this stage may be the for example, inert solvent without any particular limitations, as long as it does not inhibit the reaction, and as examples may be mentioned N,N-dimethylformamide, tetrahydrofuran, 1-methyl-2-pyrrolidinone, water and similar.

The reaction time at this stage is usually from 0.5 to 72 hours, and preferably from 1 to 12 hours.

Connection (22-2)obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 18-2) This phase is a way of interacting compounds (22-2), obtained at the stage 18-1 above, with mCPBA in obtaining compound (22).

The oxidation reaction at this stage can be carried out using the same method as in stage 3, as described above, the appropriate method or combination with the generally accepted method.

The amount of mCPBA, reaction temperature, reaction time and reaction solvent used at this stage may be consistent with those of stage 3 or the corresponding method.

As the oxidizing agents used at this stage, there may be mentioned hydrogen peroxide in water, the ox is framat sodium, sodium hypochlorite and similar.

The amount of oxidizing agent used at this stage is usually from 0.1 to 10 equivalents, and preferably 1 to 5 equivalents relative to 1 equivalent of the compound (22-2).

The solvent used at this stage is not particularly limited if only it does not interfere with the reaction, and specifically may be mentioned acetonitrile, ethanol, methanol and similar.

Compound (22), thus obtained, may be produced and purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography.

The compound (I-6) of the present invention can be obtained according to the following scheme.

[where the symbols have the same definitions specified above].

(Stage 24) At this stage the connection (21) and the compound (29) are subjected to reaction in the presence of a base, to obtain the compounds (30).

X in the compound (29)used at this stage represents a halogen atom defined above, but more specifically preferred bromine or iodine.

Examples of R in the compound (29)used at this stage include the lower alkyl is a group, defined above, and particularly preferred are methyl, ethyl, propyl and isopropyl.

As the bases used at this stage, there may be mentioned potassium phosphate, potassium acetate, tert-butyrate, potassium, triethylamine and similar.

The amount of base used at this stage is usually from 0.01 to 10 equivalents, and preferably from 0.1 to 2 equivalents, relative to 1 equivalent of the compound (21).

In the reaction system for this stage may also together be present salt of palladium, such as palladium (II) acetate or palladium (II)chloride, and a ligand such as 2-(di-tert-butylphosphino)biphenyl or triphenylphosphine.

The amount of palladium salt used at this stage is usually from 0.01 to 10 equivalents, and preferably from 0.1 to 2 equivalents, relative to 1 equivalent of the compound (21).

The amount of ligand used at this stage is usually from 0.1 to 10 equivalents, and preferably from 0.5 to 2 equivalents, relative to compound (21).

The reaction temperature is usually from room temperature to the boiling temperature under reflux, the reaction solvent, and preferably from 50°C to the boiling temperature under reflux, the reaction solvent.

Used solvent for the reaction which may be any solvent, which does not interfere with the reaction, and can be mentioned, for example, toluene, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, 1-methyl-2-pyrrolidinone and similar.

The reaction time at this stage is usually from 0.5 to 72 hours, and preferably from 1 to 12 hours.

The compound (30)obtained in this way can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 25) At this stage protective group R4for the hydroxy-group in the compound (30)obtained in stage 24 above, is removed, giving the compound (31). The reaction of removal of the hydroxy-group of the compound (30) can be carried out using the method described in the literature (for example, Protective groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method, or alternatively, the target compound can be obtained by using the same method that on stage 19 above, the appropriate method or combination with the conventional method.

The compound (31), thus obtained, may be produced and purified by the known methods of separation and purification, such as, for example, the R, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 26) At this stage the connection (31), obtained in stage 25 above, is subjected to reaction with R22IT to obtain the compound (32).

The reaction is carried out at this stage is reaction Mitsunobu, which can be carried out in the presence of phosphine compounds and azo compounds in accordance with the above-mentioned method described in literature (for example, Mitsunobu, O., The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products, Synthesis, Vol. 1., 1981, p.1-28), the appropriate method or combination with the generally accepted method.

The amount of alcohol compounds (25)used at this stage is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalents, relative to 1 equivalent of compound (31).

As examples of phosphine compounds used for this stage may be mentioned triphenylphosphine and triethylphosphine.

The amount of phosphine compounds is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalents relative to 1 equivalent of compound (31).

As examples of azo compounds which may be mentioned diethylazodicarboxylate, diisopropylsalicylic and similar.

The amount of azo compounds is usually from 0.5 to 10 equivalents, and preferably 1 to 3 equivalents relative to 1 equivalent of compound (31).

The reaction time at this stage is usually from 1 to 48 hours, and preferably from 4 to 12 hours.

The reaction temperature at this stage is usually from 0°C to the boiling temperature under reflux, the reaction solvent, and preferably from 15 to 30°C.

The solvent for the reaction, is used at this stage is not particularly limited if only it does not interfere with the reaction, and as examples may be mentioned tetrahydrofuran and toluene.

Compound (32)obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 27) At this stage protective group for the carboxyl group of compound (32) above is removed, giving the compound (33). This stage can be carried out using the same method as on the stage 21, and others described above, a corresponding method, or a combination of it with about marinatin method.

The compound (33)obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification.

(Stage 28) At this stage, the compound (33), obtained at the stage 27 is subjected to an interaction with the compound represented by formula (III), to obtain compound (34).

The reaction at this stage is reaction formation of amide bond can be carried out using the same method that stage 22 above, the appropriate method or combination with the generally accepted method.

Compound (34)obtained by this method, can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography, or it may be supplied to the next stage without isolation and purification. When in the compound (34) for R3and/or R22there is no protective group, compound (34) corresponds to the compound of the present invention.

(Stage 29) When R3and/or R22in the compound (34), obtained is Tadei 28 above, has a protective group, the protective group is removed at this stage, giving the compound (I-5) of the present invention.

The reaction at this stage can be carried out using the above-mentioned method described in literature (for example, Protective Groups in Organic Synthesis, T.W. Green, 2-e edition, John Wiley & Sons, 1991), a corresponding method, or a combination of it with the conventional method.

The compound (I-5)obtained in this way can stand out and be purified by the known methods of separation and purification, such as, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, pereosazhdeniya or chromatography.

Derivatives heteroarylboronic of the present invention can be in the form of pharmaceutically acceptable salts, and such salts may be obtained in accordance with conventional methods using compounds of formulas (I-1), (I-2), (I-3), (I-4), (I-5) and (I-6), which are in the scope of the definition of compound (I) of the present invention.

In particular, when the above-mentioned compound (I-1), (I-2), (I-3), (I-4), (I-5) or (I-6) has a core group derived from amino, pyridyl or similar, in the molecule, the compound can be treated with acid to convert into a corresponding pharmaceutically acceptable salt.

As examples of such acid additive salts can be KJV is anuty hydrogenogenic, such as hydrochloride, hydrohloride, hydrobromide and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates, phosphates and carbonates; lower alkyl sulphonates, such as methanesulfonate, triftoratsetata and econsultancy; arylsulfonate, such as benzosulfimide, p-toluensulfonate; organic acid salts such as fumarate, succinate, citrates, tartratami, oxalates and maleate; and acid additive salts with organic acids, such as acidic amino acids, including glutamine and aspartate. When the compounds of the invention are such groups, acid groups, for example, when they have a carboxyl group or a similar connection can be processed grounds for conversion into the corresponding pharmaceutically acceptable salt. As examples of such additive soy reasons can be mentioned alkali metal salts such as sodium and potassium, salts of alkaline-earth metals such as calcium and magnesium, and salts of organic bases, such as ammonium salts, guanidine, triethylamine and dicyclohexylamine. Compounds of the invention can also be in the form of any desired hydrate or solvate of the free compounds or their salts.

To get drugs for prevention or treatment of type II diabetes or diseases or si is of Tomov, related, the compound of formula (I) of the present invention can be used in combination with a carrier substance.

There is no need to mention that the injected dose of the compounds of formula (I) of the present invention for the prevention or treatment will depend on the nature of the symptoms being treated, the specific compound and the method of drug administration.

The dosage will also vary depending on age, body weight and sensitivity of each patient. The daily dose is generally from about 0.001 mg to about 100 mg, preferably about 0.01 to 50 mg, and more preferably about 0.1 to 10 mg per kilogram of body weight, or as a single dose or in divided doses. Sometimes it may be necessary dosages outside these intervals.

An example of appropriate oral dose is at least about 0.01 mg up to a maximum of 2.0 g, or in the form of single or split among 2 - to 4-fold doses per day. The preferred spacing of doses is between about 1.0 mg and 200 mg per day, or with one or two injections. A more preferred range of doses is between about 10 mg and 100 mg, administered as a single daily dose.

In the case of intravenous or oral administration of typical dosing interval is from about 0.001 to 100 mg (preferably from the eye is about 0.01 to about 10 mg) of the compounds of formula (I) per day per kilogram of body weight, and more preferably from about 0.1 mg to about 10 mg of the compounds of formula(I) per day per kilogram of body weight.

As mentioned above, the pharmaceutical composition includes the compound of formula (I) and a pharmaceutically acceptable carrier. The term "composition" refers to the product obtained by using directly or indirectly, combining, compounding or aggregation of two or more components to the product resulting from dissociation of one or more components, or product resulting from any other type of action or interaction between the components, and this term also includes active and inactive components (pharmaceutically acceptable excipients), including the media.

Preferred are compositions containing a number of compounds of the formula (I), effective for the treatment, prophylaxis or prevention, or delay of onset of type II diabetes, when used in conjunction with a medically acceptable carriers.

An effective amount of the compounds of the present invention may be administered via any appropriate route of administration mammals, and especially humans. Examples of routes of administration include oral, vnutriskalnyh, local, intravenous, ocular, pulmonary and nasal route. Examples of dosage forms include tablets is key, lozenges, powder agents, suspensions, solutions, capsules, creams and aerosols, among which preferred are tablets.

The oral composition may be prepared using any conventional medical environments, examples of which include water, glycol, oil, alcohol, flavoring agents, preservatives, coloring agents and similar. Oral liquid compositions can be prepared, for example, in the form of suspensions, elixirs and solutions using starch, sucrose, microcrystalline cellulose, diluents, granulating machines, lubricants, binders, disintegrators and similar as carriers, while the oral solid composition can be prepared, for example, in the form of powders, capsules, tablets or similar, among which preferred solid oral composition.

Tablets and capsules represent the most advantageous oral dosage forms, because they are easy to handle. If necessary, the tablets can be coated using standard aqueous or nonaqueous techniques.

In addition to the common dosage forms mentioned above, the compounds of formula (I) can also be entered by means of the controlled release and/or delivery devices described, for example, in U.S. patents№ 3845770, 3916899, 3536809, 3598123, 3630200 � 4008719.

The pharmaceutical composition of the present invention, which is suitable for oral administration may be in the form of granules, tablets or capsules containing a given amount of powder or granules of the active ingredient, in the form of a water-soluble liquid or water-insoluble liquid, or emulsion of the type oil-in-water or emulsion water-in-oil. Such compositions can be prepared using any pharmaceutical methods, but all methods include combining the active ingredient with a carrier that includes one or more required components.

The composition can be obtained by uniform and thorough mixing of the active ingredient with liquid media, with a completely separate solid carrier, or both, and then shaping the product into the appropriate form, if necessary. For example, tablets are obtained by pressing and forming, together with one or more secondary ingredients, depending on the need. Molded tablets are obtained using the appropriate device for the mixing of the active ingredient in powdered or granular form with a binder, lubricant agent, inert excipients, surface-active or dispersing agent, depending on the need, and compressing the mixture.

Molded tabledirect using the appropriate device for forming a mixture of hydrated compounds in the form of a powder and an inert liquid diluent.

Each tablet contains from about 1 mg to 1 g of the active ingredient, granules or capsules, preferably contain from about 1 mg to 500 mg of active ingredient.

Examples of medical dosages for compounds of formula (I) below.

Table 1
Suspension for injection (I.M.)
Mg/ml
The compound of formula (I)10
The methylcellulose5,0
Tween 800,5
Benzyl alcohol : 9,0
Benzalkonium1,0

Water for injection is added to 1.0 ml.

Table 2
Tablets
Mg tablet
The compound of formula (I)25
The methylcellulose415
Tween 8014,0
Benzyl alcohol : 43,5
Magnesium stearate2,5

500 mg

The table is 3
Capsules
Mg/capsule
The compound of formula (I)25
Powder lactose573,5
Magnesium stearate1,5

Only 600 mg

Table 4
Aerosol
On the container
The compound of formula (I)24 mg
Lecithin, Conc. Fluidly. NF1.2 mg
Trichlorofluoromethane, NF4,025 g
DICHLORODIFLUOROMETHANE, NF12,15 g

The compounds of formula (I) can be used not only for treatment of diseases or symptoms associated with type II diabetes, but also in combination with other medicines for the treatment, prevention or delay of type II diabetes. Such other drugs may be administered either simultaneously or separately from the compounds of formula (I), using conventional routes of administration and dosages.

When the compound of formula (I) is used simultaneously with one or more drugs, it is preferable to use a pharmaceutical composition comprising a compound of formula (I) and other drugs is. Thus, the pharmaceutical composition of the present invention includes a compound of formula (I) together with one or more other active ingredients. Examples of active ingredients used in combination with compounds of the formula (I)include, but are not limited to, the following, which may be administered separately or in the same pharmaceutical composition:

(a) biguanide (such as buformin, Metformin and phenformin),

(b) PPAR agonists (for example, troglitazone, pioglitazone and rosiglitazone),

(C) insulin,

(d) somatostatin,

(e) inhibitors α-glucosidase (e.g., voglibose, miglitol and acarbose), and

(f) means for stimulating insulin secretion (for example, acetohexamide, carbutamide, hlorpropamid, glibornuride, gliclazide, glimepiride, glipizide, gliadin, glisoxepide, gliburid, glyhexamide, pipename, fenbutatin, tolazamide, tolbutamide, tolciclate, nateglinide and Repaglinide).

The weight ratio of the compounds of formula (I) to any one active ingredient may be varied within wide limits and depends on the effective amount of each active ingredient. For example, in the case of a combination of compounds of formula (I) PPAR agonist weight ratio of compounds of formula (I) PPAR agonist is typically from about 1000:1 to 1:1000, and preferably from about 200:1 to 1:200. Combination the compound of formula (I) and other active ingredients will also be in the above range, but in each case you should use an effective dose of each active ingredient.

The ability of activating glucokinase compounds represented by compound (I) of the present invention, and used test methods will be explained below.

Excellent action of the compounds represented by formula (I)in respect of activating glucokinase can be measured using a method described in the literature (e.g., Diabetes, Vol. 45, str-1677, 1996), or the appropriate way.

The activity of glucokinase represents the degree of activation of glucokinase defined not by direct measurement of glucose-6-phosphate, and by measuring the amount of thio-NADH produced upon receipt of phosphogluconolactonase of glucose-6-phosphate reporter enzyme glucose-6-phosphatedehydrogenase.

Recombinant GK human liver used in this analysis, expressives in E. coli as fusion protein FLAG, and it was purified using ANTIFLAG M2 AFFINITY GEL (Sigma).

The analysis was carried out using a flat-bottomed 96-well tablets at 30°C. Distributed 69 μl portion of the buffer for analysis (25 mm Hepes buffer: pH 7.2, 2 mm MgCl2, 1 mm ATP, 0.5 mm TNAD, 1 mm dithiothreitol) and was added or solution in DMSO connection, or 1 μl of DMSO as control. Then was distributed in 20 μl of EN zymes is Noah mixture (FLAG-GK, 20 u/ml G6PDH), pre-cooled in an ice bath, and then was added 10 μl of 25 mm glucose as substrate and the reaction was initiated (final glucose concentration = 2.5 mm).

After initiation of the reaction every 30 seconds for a 10-minute period was measured increase in absorption at 405 nm, and to evaluate the activity of compounds was used to increase within the first 5 minutes. After 5 minutes, in the presence of 1% DMSO was added FLAG-GK to gain absorption from 0.05 to 0.1.

The OD values were measured at each concentration of the evaluated compounds, using the value OD DMSO control as 100%. Value Emax (%) EC50 (μm) was calculated from the OD values at each concentration and were used as indicators of the strength of the connection by activating GK.

This method measured the ability of the compounds of the invention activate GK. The results are shown in Table 5 below.

Table 5
The ability of compounds of the invention activate GK
Connection # Emax (%)EC50 (μm)
Example obtain 19570,25
Example of getting 28440,08
Example retrieve 59 9360,53

As shown in Table 5, the compounds of the invention exhibit an excellent effect of activation of GK on the basis of the values of Emax and EC50 values.

The best ways of carrying out the invention

The present invention is illustrated in more detail by using Examples of completed forms and Examples of the preparation, and it should be understood that the invention is in no way limited to these examples.

Example of form 1

Ten parts of the compound of example obtaining 1, 15 parts of heavy magnesium oxide and 75 parts of lactose were mixed uniformly to obtain pulverizing or finely granulated powdered drug with a particle size of not more than 350 μm. Powdered medicinal substance was placed in a container in the form of capsules to obtain capsules.

Example form 2

Forty-five parts of the compound of example obtaining 1, 15 parts of starch, 16 parts of lactose, 21 parts microcrystalline cellulose, 3 parts of polyvinyl alcohol and 30 parts of distilled water were mixed uniformly, and the mixture is subsequently crushed, granulated and dried, and then was filtered to obtain granules having a size of diameter 1410-177 microns.

Example form 3

After receiving the pellets using the same method as in the case of the example form 2, we use the axis 3 parts of calcium stearate in relation to 96 parts of the granules, and the mixture was formulas pressed to form tablets with a diameter of 10 mm

Example form 4

Ten parts of microcrystalline cellulose and 3 parts of calcium stearate were added in relation to 90 parts of the granules obtained by the method of example form 2, and the mixture was formulas pressed to form tablets with a diameter of 8 mm, and then was added to a mixed suspension of gelatin syrup and sedimentary calcium carbonate to obtain tablets coated with sugar.

The present invention is now explained in more detail using the Examples of how to retrieve and Reference Examples, it should be understood that the invention is in no way limited to these examples.

When thin-layer chromatography carried out in the examples used Silica gel 60F245(Merck) as a plate and a UV detector as a method of detection. Used silicagel column was Wakogel™ C-300 (Wako Pure Chemical Industries), and used silicagel column with reversed phase LC-SORB™ SP-B-ODS (Chemco) or YMC-GEL™ ODS-AQ 120-S50 (Yamamura Depending Kenkyujo).

Below explains the abbreviations used in the examples.

i-Bu: isobutyl

n-Bu: n-butyl

t-Bu: tert-butyl

Me: methyl

Et: ethyl

Ph: phenyl

i-Pr: isopropyl

n-Pr: n-propyl

CDCl3: heavy chloroform

CD3OD: heavy methanol

DMO-d 6: heavy dimethyl sulfoxide

Below explains the abbreviations for the spectra of nuclear magnetic resonance.

s: singlet

d: doublet

DD: double doublet

t: triplet

m: multiplet

ush.: extended

kV: Quartet

J: constant combination

Hz: Hertz

Example obtain 1

Receive

5-isopropoxy-3-(4-methysulfonylmethane)-N-(4-methylthiazole-2-yl)benzamide

After you have added 29.0 g of molecular sieve 4Å, 22,0 g (0.13 mol) of p-methyldiphenylamine acid, 21,6 g (0.13 mol) of copper acetate (II) and 83,0 ml (0.59 mol) of triethylamine to a solution of 20.0 g (0.12 mol) of the methyl ester of 3,5-dihydroxybenzoic acid in methylene chloride (1.2 l), and the mixture was mixed at room temperature overnight in an atmosphere of oxygen. The reaction mixture was filtered and then concentrated under reduced pressure and the resulting residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 2:1)to give 12.4 g of methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid (yield: 36%) as a yellow solid.

After adding 129 mg (0,94 mmol) of potassium carbonate and 0,053 ml high (0.56 mmol) of 2-bromopropane to a solution of 54.4 mg (0,19 mmol) obtained phenolic compounds in N,N-dimethylformamide (2.5 ml) the reaction mixture is stirred at 80&#HWS for 4 hours. To the reaction mixture, water was added, extraction was carried out with ethyl ether, acetic acid, and then the organic layer was washed with brine (brine), dried and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 2:1), giving a 55.4 mg methyl ester 5-isopropoxy-3-(4-methylthiophene)benzoic acid (yield: 89%) as a colourless oil. After adding 64,0 mg (from 0.37 mmol) m-chloroperbenzoic acid to a solution of 41.0 mg (0.12 mmol) of the obtained ester compound in chloroform (2.0 ml) while cooling on ice, the reaction mixture was stirred for 20 minutes while cooling on ice. To the reaction mixture was added aqueous sodium thiosulfate, and the organic layer was washed with saturated aqueous sodium bicarbonate and with brine, dried and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 1:1), giving 43,9 mg methyl ester 5-isopropoxy-3-(4-methysulfonylmethane)benzoic acid (yield: 98%) as a colourless oil.

After addition of 0.28 ml (0,56 mmol) of aqueous 2n. sodium hydroxide to a solution of 41.0 mg (0.11 mmol) of the obtained sulfonic with the unity in methanol (1.0 ml), the reaction mixture was stirred over night. To the reaction mixture was added 2n. an aqueous solution of hydrochloric acid, extraction was carried out with ethyl ether, acetic acid, and the organic layer was washed with brine, dried and concentrated under reduced pressure, giving crude carboxylic connection. After adding 5,90 mg (0.51 mol) of 2-amino-4-methylthiazole, of 9.30 mg (0,068 mmol) hydrate of 1-hydroxybenzotriazole and 13.0 mg (0,068 mol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to a solution of 12.0 mg (0,034 mmol) obtained carboxyl compounds in methylene chloride (0.5 ml) and the mixture was mixed at room temperature over night. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 1:1), giving the target compound as a white solid. Data analysis for compound obtained in example obtain 1 below.

1H NMR (CDCl3) δ: of 1.34 (6H, d, J=6.0 Hz), 2,22 (3H, d, J=0.7 Hz), is 3.08 (3H, s), 4.53-in-of 4.57 (1H, m), to 6.57 (1H, d, J=0.7 Hz), to 6.80 (1H, t, J=2.0 Hz), 7,11 (1H, d, J=2.0 Hz), 7,12 (2H, d, J=8,8 Hz), 7,27 (1H, d, J=2.0 Hz), 7,92 (2H, d, J=8,8 Hz);

ESI-MS (m/e): 447[M+H]+.

Example of getting 2

Receive

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-what lanconference)-N-thiazol-2-yl-benzamide

After you have added 1.40 g (7.40 mmol) of (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 2.00 g (7.40 mmol) of triphenylphosphine to a solution of 1.20 g (4,13 mmol) of methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example obtain 1, in tetrahydrofuran (10 ml), was added 3,20 ml (7.40 mmol) of diethyl azodicarboxylate while cooling on ice, and the mixture is stirred at room temperature for 2 hours. To the reaction mixture, water was added, extraction was carried out with ethyl ether, acetic acid, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 95:5)to give 1.63 g of methyl ester of 5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methylthiophene)benzoic acid (yield: 95%) as a colourless oil. After addition of 2.06 g (12,0 mmol) m-chloroperbenzoic acid to a solution of 1.84 g (of 3.97 mmol) of the obtained ester compound in chloroform (40 ml) while cooling on ice, the reaction mixture was stirred 0.5 hour while cooling on ice. To the reaction mixture was added aqueous sodium thiosulfate, and the organic layer was washed with saturated aqueous sodium bicarbonate and Olenin solution were dried and concentrated under reduced pressure, giving crude sulfonic connection.

After the addition of 4.00 ml (20.0 mmol) of 5h. aqueous sodium hydroxide to the solution obtained sulfonic compounds in methanol (20 ml) the reaction mixture is stirred for 1.5 hours. To the reaction mixture was added 5% aqueous citric acid solution (30 ml), extraction was carried out with ethyl ether, acetic acid, and then the organic layer was washed with brine, dried and concentrated under reduced pressure, giving crude carboxylic connection. After you have added 1.20 g (12,0 mmol) of 2-aminothiazole, of 1.62 g (12,0 mmol) hydrate of 1-hydroxybenzotriazole and 1.53 g (of 8.00 mmol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to a solution of the crude carboxylic compounds in methylene chloride (40 ml) and the mixture was mixed at room temperature over night. Then the reaction mixture is stirred for 1.5 hours. To the reaction mixture, water was added, extraction was carried out with ethyl ether, acetic acid, and the organic layer was washed with 5% aqueous citric acid solution were washed with brine, dried and concentrated under reduced pressure, giving crude amide compound.

After adding 20 ml of 4n. aqueous hydrochloric acid to a solution of the obtained amide compound in 1,4-dioxane (60 ml) and the mixture was mixed at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, then was added triethylamine and the reaction mixture was again concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 1:2), giving the target compound as a white solid. Data analysis for compound obtained in example getting 2 below.

1H NMR (CDCl3) δ: of 1.33 (d, 3H, J=6.2 Hz), 3,10 (s, 3H), 3,80 (m, 2H), 4,56 (m, 1H), to 6.88 (m, 1H), 7,03 (d, 1H, J=3.6 Hz), 7,17 (d, 2H, J=8,8 Hz), 7,22 (m, 1H), 7,38 (m, 2H), of 7.96 (d, 2H, J=8,8 Hz), 10,8 (ush, 1H);

ESI-MS (m/e): 449[M+H]+.

