Novel phenyl pyrrole derivative

FIELD: chemistry.

SUBSTANCE: invention relates phenyl pyrrole derivatives formula (I) where: A denotes =NOR4, O; R4 denotes, C1-C6 alkyl; R1 denotes C1-C6 alkyl, C1-C6 alkoxy, halogen-C1-C6 alkyl, halogen-C1-C6 alkoxy, NH2, mono- C1-C6 alkylamino, halogen-mono-C1-C6 alkylamino, di(C1-C6 alkyl)amino, halogen-di-(C1-C6 alkyl)amino; or A and R1 together with the carbon atom with which they are bonded form a 5- or 6-member heterocyclic aromatic group or a heterocyclic group with partially or completely reduced saturation, which can be benzo-condensed, can contain 1-3 heteroatoms selected from N, O and S, which can be substituted and contain 1 or 2 α substitutes; R2 denotes phenyl which can be substituted with 1 or 2 α substitutes, or a 6-member heteroaryl group containing 1 or 2 N atoms, which can be substituted with 1 or 2 α substitutes; R3 denotes OH, C1-C6 alkoxy, values of α are given in claim 1, or a pharmaceutically acceptable salt thereof.

EFFECT: compounds exhibit glucokinase activating activity, which enables use thereof in treating diabetes.

51 cl, 1 tbl, 132 ex

 

The technical FIELD

The present invention relates to vinylpyrrolidone the compound or its pharmaceutically acceptable salts, which have an excellent trigger activity in respect of glucokinase and can be used as a therapeutic agent for the treatment of diabetes, etc.

The LEVEL of TECHNOLOGY

Glucokinase (indicated in the present description abbreviation SC; EC 2.7.1.1) is gexokinaza one of the four types of hexokinase (glucokinase IV)found in mammals. Hexokinase are enzymes that catalyze the conversion of glucose into glucose-6-phosphate in the first stage of the system of glycolysis in cells, and expression of GK localized mainly in the liver and pancreatic beta-cells. In pancreatic beta-cells of GK functions as a "probe device" concentration of extracellular glucose and regulates glucosestimulated insulin secretion, whereas in the liver enzymatic reaction Ledger serves as a factor limiting the speed of the subsequent reactions such as glycolysis and glycogen synthesis. Despite the fact that Ledger was detected in the liver, is different from the Ledger found in pancreatic beta-cells, a sequence consisting of 15 amino acids from the N-Terminus, due to differences in splicing, their enzymatic what properties are identical. Unlike enzymatic activities hexagons the other three types (types I, II and III), which become saturated with glucose concentrations of 1 mm or less, the Ledger shows low affinity to glucose, its value Km is close to the physiological level of glucose in the blood and is in the range from 8 to 15 mm. Thus, in response to the deviation of the level of glucose in blood from normal value (about 5 mm) to levels that occurs after a meal (from 10 to 15 mm), there is an acceleration GK-held intracellular metabolism of glucose.

The hypothesis that GK functions as a glucose sensor in liver and pancreatic beta-cells, was maintained for a long time (non-patent documents 1-3). Recent studies have shown that GK does play an important role in maintaining systemic glucose homeostasis, confirming thus this hypothesis. For example, a mouse which was destroyed glucokinase gene, showed symptoms of hyperglycemia and died shortly after birth, while it was found that GK hetero-deficient mice showed impaired glucose tolerance and impaired glucosestimulated insulin secretion (non-patent document 4). On the other hand, it was found that normal mice, excessively expressing Ledger showed the reduced levels of glucose in the blood and high content of glycogen in the liver, and these symptoms were similar to the symptoms observed in mice in organisms which was artificially induced diabetes (non-patent document 5).

In addition, in humans Ledger functions as a glucose sensor and, as has been shown in recent studies, plays an important role in maintaining glucose homeostasis. In some HK genes are inherited, were detected abnormalities, manifested in the form of juvenile diabetes, called insulinorezistentne diabetes mellitus (MODY2), and showed a clear correlation between the occurrence of this disease and the activity of GK (non-patent document 6). On the other hand, have also been found in the genealogical line with a mutation that increases the activity of GK, and there were signs of hypoglycemia fasting, accompanied by increased concentrations of insulin in plasma in such genealogical lines (non-patent document 7). Based on these studies, Ledger plays an important role in the regulation of glucose in the blood, functioning as a sensor of glucose in mammals, including humans. Thus, it is believed that compounds with GC-activating activity, can be used as medicines for the treatment of glycometabolism diseases, including diabetes mellitus type II. Since may hidatsa, that connection, activating the Ledger, are simultaneously promoting activity against absorption of glucose and inhibitory activity against the release of glucose in the liver, and, in particular, promotirovat insulin secretion in pancreatic beta-cells, it is assumed that they are able to demonstrate a highly efficient therapeutic effect, which cannot be achieved using currently available drugs.

Recent studies have shown that GK type of pancreatic beta-cells expressed and localized in ventromedial hypothalamus (VMH) of rat brain. It is well known that the VMH is the site of neurons that respond to the concentration of glucose. In contrast, reducing the absorption of food in the introduction of glucose in the rat stomach, absorption of food increases when glucose metabolism is inhibited by introduction of a similar glucose - glucosamine (non-patent document 8). Electrophysiological experiments showed that glycosidically neurons are activated through reaction to physiological changes in concentrations of glucose (5 to 20 mm), and it was found that glucokinase has a similar function as a glucose sensor in the peripheral tissues (non-patent document 9). Thus, it can be expected that the connection to the e induce the activation of glucokinase not only in the liver and pancreatic beta-cells, but in the VMH, active reduction of glucose in the blood and the activity of correction of obesity, which is a problem for many patients with diabetes mellitus type II.

Based on the above data, compounds with GC-activating activity, can be used as therapeutic and prophylactic agents against diabetes or as therapeutic and prophylactic agents of the complications that accompany diabetes, including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic heart disease and arteriosclerosis.

In addition, despite the fact that previously been described many compounds with GC-activating activity, the structures of all these compounds differ from the connection structure according to this invention. For example, although in the patent document 1 describes a compound containing amide fragment as the main constituent fragment of the structure, the connection according to the present invention contains as a major constituent fragment of the structure of pyrrole, not amide fragment as the main component of the fragment patterns. Further, although patent document 2 describes a compound containing a condensed pyrrole, compound according to Nast is Adamu invention contains unfused pyrrole as the main component of the fragment patterns. Moreover, although patent document 1 describes a compound containing 3,5-disubstituted pyrazol-or 1,2,4-triazole fragment, it differs from 2,5-disubstituted pyrrole link structure according to the present invention.

Although in addition to the compounds disclosed in the above publications, it is described a significant number of compounds with GC-activating activity, the structures of all these compounds differ from the compounds according to the present invention (see, for example, patent documents 4 through 15 and non-patent documents 10 and 11).

[Patent document 1] international publication number WO2005/080359.

[Patent document 2] international publication number WO2007/031739.

[Patent document 3] international publication number WO2007/061923.

[Patent document 4] international publication No. WO2000/058293.

[Patent document 5] international publication number WO2003/080585.

[Patent document 6] international publication number WO2005/066145.

[Patent document 7] international publication number WO2005/090332.

[Patent document 8] international publication number WO2006/112549.

[Patent document 9] international publication number WO2007/007886.

[Patent document 10] international publication number WO2007/037534.

[Patent document 11] international publication number WO2007/053765.

[Patent document 12] international publication number WO2007/11381.

[Patent document 13] international publication number WO2005/044801.

[Patent document 14] international publication number WO2007/053662.

[Patent document 15] international publication number WO2003/136428.

[Non-patent document 1] Am. J. Physiol. 1984 Sep.; 247(3 Pt. 2):R527-36.

[Non-patent document 2] Diabetes. 1986 Jan.; 35(1):61-7.

[Non-patent document 3] Diabetes. 1986 Oct; 35(10):1163-73.

[Non-patent document 4] Cell. 1995 Oct. 6; 83(l):69-78.

[Non-patent document 5] Proc. Natl. Acad. Sci. USA. 1996 Jul. 9; 93(14):7225-30.

[Non-patent document 6] Nature. 1992 Apr. 23; 356(6371):721-2.

[Non-patent document 7] N. Engl. J. Med. 1998 Jan. 22; 338(4):226-30.

[Non-patent document 8] Life Sci. 1985 Dec 30; 37(26):2475-82.

[Non-patent document 9] Diabetes. 2006 Feb; 55(2):412-20. Erratum in: Diabetes. 2006 Mar; 55(3):862.

[Non-patent document 10] Science. 2003 Jul. 18; 301(5631):370-3.

[Non-patent document 11] J. Biol. Chem. 2006 Dec. 8; 281(49):37668-74. Epub 2006 Oct 6.

Description of the INVENTION

Tasks that should be solved by this invention

The subject of this invention is to provide a new derived phenylpyrrole and activator of GC, which uses the specified new derived phenylpyrrole, and, in particular, the provision of therapeutic and prophylactic agent for the treatment and prevention of diabetes and disorders of glucose tolerance. In the study of compounds with GC-activating activity, the applicants of the present invention installed, is then derived phenylpyrrole specific chemical structure has excellent GK-activating activity. In addition, the connection according to the present invention has excellent CC selectivity, low toxicity and low number of adverse side effects. The applicants of the present invention also found that this derived phenylpyrrole applicable as an active ingredient of pharmaceutical agents for the treatment and/or prevention of diseases selected from the group including diabetes, impaired glucose tolerance, gestational diabetes (gestational diabetes), chronic diabetic complications (including diabetic peripheral neuropathy, diabetic retinopathy and diabetic macroangioapthy) and metabolic syndrome. The present invention is based on the above data.

The solution to the above problems

The object of the present invention is:

(1) the compound of General formula (I):

,

where

A represents a group of formula =NOR4, an oxygen atom or a sulfur atom,

R4represents a hydrogen atom or a C1-C6alkyl group,

R1represents a C1-C6alkyl group, a C1-C6alkoxygroup, halogenated C1-C6alkyl group, halogenated C1-C6alkoxygroup, amino, mono-C1 -C6alkylamino, halogenated mono-C1-C6alkylamino, di(C1-C6alkyl)amino group or halogenated di(C1-C6alkyl)amino group, or

A and R1together with the carbon atom to which they are attached, form a heterocyclic group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α,

R2represents a phenyl group which may be substituted and can contain from 1 to 5 substituents independently selected from the group of substituents α, or a heterocyclic group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α,

R3represents a hydroxyl group or a C1-C6alkoxygroup, and

the group of substituents α represents a group of substituents selected from a halogen atom, a C1-C6alkyl groups, halogenated C1-C6alkyl group, a C2-C6alkenylphenol group, C2-C6alkenylphenol group, a hydroxyl group, a C1-C6alkyl group substituted by 1 or 2 hydroxyl groups, C1-C6alkoxygroup, halogenated C1-C6alkoxygroup, group (C1-C6alkoxy)-(C1-C6lcil), (C1-C6alkoxy)-(C1-C6alkoxy) group, formyl group, carboxyl group, C2-C7alkylcarboxylic group, C2-C7alkoxycarbonyl group, C2-C7alkylcarboxylic, C2-C7alkoxycarbonylmethyl, nitro, amino, mono-C1-C6alkylamino, di(C1-C6alkyl)amino, C1-C6allylthiourea, C1-C6alkylsulfonyl group, C3-C6cycloalkylcarbonyl group, C1-C6hydroxyacetophenones groups, (C1-C6alkoxy)-(C1-C6alkylsulfonyl), groups of formula-V-NR5R6(where V represents a carbonyl group or sulfonyloxy group, R5and R6may be the same or different and respectively represent a hydrogen atom or a C1-C6alkyl group, or R5and R6together with the nitrogen atom to which they are attached, form a 4-6-membered saturated, a heterocycle which may be substituted and may contain 1 or 2 substituent, independently selected from C1-C6alkyl group and hydroxyl group, and a 4-6-membered saturated the heterocycle may optionally contain one oxygen atom or one nitrogen atom), mono-C2-C7alkylcarboxylic the dust, mono-C1-C6alkylaminocarbonyl, di(C1-C6alkyl)aminocarbonylmethyl, mono-C2-C7alkoxycarbonylmethyl, mono-C1-C6alkylsulfonamides, ceanography, 1,3,4-oxadiazol-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group, 1,3,4-thiadiazole-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group, and the carbonyl group; or its pharmaceutically acceptable salt;

(2) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where

the group of substituents α represents a group of substituents selected from a halogen atom, a C1-C6alkyl groups, halogenated C1-C6alkyl group, a C2-C6alkenylphenol group, C2-C6alkenylphenol group, a hydroxyl group, a C1-C6alkyl group substituted by 1 or 2 hydroxyl groups, C1-C6alkoxygroup, halogenated C1-C6alkoxygroup, group (C1-C6alkoxy)-(C1-C6alkyl), (C1-C6alkoxy)-(C1-C6alkoxy) group, formyl group, carboxyl group, C2-C7alkylcarboxylic group, C2-C7alkoxycarbonyl group, C2-C7alkylboron is lexigraphy, C2-C7alkoxycarbonylmethyl, nitro, amino, mono-C1-C6alkylamino, di(C1-C6alkyl)amino, C1-C6allylthiourea, C1-C6alkylsulfonyl group, C3-C6cycloalkylcarbonyl group, C1-C6hydroxyacetophenones groups, (C1-C6alkoxy)-(C1-C6alkylsulfonyl), groups of formula-V-NR5R6(where V represents a carbonyl group or sulfonyloxy group, and R5and R6may be the same or different and respectively represent a hydrogen atom or a C1-C6alkyl group, or R5and R6together with the nitrogen atom to which they are attached, form a 4-6-membered saturated, a heterocycle which may be substituted and may contain 1 or 2 substituent, independently selected from C1-C6alkyl group and hydroxyl group, and a 4-6-membered saturated the heterocycle may optionally contain one oxygen atom or one nitrogen atom), mono-C2-C7alkylcarboxylic, mono-C1-C6alkylaminocarbonyl, di(C1-C6alkyl)aminocarbonylmethyl, mono-C2-C7alkoxycarbonylmethyl, mono-C1-C6alkylsulfonamides, ceanography, 1,3,4-oxa shall eazol-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group, and 1,3,4-thiadiazole-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group;

(3) the compound or its pharmaceutically acceptable salt as defined above in paragraphs (1) or (2), where

General formula (I) represents a General formula (Ia):

;

(4) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (3), where A represents an oxygen atom;

(5) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (4), where R1represents a C1-C6alkyl group, a C1-C6alkoxygroup or halogenated mono-C1-C6alkylamino;

(6) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (4), where R1represents a methyl group or 2-chloroethylamino;

(7) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (4), where the heterocyclic group formed by A and R1together with the carbon atom to which they are attached, can be substituted and can contain from to 3 substituents, independently selected from the group of substituents α, and is a 2-pyridyloxy group, 5,6-dihydro-4H-1,3-oxazin-2-ilen group, 1,3-thiazol-2-ilen group, 1,3-oxazol-2-ilen group, 1,3,4-oxadiazol-2-ilen group, 1,3,4-thiadiazole-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-ilen group, or 1,3-benzothiazol-2-ilen group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents γ, and

the group of substituents γ is a group of substituents comprising halogen atom, a C1-C6alkyl group, halogenated C1-C6alkyl group, a C1-C6alkyl group, substituted by 1 or 2 hydroxyl groups, C1-C6alkoxygroup, carboxyl group, mono-C1-C6alkylaminocarbonyl group, di(C1-C6)alkylaminocarbonyl group and hydroxyl group;

(8) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (3), where the heterocyclic group formed by A and R1together with the carbon atom to which they are attached, can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, and represents 1,3-thiazol-2-ilen group, 5-methyl-1,3-thiazol-2-the optimum group, 5-methyl-1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-4-hydroxy-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 5-carboxy-1,3-thiazol-2-ilen group, 5-dimethylaminoethyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-thiadiazole-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-ilen group;

(9) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (3), where the heterocyclic group formed by A and R1together with the carbon atom to which they are attached, can be substituted and can contain from 1 to 3 substituents independently selected from the group Deputy α, and represents a 4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 1,3-thiazol-2-ilen group, 5-carboxy-1,3-thiazol-2-ilen group, 5-dimethylaminoethyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-thiadiazole-2-ilen group, 5-methyl-1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-ilen group;

(10) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (3), where the heterocyclic group formed by A and R1together with the carbon atom to which they are attached, can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, and represents a 4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group or (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group;

(11) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (10), where R2represents a phenyl group which may be substituted and can contain from 1 to 5 substituents independently selected from the group of substituents δ, or 2-pyridyloxy group, 3-pyridyloxy group or 2-personilnya group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents δ, and

the group of substituents δ is a group of substituents comprising halogen atom, a C1-C6alkyl group, halogenated C1-C6alkyl group, a C1-C6alkyl group, substituted by 1 or 2 hydroxyl groups, C2-C7alkylcarboxylic group, C2-C7alkoxycarbonyl group, C1-C6alkyls Honiley group, a group of the formula-V-NR5R6(where V represents a carbonyl group or sulfonyloxy group, and R5and R6may be the same or different and respectively represent a hydrogen atom or a C1-C6alkyl group, or R5and R6together with the nitrogen atom to which they are attached, form a 4-6-membered saturated, a heterocycle which may be substituted and may contain 1 or 2 substituent, independently selected from C1-C6alkyl group and hydroxyl group, and a 4-6-membered saturated the heterocycle may optionally contain one oxygen atom or one nitrogen atom), 1,3,4-oxadiazol-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group, and 1,3,4-thiadiazole-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group;

(12) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (10), where R2is a 4-methylsulfinylphenyl group, 4-(1-azetidine)carbonyl-2-florfenicol group, 2-fluoro-4-(1-pyrrolidinyl)Carboniferous group, 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group, 2-methylsulphonyl-5-pyridyloxy group, 5-(4-methyl-1-piperazinil)carbonyl-2-personilnya group, 2-methylaminomethyl-5-pyridyloxy g is the SCP, 2-methylaminomethyl-5-pyridyloxy group or 5-methylsulphonyl-2-personilnya group;

(13) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (10), where R2is a 4-methylsulfinylphenyl group, 2-methylsulphonyl-5-pyridyloxy group, 5-methylsulphonyl-2-personilnya group or 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group;

(14) the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (13), where R3represents a hydroxyl group or a methoxy group;

(15) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the General formula (I) represents a General formula (Ia), A is an oxygen atom, R1represents a C1-C6alkyl group, a C1-C6alkoxygroup or halogenated mono-C1-C6alkylamino, R2represents a phenyl group which may be substituted and can contain from 1 to 5 groups independently selected from the group of substituents δ, or 2-pyridyloxy group, 3-pyridyloxy group or 2-personilnya group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents δ, and R3the stand is made by a hydroxyl group or a methoxy group;

(16) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the General formula (I) represents a General formula (Ia), A is an oxygen atom, R1represents a methyl group or 2-chloroethylamino, R2is a 4-methylsulfinylphenyl group, 4-(1-azetidine)carbonyl-2-florfenicol group, 2-fluoro-4-(1-pyrrolidinyl)Carboniferous group, 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group, 2-methylsulphonyl-5-pyridyloxy group, 5-(4-methyl-1-piperazinil)carbonyl-2-personilnya group, 2-methylaminomethyl-5-pyridyloxy group, 2-methylaminomethyl-5-pyridyloxy group or a 5-methylsulphonyl-2-personilnya group, and R3represents a hydroxyl group or a methoxy group;

(17) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the General formula (I) represents a General formula (Ia), A is an oxygen atom, R1represents a methyl group or 2-chloroethylamino, R2is a 4-methylsulfinylphenyl group, 2-methylsulphonyl-5-pyridyloxy group, 5-methylsulphonyl-2-personilnya group or 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group, and R3represents a hydroxyl group or a methoxy group;

(18) the compound or the th pharmaceutically acceptable salt, as defined above in paragraph (1), where the General formula (I) represents a General formula (Ia), heterocyclic group formed by A and R1together with the carbon atom to which they are attached, can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, is a 2-pyridyloxy group, 5,6-dihydro-4H-1,3-oxazin-2-ilen group, 1,3-thiazol-2-ilen group, 1,3-oxazol-2-ilen group, 1,3,4-oxadiazol-2-ilen group, 1,3,4-thiadiazole-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-ilen group, or 1,3-benzothiazol-2-ilen group and can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents γ, R2represents a phenyl group which may be substituted and can contain from 1 to 5 substituents independently selected from the group of substituents δ, or 2-pyridyloxy group, 3-pyridyloxy group or 2-personilnya group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents δ, and R3represents a hydroxyl group or a methoxy group;

(19) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the General formula (I) represents a General formula (Ia), heterocyclic group formed by A and R1 together with the carbon atom to which they are attached, can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, and represents 1,3-thiazol-2-ilen group, 5-methyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-4-hydroxy-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 5-carboxy-1,3-thiazole-2-strong group, 5-dimethylaminoethyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-thiadiazole-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-ilen group, R2is a 4-methylsulfinylphenyl group, 4-(1-azetidine)carbonyl-2-forfinal the second group, 2-fluoro-4-(1-pyrrolidinyl)Carboniferous group, 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group, 2-methylsulphonyl-5-pyridyloxy group, 5-(4-methyl-1-piperazinil)carbonyl-2-personilnya group, 2-methylaminomethyl-5-pyridyloxy group, 2-methylaminomethyl-5-pyridyloxy group or 5-methylsulphonyl-2-personilnya group, and R3represents a hydroxyl group or a methoxy group;

(20) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the General formula (I) represents a General formula (Ia), heterocyclic group formed by A and R1together with the carbon atom to which they are attached, can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, and represents a 4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5R)-5-hydroxymet the l-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 1,3-thiazol-2-ilen group, 5-carboxy-1,3-thiazol-2-ilen group, 5-dimethylaminoethyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-thiadiazole-2-ilen group, 5-methyl-1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-ilen group, R2is a 4-methylsulfinylphenyl group, 2-methylsulphonyl-5-pyridyloxy group, 5-methylsulphonyl-2-personilnya group or 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group, and R3represents a hydroxyl group or a methoxy group;

(21) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the General formula (I) represents a General formula (Ia), heterocyclic group formed by A and R1together with the carbon atom to which they are attached, can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, and represents a 4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group or (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, R2is a 4-methylsulfinylphenyl group, 2-methylsulphonyl-5-pyridyloxy group, 5-methylsulphonyl-2-personilnya group or 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group, and R3represents a hydroxyl group or a methoxy group;

(22) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the compound of General formula represents:

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

(2S)-2-{3-[4-(methylsulphonyl)phenoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}propan-1-ol,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylic acid,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-N,N-dimethyl-1,3-thiazole-5-carboxamide,

1-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)Etalon,

(2S)-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-thiadiazole,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pee the rol-2-yl)-4,5-dihydro-1,3-thiazole,

(2S)-2-{3-[5-(4,5-dihydro-1,3-thiazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulphonyl)phenoxy]phenoxy)propan-1-ol,

2-(5-{3-[(1S)-2-methoxy-l-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5,6-dihydro-4H-1,3-oxazin,

(2S)-2-(3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy)propan-1-ol,

(2S)-2-(3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1 r3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R,5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-5-yl}methanol,

{(4R,5S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(1R)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(2S)-2-(3-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}f is noxi)propan-1-ol,

{(4R,5S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol or

(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol;

(23) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the compound of General formula (I) represents:

(2S)-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulphonyl)phenoxy]phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]ox is}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R,5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-5-yl}methanol,

{(4R,5S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(1R)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-{methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(4R,5S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(matilal is of IMT)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol or

(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol;

(24) a compound as defined above in paragraph (1), where the compound of General formula (I) represents:

(2S)-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulphonyl)phenoxy]phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R,5R)2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-5-yl}methanol,

{(4R,5S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(1R)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(4R,5S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol or

(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]the XI}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol.