Compounds of the following examples, 358 for receiving was obtained in the same manner as in the Example of getting 1 or 2 above. Structural formulas and data analysis for these compounds is shown below.

Example for the preparation of 3

Receive

5-ethoxy-3-(4-methysulfonylmethane)-N-(4-methoxymethyl-thiazol-2-yl)benzamide

Connection example for the preparation of 3 was obtained as a colorless oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example obtain 1, brometane and 2-amino-4-methoxymethyl-thiazole, by using the same method as in the example of a 1, a corresponding method, or a combination of its common the m method.

1H NMR (CDCl3)δ: 1,45 (1H, t, J=7.0 Hz), 3,10 (3H, s), 3,44 (3H, s), 4,10 (2H, q, J=7.0 Hz), of 4.45 (2H, s), 6,85 (1H, t, J=2.0 Hz), 6,92 (1H, s), 7,14 (1H, s), to 7.15 (2H, d, J=8,8 Hz), 7,29 (1H, s), 7,94 (2H, d, J=8,8 Hz);

ESI-MS (m/e): 463[M+H]+.

Example 4

Receive

5-cyclopentyloxy-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide

The compound of example 4 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example obtain 1, cyclopentylamine and 2-amino-thiazole, by using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 1,61-of 1.93 (8H, m), of 3.07 (3H, s), 4.75 V-rate 4.79 (1H, m), for 6.81 (1H, d, J=2.0 Hz), 6,97 (1H, d, J=3.6 Hz), 7,13 (2H, d, J=8.6 Hz), 7,20 (1H, s), 7,21 (1H, d, J=3.6 Hz), 7,33 (1H, d, J=2.0 Hz), 7,92 (2H, d, J=8.6 Hz);

ESI-MS (m/e): 459[M+H]+.

Example of getting 5

Receive

3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide

Connection example of getting 5 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example produce 1, 3-hydroxymitragynine and 2-amino-thiazole, by the same method that PR is a 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 2,14-of 2.27 (2H, m), is 3.08 (3H, s), 3,91-3,99 (4H, m), 4,96 is equal to 4.97 (1H, m), PC 6.82 (1H, d, J=1.7 Hz), of 6.99 (1H, d, J=3.6 Hz), 7,13 (2H, d, J=8,9 Hz), 7,18 (1H, d, J=3.6 Hz), 7,25 (1H, s), 7,30 (1H, d, J=1.7 Hz), to 7.93 (2H, d, J=8,9 Hz);

ESI-MS (m/e): 461[M+H]+.

An example of obtaining 6

Receive

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide

Connection example of obtaining 6 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-methoxy-2-hydroxy-propane and 2-amino-thiazole, by using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (d, 3H, J=6.3 Hz), of 3.07 (s, 3H), 3,38 (s, 3H), 3,55 (m, 2H), 4,59 (m, 1H), 6.89 in (m, 1H), 6,98 (d, 1H, J=3.6 Hz), 7,13 (d, 2H, J=8,8 Hz), 7,22 (m, 1H), 7,25 (d, 1H, J=3.6 Hz), 7,38 (m, 1H), 7,92 (d, 2H, J=8,8 Hz);

ESI-MS (m/e): 463[M+H]+.

Example of getting 7

Receive

3-(4-methysulfonylmethane)-5-(2-methoxy-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide

Connection example of getting 7 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)what antinoi acid, received in the sample receiving 1, 1,3-dimethoxy-2-hydroxy-propane and 2-amino-thiazole, by using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: is 3.08 (s, 3H), 3,39 (s, 6H), 3,63 (d, 4H, J=4,7 Hz), of 4.57 (m, 1H), 6,98 (m, 2H), 7,15 (d, 2H, J=8,9 Hz), 7,27 (m, 2H), 7,45 (m, 1H), to 7.93 (d, 2H, J=8,9 Hz);

ESI-MS (m/e): 493[M+H]+.

Example obtain 8

Receive

3-(2-fluoro-4-methysulfonylmethane)-5-isopropoxy-N-thiazol-2-yl-benzamide

Connection example of getting 8 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(2-fluoro-4-methysulfonylmethane)benzoic acid obtained in example a 1, 2-bromopropane and 2-amino-thiazole, by using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.37 (6H, d, J=6,1 Hz), 3,11 (3H, s), 4,60 with 4.64 (1H, m), for 6.81 (1H, t, J=2.2 Hz), 7,02 (1H, d, J=3.6 Hz), to 7.15 (1H, t, J=2.2 Hz), 7,21 (1H, DD, J=7,5, 8,5 Hz), 7,31 (1H, t, J=2.2 Hz), 7,40 (1H, d, J=3.6 Hz), 7,72 (1H, DDD, J=1,2, 2,2, 7.5 Hz);

ESI-MS (m/e): 451[M+H]+.

Example of getting 9

Receive

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)benzamide

Connection example of getting 9 was obtained as white as Ortega substances using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid, received in the sample receiving 1, 2-hydroxy-1-methoxy-butane and 2-amino-4-methyl-thiazole, by using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 0.97 (t, 3H, J=7,3 Hz), 1,71 (quintet, 2H, J=7,3 Hz), of 2.23 (s, 3H), is 3.08 (s, 3H), on 3.36 (s, 3H), of 3.54 (m, 2H), 4,32 (m, 1H), 6,56 (s, 1H), 6.90 to (m, 1H), 7,13 (d, 2H, J=8,9 Hz), to 7.15 (m, 1H), 7,35 (m, 1H), 7,92 (d, 2H, J=8,9 Hz), 10,6 (ush, 1H);

ESI-MS (m/e): 491[M+H]+.

Example 10

Receive

5-isopropoxy-3-(4-methysulfonylmethane)-N-pyrazole-3-yl-benzamide

The compound of example 10 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-bromopropane and 3-aminopyrazole, using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.35 (d, 6H, J=6.0 Hz), 3,06 (s, 3H), 4,58 (septet, 1H, J=6.0 Hz), 6,00 (d, 1H, J=3.0 Hz), 6,78 (m, 1H), 7,15 (d, 2H, J=8,9 Hz), 7,32 (m, 1H), 7,41 (m, 1H), of 7.90 (d, 2H, J=8,9 Hz)to 8.14 (d, 1H, J=3.0 Hz);

ESI-MS (m/e): 416[M+H]+.

Example of getting 11

Receive

5-isopropoxy-3-(4-methysulfonylmethane)-N-pyrazin-2-yl-benzamide

Connection example of getting 11 was obtained in the form of below the amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid, received in the sample receiving 1, 2-bromopropane and 2-aminopyrazine, using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.39 (d, 6H, J=6.0 Hz), to 3.09 (s, 3H), 4,62 (septet, 1H, J=6.0 Hz), PC 6.82 (m, 1H), 7,14 (m, 1H), 7,17 (d, 2H, J=8.6 Hz), 7,39 (m, 1H), 7,95 (d, 2H, 8.6 Hz), 8,30 (m, 1H), to 8.41 (m, 2H), 9,68 (USS, 1H);

ESI-MS (m/e): 428[M+H]+.

Example 12

Receive

3-(4-methysulfonylmethane)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide

The compound of example 12 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-bromo-4-methoxybutan and 2-aminothiazole, using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.34 (d, 3H, J=6,1 Hz)to 1.87 (m, 1H), 2,02 (m, 1H), of 3.07 (s, 3H), of 3.32 (s, 3H), 3,50 (m, 2H), br4.61 (m, 1H), 6.87 in (m, 1H), 6,98 (d, 1H, J=3,4 Hz), 7,14 (d, 2H, J=8,8 Hz), 7,21 (m, 1H), 7,25 (d, 1H, J=3,4 Hz), 7,39 (m, 1H), 7,92 (d, 2H, J=8,8 Hz), 11,6 (ush, 1H)

ESI-MS (m/e): 477[M+H]+.

Example of getting 13

Receive

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide

The compound of example obtaining molecules in the form of a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid, received in the sample receiving 1, 1-(tert-butyldimethylsiloxy)-3-hydroxy-butane and 2-amino-thiazole, by using the same method as in Example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.39 (d, 3H, J=6,1 Hz), a 1.88 (m, 1H), 2,02 (m, 1H), 3,10 (s, 3H), of 3.84 (m, 2H), 4,71 (m, 1H), to 6.88 (m, 1H), 7,01 (d, 1H, J=3.5 Hz), 7,17 (d, 2H, J=8,9 Hz), 7,24 (m, 1H), 7,35 (d, 1H, J=3,5 Hz), of 7.48 (m, 1H), 7,95 (d, 2H, J=8,9 Hz), 11,0 (ush, 1H);

ESI-MS (m/e): 463[M+H]+.

Example of getting 14

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5-isopropoxy-3-(4-methysulfonylmethane)-N-pyrimidine-4-yl-benzamide

Connection example of getting 14 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-bromopropane and 4-amino-pyrazine, using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: to 1.38 (d, 6H, J=6.0 Hz), 3,90 (s, 3H), 4,63 (septet, 1H, J=6.0 Hz), 6,83 (m, 1H), 7,16 (m, 1H), 7,16 (d, 2H, J=8,9 Hz), 7,29 (m, 1H), 7,95 (d, 2H, J=8,9 Hz), 8,31 (DD, 1H, J=1,2, 5,6 Hz), 8,61 (ush, 1H), to 8.70 (d, 1H, J=5.6 Hz), of 8.90 (d, 1H, J=1.2 Hz);

ESI-MS (m/e): 428[M+H]+.

Example get 15

Receive

5-isopropoxy-3-(4-methysulfonylmethane)-N-(pyrimidine-2-yl)benzamide

Obedinenie example, receive 15 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid, received in the sample receiving 1, 2-bromopropane and 2-amino-pyrazine, using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.37 (d, 6H, J=6.0 Hz), is 3.08 (s, 3H), 4,62 (septet, 1H, J=6.0 Hz), 6,79 (t, 1H, J=2.2 Hz), 7,05-7,20 (m, 4H),7,31 (t, 1H, J=2.2 Hz), to 7.93 (d, 2H, J=8,8 Hz), 8,60 (ush, 1H), 8,68 (d, 2H, J=5,9 Hz);

ESI-MS (m/e): 428[M+H]+.

Example 16

Receive

N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamide

The compound of example 16 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-bromopropane and 2-amino-4-(tert-butyldimethylsiloxy)thiazole, using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: to 1.38 (6H, d, J=6.0 Hz), is 3.08 (3H, s), br4.61 with 4.65 (3H, m), 6,83 (1H, t, J=2.2 Hz), 6.87 in (1H, s), 7,17 (2H, d, J=8,9 Hz), 7,18 (1H, d, J=2.0 Hz), 7,34 (1H, d, J=2.0 Hz), 7,95 (2H, d, J=8,9 Hz)

ESI-MS (m/e): 463[M+H]+.

Example of getting 17

Receive

N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide

Connection example of getting 17 received is camping in the form of a colorless oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid, received in the sample receiving 1, 2-hydroxy-1-methoxy-butane and 3-amino-oxazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 0,99 (t, 3H, J=7.5 Hz), total 1.74 (quintet, 2H, J=7.5 Hz), 3,01 (s, 3H), 3,38 (s, 3H), 3, 57 (m, 2H), 4,39 (m, 1H), 6.89 in (m, 1H), 7,16 for 7.12 (m, 2H), 7,14 (d, 2H, J=8,8 Hz), 7,32 (m, 1H), to 7.93 (d, 2H, J=8,8 Hz), with 8.33 (s, 1H, J=1.9 Hz), 8,64 (ush, 1H)

ESI-MS (m/e): 461[M+H]+.

Example of getting 18

Receive

3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazole-2-yl-benzamide

Connection example of getting 18 was obtained as a colorless oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-hydroxy-1-methoxy-butane and 2-amino-1,3,4-thiadiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: and 0.98 (t, 3H, J=7.5 Hz), a 1.75 (quintet, 2H, J=7.5 Hz), of 3.07 (s, 3H), 3,37 (s, 3H), of 3.56 (m, 2H), of 4.45 (m, 1H), 6,93 (m, 1H), 7,14 (d, 2H, J=8,9 Hz), 7,44 (m, 1H), 7,53 (m, 1H), to $ 7.91 (d, 2H, J=8,9 Hz), 8,73 (s, 1H), 12,0 (ush, 1H);

ESI-MS (m/e): 478[M+H]+.

Example of getting 19

Receive

5-(1-hydroxymethyl-propoxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamid the

The compound of example obtaining 19 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-2-hydroxy-butane and 2-amino-4-methyl-thiazole, by using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 0,99 (t, 3H, J=7,3 Hz), 1,68 (m, 2H), 2,28 (d, 3H, J=1.0 Hz), to 3.09 (s, 3H), 3,82 (m, 2H), 4,36 (m, 1H), to 6.57 (d, 1H, J=1.0 Hz), 6.75 in (m, 1H), 7,11 (m, 1H), 7,13 (d, 2H, J=8,9 Hz), 7,28 (m, 1H), to 7.93 (d, 2H, J=8,9 Hz), 10,8 (ush, 1H);

ESI-MS (m/e): 477[M+H]+.

Example of getting 20

Receive

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide

Connection example of getting 20 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-hydroxy-1-methoxy-butane and 2-amino-4-(tert-butyldimethylsiloxy)thiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: a 1.01 (t, 3H, J=7.5 Hz), of 1.76 (quintet, 2H, J=7.5 Hz), 3,10 (s, 3H), 3,40 (s, 3H)and 3.59 (m, 2H), 4,43 (m, 1H), with 4.64 (s, 2H), 6.89 in (s, 1H), 6,94 (m, 1H), and 7.8 (d, 2H, J=9.0 Hz), 7,20 (m, 1H), 7,40 (m, 1H), of 7.96 (d, 2H, J=9.0 Hz), 10,0 (ush, 1H);

ESI-MS (m/e): 507[M+H]+.

Example of getting 21

Receive

5-(2-amino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide

Connection example of getting 21 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butoxycarbonylamino)-2-hydroxypropane and 2-aminothiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.30 (d, 3H, J=6.0 Hz), 2,92 (d, 2H, J=6.0 Hz), to 3.09 (s, 3H), to 4.41 (sextet, 1H, J=6.0 Hz), 6,86 (m, 1H), 6,98 (d, 1H, J=3.5 Hz), 7,14 (d, 2H, J=8,9 Hz), 7,21 (d, 1H, J=3.5 Hz), 7,25 (m, 1H), 7,42 (m, 1H) 8,87 (d, 2H, J=8,9 Hz);

ESI-MS (m/e): 448[M+H]+.

Example of getting 22

Receive

5-(2-dimethylamino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide

The compound of example obtaining 22 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-dimethylamino-2-hydroxypropane and 2-amino-thiazole, by using the same method as in example getting 2 corresponding to m is Toda or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.28 (d, 3H, J=6.2 Hz), is 2.30 (s, 6H), 2,42 (DD, 1H, J=4,4, 13,0 Hz), 2,68 (DD, 1H, J=6,2 Hz, 13.0 Hz), to 3.09 (s, 3H), 4,56 (dt, 1H, J=4,5, 6.2 Hz), 6.89 in (m, 1H), 7,00 (d, 1H, J=3.6 Hz), to 7.15 (d, 2H, J=8,9 Hz), 7,22 (m, 1H), 7,28 (d, 1H, 3.6 Hz), 7,41 (m, 1H), to 7.93 (d, 2H, J=8,9 Hz), 11,4 (ush, 1H)

ESI-MS (m/e): 476[M+H]+.

An example of retrieving 23

Receive

5-(2-hydroxy-propoxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamide

The compound of example, receiving 23 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-(tert-butyldimethylsiloxy)-1-hydroxypropane and 2-amino-4-methylthiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.28 (d, 3H, J=6.4 Hz), measuring 2.20 (d, 3H, J=1.0 Hz), is 3.08 (s, 3H), 3,79 (m, 1H), 3,93 (m, 1H), 4,20 (m, 1H), to 6.57 (d, 1H, J=1.0 Hz), 6,78 (m, 1H), to 7.09 (d, 2H, J=8,9 Hz), 7,16 (m, 1H), 7,25 (m, 1H), 7,92 (d, 2H, J=8,9 Hz), and 11.2 (ush, 1H);

ESI-MS (m/e): 463[M+H]+.

Example of getting 24

Receive

3-(4-methysulfonylmethane)-5-(2-methoxy-propoxy)-N-(4-methyl-thiazol-2-yl)benzamide

Connection example completion of 24 was obtained as a colorless oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzo who Inoi acid, received in the sample receiving 1, 1-hydroxy-2-methoxy-propane and 2-amino-4-methylthiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1NMR (CDCl3) δ: of 1.26 (d, 3H, J=6.3 Hz), 2,22 (d, 3H, J=1.1 Hz), is 3.08 (s, 3H), 3.43 points (s, 3H), and 3.72 (m, 1H), 3,93 (m, 2H), to 6.57 (d, 1H, J=1.1 Hz), 6,86 (m, 1H), 7,12 (d, 2H, J=8.6 Hz), 7,16 (m, 1H), 7,29 (m, 1H), 7,92 (d, 2H, J=8.6 Hz), 10,6 (ush, 1H);

ESI-MS (m/e): 477[M+H]+.

Example get 25

Receive

5-isopropoxy-3-(4-methysulfonylmethane)-N-(thiazolo[5,4-b]pyridine-2-yl)benzamide

Connection example get 25 was obtained as a pale yellow solid using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-bromopropane and 2-amino-thiazolo[5,4-b]pyridine, using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.37 (6H, d, J=6.0 Hz), to 3.09 (3H, s), 4,59-4,63 (1H, m), at 6.84 (1H, t, J=1,8 Hz), 7,14 (2H, d, J=8,9 Hz), 7,19 (1H, t, J=1,8 Hz), 7,34 (1H, t, J=1,8 Hz), 7,38 (1H, DD, J=4,7 and 8.1 Hz), 7,92 (1H, DD, J=1.5 and 8.1 Hz), 7,94 (2H, d, J=8,9 Hz), 8,53 (1H, DD, J=1,5, a 4.7 Hz);

ESI-MS (m/e): 484[M+H]+.

Example of getting 26

Receive

5-(2-hydroxymethyl-allyl)-3-(4-methysulfonylmethane)-N-thiazol-2-the-benzamide

1H NMR (CDCl3) δ: is 3.08 (3H, s)to 3.49 (2H, s)4,06 (2H, s), 4,91 (1H, s), 5,19 (1H, s), 7,00 (1H, d, J=3.3 Hz), 7,11 (2H, d, J=9.0 Hz), 7,13 (1H, d, J=3.3 Hz), 7,20 (1H, s), 7,55 (1H, s), to 7.67 (1H, s), 7,92 (2H, d, J=9.0 Hz);

ESI-MS (m/e): 445[M+H]+.

Example of getting 27

Receive

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N - thiazolo[5,4-b]pyridine-2-yl-benzamide

The compound of example, receiving 27 was obtained as a pale yellow solid using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-2-hydroxy-propane and 2-amino-thiazolo[5,4-b]pyridine, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.34 (6H, d, J=6.2 Hz), 3,11 (3H, s), 3,74 (2H, d, J=4.6 Hz), 4,57-to 4.62 (1H, m), 6,92 (1H, t, J=1,8 Hz), 7,19 (2H, d, J=8,9 Hz), was 7.36 (1H, t, J=1,8 Hz), the 7.43 (1H, DD, J=4,7, 8,2 Hz), 7,49 (1H, t, J=1,8 Hz), 7,94 (2H, d, J=8,9 Hz), 8,03 (1H, DD, J=1,4, and 8.2 Hz), 8,49 (1H, DD, J=1,4, 4,7 Hz);

ESI-MS (m/e): 484[M+H]+.

Example of getting 28

Receive

5-(3-hydroxy-2-methyl-propyl)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide

1H NMR (CDCl3) δ: of 0.94 (6H, d, J=6,7 Hz), 1,97-2,05 (1H, m), 2,50-to 2.94 (2H, m), is 3.08 (3H, s), 3,50 of 3.56 (2H, m), 7,03 (1H, d, J=3.5 Hz), 7,13 (2H, d, J=8,8 Hz), 7,17 (1H, s), 7,42 (1H, d, J=35 Hz), 7,52 (1H, s), 7,63 (1H, s), to 7.93 (2H, d, J=8,8 Hz);

ESI-MS (m/e): 447[M+H]+.

An example of obtaining 29

Receive

Hydrochloride 3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)-5-(piperidine-4-yl-oxy)benzamide

The compound of example, receiving 29 was obtained as white crystals using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butoxycarbonyl)-4-hydroxy-piperidine and 2-amino-4-methyl-thiazole, by using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CD3OD) δ: of 1.93 (m, 2H), 2,11 (m, 2H), 2,31 (s, 3H), 2,99 (s, 3H), of 3.13 (m, 2H), 3,30 (m, 2H), and 4.75 (m, 1H), 6.89 in (s, 1H), 7,11 (m, 2H, J=8,9 Hz), 7,27 (m, 1H), 7,52 (m, 1H), to 7.84 (d, 2H, J=8,9 Hz).

Example 30

Receive

5-(1-acetyl-piperidine-4-yloxy)-3-(4-methysulfonylmethane)-N-(4-methyl-thiazol-2-yl)benzamide

The compound of example 30 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-acetyl-4-hydroxy-piperidine and 2-amino-4-thiazole, by using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

p> 1H NMR (CDCl3) δ: of 1.80 (m, 3H), 2,20-2,00 (m, 2H), and 2.14 (s, 3H), of 2.51 (s, 3H), 3,10 (s, 3H), 3,50 (m, 1H, in), 3.75 (m, 1H), 4,01 (m, 1H), 4,84 (m, 1H), 4,84 (m, 1H), of 6.71 (s, 1H), 6,92 (m, 1H), 7,18 (d, 2H, J=the 8.9 Hz), the 7.43 (m, 1H), 7,76 (m, 1H), of 7.96 (d, 2H, J=8,9 Hz);

ESI-MS (m/e): 530[M+H]+.

An example of retrieving 31

Receive

2-[3-(4-methysulfonylmethane)-5-(4-methyl-thiazol-2-yl-carbarnoyl)phenoxy]propionic acid

The compound of example obtaining 31 was obtained as white crystals using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example obtain 1,tert-butyl ester 2-bromopropionic acid and 2-amino-4-methyl-thiazole, by the same method as shown in the example of a 1, a corresponding method, or its combination with the conventional method. Way to remove thetert-butilkoi group, serving as a protective group for the carboxyl group, for obtaining this compound may be the method described in related to this field of literature (for example, Protective Groups in Organic Syntesis, T.W. Green, 2nd edition, John Wiley & Sons, 1991), by using the appropriate method or combination with the generally accepted method.

1H NMR (DMSO-d6) δ: of 1.53 (d, 3H, J=6.8 Hz), 2,28 (s, 3H), of 3.27 (s, 3H), 5,03 (septet, 1H, J=6,8 Hz), PC 6.82 (m, 1H), 6,94 (m, 1H), 7,25 (d, 2H, J=8,8 Hz), 7,42 (m, 1H), 7,50 (m, 1H), 7,95 (d, 2H, J=8,8 Hz);

ESI-MS (m/e): 477[M+H]+

Example of getting 32

Receive

5-(3-hydroxy-1-methyl-propoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide

The compound of example obtaining 32 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-3-hydroxybutane and 2-aminothiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.35 (d, 3H, J=6.0 Hz)and 1.83 (m, 1H), 2,00 (m, 1H), is 3.08 (s, 3H), of 3.78 (m, 2H)and 4.65 (m, 1H), 6,86 (m, 1H), 6,98 (m, 1H, J=3.5 Hz), 7,13 (d, 2H, J=8,8 Hz), 7,21 (d, 1H, J=3.5 Hz), 7.23 percent (m, 1H), 7,45 (m, 1H), to $ 7.91 (d, 2H, J=8,8 Hz), 12,1 (ush, 1H);

ESI-MS (m/e): 463[M+H]+.

An example of obtaining 33

Receive

3-(4-methysulfonylmethane)-5-(1-methylcarbamoyl-ethoxy)-N-(4-methyl-thiazol-2-yl)benzamide

Connection example of obtaining 33 was obtained as a white amorphous substance using the reaction between 2-[3-(4-methysulfonylmethane)-5-(4-methyl-thiazol-2-yl-carbarnoyl)phenoxy]propionic acid obtained in Example 31 and receive a methylamine. The reaction between the compound obtained in Example 31 and receive a methylamine reaction is the formation of amide linkages way, opican is m related to this field of literature (for example, Peptide Gosei no Kiso to Jikken, Izumiya, N. et al., Maruzen Publ., 1983, Comprehensive Organic Synthesis, Vol. 6, Pergamon Press, 1991), by using the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.59 (s, 3H), and 2.26 (s, 3H), of 2.86 (d, 3H, J=4,7 Hz), 3,10 (s, 3H), to 4.73 (q, 1H, J=6.6 Hz), 6,47 (ush, 1H), to 6.57 (m, 1H), 6,83 (m, 1H), 7,12 (d, 2H, J=8,8 Hz), 7,22 (m, 1H), 7,31 (m, 1H), 7,93 (d, 2H, J=8,8 Hz), 11,0 (ush, 1H);

ESI-MS (m/e): 490[M+H]+.

An example of retrieving 34

Receive

5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide

The compound of example, receiving 34 was obtained as a white amorphous substance using the reaction between acetic acid and 5-(2-amino-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-thiazol-2-yl-benzamide obtained by converting the hydroxy group of 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-thiazol-2-yl-benzamide obtained in Example getting 2, amino group.

The reaction of converting the hydroxy group in the amino group can be performed by converting the hydroxy-group in the mesyl group, and then by the interaction of the mesyl compound with sodium azide to obtain azide compounds, and restoration of the azide group with triphenylphosphine or similar connection. The reaction conversion can be carried out by the method described in Comprehensive Organic Transformations, Ricard C. Larock, 2nd edition, John Wiley & Sons, 1999), the appropriate method or combination with the conventional method.

The reaction between 3-(2-amino-1-methyl-ethoxy)-5-(4-methanesulfonyl-phenoxy)-N-thiazol-2-yl-benzamide and acetic acid is the reaction of amide bond formation, and it can be carried out in the same manner as the reaction of the formation of amide linkages in Stage 1 or stage, by using the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.33 (d, 3H, J=6.0 Hz), 2,03 (s, 3H), 3,10 (s, 3H), 3,49 (t, 2H, J=5.8 Hz), 4,56 (sextet, 1H, J=6.0 Hz), 5,98 (t, 1H, J=5.8 Hz), 6.87 in (m, 1H), 7,00 (d, 1H, J=3.6 Hz), to 7.15 (d, 2H, J=8.7 Hz), 7,28 (m, 2H), 7,54 (m, 1H), 7,94 (d, 2H, J=8.7 Hz), 11,9 (ush, 1H);

ESI-MS (m/e): 490[M+H]+.

Example of getting 35

Receive

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-isopropoxy-3-(4-methysulfonylmethane)- benzamide

The compound of example obtaining 35 was obtained as a white solid using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-bromopropane and 2-amino-4-(1-tert-butyldimethylsiloxy-ethyl)thiazole, using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: to 1.38 (6H, d, J=6.0 Hz), 1,55-1,60 (3H, ush.), is 3.08 (3H, s), 4,63 (1H, KVI is tet, J=6.0 Hz), the 4.90 (1H, q, J=6.6 Hz), 6,79-6,85 (2H, m), 7,16 (2H, d, J=8,8 Hz), 7,20 (1H, ush.), of 7.36 (1H, ush.), 7,94 (2H, d, J=8,8 Hz);

ESI-MS (m/e): 477[M+H]+.

Example of getting 36

Receive

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-pyridin-2-yl-benzamide

Connection example of getting 36 was obtained as white crystals using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-aminopyridine, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (3H, d, J=3.2 Hz), is 3.08 (3H, s), 3,76-with 3.79 (2H, m), 4,57-4,63 (1H, m), 6.48 in (1H, t, J=2.0 Hz), 7,13-7,17 (1H, m), to 7.15 (2H, d, J=8,8 Hz), 7,18 (1H, d, J=2.0 Hz), 7,35 (1H, d, J=2.0 Hz), 7,76 (1H, DDD, J=1,6, 5,1, 8,4 Hz), to 7.93 (2H, d, J=8,8 Hz), 8,30 (1H, d, J=5,1 Hz), a 8.34 (1H, d, J=8,4 Hz);

ESI-MS (m/e): 443[M+H]+.

An example of retrieving 37

Receive

5-(2-hydroxy-ethoxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide

The compound of example, receiving 37 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-dimethylsiloxy)-2-hydroxyethane and 2-aminothiazol is, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 3,10 (s, 3H), 4,01 (t, 2H, J=4.5 Hz), 4,14 (t, 2H, J=4.5 Hz), 6.87 in (m, 1H), 7,02 (d, 1H, J=3.0 Hz), 7,16 (d, 2H, J=8,4 Hz), 7,30 (m, 2H), 7,38 (m, 1H), 7,95 (d, 2H, J=8,4 Hz), 11,3 (ush, 1H);

ESI-MS (m/e): 435[M+H]+.

An example of retrieving 38

Receive

5-(2-hydroxy-cyclopentyloxy)-3-(4-methysulfonylmethane)-N-thiazol-2-yl-benzamide

The compound of example obtaining 38 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldiphenylsilyl)-2-hydroxycyclopent and 2-aminothiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 1,62-of 2.08 (6H, m), is 3.08 (3H, s), 4,24-4,30 (1H, m), 4,55-4,60 (1H, m), 6.87 in (1H, t, J=2.0 Hz), 7,00 (1H, d, J=3.6 Hz), 7,14 (2H, d, J=8,8 Hz), 7,25 (1H, t, J=2.0 Hz), 7,25 (1H, d, J=3.6 Hz), 7,40 (1H, t, J=2.0 Hz), to 7.93 (2H, d, J=8,8 Hz);

ESI-MS (m/e): 475[M+H]+.

An example of retrieving 39

Receive

N-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamide

The compound of example, receiving 39 was obtained as a white amorphous substance and the use of the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid, received in the sample receiving 1, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 4-acetyl-2-aminothiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (3H, d, J=6.2 Hz), 2,58 (3H, s), 3,10 (3H, s), 3,80 (2H, d, J=5,2 Hz), 4,63 (1H, q, J=5.6 Hz), for 6.81-6.89 in (1H, m), 7,12-7,19 (3H, m), 7,38 (1H, ush.), 7,83 (1H, d, J=2.0 Hz), 7,95 (2H, DD, J=8,9 Hz);

ESI-MS (m/e): 491[M+H]+.

Example of getting 40

Receive

5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)benzamide

Connection example getting 40 was obtained as a white solid using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-4-tert-butyldimethylchlorosilane, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (3H, d, J=6.2 Hz), to 3.09 (3H, s), 3.75 to of 3.80 (2H, m), 4,55-of 4.66 (3H, m), 6,83-6,86 (1H, m), to 6.88 (1H, s), 7,12-7,20 (3H, m), 7,33 and 7.36 (1H, m), 7,94 (2H, d, J=8.6 Hz);

ESI-MS (m/e): 479[M+H]+.

An example of retrieving 41

Receive

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-5-(2-hydroxy-1-IU the Il-ethoxy)-3-(4-methysulfonylmethane)benzamide

The compound of example, receiving 41 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-4-(1-tert-butyldimethylsiloxy-ethyl)thiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (3H, d, J=6.2 Hz), for 1.49 (3H, d, J=6.5 Hz), of 3.12 (3H, s), 3,68 (2H, d, J=5.0 Hz), 4,60 (1H, q, J=6.2 Hz), 4.80 to the 4.90 (1H, m)6,94 (1H, s), of 6.96-6,99 (1H, m), 7.23 percent (2H, d, J=8,9 Hz), 7,29-to 7.32 (1H, m), 7,47-7,50 (1H, m), 7,89 (1H, s), of 7.96 (2H, d, J=8,9 Hz);

ESI-MS (m/e): 493[M+H]+.

An example of retrieving 42

Receive

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide

After addition of 20.4 g (of 0.68 mol) of 1-bromo-2-fluoro-4-iodobenzoyl, 20,8 g (0.64 mol) of cesium carbonate and 5,07 g (0.64 mol) of copper oxide (II) to a solution of 9.00 g (0.43 mol) of methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid in pyridine (50,0 ml) and the mixture was mixed at 130°C for 8 hours in nitrogen atmosphere. The reaction mixture was filtered and then concentrated under reduced pressure, to the obtained residue were added ethyl ester of acetic acid and a saturated aqueous solution of ammonium chloride, and organic is the cue layer was washed with brine, were dried and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 9:1)to give 10.6 g of methyl ester of 3-(4-bromo-3-fluoro-phenoxy)-5-methoxyethoxymethyl acid (yield: 65%) as a yellow oil.

After adding 757 mg (7.41 mmol) of methanesulfonate sodium and 1.41 g (7.41 mmol) of copper iodide to a solution of 357 mg (0,93 mmol) obtained ester compound in dimethyl sulfoxide (6,0 ml) the reaction mixture is stirred at 120°C for 6 hours. To the reaction mixture were added an aqueous solution of sodium chloride and ammonia water (9:1) and was conducted by extraction with ethyl ether, acetic acid, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 2:1)to give 170 mg of methyl ester of 3-(3-fluoro-4-methanesulfonyl-phenoxy)-5-methoxyethoxymethyl acid (yield: 48%) as a colourless oil.

After adding 30,0 ml triperoxonane acid to the solution to 3.34 g (8.69 mmol) of the obtained ester compound in methylene chloride (60,0 ml) the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture of concentri who was ovals under reduced pressure, and the obtained residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 3:7), giving 2,59 g of methyl ester of 3-(3-fluoro-4-methanesulfonyl-phenoxy)-5-hydroxybenzoic acid (yield: 88%) as a colourless oil.

After addition of 87.0 mg (0.46 mmol) of (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 119 mg (0.46 mmol) of triphenylphosphine to a solution of 77.5 mg (0.23 mmol) of the obtained phenolic compounds in tetrahydrofuran (1.0 ml) and to it was added a solution of 0.25 ml (or 0.57 mmol) of diethyl azodicarboxylate 40% toluene, and the mixture is stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 2:1), giving 80.0 mg methyl ester 5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(3-fluoro-4-methanesulfonyl-phenoxy)benzoic acid (yield: 69%) as a colourless oil.

The compound of example obtaining 42 was obtained as a colorless oil using the obtained methyl ester 5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(3-fluoro-4-methanesulfonyl-phenoxy)benzoic acid and 2-amino-thiazole, by using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (3H, d, J=6.3 Hz), 3,23 (3H, s), 3,78-of 3.80 (2H, m), 4,56-br4.61 (1H, m), 6,83-6,94 (3H, m), 7,01 (1H, d, J=3.5 Hz), 7.23 percent (1H, t, J=1,8 Hz), 7,37 (1H, d, J=3.5 Hz), 7,41 (1H, t, J=1,8 Hz), 7,94 (1H, t, J=8,2 Hz);

ESI-MS (m/e): 467[M+H]+.

An example of retrieving 43

Receive

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methyl-thiazol-2-yl)benzamide

The compound of example, receiving 43 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-5-methylthiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.29 (3H, d, J=6.2 Hz), is 2.37 (3H, s), is 3.08 (2H, s), 3,69 is 3.76 (2H, m), to 4.52-of 4.57 (1H, m), PC 6.82 (1H, t, J=2.0 Hz), to 6.88 (1H, s), 7,12 (2H, d, J=8,8 Hz), 7,20 (1H, d, J=2.0 Hz), 7,35 (1H, d, J=2.0 Hz), 7,92 (2H, d, J=8,8 Hz);

ESI-MS (m/e): 463[M+H]+.

An example of retrieving 44

Receive

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-([1,2,4]thiadiazole-5-yl)benzamide

The compound of example, receiving 44 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(Tr is t -butyldimethylsiloxy)-2-hydroxypropane and 5-amino-1,2,4-thiadiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.30 (3H, d, J=6.2 Hz), of 3.12 (3H, s), 3,68 (2H, d, J=5,1 Hz), 4,58-is 4.85 (1H, m), 7,00 (1H, s), 7.23 percent (2H, d, J=8,9 Hz), 7,37 (1H, s), 7,56 (1H, s), 7,95 (2H, d, J=8,9 Hz), of 8.37 (1H, s);

ESI-MS (m/e): 450[M+H]+.

An example of retrieving 45

Receive

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide

The compound of example obtaining 45 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-hydroxy-1-methoxypropane and 2-amino-4-tert-butyldimethylchlorosilane, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.35 (3H, d, J=6.3 Hz), to 3.09 (3H, s)to 3.41 (3H, s), 3,49-of 3.64 (2H, m), 4,58-of 4.67 (3H, m), 6.87 in-6,92 (2H, m), 7,13-7,20 (3H, m), 7,35-7,38 (1H, ush.), 7,94 (2H, d, J=8,8 Hz);

ESI-MS (m/e): 493[M+H]+.

An example of retrieving 46

Receive

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(5-methoxycarbonyl-pyridine-2-yl)benzamide

Connection premenapause 46 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid, received in the sample receiving 1, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-5-methoxycarbonyl-pyridine, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.34 (d, 3H, J=6.0 Hz), 3,10 (s, 3H), 3,80 (m, 2H), 3.96 points (s, 3H), br4.61 (m, 1H), 6,80 (m, 1H), 7,16 (d, 2H, J=8,8 Hz), 7,20 (m, 1H), 7,37 (m, 1H), 7,94 (d, 2H, J=8,8 Hz), 8,33-8,46 (m, 2H), 8,80 (ush, 1H), 8,93 (m, 1H)

ESI-MS (m/e): 501[M+H]+

An example of retrieving 47

Receive

6-[5-isopropoxy-3-(4-methysulfonylmethane)benzoylamine]nicotinic acid

The compound of example, receiving 47 was obtained as a white solid using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 6-amino-nicotinic acid, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (DMSO-d6) δ: of 1.29 (d, 6H, J=6.0 Hz), 3,20 (s, 3H), 4,76 (septet, 1H, J=6.0 Hz), 6,94 (m, 1H), 7.23 percent (d, 2H, J=8,8 Hz), 7,33 (m, 1H), 7,49 (m, 1H), 7,94 (d, 2H, J=8,8 Hz), 8,29 (m, 2H), 8,87 (m, 1H), and 11.2 (s, 1H)

ESI-MS (m/e): 471[M+H]+.

Example obtain 48

Receive

5-(2-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonyl is phenoxy)-N-thiazol-2-yl-benzamide

The compound of example obtaining 48 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-(tert-butyldimethylsiloxy-3-hydroxy)butane and 2-aminothiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 1,25 (s, 3H, J=6.2 Hz), 1.28 (in, 3H, J=6.2 Hz), is 3.08 (s, 3H), a 3.87 (m, 1H), 4,22 (m, 1H), 6,85 (m, 1H), 6,99 (m, 1H), 7,13 (d, 2H, J=8,8 Hz), 7.23 percent (m, 2H), 7,38 (m, 1H), 7,92 (d, 2H, J=8,8 Hz), 12, 0 (ush, 1H);

ESI-MS (m/e): 463[M+H]+.

An example of retrieving 49

Receive

5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methysulfonylmethane)benzamide

The compound of example, receiving 49 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-aminoanisole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.0 Hz), 2,04 (ush, 1H), is 3.08 (s, 3H), of 3.77 (m, 2H), 4,60 (m, 1H), 6.87 in (m, 1H), 7,15 (d, 2H, J=8,8 Hz), 7,19 (m, 2H), 7,35 (m, 1H), 7,94 (d, 2H, J=8,8 Hz), 8,30 (d, 1H, J=1,6 Hz), 9,24 (ush, 1H);

ESI-MS (m/e): 433[M+H]+./p>

Example of getting 50

Receive

N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methysulfonylmethane)benzamide

Connection example of getting 50 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-bromopropane and 2-amino-5-formulate, using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.36 (d, 6H, J=6.0 Hz), is 3.08 (s, 3H), 4,59 (septet, 1H, J=6.0 Hz), 4,79 (s, 2H), PC 6.82 (s, 1H), 7,14 (d, 2H, J=8,4 Hz), 7,13-of 1.18 (m, 2H), 7,31 (s, 1H), 7,92 (d, 2H, J=8,4 Hz), and 11.2 (ush, 1H);

ESI-MS (m/e): 463[M+H]+.

An example of retrieving 51

Receive

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide

The compound of example obtaining 51 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-methoxy-2-hydroxypropane and 2-amino-4-(1-tert-butyldimethylsiloxy)thiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) #x003B4; : to 1.35 (3H, d, J=6.3 Hz), of 1.55 (3H, d, J=6.3 Hz), is 3.08 (3H, s)to 3.41 (3H, s), 3,49-of 3.64 (2H, m), 4,59-4,70 (1H, m), the 4.90 (1H, q, J=6.3 Hz), to 6.80 (1H, USS), of 6.90 (1H, ush.), 7,16 (2H, d, J=8,9 Hz), 7.23 percent-7,26 (1H, ush.), 7,42 (1H, USS), 7,94 (2H, d, J=8,9 Hz);

ESI-MS (m/e): 507[M+H]+.

An example of retrieving 52

Receive

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide

The compound of example, receiving 52 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example produce 1, 3-hydroxy-tetrahydrofuran and 2-amino-4-tert-butyldimethylchlorosilane, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 2,10-of 2.36 (2H, m)to 3.09 (3H, s), 3,39-4,07 (4H, m), of 4.66 (2H, s), 4,96-of 5.05 (1H, m), at 6.84 (1H, t, J=2.0 Hz), 7,15-7,20 (3H, m), 7,30 (1H, ush.), of 7.96 (2H, d, J=8,8 Hz);

ESI-MS (m/e): 491[M+H]+.

Example of getting 53

Receive

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(2-methylthiazole-4-yl)benzamide

Connection example of getting 53 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(Tr is t -butyldimethylsiloxy)-2-hydroxypropane and 4-amino-2-methylthiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.0 Hz), 2,31 (ush, 1H), 2,66 (s, 3H), to 3.09 (s, 3H), of 3.78 (m, 2H), 4,59 (m, 1H), 7,13-7,16 (m, 1H), 7,15 (d, 2H, J=8,8 Hz), 7,32 (m, 1H), 7,60 (s, 1H), 7,94 (d, 2H, J=8,8 Hz), 8,90 (ush, 1H);

ESI-MS (m/e): 463[M+H]+.

An example of retrieving 54

Receive

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4-methoxymethyl-thiazol-2-yl)benzamide

The compound of example obtaining 54 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-4-methoxymethanol, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (d, 3H, J=6.0 Hz), to 3.09 (s, 3H), 3,42 (s, 3H), of 3.78 (m, 2H), of 4.44 (m, 2H), 4,57 (m, 1H), 6,86 (m, 1H), 6, 91 (s, 1H), 7,10-7,26 (m, 3H), 7,31 (m, 1H), of 7.97 (d, 2H, J=8,9 Hz), 9,67 (ush, 1H);

ESI-MS (m/e): 493[M+H]+.

Example of getting 55

Receive

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide

The compound of example obtaining 55 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 2-hydroxy-1-methoxypropane and 2-amino-4-(1-tert-butyldimethylsiloxy)thiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.35 (3H, d, J=6.3 Hz), of 1.55 (3H, d, J=6.3 Hz), is 3.08 (3H, s)to 3.41 (3H, s), 3,49-of 3.64 (2H, m), 4,59-4,70 (1H, m), the 4.90 (1H, q, J=6.3 Hz), to 6.80 (1H, USS), of 6.90 (1H, ush.), 7,16 (2H, d, J=8,9 Hz), 7.23 percent-7,26 (1H, ush.), 7,42 (1H, USS), 7,94 (2H, d, J=8,9 Hz);

ESI-MS (m/e): 507[M+H]+.

An example of receiving 56

Receive

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide

Connection example of receiving 56 was obtained as a white solid using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example produce 1, 3-hydroxymitragynine and 2-amino-4-(1-tert-butyldimethylsiloxy)thiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 2,10-of 2.36 (2H, m), 0,39 (3H, s), 3,89-4,07 (4H, m), 4,85-of 4.95 (1H, m), equal to 4.97-5,04 (1H, m), for 6.81-6,85 (2H, m), 7,16 (2H, d, J=8.7 Hz), 7.23 percent (1H, USS), 7,34 (1H, USS), of 7.96 (2H, d, J=8.7 Hz);

ESI-MS (m/e): 505[M+H]+.

An example of retrieving 57

Receive

N-[4-(1-hydroxy-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)-5-(tetrahydrofuran-3-yl-oxy)benzamide (diastereoisomer Example, receiving 56)

The compound of example, receiving 57 was obtained as a white solid using the same method as in the example of obtaining 56, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 2.10 to 2.35 (2H, m)to 3.09 (3H, s), 3,89-4,06 (4H, m), 4,86-of 4.95 (1H, m), equal to 4.97-of 5.05 (1H, m), for 6.81-6,85 (2H, m), 7,16 (2H, d, J=8.7 Hz), 7,22 (1H, USS), 7,34 (1H, USS), of 7.96 (2H, d, J=8.7 Hz);

ESI-MS (m/e): 505[M+H]+.

An example of retrieving 58

Receive

N-(2,5-dimethylthiazol-4-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamide

The compound of example, receiving 58 was obtained as a light yellow oil using methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example a 1, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 4-amino-2,5-dimethylthiazole, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.28 (d, 3H, J=6.0 Hz), 2,32 (s, 3H), of 2.56 (s, 3H), of 3.07 (s, 3H), and 3.72 (m, H), a 4.53 (m, 1H), 6,79 (t, 1H, J=2.0 Hz ), was 7.08 (DD, 2H, J=2,0, 6,8 Hz), 7,18 (s, 1H), 7,32 (s, 1H), 7,89 (DD, 2H, J=2,0, 6,8 Hz ), 8,67 (ush, 1H);

ESI-MS (m/e): 477[M+H]+.

Example retrieve 59

Receive

5-isopropoxy-3-(4-methoxycarbonylaminophenyl)-N-thiazol-2-yl-benzamide

After addition of 41.0 g (0.30 mmol) of potassium carbonate and 23.8 g (0,19 mmol) of 2-bromopropane to a solution of 25.0 grams (0.15 mol) of the methyl ester of 3,5-dihydroxybenzoic acid in N,N-dimethylformamide (250 ml), the reaction mixture was stirred at 80°C for 4 hours. To the reaction mixture, water was added, extraction was carried out with ethyl ether, acetic acid, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 5:1), giving 12.0 g of methyl ester of 5-hydroxy-3-isopropoxybenzoic acid (yield: 38%) as a colourless oil.

After addition of 1.05 g of molecular sieves 4A, and 1.00 g (6,70 mol) p-formylphenylboronic acid, 605 mg (3,30 mol) of copper acetate (II) and (2,32 ml (16,6 mol) of triethylamine to a solution of 700 mg (3,30 mmol) obtained phenolic compounds in methylene chloride (30 ml) and the mixture was mixed at room temperature in oxygen atmosphere during the night. The reaction mixture is filtered and concentrated under reduced pressure, and the obtained residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 5:1)to give 593 mg of methyl ester of 3-(4-formylphenoxy)-5-isopropoxybenzoic acid (yield: 57%) as a colourless oil.

After adding 85,0 mg (2.25 mmol) of sodium borohydride to a solution of 590 mg (1.88 mmol) obtained formyl compounds in methanol (20 ml) the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture was concentrated, and then added saturated aqueous sodium bicarbonate solution, extraction was carried out with chloroform, and the organic layer was dried and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane: ethyl ester of acetic acid = 2:1), giving 567 mg of methyl ester of 3-(4-hydroxymethylene)-5-isopropoxybenzoic acid (yield: 95%) as a colourless oil.

After the addition of 0.18 ml (1,26 mmol) of triethylamine and 0,073 ml (0.95 mmol) of methanesulfonamide to a solution of 200 mg (to 0.63 mmol) obtained alcohol compound in chloroform (10 ml) the reaction mixture is stirred at 50°C for 15 minutes. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, extraction was carried out with chloroform, and the organic classutils and then concentrated under reduced pressure. After addition of 5.0 ml of DMF to the obtained residue, and dissolved therein was added 123 mg (1,90 mmol) of sodium azide and the mixture is stirred at 80°C for 1 hour. To the reaction mixture, water was added, extraction was carried out with ethyl ether, acetic acid, and the organic layer was dried and then concentrated under reduced pressure, giving crude azide compound.

After adding 247 mg (1,26 mmol) of triphenylphosphine to a solution of 11 ml of the obtained azide compound in a mixture of tetrahydrofuran-water (10:1), the reaction mixture was stirred at 90°C for 14 hours. To the reaction mixture was added 2n. an aqueous solution of hydrochloric acid for acidification of an aqueous solution. The mixture was washed with ethyl ether, acetic acid, and then the aqueous layer was added 4n. aqueous sodium hydroxide solution to obtain an alkaline aqueous solution, followed by extraction with chloroform, and the organic layer was dried and concentrated under reduced pressure giving and 67.8 mg of the crude amine compound (yield: 34%).

After adding 0,057 ml (0.41 mmol) of triethylamine and 0.024 ml (0.31 mmol) of methyl ether of Harborview acid to the solution obtained amine compound in chloroform (5.0 ml), the reaction mixture was stirred at room temperature for 1 hour. To reactio the Noah mixture was added saturated aqueous sodium bicarbonate solution, then extraction was carried out with chloroform, and the organic layer was dried and concentrated under reduced pressure, giving crude methoxycarbonylaminophenyl connection.

After adding 1.0 ml (4.00 mmol) of 4h. an aqueous solution of sodium hydroxide to a solution of 5:3 received methoxycarbonylaminophenyl compounds in tetrahydrofuran-methanol (8.0 ml), the reaction mixture is stirred at 50°With during the night. To the reaction mixture were added saturated aqueous solution of ammonium chloride was carried out extraction with chloroform, the organic layer was dried and concentrated under reduced pressure and the resulting residue was purified using column chromatography on silica gel (chloroform: methanol = 30:1), giving a total of 63.1 mg 5-isopropoxy-3-(4-methoxycarbonylaminophenyl)benzoic acid (yield: 85%) as a white solid.