(25) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the compound of General formula (I) represents:

1-(4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)Etalon,

1-(4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)ethanol

1-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)Etalon,

N-(2-chloroethyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamid,

6-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)nicotinic acid,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5,6-dihydro-4H-1,3-oxazin,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3-thiazole,

[2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]methanol,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylic acid,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-N,N-dimethyl-1,3-thiazole-5-carboxamide,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]the dryer is l}-1H-pyrrol-2-yl)-1,3-oxazol,

5-methoxy-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-oxazol,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-oxadiazol,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-thiadiazole,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-thiazole,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol,

(5S)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol,

(5R)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5,5-dimethyl-4,5-dihydro-1,3-oxazol,

[2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-benzothiazole,

2-(5-{3-[4-(azetidin-1-ylsulphonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

methyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoate,

3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-ti is evil-2-yl)-1H-pyrrol-2-yl]phenoxy}benzamide,

3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-N-methylbenzamide,

3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-N,N-dimethylbenzamide,

2-(5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

2-(5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-oxadiazol,

2-(5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol,

(5S)-2-(5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol,

2-(5-{3-[2-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

4-(3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoyl)morpholine,

3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-N-methylbenzenesulfonamide,

2-(5-{3-[4-(azetidin-1-ylsulphonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

2-(3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)-5-methyl-1,3,4-oxadiazol,

2-(3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)-5-methyl-1,3,4-thiadiazole,

2-(5-{3-[4-(azetidin-1-ilkar is of IMT-2 methylphenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

2-(5-{3-[4-(azetidin-1-ylcarbonyl)-2-(trifluoromethyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

5-(azetidin-1-ylcarbonyl)-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine,

5-(azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine,

5-(azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine,

5-(azetidin-1-ylcarbonyl)-3-chloro-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}pyridine,

5-(azetidin-1-ylcarbonyl)-3-chloro-2-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine,

5-(azetidin-1-ylcarbonyl)-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylpyridin,

5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-2-(methylsulphonyl)pyridine,

5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine,

2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin,

5-(permitil)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol,

(5R)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methyl who sulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-(trifluoromethyl)-4,5-dihydro-1,3-oxazol,

[(5R)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-N,N-dimethyl-4,5-dihydro-1,3-oxazol-5-carboxamid,

N-(2-chloroethyl)-5-{3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamid,

(2S)-2-{3-[4-(methylsulphonyl)phenoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}propan-1-ol,

(2S)-2-{3-[5-(4,5-dihydro-1,3-thiazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,

(2S)-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulphonyl)phenoxy]phenoxy)propan-1-ol,

(2S)-2-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}propan-1-ol,

(2S)-2-(3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)propan-1-ol,

(2S)-2-(3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy)propan-1-ol,

(2S)-2-(3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)propan-1-ol or

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]OK and}phenoxy)propan-1-ol;

(26) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the compound of General formula (I) represents:

1-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)Etalon,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3-thiazole,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-thiazole,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol,

(5S)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol,

(5R)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol,

[2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol,

2-(5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

2-(5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol,

(5S)-2-(5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro,3-oxazol,

2-(5-{3-[2-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

5-(azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine,

5-(azetidin-1-ylcarbonyl)-3-chloro-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}pyridine,

5-(azetidin-1-ylcarbonyl)-3-chloro-2-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine,

5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-2-(methylsulphonyl)pyridine,

5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine,

2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin,

[(5R)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol,

(2S)-2-{3-[4-(methylsulphonyl)phenoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}propan-1-ol,

(2S)-2-{3-[5-(4,5-dihydro-1,3-thiazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,

(2S)-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulphonyl)phenoxy]phenoxy)propan-1-ol,

(2)-2-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}propan-1-ol,

(2S)-2-(3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)propan-1-ol,

(2S)-2-(3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)propan-1-ol or

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol;

(27) a compound as defined above in paragraph (1), where the compound of General formula (I) represents:

1-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)Etalon,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3-thiazole,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-thiazole,

2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol,

(5S)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol,

(5R)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol,

[2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol,

2-(5-{3-[4-(is seiden-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

2-(5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol,

(5S)-2-(5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol,

2-(5-{3-[2-fluoro-4-(pyrrolidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole,

5-(azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine,

5-(azetidin-1-ylcarbonyl)-3-chloro-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}pyridine,

5-(azetidin-1-ylcarbonyl)-3-chloro-2-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine,

5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-2-(methylsulphonyl)pyridine,

5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine,

2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin,

[(5R)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol,

(2S)-2-{3-[4-(methylsulphonyl)phenoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}propan-1-ol,

(2S)-2-{3-[5-(4,5-dihydro-1,3-thiazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(metralha the Il)phenoxy]phenoxy}propan-1-ol,

(2S)-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulphonyl)phenoxy]phenoxy)propan-1-ol,

(2S)-2-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}propan-1-ol,

(2S)-2-(3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)propan-1-ol,

(2S)-2-(3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)propan-1-ol or

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol;

(28) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the compound of General formula (I) represents:

(2S)-2-(3-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R)-2-[5-(3-[-(1S)-2-IU is hydroxy-1-methylethoxy]-5-{[6-(methylsulphonyl}pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R,5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-5-yl}methanol,

{(4R,5S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(1R)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(2S)-2-(3-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(5S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-ol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(4R,5S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

5-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-sulfonamide,

5-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-carboxamid,

5-(3-{5-[(5R)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-N-methylpyridin-2-carboxamide or

5-(3-{5-[(5R)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-N-methylpyridin-2-sulfonamide;

(29) the compound or its pharmaceutically acceptable salt as defined above in paragraph (1), where the compound of General formula (1) represents:

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R,5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-5-yl}methanol,

{(4R,5S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(1R)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-p is rol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(4R,5S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol or

(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol;

(30) a compound as defined above in paragraph (1), where the compound of General formula (I) represents:

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methyls Lionel)pyridine-3-yl]oxy}phenoxy)propan-1-ol,

{(4R,5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy)phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-5-yl}methanol,

{(4R,5S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(1R)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,

(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,

{(4R,5S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,

(1S)-1-{(4S)-2-[5-(3-{[2S)-1-methoxypropan-2-and the]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol or

(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol;

(31) a glucokinase activator containing as active ingredient the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (30);

(32) a pharmaceutical composition comprising as active ingredient the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (30);

(33) the pharmaceutical composition defined above in paragraph (32), where the pharmaceutical composition has an activity of activating glucokinase;

(34) the pharmaceutical composition defined above in paragraph (32), where the pharmaceutical composition is a pharmaceutical composition for the treatment and/or prophylaxis of diseases which can be treated or prevented by the activity of activating glucokinase;

(35) the pharmaceutical composition defined above in paragraph (32), where the pharmaceutical composition is a pharmaceutical composition for the treatment and/or prevention of disease, symptoms of which are treated, alleviated, decreasing and/or preventing activation of glucokinase and the maintenance of glucose homeostasis or regulation of the level of soderjaniyu blood glucose;

(36) the pharmaceutical composition defined above in paragraph (32), where the pharmaceutical composition is a pharmaceutical composition for the treatment and/or prevention of diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macroangioapthy) or metabolic syndrome;

(37) the pharmaceutical composition defined above in paragraph (32), where the pharmaceutical composition is a pharmaceutical composition for the treatment and/or prevention of diabetes and impaired glucose tolerance;

(38) use of the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (30), to obtain pharmaceutical compositions;

(39) the use as defined above in paragraph (38), where the pharmaceutical composition is a composition for activating glucokinase;

(40) the use as defined above in paragraph (38), where the pharmaceutical composition is a composition for the treatment and/or prevention of diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic the kind of nephropathy, diabetic retinopathy and diabetic macroangioapthy) or metabolic syndrome;

(41) the use as defined above in paragraph (38), where the pharmaceutical composition is a composition for the treatment and/or prevention of diabetes or impaired glucose tolerance;

(42) a method of activating glucokinase including the introduction of a warm-blooded animal a pharmaceutically effective amount of the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (30);

(43) the method of treatment and/or prevention of disease involving the introduction of a warm-blooded animal a pharmaceutically effective amount of the compound or its pharmaceutically acceptable salt as defined above in any item selected from items (1) through (30);

(44) the method defined above in paragraph (43), where the disease is a diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macroangioapthy) or metabolic syndrome;

(45) the method defined above in paragraph (43), where the disease is a diabetes or impaired glucose tolerance; and

(46) the method defined above in any pun is those selected from (42) to (45), where warm-blooded animal is a human.

In the present invention, the term "halogen atom" refers to fluorine atom, chlorine atom, bromine atom or iodine atom. The halogen atom is preferably a fluorine atom or a chlorine atom, more preferably a chlorine atom.

In the present invention, the term "C1-C6alkyl group" refers to linear or branched alkyl group containing from 1 to 6 carbon atoms. Examples of C1-C6alkyl groups include methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexoloy group, isohexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group and 1,2-dimethylbutyl group, and C1-C6the alkyl group preferably represents a linear or branched alkyl group containing from 1 to 4 carbon atoms (C1-C4alkyl group), more preferably methyl group or ethyl group, (C -C2alkyl group), more preferably a methyl group.

In the present invention, the term "halogenated C1-C6alkyl group" refers to a group in which 1 to 5 identical or different groups referred to above as the "halogen atom"that is attached to the above-mentioned "C1-C6alkyl group". Examples of halogenated C1-C6alkyl groups include triptorelin group, trichlorethylene group, deformational group, dichloromethylene group, dibromomethyl group, formeterol group, 2,2,2-triptorelin group, 2,2,2-trichlorethylene group, 2-bromatology group, 2-chloraniline group and 2-foretelling group, and halogenated C1-C6the alkyl group preferably is a group in which 1 to 5 identical or different groups referred to above as the "halogen atom"that is attached to the group mentioned above as "C1-C4alkyl group (halogenated C1-C4alkyl group), more preferably a group in which 1 to 5 identical or different groups referred to above as the "halogen atom"that is attached to the group mentioned above as "C1-C2alkyl group (halogenated C1-C2alkyl group), more preferably triptorelin is the Rupp or formeterol group.

In the present invention, the term "C2-C6Alchemilla group" refers to a group referred to above as "C1-C6alkyl group containing one double bond and from 2 to 6 carbon atoms. Examples of C2-C6alkenylphenol groups include atenolol group, 1-propenyloxy group, 2-propenyloxy group, 1-methyl-2-propenyloxy group, 1-methyl-1-propenyloxy group, 2-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-pentanediol group, 4-pentanediol group, 1-methyl-4-pentanediol group and 5-hexenyl group, and C2-C6Alchemilla group preferably represents alkenylphenol group containing from 2 to 4 carbon atoms (C2-C4alkenylphenol group), more preferably 2-propenyloxy group.

In the present invention, the term "C2-C6Alchemilla group" refers to a group referred to above as "C1-C6alkyl group containing one triple bond and from 2 to 6 carbon atoms. Examples of C2-C6alkenylphenol groups include etinilnoy group, 1-propenyloxy group, 2-propenyloxy group, 1-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 1-methyl-2-butenyloxy group, 3-butenyloxy group, 2-pantanillo group and 5-hexylamino gr the PPU, and C2-C6Alchemilla group preferably represents alkylamino group containing from 2 to 4 carbon atoms (C2-C4alkylamino group), more preferably 2-propenyloxy group or 2-butenyloxy group.

In the present invention, the term "C1-C6alkyl group substituted by 1 or 2 hydroxyl groups" refers to a group in which 1 or 2 hydroxyl groups attached to the group mentioned above as "C1-C6alkyl group". Examples of C1-C6alkyl group substituted by 1 or 2 hydroxyl groups, include hydroxymethylene group, 2-hydroxyethyloxy group, 1-hydroxyethylene group, 3-hydroxypropyl group, 1,2-dihydroxyethylene group and 2,3-dihydroxypropyl group, and C1-C6alkyl group substituted by 1 or 2 hydroxyl groups, preferably represents a group in which 1 or 2 hydroxyl groups attached to the group mentioned above as "C1-C4alkyl group, more preferably a group in which 1 or 2 hydroxyl groups attached to the group mentioned above as "C1-C2alkyl group, even more preferably hydroxymethylene group or hydroxyethylene group.

In the present invention, the term "C1-C6alkoxygroup" from OSISA to the group, in which the group referred to above as "C1-C6alkyl group linked to an oxygen atom and which is a linear or branched alkoxygroup containing from 1 to 6 carbon atoms. Examples of C1-C6alkoxygroup include a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, phenoxypropan, 2-methylbutoxy, 3-ethylpropoxy, Papantoniou, hexyloxy and 2,3-Dimethylbutane, and C1-C6alkoxygroup preferably represents a linear or branched alkoxygroup containing from 1 to 4 carbon atoms (C1-C4alkoxygroup), more preferably a methoxy group, ethoxypropan, propoxylate or isopropoxide (C1-C3alkoxygroup), more preferably a methoxy group or ethoxypropan (C1-C2alkoxygroup), and particularly preferably a methoxy group.

In the present invention, the term "halogenated C1-C6alkoxygroup" refers to a group in which 1 to 5 identical or different groups referred to above as the "halogen atom"that is attached to the group mentioned above as "C1-C6alkoxygroup". Examples of halogenated C1-C6alkoxygroup R is t cryptometer, trichlormethiazide, dipterocarp, dichloromethoxy, dibromochloro, formatexpr, 2,2,2-triptracker, 2,2,2-trichlorethene, 2-chlorethoxyfos, 2-floridacheap and pentafluoropropyl, and halogenated C1-C6alkoxygroup preferably represents a group in which 1 to 5 identical or different groups referred to above as the "halogen atom"that is attached to the group mentioned above as "C1-C4alkoxygroup" (halogenated C1-C4alkoxygroup), more preferably a group in which 1 to 5 identical or different groups referred to above as the "halogen atom"that is attached to the group mentioned above as "C1-C2alkoxygroup" (halogenated C1-C2alkoxygroup), and even more preferably cryptometer.

In the present invention, the term "group (C1-C6alkoxy)-(C1-C6alkyl)" refers to a group in which the group referred to above as "C1-C6alkoxygroup"attached to the group mentioned above as "C1-C6alkyl group". Examples (C1-C6alkoxy)-(C1-C6alkyl) groups include methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxyethanol group, butoxymethyl is inuu group, second-butoxymethyl group, tert-butoxymethyl group, 2-methoxyaniline group and 3-isopropoxypropylamine group, and (C1-C6alkoxy)-(C1-C6the alkyl group preferably is a group in which the group referred to above as "C1-C4alkoxygroup"attached to the group mentioned above as "C1-C4alkyl group ((C1-C4alkoxy)-(C1-C4alkyl) group, more preferably a group in which the group referred to above as "C1-C2alkoxygroup"attached to the group mentioned above as "C1-C2alkyl group ((C1-C2alkoxy)-(C1-C2alkyl) group, more preferably methoxymethyl group.

In the present invention, the term "(C1-C6alkoxy)-(C1-C6alkoxy) group" refers to a group in which the group referred to above as "C1-C6alkoxygroup"attached to the group mentioned above as "C1-C6alkoxygroup". Examples (C1-C6alkoxy)-(C1-C6alkoxy) group include methoxyethoxy, ethoxyethoxy, proximitysensor, butoxyethoxy, 2-methoxyethoxy and 3-isopropoxypropylamine, and (C1-C6alkoxy)-(C1-C6alkoxy) group is and preferably represents a group in which the group referred to above as "C1-C4alkoxygroup"attached to the group mentioned above as "C1-C4alkoxygroup" ((C1-C4alkoxy)-(C1-C4alkoxy) group, more preferably a group in which the group referred to above as "C1-C2alkoxygroup"attached to the group mentioned above as "C1-C2alkoxygroup" ((C1-C2alkoxy)-(C1-C2alkoxy group), more preferably methoxyethoxy.

In the present invention, the term "C2-C7acylcarnitine group" refers to a group in which the group referred to above as "C1-C6alkyl group", is connected with the carbonyl group. Examples of C2-C7alkylcarboxylic group include acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, pentanoyl group, pivaloyloxy group and valerino group, and C2-C7acylcarnitine group preferably is a group in which the group referred to above as "C1-C4alkyl group", is connected with the carbonyl group (C2-C5alkylcarboxylic group), more preferably acetyl group or propenyloxy group (C2-C3alkylcarboxylic group), and even more preferably the acetyl group.

In the present invention, the term "C2-C7alkoxycarbonyl group" refers to a group in which the group referred to above as "C1-C6alkoxygroup", is connected with the carbonyl group. Examples of C2-C7alkoxycarbonyl groups include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxyethanol group, sec-butoxycarbonyl group and tert-butoxycarbonyl group, and C2-C7alkoxycarbonyl group preferably is a group in which the group referred to above as "C1-C4alkoxygroup", is connected with the carbonyl group (C2-C5alkoxycarbonyl group), more preferably methoxycarbonyl group or ethoxycarbonyl group (C2-C3alkoxycarbonyl group), more preferably methoxycarbonyl group.

In the present invention, the term "C2-C7alkylcarboxylic" refers to a group in which a carbonyl group is attached to the group mentioned above as "C1-C6alkyl group linked to the oxygen atom. Examples of C2-C7alkylcarboxylic include acetochlor, propionyloxy, butere is oxygraph, isobutyryloxy, partnershop, pivaloyloxy, valeriansoup and isovaleraldehyde, and C2-C7alkylcarboxylic preferably represents a group in which a carbonyl group is attached to the group mentioned above as "C1-C4alkyl group linked to the oxygen atom (C2-C5alkylcarboxylic), more preferably acetoxy or propionyloxy (C2-C3alkylcarboxylic), more preferably acetoxy.

In the present invention, the term "C2-C7alkoxycarbonyl" refers to a group in which a carbonyl group is attached to the group mentioned above as "C1-C6alkoxygroup", connected with an oxygen atom. Examples of C2-C7alkoxycarbonylmethyl include methoxycarbonylamino, ethoxycarbonylmethoxy, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonylamino, sec-butoxycarbonylamino and tert-butoxycarbonylamino, and C2-C7alkoxycarbonylmethyl preferably represents a group in which a carbonyl group to which is attached the above-mentioned "C1-C4alkoxygroup", connected with an oxygen atom, a (C2-C alkoxycarbonylmethyl), more preferably methoxycarbonylamino or ethoxycarbonylmethoxy (C2-C3alkoxycarbonylmethyl), more preferably methoxycarbonylamino.

In the present invention, the term "mono-C1-C6alkylamino" refers to a group in which the group referred to above as "C1-C6alkyl group attached to the amino group. Examples of mono-C1-C6alkylamino include methylaminopropyl, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, intellimorph, isopentylamine, 2-methylbutylamine, neopentylene, 1-ethylpropylamine, hexylamino and isohexanoate, and mono-C1-C6alkylamino preferably represents a group in which the group referred to above as "C1-C4alkyl group attached to the amino group (mono-C1-C4alkylamino), more preferably methylaminopropyl or ethylamino (mono-C1-C2alkylamino), more preferably methylaminopropyl.

In the present invention, the term "halogenated mono-C1-C6alkylamino" refers to a group in which the group mentioned above as "halogenated C 1-C6alkyl group attached to the amino group. Examples of halogenated mono-C1-C6alkylamino include triptoreline, trichloromethylmercapto, diftormetilirovaniya, Dichlorotoluene, dibromochloropropane, formatimaging.com, 2,2,2-triptoreline, 2,2,2-trichlorethylene, 2-bromethylamine, 2-chloroethylamines and 2-foretelling, and mono-(halogenated C1-C6alkyl)amino group preferably is a group in which the group referred to above as "halogenated C1-C4alkyl group attached to the amino group (halogenated mono-C1-C4alkylamino), more preferably a group in which the group referred to above as "halogenated C1-C2alkyl group attached to the amino group (halogenated mono-C1-C2alkylamino), even more preferably 2-chloroethylamino.

In the present invention, the term "di(C1-C6alkyl)amino group" refers to a group in which two identical or different groups mentioned above as "C1-C6alkyl group attached to the amino group. Examples of di(C1-C6alkyl)amino group include dimethylaminopropyl, diethylaminopropyl, dipropylamino the PU, diisopropylamino, dibutylamino, diisobutylamine, dimetilaminovogo, diisobutylamine, dineopentyl, Vexillology, N-ethyl-N-methylaminopropyl, N-methyl-N-propylamino, N-isopropyl-N-methylaminopropyl, N-butyl-N-methylaminopropyl, N-isobutyl-N-methylaminopropyl, N-methyl-N-pentylamine, N-isopentyl-N-methylaminopropyl, N-ethyl-N-propylamino, N-ethyl-N-isopropylamino, N-butyl-N-ethylamino and N-ethyl-N-isopentylamine, and di(C1-C6alkyl)amino group preferably is a group in which two identical or different groups mentioned above as "C1-C4alkyl group attached to the amino group (di(C1-C4alkyl)amino group), more preferably dimethylaminopropyl, diethylaminopropyl or N-ethyl-N-methylaminopropyl (di(C1-C2alkyl)amino group), more preferably dimethylaminopropyl.

In the present invention, the term "halogenated CI-C1-C6alkylamino" refers to a group in which two identical or different groups mentioned above as "halogenated C1-C6alkyl group attached to the amino group. Examples of the "halogenated di(C1-C6alkyl)amino group" include di-(trifluoromethyl)amino, di-(formati is)amino group, di-(2,2,2-trichloroethyl)amino group, di(2-chloroethyl)amino and N-(2-chloroethyl)-N-(2-foradil)amino group, and halogenated di(C1-C6alkyl)amino group preferably is a group in which two identical or different groups mentioned above as "halogenated C1-C4alkyl group attached to the amino group (halogenated di(C1-C4alkyl)amino group), more preferably di-(2-chloroethyl)amino group.

In the present invention, the term "C1-C6allylthiourea" refers to a group in which the group referred to above as "C1-C6alkyl group, connected to the sulfur atom, and a represents a linear or branched allylthiourea containing from 1 to 6 carbon atoms. Examples of C1-C6ancilliary include metalcorp, ethylthiourea, PropertyGroup, isopropylthio, butylthiourea, isobutylthiazole, sec-butylthiourea, intelligroup, 1-ethylpropylamine and vexillographer, and C1-C6allylthiourea preferably represents a linear or branched allylthiourea containing from 1 to 4 carbon atoms (C1-C4allylthiourea), more preferably metalcorp or ethylthiourea (C1-C2allylthiourea), even more preferably matitiahu the PU.

In the present invention, the term "C1-C6alkylsulfonyl group" refers to a group in which the group referred to above as "C1-C6alkyl group attached to sulfonyloxy group and represents a linear or branched alkylsulfonyl group containing from 1 to 6 carbon atoms. Examples of C1-C6alkylsulfonyl groups include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylphenyl group, butylsulfonyl group, isobutylamino group, sec-butylsulfonyl group and pentylaniline group, and C1-C6alkylsulfonyl group preferably represents a linear or branched alkylsulfonyl group containing from 1 to 4 carbon atoms (C1-C4alkylsulfonyl group), more preferably methylsulfonyl group or ethylsulfonyl group (C1-C2alkylsulfonyl group), more preferably methylsulfonyl group.

In the present invention, the term "C3-C6cycloalkylcarbonyl group" refers to cyclopropylalanine group, cyclobutylmethyl group, cyclopentylmethyl group or cyclohexanesulfonyl group. C3-C6cycloalkylcarbonyl preferably represents ciprodropsinnoseforsinusbu group.

In the present invention, the term "C1-C6gidroksiatsyetanilida group" refers to a group in which the group referred to above as "C1-C6alkyl group to which is attached one hydroxyl group connected with sulfonyloxy group represents a linear or branched hydroxyacetylamino group containing from 1 to 6 carbon atoms. Examples of C1-C6hydroxyacetophenones groups include gidroksimetilfurfuralya group, 2-hydroxyethylsulphonic group, 1-hydroxyethylsulphonic group and 3-hydroxypropionitrile group, and C1-C6gidroksiatsyetanilida group preferably represents a linear or branched hydroxyacetylamino group containing from 1 to 4 carbon atoms (C1-C4hydroxyacetylamino group), more preferably gidroksimetilfurfuralya group or hydroxyethylsulphonic group (C1-C2hydroxyacetylamino group), more preferably gidroksimetilfurfuralya group.

In the present invention, the term "(C1-C6alkoxy)-(C1-C6alkylsulfonyl) group" refers to a group in which the group referred to above as "C1-C6alkoxygroup", connected with the group mentioned in the above as "C 1-C6alkylsulfonyl group". Examples (C1-C6alkoxy)-(C1-C6-alkylsulfonyl) groups include ethoxymethyleneamino group, ethoxymethyleneamino group, propoxymethyl group, isopropoxycarbonyl group, butoxyethoxyethanol group and second-butoxyethanol group, and (C1-C6alkoxy)-(C1-C6alkylsulfonyl) group is preferably a group in which the group referred to above as "C1-C4alkoxygroup", connected with the above-mentioned "C1-C4alkylsulfonyl group ((C1-C4alkoxy)-(C1-C4alkylsulfonyl) group, more preferably a group in which the above-mentioned "C1-C2alkoxygroup" connected with the above-mentioned "C1-C2alkylsulfonyl group ((C1-C2alkoxy)-(C1-C2alkylsulfonyl) group), more preferably ethoxymethyleneamino group.

In the present invention, the term "group of the formula-V-NR5R6(where V represents a carbonyl group or sulfonyloxy group, and R5and R6may be the same or different and respectively represent a hydrogen atom or a C1-C6alkyl group, or R5 and R6together with the nitrogen atom to which they are attached, form a 4-6-membered saturated, a heterocycle which may be substituted and may contain 1 or 2 substituent, independently selected from C1-C6alkyl group and hydroxyl group, and a 4-6-membered saturated the heterocycle may optionally contain one oxygen atom or nitrogen atom)" refers to the group of the formula-C(=O)-NR5R6or a group of the formula-SO2-NR5R6"where "a group of the formula-C(=O)-NR5R6" represents karbamoilnuyu group, mono-C1-C6alkylaminocarbonyl group (the group in which the amino group that is attached to the group mentioned above as "C1-C6alkyl group, connected to the carbonyl group)", "di(C1-C6alkyl)aminocarbonyl group (the group in which the amino group, is attached to two identical or different groups defined above as "C1-C6alkyl group, connected to a carbonyl group)or the group in which the nitrogen atom 4-6-membered saturated heterocycle which may be substituted and may contain 1 or 2 substituent, independently selected from C1-C6alkyl groups and hydroxyl groups (4-6-membered heterocyclic group with a fully restored saturation, which contains od is N. the nitrogen atom and may optionally contain one oxygen atom or one nitrogen atom), connected to the carbonyl group"and "group of the formula-SO2-NR5R6" represents sulfamoyl group, mono-C1-C6alkylaminocarbonyl group (the group in which the amino group that is attached to the group mentioned above as "C1-C6alkyl group, connected with sulfonyloxy group", "di(C1-C6alkyl)aminosulfonyl group (the group in which the amino group, is attached to two identical or different groups mentioned above as "C1-C6alkyl group, connected with sulfonyloxy group)"or "the group in which the nitrogen atom 4-6-membered saturated heterocycle which may be substituted and may contain 1 or 2 substituent, independently selected from C1-C6alkyl groups and hydroxyl groups (4-6-membered heterocyclic group with a fully restored saturation, which contains one nitrogen atom and may optionally contain one oxygen atom or nitrogen atom), connected with sulfonyloxy group". Examples of the above group include karbamoilnuyu group, methylaminomethyl group, ethylaminomethyl group, propylaminoethyl group, dimethylaminocarbonylmethyl group, diethylaminoethyl group, dipropylthiocarbamate group, N-ethyl-N-methylaminoethanol GRU is PU, N-methyl-N-propylaminoethyl group, (1-azetidinol)carbonyl group, (3-hydroxy-1-azetidine)carbonyl group, (1-pyrrolidinyl)carbonyl group, (4-morpholinyl)carbonyl group, (4-methyl-1-piperazinil)carbonyl group, sulfamoyl group, methylaminomethyl group, ethylaminomethyl group, propylaminosulfonyl group, dimethylaminomethyl group, diethylaminomethyl group, dipropylenetriamine group, N-ethyl-N-methylaminomethyl group, N-methyl-N-propylaminosulfonyl group and (1-azetidinol)sulfonyloxy group, and the above group preferably represents karbamoilnuyu group, methylaminomethyl group, dimethylaminocarbonylmethyl group, (1-azetidinol)carbonyl group, (1-pyrrolidinyl)carbonyl group, (4-morpholinyl)carbonyl group, (4-methyl-1-piperazinil)carbonyl group, methylaminomethyl group or a (1-azetidinol)sulfonyloxy group, more preferably dimethylaminocarbonylmethyl group, (1-azetidinol)carbonyl group, (1-pyrrolidinyl)carbonyl group, or (4-methyl-1-piperazinil)carbonyl group, even more preferably dimethylaminocarbonylmethyl group or a (1-azetidinol)carbonyl group.

In the present invention, the term "mono-C2-C7alkylcarboxylic is a" refers to the group in which the carbonyl group is attached to the group mentioned above as "C1-C6alkyl group, connected to the amino group. Examples of mono-C2-C7alkylcarboxylic include acetaminoph, ethylcarbodiimide, propylnitrosamine, isopropylcarbodiimide, BUTYLCARBAMATE and isobutyleneisoprene, and mono-C2-C7alkylcarboxylic preferably represents a group in which a carbonyl group is attached to the group mentioned above as "C1-C4alkyl group, connected to the amino group (mono-C2-C5alkylcarboxylic), more preferably acetaminoph or ethylcarbodiimide (mono-C2-C3alkylcarboxylic), more preferably acetaminoph.

In the present invention, the term "mono-C1-C6alkylaminocarbonyl" refers to a group in which a carbonyl group is attached to the amino group connected to the group mentioned above as "C1-C6alkyl group linked to the oxygen atom.

Examples of mono-C1-C6alkylaminocarbonyl include methylaminoacetaldehyde, ethylenedicarboxylic, propylenecarbonate, Isopropylamine is veloxigrup and butylaminoethyl, and mono-C1-C6alkylaminocarbonyl preferably represents methylaminoacetaldehyde or ethylenedicarboxylic (mono-C1-C2alkylaminocarbonyl), more preferably methylaminoacetaldehyde.

In the present invention, the term "di(C1-C6alkyl)aminocarbonylmethyl" refers to a group in which a carbonyl group is attached to the amino group connected to two identical or different groups mentioned above as "C1-C6alkyl group linked to the oxygen atom. Examples of di(C1-C6alkyl)aminocarbonylmethyl include dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, dipropylenetriamine, N-ethyl-N-methylaminoacetaldehyde and N-methyl-N-propylenecarbonate, and di(C1-C6alkyl)aminocarbonylmethyl preferably represents dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl or N-ethyl-N-methylaminoacetaldehyde (di(C1-C2alkyl)aminocarbonylmethyl), more preferably dimethylaminocarbonylmethyl.