After addition of 33.0 mg (0.33 mol) of 2-aminothiazole, 76,0 mg (0.49 mmol) of hydrate of 1-hydroxybenzotriazole and 63,0 mg (0.33 mol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to a solution of the obtained carboxyl compound in N,N-dimethylformamide (3.0 ml) and the mixture was mixed at room temperature over night. To the reaction mixture, water was added, extraction was carried out with ethyl ether acetic acid, the reaction mixture was concentrated PR is the reduced pressure, and the obtained residue was purified using column chromatography on silica gel (chloroform: methanol = 100:1), giving the target compound as a white solid. Data analysis for compound obtained in the example of a 59 below.

1H NMR (CDCl3) δ: of 1.34 (6H, d, J=6.0 Hz), 3,71 (3H, s), 4,36 (2H, d, J=5.5 Hz), of 4.57 (1H, m), 4,99-5,10 (1H, ush.), to 6.75 (1H, USS), of 6.96-7,05 (4H, m), 7,20 (1H, ush.), 7,27-7,34 (3H, m), 10,70-10,88 (1H, ush.);

ESI-MS (m/e): 442[M+H]+.

Connection examples get 60-64 were obtained in the same manner as in the example of a 59 above. Structural formulas and data analysis for these compounds is shown below.

Example of getting 60

Receive

5-isopropoxy-3-(4-methylcarbamoyl-phenoxy)-N-thiazol-2-yl-benzamide

Connection example of getting 60 was obtained as a colorless amorphous substance using 2-aminothiazole and methyl ester of 3-(4-methylcarbamoyl-phenoxy)-5-isopropoxybenzoic acid, obtained by or through reaction between methylamine and methyl ether 3-(4-carboxyphenoxy)-5-isopropoxybenzoic acid obtained by oxidation of the formyl group of the methyl ester of 3-(4-formylphenoxy)-5-isopropoxybenzoic acid obtained in example retrieve 59, in the same manner as described in example getting 2, with the appropriate way, or a similar method.

1H NMR (CDCl3) δ: of 1.36 (6H, d, J=6,1 Hz)of 3.00 (3H, d, J=4,8 Hz), 4,58 (1H, m), 6,12-6,21 (1H, ush.), 6,79 (1H, t,J=2.2 Hz), 6,99-7,06 (4H, m), 7.24 to 7,27 (1H, m), 7,34 (1H, d, J=3.6 Hz), 7,72 (2H, m);

ESI-MS (m/e): 412[M+H]+.

An example of retrieving 61

Receive

3-(4-dimethylcarbamoyl-phenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide

The compound of example, receiving 61 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-carboxyphenoxy)-5-isopropoxybenzoic acid obtained in example obtaining 60, dimethylamine and 2-aminothiazole, in the same way as shown in the example of a 60, a corresponding method, or similar method.

1H NMR (CDCl3) δ: of 1.34 (6H, d, J=6.0 Hz), 2,98 is 3.15 (6H, ush.), 4,56 (1H, m), 6,78 (1H, t, J=2.3 Hz), 6,98 (1H, d, J=3.6 Hz), 7,00-7,06 (2H, m), 7,14-7,17 (1H, m), 7.24 to 7,28 (2H, m), 7,40-7,47 (2H, m);

ESI-MS (m/e): 426[M+H]+.

An example of retrieving 62

Receive

5-isopropoxy-3-(4-methylcarbamoylmethyl-phenoxy)-N-thiazol-2-yl-benzamide

The compound of example, receiving 62 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-aminomethylphenol)-5-isopropoxybenzoic acid obtained in Example retrieve 59, acetylchloride and 2-aminothiazole, using the same method as in the example is Holocene 59, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.35 (6H, d, J=6.0 Hz), was 2.05 (3H, s), and 4.40 (2H, d, J=5.6 Hz), of 4.57 (1H, m), 5,95-6,07 (1H, ush.), is 6.78 (1H, t, J=2.2 Hz), 6,93-7,02 (4H, m), 7,20-to 7.32 (4H, m);

ESI-MS (m/e): 426[M+H]+.

An example of retrieving 63

Receive

5-isopropoxy-3-(4-methanesulfonylaminoethyl-phenoxy)-N-thiazol-2-yl-benzamide

The compound of example, receiving 63 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-aminomethylphenol)-5-isopropoxybenzoic acid obtained in example retrieve 59, methanesulfonamide and 2-aminothiazole, using the same method as in the example of obtaining 59, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.36 (6H, d, J=6.0 Hz), to 2.94 (3H, s), 4,32 (2H, d, J=6,1 Hz), 4,60 (1H, m), 4,79-4,88 (1H, m), 6,77 (1H, m), 6,98-7,38 (8H, m);

ESI-MS (m/e): 462[M+H]+.

Example of getting 64

Receive

3-[4-(1-hydroxy-propyl)phenoxy]-5-isopropoxy-N-thiazol-2-yl-benzamide

Connection example obtain the 64 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-formylphenoxy)-5-isopropoxybenzoic acid obtained in example retrieve 59, ethylacetamide and 2-aminothiazole using the same meth is Yes, in the example of obtaining 59, the appropriate method or combination with the generally accepted method.

The reaction between methyl ether 3-(4-formylphenoxy)-5-isopropoxybenzoic acid and ethylmagnesium is a Grignard reaction, it can be carried out according to the method described in the literature (for example, Comprehensive Organic Transformations, Richard L. et al., VCH Publishers, 1988), the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: to 0.92 (3H, t, J=7.4 Hz), of 1.34 (6H, d, J=6,1 Hz), 1,67-of 1.88 (2H, m), 4,51-4,63 (2H, m), 6,76 (1H, t, J=2.3 Hz), 6,95-7,07 (3H, m),? 7.04 baby mortality-7,07 (1H, m), 7,20-7,24 (2H, m), 7,32 (2H, d, J=8.5 Hz);

ESI-MS (m/e): 413[M+H]+.

Example getting 65

Receive

methyl ester of 6-[3-isopropoxy-5-(thiazol-2-ylcarbonyl)phenoxy]-nicotinic acid

After adding 10 ml of 4n. an aqueous solution of hydroperoxide sodium to a solution of 3.0 g (14.3 mmole) of methyl ester of 5-hydroxy-3-isopropoxybenzoic acid obtained in example retrieve 59, in methanol (50 ml) and the mixture was mixed at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and then was added a saturated aqueous ammonium chloride, extraction was conducted with chloroform, and the organic layer was dried, and then concentrated under reduced pressure. The remainder of what was salsa using chromatography on silica gel (chloroform:methanol = 50:1) obtaining of 2.44 g of 5-hydroxy-3-isopropoxybenzoic acid (yield: 87%) as a white solid.

After addition of 2.45 g (24.5 mmol) of 2-aminothiazole, 3,40 ml (24.5 mmol) of triethylamine and 4,14 g (24.5 mmol) of 2-chloro-1,3-dimethylimidazolidine to a solution of 2.40 g (12.2 mmol) of the obtained carboxylic acid in chloroform (50 ml) while cooling on ice and the mixture was mixed at room temperature for 13 hours. To the reaction mixture were added saturated aqueous ammonium chloride, extraction was conducted with chloroform, and the organic layer was dried, and then concentrated under reduced pressure. After adding 10 ml of 4n. aqueous sodium hydroxide to a solution of the obtained residue in methanol (40 ml) and the mixture was mixed at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then was added a saturated aqueous ammonium chloride, extraction was conducted with chloroform, and the organic layer was dried, and then concentrated under reduced pressure. The obtained residue was purified using chromatography on silica gel (chloroform:methanol = 100:1) obtaining of 1.81 g of 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide (yield: 53%) as a white solid.

After adding 123 mg (0.72 mmole) of the methyl ester of 6-chloronicotinic acid and 199 mg (1.44 mmole) of potassium carbonate to a solution of 100 mg (of 0.36 mmole) obtained amide compound in N,N-dimethylformamide (10.0 ml) and the mixture was mixed PR is 80° C for 18 hours under nitrogen atmosphere. To the reaction mixture, water was added, extraction was performed with ethyl acetate, and the organic layer was dried, and then concentrated under reduced pressure. The obtained residue was purified using chromatography on silica gel (hexane:ethyl acetate = 3:1) obtaining mentioned in the title compounds as white solids. Data analysis for compound obtained in example getting 65, shown below.

1H NMR (CDCl3) δ: of 1.36 (6H, d, J=6.0 Hz), 3,93 (3H, s), 4,60 (1H, m), 6,91-7,02 (3H, m), 7,29-7,40 (3H, m), 8,31 (1H, DD, J=8,6, 2.4 Hz), 8,81 (1H, d, J=2.4 Hz);

ESI-MS (m/e): 414[M+H]+.

An example of retrieving 66

Receive

3-(5-hydroxymethyl-pyridine-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide

After adding 6.0 mg (0.16 mmole) of sociallyengaged to the solution 60,0 mg (0.15 mmole) of the methyl ester of 6-[3-isopropoxy-5-(thiazol-2-ylcarbonyl)phenoxy]-nicotinic acid, obtained in example getting 65, in tetrahydrofuran (5.0 ml) under cooling on ice, the reaction mixture was stirred at 0°C for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate, extraction was conducted with ethyl acetate, and the organic layer was dried, and then concentrated under reduced pressure. The obtained residue was purified using chrome is ographie on silica gel (chloroform:methanol = 30:1) to obtain specified in the title compounds as white solids. Data analysis for compound obtained in example getting 66, shown below.

1H NMR (CDCl3) δ: of 1.36 (6H, d, J=6.0 Hz), 4,54 with 4.64 (1H, m), and 4.68 (2H, s), make 6.90 (1H, t, J=2.1 Hz), 6,92-6,98 (2H, m), 7,22 (1H, t, J=1.7 Hz), 7,31-7,37 (2H, m), to 7.77 (1H, DD, J=2,8, 8,3 Hz), 8,14 (1H, ush.);

ESI-MS (m/e): 386[M+H]+.

Connection examples get 67-73 was obtained using the same method as in the example of a 65 or 66 above. Data analysis data of the compounds shown below.

An example of retrieving 67

Receive

5-isopropoxy-3-(5-methanesulfonamido-2-yl)-N-thiazol-2-yl-benzamide

Connection example getting 67 was obtained as a light yellow oil using the 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide obtained in example getting 65, and 2.5-bistanbulholiday using the same method as in example getting 65, the appropriate method or combination with the generally accepted method.

2.5-Bistanbulholiday was obtained by the reaction of 2,5-dibromopyridine with thiomethoxam sodium obtaining 2,5-bis-methylthiopyridine, and then by its oxidation by metacompetencies acid. The reaction between 2,5-dibromopyridine and sodium methoxide and the oxidation of 2,5-bis-methylthiopyridine metacompetencies acid may be carried out in accordance with conventional methods.

1H NMR (CDCl3) δ: 1,37 (6, d, J=6,1 Hz), 3,11 (3H, s), 4,58-of 4.66 (1H, m), 6,93 (1H, t, J=1,8 Hz), of 6.99 (1H, d, J=3.6 Hz), 7,12 (1H, d, J=8.7 Hz), 7,29 (1H, d, J=1,8 Hz), was 7.36 (1H, d, J=3.6 Hz), 7,40 (1H, d, J=1,8 Hz), 8,21 (1H, DD, J=2,6, and 8.7 Hz), 8,71 (1H, d, J=2.6 Hz);

ESI-MS (m/e): 434[M+H]+.

Example of getting 68

Receive

3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide

Connection example of getting 68 was obtained as a white solid substance using 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide obtained in the same manner as in example getting 65, and 2-chloro-5-acetylpyridine using the same method as in example getting 65, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.37 (6H, d, J=6.0 Hz), at 2.59 (3H, s), br4.61 (1H, m), 6,93 (1H, t, J=2.1 Hz), 6,98 (1H, d, J=3.6 Hz),? 7.04 baby mortality (1H, d, J=8.6 Hz), 7,29 (1H, t, J=2.1 Hz), 7,38 (2H, m), 8,30 (1H, DD, J=2.5 and 8.6 Hz)that is 8.75 (1H, d, J=2.5 Hz);

ESI-MS (m/e): 398[M+H]+.

Example of getting 69

Getting 5-isopropoxy-3-(5-methoxycarbonyl-pyrazin-2-yl-oxy)-N-thiazol-2-yl-benzamide

Connection example of getting 69 was obtained as a colorless amorphous substance using 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide obtained in the same manner as in example getting 65, and 2-chloro-5-methoxycarbonylamino using the same method as in example recip is of 65, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: to 1.38 (6H, d, J=6.0 Hz), a 4.03 (3H, s), 4,57 with 4.65 (1H, m), to 6.95 (1H, t, J=2.1 Hz), 7,00 (1H, d, J=3.6 Hz), 7,33-to 7.35 (1H, m), 7,37-7,42 (2H, m), 8,54 (1H, d, J=1.2 Hz), cent to 8.85 (1H, d, J=1.2 Hz);

ESI-MS (m/e): 415[M+H]+.

Example of getting 70

Obtain 3-(5-cyano-pyridine-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide

Connection example of getting 70 was obtained as a colorless amorphous substance using 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide obtained in the same manner as in example getting 65, and 2.5-dibromopyridine using the reaction between 3-(5-bromo-pyridine-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide obtained in the same manner as in example getting 65, and copper cyanide (I).

The reaction between 3-(5-bromo-pyridine-2-yl-oxy)-5-isopropyl-N-thiazol-2-yl-benzamide and copper cyanide can be carried out according to the method described in the literature (for example, Comprehensive Organic Transformations, Richard L. et al., VCH Publishers, 1988), the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.37 (6H, d, J=6,1 Hz), br4.61 (1H, m), 6.89 in-6,92 (1H, m), 6,97-7,01 (1H, m), 7,06-to 7.09 (1H, m), 7,26-7,29 (1H, m), 7,35-7,40 (1H, m), 7,93-7,98 (1H, m), of 8.47-8,49 (1H, m);

ESI-MS (m/e): 381[M+H]+.

Example of getting 71

Getting 5-isopropoxy and-3-(2-oxo-1,2-dihydro-pyridine-4-yl-oxy)-N-thiazol-2-yl-benzamide

Connection example of getting 71 was obtained as a white solid using methyl ester of 5-hydroxy-3-isopropoxybenzoic acid obtained in the same manner as in the example of obtaining 59, hydrochloride 4-bromo-pyridine and 2-aminothiazole using the same method as in example getting 65, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (6H, d, J=6.0 Hz), 4,73 of 4.83 (1H, m), the 5.51 (1H, d, J=2.6 Hz), 6,03 (1H, DD, J=2.5 and 7.4 Hz), of 6.99 (1H, t, J=2.2 Hz), 7,30 (1H, d, J=3.6 Hz), 7,38-7,44 (2H, m), 7,55-to 7.59 (2H, m);

ESI-MS (m/e): 372[M+H]+.

Example of getting 72

Getting 5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-3-yl-oxy)-N-thiazol-2-yl-benzamide

Connection example of getting 72 was obtained as white crystals using methyl ester of 5-hydroxy-3-isopropoxybenzoic acid obtained in the same manner as in the example of obtaining 59, 3-bromo-2-hydroxy-pyridine and 2-aminothiazole using the same method as in example getting 65, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.34 (6H, d, J=6.0 Hz), to 4.62-4.72 in (1H, m), 6,41 (1H, DD, J=6,7, 7,2 Hz), 6,76 (1H, t, J=2.3 Hz), 7,10-7,13 (1H, DD, J=1.5 and 2.2 Hz), 7,14 (1H, d, J=3.6 Hz), 7,27-7,29 (1H, m), 7,30-7,37 (2H, m), of 7.48 (2H, d, J=3.6 Hz);

ESI-MS (m/e): 372[M+H]+.

Example of getting 73

Getting 5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridine-3-yl-oxy)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide

Connection example of getting 73 was obtained as a white solid using methyl ester of 5-hydroxy-3-isopropoxybenzoic acid obtained in the same manner as in the example of obtaining 59, 3-bromo-2-hydroxy-pyridine and 2-amino-thiazolo[5,4-b]pyridine using the same method as in example getting 65, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (6H, d, J=6.0 Hz), 4,68-to 4.81 (1H, m), and 6.25 (1H, t, J=6.9 Hz), 6,68-6,72 (1H, m), 7,13-7,16 (1H, m), 7,31-7,40 (2H, m), 7,44-rate of 7.54 (2H, m)to 8.12 (1H, d, J=7.8 Hz), 8,46-charged 8.52 (1H, m);

ESI-MS (m/e): 423[M+H]+.

Example of getting 74

Getting 5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazolo[5,4-b]pyridine-2-yl-benzamide

After adding 298 mg (2,16 mmole) of potassium carbonate and 0.12 ml (1,29 mmole) of 2-bromopropane to a solution of 120 mg (of 0.43 mole) of methyl ester of 3-hydroxy-5-iodobenzoyl acid in N,N-dimethylformamide (4.0 ml), the reaction mixture was stirred at 80aboutWith throughout the night. To the reaction mixture, water was added, extraction was performed with ethyl ether, acetic acid, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. Received OS is atok was purified using chromatography on silicagel column (hexane:ethyl ester of acetic acid = 5:1) to give 133 mg of methyl ester of 5-iodine-3-isopropoxybenzoic acid (yield: 96%) as a colourless oil.

After adding 292 mg (2,47 mol) 2-mercapto-1,3,4-thiadiazole, 456 mg (3,30 mole) of potassium carbonate, 27.0 mg (0.25 mmole) of hydroquinone and of 35.0 mg (0.25 mmole) of copper bromide (I) to a solution of 132 mg (0,41 mmole) obtained iodine compound in N,N-dimethylformamide (10 ml) and the mixture was mixed at 130°C for 40 minutes in a nitrogen atmosphere. To the reaction mixture, water was added, extraction was performed with ethyl ether, acetic acid, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified using chromatography on silicagel column (hexane:ethyl ester of acetic acid = 1:1) to obtain the 8,90 mg methyl ester 5-isopropoxy-3-(1,3,4-thiadiazole-2-yl-thio)benzoic acid (yield: 7%) as a colourless oil.

After addition of 0.14 ml (0,29 mmole) 2n. an aqueous solution of sodium hydroxide to the solution obtained ester compound in methanol (1.0 ml), the reaction mixture was stirred at room temperature for 5 hours. To the reaction mixture was added 2n. an aqueous solution of hydrochloric acid, extraction was performed with ethyl ether, acetic acid, and then the organic layer was washed with brine, dried and concentrated under reduced pressure to get crude or crude carboxylic connection.

After adding 8,20 is g (0,054 mole) 2-amino-thiazolo[5,4-b]-pyridine, 5,00 mg (0,037 mole) of hydrate of 1-hydroxybenzotriazole and 7.10 mg (0,037 mole) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to a solution of the obtained carboxyl compound in N,N-dimethylformamide (1.2 ml) and the mixture was mixed at room temperature over night. The reaction mixture was concentrated under reduced pressure, and the residue was purified using chromatography on silicagel column (hexane:ethyl ester of acetic acid = 1:1) to obtain the specified title compound as a white solid.

Data analysis for compound obtained in the example of getting 74, shown below.

1H NMR (CDCl3) δ: of 1.32 (6H, d, J=6.0 Hz), 4,54-to 4.62 (1H, m), 7,32 (1H, DD, J=4,6, and 8.2 Hz), 7,37 (1H, t, J=1,8 Hz), 7,56 (1H, t, J=1,8 Hz), 7,74 (1H, DD, J=1,4, and 8.2 Hz), 7,79 (1H, t, J=1,8 Hz), charged 8.52 (1H, DD, J=1,4, 4.6 Hz), 9,07 (1H, s);

ESI-MS (m/e): 430[M+H]+.

Connection with an example of receiving 75 to example get - 88 was obtained using the same method as in example getting 74 above. Data analysis of representative compounds among them are shown below.

Example of getting 75

Getting 5-isopropoxy-3-(4-methyl-[1,2,4]triazole-3-ylsulphonyl)-N-thiazol-2-yl-benzamide

The compound of example obtaining 75 was obtained as a colorless amorphous substance using the methyl ester of 5-iodine-3-isopropoxybenzoic the Noah acid, received in the sample receiving 74, 2-aminothiazole and 3-mercapto-4-methyl[1,2,4]triazole using the same method as in example getting 74, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (6H, d, J=5,9 Hz), the 3.65 (3H, s), 4.53-in-of 4.57 (1H, m), 6,98 (1H, q, J=3.5 Hz), 7,06 (1H, s), 7,20 (1H, d, J=3.5 Hz), 7,41 (1H, s), 7,53 (1H, s), 8,29 (1H, s);

ESI-MS (m/e): 374[M-H]-.

Example of getting 76

Getting 5-isopropoxy-3-thiazol-2-ylsulphonyl)-N-thiazol-2-yl-benzamide

Connection example of getting 76 was obtained as a colorless amorphous substance using the methyl ester of 5-iodine-3-isopropoxybenzoic acid obtained in example obtain 75, 2-aminothiazole and 2-mercapto-thiazole using the same method as in example getting 74, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.33 (6H, d, J=6.0 Hz), 4,54-to 4.62 (1H, m), to 6.95 (1H, d, J=3.6 Hz), to 7.15 (1H, d, J=3.6 Hz), 7,29-to 7.32 (2H, m)to 7.50 (1H, DD, J=1.5 and 2.2 Hz), 7,69 (1H, d, J=1.5 Hz), to 7.77 (1H, d, J=3,4 Hz).

Example of getting 77

Getting 5-isopropoxy-3-(4H-[1,2,4]triazole-3-ylsulphonyl)-N-thiazol-2-yl-benzamide

Connection example of getting 77 was obtained as a colorless amorphous substance using the methyl ester of 5-iodine-3-isopropoxybenzoic acid, receive the frame in the example of getting 74, 2-aminothiazole and 3-mercapto-[1,2,4]triazole using the same method as in example getting 74, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.34 (6H, d, J=6.0 Hz), 4,59-4,63 (1H, m),? 7.04 baby mortality (1H, d, J=2.5 Hz), 7,44 (1H, DD, J=1.0 Hz), 7,49 (1H, t, J=1.0 Hz), 7,49 (1H, d, J=2.5 Hz), to 7.67 (1H, t, J=1.0 Hz), 8,24 (1H, s);

ESI-MS (m/e): 362[M+H]+.

An example of retrieving 78

Getting 5-isopropoxy-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide

Connection example getting 78 was obtained as a colorless amorphous substance using the methyl ester of 5-iodine-3-isopropoxybenzoic acid obtained in example getting 74, 2-aminothiazole and 2-mercapto-[1,3,4]thiadiazole using the same method as in example getting 74, a corresponding method, or its combination with the generally accepted method.

1H NMR (CD3OD) δ: of 1.37 (6H, d, J=6.0 Hz), 4,71-to 4.81 (1H, m), 7,14 (1H, d, J=3,7 Hz), was 7.45 (1H, t, J=1,8 Hz), to 7.50 (1H, d, J=3,7 Hz), to 7.68 (1H, t, J=1,8 Hz), 7,89 (1H, t, J=1,8 Hz), to 9.32 (1H, s);

ESI-MS (m/e): 379[M+H]+.

Example of getting 79

Getting 5-isopropoxy-3-(5-methylsulfanyl-[1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide

Connection example of getting 79 was obtained as a colorless oil using methyl ester 5-iodine-3-isopropoxybenzoic acids is, received in the sample receiving 74, 2-aminothiazole and 2-mercapto-5-methylsulfanyl-[1,3,4]thiadiazole using the same method as in example getting 74, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.34 (6H, d, J=6.0 Hz), a 2.75 (3H, s), 4,55-4,63 (1H, m), 6,97 (1H, d, J=3.6 Hz), 7,13 (1H, d, J=3.6 Hz), 7,32 (1H, t, J=1,8 Hz), 7,53 (1H, t, J=1,8 Hz), 7,72 (1H, t, J=1.8 Hz);

ESI-MS (m/e): 425[M+H]+.

Example of getting 80

Getting 5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide

Connection example of getting 80 was obtained as a colorless amorphous substance using the methyl ester of 5-iodine-3-isopropoxybenzoic acid obtained in example getting 74, 2-aminothiazole and 2-mercapto-5-methyl[1,3,4]thiadiazole using the same method as in example getting 74, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.35 (6H, d, J=6.0 Hz), of 2.72 (3H, s), 4,56 with 4.64 (1H, m), 6,97 (1H, d, J=3.6 Hz), 7,17 (1H, d, J=3.6 Hz), 7,35 (1H, t, J=1,8 Hz), 7,54 (1H, t, J=1,8 Hz), 7,73 (1H, t, J=1.8 Hz);

ESI-MS (m/e): 393[M+H]+.

Example of getting 81

Getting 5-(tetrahydrofuran-3-yl-oxy)-N-thiazol-2-yl-3-(4H-[1,2,4]triazole-3-ylsulphonyl)benzamide

Connection example of getting 81 was obtained as a colourless oil with the aid of the people the same way, as in the example of getting 74, a corresponding method, or a combination of its conventional way, using (3R)-3-bromopropane instead of 2-bromopropane and using methyl ester 5-iodine-3-(tetrahydrofuran-3-yloxy)benzoic acid, obtained using the same method as in example getting 74, 2-aminothiazole and 3-mercapto-[1,2,4]triazole.