In the present invention, the term "mono-C2-C7alkoxycarbonylmethyl" refers to a group in which a carbonyl group, to which also is Diana group, mentioned above as "C1-C6alkoxygroup", connected to the amino group. Examples of mono-C2-C7alkoxycarbonylmethyl include methoxycarbonylamino, ethoxycarbonylmethoxy, propoxycarbonyl, isopropoxycarbonyl and butoxycarbonylamino, and mono-C2-C7alkoxycarbonylmethyl preferably represents methoxycarbonylamino or ethoxycarbonylmethoxy (C2-C3alkoxycarbonylmethyl), more preferably methoxycarbonylamino.

In the present invention, the term "mono-C1-C6alkylsulfonamides" refers to a group in which sulfonylurea group that is attached to the group mentioned above as "C1-C6alkyl group, connected to the amino group. Examples of mono-C1-C6alkylsulfonamides include methylsulfonylamino, ethylsulfonylimidazo, propylsulfonyl, isopropylbenzylamine, butylsulfonyl, tert-butylsulfonyl and 2-ethylbutylamine, and mono-C1-C6alkylsulfonamides preferably represents a group in which sulfonylurea group that is attached to the group mentioned above as "C1-C4alkyl group", the soybean is inane with amino group (mono-C 1-C4alkylsulfonamides), more preferably methylsulfonylamino or ethylsulfonylimidazo (mono-C1-C2alkylsulfonamides), more preferably methylsulfonylamino.

In the present invention, the term "1,3,4-oxadiazol-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group" refers to a group in which C1-C6the alkyl group is a substituent in the 5-position of the 1,3,4-oxadiazol-2-ilen group. Examples of such groups include 5-methyl-1,3,4-oxadiazol-2-ilen group and 5-ethyl-1,3,4-oxadiazol-2-strong group, and the above-mentioned group preferably represents 5-methyl-1,3,4-oxadiazol-2-ilen group.

In the present invention, the term "1,3,4-thiadiazole-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group" refers to a group in which C1-C6the alkyl group is a substituent in the 5-position of 1,3,4-thiadiazole-2-ilen group. Examples of such groups include 5-methyl-1,3,4-thiadiazole-2-ilen group and 5-ethyl-1,3,4-thiadiazole-2-strong group, and the above-mentioned group preferably represents 5-methyl-1,3,4-thiadiazole-2-ilen group.

In the present invention, the term "heterocyclic group" refers to a 4-7-membered heterocyclic group is e, which contains from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms and may optionally contain 1 or 2 nitrogen atom, and in which the atom(s) sulfur can be connected with 2 atoms of oxygen. Examples of the heterocyclic group include aromatic heterocyclic group", such as furilla group, thienyl group, pyrrolidino group, sepanlou group, pyrazolidine group, imidazolidinyl group, oxazolidinyl group, isoxazolyl group, thiazolidine group, isothiazolinone group, 1,3,4-oxadiazolyl group, 1,3,4-thiadiazolyl group, triazolyl group, tetrazolyl group, thiadiazolyl group, pyranyloxy group, pyridyloxy group, pyridazinyl group, pyrimidinyl group and personilnya group, and heterocyclic group is partially or fully restored by saturation, such as tetrahydropyranyloxy group, tetrahydrocannibinol group, morpholinyl group, thiomorpholine group, pyrrolidinyl group, pyrrolidino group, imidazolidinyl group, pyrazolidine group, piperidinyl group, piperazinilnom group, oxazolidinyl group, oxazolidinyl group, isoxazolidinone group, thiazolidine group, diazolidinyl group, pyrazolidine group, DIOXOLANYL group, dioxinlike groups and 5,6-dihydro-4H-1,3-oxazino group, and the above heterocyclic group may be fused with another cyclic group, such as benzene ("condensed bicyclic heteroaryl group"), and represent, for example, benzothiazoline group, benzothiazolyl group, benzoxazolyl group, isobenzofuranyl group, 1,3-dihydroisobenzofuran group, pinolillo group, 1,3-benzodioxolyl group, 1,4-benzodioxolyl group, indolenine group, isoindolyl group and indolinyl group. Heterocyclic group formed by A and R1together with the carbon atom to which they are attached, which can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, preferably represent 2-pyridyloxy group, 5,6-dihydro-4H-1,3-oxazin-2-ilen group, 1,3-thiazol-2-ilen group, 1,3-oxazol-2-ilen group, 1,3,4-oxadiazol-2-ilen group, 1,3,4-thiadiazole-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-ilen group, or 1,3-benzothiazol-2-ilen group, more preferably 1,3-thiazol-2-ilen group, 1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-ilen group, 1,3,4-thiadiazole-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-ilen group, even more preferably, 4,5-dihydro-1,3-about Sasol-2-ilen group. In R2heterocyclic group is preferably a 6-membered heterocyclic group containing 1 or 2 nitrogen atom, more preferably pyridyloxy group or personilnya group, even more preferably 2-pyridyloxy group, 3-pyridyloxy group or 2-personilnya group.

In the present invention, the term "group of the formula =NOR4" refers to a group in which one hydroxyl group or one group mentioned above as "C1-C6alkoxygroup", connected with aminogroups. A group of the formula =NOR4preferably represents a group of formula =NOH.

In the present invention, the term "heterocyclic group formed by A and R1together with the carbon atom to which they are attached, which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α"refers to the group mentioned above as the "heterocyclic group", or to the group mentioned above as the "heterocyclic group"which is substituted and contains from 1 to 3 substituents independently selected from the group of substituents α. The above group preferably represents 2-pyridyloxy group, 5,6-dihydro-4H-1,3-oxazin-2-ilen group, 1,3-thiazol-2-ilen group, 1,3-oxazol-2-ilen group, 1,3,4-oxadiazol-2-ilen group, 1,3,4-tadias the l-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-ilen group, or 1,3-benzothiazol-2-strong group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents γ, more preferably 1,3-thiazol-2-ilen group, 5-methyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-strong group, 4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-4-hydroxy-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 5-carboxy-1,3-thiazol-2-ilen group, 5-dimethylaminoethyl-1,3-thiazol-2-ilen group, 5-methyl-l,3,4-thiadiazole-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-yl group, more preferably 4,5-dihydro-1,3-ox is evil-2-ilen group, (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-strong group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 1,3-thiazol-2-ilen group, 5-carboxy-1,3-thiazol-2-ilen group, 5-dimethylaminoethyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-thiadiazole-2-ilen group, 5-methyl-1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-ilen group, particularly preferably 4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-strong group, (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-m is Teal-4,5-dihydro-1,3-oxazol-2-ilen group or (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group.

In the present invention, the term "phenyl group which may be substituted and can contain from 1 to 5 substituents independently selected from the group of substituents α" refers to a phenyl group or a phenyl group containing from 1 to 5 substituents independently selected from the group of substituents α. The above group preferably represents a phenyl group which may be substituted and can contain from 1 to 5 substituents independently selected from the group of substituents δ, more preferably 4-acetylphenyl group, 4-(1-hydroxyethyl)phenyl group, 4-methylsulfinylphenyl group, 4-(1-azetidine)sulfonylamino group, 2-fluoro-4-ethoxycarbonylphenyl group, 4-carbarnoyl-2-florfenicol group, 2-fluoro-4-methylaminoethanol group, 4-dimethylaminoethyl-2-florfenicol group, 4-(1-azetidinol)carbonyl-2-florfenicol group, 2-fluoro-4-(1-pyrrolidinyl)Carboniferous group, 2-fluoro-4-(4-morpholinyl)Carboniferous group, 2-fluoro-4-methylaminoethanol group, 4-(1-azetidine)sulfonyl-2-florfenicol group, 2-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl group, 2-fluoro-4-(5-methyl-1,3,4-thiadiazole-2-yl)phenyl group, 4-(1-azetidine)carbonyl-2-methylphenylene group or 4-(1-azetidine)carbonyl-2-triftormetilfullerenov group, even more preferably 4-methylsulfinylphenyl the th group, 4-(1-azetidine)carbonyl-2-florfenicol group or 2-fluoro-4-(1-pyrrolidinyl)Carboniferous group, particularly preferably 4-methylsulfinylphenyl group.

In the present invention, the term "heterocyclic group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α in R2belongs to the group mentioned above as the "heterocyclic group" or the above-mentioned as the "heterocyclic group which is substituted and contains from 1 to 3 substituents independently selected from the group of substituents α". The above group preferably represents 2-pyridyloxy group, 3-pyridyloxy group or 2-personilnya group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents δ, more preferably 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group, 2-methylsulphonyl-5-pyridyloxy group, 5-(4-methyl-1-piperazinil)carbonyl-2-personilnya group, 2-methylaminomethyl-5-pyridyloxy group, 2-methylaminomethyl-5-pyridyloxy group or 5-methylsulphonyl-2-personilnya group, even more preferably 2-methylsulphonyl-5-pyridyloxy group, 5-methylsulphonyl-2-personilnya group or 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group.

In the present invention the General fo the mule (I) preferably represents a General formula (Ia).

In the present invention, A preferably represents a group of formula =NOH or an oxygen atom, more preferably an oxygen atom.

In the present invention R1preferably represents C1-C6alkyl group, a C1-C6alkoxygroup or halogenated mono-C1-C6alkylamino, more preferably methyl group or 2-chloroethylamino.

In the present invention the heterocyclic group formed by A and R1together with the carbon atom to which they are attached, which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, preferably represents 2-pyridyloxy group, 5,6-dihydro-4H-1,3-oxazin-2-ilen group, 1,3-thiazol-2-ilen group, 1,3-oxazol-2-ilen group, 1,3,4-oxadiazol-2-ilen group, 1,3,4-thiadiazole-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-ilen group, or 1,3-benzothiazol-2-strong group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents γ, more preferably 1,3-thiazol-2-ilen group, 5-methyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-strong group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl) - Rev. ing group, (5R)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-4-hydroxy-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 5-carboxy-1,3-thiazol-2-ilen group, 5-dimethylaminoethyl-1,3-thiazole-2-strong group, 5-methyl-1,3,4-thiadiazole-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-ilen group, even more preferably, 4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydro is simetal-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 1,3-thiazol-2-ilen group, 5-carboxy-1,3-thiazol-2-ilen group, 5-dimethylaminoethyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-thiadiazole-2-ilen group, 5-methyl-1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-ilen group, particularly preferably 4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group or (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group.

In the present invention R2preferably represents a phenyl group which may be substituted and can contain from 1 to 5 substituents independently selected from the group of substituents δ, or 2-pyridyloxy group, 3-pyridyloxy group or 2-personilnya group which may be substituted and can contain from 1 to 3 substituents independently selected from the group is amestitelj δ, more preferably 4-methylsulfinylphenyl group, 4-(1-azetidine)carbonyl-2-florfenicol group, 2-fluoro-4-(1-pyrrolidinyl)Carboniferous group, 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group, 2-methylsulphonyl-5-pyridyloxy group, 5-(4-methyl-1-piperazinil)carbonyl-2-personilnya group, 2-methylaminomethyl-5-pyridyloxy group, 2-methylaminomethyl-5-pyridyloxy group or a 5-methylsulphonyl-2-personilnya group, even more preferably 4-methylsulfinylphenyl group, 2-methylsulphonyl-5-pyridyloxy group, 5-methylsulphonyl-2-personilnya group or 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group.

In the present invention R3preferably represents a hydroxyl group or a methoxy group.

In the present invention R4preferably represents a hydrogen atom.

The compound or its pharmaceutically acceptable salt of General formula (I) according to the present invention has all the isomers (such as keto-enol isomer, diastereoisomer, optical isomer, rotamer etc).

The compound or its pharmaceutically acceptable salt of General formula (I) according to the present invention has various isomers due to the fact that the molecule has asymmetric(s) atom(s) of carbon. All of these isomers and mixtures of such isomers according to the present izopet who were represented by a single formula, in particular the General formula (I). Accordingly, the present invention includes all of these isomers and mixtures thereof in an arbitrary ratio.

The above stereoisomers can be obtained by synthesis of the compounds according to the present invention with an optically active starting compound, asymmetric synthesis, asymmetric method input or selection of the synthesized compounds according to the present invention the standard method of optical separation, or separation method, if necessary.

The compound or its pharmaceutically acceptable salt of General formula (Ia) according to the present invention is preferable compound or its pharmaceutically acceptable salt of General formula (Ib) according to the present invention.

The term "its pharmaceutically acceptable salt" refers to salts that do not have significant toxicity and can be used as pharmaceutical agents. The compound of General formula (I) according to the present invention can turn into a salt by reaction with acid, if the compound contains a basic group such as amino group, or interaction with the base when the compound contains an acidic group such as carboxyl group.

Examples of the salts polucen the x in the result of interaction with the main group, include salts of halogen acids, such as hydrohloride, hydrochloride, hydrobromide or hydroiodide, inorganic salts such as nitrates, perchlorates, sulfates or phosphates; C1-C6the alkyl sulphonates, such as methanesulfonate, triftoratsetata or econsultancy, arylsulfonate, such as benzosulfimide or p-toluensulfonate; organic acid salts such as acetates, malaty, fumarate, succinate, citrates, ascorbates, tartratami, oxalates or maleate; and salts of amino acids such as salts of glycine, lysine, arginine, ornithine, glutamic acid and aspartic acid.

On the other hand, examples of the salts obtained by the interaction with the acidic groups include metal salts, such as alkali metal salts, e.g. sodium, potassium salts or lithium salts, alkaline earth metals such as calcium salts or magnesium salts, salts of metals such as aluminum or iron; amine salts such as inorganic salts, for example, ammonium salts, or organic salts such as salts of tert-octylamine, dibenzylamine, research, glucosamine, phenylglycylamino ethers, Ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N' -dibenziletilendiaminom, chloroprocaine, procaine, diethanolamine, N-benzylphenol the amine, piperazine, Tetramethylammonium or Tris(hydroxymethyl)aminomethane; and salts of amino acids such as salts of glycine, lysine, arginine, ornithine, glutamic acid and aspartic acid.

The compound or its pharmaceutically acceptable salt of General formula (I) according to the present invention can turn into hydrate the introduction of molecules (molecules) of water during curing compounds in the atmosphere or recrystallization, and such hydrates are also included in the definition of the salts according to the present invention.

The compound or its pharmaceutically acceptable salt of General formula (I) according to the present invention can turn into a MES in the absorption solvent of a different type, and such a solvate is also included in the definition of the salts according to the present invention.

In the present invention, the term "metabolic syndrome" refers to a painful condition, which is based on insulin resistance and which has a higher risk of coronary artery disease due to the accumulation of multiple risk factors of coronary vessels (including diseases of lifestyle, such as hyperlipemia, diabetes, obesity and hypertension) (Diabetes, Obesity and Metabolism, 9, 2007, 246-258; Journal of the American Medical Association, 285, 2486-2497 (2001); Diabet. Med., 15, 539-553 (1998)).

The effect of the invention

The compound of General formula (I) according to the present invention or its pharmaceutically acceptable salt has excellent activity of GC activation and applicable(a) as a pharmaceutical for the prophylaxis and/or treatment of disease, selected from the group including diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macroangioapthy) and metabolic syndrome in warm-blooded animals (preferably mammals, including humans). In addition, a new compound of General formula (I) according to the present invention or its pharmaceutically acceptable salt has excellent activity of GC activation and applicable as an active ingredient of pharmaceutical products for the prevention and/or treatment of the above diseases in warm-blooded animals (preferably mammals, including humans). Preferred examples of the diseases include diabetes and impaired glucose tolerance. The compound of General formula (I) according to the present invention or its pharmaceutically acceptable salt may preferably be used as a pharmaceutical for the treatment of the above diseases.

The BEST WAY of carrying out the INVENTION

The compound of General formula (I) according to the present invention can be obtained according to methods A-L, described below.

There are no special restrictions on the use of solvent in reacceptance of the stages of the following methods a to L if the solvent to some extent dissolves the starting material without influence on the reaction and, for example, selected from the group of solvents, are presented below. The group of solvents include hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin or cyclohexane; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl-2-pyrrolidinone or hexamethylphosphorotriamide; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylethylenediamine; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, 2-methyl-1-propanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; sulfoxidov, such as dimethyl sulfoxide; sulfones, such as sulfolane; NITRILES, such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate or diethylmalonate; ketones, such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone or cyclohexanone; nitro compounds such as nitroethane or nitrobenzene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform or tetrachlorophenol; aromatizes the e hydrocarbons, such as benzene, toluene or xylene; carboxylic acids such as acetic acid, formic acid, propionic acid, butyric acid or triperoxonane acid; amines such as N-methylmorpholine, triethylamine, Tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinedione, picoline, 4-dimethylaminopyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or piperidine; water; and mixtures thereof.

Examples of bases applicable in the reactions of each of the stages of the following methods of synthesis And L include inorganic bases such as carbonates of alkali metals, e.g. sodium carbonate, potassium carbonate, lithium carbonate or cesium carbonate; bicarbonates of alkali metals, e.g. sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; the acetates of alkali metals, e.g. sodium acetate, potassium acetate, lithium acetate or cesium acetate; hydrides of alkali metals such as lithium hydride, sodium hydride or potassium hydride; hydroxides of alkali metals such as sodium hydroxide, hydroxide potassium, barium hydroxide or lithium hydroxide; and alkali metal fluorides, such as sodium fluoride or fluoride to the lia; alkoxides of alkali metals, e.g. sodium methoxide, ethoxide sodium tert-piperonyl sodium, potassium methoxide, ethoxide potassium tert-piperonyl potassium or lithium methoxide; trialkylsilyl alkali metals, for example, trimethylsiloxy sodium, trimethylsiloxy potassium or trimethylsiloxy lithium; mercaptans alkali metals, for example, thiamethoxam sodium or titoxd sodium; organic bases, for example, N-methylmorpholine, triethylamine, Tripropylamine, tributylamine, N,N-diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinedione, picoline, 4-dimethylaminopyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); ORGANOMETALLIC base, for example, n-utility, diisopropylamide lithium or bis(trimethylsilyl)amide and lithium; and amino acids, such as Proline.

Examples of the condensing agents used in the reactions of each stage of the following methods of synthesis of A-L, include hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (HATU), cyclic anhydride 1-papapostolou acid (TR), dicyclohexylcarbodiimide (into), the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide (WSCI-HCl), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDl), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (DMT-MM), isobutylparaben (IBCF), 1,1' -carbonyl-bis-1H-imidazole (CDI), diethylthiophosphate (DEPC), diphenylphosphide (DPPA), N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide and dipyridamole, and they can be used in the presence of 1-of hydroxybenzotriazole (HOBt) or monohydrate of 1-hydroxybenzotriazole, if necessary.

Examples demetrious agents used in the reactions of each stage of the following methods of synthesis of A-L, include thiamethoxam sodium, titoxd sodium, thiophenoxide sodium, attributively, aluminum chloride, aluminum bromide, tribromide boron, triode boron, iodide Metalmania and hydrogen bromide.

Examples of palladium catalysts used in the reactions of each stage of the following methods of synthesis of A-L, include palladium catalysts with a degree of oxidation of palladium zero or palladium catalysts with a degree of oxidation equal to two, such as tetrakis(triphenylphosphine)palladium(0), palladium on charcoal, palladium(II)acetate, triptorelin palladium(II), palladium black, palladium bromide(II), palladium chloride(II)iodide, palladium (II)cyanide, palladium(II)nitrate, palladium(II)oxide palladium(II)sulfate, palladium(II), dichlorobis(acetonitrile) ballad is I(II), dichlorobis(benzonitrile) palladium(II)dichloro-(1, 5cyclooctadiene) palladium(II), palladium acetylacetone(II), sulfide, palladium(II)dichloride, [1,1' -bis(diphenylphosphino)ferrocene] palladium(II), Tris(dibenzylideneacetone)dipalladium(0), tetrafluoroborate tetrakis(acetonitrile) palladium(II) and dimers of artilharia and palladium.

Temperature reactions of each of the stages of the following ways of obtaining And L vary depending on the solvent, the starting materials, reagents and the like, while the duration of the reaction varies depending on the solvent, the starting materials, reagents, reaction temperature, etc.

In the reactions of each of the stages of the following ways of obtaining And L each target connection stands out from the reaction mixture after completion of the reaction in accordance with standard methods. The target connection receive, for example, as follows. The reaction mixture is appropriately neutralized, and insoluble substances, if present, is removed by filtration. Then add water and is not miscible organic solvent, such as ethyl acetate, and the organic layer containing the target compound is separated. The organic layer is washed with water or similar solvent and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous bicarbonato the sodium or the like and filtered. Then the solvent is evaporated. The obtained target compound may be produced and purified, if necessary, a suitable combination of conventional methods, for example, by methods appropriate for the isolation and purification of organic compounds, such as recrystallization, re-precipitation and elution with a suitable eluent in the application of chromatography. The target compound is not soluble in the solvent can be purified by washing the resulting crude solid product with a solvent. Obtained at each stage of the target compound can also be used in subsequent reactions without further purification.

Method a is a method of obtaining compounds of General formula (Ic), where R3represents a C1-C6alkoxygroup specified connection relates to compounds of General formula (I).

In the present invention, R1and R2take the values defined above, R3brepresents a C1-C6alkoxygroup, X represents a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom, more preferably a bromine atom), Y represents a halogen atom, a C1-C6alkylsulfonates,1-C6alkoxycarbonylmethyl or6-C10aresult is lexigraphy (preferably a halogen atom, more preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom), andand, R1aand R2arepresent the group in which the amino group, hydroxyl group and/or carboxyl group is present as substituents in the A, R1and R2are optionally protected or accept the values defined for the groups A, R1and R2.

Stage A1

This stage represents the stage of obtaining compounds of General formula (III).

This stage is carried out by the interaction of the compounds of General formula (II) with the demethylation agent in a solvent.

The compound of General formula (II)used in this stage is either a known compound or compound obtained in accordance with a known method or a method similar to a known method using a known compound as a starting material.

The solvent used in this stage is preferably an amide, more preferably N-methyl-2-pyrrolidone.

The demethylation agent used in this stage, preferably represents thiamethoxam sodium.

The reaction temperature of this stage is typically in the range from 50 to 140°C, preferably from 80 to 120°C.

The duration of reaction this stage obynomartins in the range from 0.5 to 12 hours, preferably from 1 to 5 hours.

Stage A2

This stage represents the stage of obtaining compounds of General formula (V).

This stage is carried out by the interaction of the compounds of General formula (III) with a compound of General formula (IV) in a solvent and in the presence of a base.

The compound of General formula (IV)used in this stage is either a known compound or compound obtained in accordance with a known method or a method similar to a known method using a known compound as a starting material.

The solvent used in this stage is preferably an amide, preferably N,N-dimethylformamide.

The base used in this stage is preferably a carbonate of an alkali metal, preferably potassium carbonate.

The reaction temperature of this stage is typically in the range from 50 to 140°C, preferably from 80 to 120°C.

Duration of response of this stage is typically in the range from 12 to 72 hours, preferably from 24 to 48 hours.

Stage A3

This stage represents the stage of obtaining compounds of General formula (VI).

This stage is carried out by the interaction of the compounds of General formula (V) with demetrious agent in a solvent.

R is storytell, used in this stage is preferably a halogenated hydrocarbon, preferably dichloromethane.

Demetrious agent used in this stage, preferably represents tribromide boron.

The reaction temperature of this stage is typically in the range from -100 to 40°C., preferably from -78 to 25°C.

Duration of response of this stage is typically in the range from 1 to 72 hours, preferably from 12 to 36 hours.

Stage A4

This stage represents the stage of obtaining compounds of General formula (VII).

This stage is carried out by the interaction of the compounds of General formula (VI) with bis(pinacolato)diboron in a solvent and in the presence of a palladium catalyst and an inorganic base.

The solvent used in this stage is preferably an amide, preferably N,N-dimethylformamide.

The palladium catalyst used in this stage, preferably represents a catalyst of divalent palladium, more preferably complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane.

The inorganic base used in this stage, preferably represents an alkali metal acetate, preferably potassium acetate.

Tempera is ur reaction this stage is usually in the range from 50 to 130°C, preferably from 70 to 110°C.

The duration of this stage reaction is usually from 1 to 24 hours, preferably from 2 to 10 hours.

Stage A5

This stage represents the stage of obtaining compounds of General formula (IX).

This stage is carried out by the interaction of the compounds of General formula (VII) with a compound of General formula (VIII) in a solvent and in the presence of triphenylphosphine and diethylazodicarboxylate.

The compound of General formula (VIII)used in this stage, and its optical isomers are either known compounds, or compounds obtained in accordance with a known method or a method similar to a known method using a known compound as a starting material.

The solvent used in this stage, preferably is a simple ether, more preferably tetrahydrofuran.

The reaction temperature of this stage is typically in the range from -20 to 40°C, preferably from 0 to 25°C.

Duration of response of this stage is usually from 0.5 to 72 hours, preferably from 1 to 36 hours.

Stage A6

This stage represents the stage of obtaining compounds of General formula (XI) and compounds of General formula (Ic).

This stage is carried out by the interaction of the compounds of General formula (IX) in connection with the discharge of the General formula (X) in a solvent and in the presence of a palladium catalyst and an inorganic base, followed by removal of the protective group of amino group, hydroxyl group and/or carboxyl group in Aa, R1aand R2awhen it is necessary.

The solvent used in this stage, preferably is a simple ether, aromatic hydrocarbon, alcohol, water or a solvent, representing a mixture thereof, more preferably dioxane, toluene, ethanol, water or a mixture of dioxane and water, or a mixture of toluene, ethanol and water.

The palladium catalyst used in this stage, preferably represents a catalyst of divalent palladium, more preferably complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane.

The inorganic base used in this stage is preferably a carbonate of an alkali metal, preferably potassium carbonate.

The reaction temperature of this stage is typically in the range from 25 to 100°C, preferably from 40 to 70°C.

Duration of response of this stage is usually from 0.5 to 12 hours, preferably from 1 to 5 hours.

Stage A7

This stage represents the stage of obtaining compounds of General formula (Ic).

This stage is carried out by the interaction of the compounds of General formula (XI) with an acid in a solvent.

The solvent used in this stage is preferably with the battle halogenated hydrocarbon, more preferably dichloromethane.

The acid used in this stage is, for example, hydrogen halides), such as gaseous hydrogen chloride or gaseous hydrogen bromide; mineral acids such as sulfuric acid, Hydrobromic acid or hydrochloric acid; organic sulfonic acids, such as methanesulfonate acid, p-toluensulfonate acid, p-toluensulfonate pyridinium (PPTS), camphorsulfonic acid or triftormetilfullerenov acid; carboxylic acids such as acetic acid, formic acid or triperoxonane acid; a Lewis acid such as aluminum chloride, zinc chloride, zinc iodide, tin tetrachloride, trichloride titanium TRIFLUORIDE boron, tribromide boron or methyl sulfate; or an acidic ion-exchange resin, preferably carboxylic acid, more preferably triperoxonane acid.

The reaction temperature of this stage is typically in the range from -20 to 60°C, preferably from 0 to 40°C.

Duration of response of this stage is usually from 0.1 to 5 hours, preferably from 0.5 to 3 hours.