1H NMR (CDCl3) δ: 2,05-of 2.24 (2H, m), 3,89-was 4.02 (4H, m), 4,94-to 4.98 (1H, m), 7,06 (1H, d, J=3.6 Hz), 7.23 percent (1H, t, J=1,8 Hz), 7,40 (1H, d, J=1,8 Hz), of 7.48 (1H, d, J=3.6 Hz), to 7.68 (1H, d, J=1,8 Hz), 8,32 (1H, s);

ESI-MS (m/e): 390[M+H]+.

Example of getting 82

Getting 5-(2-hydroxy-1-methyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazole-2-ylsulphonyl)benzamide

Connection example of getting 82 was obtained as a colorless oil using methyl ester of 3-hydroxy-5-iodine-benzoic acid, 1-tert-dimethylsiloxy-2-hydroxypropane and 2-amino-4-methyl-thiazole, and using 3-(2-tert-butyldimethylsiloxy-1-methyl-ethoxy)-5-iodine-N-(4-methyl-thiazol-2-yl)benzamide obtained in the same manner as in example getting 65, and 2-mercapto-[1,3,4]thiadiazole, by using the same method as in the example of getting 74, a corresponding method, or a combination of its conventional way. The removal of the tert-butyldimethylsiloxy group, serving as a protective group for a hydroxy group may undertake is taken using the same method, in the example of a 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.2 Hz), of 2.38 (s, 3H), 4,79 (m, 2H)and 4.65 (m, 1H), 6,63 (s, 1H), 7,38 (m, 1H), 7,72 (m, 1H), 7,82 (m, 1H), remaining 9.08 (s, 1H);

ESI-MS (m/e): 409[M+H]+.

Example of getting 83

Getting 5-(3-hydroxy-1-methyl-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazole-2-ylsulphonyl)benzamide

Connection example of getting 83 was obtained as a white amorphous substance using the methyl ester of 3-hydroxy-5-iodine-benzoic acid, 5-tert-butyldimethylsiloxy-pentane-2-ol and 2-amino-4-methylthiazole, and using 3-(3-tert-butyldimethylsiloxy-1-methyl-propoxy)-5-iodine-N-(4-methyl-thiazol-2-yl)benzamide obtained in the same manner as in example getting 65, and 2-mercapto-[1,3,4]thiadiazole, by using the same method as in the example of getting 74, a corresponding method, or a combination of its conventional way. The removal of the tert-butyldimethylsiloxy group, serving as a protective group for a hydroxy group may be carried out using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.33 (d, 3H, J=6,1 Hz), 2,10-of 1.75 (m, 4H), 2,18 (d, 1H, J=1.0 Hz), of 3.78 (m, 2H), 4,63 (m, 1H), 6,56 (d, 1H, J=1.0 Hz), 7,38 (m, 1H), to 7.61 (m, 1H), 7,73 (m, 1H), 9,05 (s, 1H), 11,1 (ush, 1H;

ESI-MS (m/e): 423[M+H]+.

Example of getting 84

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazole-2-ylsulphonyl)-N-thiazol-2-yl-benzamide

Connection example of getting 84 was obtained as a colorless oil using methyl ester of 3-hydroxy-5-iodine-benzoic acid, 1-tert-butoxy-2-ol and 2-aminothiazole, and using 3-(2-tert-butyldimethylsiloxy-1-methyl-propoxy)-5-iodine-N-(thiazol-2-yl)benzamide obtained in the same manner as in example getting 65, and 2-mercapto-[1,3,4]thiadiazole, by the same way that in the example of getting 74, a corresponding method, or a combination of its conventional way. The removal of the tert-butyldimethylsiloxy group, serving as a protective group for a hydroxyl group may be carried out using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ δ: of 1.30 (d, 3H, J=6.0 Hz), 3,80 (m, 2H), 4,62 (sextet, 1H, J=6.0 Hz), 7,00 (d, 1H, J=3.6 Hz), 7,27 (d, 1H, J=3.6 Hz), 7,40 (m, 1H), 7.62mm (m, 1H), 7,81 (m, 1H), which is 9.09 (s, 1H);

ESI-MS (m/e): 395[M+H]+.

An example of retrieving 85

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylaminoethyl)-N-thiazol-2-yl)benzamide

Connection example getting 85 was obtained in the form of bestsitegames using methyl ester of 3-hydroxy-5-iodine-benzoic acid, 1-tert-butyldimethylsiloxy-butane-2-ol and 2-aminothiazole, and using 3-(2-tert-butyldimethylsiloxy-1-methyl-propoxy)-5-iodine-N-(thiazol-2-yl)benzamide obtained in the same manner as in example getting 65, and 2-mercapto-[1,3,4]thiadiazole, by using the same method as in the example of getting 74, a corresponding method, or a combination of its conventional way. The removal of the tert-butyldimethylsiloxy group, serving as a protective group for a hydroxyl group may be carried out using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ δ: of 1.31 (d, 3H, J=6.2 Hz), of 3.07 (s, 3H), of 3.78 (m, 2H), 4,58 (m, 1H), 7,01 (d, 1H, J=3.6 Hz), 7,24 (m, 2H), 7,37 (d, 2H, J=8.6 Hz), 7,55 (m, 1H), to 7.61 (m, 1H), to 7.84 (d, 2H, J=8.6 Hz), 11,3 (ush, 1H);

ESI-MS (m/e): 465[M+H]+.

An example of retrieving 86

Obtaining 3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide

Connection example getting 86 was obtained as a white amorphous substance using the methyl ester of 3-hydroxy-5-iodine-benzoic acid, 1-(tert-dimethylsiloxy)-2-hydroxypropane and 2-aminothiazole, and using 3-(2-tert-butyldimethylsiloxy-1-methyl-ethoxy)-5-iodine-N-(thiazol-2-yl)benzamide obtained in the same manner as in example getting 65, and 3-portifino, with the aid of the people the same way, in the example of getting 74, a corresponding method, or a combination of its conventional way. The removal of the tert-butyldimethylsiloxy group, serving as a protective group for a hydroxy group may be carried out using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.27 (d, 3H, J=6.2 Hz in), 3.75 (m, 2H), 4,54 (m, 1H), 7.18 in-to 6.95 (m, 4H), 7,21 (m, 1H), 7,30 (m, 1H), 7,52-7,40 (m, 2H);

ESI-MS (m/e): 405[M+H]+.

Example of getting 87

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-pyridin-4-ylsulphonyl)-N-thiazol-2-yl-benzamide

Connection example of getting 87 was obtained as a yellow oil using methyl ester of 3-hydroxy-5-iodine-benzoic acid, 1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-thiazole, and using 3-(2-tert-butyldimethylsiloxy-1-methyl-ethoxy)-5-iodine-N-(thiazol-2-yl)benzamide obtained in the same manner as in example getting 65, and 4-mercaptopyridine, using the same method as in the example of getting 74, a corresponding method, or a combination of its conventional way. The removal of the tert-butyldimethylsiloxy group, serving as a protective group for a hydroxy-group, can be carried out using the same method as in the example of a 2, a corresponding method, the sludge is its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.36 (d, 3H, J=6,1 Hz), and 3.72 (d, 2H, J=6,1 Hz), 4,68 (sextet, 1H, J=6,1 Hz), 7,20 (m, 3H), 7,45 (m, 1H), 7,54 (m, 1H), to 7.75 (m, 1H), a 7.85 (m, 1H), at 8.36 (m, 2H);

ESI-MS (m/e): 388[M+H]+.

Example of getting 88

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridine-3-ylsulphonyl)-N-thiazol-2-yl-benzamide

Connection example of getting 88 was obtained as a white amorphous substance using the methyl ester of 3-hydroxy-5-iodine-benzoic acid, 1-(tert-dimethylsiloxy)-2-hydroxypropane and 2-aminothiazole, and using 3-(2-tert-butyldimethylsiloxy-1-methyl-ethoxy)-5-iodine-N-(thiazol-2-yl)benzamide obtained in the same manner as in example getting 65, and 3-mercapto-6-methyl-pyridine, using the same way as in the example of getting 74, a corresponding method, or a combination of its conventional way. The removal of the tert-butyldimethylsiloxy group, serving as a protective group for a hydroxy-group, can be carried out using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 1,24 (d, 3H, J=6.2 Hz), of 2.54 (s, 3H), and 3.72 (m, 2H), to 4.52 (m, 1H), 6,97 (m, 2H), 7,16 (m, 2H), 7,33 (m, 1H), to 7.59 (m, 1H), charged 8.52 (m, 1H), 12,0 (ush, 1H);

ESI-MS (m/e): 402[M+H]+.

Example of getting 89

Getting 5-(2-hydroxy-1-methylethoxy)-3-(4-methysulfonylmethane)-N-(3-methyl-[1,2,4]thiadiazole-5-yl-benzamide

After addition of 33.4 g (142 mmole) 4-methanesulfonyl-bromine benzol, 2.67 g (11.9 mmole) of palladium acetate, 5.31g (17.8 mmole) of 2-(di-tert-butylphosphino)biphenyl and 50.3 g (237 mmole) of potassium phosphate to a solution of 25.0 g (119 mmol) of methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid in toluene (375 ml) of the reactor was sealed, and the mixture is subsequently stirred at 130°C for 6 hours. To the reaction mixture were added ethyl ester acetic acid, the mixture was then filtered and concentrated under reduced pressure. The obtained residue was purified using chromatography on silicagel column (hexane:ethyl ester of acetic acid = 2:1) to give 31.0 g of methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid (yield: 69%) as a white solid.

After adding 60 ml triperoxonane acid to a solution of 30.9 g (84,3 mmole) obtained methyl ester 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid in methylene chloride (100 ml) while cooling on ice, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified using chromatography on silicagel column (hexane:ethyl ester of acetic acid = 1:1) to give 15.2 g of methyl ester of 5-hydroxy-3-(4-methanesulfonyl-f is noxi)benzoic acid (yield: 56%) as a white solid.

After addition of 11.8 g (62.1 mmole) of (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 16.3 g (62,1 mmole) of triphenylphosphine to a solution of 10.0 g (31,0 mmol) obtained methyl ester 5-hydroxy-3-(4-methanesulfonyl-phenoxy)benzoic acid in tetrahydrofuran (200 ml) was added to 33.8 ml (77,6 mmole) solution of diethylazodicarboxylate 40% toluene while cooling on ice, and the mixture is stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified using chromatography on silicagel column (hexane:ethyl ester of acetic acid = 8:2) to give the methyl ester 5-((1S)-2-(tert-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)benzoic acid as a yellow oil.

Connection example of getting 89 was obtained as a colorless amorphous substance using 200 mg (0.40 mmole) obtained methyl ester 5-((1S)-(2-tert-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)benzoic acid and 5-amino-3-methyl-[1,2,4]thiadiazole using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CD3OD) δ: of 1.30 (d, 6H, J=6.2 Hz), 2,50 (s, 3H), of 3.12 (s, 3H), 3,68 (d, 2H, J=5.0 Hz), 4,58-4,63 (m, 1H), 7,01 (s, 1H), 7.23 percent (d, 2H, J=8,8 Hz), was 7.36 (s, 1H), 7,54 (s, 1H), of 7.97 (d, 2H, J=8,8 Hz);

ESI-MS (m/e): 464[M+H]+ .

Example of getting 90

Obtaining N-[3-hydroxymethyl-1,2,4-thiadiazole-5-yl]-3-(4-methysulfonylmethane)-5-(2-methoxy-1-methyl-ethoxy)benzamide

Connection example of getting 90 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-methoxy-2-propanol and 5-amino-3-(tert-butyldimethylsiloxy)-[1,2,4]thiadiazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.34 (3H, d, J=6.3 Hz), to 3.09 (3H, s)to 3.41 (3H, s), 3,49-of 3.64 (2H, m), 4,60-4,72 (1H, m), 4,79 (2H, s), 6,92 (1H, t, J=2.0 Hz), 7,16 (2H, d, J=8.7 Hz), the 7.43 (1H, ush.), to 7.93 (2H, d, J=8.7 Hz);

ESI-MS (m/e): 494[M+H]+.

Example of getting 91

Getting 5-[3-hydroxy-1-methylethoxy)-3-(4-methysulfonylmethane)-N-[5-methyl-1,2,4-thiadiazole-3-yl]benzamide

Connection example of getting 91 was obtained as a white solid using methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-5-methyl-[1,2,4]thiadiazole using the same method as in the example of getting 89, a corresponding method is or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.29 (d, 3H, J=6.3 Hz), was 2.76 (s, 3H), of 3.07 (s, 3H), 3,79 (m, 2H), 4,57 (m, 1H), for 6.81 (m, 1H), 7,12 (d, 2H, J=8,8 Hz), 7,17 (m, 1H), 7,33 (mn), to $ 7.91 (d, 2H, J=8,8 Hz), 9,27 (ush, 1H);

ESI-MS (m/e): 464[M+H]+.

Example of getting 92

Getting 5-(hydroxy-1-methylethoxy)-3-(4-methysulfonylmethane)-N-(3-methoxy-1,2,4-thiadiazole-5-yl)benzamide

Connection example of getting 92 was obtained as a white amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 5-amino-3-methoxy-[1,2,4]thiadiazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.3 Hz), of 3.12 (s, 3H), 3,80 (d, 2H, J=5,5 Hz)to 3.99 (s, 3H), br4.61 (m, 1H), 6.87 in (m, 1H), 7,17 (d, 2H, J=8,8 Hz), 7.23 percent (m, 1H), 7,35 (m, 1H), of 7.96 (d, 2H, J=8,8 Hz), 11, 2 (ush, 1H);

ESI-MS (m/e): 480[M+H]+.

Example of getting 93

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(1,2,5-thiadiazole-3-yl)benzamide

Connection example of getting 93 was obtained as a pale yellow amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example recip is of 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-[1,2,5]thiadiazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.34 (d, 3H, J=6.3 Hz), 1.91 a (t, 1H, J=5.7 Hz), to 3.09 (s, 3H), 3,80 (m, 2H), 4,60 (m, 1H), 6.89 in (m, 1H), 7,17 (d, 2H), 7,18 (m, 1H), 7,35 (m, 1H), of 7.96 (d, 2H, J=8,8 Hz), 8,92 (ush, 1H), to 9.32 (s, 1H);

ESI-MS (m/e): 450[M+H]+.

Example of getting 94

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4-trifluoromethyl-thiazol-2-yl)benzamide

Connection example of getting 94 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-4-trifluoromethyl-thiazol using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.2 Hz), 3,11 (s, 3H), of 3.78 (d, 2H, J=5,1 Hz), 4,57-4,63 (m, 1H), 6,91 (s, 1H), 7,16-7,17 (m, 1H), 7,17 (d, 2H, J=8,8 Hz), 7,34 and 7.36 (m, 1H), 7,44-7,46 (m, 1H), of 7.96 (d, 2H, J=8,8 Hz);

ESI-MS (m/e): 517[M+H]+.

Example obtain 95

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(4,5,6,7-tetrahydroindazole-2-yl)benzo is the Ministry of foreign Affairs

The compound of example obtaining 95 was obtained as a colorless oil using methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy-2-hydroxypropane and 2-amino-4,5,6,7-tetrahydroindazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: 1,26-of 1.29 (m, 3H), 1,82 is 1.86 (m, 4H), 2.57 m-2,72 (m, 4H), to 3.09 (s, 3H), of 3.73-of 3.78 (m, 2H), 4,54-4,56 (m, 1H), 6,78-for 6.81 (m, 1H), 7,09-7,14 (m, 3H), 7,22-7,29 (m, 1H), of 7.90-to 7.95 (m, 2H);

ESI-MS (m/e): 503[M+H]+.

An example of retrieving 96

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)-N-(pyridazin-3-yl)benzamide

Connection example getting 96 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy-2-hydroxypropane and 3-amino-pyridazine using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.30 (d, 3H, J=5,9 Hz), 2,55 (USS, 1H), of 3.07 (s, 3H), 3,76 (m, 2H), 4,59 (kW, 1H, J=5,9, 5,5 Hz), 6,83 (s, 1H), 7,11 (d, 2H, J=8,4 Hz), 7,24 (s, 1H), 7,39 (s, 1H), 7,52 (DD, 1H, 9,2, J=4,8 Hz), of 7.90 (d, 2H, J=8,4 Hz), 8,55 (d, 1H, J=9,2 Hz), 8,93 (m, 1H), 9,54 (USS, 1H);

ESI-MS (m/e): 444[M+H]+, 442[M-H]-.

Example of getting 97

Getting 5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]-triazole-5-yl)-3-(4-methysulfonylmethane)benzamide

Connection example of getting 97 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy-2-hydroxypropane and 5-amino-3-isopropyl-[1,2,4]triazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.33 (d, 6H, J=7,3 Hz)of 1.35 (d, 6H, J=7.0 Hz), 3,10 (s, 3H), 3,16-is 3.21 (m, 1H), of 3.77-with 3.79 (m, 2H), 4,57-to 4.62 (m, 1H), 6,91 (s, 1H), 7,16 (d, 2H, J=8,9 Hz), 7,17 (d, 1H, J=1.7 Hz), 7,35 (d, 1H, J=1.7 Hz), 7,95 (d, 2H, J=8,9 Hz);

ESI-MS (m/e): 492[M+H]+.

An example of retrieving 98

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(3-methyl-[1,2,4]-oxadiazol-5-yl)benzamide

Connection example getting 98 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy-2-hydroxypropane and 5 am is but-3-methyl-[1,2,4]oxadiazol using the same method, in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.28 (d, 3H, J=5,9 Hz), 2,31 (s, 3H), is 3.08 (s, 3H), 3.75 to is 3.76 (m, 2H), 4,57-4,58 (m, 1H), ceiling of 5.60 (USS, 1H), 6,84 (s, 1H), to 7.09 (d, 2H, J=8.6 Hz), 7,24 (s, 1H), 7,35 (s, 1H), 7,87 (d, 2H, J=8.6 Hz), 10,52 (USS, 1H);

ESI-MS (m/e): 448[M+H]+, 446[M-H]-.

Example of getting 99

Getting 5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)thiazol-2-yl]-3-(4-methysulfonylmethane)benzamide

Connection example of getting 99 was obtained as a white solid using methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy-2-hydroxypropane and 2-amino-4-(1-hydroxy-1-methyl-ethyl)thiazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.33 (3H, d, J=6.2 Hz), to 1.61 (6H, s), is 3.08 (3H, s), 3.75 to-a-3.84 (2H, m), 4,55 with 4.65 (1H, m), 6,77 (1H, s), to 6.88 (1H, t, J=2.0 Hz), 7,16 (2H, d, J=8.7 Hz), 7,28 (1H, ush.), was 7.45 (1H, ush.), of 7.95 (2H, d, J=8.7 Hz);

ESI-MS (m/e): 507[M+H]+.

Example 100

Obtaining N-(4-cyano-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methysulfonylmethane)benzamide

The compound of example 100 was obtained in the form of bestwe the aqueous amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid, received in the sample receiving 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-4-cyano-thiazol using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.2 Hz), 2,48 (USS, 1H), 3,12 (s, 3H), 3.75 to of 3.85 (m, 2H), 4,59-to 4.62 (m, 1H), to 6.88 (s, 1H), 7,15 (d, 2H, J=8,8 Hz), 7,22 (s, 1H), 7,38 (s, 1H), of 7.70 (s, 1H), 7,94 (d, 2H, J=8,8 Hz), 10,52 (USS, 1H);

ESI-MS (m/e): 474[M+H]+, 472[M-H]-.

An example of retrieving 101

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example getting 101 was obtained as white crystals using methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (d, 3H, J=6.3 Hz), is 3.08 (s, 3H), of 3.77 (m, 2H), 3,81 (s, 3H), of 4.57 (m, 1H), 6,78 (m, 1H), PC 6.82 (m, 1H), 7,11 (m, 1H), 7,15 (d, 2H, J=8,9 Hz), 7,30 (m, 2H), to 7.93 (d, 2H, J=8,9 Hz), 8,45 (ush, 1H)

ESI-MS (m/e): 466[M+H]+.

Example of getting 102

Getting 5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonyl-phenoxy)--(pyridin-2-yl)benzamide

Connection example of getting 102 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxybutane instead of (2R)-1-(tert-butyldimethylsiloxy-2-hydroxypropane and 2-amino-pyridine using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: a 1.01 (t, 3H, J=7,7 Hz), 1,76 (arcs, 2H, J=7,7, 6.2 Hz), 2,10 (USS, 1H), to 3.09 (s, 3H), 3,78-3,88 (m, 2H), to 4.38-of 4.44 (m, 1H), 6,86 (s, 1H), 7,10 (DD, 1H, J=4,0, 8,4 Hz), to 7.15 (d, 2H, J=9,2 Hz), 7,17 (, 1H), 7,37 (s, 1H), to 7.77 (DD, 1H, J=8,4, and 8.4 Hz), to 7.93 (d, 2H, J=9,2 Hz), 8,29 (d, 1H, J=4.0 Hz), a 8.34 (d, 1H, J=8,4 Hz), 8,62 (USS, 1H);

ESI-MS (m/e): 457[M+H]+.

Example of getting 103

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(5-methyl-isothiazol-3-yl)benzamide

Connection example of getting 103 was obtained as a white amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-5-methyl-isothiazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.30 (d, 3H, J=6.2 Hz), 2,58 (s, 3H), of 3.07 (s, 3H), of 3.75 (m, 2H), 4,57 (m, 1H), PC 6.82 (m, 1H), 7,13 (d, 2H, J=8,9 Hz), to 7.15 (m, 1H), 7,31 (m, 1H), 7,73 (m, 1H), 7,92 (d, 2H, J=8,9 Hz), 9,12 (ush, 1H);

ESI-MS (m/e): 463[M+H]+.

Example of getting 104

Getting 5-(3-hydroxy-cyclopentyloxy)-3-(4-methanesulfonyl-phenoxy)-N-(thiazol-2-yl)benzamide

Connection example of getting 104 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, 3-(tert-butyldiphenylsilyl)Cyclopentanol instead of (2R)-1-(tert-butyldimethylsiloxy-2-hydroxypropane and 2-amino-thiazol using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.92 (m, 6H), is 3.08 (s, 3H), 4,39 (s, 1H), 4,82-4,84 (s, 1H), PC 6.82 (t, 1H, J=1.9 Hz), 7,00 (d, 1H, J=3.6 Hz), 7,13 (d, 2H, J=8.6 Hz), 7,16 (d, 1H, J=1.9 Hz), of 7.23 (d, 1H, J=3.6 Hz), 7,34 (d, 1H, J=1.9 Hz), 7,92 (d, 2H, J=8.6 Hz);

ESI-MS (m/e): 475[M+H]+.

Example of getting 105

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(5-methoxy-thiazol-2-yl)benzamide

Connection example of getting 105 was obtained as a white solid using methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxymethyl the-benzoic acid, received in the sample receiving 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-5-methoxy-thiazol using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3)δ: of 1.28 (d, 3H, J=6.2 Hz), of 3.07 (s, 3H), of 3.75 (d, 2H, J=5.6 Hz), a 3.87 (s, 3H), of 4.57 (m, 1H), of 6.52 (s, 1H), for 6.81 (m, 1H), 7,12 (d, 2H, J=8,8 Hz), 7,17 (m, 1H), 7,31 (m, 1H), of 7.90 (d, 2H, J=8,8 Hz), and 11.5 (ush, 1H);

ESI-MS (m/e): 479[M+H]+.

Example of getting 106

Getting 5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methysulfonylmethane)-N-(thiazol-2-yl)benzamide

Connection example of getting 106 was obtained as a white amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, 1-(tert-butyldimethylsiloxy)-3-methyl-butane-2-ol instead of (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-thiazol using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: 0,97 (m, 6H), was 2.05 (m, 1H), of 3.07 (s, 3H), 3,83 (m, 2H), 4,22 (m, 1H), 6,84 (m, 1H), of 6.96 (d, 1H, J=3,7 Hz), 7,11 (d, 2H, J=8,9 Hz), 7,18 (m, 1H), 7.23 percent (d, 1H, J=3,7 Hz), 7,39 (m, 1H), to $ 7.91 (d, 2H, J=8,8 Hz), 12,0 (ush, 1H)

ESI-MS (m/e): 477[M+H]+.

Example of getting 107

Getting 5-(2-guide is hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(1H-[1,2,3]triazole-4-yl)benzamide

Connection example of getting 107 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 4-amino-1H-[1,2,3]-triazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (d, 3H, J=6.2 Hz), 3,11 (s, 3H), 3,34 (s, 1H), 3,67-3,68 (m, 2H), 4,56-4,60 (m, 2H), 6,93 (s, 1H), 7,21 (d, 2H, J=8,8 Hz), 7,25 (s, 1H), 7,43 (s, 1H), 7,94 (d, 2H, J=8,8 Hz), 8,08 (USS, 1H);

ESI-MS (m/e): 433[M+H]+, 431[M-H]-.

Example of getting 108

Obtaining N-(1-acetyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)benzamide

Connection example of getting 108 was obtained as a white amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-acetyl-1H-pyrazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.36 (d, 3H, J=6.3 Hz), 2,65 (s, 3H), of 3.12 (s, 3H), 3,82 (m, 2H), br4.61 (m, 1H), 6.89 in (m, 1H), 7,16-7,22 (m, 4H), 7,35 (m, 1H), 7,98 (d, 2H, J=8,8 Hz), 822 (d, 1H, J=3.0 Hz), 8,46 (ush, 1H)

ESI-MS (m/e): 474[M+H]+.

Example of getting 109

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(pyrazole-3-yl)benzamide

Connection example of getting 109 was obtained as a white amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-pyrazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.26 (d, 3H, J=6.3 Hz), 3,05 (s, 3H), of 3.73 (m, 2H), to 4.52 (m, 1H), 6.75 in (m, 2H), 7,06 (d, 2H, J=8,8 Hz), 7,14 (m, 1H), 7,32 (m, 1H), 7,46 (m, 1H), a 7.85 (d, 2H, J=8,8 Hz), 9,72 (ush, 1H);

ESI-MS (m/e): 432[M+H]+.

An example of retrieving 110

Obtaining N-(5,6-dihydro-4H-cyclopentadiene-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)benzamide

The compound of example obtaining 110 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-5,6-dihydro-4H-cyclopentanediol using the same method as in example recip is of 89, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.28 (d, 3H, J=6.2 Hz), 2,44 (TT, 2H, J=7,0, 7,0 Hz), 2,61 (t, 2H, J=7.0 Hz), 2,90 (t, 2H, J=7.0 Hz), is 3.08 (s, 3H), 3,70 is 3.76 (m, 2H), 4,51-4,55 (m, 1H), 6,76 (s, 1H), 7,10 (d, 2H, J=8,8 Hz), for 7.12 (s, 1H), 7,28 (s, 1H), of 7.90 (d, 2H, J=9,2 Hz);

ESI-MS (m/e): 489[M+H]+, 487[M-H]-.

Example of getting 111

Getting 5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonyl-phenoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 111 was obtained as a white amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-butane-2-ol instead of (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole using the same method as in the example of getting 89, a corresponding method, or a combination of its the generally accepted method.

1H NMR (CDCl3) δ: of 0.93 (t, 3H, J=7.5 Hz), 1.69 in (quintet, 1H, J=7.5 Hz), a 2.75 (t, 1H, J=6.2 Hz), 3,06 (s, 3H), 3,74 (s, 3H), 3,70-of 3.80 (m, 2H), 4,33 (m, 1H), 6,77 (m, 2H), to 7.09 (d, 2H, J=8,8 Hz), 7,11 (m, 1H), 7,27 (m, 2H), to 7.99 (d, 2H, J=8,8 Hz), 9,03 (ush, 1H);

ESI-MS (m/e): 460[M+H]+.

Example of getting 112

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(thieno[3,2-d]thiazole-2-yl)benzamide

The connection p is the iMER obtain 112 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid, received in the sample receiving 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-thieno[3,2-d]thiazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.30 (d, 3H, J=6.2 Hz), 2,05 (USS, 1H), to 3.09 (s, 3H), 3,76-of 3.78 (m, 2H), 4,55-of 4.57 (m, 1H), 6,84 (s, 1H), 7,11 (d, 2H, J=8,8 Hz), 7,11 (s, 1H), 7,19 (s, 1H), was 7.36 (s, 1H), 7,38 (s, 1H), 7,92 (d, 2H, J=8,8 Hz), 10,42 (USS, 1H);

ESI-MS (m/e): 505[M+H]+, 503[M-H]-.

Example of getting 113

Obtaining 3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 113 was obtained as white crystals using methyl ester 3-(3-fluoro-4-methysulfonylmethane)-5-hydroxy-benzoic acid, obtained in the same manner as in the example of obtaining 42, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (d, 3H, J=6.3 Hz), 2,20 (t, 1H, J=6.5 Hz), 3,23 (s, 3H), of 3.77 (m, 2H), 3,80 (s, 3H), 4,57 (sextet, 1H, J=4.5 Hz), 6,79-6,93 (m, 4H), 7,14 (m, 1H), 7,30 (m, 1H), 7,33 (m, 1H), 7,92 (t, 1H, J=8,4 Hz), to 8.57 (ush, 1H);

ESI-MS (m/e): 464[M+H]+.

Example of getting 114

Obtaining 3-(4-what econsultancy-phenoxy)-5-(2-methoxy-1-methyl-ethoxy)- N-(pyrazole-3-yl)benzamide

Connection example of getting 114 was obtained as a white amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-methoxy-2-propanol and 3-amino-pyrazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.2 Hz), 3,05 (s, 3H), 3,39 (s, 3H), 3,50-3,60 (m, 2H), 4,60 (m, 1H), 6,80 (t, 1H, J=2.2 Hz), 6,85 (d, 1H, J=2.2 Hz), to 7.09 (d, 2H, J=8,8 Hz), 7,16 (t, 1H, J=2.2 Hz), 7,39 (t, 1H, J=2.2 Hz), 7,47 (d, 1H, J=2.2 Hz), 7,87 (d, 2H, J=8,8 Hz), 9,80 (ush, 1H);

ESI-MS (m/e): 446[M+H]+.

Example of getting 115

Obtaining 3-(4-cyano-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 115 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid and p-cyanoaniline acid using methyl ester of 3-(4-cyano-phenoxy)-5-methoxyethoxy-benzoic acid obtained in the same manner as in example a 1, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole using the same method as in the example of getting 89 appropriate method or combination with the generally accepted method.

1H I Is R (CDCl 3) δ: of 1.30 (d, 3H, J=6.2 Hz), 2,31 (USS, 1H), 3,76-with 3.79 (m, 2H), 3,79 (s, 3H), 4,54 (kW, 1H, J=6.2 Hz, 4.0 Hz), 6,77 (d, 1H, J=2.2 Hz), 6,78 (s, 1H), 7,07 (d, 2H, J=8,8 Hz), to 7.09 (s, 1H), 7,27 (s, 1H), 7,28 (d, 1H, J=2.2 Hz), 7,63 (d, 2H, 8,8 Hz)8,64 (USS, 1H);

ESI-MS (m/e): 393[M+H]+.

Example of getting 116

Obtaining 3-(4-metilsulfonilmetane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 116 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-ethylthio-phenoxy)-5-hydroxy-benzoic acid, obtained by using unprotect methoxymethyl group methyl ester 3-(4-ethylthio-phenoxy)-5-methoxyethoxy-benzoic acid, obtained using methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid and p-aterciopelados acid according to the same method as in example obtain 1, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.2 Hz), of 1.33 (t, 3H, J=7,7 Hz), 2,05 (USS, 1H), 3,14 (q, 2H, J=7,7 Hz), 3.75 to with 3.79 (m, 2H), 3,81 (s, 3H), 4,56 (kW, 1H, J=6,2, and 3.7 Hz), 6,78 (s, 1H), for 6.81 (d, 1H, J=2.2 Hz), 7,11 (s, 1H), 7,12 (d, 2H, J=8,8 Hz), 7,28 (d, 1H, J=2.2 Hz), 7,28 (s, 1H), 7,87 (d, 2H, J=8,8 Hz), to 8.41 (USS, 1H);

ESI-MS (m/e): 460[M+H]+, 458[M-H]-.

the example of obtaining 117

Obtaining 3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

After adding 178 mg (of 0.71 mmole) of 5-bromo-2-acanaloniidae and 232 mg (of 0.71 mmole) of cesium carbonate to a solution of 100 mg (of 0.47 mmole) of methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid in N,N-dimethylformamide (1.0 ml) and the mixture was mixed at 100°C for 2.5 hours in a nitrogen atmosphere. To the reaction mixture were added ethyl ester of acetic acid and aqueous ammonium chloride, the aqueous layer was extracted with ethyl ether, acetic acid, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified using chromatography on silicagel column (hexane:ethyl ester of acetic acid = 1:1) to give 165 mg of methyl ester of 3-(6-econsultancy-pyridine-3-yloxy)-5-methoxyethoxymethyl acid (yield: 91%) as a colourless oil.

After adding 30,0 ml triperoxonane acid to a solution of 11.8 g (30,9 mmole) obtained ester compound in methylene chloride (50,0 ml) the reaction mixture is stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified using chromatography on silicagel colon is e (hexane:ethyl ester of acetic acid = 2:1) to obtain the 8,86 g of methyl ester of 3-(6-econsultancy-pyridine-3-yloxy)-5-hydroxybenzoic acid (yield: 85%) as a colourless oil.

After addition of 1.02 g (5,34 mmole) of (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 1.40 g (5,34 mmole) of triphenylphosphine to a solution of 1.00 g (2.97 mmole) obtained phenolic compounds in tetrahydrofuran (30,0 ml), 2,42 ml (5,34 mmole) solution of diethylazodicarboxylate 40% toluene was added while cooling on ice, and the mixture is stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified using chromatography on silicagel column (hexane:ethyl ester of acetic acid = 3:2) to give 1.31 g of the methyl ester of 3-((1S)-2-(tert-butyldimethylsiloxy)-1-methyl-ethoxy)-5-(6-econsultancy-pyridine-3-yloxy)benzoic acid (yield: 87%) as a colourless oil.

Connection example of getting 117 was obtained as a colorless amorphous substance using the obtained methyl ester 3-((1S)-2-(tert-butyldimethylsiloxy)-1-methyl-ethoxy)-5-(6-econsultancy-pyridine-3-yloxy)benzoic acid and 3-amino-1-methylpyrazole using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.2 Hz), of 1.33 (t, 3H, J=7,3 Hz), 3,40 (q, 2H, J=7,3 Hz), 3.75 to of 3.77 (m, 2H), 3,81 (s, 3H), 4,54-4,59 (m, 1H, J=6.2 Hz), 6,76 (d, 1H, J=2.2 Hz), for 6.81 (DD, 1H, J=2,2, 2,2 Hz), 7,14 (DD, 1H, J=2.2, while the 1.7 Hz), 7,28 (d, 1H, J=2.2 Hz), 7,32 (d, 1H, J=2.2, while the 1.7 Hz), the 7.43 (DD, 1H, J=8,8, and 2.6 Hz), with 8.05 (d, 1H, J=8,8 Hz), 8,45 (USS, 1H), of 8.47 (d, 1H, J=2.6 Hz);

ESI-MS (m/e): 461[M+H]+, 459[M-H]-.

Example of getting 118

Getting 5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonyl-phenoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 118 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, 4-(tert-butyldimethylsiloxy)-butane-2-ol and 3-amino-1-methyl-1H-pyrazole using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.37 (3H, d, J=6.2 Hz), 1,88-of 1.93 (2H, m), 1,96-of 2.09 (1H, m), is 3.08 (3H, s), 3,78-a 3.87 (2H, m), 3,81 (3H, s), is 6.78 (1H, d, J=2.0 Hz), for 6.81 (1H, t, J=2.1 Hz), 7,11-to 7.18 (3H, m), 7,29 (1H, d, J=the 2.2 Hz), 7,35 (1H, ush.), a 7.92 (2H, d, J=9.0 Hz), 8,51 (1H, ush.);

ESI-MS (m/e): 460[M+H]+.

Example of getting 119

Obtaining 3-(4-acanaloniidae)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide

Connection example of getting 119 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-ethylthio-phenoxy)-5-hydroxy-benzoic acid, obtained by using unprotect methoxymethyl group methyl ester 3-(4-ethylthio-phenoxy)-5-is ethoxyethoxy-benzoic acid, obtained using methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid and p-aterciopelados acid according to the same method as in example obtain 1, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-isoxazol using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (t, 3H, J=7.4 Hz), 1,32 (d, 3H, J=6.3 Hz), of 3.13 (q, 2H, J=7.4 Hz), 3,76-with 3.79 (m, 2H), 4,56-to 4.62 (m, 1H), 6.87 in (t, 1H, J=1.8 Hz), 7,14 (d, 2H, J=8.7 Hz), 7,16 (d, 1H, J=1.8 Hz), 7,26 (d, 1H, J=1.8 Hz), 7,31 (s, 1H), to 7.93 (d, 2H, J=8.7 Hz), a 8.34 (s, 1H);

ESI-MS (m/e): 477[M+H]+.

Example obtain 120

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-isopropylphenyl-phenoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

The compound of example obtaining 120 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-isopropylthio-phenoxy)-5-hydroxy-benzoic acid, obtained by using unprotect methoxymethyl group methyl ester 3-(4-isopropylthio-phenoxy)-5-methoxyethoxy-benzoic acid, obtained using methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid and p-isopropylaniline acid according to the same method as in example obtain 1, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino--methyl-1H-pyrazole using the same method, in the example of a 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.2 Hz), 1,32 (d, 6H, J=7.0 Hz), 3,20 (septet, 1H, J=7,0 Hz), 3,76-of 3.77 (m, 2H), 3,79 (s, 3H), 4,55 (kW, 1H, J=6,2, 4.0 Hz), 6,79 (d, 1H, J=2.2 Hz), to 6.80 (s, 1H), 7,10 (d, 2H, J=8,8 Hz), 7,13 (s, 1H), 7,29 (d, 1H, J=2.2 Hz), 7,29 (s, 1H), 7,83 (d, 2H, J=8,8 Hz), 8,61 (USS, 1H);

ESI-MS (m/e): 474[M+H]+, 472[M-H]-.

Example of getting 121

Getting 5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxy-4-methyl-4,5,6,6A-tetrahydro-an-cyclopentadiene-2-yl)-3-(4-methane-sulfanilamide)benzamide

Connection example of getting 121 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-4-hydroxy-4-methyl-4,5,6,6A-tetrahydro-an-cyclopentolate using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.27 and 1.33 (3H, m)to 1.60 (3H, s), of 2.56 (2H, m), 2,75-of 3.07 (2H, m), is 3.08 (3H, s), 3,74-3,82 (2H, m), 4.53-in-the 4.65 (1H, m), 6.75 in-6,83 (1H, m), 7,11-7,20 (3H, m), 7,29-to 7.35 (1H, m), to 7.93 (2H, d, J=8,9 Hz);

ESI-MS (m/e): 519[M+H]+.

Example of getting 122

Obtaining 3-(4-dimethylcarbamoyl-phenoxy)-5-(2-hydroxy-1-IU the Il-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 122 was obtained as a colorless amorphous substance using the same method as in the example of a 2, a corresponding method, or a combination of its conventional way, using (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane, 3-amino-1-methyl-1H-pyrazole and methyl ester of 3-(4-dimethylcarbamoyl-phenoxy)-5-hydroxy-benzoic acid, obtained by using unprotect methoxymethyl group methyl ester 3-(4-dimethylcarbamoyl-phenoxy)-5-methoxyethoxy-benzoic acid, obtained by conversion of the formyl group of the methyl ester of 3-(4-formyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in the same manner as in example a 1, using methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid and p-formylphenylboronic acid, carboxyl, followed by condensation with dimethylamine.

1H NMR (CDCl3) δ: of 1.33 (d, 3H, J=6.2 Hz), 2,11 (USS, 1H), is 3.08 (s, 3H), of 3.13 (s, 3H), 3,74-3,81 (m, 2H), 3,83 (s, 3H), 4,54-4,58 (m, 1H), 6,77 (s, 1H), 6,80 (s, 1H), 7,06 (d, 2H, J=7,7 Hz), 7,10 (s, 1H), 7,26 (, 1H), 7,30 (s, 1H), 7,46 (d, 2H, J=7,7 Hz), 8,49 (USS, 1H);

ESI-MS (m/e): 439[M+H]+, 437[M-H]-.

Example of getting 123

Obtaining 3-(4-acetylphenol)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 123 was obtained in the ideal colorless amorphous substance using the same method, in the example of a 2, a corresponding method, or a combination of its conventional way, using (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane, 3-amino-1-methyl-1H-pyrazole and methyl ester of 3-(4-acetyl-phenoxy)-5-hydroxy-benzoic acid, obtained by using unprotect methoxymethyl group methyl ester 3-(4-acetyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained by the reaction of the formyl group of the methyl ester of 3-(4-formyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in the same manner as in the example of getting 122, methylacrylamide, with subsequent oxidation.

1H NMR (CDCl3) δ: of 1.30 (d, 3H, J=6.2 Hz), at 2.59 (s, 3H), 3.75 to is 3.76 (m, 2H), 3,79 (s, 3H), to 4.52-4,56 (m, 1H, J=6.2 Hz), 6,78 (d, 1H, J=2.2 Hz, DD, 1H, J=2,2, 1.8 Hz),? 7.04 baby mortality (d, 2H, J=8,8 Hz), 7,07 (DD, 1H, J=1,8, 1,8 Hz), 7,25 (DD, 1H, J=2,2, 1.8 Hz), 7,26 (d, 1H, J=2.2 Hz), 7,95 (d, 2H, J=8,8 Hz), charged 8.52 (USS, 1H);

ESI-MS (m/e): 410[M+H]+, 408[M-H]-.

Example of getting 124

Getting 5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(1,3,4-thiadiazole-2-ylsulphonyl)benzamide

Connection example of getting 124 was obtained as a colorless amorphous substance using the methyl ester of 3-hydroxy-5-iodobenzoyl acid, 1-tert-dimethylsiloxy-2-hydroxypropane, 2-mercapto-[1,3,4]thiadiazole and 3-amino-1-methyl-1H-pyrazole using the same method, Thu is in the example of getting 74 or 82, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (3H, d, J=6.2 Hz), 3,74-with 3.79 (2H, m), 3,82 (3H, s), 4,54-4,63 (1H, m), is 6.78 (1H, d, J=2.2 Hz), 7,30 (1H, d, J=2.3 Hz), 7,39 (1H, m), 7,54 (1H, m), 7,69 (1H, m), 8,55 (1H, ush.), 9,05 (1H, s);

ESI-MS (m/e): 392[M+H]+.

An example of retrieving 125

Obtaining N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methane-sulfanilamide)benzamide

Connection example getting 125 was obtained as a white amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxy-benzoic acid obtained in example getting 89, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-ethyl-1H-pyrazole, using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.30 (d, 3H, J=6.2 Hz), USD 1.43 (t, 3H, J=7,3 Hz), of 3.07 (s, 3H), 3,76 (m, 2H), of 4.05 (q, 2H, J=7,3 Hz), 4,56 (m, 1H), 6,79 (m, 2H), 7,12 (d, 2H, J=8,8 Hz), 7,14 (m, 1H), 7,30 (m, 1H), 7,33 (m, 1H), 7,92 (d, 2H, J=8,8 Hz), 8,70 (ush, 1H);

ESI-MS (m/e): 460[M+H]+.

Example of getting 126

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methane-sulfanilamide-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 126 was obtained as a white amorphous substance using methyl who Fira 5-hydroxy-3-methoxyethoxymethyl acid, 5-bromo-2-methysulfonylmethane, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-ethyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.29 (d, 3H, J=6.3 Hz), up 3.22 (s, 3H), of 3.75 (m, 2H), of 3.78 (s, 3H), 4,55 (m, 1H), 6.75 in (m, 1H), 6,78 (m, 1H), 7,11 (m, 1H), 7,26 (m, 1H), 7,29 (m, 1H), 7,42 (DD, 1H, J=2,9, 8.5 Hz), 8,03 (d, 1H, J=8.5 Hz), 8,44 (d, 1H, J=2,9 Hz), 8,65 (ush, 1H);

ESI-MS (m/e): 447[M+H]+.

Example of getting 127

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminophenyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazole-5-yl)benzamide

Connection example of getting 127 was obtained as a colorless amorphous substance using the same method as in the example of a 2, a corresponding method, or a combination of its conventional way, using (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane, 5-amino-3-methyl-[1,2,4]thiadiazole and methyl ester of 3-(4-methoxycarbonylaminophenyl)-5-hydroxy-benzoic acid, obtained by removing the protection methoxymethyl group methyl ester 3-(4-methoxycarbonylaminophenyl)-5-methoxyethoxy-benzoic acid obtained in the same manner as in the example of obtaining 59, using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid instead metrov the th ester 5-hydroxy-3-isopropoxybenzoic acid.

1H NMR (CDCl3) δ: of 1.29 (d, 3H, J=6.2 Hz), a 2.45 (s, 3H), 3,71 (s, 3H), of 3.73-of 3.78 (m, 2H), 4,35 (d, 2H, J=6.2 Hz), 4,50-of 4.57 (m, 1H, J=6.2 Hz), 5,08 (USS, 1H), 6,76 (s, 1H), 6,97 (d, 2H, J=8,3 Hz), 7,01 (s, 1H), 7,16 (s, 1H), 7,27 (d, 2H, J=8,3 Hz), 10,8 (USS, 1H);

ESI-MS (m/e): 495[M+Na]+, 473[M+H]+, 471[M-H]-.

Example of getting 128

Getting 5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 128 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, 5-bromo-2-methysulfonylmethane, (2S)-1-(tert-butyldimethylsiloxy)-2-hydroxybutanal and 3-amino-1-ethyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: 0,99 (t, 3H, J=7.5 Hz), 1.70 to 1.77 in (m, 2H), 3,24 (s, 3H), 3,79-3,82 (m, 5H), 4,36-and 4.40 (m, 1H), 6,78 (d, 1H, J=1.8 Hz), 6,85 (d, 1H, J=1.8 Hz), 7,13 (s, 1H), 7,29 (d, 1H, J=2.3 Hz), 7,34 (d, 1H, J=2.3 Hz), 7,46 (DD, 1H, J=2,6, a 8.9 Hz), 8,08 (d, 1H, J=8,9 Hz), 8,48 (d, 1H, J=2.6 Hz);

ESI-MS (m/e): 461[M+H]+.

Example of getting 129

Obtaining 3-(6-methanesulfonamido-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 129 was obtained as a colorless amorphous substance use is the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, 5-bromo-2-methysulfonylmethane, (2S)-1-methoxy-2-hydroxybutanal and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: 0,99 (t, 3H, J=7.4 Hz), 1,74-to 1.79 (m, 2H), 3,24 (s, 3H), 3,37 (s, 3H), 3,56 is 3.57 (m, 2H), 3,79 (s, 3H), 4,37-and 4.40 (m, 1H), 6,79 (s, 1H), 6.87 in (t, 1H, J=1.2 Hz), 7,14 (s, 1H), 7,29 (d, 1H, J=1.2 Hz), 7,34 (d, 1H, J=1.2 Hz), was 7.45 (DD, 1H, J=2,0, 8.6 Hz), of 8.06 (d, 1H, J=8.6 Hz), 8,48 (d, 1H, J=2.0 Hz);

ESI-MS (m/e): 475[M+H]+.

An example of retrieving 130

Getting 5-isopropoxy-3-(6-methanesulfonamido-3-yloxy)- N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example getting 130 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, 5-bromo-2-methanesulfonamide, 2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.35 (d, 6H, J=6.2 Hz), up 3.22 (s, 3H), of 3.77 (s, 3H), 6.75 in (septet, 1H, J=6.2 Hz), 6,74 (m, 1H), 6,76 (m, 1H), was 7.08 (m, 1H), 7,24 (m, 1H), 7,26 (m, 1H), 7,41 (DD, 1H, J=2,9, 8,8 Hz), 8,03 (d, 1H, J=8,8 Hz), 8,44 (d, 1H, J=2,9 Hz), 8,64 (ush, 1H);

ESI-MS (m/e): 431[M+H]+.

Example of getting 131

Getting 5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonyl the Dean-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 131 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, 5-bromo-2-methysulfonylmethane, 1,3-debtor-2-propanol and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: 3,23 (s, 3H), of 3.75 (s, 3H), 4,55-br4.61 (m, 2H), br4.61-4,80 (m, 3H), 6.75 in (m, 1H), to 6.88 (m, 1H), 7,18 (m, 1H), 7,27 (m, 1H), 7,34 (m, 1H), 7,43 (DD, 1H, J=2,4, and 8.4 Hz), of 8.04 (d, 1H), 8,44 (d, 1H, J=2.4 Hz), 8,84 (ush, 1H);

ESI-MS (m/e): 467[M+H]+.

Example of getting 132

Obtaining 3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide

Connection example of getting 132 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, 5-bromo-2-acanaloniidae, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-isoxazol using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (d, 3H, J=6.2 Hz), 1,32 (t, 3H, J=7,3 Hz), 2,22 (USS, 1H), 3,40 (q, 2H, J=7,3 Hz), 3.75 to of 3.77 (m, 2H), 4,56-br4.61 (m, 1H, J=6.2 Hz), 6,86 (d, 1H, J=2.2 Hz), 7,17 (d, 1H, J=2.2 Hz), 7,26 (d, 1H, 0.7 Hz), 7,40 (d, 1H, J=2.2 Hz), the 7.43 (DD, 1H, J=8,8, 2,9 Hz), 8,04 (who, 1H, J=8,8 Hz), compared to 8.26 (d, 1H, J=0.7 Hz), 8,46 (d, 1H, J=2,9 Hz), 9,83 (USS, 1H);

ESI-MS (m/e): 448[M+H]+, 446[M-H]-.

Example of getting 133

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylaminoethyl)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 133 was obtained as a colorless amorphous substance using the methyl ester of 3-hydroxy-5-iodobenzoyl acid, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane, 4-methanesulfonylaminoethyl and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 74 or 82, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.30 (3H, d, J=6.2 Hz), 3,05 (3H, s), 3,74-with 3.79 (2H, m), 3,81 (3H, s), to 4.52-4.63 to (1H, m), is 6.78 (1H, d, J=2.3 Hz), 7,21 (1H, m), 7,30 (1H, d, J=2.2 Hz), 7,34 (2H, d, J=8.6 Hz), 7,47-7,50 (1H, m,), 7,51-rate of 7.54 (1H, m), 7,82 (2H, d, J=8.6 Hz), 8,53 (1H, ush.);

ESI-MS (m/e): 392[M+H]+.