The method is a method of obtaining compounds of General formula (Ic), where R3represents a C1-C6alkoxygroup specified connection relates to compounds of General formula (I).

In this invention A, R1, R2, R3b, Aa, R1, R2aX and Y take the values defined above.

Stage B1

This stage represents the stage of obtaining compounds of General formula (XII).

This stage is carried out by the interaction of the compounds of General formula (III)obtained in the above stage A1 of the way And, with the compound of General formula (VIII) in a solvent and in the presence of triphenylphosphine and diethylazodicarboxylate.

The solvent used in this stage, preferably represents an aromatic hydrocarbon, more preferably toluene.

The reaction temperature of this stage is typically in the range from -20 to 40°C, preferably from 0 to 25°C.

Duration of response of this stage is usually from 0.1 to 72 hours, preferably from 0.5 to 36 hours.

Stage B2

This stage represents the stage of obtaining compounds of General formula (XIII).

This stage is carried out, as described above stage A1 of the way And, by the interaction of the compounds of General formula (XII) with a demethylation agent.

Stage B3

This stage represents the stage of obtaining compounds of General formula (XIV).

This stage is carried out, as described above stage A4 ways And, by the interaction of the compounds of General formula (XIII) with the IP(pinacolato)diboron in a solvent and in the presence of a palladium catalyst and an inorganic base.

Stage B4

This stage represents the stage of obtaining compounds of General formula (XV).

This stage is carried out, as described above stage A6 ways And, by the interaction of the compounds of General formula (XIV) with a compound of General formula (X) in a solvent and in the presence of a palladium catalyst and an inorganic base.

Stage B5

This stage represents the stage of obtaining compounds of General formula (XI) and compounds of General formula (Ic).

This stage is carried out by the interaction of the compounds of General formula (XV) with a compound of General formula (IV) in a solvent and in the presence of base, followed by removal of the protective group of amino group, hydroxyl group and/or carboxyl group in Aa, R1aand R2aif it is necessary.

The solvent used in this stage, preferably represents a sulfoxide or amide, more preferably dimethyl sulfoxide or N,N-dimethylformamide.

The base used in this stage, preferably represents an alkali metal hydride or carbonate of an alkali metal, preferably sodium hydride or potassium carbonate.

The reaction temperature of this stage is typically in the range from 50 to 140°C, preferably from 80 to 120°C.

The duration of reaction this stage usually with the hat from 1 to 72 hours, preferably from 3 to 36 hours.

The method is a method of obtaining compounds of General formula (Ic), where R3represents a C1-C6alkoxygroup specified connection relates to compounds of General formula (I).

In the present invention A, R1, R2, R3b, Aa, R1a, R2aand X take the values defined above, and R7represents a C1-C6alkyl group (preferably n-boutelou group).

Stage C1

This stage represents the stage of obtaining compounds of General formula (XVI).

This stage is carried out, as described above stage B1 of the way, the interaction of the compounds of General formula (VI)obtained in the above stage A3 of the way And, with the compound of General formula (VIII) in a solvent and in the presence of triphenylphosphine and diethylazodicarboxylate.

Stage C2

This stage represents the stage of obtaining compounds of General formula (XVII).

This stage is carried out by the interaction of the compounds of General formula (XVI) c 1-(tert-butoxycarbonyl)pyrrol-2-Bronevoy acid in a solvent in the presence of a palladium catalyst, triphenylphosphine and inorganic bases.

The solvent used in this stage, preferably represents Rostow ether, water or a mixture thereof, more preferably dimethoxyethane, water, or their mixture, preferably a mixture of dimethoxyethane and water.

The palladium catalyst used in this stage, preferably represents a catalyst of divalent palladium, more preferably palladium(II)acetate.

The base used in this stage is preferably a carbonate of an alkali metal, preferably potassium carbonate.

The reaction temperature of this stage is usually in the range of from 40 to 100°C, preferably from 60 to 90°C.

The duration of this stage reaction is usually from 1 to 72 hours, preferably from 3 to 24 hours.

Stage C3

This stage represents the stage of obtaining compounds of General formula (XVIII).

This stage is carried out by the interaction of the compounds of General formula (XVII) with a halogenation agent in a solvent.

The solvent used in this stage, preferably is a simple ester or a simple mixture of ether and alcohol, more preferably tetrahydrofuran or a mixture of tetrahydrofuran and methanol.

Halogenation agent used in this stage is, for example, inorganic acid such as hydrochloric acid, Hydrobromic acid or uudistoodetena acid; Molek is Lou halogen, such as chlorine, bromine or iodine; or succinimide, such as N-chlorosuccinimide, N-bromosuccinimide or N-jodatime, preferably succinimide, more preferably N-bromosuccinimide.

The reaction temperature of this stage is typically in the range from -20 to 40°C, preferably from 0 to 25°C.

Duration of response of this stage is usually from 0.5 to 24 hours, preferably from 1 to 12 hours.

Stage C4

This stage represents the stage of obtaining compounds of General formula (XI).

This stage is carried out by the interaction of the compounds of General formula (XVIII) with a compound of General formula (XIX) in a solvent and in the presence of a palladium catalyst, followed by removal of the protective group of amino group, hydroxyl group and/or carboxyl group in Aa, R1aand R2aif it is necessary.

The compound of General formula (XIX)to be used in this stage is either a known compound or compound obtained in accordance with a known method or a method similar to a known method using a known compound as a starting material.

The solvent used in this stage, preferably represents an aromatic hydrocarbon, more preferably toluene.

The palladium catalyst used in this is Tadei, preferably represents a catalyst of palladium with a zero oxidation state, preferably tetrakis(triphenylphosphine)palladium(0).

The reaction temperature of this stage is usually in the range from 90 to 130°C, preferably from 100 to 120°C.

The duration of this stage reaction is usually from 1 to 72 hours, preferably from 3 to 24 hours.

Stage C5

This stage represents the stage of obtaining compounds of General formula (Ic).

This stage is carried out, as well as stage A7 ways And, by the interaction of the compounds of General formula (XI) with an acid.

Stage C6

This stage represents the stage of obtaining compounds of General formula (Ic).

This stage is carried out by the interaction of the compounds of General formula (XVIII) with a compound of General formula (XX) in a solvent and in the presence of a palladium catalyst and an inorganic base, followed by removal of the protective group of amino group, hydroxyl group and/or carboxyl group in Aa, R1aand R2aif it is necessary.

The compound of General formula (XX)used in this stage is either a known compound or compound obtained in accordance with a known method or a method similar to a known method using a known connection quality is TBE source of the substance.

The solvent used in this stage, preferably is a simple ether, water, or their mixture, more preferably dimethoxyethane, water or a mixture thereof, more preferably a mixture of dimethoxyethane and water.

The palladium catalyst used in this stage, preferably represents a catalyst of divalent palladium, more preferably complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane.

The inorganic base used in this stage is preferably a carbonate of an alkali metal, preferably potassium carbonate.

The reaction temperature of this stage is typically in the range from 60 to 120°C, preferably from 80 to 100°C.

The duration of this stage reaction is usually from 1 to 480 hours, preferably from 12 to 240 hours.

Method D is a method of obtaining compounds of General formula (Ie), where R3represents a hydroxyl group, the specified connection relates to compounds of General formula (I).

In the present invention Aa, R1aand R2atake the values defined above.

Stage D1

This stage represents the stage of obtaining compounds of General formula (Ie).

This stage is Samadashvili compounds of General formula (Id), where R3brepresents a methoxy group, which relates to the compounds of General formula (Ic) and obtained in the above stage A6 method As described above stage A7 method As described above stage B5 method described above C5 stage of the method described above stage C6 of the way, with the demethylation agent in a solvent.

The solvent used in this stage is preferably a halogenated hydrocarbon, preferably dichloromethane.

The demethylation agent used in this stage, preferably represents attributively or tribromide boron, more preferably tribromide boron.

The reaction temperature of this stage is typically in the range from -100 to 40°C., preferably from -78 to 25°C.

Duration of response of this stage is usually from 0.05 to 12 hours, preferably from 0.1 to 3 hours.

Method E is a method of obtaining compounds of General formula (X)used in the above-described stage A6 method As in the above-described stage stage B4 Century

In the present invention Aa, R1aand X take the values defined above.

Stage E1

This stage represents the stage of obtaining compounds of General formula (XXIII).

This stage is also the AC and phase described above C2 method C, the interaction of 1-(tert-butoxycarbonyl)pyrrol-2-boron acid (XXI) with a compound of General formula (XXII) in a solvent and in the presence of a palladium catalyst, triphenylphosphine and inorganic bases.

1-(tert-Butoxycarbonyl)pyrrol-2-baronova acid (XXI), used in this stage, obtained in accordance with a known method or a method similar to a known method using a known compound as a starting material.

The compound of General formula (XXII), used in this stage is either a known compound or compound obtained in accordance with a known method or a method similar to a known method using a known compound as a starting material.

Stage E2

This stage represents the stage of obtaining compounds of General formula (X).

This stage is carried out, as described above stage C3 of the way, the interaction of compounds of General formula (XXIII) with a halogenation agent in a solvent.

Method F is a method of obtaining compounds of General formula (X)used in the above-described stage A6 fashion and stage B4 method C.

In this invention Aa, R1aand X take the values defined above.

The F1 stage

Dunn is I the stage represents the stage of obtaining compounds of General formula (XXV).

This stage is carried out, as described above stage C3 of the way, the interaction of compounds of General formula (XXIV) with a halogenation agent in a solvent.

The compound of General formula (XXIV), is used in this stage is either a known compound or compound obtained in accordance with a known method or a method similar to a known method using a known compound as a starting material.

Stage F2

This stage represents the stage of obtaining compounds of General formula (X).

This stage is carried out by the interaction of the compounds of General formula (XXV) with di-tert-BUTYLCARBAMATE in a solvent and in the presence of a base.

The solvent used in this stage is preferably a halogenated hydrocarbon, preferably dichloromethane.

The base used in this stage is preferably an organic base, more preferably triethylamine, 4-dimethylaminopyridine or a mixture thereof, more preferably a mixture of triethylamine and 4-dimethylaminopyridine.

The reaction temperature of this stage is usually from -20 to 40°C, preferably from 0 to 25°C.

Duration of response of this stage is usually from 0.1 to 12 hours, preferably from 0.5 mm to 3 hours.

Method G is a method of obtaining compounds of General formula (X)used in the above-described stage A6 method As in the above-described stage B4 method C.

In the present invention Aa, R1aand X take the values defined above.

Stage G1

This stage represents the stage of obtaining compounds of General formula (XXVII).

This stage is carried out, as described above stage C3 of the way, the interaction of tert-butylphenol-1-carbonate (XXVI) with a halogenation agent in a solvent.

Tert-butylphenol-1-carbonate (XXVI)used in this stage are in accordance with the known method or a method similar to a known method using a known compound as a starting material.

Stage G2

This stage represents the stage of obtaining compounds of General formula (X).

This stage is carried out by the interaction of the compounds of General formula (XXVII) with a compound of General formula (XXII) in a solvent and in the presence of a base.

The solvent used in this stage, preferably is a simple ether, preferably diethyl ether.

The base used in this stage is preferably an ORGANOMETALLIC base, more predpochtite the flax n-utility.

The reaction temperature of this stage is typically in the range from -100 to 40°C., preferably from -78°C to 25°C.

Duration of response of this stage is usually from 0.5 to 24 hours, preferably from 1 to 12 hours.

The compound of General formula (I), where a and R1together with the carbon atom to which they are attached, form a heterocyclic group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, can also be obtained in accordance with the method, which ultimately leads to the formation of heterocyclic rings. For example, methods H and I represent the ways, when the heterocyclic group represents a 4,5-dihydro-1,3-oxazol-2-ilen group or a 1,3,4-oxadiazol-2-ilen group. Other heterocyclic groups just can be obtained in accordance with the same methods.

Method H is a method of obtaining compounds of General formula (If), where the heterocyclic group formed by a and R1together with the carbon atom to which they are attached, can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, represents a 4,5-dihydro-1,3-oxazol-2-strong group which may be substituted and can contain from 1 to 3 substituents, independently is selected from the group of substituents α, and R3represents a C1-C6alkoxygroup specified connection relates to compounds of General formula (I).

In the present invention R2, R3band R2atake the values defined above, R8, R9, R10and R11represent a hydrogen atom or a group belonging to the group of substituents α, and R8a, R9a, R10aand R11arepresent the group in which the amino group, hydroxyl group and/or carboxyl group is contained as substituents in the groups R8, R9, R10and R11are optionally protected amino group, a hydroxyl group and/or carboxyl group, or accept the values defined for group R8, R9, R10and R11.

Stage N1

This stage represents the stage of obtaining compounds of General formula (XXX).

This stage is carried out by the interaction of the compounds of General formula (XXVIII) with a compound of General formula (XXIX) in a solvent in the presence of a condensing agent and in the presence or in the absence of base.

The compound of General formula (XXIX)used in this stage is either a known compound or compound obtained in accordance with a known method or a method similar to sistemu method, with the use of known compounds as the starting material.

The solvent used in this stage is preferably an alcohol, a halogenated hydrocarbon or an amide, more preferably methanol, dichloromethane or N,N-dimethylformamide.

The condensing agent used in this stage, preferably represents a DMT-MM, WSCl·HCl or HATU.

The base used in this stage is preferably an organic base, preferably N-methylmorpholine, 4-dimethylaminopyridine or N,N-diisopropylethylamine.

The reaction temperature of this stage is typically in the range from -20 to 60°C, preferably from 0 to 30°C.

Duration of response of this stage is usually from 0.5 to 72 hours, preferably from 1 to 24 hours.

Stage N2

This stage represents the stage of obtaining compounds of General formula (If).

This stage is carried out by the interaction of the compounds of General formula (XXX) with a base and anhydride methanesulfonic acid or TRIFLUORIDE bis-(2-methoxyethyl)uminosity in a solvent, followed by removal of the protective group of amino group, hydroxyl group and/or carboxyl group in R2a, R8a, R9a, R10aand R11a.

The solvent used in this stage, preferably pre is is a simple ester, more preferably tetrahydrofuran or dimethoxyethane.

In the case of anhydride methanesulfonic acid base used in this stage is preferably an organic base, more preferably triethylamine. In the case of applying TRIFLUORIDE bis-(2-methoxyethyl)uminosity base preferably is a carbonate of an alkali metal, preferably potassium carbonate.

The reaction temperature of this stage is typically in the range from -100°C to 85°C, in the case of anhydride methanesulfonic acid is preferably in the range from 10°C to 60°C. In the case of applying TRIFLUORIDE bis-(2-methoxyethyl)uminosity the reaction temperature is preferably in the range from -78 to 30°C.

Duration of response of this stage is usually from 0.5 to 72 hours, preferably from 1 to 24 hours.

Method I is a method of obtaining compounds of General formula (Ig), where the heterocyclic group formed by a and R1together with the carbon atom to which they are attached, which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, represents a 1,3,4-oxadiazol-2-strong group which may be substituted and can contain 1 Deputy selected from the group of substituents α, the R 3represents a C1-C6alkoxygroup specified connection relates to compounds of General formula (I).

In the present invention R2, R3b, R8, R2aand R8atake the values defined above.

Stage I1

This stage represents the stage of obtaining compounds of General formula (XXXII).

This stage is carried out, as described above stage N1 ways, the interaction of the compounds of General formula (XXVIII) with a compound of General formula (XXXI) in a solvent in the presence of a condensing agent and in the presence or in the absence of base.

The compound of General formula (XXXI), is used in this stage is either a known compound or compound obtained in accordance with a known method or a method similar to a known method using a known compound as a starting material.

Stage I2

This stage represents the stage of obtaining compounds of General formula (Ig).

This stage is carried out by the interaction of the compounds of General formula (XXXII) with p-toluensulfonate and a base in a solvent followed by removal of the protective group of amino group, hydroxyl group and/or carboxyl group in R2aand R8aif it is necessary.

The solution is tel, used in this stage is preferably a halogenated hydrocarbon, preferably dichloromethane.

The base used in this stage is preferably an organic base, more preferably triethylamine.

The reaction temperature of this stage is typically in the range from -20 to 40°C, preferably from 0 to 30°C.

Duration of response of this stage is usually from 0.5 to 24 hours, preferably from 1 to 12 hours.

The way J is a method of obtaining compounds of General formula (XXVIII)used in the above-described stage N1 of way N, in the above-described phase I1 of the way I and in the following stage L1 method L.

In the present invention R2a, R3bX and Y take the values defined above.

Stage J1

This stage represents the stage of obtaining compounds of General formula (XXXIV).

This stage is carried out, as described above stage A6 ways And, by the interaction of the compounds of General formula (XIV)obtained in the above stage B3 of the way In, with the compound of General formula (XXXIII) in a solvent in the presence of a palladium catalyst and an inorganic base.

Stage J2

This stage represents the stage of obtaining compounds of General Faure the uly (XXXV).

This stage is carried out by the interaction of the compounds of General formula (XXIV) with a compound of General formula (IV) in a solvent and in the presence of a base.

The solvent used in this stage is preferably an amide or nitrile, more preferably N,N-dimethylformamide or acetonitrile.

The base used in this stage is preferably a carbonate of an alkali metal, preferably potassium carbonate.

The reaction temperature of this stage is typically in the range from 50 to 140°C, preferably from 60 to 100°C.

The duration of this stage reaction is usually from 1 to 72 hours, preferably from 2 to 24 hours.

Stage J3

This stage represents the stage of obtaining compounds of General formula (XXXVI).

This stage is carried out, as described above stage A7 ways And, by the interaction of the compounds of General formula (XXXV) with acid.

Stage J4

This stage represents the stage of obtaining compounds of General formula (XXVIII).

This stage is carried out by the interaction of the compounds of General formula (XXXVI) in a solvent and in an atmosphere of hydrogen in the presence of palladium catalyst.

The solvent used in this stage, preferably is a simple ether, alcohol or ester, more is predpochtitelno tetrahydrofuran, methanol, ethanol or ethyl acetate.

The palladium catalyst used in this stage, preferably represents a catalyst of palladium zero valence, more preferably palladium on charcoal.

The reaction temperature of this stage is typically in the range from -10 to 40°C, preferably from 0 to 30°C.

Duration of response of this stage is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours.

Way To is a method of obtaining compounds of General formula (Ih), where the heterocyclic group formed by a and R1together with the carbon atom to which they are attached, can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, represents a 4,5-dihydro-1,3-oxazol-2-strong group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, or 1,3,4-oxadiazol-2-strong group which may be substituted and can contain 1 Deputy, is independently selected from the group of substituents α, and R3represents a C1-C6alkoxygroup specified connection relates to compounds of General formula (I).

In the present invention R2, R3b, Y and R2atake the values defined above, and 12represents a 4,5-dihydro-1,3-oxazol-2-strong group which may be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, or 1,3,4-oxadiazol-2-strong group which may be substituted and can contain 1 Deputy selected from the group of substituents α.

Stage K1

This stage represents the stage of obtaining compounds of General formula (XXXVII).

This stage is carried out, as described above stage A7 ways And, by the interaction of the compounds of General formula (XXXIV)obtained in the above stage J1 method J with acid in a solvent.

Stage K2

This stage represents the stage of obtaining compounds of General formula (XXXVIII).

This stage is carried out by the interaction of the compounds of General formula (XXXVII) with triisopropylsilane in a solvent and in the presence of a base.

The solvent used in this stage is preferably a halogenated hydrocarbon, preferably dichloromethane.

The base used in this stage is preferably an organic base, more preferably triethylamine or a mixture of triethylamine and 4-dimethylaminopyridine.

The reaction temperature of this stage is typically in the range from -10 to 40°C, preferably from 0 to 30°C.

Duration of response of this stage is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours.

Stage K3

This stage represents the stage of obtaining compounds of General formula (XXXIX).

This stage is carried out, as described above stage J4 method J, the interaction of compounds of General formula (XXXVIII) in a solvent and in an atmosphere of hydrogen in the presence of palladium catalyst.

Stage K4

This stage represents the stage of obtaining compounds of General formula (XXXX).

This stage is carried out in accordance with the method N (stage N1 stage N2) or I (stage I1 and stage I2).

Stage K5

This stage represents the stage of obtaining compounds of General formula (XXXXI).

This stage is carried out by the interaction of the compounds of General formula (XXXX) with tetrabutylammonium fluoride in a solvent.

The solvent used in this stage, preferably is a simple ether, more preferably tetrahydrofuran.

The reaction temperature of this stage is typically in the range from -10 to 40°C, preferably from 0 to 30°C.

Duration of response of this stage is usually from 0.1 to 12 hours, preferably from 0.5 to 3 hours.

Stage K6

This stage represents the stage of obtaining compounds of General f is rmula (Ih).

This stage is carried out by the interaction of the compounds of General formula (XXXXI) with a compound of General formula (IV) in a solvent and in the presence of base, followed by removal of the protective group of amino group, hydroxyl group and/or carboxyl group in R2awhen it is necessary.

The solvent used in this stage is preferably an amide or nitrile, more preferably N,N-dimethylformamide or acetonitrile.

The base used in this stage is preferably a carbonate of an alkali metal, preferably potassium carbonate or cesium carbonate.

The reaction temperature of this stage is typically in the range from 10 to 140°C, preferably from 20 to 120°C.

The duration of this stage reaction is usually from 1 to 72 hours, preferably from 2 to 24 hours.

The way L is a method of obtaining compounds of General formula (If), where the heterocyclic group formed by a and R1together with the carbon atom to which they are attached, can be substituted and can contain from 1 to 3 substituents independently selected from the group of substituents α, and represents a 4,5-dihydro-1,3-oxazol-2-strong group which may be substituted and can contain from 1 to 3 substituent independently selected from the group of substituents α, and R3PR is dstanley a 1-C6alkoxygroup specified connection relates to compounds of General formula (I).

In the present invention R2, R8, R9, R10, R11, R2a, R3b, R8a, R9a, R10a, R11aand Y take the values defined above.

Stage L1

This stage represents the stage of obtaining compounds of General formula (XXXXIII).

This stage is carried out, as described above stage N1 ways, the interaction of the compounds of General formula (XXVIII) with a compound of General formula (XXXXII) in a solvent and in the presence of a condensing agent and base.

The compound of General formula (XXXXII)used in this stage is either a known compound or compound obtained in accordance with a known method or a method similar to a known method using a known compound as a starting material.

Stage L2

This stage represents the stage of obtaining compounds of General formula (If).

This stage is carried out by the interaction of the compounds of General formula (XXXXIII) with a base in a solvent followed by removal of the protective group of amino group, hydroxyl group and/or carboxyl group in R2a, R8a, R9a, R10aand R11awhen it is necessary.

<> The solvent used in this stage, preferably is a simple ether, more preferably tetrahydrofuran.

The base used in this stage, preferably represents an alkali metal hydride, preferably sodium hydride.

The reaction temperature of this stage is typically in the range from -20 to 40°C, preferably from 0 to 25°C.

Duration of response of this stage is usually from 0.5 to 48 hours, preferably from 1 to 24 hours.

In the above description, the term "protective group" in the expression "optionally protected amino group", "optionally protected hydroxyl group" and "optionally protected carboxyl group" in the definition of Aa, R1a, R2a, R8a, R9a, R10aand R11arefers to a protective group that can be subjected to cleavage by chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis, which is typically used in the synthesis of organic compounds (see, for example, by T.W. Greene, et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

In the above descriptions, there are no special restrictions to the term "protective group" of the "optionally protected hydroxyl group" in the definitions of Aa, R1a, R2a, R8a, R9a, R10aand R11awhen the conditions is, she is a protective group of hydroxyl group used in the synthesis of organic compounds, and examples of such groups include "alkylcarboxylic groups, such as formyl group as defined above With2-C7alkylcarboxylic group, halogenated alkylcarboxylic groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and TRIFLUOROACETYL, alkoxycarbonyl groups, such as methoxyacetyl, and unsaturated alkylcarboxylic groups, such as acryloyl, propiolic, methacryloyl, crotonoyl, isocrotonic and (E)-2-methyl-2-butanol; "arylcarbamoyl groups, such as arylcarbamoyl groups such as the benzoyl, α-naphtol and β-naphtol, halogenated arylcarboxylic groups such as 2-bromobenzoyl and 4-chlorobenzoyl,1-C6alkylated arylcarbamoyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl,1-C6alkoxysilane arylcarbamoyl groups such as 4-anisoyl, nitroacetanilide groups such as 4-nitrobenzoyl and 2-nitrobenzoyl,2-C7alkoxycarbonylmethyl arylcarbamoyl groups such as 2-(methoxycarbonyl)benzoyl, and allrounda arylcarbamoyl groups such as 4-phenylbenzyl; "alkoxycarbonyl groups, such as the aforementioned "C2-C7alkoxycarbonyl group", and2 -C7alkoxycarbonyl group substituted with halogen or three(C1-C6alkyl)silicom, such as 2,2,2-trichlorocarbanilide and 2-trimethylsilylethynyl group; "tetrahydropyranyloxy or tetrahydropyranyloxy groups, such as tetrahydropyran-2-yl, 3-bromotetradecane-2-yl, 4-methoxyacridine-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytryptamine-4-yl; "tetrahydropyranyloxy" or "tetrahydropyranyloxy group"such as tetrahydrofuran-2-yl and tetrahydrofuran-2-yl; "silyl groups", such as three(C1-C6alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, methyldiisopropanolamine, methyl-di-tert-Boticelli and triisopropylsilyl, and (C1-C6alkyl)derisorily and di-(C1-C6alkyl)arylimino groups, such as diphenylmethylene, diphenylbutyric, diphenylethylene and phenyldimethylsilane; "alkoxymethyl groups, such as (C1-C6alkoxy)methyl group, for example, methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl and tert-butoxymethyl, (C1-C6alkoxy)-(C1-C6alkoxy)methyl group, such as 2-methoxyethoxymethyl, and (halogenated1-C6ALCO is si)methyl group, such as 2,2,2-trichloroacetyl and bis(2-chloroethoxy)methyl; "substituted ethyl group such as a (C1-C6alkoxy)ethyl groups such as 1-ethoxyethyl and 1-(isopropoxy)ethyl and halogenated ethyl group such as 2,2,2-trichloroethyl; "kalkilya groups, such as C1-C6alkyl groups, substituted from 1 to 3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthylmethyl and 9-antimetal, and C1-C6alkyl groups, substituted from 1 to 3 aryl substituents, in which aryl cycle is substituted and contains as Deputy1-C6alkyl, C1-C6alkoxygroup, a nitrogroup, halogen or cyano, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylalanine, 2-nitrobenzyl, 4-nitrobenzyl, 4-Chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl; "altneratively groups, such as vinyloxycarbonyl and allyloxycarbonyl; and "aracelikarsaalyna group, in which aryl cycle is optionally substituted by 1 or 2 groups selected from C1-C6alkoxy - or nitro, such as benzyloxycarbonyl, 4-methoxybenzenesulfonyl, 3,4-dimethoxyphenylacetone, 2-nitrobenzenesulfonyl and 4 nitrobenzisoxazole is, preferably acylcarnitine group, silyl group or kalkilya group.