Example of getting 134

Getting 5-cyclopropylamino-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 134 was obtained as colorless oil by the same method as in the example of a 1, a corresponding method, or a combination of its conventional way, using methyl ester 5-methoxyethoxy-3-vinyloxy-benzoic acid, poluchennogo is the reaction of the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, terminiology and copper acetate, and then using p-methyldiphenylamine acid, 3-amino-1-methyl-1H-pyrazole and methyl ester of 3-cyclopropylamino-5-methoxyethoxy-benzoic acid obtained by the reaction between diethylzinc and diiodomethane.

1H NMR (CDCl3) δ: 0,70-0,85 (m, 4H), is 3.08 (s, 3H), of 3.78 (m, 1H), 3,79 (s, 3H), 6,78 (m, 1H), 6,91 (m, 1H), 7,10-7,14 (m, 3H), 7,27 (m, 1H), 7,41 (m, 1H), of 7.90 (d, 2H, J=8,8 Hz), charged 8.52 (ush, 1H);

ESI-MS (m/e): 428[M+H]+.

Example of getting 135

Obtaining 3-(6-methanesulfonamido-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazole-3-yl)benzamide

Connection example of getting 135 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, 5-bromo-2-methysulfonylmethane, (2R)-1-methoxy-2-hydroxybutanal and 3-amino-pyrazole using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: and 0.98 (t, 3H, J=7.4 Hz), 1,69-of 1.78 (m, 2H), up 3.22 (s, 3H), 3,38 (s, 3H), to 3.58-3,59 (m, 2H), 4,37-4,43 (m, 1H), 6,84-6,85 (m, 2H), 7,20 (s, 1H), 7,41-7,49 (m, 3H), of 8.04 (d, 1H, J=8.6 Hz), to 8.45 (d, 1H, J=2.6 Hz), 9,92 (USS, 1H);

ESI-MS (m/e): 461[M+H]+.

Example of getting 136

Getting 5-(2-fluoro-1-vermeil-ethoxy)-3-(4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

With the unity of the example of getting 136 was obtained as a colorless amorphous substance using the methyl ester of 3-(4-methanesulfonyl-phenoxy)-5-methoxyethoxymethyl acid, received in the sample receiving 89, 1,3-debtor-2-propanol and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: to 3.09 (s, 3H), of 3.77 (s, 3H), 4,59 was 4.76 (m, 5H), 6,78 (s, 1H), 6.89 in (t, 1H, J=2.0 Hz), 7,13 (d, 2H, J=8.6 Hz), 7,18 (s, 1H), 7,29 (d, 1H, J=2.0 Hz), 7,33 (d, 1H, J=2.0 Hz), to 7.93 (d, 2H, J=8,6 Hz), 8,76 (USS, 1H);

ESI-MS (m/e): 466[M+H]+.

Example of getting 137

Obtaining 3-(6-acanaloniidae-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 137 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-acanaloniidae, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxybutanal and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 0.97 (t, 3H, J=7.4 Hz), 1,32 (t, 3H, J=7.4 Hz), 1,67-of 1.84 (m, 2H), 3,40 (q, 2H, J=7.4 Hz), 3,74-a-3.84 (m, 5H), 4,33-and 4.40 (m, 1H), 6,77 (s, 1H), 6,79 (s, 1H), 7,15 (s, 1H), 7,28 (s, 1H), 7,33 (, 1H), 7,43 (DD, 1H, J=2,6, 8,8 Hz), with 8.05 (d, 1H, J=8,8 Hz), of 8.47 (d, 1H, J=2.6 Hz);

ESI-MS (m/e): 475[M+H]+.

Example of getting 138

Getting 5-(6-acanaloniidae-3-yloxy)-3-(2-labels and-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 138 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-acanaloniidae, (2R)-2-hydroxy-1-methoxypropane and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.34 (t, 3H, J=7,3 Hz)of 1.34 (d, 3H, J=4.0 Hz), 3,40 (s, 3H), 3,41 (q, 2H, J=7,3 Hz), 3,49-of 3.60 (m, 2H), 3,80 (s, 3H), 4,60 (kW, 1H, J=4,0, 6.2 Hz), 6,78 (s, 1H), 6,83 (d, 1H, J=2.2 Hz), 7,14 (s, 1H), 7,28 (d, 1H, J=2.2 Hz), 7,31 (s, 1H), 7,42 (DD, 1H, J=8,4, and 2.6 Hz), with 8.05 (d, 1H, J=8,4 Hz), 8,48 (d, 1H, J=2.6 Hz), 8,49 (USS, 1H)

ESI-MS (m/e): 475[M+H]+, 473[M-H]-.

Example of getting 139

Obtain tert-butyl ester 2-[3-(4-methysulfonylmethane)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid

Connection example of getting 139 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-(4-methylthiophene)benzoic acid obtained in example obtain 1, tert-butyl methyl ether 2-bromopropionic acid and 3-amino-1-methyl-1H-pyrazole using the same method as in the example of a 1, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.44 (9H, s)to 1.60 (3H, d, J=6,8 Hz), and 3.0 (3H, C)3,81 (3H, s), 4,69 (1H, q, J=6.8 Hz), 6,77 (1H, ush.), 7,10-7,16 (3H, m), 7,24 (1H, ush.), 7,29 (1H, d, J=2.2 Hz), 7,92 (2H, d, J=8,9 Hz), scored 8.38 (1H, ush.);

ESI-MS (m/e): 516[M+H]+.

An example of retrieving 140

Obtaining 3-(6-acanaloniidae-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamide

The compound of example obtaining 140 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-acanaloniidae, (2R)-2-hydroxy-1-methoxypropane and 3-amino-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.33 (t, 3H, J=7,3 Hz)of 1.34 (d, 3H, J=6.2 Hz), 3,40 (q, 2H, J=7,3 Hz)to 3.41 (s, 3H), 3,52-3,62 (m, 2H), 4,60 with 4.65 (m, 1H, J=6.2 Hz Hz), 6,83 (d, 1H, J=2.2 Hz), 6,86 (s, 1H), 7,20 (s, 1H), 7,42 (d, 1H, J=2.2 Hz), 7,42 (DD, 1H, J=8,8, and 2.6 Hz), 7,49 (s, 1H),? 7.04 baby mortality (d, 1H, J=8,8 Hz), of 8.47 (d, 1H, J=2.6 Hz), for 9.47 (USS, 1H);

ESI-MS (m/e): 461[M+H]+, 459[M-H]-.

Example of getting 141

Obtaining 3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)-5-(tetrahydrofuran-3-yl)benzamide

Connection example of getting 141 was obtained as a colorless oil using methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-methysulfonylmethane, (S)-(+)-3-hydroxytyramine the uranium and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: 2,15-of 2.26 (m, 1H), 2.26 and-of 2.30 (m, 1H), 3,24 (s, 3H), of 3.80 (s, 3H), 3,88-a 4.03 (m, 4H), equal to 4.97 (m, 1H), 6,76 (m, 2H), 7,11 (t, 1H, J=2.2 Hz), 7,24 (d, 1H, J=2.2 Hz)7,28 (d, 1H, J=2.2 Hz), 7,44 (DD, 1H, J=2,9, and 8.4 Hz), with 8.05 (d, 1H, J=8,4 Hz), 8,44 (ush, 1H), 8,45 (d, 1H, J=2,9 Hz);

ESI-MS (m/e): 459[M+H]+.

Example of getting 142

Obtaining N-(1-ethyl-1H-pyrazole-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)benzamide

Connection example of getting 142 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-methysulfonylmethane, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-ethyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.33 (d, 3H, J=6.2 Hz), 1,47 (t, 3H, J=7,3 Hz)to 1.98 (m, 1H), 3,24 (s, 3H)of 3.77 (m, 2H), 4,07 (q, 2H, J=7,3 Hz), 4,58 (m, 1H), 6,77 (d, 1H, J=2.6 Hz), PC 6.82 (t, 1H, J=2.6 Hz), 7,13 (m, 1H), to 7.32 (m, 2H), 7,45 (DD, 1H, J=2,6, and 8.4 Hz), of 8.06 (d, 1H, J=8,4 Hz), 8.34 per (ush, 1H), of 8.47 (d, 1H, J=2.6 Hz);

ESI-MS (m/e): 461[M+H]+.

Example of getting 143

Getting 5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(pyrazole-3-yl) Ben the amide

Connection example of getting 143 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-methysulfonylmethane, 1,3-debtor-2-propanol and 3-amino-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: 3,23 (s, 3H), 4,55-4,70 (m, 2H), 4,70-of 4.90 (m, 3H), 6,79 (m, 1H), 6,91 (m, 1H), 7,28 (m, 1H), 7,42-7,51 (m, 3H), of 8.04 (d, 1H, J=8,9 Hz), 8,44 (d, 1H, J=2.6 Hz), 9,60 (ush, 1H);

ESI-MS (m/e): 453[M+H]+.

Example of getting 144

Obtaining 3-(6-methanesulfonamido-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 144 was obtained as a colorless oil using methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-methysulfonylmethane, (2R)-2-hydroxy-1-methoxypropane and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (d, 3H, J=6.4 Hz), 3,23 (s, 3H), 3,40 (s, 3H), of 3.54 (m, 2H), of 3.78 (s, 3H), 4,59 (m, 1H), 6,78 (m, 1H), 6,84 (m, 1H), 7,14 (m, 1H), 7,29 (m, 1H), 7,32 (m, 1H), 7,44 (DD, 1H, J=2,6, 8.6 Hz), with 8.05 (d, 1H, J=8.6 Hz), of 8.47 (d, 1H, J=2.6 Hz), 8,66 (ush, 1H);

ESI-MS (m/e): 461[M+H]+.

Example of getting 145

Obtaining 3-(6-acanaloniidae-3-yloxy)-5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 145 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-acanaloniidae, 1,3-debtor-2-propanol and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.33 (t, 3H, J=7,42 Hz)to 3.41 (q, 2H, J=7.4 Hz), 3,80 (s, 3H), br4.61 with 4.65 (m, 2H), 4,73-4,78 (m, 3H), 6,78 (DD, 1H, J=2,0, 1.8 Hz), 6,91 (d, 1H, J=2.3 Hz), 7.23 percent (DD, 1H, J=1,8, 1,6 Hz), 7,30 (d, 1H, J=2.3 Hz), 7,38 (DD, 1H, J=2.0 a, and 1.6 Hz), 7,16 (DD, 1H, J=8,6, 2.7 Hz), 8,08 (d, 1H, J=8.6 Hz), and 8.50 (d, 1H, J=2.7 Hz), 8,63 (USS, 1H);

ESI-MS (m/e): 481[M+H]+, 479[M-H]-.

Example of getting 146

Getting 2-[3-(4-methysulfonylmethane)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid

Connection example of getting 146 was obtained as a white solid using the conversion of tert-butilkoi ester part tert-butyl ester 2-[3-(4-methysulfonylmethane)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid obtained in example getting 139, in the carboxyl group. The transformation of the ester part of the carboxy group made Tullos using the method described in Comprehensive Organic Transfotmations, Richard L. et al., VCH Publishers, 1988, the appropriate method or combination with the generally accepted method.

1H NMR (CD3OD) δ: to 1.60 (3H, d, J=6.8 Hz), 3,11 (3H, s), 3,82 (3H, s), 6,54 return of 6.58 (1H, ush.), at 6.84 (1H, ush.), 7,16-7,28 (3H, m), 7,34 (1H, ush.), 7,49 (1H, d, J=2.1 Hz), 7,95 (2H, d, J=8,9 Hz);

ESI-MS (m/e): 460[M+H]+.

Example of getting 147

Obtaining 3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(pyrazole-3-yl)benzamide

Connection example of getting 147 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-acanaloniidae, 2-hydroxypropane and 3-amino-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.32 (t, 3H, J=7,3 Hz)to 1.37 (d, 6H, J=5,9 Hz), 3,39 (q, 2H, J=7,3 Hz), 4,60 (septet, 1H, J=5,9 Hz), 6,76 (DD, 1H, J=2,2, 2,2 Hz), at 6.84 (s, 1H), 7,16 (s, 1H), 7,33 (s, 1H), 7,40 (DD, 1H, J=8,8, 2,6 Hz), 7,51 (DD, 1H, J=2.2, while the 2.6 Hz), 8,03 (DD, 1H, J=8,8, and 2.6 Hz), 8,46 (DD, 1H, J=2,6, and 2.6 Hz), 9,03 (USS, 1H);

ESI-MS (m/e): 431[M+H]+, 429[M-H]-.

Example of getting 148

Obtaining 3-(6-acanaloniidae-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 148 was obtained as colorless amorphous, washes the VA using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-acanaloniidae, 2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.34 (t, 3H, J=7,3 Hz)to 1.37 (d, 6H, J=5,9 Hz), to 3.41 (q, 2H, J=7,3 Hz), 3,81 (s, 3H), 4,60 (septet, 1H, J=5,9 Hz), 6.75 in-is 6.78 (m, 2H), 7,11 (s, 1H), 7,26 (s, 1H), 7,28 (d, 1H, J=2.2 Hz), 7,42 (DD, 1H, J=8,8, 2,9 Hz), with 8.05 (d, 1H, J=8,8 Hz), at 8.36 (USS, 1H), 8,48 (d, 1H, J=2,9 Hz);

ESI-MS (m/e): 445[M+H]+, 443[M-H]-.

Example of getting 149

Obtaining 3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazole-3-yl)benzamide

Connection example of getting 149 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-acanaloniidae, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3(one drop to CD3OD)) δ: of 1.29 (d, 3H, J=6.3 Hz), is 1.31 (t, 3H, J=7.4 Hz), 3,39 (q, 2H, J=7.4 Hz), 3,70 is 3.76 (m, 2H), 4,55 (septet, 1H, J=6.3 Hz), 6,77 (s, 1H), 6,79 (d, 1H, J=2.3 Hz), 7,20 (s, 1H), 7,37 (s, 1H), 7,41 (DD, 1H, J=8,6, 2.7 Hz), 7,49 (d, 1H, J=2.3 Hz), 8,02 (d, 1H, J=8.6 Hz), 8,44 (d, 1H, J=2.7 Hz), of 9.55 (USS, 1H);

ESI-MS (m/e): 447[M+H]+, 445[M-H]-.

Example of getting 150

Obtaining 3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyridin-2-yl)benzamide

Connection example of getting 150 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-acanaloniidae, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-pyridine, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.33 (d, 3H, J=6,1 Hz)of 1.33 (t, 3H, J=7.4 Hz), to 3.41 (q, 2H, J=7.4 Hz), 3,78-of 3.80 (m, 2H), 4,62 (DQC, 1H, J=4,5, 6,1 Hz), at 6.84 (s, 1H), 7,11 (DD, 1H, J=6,6, 5,1 Hz), 7,22 (s, 1H), 7,38 (s, 1H), was 7.45 (DD, 1H, J=8,8, 2,5 Hz), 7,78 (DD, 1H, J=8,4, and 6.6 Hz), 8,08 (d, 1H, J=8,8 Hz), 8,30 (d, 1H, J=5,1 Hz), a 8.34 (d, 1H, J=8,4 Hz)and 8.50 (d, 1H, J=2.5 Hz), 8,63 (USS, 1H);

ESI-MS (m/e): 481[M+H]+.

Example of getting 151

Obtaining 3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy-N-thiazol-2-yl-benzamide

Connection example of getting 151 was obtained as a colorless amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-acanaloniidae, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-amino-thiazole, by using the same method as in the example of getting 117, sootvetstvujushej the method or combination with the generally accepted method.

1H NMR (CDCl3)δ: of 1.31 (d, 3H, J=6.3 Hz), of 1.33 (t, 3H, J=7.4 Hz), to 3.41 (q, 2H, J=7.4 Hz), 3,76-of 3.78 (m, 2H), 4,55-4,60 (m, 1H), 6,86 (m, 1H), 7,02 (d, 1H, J=3.5 Hz), 7,26 (m, 1H), 7,29 (d, 1H, J=3.5 Hz), 7,42 (m, 1H), 7,46 (DD, 1H, J=8,6, 2.7 Hz), 8,08 (d, 1H, J=8.6 Hz), 8,49 (d, 1H, J=2.7 Hz);

ESI-MS (m/e): 464[M+H]+, 462[M-H]-.

Example of getting 152

Getting 5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 152 was obtained as a colorless amorphous substance using the transformation of the hydroxyl group of 5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide obtained in example getting 126, in mesilate using triethylamine and methanesulfonanilide followed by reaction with tetrabutylammonium chloride.

1H NMR (CDCl3) δ: of 1.35 (DD, 3H, J=1,6, 6.2 Hz), 3,24 (s, 3H), of 3.77 (s, 3H), of 4.45 (m, 1H), 4,57 (m, 1H), 4,67 (m, 1H), 6,79 (d, 1H, J=2.3 Hz), at 6.84 (t, 1H, J=2.3 Hz), 7,16 (t, 1H, J=2.3 Hz), 7,30 (d, 1H, J2,3 Hz), 7,32 (m, 1H), 7,45 (d, 1H, J=2,3, 8.6 Hz), of 8.06 (d, 1H, J=8.6 Hz), of 8.47 (d, 1H, J=2.3 Hz), 8,79 (ush, 1H);

ESI-MS (M/E):449[M+H]+.

Example of getting 153

Getting 5-(2-chloro-1-methyl-ethoxy)-3-(6-acanaloniidae-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 153 was obtained as a colorless amorphous substance in the course of transformation hydroximino the group 3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide, received in the sample receiving 117, in mesilate using triethylamine and methanesulfonanilide.

1H NMR (CDCl3) δ: of 1.33 (t, 3H, J=7.4 Hz), a 1.45 (d, 3H, J=6.2 Hz), to 3.41 (q, 2H, J=7.4 Hz), 3,63 (DD, 1H, J=5.0 and 11.5 Hz), of 3.69 (DD, 1H, J=5.0 and 11.5 Hz), 3,79 (s, 3H), to 4.62 (m, 1H), 6,79 (d, 1H, J=2.2 Hz), 6,83 (t, 1H, J=2.2 Hz), 7,18 (m, 1H), 7,29-7,35 (m, 2H), 7,45 (DD, 1H, J=2.7, and 8.6 Hz), 8,07 (d, 1H, J=8.6 Hz), 8,49 (d, 1H, J=2.7 Hz), 8,67 (ush, 1H);

ESI-MS (M/E):479[M+H]+.

Example of getting 154

Getting 5-(2-fluoro-1-vermeil-ethoxy)-N-(isoxazol-3-yl)-3-(6-methanesulfonamido-3-yloxy)benzamide

Connection example of getting 154 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-methysulfonylmethane, 1,3-debtor-2-propanol and 3-amino-oxazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: 3,24 (s, 3H), 4,59-4,70 (m, 2H), 4,70-of 4.90 (m, 3H), of 6.96 (t, 1H, J=2.3 Hz), 7,19 (m, 1H), 7,32 (m, 1H), 7,45 (m, 1H), of 7.48 (DD, 1H, J=2.7, and an 8.5 Hz), of 8.09 (d, 1H, J=8.5 Hz), 8,29 (m, 1H), 8,49 (d, 1H, J=2.7 Hz), 9,60 (ush, 1H);

ESI-MS (M/E):454[M+H]+.

Example of getting 155

Getting 5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(pyridin-2-yl)benzamide

Connection example of getting 155 was obtained as a white Amor the aqueous substance, using methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-methysulfonylmethane, 1,3-debtor-2-propanol and 2-aminopyridine using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: 3,24 (s, 3H), 4,60-4,70 (m, 2H), 4,70-of 4.90 (m, 3H), 6,93 (t, 1H, J=2.1 Hz), 7,10 (m, 1H), 7,26 (m, 1H), 7,42 (mn), of 7.48 (DD, 1H, J=2,1, 8,2 Hz), 7,78 (dt, 1H, J=), of 8.09 (d, 1H, J=8,4 Hz), 8,30 (m, 1H), 8,32 (d, 1H, J=8,4 Hz), 8,49 (d, 1H, J=2.1 Hz), 8,59 (ush, 1H);

ESI-MS (M/E):464[M+H]+.

Example of getting 156

Getting 5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonamido-3-yloxy)-N-(3-methyl[1,2,4]thiadiazole-5-yl)benzamide

Connection example of getting 156 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 5-bromo-2-methysulfonylmethane, 1,3-debtor-2-propanol and 5-amino-3-methyl-[1,2,4]thiadiazole using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ δ: of 2.50 (s, 3H), of 3.27 (s, 3H), 4,57-of 4.67 (m, 2H), 4,67-of 4.90 (m, 3H), 7,01 (t, 1H, J=2.3 Hz), 7,29 (m, 1H), 7,45 (m, 1H), 7,49 (DD, 1H, J=2,3, and 8.7 Hz), of 8.09 (d, 1H, J=8.7 Hz), of 8.47 (d, 1H, J=2.3 Hz);

ESI-MS (M/E):485[M+H]+.

Example of getting 157

Obtaining 3-(4-dimethylaminoethoxy))-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide/p>

Connection example of getting 157 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxy-benzoic acid, 4-bromo-dimethylaminobenzoate, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of obtaining 42, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (d, 3H, J=6.3 Hz), 2,19 (USS, 1H), 2,74 (s, 6H), 3,76-of 3.80 (m, 2H), 3,81 (s, 3H), 4,54-4,59 (m, 1H, J=6.3 Hz), 6,79 (m, 1H), for 6.81 (m, 1H), 7,11 (d, 2H, J=9.0 Hz), 7,13 (s, 1H), 7,29-7,30 (m, 2H), to 7.77 (d, 2H, J=9.0 Hz), 8,55 (ush, 1H);

ESI-MS (m/e): 475[M+H]+, 473[M-H]-.

Example of getting 158

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(3-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 158 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, 3-methylthio-phenylboric acid, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 1 or example of getting 89, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.30 (d, 3H, J=6.2 Hz), 2,08 (t, 1H, J=6.5 Hz), of 3.07 (s, 3H), of 3.73-of 3.78 (m, 5H), to 4.52-of 4.57 (m, 1H), 6,77-of 6.78 (m, 2H), was 7.08 (d, 1H, J=2.1 Hz), 7,25-7,31 (who, 3H), 7,54 (t, 1H, J=7,6 Hz), to 7.59 (d, 1H, J=2.1 Hz), of 7.70 (d, 1H, J=7,6 Hz), 8,49 (USS, 1H);

ESI-MS (m/e): 446[M+H]+.

Example of getting 159

Getting 5-(2-hydroxy-1-methyl-ethoxy)-3-(6-isopropylacetanilide-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 159 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, 5-bromo-2-isopropylpiperazine, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (d, 3H, J=5,9 Hz), of 1.35 (d, 6H, J=6,7 Hz), 2,25 (USS, 1H), 3.72 points (septet, 1H, J=6,7 Hz), 3,70-3,81 (m, 2H), 3,81 (s, 3H), 4.53-in-4,59 (m, 1H), 6,78-6,79 (m, 1H), 6,80-PC 6.82 (m, 1H), 7,17 (m, 1H), 7.29 trend-7,31 (m, 1H), 7,32 (m, 1H), 7,43 (DD, 1H, J=8,6, 2.7 Hz), of 8.06 (d, 1H, J=8.6 Hz), and 8.50 (d, 1H, J=2.7 Hz), 8,60 (USS, 1H);

ESI-MS (m/e): 475[M+H]+, 473[M-H]-.

Example of getting 160

Obtaining 3-(3-chloro-4-methanesulfonamide-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 160 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, 4-bromo-2-chloro-methysulfonylmethane, (2R)-1-(tert-Buti is dimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of obtaining 42, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (d, 3H, J=6,1 Hz), or 3.28 (s, 3H), 3,76-of 3.80 (m, 5H), 4,54-4,59 (m, 1H), 6,80-for 6.81 (m, 2H), 7,02 (DD, 1H, J=2,3, 8,8 Hz), 7,14-to 7.15 (m, 2H), 7,30 (d, 1H, J=2.3 Hz), 7,33 (s, 1H), 8,11 (d, 1H, J=8,8 Hz), 8,75 (USS, 1H);

ESI-MS (m/e): 480[M+H]+.

Example of getting 161

Getting 5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-3-yloxy)benzamide

Connection example of getting 161 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, 3-iodopyridine, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.30 (d, 3H, J=6.3 Hz), and 2.27 (ush, 1H), 3.72 points-of 3.80 (m, 2H), 3,80 (s, 3H), 4,55 (m, 1H), 6.75 in (t, 1H, J=2.3 Hz), 6,79 (d, 1H, J=2.3 Hz), 7,05 (m, 1H), 7,22 (m, 1H), 7,29 (d, 1H, J=2.3 Hz), 7,31-7,38 (m, 2H), 8,44 (m, 2H), 8,62 (ush, 1H);

ESI-MS (M/E): 369[M+H]+.

Example of getting 162

Getting 5-(2-fluoro-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-3-yloxy)benzamide

Connection example of getting 162 was obtained as a white amorphous substance using methyl is about ester 5-hydroxy-3-methoxyethoxymethyl acid, 3-iodopyridine, 1,3-debtor-2-propanol and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 3.77 (s, 3H), 4,55-of 4.67 (m, 2H), 4,67 (m, 3H), 6,79 (d, 1H, J=2.3 Hz), PC 6.82 (t, 1H, J=2.3 Hz), 7,11 (m, 1H), 7,26 (m, 1H), 7,29 (d, 1H, J=2.3 Hz), 7,30-7,38 (m, 2H), 8,45 (m, 2H), 8,70 (ush, 1H);

ESI-MS (M/E): 389[M+H]+.

Example of getting 163

Getting 5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-4-yloxy)benzamide

Connection example of getting 163 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, hydrochloride 4-chloropyridine, (2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.31 (d, 3H, J=6.3 Hz), 2,05 (ush, 1H), of 3.77 (m, 2H), 3,82 (s, 3H), 4,56 (m, 1H), 6,79 (d, 1H, J=2.3 Hz), 6,83 (t, 1H, J=2.3 Hz), to 6.88 (DD, 2H, J=1,6, 4,7 Hz), to 7.15 (m, 1H), 7,30 (d, 1H, J=2,2 Hz), 7,33 (m, 1H), 8,42 (ush, 1H), 8,51 (DD, 2H, J=1,6, 4,7 Hz);

ESI-MS (M/E): 369[M+H]+.

Example of getting 164

Getting 5-(2-fluoro-1-vermeil-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)-3-(pyridine-4-yloxy)benzamide

Connection example the floor of the treatment 164 was obtained as a white amorphous substance using the methyl ester of 5-hydroxy-3-methoxyethoxymethyl acid, hydrochloride 4-chloropyridine, 1,3-debtor-2-propanol and 3-amino-1-methyl-1H-pyrazole, using the same method as in the example of getting 117, a corresponding method, or its combination with the generally accepted method.

1H NMR (CDCl3) δ: 3,81 (s, 3H), 4,58-of 4.67 (m, 2H), 4,67-4,82 (m, 3H), 6,79 (d, 1H, J=2.0 Hz), 6.89 in (DD, 2H, J=1,6, 4,7 Hz)6,91 (t, 1H, J=2.3 Hz), 7,21 (t, 1H, J=2.3 Hz), 7,30 (d, 1H, J=2.0 Hz), 7,38 (t, 1H, J=2.3 Hz), charged 8.52 (ush, 1H), charged 8.52 (DD, 2H, J=1,6, 4,7 Hz);

ESI-MS (M/E): 389[M+H]+.

Example of getting 165

Getting 2-[3-(6-acanaloniidae-3-yloxy)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid

Connection example of getting 165 was obtained as a white solid using the conversion of tert-butilkoi ester part tert-butyl ester 2-[3-(6-acanaloniidae-3-yloxy)-5-(1-methyl-1H-pyrazole-3-ylcarbonyl)phenoxy]propionic acid obtained in the same manner as in example a 1, a carboxyl group, using the methyl ester of 3-(6-acanaloniidae-3-yloxy)-5-hydroxy-benzoic acid obtained in example getting 117, tert-butyl ester 2-bromopropionic acid and 3-amino-1-methyl-1H-pyrazole. The transformation of the ester part in the carboxyl group was carried out using the method described in Comprehensive Organic Transfotmations, Richard L. et al., VCH Publishers, 1988, the relevant method is its combination with the generally accepted method.

1H NMR (CDCl3) δ: of 1.24 (3H, t, J=7.4 Hz), to 1.59 (3H, d, J=6.8 Hz), 3,39 (2H, q, J=7.4 Hz), 3,81 (3H, s), 4,69-4,80 (1H, m), 6,56 (1H, d, J=2.3 Hz), make 6.90 (1H, t, J=2.2 Hz), 7,25 (1H, ush.), 7,37 (1H, ush.), of 7.48 (1H, d, J=2.3 Hz), a 7.62 (1H, DD, J=8.7 Hz, 2.7 Hz), 8,07 (1H, d, J=6.4 Hz), charged 8.52 (1H, d, J=2.7 Hz);

ESI-MS (M/E): 475[M+H]+.

Example of getting 166

Getting 5-(2-fluoro-1-vermeil-ethoxy)-3-(3-fluoro-4-methysulfonylmethane)-N-(1-methyl-1H-pyrazole-3-yl)benzamide

Connection example of getting 166 was obtained as a colorless amorphous substance using the methyl ester 3-(3-fluoro-4-methysulfonylmethane)-5-hydroxy-benzoic acid, 1,3-debtor-2-propanol and 3-amino-1-methyl-1H-pyrazole obtained in the same manner as in the example of obtaining 42, using the same method as in example getting 2, the appropriate method or combination with the generally accepted method.

1H NMR (CDCl3) δ: 3,23 (3H, s), 3,82 (3H, s), br4.61-4,78 (5H, m), is 6.78 (1H, d, J=2.3 Hz), 6,83-6,94 (3H, m), 7,19 (1H, t, J=1,8 Hz), 7,30 (1H, d, J=2.3 Hz), 7,38 (1H, t, J=1,8 Hz), 7,94 (1H, t, J=8,4 Hz), of 8.37 (1H, OSS);

ESI-MS (M/E): 484[M+H]+.

INDUSTRIAL APPLICABILITY

Derivatives heteroarylboronic of the present invention represented by the formula (I)exhibit excellent glucokinase activity and therefore are useful for the treatment and/or prevention of diabetes, complications associated with diabetes or obesity in allostimulatory.

1. The compound represented by the following formula (I):

in which X1represents oxygen,

X2represents oxygen,

ring a represents a phenyl or pyridyl,

R1represents 1 or 2 substituent present in the ring And which are selected from the group consisting of C1-6alkylsulfonyl, C1-6alkanoyl, halogen atoms and hydroxys1-6of alkyl,

R2represents C1-6alkyl group with straight or branched chain or2-6alkenylphenol group having 1 or 2 substituent selected from the group consisting of halogen atoms, carboxyl, C1-6alkoxycarbonyl, hydroxy, amino (in which the amino may be optionally substituted by 1 or 2 C1-6alkanolamine or C1-6alkyl groups), C1-6alkoxy and N-(C1-6alkyl)carbamoyl,

the ring is thiazolyl, thiadiazolyl, isoxazolyl, peridotitic or pyrazolyl, in which the carbon atom of ring B, which is connected to the nitrogen atom of amide group of the formula (I), forms a C=N-bond with the ring In, and

R3represents C1-6alkyl or hydraxis1-6alkyl substituent, optionally present in the ring,

or its pharmaceutically acceptable salt.

2. With the Association according to claim 1, in which-X2-R2selected from 2-methoxy-1-methyl-ethoxy, 1-methoxymethyl-propoxy, 3-hydroxy-1-methyl-propoxy, 1-hydroxymethyl-propoxy, 2-hydroxy-1-methyl-ethoxy, 2-acetylamino-1-methyl-ethoxy, 3 metiloksi-2-methyl-propyl, 2-methoxymethyl-butyl, 4-hydroxy-2-methyl-butyl, 2-hydroxymethyl-butyl, 3-hydroxy-2-methyl-propyl, 3-acetylamino-2-methyl-propyl, 2-hydroxymethyl-3-propenyl and 2-fluoro-1-vermeil-ethoxy.

3. The compound according to claim 2, in which-X2-R2selected from 1-methoxymethyl-propoxy, 2-hydroxy-1-methyl-ethoxy and 2-fluoro-1-vermeil-ethoxy.

4. The compound according to claim 1 in which the ring B-R3represents 1-methyl-1H-pyrazole-3-yl.

5. The compound according to any one of claims 1 to 4, where R1represents methanesulfonyl or econsultancy.

6. The compound according to claim 5, in which ring a represents a phenyl group.

7. The compound according to claim 5, in which ring a is pyridyl.

8. The compound according to claim 1, chosen from:

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-thiazol-2-yl-benzamide;

N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methysulfonylmethane)-5-(1-methoxymethyl-propoxy)benzamide;

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(2-methylthiazole-4-yl)benzamide;

5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(3-methyl-[1,2,4]thiadiazole-5-yl)benzamide;

5-(2-hydroxy-1-methyl-what toxi)-3-(4-methanesulfonyl-phenoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide;

3-(3-fluoro-4-methysulfonylmethane)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide;

3-(6-acanaloniidae-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide;

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonyl-pyridine-3-yloxy)-N-(1-methyl-1H-pyrazole-3-yl)benzamide;

3-(6-econsultancy-pyridine-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide;

5-(2-fluoro-1-vermeil-ethoxy)-3-(6-methanesulfonyl-pyridine-3-yloxy)-N-(pyrazole-3-yl)benzamid,

or its pharmaceutically acceptable salt.

9. Pharmaceutical composition suitable for treatment, prevention or delay of onset of type II diabetes, comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, further containing one or more compounds selected from the

(a) other activators of glucokinase,

(b) biguanides,

(c) PPAR agonists,

(d) insulin

(e) somatostatin,

(f) inhibitors α-glucosidase and

(g) substances that promote insulin secretion.

11. The use of compounds according to any one of claims 1 to 8 to obtain drugs for treatment or prevention of diabetes.

12. The use of compounds according to any one of claims 1 to 8 to obtain drugs the frame means for the treatment or prevention of obesity.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

10 cl, 4 tbl, 26 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention proposes use of 2-amino-7-bromo-4-acetylazo[5,4-b]indol depicted by formula: against hyperbaric and hematic hypoxia and protection of liver against carbon tetrachloride poisoning. Use of this compound reduces concentration of AlAT by a factor of 2.6 and that of AcAT by a factor of 1.67.

EFFECT: increased therapeutic activity.

3 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds of formula I , or stereoisomers, or pharmaceutically acceptable salts thereof, wherein Q is SO2; n = 2 or 3; each R1 and R2 is independently H, halogen, OR22 or C1-C6-alkyl; each R3 and R4 is H; each R5 and R6 is independently H or C1-C6-alkyl optionally substituted with phenyl or R5 and R6 together with together with atom to which they are attached may form 5-7-membered ring optionally containing N as the second heteroatom optionally substituted with COOH or C1-C6-alkyl; R7 is H; R7 is optionally substituted 8013-membered bicyclic or tricyclic ring system, containing N in bridge bond and optionally 1, 2 additional heteroatoms selected from N, S wherein substituent represent 1 or 2 halogen atoms; R22 is H or C1-C6-phenyl optionally substituted with C1-C6-alkyl. Compounds of present invention specifically bond to 5-HT6 receptor and are useful in pharmaceutical compositions.

EFFECT: compounds with specific bonding to 5-HT6 receptor.

10 cl, 3 tbl, 45 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula I and pharmaceutically acceptable salt thereof, wherein R1, R3, R4, R5, and R10 are independently H, halogen, C1-C4-alkyl, etc.; R2 is H, halogen, NO2, etc.; R6 is H, C1-C6-alkyl, C1-C6-alkoxy-substituted C1-C4-alkyl, etc.; R7 is H, C1-C4-alkyl or C2-C4-alkenyl, optionally substituted with halogen; R8 and R9 are H, R11 and R12; meanings of the rest substituents are as define in specification.

EFFECT: new compounds with value biological properties and useful as drug having activity in relates to progesterone receptor.

15 cl, 3 tbl, 80 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to bicyclic 1,4-piridotiazine-1,1-dioxides of general formula I wherein R1 is chlorine or fluorine; R2 is linear or branched alkyl, cycloalkyl, optionally reduced aryl or heteroaryl, etc. Method for production of said compounds includes reaction of acyclic sulfones with primary alcohols, preferably in presence of inorganic or organic such as carbonates or alkali metal hydroxides tertiary organic amines or base mixtures, preferably in aprotic bipolar media without solvents, or mixture thereof with water.

EFFECT: safe method for production of new compounds useful as drugs.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine of the general formula (I), which possess properties of the inhibitor of CDK-kinase. In the general formula (I) R1 designates hydrogen, halogen, C1-C6alkyl, R2 designates C1-C10alkyl, C1-C10alkenyl, or C3-C10cycloalkyl which can be mono-, bi- or tricyclic or denotes one- or polysubstituted by identical or different substitutes from the number of hydroxy-group, halogen, C1-C6alkoxygroup, C1-C6kalkylthiogroup, -NH-(CH2)n-C3-C10cycloalkyl, C3-C10 cycloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, C1-C6alkanoil, -CONR3R4, -COR5, C1-C6alkylOAc, where Ac indicates C1-C4alkylCO-group, carboxygroups, phenyl, 5-6-member heteroaryl, containing 1-2-heteroatom in the ring, selected from nitrogen, -(CH2)n- phenyl, -(CH2)n-5-6-member heteroaryl containing 1-2-heteroatom in a ring, selected from nitrogen, phenyl-(CH2)n-R5, -(CH2)nPO3(R5)2 and -R6 and -NR3R4C1-C10alkyl, or C3-C10cycloalkyl, in this case phenyl, C3-C10 cycloalkyl, heteroaryl, -(CH2)n-phenyl and -(CH2)n heteroaryl can be one or polysubstituted by identical or different substitutes from halogens, hydroxygroup, C1-C6alkyl, C1-C6alkoxygroup, benzoxy-group and -CF3 groups, and ring of C3-C10 cycloalkyl and C1-C10alkyl can be separated by one or several nitrogen atoms, oxygen and/or sulfur and/or the said ring can be interrupted by one or two groups of =C=O or R2 designates the group X designates oxygen or group-NH-, and one of A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, X designates oxygen or group-NH-, either one from A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, values of R3 -R10 are specified in the formula of the invention.

EFFECT: connections can be used for the treatment of cancer, autoimmune diseases caused by chemotherapeutic means of alopecia and inflammations of mucous membrane, cardiovascular diseases, infectious diseases, chronic neurodegenerative and viral infections.

13 cl, 1 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula (I) where: X is O; Y represents a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(O)2R34), CH2O or CH2S; Z is C(O), or if Y is a bond, then Z can also be S(O)2; R1 could be substituted with phenyl; R4 is hydrogen, C1-6-alkyl (substituted possibly by C3-6-pilkoalkyl) or C3-6-cycloalkyl; R2, R3, R5, R6, R7 and R8 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; type independently indicate 0 or 1; R9 could possibly be substituted with an aryl or heterocycle; R10, R32 and R35 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; R33 and R34 are C1-6-alkyl or C3-6-cycloalkyl; where the aforesaid aryl and heterocyclic groups, when possible, can be substitute with: halogen cyanogens, nitro, hydroxyl, oxo, S(O)Kr12, OC(O)NR13R14, NR15R16, NR17C(O)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, by C1-6-alkyl (which itself can be monosubstituted with NHC(O)phenyl), C1-6-halogenalkyl, C1-6-alkoxy(C1-6)alkyl, C1-6-alkoxy, C1-6-halogenaloxy, C1-6-alkoxy(C1-6)-alkoxy, C1-6-alkylthio, C2-6-alkenyl, C2-6-alkinil, C3-10-cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkyl, morpholinyl, heteroaryl, heteroaryl(C1-4)alkyl, heteroarylhydroxy of heteroaryl(C1-4)alkoxy, where any of the said phenyl and heteroaryl groups can be substituted by halogen, hydroxyl, nitro, S(O)r(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-.4-alkyl)2, cyanogens, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), CO2H, CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3; k and r independently mean 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 independently represent hydrogen, C1-6-alkyl (probably replaced by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), C3-6-cycloalkyl, phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), NH(C1-4-alkyl)2, S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, S(O)2)(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H5 CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3); alternatively, NR13R14, NR15R16, NR20R21, NR22R23, NR26R27 can independently form 4-7-member heterocyclic ring, selected from the group, which includes: azetidine (which can be substituted by hydroxyl or C1-4-alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter is probably substituted by C1-4-alkyl on the peripheral nitrogen; R12, R25, R28 and R31 are independently C1-6-alkyl (possibly substituted by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4- alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connec to form a ring as described hereabove for R13 and R14), cyanogen, C1-4- alkyl, C1-4- alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), NHC(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3); or its N-oxide; or its pharmaceutically acceptable salt, solvate or solvate of its salt, which are modulators of activity of chemokines (especially CCR3); also described is the pharmaceutical composition on their basis and the method of treating the chemokines mediated painful condition.

EFFECT: obtaining new compounds possessing useful biological properties.

13 cl, 238 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns applications of compositions formulated as follows or its salt, solvate or prodrug of medical agent for treatment or prevention of disease state mediated by glucokinase (GLK). Besides, given invention concerns new group of composition formulated as (I) and to method of specified compositions production. The invention enables to widen range of agents used for treatment or prevention of disease conditions mediated by glucokinase (GLK) where each of R1, R2, R3, n and m has values specified in the description.

EFFECT: increased efficiency.

19 cl, 51 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention is related to the compounds of general formula (I) and their pharmaceutically acceptable salts with properties β2-adrenoreceptor agonists, to the method of their production and based on them pharmaceutical composition. The compounds can be used for treatment of conditions when the symptomatic severity can be reduced by β2- adrenoreceptor activation, e.g., obstructive or inflammatory respiratory diseases. In the general formula (I) , X means -R1-Ar-R2 or -Ra-Y; Ar means phenylen, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, phenyl, C1-C10 alcoxy, substituted by phenyl group or phenyl, substituted by C1-C10 alcoxy group; R1 and R2 are bound to the adjacent carbon atoms within Ar group, and either R1 means C1-C10alkylen, and R2 means hydrogen, C1-C10alkyl or halogen, Ra means the bond or C1-C10 alkylen optionally substituted by group of the row: hydroxy, C1-C10 alcoxy, C6-C10aryl or C7-C14aralkyl; Y means C1-C10alkyl, or C2-C10alkynil, optionally substituted by hydroxyl group, C3-C10cycloalkyl, optionally condensed with one or more benzene rings and optionally substituted by group of the row: C1-C10alkyl, C1-C10alcoxy, C3-C10cycloalkyl, C7-C14aralkyl, C7-C14aralkyloxy or C6-C10aryl, where groups C7-C14aralkyl, C7-C14aralkyloxy or C6-C10 aryl are optionally substituted by group of the row: halogen, C1-C10alkyl, C1-C10alcoxy; C6-C10aryl, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, C1-C10halogenalkyl, phenoxy, C1-C10alkylthio, C6-C10aryl, 5-6-term saturated heterocyclic ring, containing one nitrogen atom in cycle; phenoxy, optionally substituted by C1-C10alcoxy group; 5-6-term heterocyclic ring, containing one or two nitrogen or oxygen atoms in cycle, and the described heterocyclic ring is optionally substituted by group of the row: C1-C10alkyl, C6-C10aryl, C7-C14aralkyl, C1-C10alcoxycarbonil or 5-7-term heterocyclil (C1-C10)alkyl, containing one nitrogen atom in cycle; -NRdRe, where Rd means hydrogen or C1-C10alkyl, and Re means C1-C10alkyl, or Re means C6-C10aryl, or Re means 5-6-term heterocyclic ring, containing one nitrogen or sulfur atom in cycle, and the ring is optionally substituted by halogen-substituted phenyl group or Re means C6-C10arylsypfonil, optionally substituted by groups C1-C10alkylamino or di(C1-C10alkyl)amino; -SRf, where Rf means C6-C10aryl or C7-C14aralkyl, optionally substituted by group of row: halogen or C1-C10halogenalkyl; or -CONHRg, where Rg means C6-C10aryl, provided, if Ra means the bond, then Y doesn't mean C1-C5alkyl.

EFFECT: compound can prevent or reduce symptom's intensity.

15 cl, 4 tbl, 157 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel compounds with formula (I) and their pharmaceutically acceptable salts. The compounds of this invention has the properties of the NPY receptor antagonists and can be used fortreatment of such diseases as arthritis, diabetes, malnutrition, obesity. In general formula (I) , R1 means phenyl or 6-term nitrogen-containing heteroaryl, where in at least one of two meta-positions each phenyl group or 6-term nitrogen-containing heteroaryl group is substituted by group R5; R2 means hydrogen; R3 means C3-C6cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, where in at least one of two ortho-positions each group of C3-C6 cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, substituted by group R6; R4 means hydrogen, C1-C6alkyl; R5 means hydrogen, cyano, trifluoromethyl, C1-C6alkyl-SO2-, amino-SO2-, halogen, C1-C6alcoxy, C1-C6alkylcarbonil or aminocarbonil; R6 means hydrogen, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C1-C6 alcoxy or hydroxy, provided, one R5 group, and R6 doesn't mean hydrogen.

EFFECT: described compounds and based on them pharmaceutical agents are efficient in treatment and prevention of above listed diseases.

19 cl, 2 tbl, 2 dwg, 130 ex

FIELD: organic chemistry, medicine, pharmacy, cosmetology.

SUBSTANCE: invention relates to novel biphenylmethylthiazolidinedions of the general formula (I): , their salts, and to their optical and geometrical isomers possessing agonistic activity with respect to PPARγ receptors, to pharmaceutical and cosmetic compositions based on thereof, and to their using for preparing composition used in treatment of different cutaneous diseases. In compound of the formula (I) R1 means radical of the following formula (a): or (b): ; R2 and R3 mean hydrogen atom; X means binding groups showing the following structures: -CH2-N(R8)-CO-, -N(R8)-CO-N(R9)- that can be read from left to right or vice versa; R4 means phenyl substituted with group R10, pyrrolyl, naphthyl, biphenyl, indenyl, benzothienyl and all these groups can be mono- or di-substituted with group R11 and/or R12, group -(CH2)n-(CO)qR13, adamantyl, cyclopentylethyl, group -(CH2)n-O-R13; R5 means hydroxyl or alkoxyl with 1-19 carbon atoms; R6 means group -OR14. Values R8, R9, R10, R11, R12, R13, n and q are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

25 cl, 2 dwg, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of tetrahydrocarbazole of the formula (I): wherein n = 0, 1 or 2; X represents -NH or oxygen atom (O); each R is a similar or different radical and chosen independently from group consisting of halogen atom, halogenalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl, -OR2, -R10OR2, -R10C(O)R2, -C(O)R2, -CO2R2, -R10CO2R2, -R10SO2R2, -S(O)mR2, cyano- or nitro-group; each R1 is a similar or different radical and chosen independently from group consisting of halogen, halogenalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl, -OR2, -R10OR2, -R10C(O)R2, -C(O)R2, -CO2R2, -R10CO2R2, -R10SO2R2, -S(O)mR2, cyano- or nitro-group and wherein each m means 2 independently; each R10 is a similar or different radical and chosen independently from alkylene; each p and q is chosen independently from 0, 1, 2, 3, 4 or 5; each R2 is a similar or different radical and chosen independently from group consisting of hydrogen atom (H), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl and -R10OH; ring A represents phenyl, naphthyl or heteroaryl wherein heteroaryl represents monocyclic 5-7-membered aromatic ring or condensed bicyclic aromatic ring system consisting of two such aromatic rings that comprise one or two nitrogen atoms and/or sulfur atoms, and to their pharmaceutically acceptable salts, solvates, esters and amides. Compounds of the formula (I) possess effect against disorders caused by HPV-infection and useful in treatment of human papilloma. Also, invention relates to a pharmaceutical composition based on compounds of the formula (I) and its using in preparing drugs for their using in treatment and prophylactic of states or disorders caused by HPV-infection.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel pyrrolidine-2-ones of the formula (I): , wherein R1 means group chosen from the following formulae:

wherein each of them comprises optionally additional nitrogen (N) atom as a heteroatom; Z means optional substitute halogen atom, -CH2NH2, -NRaRb or -CN; Z' means optional substitute halogen atom, -CH2NH2 or -CN; alk means alkylene or alkenylene; T means sulfur atom (S), oxygen atom (O); R2 means hydrogen atom (H), -(C1-C3)-alkyl-CONRaRb, -(C1-C3)-alkyl-CO2-(C1-C4)-alkyl, -(C1-C3)-alkylmorpholino-group, -CO2-(C1-C4)-alkyl or -(C1-C3)-alkyl-CO2H; X means phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms chosen from O, N or S wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb; Y means: (i) a substitute chosen from H, halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb, or (ii) phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms, chosen from O, N or S and wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(CH2)nNRaRb, -(CH2)nN+RaRbCH2CONH2, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc, -S(O)2NRaRb, =O, oxide at N atom in cycle, -CHO, -NO2 and -N-(Ra)(SO2Rc) wherein Ra and Rb mean independently H, -(C1-C6)-alkyl; Rc means -(C1-C6)-alkyl; Rd means H, -(C1-C6)-alkyl; n means 0-2, and to their pharmaceutically acceptable salts or solvates. Compounds inhibit Xa factor that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 144 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines represented by the formula (I): wherein n means 2, 3 or 4; R1 means hydrogen atom or alkyl with 1-4 carbon atoms; R2 means pyridyl or thiazolyl that can be substituted with alkyl with 1-4 carbon atoms, halogen atom, amino-, dimethylamino-, acetylamino-, guanidino-, pyridylamino-group, thienyl, pyridyl, morpholinyl and thiazolyl substituted if necessary with alkyl with 1-4 carbon atoms or phenyl comprising if necessary up to three substitutes as halogen atom, alkyl with 1-4 carbon atoms or alkoxy-group with 1-4 carbon atoms, and to their salts, hydrates, salt hydrates and solvates, and also to substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridine of the formula (I) possessing properties of agonist of A1-adenosine receptors. Also, invention describes a medicinal agent possessing properties of agonist of A1-adenosine receptors. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal and pharmacological properties of compounds and drug.

7 cl, 3 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

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