In the above description that follows there are no special restrictions to the term "protective group" of the "optionally protected carboxyl group" in the definitions of Aa, R1a, R2a, R8a, R9a, R10aand R11aprovided that it is a protective group of carboxyl group used in the synthesis of organic compounds, and examples of such groups include the above "C1-C6alkyl group"; the above "C2-C6alkenylphenol group"; the above "C2-C6alkylamino group"; the above "halogenated1-C6alkyl group; C1-C6hydroxyalkyl groups such as hydroxymethyl and 2-hydroxyethyl; and (C2-C7alkylsulphonyl)-(C1-C6alkyl) groups, such as acetylenyl; the above "kalkilya group" and the above "silyl group", preferably1-C6alkyl group or kalkilya group.

In the given above descriptions, there are no special restrictions to the term "protective group" of the "optionally protected amino group" in the definitions of Aa, R1a, R2a, R8a, R9a, R10aand R11aprovided that it is a protective group of amino group, use the emnd in the synthesis of organic compounds, and examples of such groups include groups similar to the "alkylcarboxylic groups", "arylcarbamoyl groups", "alkoxycarbonyl groups", "silyl groups", "Uralkali groups", "alkanolammonium groups" and "aracelikarsaalyna group" in the aforementioned "protective groups of the hydroxyl group"and "substituted methylene groups, which form the base of the Shift, such as N,N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylic, diphenylmethylene and (5-chloro-2-hydroxyphenyl)phenylmethylene, preferably acylcarnitine group, arylcarbamoyl group or alkoxycarbonyl group, more preferably alkoxycarbonyl group.

Stages that require protection/erase protection shall be conducted in accordance with known methods (for example, in accordance with the methods described in Theodora W. Greene, Peter G. M. Wuts, "Protective Groups in Organic Synthesis", 1999, A Wiley-Interscience Publication, etc).

The compound or its pharmaceutically acceptable salt according to the invention can be administered in various forms. Examples of routes of administration include oral administration using tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc. and parenteral administration using injections (intravenous, intramuscular, p is dkone or intraperitoneal), drip infusions, suppositories (rectal administration), etc. Such different drugs can be obtained in the form of medication in accordance with standard methods using, in addition to the active ingredient, auxiliary additives commonly used in the field of production of medicinal preparations, such as excipients, binders, dezintegriruetsja additives, additives that increase the slip, flavorings, additives to increase the solubility, suspendresume agents and additives that make up the floor.

When used in the form of tablets examples of media that can be used include fillers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone; dezintegriruetsja additives such as dry starch, sodium alginate, powdered agar, powdered laminaran, sodium bicarbonate, calcium carbonate, complex polyoxyethylenesorbitan esters of fatty acids, sodium lauryl sulfate, monoglycerides of stearic acid, starch and lactose; disintegration inhibitors such the AK sucrose, stearin, cacao butter and gidrirovannoe oil; additives that increase the absorption, such as Quaternary ammonium salts and sodium lauryl sulfate; humectants such as glycerin and starch; binders such as starch, lactose, kaolin, bentonite and colloidal silicic acid; additives that increase the slip, such as purified talc, stearate, powder barterisation acid, polyethylene glycol, etc. in Addition, if necessary, can be normally obtained coated tablets, such as tablets, coated sugar pellets with a gelatinous coating, with intersolubility coated tablets, film-coated, double-layer tablets and multi-layered tablets.

When used in the form of pills examples of media that can be used include fillers such as glucose, lactose, cocoa butter, starch, gidrirovannoe vegetable oil, kaolin and talc; binders such as powdered gum Arabic, powdered tragakant, gelatin and ethanol; disintegrant, such as laminaran and agar, etc.

When used in the form of a suppository can be used with a wide range of media known in this field, and examples of such carriers include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.

PR is used in the form of injection preparations can be represented in the form of solutions, emulsions or suspensions. Preferably, these solutions, emulsions and suspensions are sterilized and isotonic relative to blood. The solvents to obtain these solutions, emulsions and suspensions are not specifically limited if they can be used for medical purposes as a diluent, and examples of such solvents include water, ethanol, propylene glycol, ethoxylated isostearoyl alcohol, polioksidony isostearoyl alcohol, complex polyoxyethylenesorbitan fatty acids, etc. In this case, the drug may be added a sufficient quantity of sodium chloride, glucose or glycerin to produce isotonic and traditional additives that increase the dissolution, buffers, sedatives, etc.

In addition, in the above preparation may be added colorants, preservatives, perfumes, flavors, sweeteners, etc. In the above preparation can also be added to other medicines.

In the above preparations, the number of connections, which is an active ingredient, are not specifically limited, but is usually from 0.5 to 70% (mass.) the whole composition, preferably from 1 to 30% (mass.).

The dose varies depending on symptoms, age, etc. of the patient (teplokrov what about the animal, in particular, human). In the case of oral administration the lower limit of the recommended daily dose for adults is 0.1 mg (preferably 1 mg, more preferably 10 mg), the upper limit of the recommended daily dose for an adult is up to 2000 mg, preferably 100 mg)indicated the recommended dose is divided in 1 to 6 doses, depending on symptoms.

Examples

Below is a more detailed description of the invention with examples, synthesis examples of biological tests, however, the scope of the present invention is not limited to the given examples.

Elution in column chromatography, specified in the examples is carried out with the control thin-layer chromatography (TLC). In the process of monitoring by TLC as the TLC plates using Silica Gel 60F254(Merck); the solvent used for elution in column chromatography, using as mobile phase and visualization using a UV detector. As a silica gel column using Silica Gel SK-85 (230-400 mesh mesh) manufactured by Merck or Silika Gel FL100B proizvodstva Fuji Silysia Chemical. In addition to the traditional column chromatography using automated chromatographic system (Purif-α2) and remote column (Purif-pack) manufactured by Moritex. For purification preparative TLC using a plate of Silica Gel 60F24 thickness of 0.5 mm and a size of 20x20 cm (Merck). In addition, the abbreviations used in the examples, have the following meanings: mg: milligrams; g: grams; ml: milliliter; MHz: megahertz; HATU: hexaphosphate O-(7-asobancaria-1-yl)-N,N,N' ,N' -tetramethylurea; WSCI·HCl: hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide; NOUT.H2About: monohydrate of 1-hydroxybenzotriazole.

In the following examples, the spectra of nuclear magnetic resonance (1H-NMR) is obtained using tetramethylsilane as standard, and the values of chemical shifts are reported in units of δ (ppm). Charts splitting of the singlet designated as "C", double - "d", the triplet is t, the Quartet kV, broadened peak "ush.", multiplet - "m".

Mass spectrometry (MS) is conducted by the method of fast atom bombardment (FAS), electron ionization (EI) or ionization of electrospray (ESI).

Example 1

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

(1a) 3-Bromo-5-methoxyphenol

Commercially available 1-bromo-3,5-dimethoxybenzene (18,74 g, 86,3 mmol) dissolved in 1-methyl-2-pyrrolidone (100 ml), add thiamethoxam sodium (6,74 g of 96.2 mmol) and the resulting mixture was stirred at 100°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room t is mperature, add 1 N. hydrochloric acid (200 ml) and the mixture extracted with diethyl ether (500 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-25%), obtaining the target compound (15,03 g, yield 86%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 3.77 (3H, s), 4,82 (1H, s), 6,33 (1H, t, J=2.4 Hz), is 6.61 (1H, t, J=2.0 Hz), 6,66 (1H, t, J=2.0 Hz).

(1b) 1-Bromo-3-methoxy-5-[4-(methylsulphonyl)phenoxy]benzene

3-Bromo-5-methoxyphenol (13,10 g, and 64.5 mmol)synthesized in example (1a), and commercially available 4-performership (10,45 g, 60,0 mmol) is dissolved in N,N-dimethylformamide (100 ml), add potassium carbonate (25,00 g, 181 mmol) and the resulting mixture was stirred at 100°C for 36 hours in a nitrogen atmosphere. The reaction solution is cooled to room temperature, the potassium carbonate is removed by filtration through celite, add 0.1 N. hydrochloric acid (500 ml) and the mixture was twice extracted with diethyl ether (400 ml) and ethyl acetate (100 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure, and the obtained solid residue was washed with diethyl ether, receiving relevo the connection (18,30 g, yield 79%) as a solid pale brown color.

1H-NMR (CDCl3, 400 MHz): δ of 3.07 (3H, s), of 3.80 (3H, s), 6,56 (1H, t, J=2.4 Hz), for 6.81 (1H, t, J=2.0 Hz), 6,92 (1H, t, J=2.0 Hz), 7,12 (2H, d, J=9.0 Hz), 7,92 (2H, d, J=9.0 Hz).

(1c) 3-Bromo-5-[4-(methylsulphonyl)phenoxy]phenol

1-Bromo-3-methoxy-5-[4-(methylsulphonyl)phenoxy]benzene (18,29 g, a 51.2 mmol)synthesized in example (1b)was dissolved in dichloromethane (400 ml) and cooled to -78°C and the resulting solution using a dropping funnel for 30 minutes in nitrogen atmosphere add tribromide boron (1,0M solution in dichloromethane, 100 ml, 100 mmol). The mixture was stirred at -78°C for 2 hours, then give the ability to spontaneously warm to room temperature and stirred at room temperature overnight. To the mixture while cooling in an ice bath, add saturated aqueous solution of sodium bicarbonate to neutralize the reaction solution and extracted twice with dichloromethane (500 ml) and methanol (50 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure, obtaining the target compound (16,89 g, yield 96%) as a solid pale yellow color.

1H-NMR (DMSO-D6, 400 MHz): δ 3,19 (3H, s), of 6.49 (1H, t, J=2.1 Hz), 6,77 (1H, t, J=2.0 Hz), at 6.84 (1H, t, J=2.0 Hz), 7.23 percent (2H, d, J=8.6 Hz), 7,94 (2H, d, 9.0 Hz), 10,27 (1H, s).

(1d) 3-[4-(Methylsulphonyl)the dryer is XI]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

3-Bromo-5-[4-(methylsulphonyl)phenoxy]phenol (10,10 g, 29.4 mmol)synthesized in example (1c), dissolved in N,N-dimethylformamide (100 ml), add bis(pinacolato)LIBOR (11,09 g, 43,7 mmol), complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) and dichloromethane (722 mg, 0,884 mmol) and potassium acetate (14,92 g, 152 mmol) and the resulting mixture was stirred at 90°C in for 5 hours in nitrogen atmosphere. After cooling to room temperature the solution was diluted with ethyl acetate (400 ml), and insoluble materials are removed by filtration through celite. To the filtrate add water (400 ml), after separation of the mixture of the organic layer is washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-50%)to give the target compound (11,88 g, yield ~100%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (12H, s), 3,06 (3H, s), 5,16 (1H, s), 6,69 (1H, t, J=2.4 Hz), 7,06 for 7.12 (4H, m), 7,87 (2H, t, J=9,0 Hz).

(1e) 2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

3-[4-(Methylsulphonyl)phenoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (13,20 g, 33.8 mmol)synthesized in example (1d), dissolved in tetrahydrofuran (300 ml), add (R)-(-)-1-methoxy-2-ol is panel (3,70 ml, 37.8 mmol) and triphenylphosphine (9,78 g of 37.3 mmol) and the resulting mixture is cooled to 0°C. To the mixture dropwise over 10 minutes under nitrogen atmosphere add diethylazodicarboxylate (40% solution in toluene of 16.2 ml, with 37.2 mmol), the mixture was stirred at 0°C for 30 minutes, after which enable the mixture to spontaneously warm to room temperature, and the mixture is stirred at room temperature overnight. To the reaction mixture are added water (300 ml) and ethyl acetate (300 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-40%), obtaining the target compound (11,94 g, yield 76%) as a colourless oil.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6,7 Hz)of 1.33 (12H, s), 3,05 (3H, s), 3,40 (3H, s), of 3.48 (1H, DD, J=4,3, 10,2 Hz), 3,57 (1H, DD, J=5,9, 10,2 Hz), 4,58-to 4.62 (1H, m), 6,76 (1H, t, J=2.4 Hz), 7,05-to 7.09 (3H, m), 7,24 (1H, d, J=2.4 Hz), 7,87 (2H, d, J=9.0 Hz).

(1f) of tert-Butyl 2-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate

Commercially available 1-(tert-butoxycarbonyl)pyrrol-2-Bronevoy acid (10,06 g of 47.7 mmol) was dissolved in a mixed solvent of 1,2-dimethoxyethane (150 ml) and water (25 ml), the resulting solution was added 2-bromothiazole (4,40 ml, 48.8 mmol), palladium(II) acetate (535 mg, of 2.38 mmol), three is edelfosine (2.50 g, at 9.53 mmol) and potassium carbonate (19,50 g, 141 mmol) and the resulting mixture was stirred at 90°C for 16 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (300 ml) and ethyl acetate (400 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-20%)to give the target compound (of 6.71 g, yield 56%) as oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.42 (9H, s), of 6.26 (1H, t, J=3,4 Hz), to 6.58 (1H, DD, J=1,6, 3.5 Hz), 7,37 (1H, d, J=3.1 Hz), 7,41 (1H, DD, J=1,6, 3.1 Hz), the 7.85 (1H, d, J=3.1 Hz).

(1g) of tert-Butyl 2-bromo-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate

tert-Butyl 2-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (6,70 g, 26.8 mmol)synthesized in example (1f), dissolved in tetrahydrofuran (100 ml) and cooled to 0°C. Under stirring in nitrogen atmosphere N-bromosuccinimide (4,79 g, 26.9 mmol) is divided into 5 parts, which add every 10 minutes and the resulting mixture was stirred at 0°C for 2 hours. To the mixture is added saturated aqueous sodium hydrogen carbonate solution (200 ml) and the mixture extracted with ethyl acetate (300 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent of Otho Aut under reduced pressure, and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-16%), obtaining the target compound (of 7.55 g, yield 86%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.47 (9H, s), 6,30 (1H, d, J=3,9 Hz), of 6.52 (1H, d, J=3,9 Hz), 7,29 (1H, d, J=3.1 Hz), 7,79 (1H, d, J=3.1 Hz).

(1h) tert-Butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (6,44 g, a 13.9 mmol)synthesized in example (1e), and tert-butyl 2-bromo-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (to 5.21 g, 15.8 mmol)synthesized in example (1g), dissolved in a mixed solvent of 1,4-dioxane (200 ml) and water (50 ml), add complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (564 mg, 0,691 mmol) and potassium carbonate (9,67 g, 70,0 mmol) and the resulting mixture was stirred at 50°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, the reaction solution was added water (200 ml) and the mixture extracted with ethyl acetate (400 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, e is yuushi solvent: ethyl acetate/hexane=30%-50%), receiving the target connection (7,12 g, yield 88%) as oil pale yellow color.

1H-NMR (CDCl3, 500 MHz): δ is 1.31 (9H, s)of 1.32 (3H, d, J=6.4 Hz), 3,05 (3H, s), 3,40 (3H, s), 3,49 (1H, DD, J=3,9, 10,3 Hz)to 3.58 (1H, DD, J=5,9, 10,3 Hz), 4.53-in-of 4.57 (1H, m), 6,27 (1H, d, J=3,9 Hz), to 6.58 (1H, d, J=3,9 Hz), of 6.65 (1H, s), 6,72 (1H, s), 6.89 in (1H, s), to 7.15 (2H, d, J=8,8 Hz), 7,31 (1H, d, J=3,4 Hz), 7,81 (1H, d, J=3,4 Hz), 7,89 (2H, d, J=8,8 Hz).

(1i) 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

tert-Butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (7,16 g, 12.2 mmol)synthesized in example (1h), dissolved in dichloromethane (15 ml) and the resulting solution was cooled to 0°C. To the solution under stirring in nitrogen atmosphere add triperoxonane acid (30 ml). The mixture is stirred at room temperature for 30 minutes, then at 40°C for 30 minutes. The solvent is distilled off under reduced pressure, the obtained residue was diluted with ethyl acetate (300 ml), add saturated aqueous solution of sodium bicarbonate (200 ml) and the resulting mixture is separated. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-50%)to give the target compound (5,21 g, yield 88%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 3.07 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=3,9, 10,2 Hz)and 3.59 (1H, DD, J=5,9, 10,2 Hz), 4,55-4,60 (1H, m), 6,53-6,56 (2H, m), of 6.73 (1H, DD, J=2,4, 3.5 Hz), 6,85 (1H, t, J=2.0 Hz), 7,02 (1H, t, J=2.0 Hz), 7,14 (2H, d, J=8.6 Hz), 7,17 (1H, d, J=3.5 Hz), to 7.67 (1H, d, J=3.5 Hz), to $ 7.91 (2H, d, J=8.6 Hz), 9,60 (1H, USS).

MS (ESI) m/z: 485,12291 (M+H)+.

Example 2

(2S)-2-{3-[4-(Methylsulphonyl)phenoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}propan-1-ol

In nitrogen atmosphere 2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole (88,8 mg, 0,183 mmol)synthesized in example (1i), dissolved in dichloromethane (5 ml) and to the mixture at -78°C, add a solution of tribromide boron/dichloromethane (1,0M, 220 μl, 0.22 mmol). Next, the mixture is heated to room temperature and stirred for 30 minutes. Add saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-50%)to give the target compound (52,2 mg, yield 61%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=63 Hz), of 3.07 (3H, s), 3,76-with 3.79 (2H, m), 4,56 (1H, DD, J=10,6, 6.3 Hz), 6,52-6,55 (2H, m), 6,74 (1H, DD, J=3,7, 2,5 Hz), 6.87 in (1H, t, J=1,8 Hz), 7,01 (1H, t, J=1,8 Hz), 7,14 (2H, d, J=9.0 Hz), to 7.68 (1H, d, J=3.5 Hz), to $ 7.91 (2H, dt, J=9,5, and 2.3 Hz), 9,73 (1H, s).

MS (FAB) m/z: 471 (M+H)+.

Example 3

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3-thiazole

(3a) 2-[1-(Triisopropylsilyl)-1H-pyrrol-2-yl]-1,3-thiazole

2-(1H-Pyrrol-2-yl)-1,3-thiazole (1.42 g, to 9.45 mmol), described in the scientific literature {Eur. J. Org. Chem (European Journal of Organic Chemistry), vol. 2000, no. 13, 2449-2458 (2000)}, is dissolved in N,N-dimethylformamide (100 ml) and the resulting solution was cooled to 0°C. To the solution was added sodium hydride (60% oil, 570 mg of 14.3 mmol) and triisopropylsilane (4,0 ml, to 18.7 mmol) and the mixture is stirred under nitrogen atmosphere at room temperature for 30 minutes. To the reaction solution was added water (100 ml) and diethyl ether (100 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: hexane)to give the target compound (2,33 g, yield 80%) as oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ 1,09 (18H, d, J=7,4 Hz), 1,74 (3H, m), 6,30 (1H, t, J=3.1 Hz), 6,78 (1H, DD, J=1.5 and 3.1 Hz),? 7.04 baby mortality (1H, m), 7,13 (1H, d, J=3.1 Hz), of 7.64 1H, d, J=3.1 Hz).

(3b) 5-Methyl-2-[1-(triisopropylsilyl)-1H-pyrrol-2-yl]-1,3-thiazole

2-[1-(Triisopropylsilyl)-1H-pyrrol-2-yl]-1,3-thiazole (317 mg, 1,03 mmol)synthesized in example (3a)is dissolved in tetrahydrofuran (10 ml) and the solution cooled to -78°C. To the solution are added dropwise n-utility (2,64M solution in hexane, 0.51 ml, 1.35 mmol), the mixture is stirred for 40 minutes, then add logmean (0,13 ml of 2.09 mmol) and the mixture is stirred for 3 hours, allowing the mixture gradually heated from a temperature of -78°C to room temperature. To the mixture is added water (10 ml) and the mixture extracted with diethyl ether (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: hexane)to give the target compound (215 mg, yield 65%) as a colourless oil.

1H-NMR (CDCl3, 400 MHz): δ 1,09 (18H, d, J=7.8 Hz), at 1.73 (3H, m), is 2.44 (3H, s), 6,28 (1H, m), of 6.68 (1H, m),? 7.04 baby mortality (1H, m), 7,01 (1H, m), 7,27 (1H, USS).

(3c) of 5-Methyl-2-(1H-pyrrol-2-yl)-1,3-thiazole

5-Methyl-2-[1-(triisopropylsilyl)-1H-pyrrol-2-yl]-1,3-thiazole (215 mg, 0.67 mmol)synthesized in example (3b), dissolved in tetrahydrofuran (8 ml), added tetrabutylammonium fluoride (1M solution in tetrahydrofuran, of 0.87 ml, 0.87 mmol) and the resulting mixture is in ECENA stirred for 30 minutes at room temperature in a nitrogen atmosphere. To the mixture is added water (10 ml) and the mixture extracted with diethyl ether (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=5%-30%)to give the target compound (100 mg, yield 91%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 2.46 (3H, s), and 6.25 (1H, m), is 6.61 (1H, m), 6.87 in (1H, m), 7,30 (1H, USS), 9,68 (1H, USS).

(3d) 2-(5-Bromo-1H-pyrrol-2-yl)-5-methyl-1,3-thiazole

5-Methyl-2-(1H-pyrrol-2-yl)-1,3-thiazole (100 mg, 0.61 mmol)synthesized in example (3c), dissolved in tetrahydrofuran (7 ml) and the solution cooled to 0°C. To the resulting solution was added N-bromosuccinimide (108 mg, 0.61 mmol) and the mixture is stirred at room temperature under nitrogen atmosphere for 18 hours. To the reaction mixture are added water (10 ml) and extracted with diethyl ether (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue used in the next stage without additional purification.

(3e) of tert-Butyl 2-bromo-5-(5-methyl-1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate

Crude purified product, 2-(5-bromo-1H-pyrrol-2-yl)-5-methyl-1,3-thiazole synthesis is qualified in example (3d), dissolved in dichloromethane (8 ml), the resulting solution was added di-tert-BUTYLCARBAMATE (165 mg, 1.35 mmol), triethylamine (of 0.18 ml, 1,29 mmol) and 4-dimethylaminopyridine (8.0 mg, 0,065 mmol) and the mixture is stirred under nitrogen atmosphere at room temperature for 1.5 hours. To the reaction mixture are added water (10 ml) and the mixture extracted with dichloromethane (10 ml). The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-20%)to give the target compound (172 mg, yield 84%, stage 2) in the form of a colorless oil.

1H-NMR (CDCl3, 400 MHz): δ to 1.48 (9H, s), 2,47 (3H, s), 6,28 (1H, d, J=3.5 Hz), of 6.45 (1H, d, J=3.5 Hz), 7,42 (1H, m).

(3f) 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3-thiazole

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (220 mg, 0,492 mmol)synthesized in example (1e), and tert-butyl 2-bromo-5-(5-methyl-1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (598 mg, 1,49 mmol)synthesized in example (3e), dissolved in 1,4-dioxane (10 ml)to the resulting mixture add complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (20.0 mg, 0,024 mmol) and an aqueous solution of carb is Nata sodium (3M, 0.33 ml, 0,990 mmol), after which the mixture was stirred in nitrogen atmosphere at 50°C for 20 hours. The reaction solution is cooled to room temperature, to the solution was added water (10 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

The resulting residue is dissolved in dichloromethane (10 ml) and the solution cooled to 0°C. To the solution under stirring in nitrogen atmosphere are added dropwise triperoxonane acid (10 ml). The mixture is stirred at room temperature for 30 minutes, then the solvent is distilled off under reduced pressure, the obtained residue was diluted with ethyl acetate (30 ml), add saturated aqueous solution of sodium bicarbonate (20 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-40%), obtaining the target compound (49,6 mg, yield 20%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), 2,46 (3H, USS), of 3.07 (3H, s)to 3.41 (3H, s), 3,50 (1H, DD, J=3,9, 10,2 Hz), 3,61 (1H, DD, J=5,9, 10,2 Hz), 4,56 (1H, m), 6,50-is 6.54 (2H, m), 6,63 (1H, DD, J=2,4, 3,9 Hz, 6,85 (1H, t, J=2.0 Hz), 7,02 (1H, t, J=2.0 Hz), 7,13 (1H, d, J=8.6 Hz), 7,29 (1H, t, J=2.0 Hz), of 7.90 (2H, d, J=8.6 Hz), of 9.89 (1H, USS).

MS (ESI) m/z: 521,11551 (M+Na)+.

Example 4

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-benzothiazol

(4a) of tert-Butyl 2-(1,3-benzothiazol-2-yl)-1H-pyrrole-1-carboxylate

Commercially available 1-(tert-butoxycarbonyl)pyrrol-2-Bronevoy acid (417 mg, to 1.98 mmol) dissolved in 1,2-dimethoxyethane (20 ml), the resulting solution was added 2-chloro-1,3-benzothiazole (0.25 ml, 2.02 mmol), palladium(II) acetate (23,0 mg, is 0.102 mmol), triphenylphosphine (105 mg, 0.400 mmol) and aqueous potassium carbonate solution (3M, 1.3 ml, 0,433 mmol) and the resulting mixture was stirred in nitrogen atmosphere at 100°C for 22 hours. The reaction solution is cooled to room temperature, add water (20 ml) and ethyl acetate (20 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-20%)to give the target compound (490 mg, yield 82%) as oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ to 1.38 (9H, s), 6,30 (1H, t, J=3.1 Hz), 6,72 (1H, DD, J=2.0 a, 3.1 Hz), 7,39 (1H, DDD, J=1,2, 7,0, 8.0 Hz), 7,46 (1H, DD, J=2.0 a, 3.1 Hz), 7,49 (1H, DDD, J=12, of 7.0, 8.0 Hz), 7,89 (1H, OSD, J=8.0 Hz), with 8.05 (1H, dt, J=1,2, 8.0 Hz).

(4b) of tert-Butyl 2-bromo-5-(1,3-benzothiazol-2-yl)-1H-pyrrole-1-carboxylate

tert-Butyl 2-(1,3-benzothiazol-2-yl)-1H-pyrrole-1-carboxylate (490 mg, and 1.63 mmol)synthesized in example (4a), dissolved in tetrahydrofuran (20 ml) and the resulting solution was cooled to 0°C. To the solution was added N-bromosuccinimide (290 mg, and 1.63 mmol) and the mixture is stirred under nitrogen atmosphere at room temperature for 14 hours. To the mixture is added water (20 ml) and the mixture extracted with diethyl ether (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-16%), obtaining the target compound (548 mg, yield 89%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.52 (9H, s), 6,34 (1H, d, J=3,9 Hz), 6,69 (1H, d, J=3,9 Hz), 7,37 (1H, dt, J=1,2, 8.0 Hz), 7,46 (1H, dt, J=1,2, 8.0 Hz), 7,86 (1H, OSD, J=8.0 Hz), to 7.93 (1H, OSD, J=8.0 Hz).

(4c) 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-benzothiazol

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (305 mg, 0,682 mmol)synthesized in example (1e), and tert-butyl 2-bromo-5-(1,3-benzothiazol-2-yl)-1H-pyrrole-1-carb is kilat (260 mg, China 0,686 mmol)synthesized in example (4b), dissolved in 1,2-dimethoxyethane (20 ml)to the resulting mixture add complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (28 mg, 0,034 mmol) and aqueous potassium carbonate solution (3M, of 0.44 ml of 1.32 mmol) and the resulting mixture was stirred in nitrogen atmosphere at 50°C for 17 hours. The reaction solution is cooled to room temperature, to the solution was added water (20 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

The resulting residue is dissolved in dichloromethane (10 ml) and the solution cooled to 0°C. To the solution under stirring in nitrogen atmosphere are added dropwise triperoxonane acid (10 ml). After stirring the reaction mixture at room temperature for 30 minutes, the solvent is distilled off under reduced pressure, the residue diluted with ethyl acetate (30 ml), add saturated aqueous solution of sodium bicarbonate (20 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%to 40%), receiving the target compound (174 mg, yield 48%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), of 3.07 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,61 (1H, DD, J=6,3, 10,2 Hz), 4,58 (1H, m), to 6.57 (1H, t, J=2.0 Hz), 6,60 (1H, DD, J=2.7, and a 3.9 Hz), to 6.88 (1H, DD, J=2,4, 3,9 Hz), 6,92 (1H, t, J=2.0 Hz), was 7.08 (1H, t, J=2.0 Hz), 7,13 (2H, d, J=8.6 Hz), 7,32 (1H, dt, J=1,2, 7,4 Hz), 7,44 (1H, OST, J=7,4 Hz), 7,83 (1H, OSD, J=7,4 Hz), to $ 7.91 (2H, d, J=8.6 Hz), 10,10 (1H, USS).

MS (ESI) m/z: 535,13653 (M+H)+.

Example 5

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylic acid

(5a) Ethyl-2-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-1,3-thiazole-5-carboxylate

Commercially available 1-(tert-butoxycarbonyl)pyrrol-2-Bronevoy acid (850 mg, 4.3 mmol) dissolved in 1,2-dimethoxyethane (30 ml), the resulting solution was added commercially available ethyl-2-bromo-1,3-thiazole-5-carboxylate (0,50 ml, 3.35 mmol), palladium(II) acetate (38,0 mg, 0,169 mmol), triphenylphosphine (176 mg, 0,671 mmol) and aqueous potassium carbonate solution (3M, 2,20 ml, 6,60 mmol) and the resulting mixture was stirred at 100°C for 14 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (30 ml) and ethyl acetate (40 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled the ri reduced pressure, and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-30%)to give the target compound (800 mg, yield 74%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.39 (3H, t, J=7,0 Hz)of 1.50 (9H, s), to 4.38 (2H, q, J=7.0 Hz), 6,28 (1H, DD, J=3.1 and 3.5 Hz), 6,79 (1H, DD, J=2,0, 3.5 Hz), the 7.43 (1H, DD, J=2.0 a, 3.1 Hz), 8,39 (1H, s).

(5b) Ethyl-2-[5-bromo-1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-1,3-thiazole-5-carboxylate

Ethyl-2-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-1,3-thiazole-5-carboxylate (800 mg, 2.48 mmol)synthesized in example (5a), dissolved in tetrahydrofuran (30 ml) and the resulting solution was cooled to 0°C. To the solution under stirring in an atmosphere of nitrogen was added N-bromosuccinimide (442 mg, 2.48 mmol) and the mixture is then stirred at room temperature for 19 hours. To the mixture is added saturated aqueous sodium hydrogen carbonate solution (30 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-30%)to give the target compound (598 mg, yield 60%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.39 (3H, t, J=7,0 Hz)of 1.50 (9H, s), to 4.38 (2H, q, J=7,0 Hz), 6,32 (1H, d, J=3.8 Hz), only 6.64 (1H, d, J=3.8 Hz), 8,31 (1H, s).

(5c) Ethyl-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylate

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (666 mg, 1,49 mmol)synthesized in example (1e), and ethyl-2-[5-bromo-1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-1,3-thiazole-5-carboxylate (598 mg, 1,49 mmol)synthesized in example (5b), is dissolved in a mixed solvent of toluene (14 ml) and ethanol (6 ml), the solution add complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (61,0 mg of 0.075 mmol) and an aqueous solution of sodium carbonate (2M, 1.50 ml, 3.00 mmol), the mixture was stirred at 100°C for 19 hours in a nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (10 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

The resulting residue is dissolved in dichloromethane (10 ml) and the solution cooled to 0°C. To the solution under stirring in nitrogen atmosphere are added dropwise triperoxonane acid (10 ml). After stirring the mixture at room temperature for 30 minutes, the solvent is distilled off under reduced pressure, who headed the remainder of the diluted with ethyl acetate (30 ml), add saturated aqueous sodium hydrogen carbonate solution (20 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-50%)to give the target compound (505 mg, yield 61%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), of 1.39 (3H, t, J=7.0 Hz), of 3.07 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=4,3, 10,2 Hz), 3,61 (1H, DD, J=6,3, 10,2 Hz), 4,37 (2H, q, J=7.0 Hz), 4,59 (1H, m), 6,56 (1H, DD, J=2,7, 3,9 Hz), to 6.58 (1H, t, J=2.0 Hz), 6,83 (1H, DD, J=2.7, and a 3.9 Hz), 6.87 in (1H, t, J=2.0 Hz), 7,03 (1H, t, J=2.0 Hz), 7,14 (2H, d, J=9.0 Hz), to $ 7.91 (2H, d, J=9.0 Hz), of 8.25 (1H, s), for 9.64 (1H, USS).

MS (ESI) m/z: 557,14052 (M+H)+.

(5d) 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylic acid

Ethyl-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylate (of 53.5 mg, 0,096 mmol)synthesized in example (5c), dissolved in ethanol (4 ml). To the solution was added an aqueous solution of sodium hydroxide (5M, 2 ml) and the mixture was stirred at 70°C for 30 minutes. The mixture is cooled to room temperature, to the mixture is added hydrochloric acid (2M, 5 ml) and ethyl acetate (10 ml) and the resulting mixture is separated. The organic layer is about is to see a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, obtaining the target compound (52,5 mg, yield ~100%) as a solid pale yellow color.

1H-NMR (DMSO, 400 MHz): δ 1,25 (3H, d, J=6.3 Hz), 3,19 (3H, s), 3,30 (3H, s), 3,44-to 3.52 (2H, m), 4,78 (1H, m), 6,56 (1H, OST, J=2.0 Hz), was 6.73 (1H, OSD, J=10,2 Hz), 7,21 (2H, d, J=8.6 Hz), 7,27 (1H, OST, J=2.0 Hz), 7,41 (1H, OST, J=2.0 Hz), to 7.93 (2H, d, J=8.6 Hz), 12,0 (1H, USS).

MS (ESI) m/z: 529,11053 (M+H)+.

Example 6

N-Ethyl-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxamide

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylic acid (62,8 mg, 0,119 mmol)synthesized in example (5d), dissolved in N,N-dimethylformamide (5 ml), the resulting solution was added ethylamine hydrochloride (23,3 mg, 0,286 mmol), HATU (63,8 mg, has 0.168 mmol) and N,N-diisopropylethylamine (80 μl, 0.46 mmol) and the resulting mixture was stirred in nitrogen atmosphere at room temperature for 20 hours. To the reaction solution was added water (20 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, the solution for elution: ethyl acetate/hexane=50%-80%), receiving tulevaisuuden (57,7 mg, yield 87%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.27 (3H, t, J=7.4 Hz), of 1.34 (3H, d, J=6.3 Hz), is 3.08 (3H, s), 3.43 points (3H, s), 3,47-of 3.53 (3H, m), 3,60 (1H, DD, J=6,3, 10,2 Hz), 4,56-4,60 (1H, m), 5,88 (1H, USS), 6,55-6,59 (2H, m), to 6.80 (1H, DD, J=2,3, 3,9 Hz)6,86 (1H, t, J=1.6 Hz), 7,02 (1H, t, J=1,8 Hz), 7,14 (2H, d, J=6.6 Hz), 7,92 (2H, d, J=6.6 Hz), 7,98 (1H, s), of 9.56 (1H, USS).

MS (ESI) m/z: 556,15812 (M+H)+.

Example 7

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-N,N-dimethyl-1,3-thiazole-5-carboxamide

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylic acid (62,8 mg, 0,119 mmol)synthesized in example (5d), dissolved in N,N-dimethylformamide (5 ml), the resulting solution was added dimethylamine hydrochloride (27.0 mg, 0,331 mmol), HATU (68,2 mg, 0,179 mmol) and N,N-diisopropylethylamine (80 μl, 0.46 mmol) and the resulting mixture was stirred in nitrogen atmosphere at room temperature for 20 hours. To the reaction solution was added water (20 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-90%), obtaining the target compound (59,8 mg, yield 90%) in view of the solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), of 3.07 (3H, s), 3,32 (6H, USS), 3,42 (3H, s), 3,51 (1H, DD, J=4,3, 10,2 Hz)and 3.59 (1H, DD, J=6,3, 10,2 Hz), 4,55-4,60 (1H, m), 6,55 return of 6.58 (2H, m), 6,79 (1H, DD, J=2,4, 3,9 Hz), 6,86 (1H, t, J=1,8 Hz), 7,02 (1H, t, J=1,8 Hz), 7,14 (2H, d, J=9.0 Hz), 7,89 (1H, s), to $ 7.91 (2H, d, J=9.0 Hz), 9,52 (1H, USS).

MS (ESI) m/z: 556,15717 (M+H)+.

Example 8

[2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-ylmethanol

Alumoweld lithium (22 mg, 0,580 mmol) suspended in tetrahydrofuran (2 ml). To the resulting suspension is added dropwise under nitrogen atmosphere at 0°C add ethyl-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylate (106 mg, 0,190 mmol)synthesized in example (5c)dissolved in tetrahydrofuran (2 ml). The mixture is stirred at 0°C for 30 minutes, then to the mixture slowly successively added water (22 μl) and an aqueous solution of sodium hydroxide (5M, 88 μl of). The mixture is filtered through celite, the solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-100%)to give the target compound (48 mg, yield 49%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.30 (3H, d, J=6.3 Hz), 3,06 (3H, s)to 3.41 (3H, s), 3,50 (1H, DD, J=3,9, and 10.5 Hz), to 3.58 (1H, DD, J=6.3, in the 10.5 Hz), 4,48 (1H, m), 4.2V (2H, OSS), 6,51-is 6.54 (2H, m), 6,70 (1H, DD, J=2,4, 3,9 Hz)6,86 (1H, OST, J=2.0 Hz), 7,00 (1H, OST, J=2.0 Hz), 7,12 (2H, d, J=9.0 Hz), 7,47 (1H, USS), 7,89 (2H, d, J=9.0 Hz), and 10.20 (1H, USS).

MS (ESI) m/z: 515,12920 (M+H)+.

Example 9

1-[2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazol-4-yl]ethane-1,2-diol

(9a) Ethyl-(2-bromo-1,3-thiazol-4-yl)(oxo)acetate

Commercially available ethyl-(2-formamido-1,3-thiazol-4-yl)(oxo)acetate (5,09 g of 22.3 mmol) was dissolved in a mixed solvent of ethanol (50 ml) and 1,4-dioxane, mixture of 30% sulfuric acid (12 ml) and the resulting mixture was stirred at 60°C for 1 hour. The reaction solution is cooled to room temperature, add water (20 ml) and ethyl acetate (20 ml) and the mixture is separated. The solvent is distilled off under reduced pressure, to the residue add 30% sulfuric acid (40 ml) and potassium bromide (9.3 g, 78.2 mmol), after which the mixture is cooled to 0°C. sodium Nitrite (20,0 g, 290 mmol) dissolved in water (40 ml), the resulting solution is added dropwise within 1 hour and add to the mixture and the resulting mixture was stirred at 0°C for 1 hour. The reaction mixture was extracted with ethyl acetate (200 ml), the organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica compound is spruce, the solution for elution: ethyl acetate/hexane=0%-20%)to give the target compound (of 3.07 g, yield 52%) as a yellow oil.

1H-NMR (CDCl3, 400 MHz): δ was 1.43 (3H, t, J=7.0 Hz), of 4.45 (2H, q, J=7,0 Hz) 8,55 (1H, s).

(9b) 1-(2-Bromo-1,3-thiazol-4-yl)ethane-1,2-diol

Ethyl-(2-bromo-1,3-thiazol-4-yl)(oxo)acetate (of 3.07 g, 11.6 mmol)synthesized in example (9a), dissolved in methanol (100 ml) and cooled to 0°C. To the obtained solution in small portions add borohydride sodium (1,32 g, is 34.9 mmol), the mixture was stirred at 0°C for 1.5 hours, then at room temperature for additional 2 hours. To the mixture add diluted hydrochloric acid (1M, 100 ml) and the resulting mixture extracted with ethyl acetate (200 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-80%), obtaining the target compound (1.10 g, yield 42%) as a yellow oil.

1H-NMR (CDCl3, 400 MHz): δ a 3.87 (1H, DD, J=5,9, 11.3 Hz), of 3.97 (1H, DD, J=3,5, 11.3 Hz), 4,89 (1H, DD, J=3,5, at 5.3 Hz), 7,27 (1H, s).

(9c) of tert-Butyl 2-[4-(1,2-dihydroxyethyl)-1,3-thiazol-2-yl]-1H-pyrrole-1-carboxylate

1-(2-Bromo-1,3-thiazol-4-yl)ethane-1,2-diol (1.10 g, 4,91 mmol)synthesized in example (9b), and commercially available 1-(tert-butox the carbonyl)pyrrol-2-Bronevoy acid (1.55 g, of 7.35 mmol) dissolved in 1,2-dimethoxyethane (40 ml)to the mixture of the palladium(II) acetate (55,0 mg, 0,245 mmol), triphenylphosphine (260 mg, 0,991 mmol) and aqueous potassium carbonate solution (3M, 4,9 ml, 14.7 mmol) and the resulting mixture was stirred at 100°C for 14 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (30 ml) and ethyl acetate (40 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-100%)to give the target compound (868 mg, yield 59%) as a brown oil.

1H-NMR (CDCl3, 400 MHz): δ of 1.46 (9H, s), of 3.95 (2H, m), 4,89 (1H, m), and 6.25 (1H, t, J=3.5 Hz), 6,60 (1H, DD, J=2,0, 3.5 Hz), 7,31 (1H, USS), 7,40 (1H, DD, J=2,0, 3.5 Hz).

(9d) of tert-butyl 2-bromo-5-[4-(1,2-dihydroxyethyl)-1,3-thiazol-2-yl]-1H-pyrrole-1-carboxylate

tert-Butyl 2-[4-(1,2-dihydroxyethyl)-1,3-thiazol-2-yl]-1H-pyrrole-1-carboxylate (868 mg, 2,80 mmol)synthesized in example (9c), dissolved in tetrahydrofuran (30 ml) and the resulting solution was cooled to 0°C. To the solution was added N-bromosuccinimide (498 mg, 2,80 mmol) and the mixture is stirred at room temperature for 14 hours under nitrogen atmosphere. To the mixture is added water (20 ml) and the mixture extracted with dieti the new ether (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-30%)to give the target compound (527 mg, yield 48%) as oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.53 (9H, s)to 3.92 (2H, m), to 4.87 (1H, m), of 6.31 (1H, d, J=3.5 Hz), is 6.54 (1H, d, J=3.5 Hz), 7.23 percent (1H, USS).

(9e) 1-[2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazol-4-yl]ethane-1,2-diol

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (600 mg, 1.35 mmol)synthesized in example (1e), and tert-butyl 2-bromo-5-[4-(1,2-dihydroxyethyl)-1,3-thiazol-2-yl]-1H-pyrrole-1-carboxylate (525 mg, 1.35 mmol)synthesized in example (9d), is dissolved in a mixed solvent of toluene (30 ml) and ethanol (10 ml), the resulting solution was added to the complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (55 mg, 0,067 mmol) and aqueous potassium carbonate solution (3M, of 0.90 ml, 2,70 mmol) and the resulting mixture was stirred at 100°C for 16 hours under nitrogen atmosphere. After cooling the reaction solution to room temperature, to the solution was added water (20 ml) and the mixture extracted with ethyl acetate (40 ml). Organic SL is th is washed with saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

The resulting residue is dissolved in dichloromethane (10 ml) and the solution cooled to 0°C. To the obtained solution under stirring in nitrogen atmosphere are added dropwise triperoxonane acid (10 ml). After stirring the mixture at room temperature for 30 minutes, the solvent is distilled off under reduced pressure, followed by dilution of the residue with ethyl acetate (30 ml), then add saturated aqueous solution of sodium bicarbonate (20 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-100%)to give the target compound (331 mg, yield 45%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), 3,05 (3H, s), 3,40 (3H, s), 3,50 (1H, DD, J=3,9, 10,2 Hz)and 3.59 (1H, DD, J=6,3, 10,2 Hz), 3,85-3,98 (2H, m), 4,58 (1H, m), the 4.90 (1H, USS), 6,48-is 6.54 (2H, m), to 6.67 (1H, USS), 6,89 (1H, USS), 7,07 (1H, USS), 7,12 (2H, d, J=8.6 Hz), 7,88 (2H, d, J=8.6 Hz), accounted for 10.39 (1H, USS).

MS (ESI) m/z: 545,14151 (M+H)+.

Example 10

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methylpyrazine

(10a) of tert-Butyl 2-(5-methylpyrazine-2-yl)-1H-pyrrole-1-carboxylate

Commercially available 2-bromo-5-methylpyrazine (260 mg, 1.50 mmol) and commercially available 1-(tert-butoxycarbonyl)pyrrol-2-Bronevoy acid (380 mg, of 1.80 mmol) dissolved in 1,2-dimethoxyethane (20 ml), to the solution was added palladium acetate(II) in (17.0 mg, 0,076 mmol), triphenylphosphine (79,0 mg, 0,301 mmol) and aqueous potassium carbonate solution (1,5M, 2.0 ml, 3.00 mmol) and the resulting mixture was stirred at 100°C for 19 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (20 ml) and ethyl acetate (20 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=5%-30%)to give the target compound (373 mg, yield 96%) as a yellow oil.

1H-NMR (CDCl3, 400 MHz): δ of 1.41 (9H, s)at 2.59 (3H, s), 6,28 (1H, m), 6.48 in (1H, m), 7,41 (1H, m), to 8.45 (1H, USS), 8,56 (1H, USS).

(10b) of tert-Butyl 2-bromo-5-(5-methylpyrazine-2-yl)-1H-pyrrole-1-carboxylate

tert-Butyl 2-(5-methylpyrazine-2-yl)-1H-pyrrole-1-carboxylate (373 mg, 1.44 mmol)synthesized in example (10a), dissolved in tetrahydrofuran (20 ml) and the resulting solution was cooled to 0°C. To the solution was added N-bromosuccinimide (256 mg,1.44 mmol) and the resulting mixture was stirred at room temperature for 14 hours under nitrogen atmosphere. To the mixture is added water (20 ml) and the mixture extracted with diethyl ether (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-30%)to give the target compound (425 mg, yield 87%) as oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.50 (9H, s), to 2.57 (3H, s), 6,33 (1H, d, J=3.5 Hz), is 6.54 (1H, d, J=3.5 Hz), 8,35 (1H, OSS), to 8.62 (1H, OSD, J=1,6 Hz).

(10c) of 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methylpyrazine

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (250 mg, 0,559 mmol)synthesized in example (1e), and tert-butyl 2-bromo-5-(5-methylpyrazine-2-yl)-1H-pyrrole-1-carboxylate (200 mg, 0,591 mmol)synthesized in example (10b), is dissolved in a mixed solvent of toluene (20 ml) and ethanol (8 ml), the solution add complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (23 mg, 0,028 mmol) and aqueous potassium carbonate solution (3M, and 0.40 ml, 1.20 mmol) and the resulting mixture was stirred at 100°C for 7 hours in a nitrogen atmosphere. After cooling the reaction solution to room temperature the solution was added water (20 ml) and the mixture of extras is Giroud with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

The resulting residue is dissolved in dichloromethane (10 ml) and the resulting solution was cooled to 0°C. To the solution under stirring in nitrogen atmosphere are added dropwise triperoxonane acid (10 ml). The resulting mixture was stirred at room temperature for 30 minutes, then the solvent is distilled off under reduced pressure, the residue diluted with ethyl acetate (30 ml), add saturated aqueous solution of sodium bicarbonate (20 ml) and the resulting mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-60%), obtaining the target compound (124 mg, yield 45%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), to 2.55 (3H, s), of 3.07 (3H, s), 3,42 (3H, s), 3,52 (1H, DD, J=3,9, 10,2 Hz), 3,61 (1H, DD, J=5,9, 10,2 Hz), 4,58 (1H, m), 6,55 (1H, t, J=2.0 Hz), 6,59 (1H, DD, J=2,8, 3,9 Hz), for 6.81 (1H, DD, J=2,4, 3,9 Hz), to 6.88 (1H, t, J=2.0 Hz),? 7.04 baby mortality (1H, t, J=2.0 Hz), 7,14 (2H, d, J=9.0 Hz), to $ 7.91 (2H, d, J=9.0 Hz), of 8.28 (1H, USS), 8,76 (1H, d, J=1.6 Hz), 9,62 (1H, USS).

MS (ESI) m/z: 494,17511 (M+H)+.

Example 11

6-(5-{3-[(1S)-2-Methoxy-1-mutilators the]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)nicotinic acid

(11a) Methyl-6-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]nicotinate

Commercially available methyl-6-bromonicotinate (650 mg, a 3.01 mmol) and commercially available 1-(tert-butoxycarbonyl)pyrrol-2-Bronevoy acid (960 mg, 4,34 mmol) dissolved in 1,2-dimethoxyethane (30 ml), to the solution was added palladium acetate(II) (34,0 mg, 0,151 mmol), triphenylphosphine (158 mg, 0,602 mol) and an aqueous solution of potassium carbonate (2M, 4.5 ml of 9.00 mmol) and the resulting mixture was stirred at 100°C for 15 hours in a nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (20 ml) and ethyl acetate (30 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-20%)to give the target compound (835 mg, yield 92%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.39 (9H, c), of 3.95 (3H, c), of 6.26 (1H, t, J=3.5 Hz), 6,53 (1H, m), 7,39 (1H, m), 7,47 (1H, DD, J=0,8, 8,2 Hz), of 8.27 (1H, DD, J=2,4, and 8.2 Hz), 9,19 (1H, DD, J=0.8, the 2,4 Hz).

(11b) Methyl-6-[5-bromo-1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]nicotinate

Methyl-6-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]nicotinate (835 mg, was 2.76 mmol)synthesized in example (11a), dissolved in tetrahydrofuran (30 ml) and the resulting solution was cooled to 0°C. To the solution was added N-bromosuccinimide (492 mg, was 2.76 mmol) and the mixture is stirred at room temperature for 19 hours under nitrogen atmosphere. To the mixture is added water (30 ml) and the resulting mixture extracted with diethyl ether (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-30%)to give the target compound (712 mg, yield 68%) as oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ and 1.54 (9H, c), of 3.94 (3H, c), 6,30 (1H, d, J=3.5 Hz), 6,62 (1H, d, J=3.5 Hz), 7,51 (1H, OSD, J=8.6 Hz), 8,23 (1H, DD, J=2,0, 8.6 Hz), 9,07 (1H, m).

(11C) Ethyl-6-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)nicotinate

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (398 mg, 0,890 mmol)synthesized in example (1e), and methyl-6-[5-bromo-1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]nicotinate (403 mg, 0,493 mmol)synthesized in example (11b), is dissolved in a mixed solvent of toluene (20 ml) and ethanol (8 ml), the resulting solution was added to the complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) and dichloromethane (40 mg, 0,049 mmol) and aqueous potassium carbonate solution (3M, of 0.60 ml of 1.80 mmol) and received the ing the mixture is stirred at 100°C for 20 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature, to the solution was added water (20 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and then the solvent is distilled off under reduced pressure.

The resulting residue is dissolved in dichloromethane (10 ml) and the solution cooled to 0°C. To the solution under stirring in nitrogen atmosphere are added dropwise triperoxonane acid (10 ml). The solution was stirred at room temperature for 30 minutes, then the solvent is distilled off under reduced pressure and the obtained residue was diluted with ethyl acetate (30 ml), add saturated aqueous solution of sodium bicarbonate (20 ml) and the solution separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-60%), obtaining the target compound (173 mg, yield 35%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), of 1.42 (3H, t, J=7.0 Hz), of 3.07 (3H, c), 3,42 (3H, c), 3,52 (1H, DD, J=3,9, 10,2 Hz), 3,61 (1H, DD, J=6,3, 10,2 Hz)to 4.41 (2H, q, J=7.0 Hz), 4,58 (1H, m), 6,55 (1H, t, J=2,0 Hz), 6,60 (1H, DD, J=2.0 a, 3,9 Hz), 6,85 (1H, DD, J=2.0 a, 3,9 Hz), 7,06 (1H, t, J=2.0 Hz), 7,14 (2H, d, J=9.0 Hz), EUR 7.57 (1H, DD, J=0,8, 8,GC), of 7.90 (2H, d, J=9.0 Hz), 8,21 (1H, DD, J=2,0, 8.6 Hz), 9,06 (1H, DD, J=0,8, 2.0 Hz), 9,94 (1H, USS, m).

MS (ESI) m/z: 551,18403 (M+H)+.

(11d) 6-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)nicotinic acid

Ethyl-6-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)nicotinate (42,0 mg, 0,076 mmol)synthesized in example (11C), dissolved in ethanol (4 ml). To the solution was added an aqueous solution of sodium hydroxide (5M, 2 ml) and the mixture was stirred at 70°C for 2 hours. After cooling the mixture to room temperature, add hydrochloric acid (2M, 5 ml) and ethyl acetate (10 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, obtaining the target compound (39,6 mg, yield 99%) as a solid pale yellow color.

1H-NMR (DMSO, 400 MHz): δ 1.26 in (3H, d, J=6.3 Hz), 3,20 (3H, c), and 3.31 (3H, c), 3,45-3,55 (2H, m), a 4.83 (1H, m), to 6.58 (1H, OSS), to 6.80 (1H, USS), 7,01 (1H, USS), 7,22 (2H, d, J=9.0 Hz), 7,31 (1H, OSS), was 7.45 (1H, USS), 7,88 (1H, d, J=8.6 Hz), to 7.93 (2H, d, J=9.0 Hz), 8,18 (1H, J=8.6 Hz), of 9.00 (1H, c), 11,92 (1H, USS).

MS (ESI) m/z: 523,15247 (M+H)+.

Example 12

[6-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)pyridine-3-yl]methanol

Alumoweld lithium (12 mg, 0,316 mmol) suspended in tetrahydrofuran (2 ml Ethyl-6-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)nicotinate (56,0 mg, is 0.102 mmol)synthesized in example (11c), dissolved in tetrahydrofuran (2 ml), the resulting solution at 0°C dropwise with stirring to the resulting suspension. The reaction mixture was peremeshivaniya at 0°C for 30 minutes, to the mixture is slowly added dropwise water (12 ml) and then aqueous sodium hydroxide solution (5M, 48 μl). The mixture is filtered through celite, the solvent is distilled off from the filtrate under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-100%)to give the target compound (33 mg, yield 64%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 3,06 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,60 (1H, DD, J=5,9, 10,2 Hz), of 4.57 (1H, m), 4,69 (2H, USS), of 6.52 (1H, OST, J=2.0 Hz), to 6.57 (1H, m), 6,74 (1H, m), make 6.90 (1H, OST, J=2.0 Hz), 7,06 (1H, OST, J=2.0 Hz), 7,13 (2H, d, J=8.6 Hz), 7,55 (1H, OSD, J=8,2 Hz), 7,69 (1H, OSD, J=8,2 Hz), 7,89 (2H, d, J=8.6 Hz), to 8.41 (1H, USS), 10,00 (1H, USS).

MS (ESI) m/z: 509,17476 (M+H)+.

Example 13

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-oxazol

(13a) 1-Bromo-3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]benzene

3-Bromo-5-[4-(methylsulphonyl)phenoxy]phenol (a 4.86 g of 14.2 mmol) synthesized in example (1c), dissolved in toluene (100 ml), the resulting solution was added (R)-(-)-1-methoxy-2-propanol (1.77 ml of 18.1 mmol) and triphenylphosphine (4,10 g, 15.6 mmol) and the resulting mixture is cooled to 0°C. To the mixture under nitrogen atmosphere is added dropwise within 10 minutes add diethylazodicarboxylate (40% solution in toluene of 7.75 ml of 17.1 mmol), the mixture was stirred at 0°C for 30 minutes, then enable the mixture to spontaneously warm to room temperature and stirred at room temperature over night. To the reaction mixture are added water (100 ml) and ethyl acetate (100 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-40%), obtaining the target compound (of 5.06 g, yield 86%) as oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.28 (3H, d, J=6.3 Hz), 3,05 (3H, c), 3,37 (3H, c), of 3.46 (1H, DD, J=3,9, 10,2 Hz), of 3.54 (1H, DD, J=6,3, 10,2 Hz), 4,49 (1H, m), 6,56 (1H, d, J=2.0 Hz), 6,77 (1H, d, J=2.0 Hz), 6,93 (1H, d, J=2,0 Hz), 7,10 (2H, d, J=9.0 Hz), 7,89 (2H, d, J=9.0 Hz).

(13b) of tert-Butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate

1-Bromo-3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]benzene (2.38 g, 5,73 mmol)synthesized in example (1a), and 1-(tert-butoxycarbonyl)pyrrol-2-Bronevoy acid (1.45 g, 6,87 mmol) was dissolved in a mixed solvent of 1,2-dimethoxyethane (50 ml) and water (6 ml), the solution add palladium(II) acetate (40 mg, 0,178 mmol), triphenylphosphine (180 mg, China 0,686 mmol) and potassium carbonate (2.38 g, and 17.2 mmol) and the resulting mixture was stirred at 90°C for 18 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (30 ml) and ethyl acetate (50 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-40%), obtaining the target compound (2,71 g, yield 94%) as a brown oil.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), the 1.44 (9H, c), 3,05 (3H, c), is 3.41 (3H, c), 3,49 (1H, DD, J=4,3, 10,2 Hz)to 3.58 (1H, DD, J=6,3, 10,2 Hz), a 4.53 (1H, m), is 6.19-6,23 (2H, m), is 6.61 (1H, t, J=2.4 Hz), 6,63 (1H, DD, J=1,6, 2.0 Hz), 6,79 (1H, DD, J=1,6, 2.4 Hz), to 7.15 (2H, d, J=9.0 Hz), 7,31 (1H, DD, J=2.0 a, and 3.2 Hz), 7,88 (2H, d, J=9.0 Hz).

(13c) of tert-Butyl 2-bromo-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate

tert-Butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (2.70 g, 5,38 mmol)synthesized in example (13b), dissolved in tetrahydrof is ane (50 ml) and the resulting solution was cooled to 0°C. To the solution under stirring in an atmosphere of nitrogen was added N-bromosuccinimide (960 mg, 5,38 mmol) and the mixture is stirred at room temperature for 4 hours. To the reaction mixture are added water (50 ml) and the mixture extracted with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-40%), obtaining the target compound (2,93 g, yield 94%) as a brown oil.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), of 1.42 (9H, c), 3,05 (3H, c), 3,39 (3H, c), of 3.48 (1H, DD, J=4,3, 10,2 Hz), 3,57 (1H, DD, J=6,3, 10,2 Hz), a 4.53 (1H, m), 6,21 (1H, d, J=3.5 Hz), 6,30 (1H, d, J=3.5 Hz), 6,57 (1H, t, J=2.4 Hz), is 6.61 (1H, d, J=2.4 Hz), to 6.75 (1H, d, J=2.4 Hz), 7,12 (2H, d, J=9.0 Hz), 7,89 (2H, d, J=9.0 Hz).

(13d) 2-(5-{3-[(lS)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-oxazol

tert-Butyl 2-bromo-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (102,9 mg, 0,177 mmol)synthesized in example (13c), dissolved in toluene (5 ml), the resulting solution was added 2-(tri-n-butylstannyl)oxazole (133,7 mg, 0,373 mmol) and tetrakis(triphenylphosphine)palladium (20,5 mg, 0,0177 mmol) and the mixture refluxed for 18 hours under nitrogen atmosphere. The reaction rastv the R cooled to room temperature, to the solution was added water (20 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=35%-55%)to give tert-butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-5-(1,3-oxazol-2-yl)-1H-pyrrole-1-carboxylate.

The product is dissolved in dichloromethane (1 ml)to the solution add triperoxonane acid (2 ml), the mixture is stirred at room temperature for 2 hours and then the solvent is distilled off under reduced pressure. The residue is diluted with ethyl acetate (20 ml), washed with saturated aqueous sodium bicarbonate, then washed with saturated salt solution and dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=65%), obtaining the target compound (15.6 mg, yield 19%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ ppm of 1.34 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=4,3, 10,2 Hz), 3,60 (1H, DD, J=6,3, 10,2 Hz), 4,56-4,60 (1H, m), 6,55-to 6.57 (2H, m), 6,84-6,86 (2H, m), 7,02 (1H, t, J=1.7 Hz), 7,13 (1H, c), to 7.15 (2H, d, J=8.6 Hz), to 7.61 (1H, c), to $ 7.91 (2H, d, J=9.0 Hz), 9,52 (1H OSS).

MS (ESI) m/z: 469,14163 (M+H)+.

Example 14

3-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1H-pyrazole

tert-Butyl 2-bromo-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (375 mg, 0,446 mmol)synthesized in example (13c), and commercially available 1H-pyrazole-3-Voronovo acid (120 mg, 1.00 mmol) dissolved in a mixed solvent of 1,2-dimethoxyethane (20 ml) and water (5 ml), to solution add complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) and dichloromethane (28 mg, 0,034 mmol) and aqueous potassium carbonate solution (3M, 0,65 ml of 1.95 mmol) and the mixture was stirred at 100°C for 7 days under nitrogen atmosphere. The reaction solution is cooled to room temperature, to the solution was added water (10 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-80%), obtaining the target compound (106 mg, yield 35%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,60 (1H, DD, J=6,3, 10,2 Hz), of 4.57 (1H, m), 6,549-6,55 4H, m), 6,83 (1H, USS), 7,00 (1H, USS), 7,14 (2H, d, J=9.0 Hz), EUR 7.57 (1H, d, J=2.4 Hz), of 7.90 (2H, d, J=9.0 Hz), of 9.30 (1H, USS).

MS (ESI) m/z: 468,15954 (M+H)+.

Example 15

1-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)alanon

(15a) 1-(5-Bromo-1H-pyrrol-2-yl)alanon

2-Acetylpyrrole (2.00 g, and 18.3 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 ml) and methanol (50 ml)to the solution under stirring in nitrogen atmosphere at room temperature add N-bromosuccinimide (3,26 g, and 18.3 mmol). The mixture is stirred for 1 hour, then the solvent is distilled off under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution (200 ml) and the mixture extracted with ethyl acetate (300 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-20%)to give the target compound (770 mg, yield 22%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 2.40 a (3H, c), 6,24 (1H, DD, J=2,4, 4.0 Hz), to 6.80 (1H, DD, J=2,9, 4.0 Hz), 9,37 (1H, USS).

(15b) of tert-Butyl 2-acetyl-5-bromo-1H-pyrrole-1-carboxylate

1-(5-Bromo-1H-pyrrol-2-yl)alanon (770 mg, 4.1 mmol)synthesized in example (15a), dissolve the dichloromethane (30 ml) and to the solution add triethylamine (0,57 ml, 4.1 mmol) and 4-dimethylaminopyridine (500 mg, 4.1 mmol). Di-tert-butyl-dicarbonate (930 mg, 4.3 mmol) dissolved in dichloromethane (10 ml) and added dropwise to the above solution, the mixture is stirred at room temperature for 3 hours in nitrogen atmosphere. The reaction solution was diluted with dichloromethane (200 ml), washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-20%)to give the target product (538 mg, yield 46%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.64 (9H, c), is 2.40 (3H, c), 6,24 (1H, d, J=3,9 Hz), PC 6.82 (1H, d, J=3,9 Hz).

(15c) 1-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)alanon

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (146 mg, 0.33 mmol)synthesized in example (1e), and tert-butyl 2-acetyl-5-bromo-1H-pyrrole-1-carboxylate (141 mg, 0.49 mmol)synthesized in example (15b), is dissolved in a mixed solvent of toluene (3 ml) and ethanol (1.3 ml), the solution add complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (13 mg, to 0.016 mmol) and water is actor potassium carbonate (2M, of 0.41 ml, 0.83 mmol) and the mixture was stirred at 100°C for 1.5 hours in a nitrogen atmosphere. The reaction solution is cooled to room temperature, to the solution was added water (20 ml) and the mixture extracted with ethyl acetate (60 ml). The organic layer was washed with saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

The resulting residue is dissolved in dichloromethane (2 ml)to the solution add triperoxonane acid (1 ml, at 13.0 mmol) and the resulting mixture was stirred at room temperature for 1 hour in nitrogen atmosphere. The solvent is distilled off under reduced pressure, add saturated aqueous solution of sodium bicarbonate (30 ml) and the mixture extracted with ethyl acetate (70 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-50%)to give the target compound (95 mg, yield 66%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 2,44 (3H, c), of 3.07 (3H, c), is 3.41 (3H, c), 3,51 (1H, DD, J=4,0, 10,2 Hz)and 3.59 (1H, DD, J=6,2, 10,2 Hz), 4,56-4,59 (1H, m), 6,53 (1H, DD, J=2,9, 3.5 Hz), 6,62 (1H, t, J=2.0 Hz), 6,86 (1H, t, J=1.6 Hz), 6,93 (1H, DD, J=2.5 and 3.9 Hz), 7,02 (1H, c), 7,14 (2H, d, J=8,9 Hz), to $ 7.91 (2H, d, J=8,8 Hz),for 9.64 (1H, OSS).

MS (ESI) m/z: 444,14808 (M+H)+.

Example 16

(1E)-1-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)Etalon-oxime

1-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)alanon (117 mg, 0.26 mmol)synthesized in example (15c), dissolved in methanol (6 ml), to the solution was added hydroxylamine hydrochloride (37 mg, is 0.53 mmol) and sodium acetate (26 mg, 0.32 mmol) and the obtained mixture is refluxed for 6 hours in nitrogen atmosphere. The reaction solution was diluted with dichloromethane (60 ml), washed with water and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-50%)to give the desired product (50 mg, yield 41%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.2 Hz), 2,19 (3H, c), 3,06 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=4,1, 10,2 Hz)to 3.58 (1H, DD, J=6,1, 10,2 Hz), to 4.52-of 4.57 (1H, m), 6,47 (2H, d, J=2.7 Hz), 6,53 (1H, t, J=2.0 Hz), 6,79 (1H, t, J=1.5 Hz), 6.89 in (1H, OSS), to 6.95 (1H, t, J=1,8 Hz), 7,13 (2H, d, J=8,8 Hz), of 7.90 (2H, d, J=8,8 Hz), 9,03 (1H, USS).

MS (ESI) m/z: 459,15898 (M+H)+.

Example 17

Ethyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylate

(17a) Ethyl-5-bromo-1H-pyrrole-2-carboxylate

Commercially available ethyl-1H-pyrrole-2-carboxylate (5.10 g, 30.7 mmol) was dissolved in a mixed solvent of tetrahydrofuran (120 ml) and methanol (60 ml) and the resulting solution was cooled to 0°C. To the solution was added N-bromosuccinimide (6,52 g, 30.7 mmol) and the mixture is stirred at room temperature for 18 hours under nitrogen atmosphere. To the mixture is added water (150 ml) and ethyl acetate (200 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=5%-30%)to give the target compound (3,20 g, yield 40%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.36 (3H, t, J=7,1 Hz), 4,32 (2H, q, J=7,1 Hz), 6,21 (1H, DD, J=2.7, and a 3.9 Hz), PC 6.82 (1H, DD, J=2.7, and a 3.9 Hz), of 9.21 (1H, USS).

(17b) 1-tert-Butyl-2-ethyl-5-bromo-1H-pyrrole-1,2 -, in primary forms

Ethyl-5-bromo-1H-pyrrole-2-carboxylate (3,20 g, 14.7 mmol)synthesized in example (17a), dissolved in dichloromethane (100 ml), to the solution was added di-tert-BUTYLCARBAMATE (3,85 g, 17.6 mmol), triethylamine (2,70 ml of 19.4 mmol) and 4-dimethylaminopyridine (180 mg, about 1.47 mmol) and the mixture is stirred at room temperature for 1 hour in nitrogen atmosphere. To the mixture is added water (100 m is) and the mixture extracted with dichloromethane (100 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-20%)to give the target compound as a colourless oil (4,37 g, yield 94%).

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, t, J=7,0 Hz), and 1.63 (9H, c), 4,30 (2H, q, J=7.0 Hz), 6,23 (1H, d, J=3,9 Hz), 6,83 (1H, d, J=3,9 Hz).

(17c) 1-tert-Butyl-2-ethyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-1,2 -, in primary forms

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (8,73 g of 18.9 mmol)synthesized in example (1e), and 1-tert-butyl-2-ethyl-5-bromo-1H-pyrrole-1,2 -, in primary forms (of 8.37 g of 26.3 mmol)synthesized in example (17b), is dissolved in a mixed solvent of toluene (180 ml) and ethanol (77 ml), the solution add complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (770 mg, of 0.94 mmol) and an aqueous solution of potassium carbonate (2M, with 23.7 ml, to 47.2 mmol) and the mixture was stirred at 100°C for 1 hour in nitrogen atmosphere. The reaction solution is cooled to room temperature, to the solution was added water (200 ml) and the mixture extracted with ethyl acetate (400 ml). The organic layer was washed with saturated salt solution and then dried over betwo the major magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-50%)to give the target compound (9,44 g, yield 84%) as oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), of 1.35 (3H, t, J=7,0 Hz)of 1.46 (9H, c), 3,05 (3H, c), 3,39 (3H, c), of 3.48 (1H, DD, J=4,3, 10,2 Hz), 3,57 (1H, DD, J=5,9, 10,2 Hz), 4,32 (2H, q, J=7.0 Hz), a 4.53 (1H, m), 6.22 per (1H, d, J=3,9 Hz), of 6.65 (1H, m), 6.73 x (1H, m), to 6.88 (1H, m), 6.89 in (1H, d, J=3,9 Hz), 7,12 (1H, d, J=9.0 Hz), 7,89 (2H, d, J=9.0 Hz).

(17d) Ethyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylate

1-tert-Butyl-2-ethyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-1,2 -, in primary forms (9,44 g, 16.5 mmol)synthesized in example (17c), dissolved in dichloromethane (90 ml) and the resulting solution was cooled to 0°C. To the solution under stirring in nitrogen atmosphere are added dropwise triperoxonane acid (45 ml) and the mixture was stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure, then diluted with ethyl acetate (300 ml), saturated aqueous sodium hydrogen carbonate (200 ml) and the mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified to lodochnoy chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-50%)to give the target compound (6,34 g, yield 81%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 1.37 (2H, t, J=7.0 Hz), of 3.07 (3H, c), is 3.41 (3H, c), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,60 (1H, DD, J=6,3, 10,2 Hz), 4,34 (2H, q, J=7.0 Hz), 4,58 (1H, m), 6,51 (1H, DD, J=2,5, 4.0 Hz), to 6.58 (1H, m)6,86 (1H, m), 6,93 (1H, DD, J=2.5 and 4.0 Hz), 7,01 (1H, m), 7,13 (2H, d, J=8,8 Hz), to $ 7.91 (2H, d, J=8,8 Hz), 9,41 (1H, USS).

MS (ESI) m/z: 474,16048 (M+H)+.

Example 18

N-(2-Chloroethyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide

(18a) 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid

Ethyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylate (4,36 g, 9.2 mmol)synthesized in example (17d), dissolved in ethanol (100 ml)to the solution add 4 N. aqueous sodium hydroxide solution (23 ml, 92 mmol) and the resulting mixture is refluxed for 1 hour in nitrogen atmosphere. To the reaction solution for neutralization add 2 N. hydrochloric acid (45 ml) and the solvent is distilled off under reduced pressure. 1 N. hydrochloric acid used for the acid solution and the mixture extracted with ethyl acetate (300 ml). The organic layer was washed with saturated salt solution and then dried over betwo the major magnesium sulfate. The solvent is distilled off under reduced pressure, obtaining the target product (4,06 g, yield 99%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), of 3.07 (3H, c), of 3.46 (3H, c), 3,55 (1H, DD, J=4.2, and 10.4 Hz), 3,66 (1H, DD, J=6.3, in the 10.5 Hz), 4,70-of 4.75 (1H, m), 6,53 (1H, DD, J=2,6, 3,9 Hz), 6,59 (1H, t, J=2.0 Hz), 6,91 (1H, t, J=1.6 Hz),? 7.04 baby mortality (1H, DD, J=2,3, 3,9 Hz), 7,25 (1H, m), 7,14 (2H, d, J=8,9 Hz), to $ 7.91 (2H, d, J=8,8 Hz), 10,13 (1H, USS).

(18b) N-(2-Chloroethyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (150 mg, 0.34 mmol)synthesized in example (18a), the hydrochloride of 2-chloroethylamine (78 mg, of 0.68 mmol) and 4-dimethylaminopyridine (41 mg, 0.34 mmol) dissolved in dichloromethane (15 ml)at room temperature to the solution add WSCI·HCl (71 mg, 0.37 to mmol) and the resulting mixture is stirred for 2 hours in nitrogen atmosphere. The reaction solution was diluted with dichloromethane (150 ml), the mixture was washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-60%)to give the desired product (105 mg, yield 62%) as a solid white is the first color.

1H-NMR (CDCl3, 500 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=4.0 a, 10,3 Hz)and 3.59 (1H, DD, J=6,1, 10.4 Hz), 3,70 (2H, t, J=5.4 Hz), of 3.77 (2H, t, J=5.4 Hz), 4,55-4,59 (1H, m), 6,26-of 6.29 (1H, USM), of 6.50 (1H, DD, J=2,9, 3,9 Hz), to 6.58 (1H, t, J=2.2 Hz), 6,63 (1H, DD, J=2.5 and 3.8 Hz), 6,83 (1H, t, J=1.7 Hz), of 6.99 (1H, t, J=2.0 Hz), 7,14 (2H, d, J=8,8 Hz), to $ 7.91 (2H, d, J=8,8 Hz)9,52 (1H, USS).

MS (ESI) m/z: 507,13566 (M+H)+.

Example 19

N-(2-Chloroethyl)-5-{3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide

N-(2-Chloroethyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide (88 mg, 0,17 mmol)synthesized in example (18b), dissolved in dichloromethane (5 ml), the solution cooled to -78°C and the solution in a nitrogen atmosphere add 1.0 mol/l solution of tribromide boron in dichloromethane (0,19 ml to 0.19 mmol). The mixture should be allowed the opportunity to spontaneously warm to room temperature, the mixture is stirred at room temperature for 30 minutes, then to neutralize the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with dichloromethane (60 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: etelaat the/hexane=50%-80%), receiving target product (55 mg, yield 64%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ is 1.31 (3H, d, J=6.3 Hz), 2,1 (1H, USM), is 3.08 (3H, c), 3,70 (2H, t, J=5,2 Hz), 3,76-of 3.80 (4H, m), to 4.52-4,56 (1H, m), 6,27-6,30 (1H, USM), of 6.50 (1H, DD, J=2,9, and 3.8 Hz), 6,56 (1H, t, J=2.1 Hz), only 6.64 (1H, DD, J=2,3, 3,9 Hz), 6,85 (1H, t, J=1.7 Hz), 6,98 (1H, t, J=1,8 Hz), 7,14 (2H, d, J=8,8 Hz), to $ 7.91 (2H, d, J=8,8 Hz), of 9.56 (1H, USS).

MS (FAB) m/z: 493 (M+H)+.

Example 20

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol

N-(2-chloroethyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide (177 mg, 0,349 mmol)synthesized in example (18b), dissolved in tetrahydrofuran (5 ml) and the resulting solution was cooled to 0°C. To the solution was added sodium hydride (40 mg, 0,917 mmol) and after heating to room temperature, the mixture is stirred for 19 hours at room temperature. The reaction solution was again cooled to 0°C, add water (5 ml) and the mixture extracted with ethyl acetate (10 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-100%)to give the target compound (118 mg, yield 72%) as Tverdov the substance of white color.

lH-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 3.07 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=3,9, 10,2 Hz)and 3.59 (1H, DD, J=6,3, 10,2 Hz), 3,98 (2H, t, J=9.4 Hz), and 4.40 (2H, t, J=9.4 Hz), 4,56 (1H, m), 6,50 (1H, d, J=3,9 Hz), 6,56 (1H, OST, J=2.0 Hz), to 6.75 (1H, d, J=3,9 Hz), 6,83 (1H, OST, J=2.0 Hz), 7,00 (1H, OST, J=2.0 Hz), 7,13 (2H, d, J=9.0 Hz), of 7.90 (2H, d, J=9.0 Hz).

MS (ESI) m/z: 471,16050 (M+H)+.

Example 21

(2S)-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol (3,17 g, 6,74 mmol)synthesized in example 20 was dissolved in dichloromethane (100 ml), the resulting solution was cooled to -78°C and the solution in a nitrogen atmosphere add a solution of tribromide boron in dichloromethane (1.0 mol/l) (7,07 ml, 7,07 mmol). The mixture should be allowed the opportunity to spontaneously warm to room temperature, the mixture is stirred at room temperature for 30 minutes, then to the reaction solution to neutralize the added aqueous solution of sodium bicarbonate and the mixture extracted with dichloromethane (200 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is washed with ethyl acetate (100 ml) and ethanol (50 ml)to give the target product (1,96 g, yield 64%) as a solid substance be the CSOs color.

1H-NMR (CDCl3, 500 MHz): δ of 1.29 (3H, d, J=6.3 Hz), 3,06 (3H, c), with 3.79 (2H, d, J=5,9 Hz), of 4.00 (2H, t, J=9,3 Hz), 4,42 (2H, t, J=9.4 Hz), 4,58-4,63 (1H, m), 6,40 (1H, t, J=2.2 Hz), 6,47 (1H, d, J=3,9 Hz), to 6.75 (1H, d, J=3.8 Hz), 6,79 (1H, t, J=1.7 Hz), 6,94 (1H, t, J=1,8 Hz), to 7.09 (2H, d, J=8,8 Hz), 7,88 (2H, d, J=8,8 Hz).

MS (ESI) m/z: 457,14357 (M+H)+.

Example 22

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-thiadiazole

(22a) N'-Acetyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carbohydrazide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (114,5 mg, 0,257 mmol)synthesized in example (18a), dissolved in N,N-dimethylformamide (4 ml)solution was added acetohydrazide (39,4 mg, mean HDI of 0.531 mmol), HATU (to 150.1 mg, 0,395 mol) and N,N-diisopropylethylamine (70 μl, 0.40 mmol) and the mixture is stirred at room temperature for 20 hours under nitrogen atmosphere. To the reaction solution was added water (20 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-100%)to give the target compound (73,0 mg, yield 57%) as a solid white color

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), 1,99 (3H, c), 3,06 (3H, c), 3,40 (3H, c), 3,49 (1H, DD, J=3,9, 10,2 Hz), 3,57 (1H, DD, J=6,3, 10,2 Hz), 4,58-4,63 (1H, m), 6,46 (1H, DD, J=2.7, and a 3.9 Hz), 6,53 (1H, c), is 6.78 (1H, DD, J=2,4, 3,9 Hz)6,86 (1H, c), 7,10 (2H, d, J=9.0 Hz), 7,13 (1H, c), 7,88 (2H, d, J=8.6 Hz), 8,63 (1H, USS), the remaining 9.08 (1H, USS), and 10.20 (1H, USS).

MS (ESI) m/z: 524,14725 (M+Na)+.

(22b) 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-thiadiazole

N'-Acetyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carbohydrazide (58,1 mg, 0,116 mmol)synthesized in example (22a), dissolved in toluene (4 ml)solution was added 2,4-disulfide 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphatase (63.5 mg, of) 0.157 mmol) and pyridine (20 μl, 0.25 mmol) and the resulting mixture was stirred at 90°C for 5 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, the reaction solution was added water (20 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=40%-80%), obtaining the target compound (50,6 mg, yield 87%) as a solid pale yellow color.

1H-NMR (CDCl3, 500 MHz): δ of 1.34 (3H, d, J=6.4 Hz), 2,77 (3H, c), of 3.07 (3H, ), of 3.42 (3H, c), 3,51 (1H, DD, J=4,4, 10,3 Hz), 3,60 (1H, DD, J=6,4, 10,3 Hz), 4,57-br4.61 (1H, m), 6,55 (1H, t, J=3,4 Hz), to 6.58 (1H, t, J=1.9 Hz), to 6.67 (1H, DD, J=2,4, 3,9 Hz), 6.87 in (1H, t, J=1.7 Hz), 7,03 (1H, c), 7,14 (2H, d, J=8,8 Hz), to $ 7.91 (2H, d, J=8,8 Hz), 9,74 (1H, USS).

MS (ESI) m/z: 500,12981 (M+H)+.

Example 23

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-oxadiazol

N'-Acetyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carbohydrazide (86,5 mg, 0,172 mmol)synthesized in example (22A), dissolved in acetonitrile (5 ml), the solution add hydroxide (methoxycarbonylamino)triethylamine (60,7 mg, 0,258 mmol) and triethylamine (36 μl, 0.26 mmol) and the mixture was stirred at 80°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, the reaction solution was added water (20 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-75%), obtaining the target compound (49,1 mg, yield 59%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 2,58 (3H, c), is 3.08 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,60 (1H, DD, J=6,3,10,2 Hz), 4,55-br4.61 (1H, m), 6,57-6,60 (2H, m), 6,85-6,87 (2H, m), 7,02 (1H, c), 7,14 (2H, d, J=8.6 Hz), to $ 7.91 (2H, d, J=8.6 Hz), 9,65 (1H, USS).

MS (ESI) m/z: 484,15505 (M+H)+.

Example 24

5-Methoxy-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-oxazol

(24a) Methyl-N-[(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)carbonyl]glycinate

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (275 mg, 0,617 mmol)synthesized in example (18a), dissolved in dichloromethane (10 ml), to the solution was added the hydrochloride of the methyl ester of glycine (120 mg, 0,956 mmol), WSCI·HCl (180 mg, 0,939 mmol) and 4-dimethylaminopyridine (150 mg, of 1.23 mmol), the mixture is stirred at room temperature for 2 hours in nitrogen atmosphere. To the mixture was added 1 N. hydrochloric acid (10 ml) and the mixture extracted with dichloromethane (15 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-60%), obtaining the target product (270 mg, yield 85%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), of 3.07 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=3,9, 10,2 Hz)and 3.59 (1H, DD, J=6,3, 10,2 Hz), 3,78 (H, c)4,56 (1H, m), 6.48 in (1H, OST, J=3,9 Hz), 6,54 return of 6.58 (2H, m), 6,69 (1H, DD, J=2,4, 3,9 Hz), 6.89 in (1H, t, J=2.0 Hz), 7,02 (1H, t, J=2.0 Hz), 7,12 (2H, d, J=8.6 Hz), 7,89 (2H, d, J=8,9 Hz), 10,11 (1H, USS).

(24b) 5-Methoxy-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-oxazol

Methyl-N-[(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)carbonyl]glycinate (270 mg, 0,523 mmol)synthesized in example (24a), dissolved in acetonitrile (10 ml)solution was added triphenylphosphine (410 mg, 1.56 mmol), triethylamine (0,22 ml, was 1.58 mmol) and carbon tetrachloride (0.33 ml, 3,42 mmol) and the resulting mixture was stirred at room temperature for 15 hours under nitrogen atmosphere. To the solution was added water (10 ml) and the mixture extracted with ethyl acetate (15 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-40%), obtaining the target product (162 mg, yield 62%) as a solid orange color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), of 3.07 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=3,9, 10,2 Hz)and 3.59 (1H, DD, J=6,3, 10,2 Hz)to 3.92 (3H, c), 4,55 (1H, m), between 6.08 (1H, c), 6,51-6,55 (2H, m), 6,70 (1H, DD, J=2,4, 3,9 Hz), 6,83 (1H, t, J=2.0 Hz), of 6.99 (1H, t, J=2.0 Hz), 7,12 (2H, d, J=9.0 Hz), of 7.90 (2H, d, J=9.0 Hz), 9,77 (1H, USS).

MS (ESI) m/z: 499,15601(M+H) +.

Example 25

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-thiazole

(25a) 2-(Tricity)ethanamine

Hydrochloride of 2-aminoethanethiol (5,16 g of 45.4 mmol) dissolved in dichloromethane (80 ml), add triperoxonane acid (7.0 ml, the 90.8 mmol) and chloride triphenylmethyl (to 13.29 g of 47.7 mmol) and the resulting mixture was stirred at room temperature for 1 hour. To the mixture was added 1 N. aqueous sodium hydroxide solution (150 ml) and the mixture extracted with dichloromethane (500 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is added methanol (100 ml) and precipitated by-product is removed by filtration. For acidification of the solution add 1 N. hydrochloric acid (300 ml) and the precipitate removed by filtration. After washing the by-product dichloromethane (50 ml) to remove the solution is alkalinized 1 N. aqueous sodium hydroxide solution and the mixture extracted with dichloromethane (600 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, obtaining the target product (8,77 g, yield 60%) as a solid white color.

1H-NMR (CDCl3,400 MHz): δ of 2.33 (2H, t, J=6.6 Hz), at 2.59 (2H, t, J=6.6 Hz), 7,19-of 7.23 (3H, m), 7,26-7,30 (6H, m), 7,41-7,44 (6H, m).

(25b) 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-N-[2-(Tricity)ethyl]-1H-pyrrol-2-carboxamide

To 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (940 mg, 2.1 mmol)synthesized in example (18a), add 2-(Tricity)ethanamine (1.01 g, 3,17 mmol)synthesized in example (25a), and 4-dimethylaminopyridine (13 mg, 0.1 mmol), the mixture was dissolved in dichloromethane (50 ml), then add WSCI·HCl (445 mg, 2.3 mmol) at room temperature and the mixture is stirred for 1 hour in nitrogen atmosphere. The reaction solution was diluted with dichloromethane (150 ml), washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-55%), obtaining the target product (1.08 g, yield 69%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 2,50 (2H, t, J=6.5 Hz), of 3.07 (3H, c), with 3.27 (2H, dt, J=5,9, 6.2 Hz), 3,42 (3H, c), 3,51 (1H, DD, J=4,0, 10.4 Hz)and 3.59 (1H, DD, J=5,9, 10.4 Hz), 4,55-4,59 (1H, m), of 5.99 (1H, USM), 6,48 (1H, DD, J=2,8, 3,9 Hz), 6,53 (1H, DD, J=2.5 and 3.9 Hz), to 6.57 (1H, t, J=2.3 Hz), for 6.81 (1H, t, J=2.2 Hz), 6,98 (1H, t, J=2.1 Hz), 7,14 (2H, d, J=8,9 Hz), 7,19-7,30 (9H, m) 7,42 (6H, DD, J=1,6, and 7.3 Hz), to $ 7.91 (2H, d, J=8,9 Hz), 9,41 (1H, USS).

(25c) 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-thiazole

The triphenylphosphine oxide (2,41 g, 8,7 mmol) dissolved in dichloromethane (20 ml)to the solution at 0°C is slowly added dropwise to the anhydride triftormetilfullerenov acid (0,73 ml, 4.3 mmol). The mixture is stirred for 10 minutes, then add a solution of 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-N-[2-(Tricity)ethyl]-1H-pyrrole-2-carboxamide, synthesized in example (25b), in dichloromethane. The reaction solution was stirred at room temperature for 30 minutes, then the solvent is distilled off under reduced pressure, to the residue is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate (200 ml). The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-80%), obtaining the target product (636 mg, yield 90%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,39 (2H, t, J=8,4 Hz)to 3.41 (3H, c), 3,50 (1H, DD, J=3,9, 10,3 Hz)and 3.59 (1H, DD, J=5,9, 10,3 Hz)to 4.33 (2H, t, J=8.7 Hz), 4,55-4,59 (1H, m), 6,50 (1H, d, J=3,9 Hz), 6,56 (1H, t, J=2.5 Hz), only 6.64 (1H, d, J=3,9 Hz), 6,83 (1H, t, J=2.0 Hz), 7,00 (1H, t, J=2.4 Hz), 7,13 (2H, d, J=8,8 Hz), of 7.90 (2H, d, J=8,8 Hz).

MS (ESI) m/z: 487,13595 (M+H)+.

Example 26

(2S)-2-{3-[5-(4,5-Dihydro-1,3-thiazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-thiazole (88 mg, 0.18 mmol)synthesized in example (25c), dissolved in dichloromethane (5 ml), the solution cooled to -78°C and the resulting solution under nitrogen atmosphere add solution (1.0 mol/l) tribromide boron in dichloromethane (0,22 ml, 0.22 mmol). The reaction solution provide the ability to spontaneously warm to room temperature, and the reaction solution was stirred at room temperature for 1 hour, then add saturated aqueous solution of sodium bicarbonate for neutralization, and the mixture extracted with dichloromethane (60 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=40%-100%)to give the desired product (46 mg, yield 54%) as a solid pale yellow color.

1H-NMR (CDCl3, 500 MHz): δ of 1.29 (3H, d, J=6.4 Hz), with 3.27 (3H, c), 3,40 (2H, t, J=8.1 Hz), 3,76-of 3.78 (2H, m), 4,33 (2, t, J=8,2 Hz), 4,55-4,59 (1H, m), 6,47 (1H, d, J=2.4 Hz), of 6.49 (1H, d, J=3,7 Hz), of 6.65 (1H, d, J=3,7 Hz), PC 6.82 (1H, c), of 6.96 (1H, c), 7,11 (2H, d, J=8.7 Hz), of 7.90 (2H, d, J=8.7 Hz).

MS (ESI) m/z: 473,12049 (M+H)+.

Example 27

Methyl-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-carboxylate

(27a) Methyl-2-hydroxy-3-{[(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)carbonyl]amino}propanoate

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (420 mg, 0,943 mmol)synthesized in example (18a), dissolved in dichloromethane (10 ml), add the hydrochloride of the methyl ester of DL-azaserine (300 mg, of 1.93 mmol), WSCI·HCl (270 mg, of 1.41 mmol) and 4-dimethylaminopyridine (230 mg, 1.88 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours under nitrogen atmosphere. To the mixture was added 1 N. hydrochloric acid (10 ml) and the mixture extracted with dichloromethane (15 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-80%), obtaining the target product (400 mg, yield 78%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): what to 1.32 (3H, d, J=6.3 Hz), of 3.07 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=3,9, 10,2 Hz), 3,60 (1H, DD, J=6,3, 10,2 Hz), 3.72 points-of 3.85 (2H, m), 3,80 (3H, c), to 4.38 (1H, OST, J=4,7 Hz), 4,58 (1H, m), to 6.43 (1H, USS), 6,47 (1H, m), 6,56 (1H, t, J=2.0 Hz), 6,63 (1H, DD, J=2,4, 3,9 Hz)6,86 (1H, t, J=2.0 Hz), 7,01 (1H, t, J=2.0 Hz), 7,12 (2H, d, J=9.0 Hz), of 7.90 (2H, d, J=9.0 Hz), 9,85 (1H, USS).

(27b) Methyl-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-carboxylate

Methyl-2-hydroxy-3-{[(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)carbonyl]amino}propanoate (686 mg, of 1.26 mmol)synthesized in example (27a), dissolved in tetrahydrofuran (15 ml), add anhydride methanesulfonic acid (330 mg, 1,89 mmol) and triethylamine (0,53 ml of 3.80 mmol) and the resulting mixture was stirred at room temperature for 19 hours under nitrogen atmosphere. To the mixture is added saturated aqueous sodium hydrogen carbonate solution (10 ml), the mixture is extracted with ethyl acetate and the resulting mixture is separated (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-70%), obtaining the target product (586 mg, yield 88%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 3.07 (3H, c), is 3.41 (3H, c), 3,50 1H, DD, J=3,9, 10,2 Hz), 3,60 (1H, DD, J=6,3, 10,2 Hz), 4,10 (1H, DD, J=7,0, 14,5 Hz), 4,30 (1H, DD, J=10,6, 14,5 Hz), 4,56 (1H, m), 5,07 (1H, DD, J=7,0, a 10.6 Hz), of 6.52 (1H, d, J=3,9 Hz), to 6.57 (1H, t, J=2.0 Hz), 6,83 (1H, t, J=2.0 Hz), 6,86 (1H, d, J=3,9 Hz), 7,00 (1H, t, J=2.0 Hz), 7,14 (2H, d, J=9.0 Hz), of 7.90 (2H, d, J=9.0 Hz), to 9.66 (1H, USS).

MS (ESI) m/z: 529,16412 (M+H)+.

Example 28

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-N,N-dimethyl-4,5-dihydro-1,3-oxazol-5-carboxamid

(28a) 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-carboxylic acid

Methyl-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-carboxylate (of 60.5 mg, 0,114 mmol)synthesized in example (27b), dissolved in ethanol (4 ml). Add aqueous sodium hydroxide solution (5M, 2 ml) and the mixture was stirred at 70°C for 2.5 hours. After cooling the mixture to room temperature, to the mixture is added hydrochloric acid (2M, 5 ml) and ethyl acetate (10 ml) and the resulting mixture is separated. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, obtaining the target compound (69,3 mg, yield ~100%) as a solid pale yellow color.

1H-NMR (CDCl3, 500 MHz): δ of 1.34 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,42 (3H, c), 3,55-3,63 (2H, m), 4,28-of 4.44 (2H, m, 4,78 (1H, m), 5,49 (1H, USS), 6,60 of 6.68 (2H, m), 7,10 (1H, USS), 7,14 (2H, d, J=8,3 Hz), 7,26 (1H, m), 7,39 (1H, OSD, J=8,3 Hz), 7,89 (2H, d, J=8,3 Hz), 13,10 (1H, USS).

MS (ESI) m/z: 515,14638 (M+H)+.

(28b) 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-N,N-dimethyl-4,5-dihydro-1,3-oxazol-5-carboxamid

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-carboxylic acid (154 mg, 0,299 mmol)synthesized in example (28a), dissolved in dichloromethane (10 ml), added dimethylamine hydrochloride (75,0 mg, 0,920 mmol), WSCI·HCl (115 mg, 0,600 mmol) and 4-dimethylaminopyridine (110 mg, to 0.900 mmol) and the resulting mixture was stirred at room temperature for 2 days under nitrogen atmosphere. To the reaction mixture are added water (10 ml) and the solution separated dichloromethane (15 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=70%-100%)to give the desired product (107 mg, yield 66%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), to 3.02 (3H, c), of 3.07 (3H, c)and 3.15 (3H, c), 3,42 (3H, c), 3,50 (1H, DD, J=3,9, 10,2 Hz), 3,60 (1H, DD, J=5,9, 10,2 Hz), 4,19 (1H, DDD, J=1,2, 10,2, 14.1 Hz), 4,33 (1H, OSD, J=7,8, a 14.1 Hz), of 4.57 (1H, m), 5,27 (1H, DD, J=7,8, 10,2 Hz), 6,50 (1H, q, j =3,9 Hz), 6,56 (1H, d, J=2.0 Hz), 6,78 (1H, d, J=3,9 Hz), 6,83 (1H, t, J=2.0 Hz), 7,01 (1H, d, J=2.0 Hz), 7,13 (2H, d, J=8.6 Hz), of 7.90 (2H, d, J=8,9 Hz), 9,80 (1H, USS).

MS (ESI) m/z: 542,19865 (M+H)+.

Example 29

[2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol

Alumoweld lithium (17,0 mg, 0,448 mmol) suspended in tetrahydrofuran (2 ml). Methyl-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-carboxylate (77.0 mg, 0,146 mmol)synthesized in example (27b), dissolved in tetrahydrofuran (2 ml) and at 0°C under nitrogen atmosphere is added to a suspension of lithium aluminum hydride. The mixture is stirred at 0°C for 30 minutes, then the mixture is slowly added dropwise water (17 ml) and aqueous sodium hydroxide solution (5M, 68 μl). The mixture is filtered through celite, the solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-100%)to give the target compound (54,1 mg, yield 74%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ of 1.29 and 1.33 (3H, m), 3,06 (3H, c), is 3.41 (3H, c), 3,49 (1H, m)to 3.58 (1H, m), 3,63 is 3.76 (2H, m), 3,83 (1H, m), of 3.97 (1H, m), 4,59 (1H, m), was 4.76 (1H, m), 6,46 (1H, m), is 6.54 (1H, USS), 6,72 (1H, m), 6,69 (1H, USS), 7,05 (1H, m), 7,13 (2H, d, J=8,8 Hz), 7,89 (2H, d, J=8,8 Hz).

MS (ESI) m/z: 501,17097 (M+H)+.

Example 30/b>

5-(Permitil)-2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol

[2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol (100 mg, 0.20 mmol)synthesized in example (29), dissolved in dichloromethane (5 ml), the solution is cooled to 0°C and to the solution add TRIFLUORIDE bis(2-methoxyethyl)aminocore (81 μl, 0.44 mmol). The mixture is stirred at room temperature for 6 hours, then add saturated aqueous solution of sodium bicarbonate and the mixture extracted with dichloromethane (60 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=80%-100%)to give the desired product (61 mg, yield 61%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=4,1, 10,3 Hz)and 3.59 (1H, DD, J=6,3, 10,3 Hz), 3,82 (1H, DD, J=7,4, 14,5 Hz), 4,10 (1H, DDD, J=1,4, 10,1,, 14.6 Hz), 4,49 (1H, DDD, J=5,5, 10,5, to 37.9 Hz), 4,54-4,58 (1H, m), to 4.62 (1H, DDD, J=3,0, 10,6, 33.3 Hz), 4,85-4,96 (1H, m), 6,51 (1H, d, J=3,9 Hz), to 6.57 (1H, t, J=2.1 Hz), to 6.80 (1H, d, J=3.6 Hz), for 6.81 (1H, t, J=1.9 Hz), 6,98 (1H, t, J=1,8 Hz), 7,13 (2H, d, J=8,9 Hz), to $ 7.91 (2H, d, J=8,9 Hz).

MS (ESI) m/z: 503,16398 (M+H)+.

P the emer 31

(5S)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol

(31a) N-[(2R)-2-Hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (204 mg, 0,458 mmol)synthesized in example (18a), dissolved in dichloromethane (10 ml)solution was added (R)-(-)-1-amino-2-propanol (72,0 μl, 0,914 mmol), WSCI·HCl (130 mg, 0,678 mmol) and 4-dimethylaminopyridine (115 mg, 0,941 mmol) and the resulting mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. To the mixture was added 1 N. hydrochloric acid (10 ml) and the mixture extracted with dichloromethane (15 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-100%)to give the target product (191 mg, yield 83%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ to 1.21 (3H, d, J=6.3 Hz), is 1.31 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,24 (3H, c), is 3.41 (3H, c), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,57 (1H, m)and 3.59 (1H, DD, J=6,3, 10,2 Hz), 3,98 (1H, m), 4,56 (1H, m), 6,47 (1H, DD, J=2.7, and a 3.9 Hz), 6,50 (1H, USS), 6,55 (1H, t, J=2.0 Hz), only 6.64 (1H, DD, J=2,4, 3,9 Hz), 6.87 in (1H, t, J=2.0 Hz), of 7.00 (1H, t, J=2.0 Hz), 7,12 (2H, d, J=9.0 Hz), 7,89 (2H, d, J=9.0 Hz), to 10.09 (1H, USS).

(31b) (5S)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol

N-[(2R)-2-Hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide (191 mg, 0,380 mmol)synthesized in example (31a), dissolved in tetrahydrofuran (10 ml)to the mixture of anhydrous methansulfonate acid (100 mg, 0,574 mmol) and triethylamine (0.16 ml, 1.15 mmol) and the resulting mixture is stirred at room temperature for 18 hours under nitrogen atmosphere. To the mixture is added saturated aqueous sodium hydrogen carbonate solution (10 ml), the mixture is extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-70%), obtaining the target product (136 mg, yield 74%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 1.42 (3H, d, J=6.3 Hz), of 3.07 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=4,3, 10,2 Hz), 3,52 (1H, DD, J=7,4, a 14.1 Hz)and 3.59 (1H, DD, J=6,3, 10,2 Hz)4,06 (1H, DD, J=9,4, 14.1 Hz), of 4.57 (1H, m), 4,82 (1H, m), 6,50 (1H, d, J=3,9 Hz), 6,55 (1H, t, J=2.0 Hz), to 6.75 (1H, d, J=3,9 Hz), 6,83 (1H, t, J=2.0 Hz), 7,00 (1H, t, J=2.0 Hz), 7,13 (2H, d, J=9.0 Hz), of 7.90 (2H, d, J=9.0 Hz).

MS (EI) m/z: 485,17394 (M+H) +.

Example 32

(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulphonyl)phenoxy]phenoxy)propan-1-ol

(5S)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol (280 mg, of 0.58 mmol)synthesized in example (31b), dissolved in dichloromethane (10 ml), the solution cooled to -78°C and under nitrogen atmosphere to a solution add solution (1.0 mol/l) tribromide boron in dichloromethane (of 0.61 ml, 0.61 mmol). Solution allow to warm to room temperature and stirred at room temperature for 30 minutes to neutralize the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and then the solution is extracted with dichloromethane (60 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate) receiving the target product (222 mg, yield 82%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ of 1.28 (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,55 (1H, DD, J=7,3, a 13.9 Hz), with 3.79 (2H, d, J=5.4 Hz), 4.09 to (1H, DD, J=9,2, of 14.0 Hz), 4,60 with 4.64 (1H, m), 4,81-to 4.87 (1H, m), 6,36 (1H, t, J=2.3 Hz), 6,46 (1H, d, J=3,9 Hz), to 6.75 (1H, d, J=3,9 Hz)6,91 (1H, t, J=l,9 Hz), was 7.08 (2H, d J=a 8.9 Hz), 7,88 (2H, d, J=8,9 Hz).

MS (ESI) m/z: 471,15892 (M+H)+.

Example 33

(5R)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol

(33a) N-[(2S)-2-Hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (305 mg, 0,685 mmol)synthesized in example (18a), dissolved in dichloromethane (10 ml)solution was added (S)-(+)-1-amino-2-propanol (110 μl, of 1.40 mmol), WSCI·HCl (200 mg, 1.04 mmol) and 4-dimethylaminopyridine (170 mg, of 1.39 mmol) and the resulting mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. To the mixture was added 1 N. hydrochloric acid (10 ml) and the mixture is separated with dichloromethane (15 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-100%)to give the target product (285 mg, yield 83%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1,24 (3H, d, J=6.3 Hz), of 1.33 (3H, d, J=6.3 Hz), of 3.07 (3H, c), or 3.28 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,56-the 3.65 (2H, m)to 4.01 (1H, m), 4,58 (1H, m), 6.35mm (1H, OST, J=5.5 Hz), of 6.49(1H, DD, J=2.7, and a 3.9 Hz), to 6.57 (1H, t, J=2.0 Hz), 6,62 (1H, DD, J=2,4, 3,9 Hz), at 6.84 (1H, t, J=2.0 Hz), 7,00 (1H, t, J=2.0 Hz), 7,13 (2H, d, J=8.6 Hz), of 7.90 (2H, d, J=8.6 Hz), to 9.66 (1H, USS).

(33b) (5R)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol

N-[(2S)-2-Hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide (285 mg, 0,567 mmol)synthesized in example (33a), dissolved in tetrahydrofuran (10 ml), to the solution was added anhydrous methansulfonate acid (130 mg, 0,746 mmol) and triethylamine (of 0.24 ml, 1,72 mmol) and the resulting mixture is stirred at room temperature for 21 hours under nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (10 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-70%), obtaining the target product (155 mg, yield 56%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), of 1.41 (3H, d, J=6.3 Hz), 3,06 (3H, c), 3,40 (3H, c), 3,50 (1H, DD, J=3,9, 10,2 Hz), 3,51 (1H, DD, J=8,2, 14.1 Hz), to 3.58 (1H, DD, J=5,9, 10,2 Hz), Android 4.04 (1H, DD, J=9,4, 14.1 Hz), 4,56 (1H, m), 4,80 (1H, m), 6,50 (1H, d, J=3,9 Hz), 6,55 (1H, t, J=2.0 Hz), 6,4 (1H, d, J=3,9 Hz), at 6.84 (1H, t, J=2.0 Hz), 7,00 (1H, t, J=2.0 Hz), 7,12 (2H, d, J=9.0 Hz), 7,89 (2H, d, J=9.0 Hz).

MS (ESI) m/z: 485,17398 (M+H)+.

Example 34

(5R)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-(trifluoromethyl)-4,5-dihydro-1,3-oxazol

(34a) 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-N-[(2S)-3,3,3-Cryptor-2-hydroxypropyl]-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (408 mg, of 0.94 mmol)synthesized in example (18a), (2S)-3-amino-1,1,1-Cryptor-2-propanol (177 mg, 1.37 mmol) and 4-dimethylaminopyridine (224 mg, of 1.87 mmol) dissolved in dichloromethane (20 ml)to the solution at room temperature add WSCI·HCl (193 mg, 1.01 mmol) and the mixture is then stirred for 2 hours in nitrogen atmosphere. The reaction solution was diluted with dichloromethane (200 ml), washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-70%), obtaining the target product (339 mg, yield 67%) as a white amorphous substance.

1H-NMR (CDCl3, 500 MHz): δ is 1.31 (3H, d, J=6.3 Hz), is 3.08 (3H, c), 3,42 (3H, c), 352 (1H, DD, J=3,9, 10,3 Hz), 3,60 (1H, DD, J=6,2, 10,2 Hz), to 3.58-the 3.65 (1H, m), 3,85 (1H, DDD, J=2.7, and 6,6, and 14.9 Hz), 4,08-to 4.15 (1H, USM), 4,53-4,60 (1H, m), 4,74 (1H, d, J=5.5 Hz), 6,37 (1H, t, J=6,1 Hz), 6,50 (1H, DD, J=3,0, 4.0 Hz), to 6.58 (1H, t, J=2.2 Hz), to 6.67 (1H, DD, J=2.7, and 4.0 Hz), at 6.84 (1H, t, J=1.7 Hz), of 6.99 (1H, t, J=2.0 Hz), 7,13 (2H, d, J=8,9 Hz), to $ 7.91 (2H, d, J=8,9 Hz), 9,82 (1H, USS).

(34b) (5R)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-(trifluoromethyl)-4,5-dihydro-1,3-oxazol

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-N-[(2S)-3,3,3-Cryptor-2-hydroxypropyl]-1H-pyrrol-2-carboxamide (339 mg, 0.61 mmol)synthesized in example (34a), dissolved in tetrahydrofuran (10 ml)to the solution at 0°C. add triethylamine (0.51 ml, 3,66 mmol) and anhydrous methansulfonate acid (296 mg, 1,71 mmol), after which the mixture is heated to 120°C and maintained at this temperature for 30 hours. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate (60 ml). The mixture was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-50%)to give the target product (328 mg, yield 84%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ of 1.33 (3H, d, J=6.3 Hz), is 3.08 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=3,9, 10,4 is C), 3,59 (1H, DD, J=6,3, 10.1 Hz), 4,15 (1H, DD, J=6,5, to 15.4 Hz), 4,22 (1H, DD, 10,0, to 15.4 Hz), 4,55-4,59 (1H, m), 4,88 to 4.92 (1H, m), of 6.52 (1H, DD, J=2,4, 4.0 Hz), to 6.58 (1H, t, J=2.2 Hz), PC 6.82 (1H, t, J=1,8 Hz), at 6.84 (1H, DD, J=2,3, 3,9 Hz), 6,98 (1H, t, J=2.0 Hz), 7,13 (2H, d, J=8,8 Hz), to $ 7.91 (2H, d, J=8,8 Hz), the 9.25 (1H, USS).

MS (ESI) m/z: 539,14603 (M+H)+.

Example 35

[(5R)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol

(35a) N-[(2S)-2,3-Dihydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (338 mg, 0,759 mmol)synthesized in example (18a), dissolved in dichloromethane (10 ml)solution was added (S)-(-)-3-amino-1,2-propandiol (105 mg, 1.15 mmol), WSCI·HCl (220 mg, 1.15 mmol) and 4-dimethylaminopyridine (185 mg and 1.51 mmol) and the resulting mixture was stirred at room temperature for 3 days under nitrogen atmosphere. To the reaction solution was added 1 N. hydrochloric acid (10 ml) and the solution share with dichloromethane (15 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=70%-100%), receiving targeted about the SPS (265 mg, yield 68%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,553-of 3.64 (4H, m), 3,85 (1H, m), of 4.57 (1H, m), 6,38 (1H, m), 6,50 (1H, DD, J=2.7, and a 3.9 Hz), to 6.58 (1H, t, J=2.0 Hz), only 6.64 (1H, DD, J=2,4, 3,9 Hz), at 6.84 (1H, t, J=2.0 Hz), 7,00 (1H, t, J=2.0 Hz), 7,13 (2H, d, J=9.0 Hz), to $ 7.91 (2H, d, J=9.0 Hz), 9,59 (1H, USS).

(35b) N-{(2S)-2-Hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide

N-[(2S)-2,3-Dihydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide (265 mg, 0,514 mmol)synthesized in example (35a), dissolved in dichloromethane (10 ml)and to the solution add triisopropylsilane (0,12 ml, 0,691 mmol), triethylamine (0.21 in ml and 1.51 mmol) and 4-dimethylaminopyridine (6.0 mg that 0,049 mmol) and the resulting mixture was stirred at room temperature for 24 hours under nitrogen atmosphere. To the reaction solution was added water (10 ml) and the resulting mixture is separated dichloromethane (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-50%)to give the target product (177 mg, 51%yield) as a solid white color.

1H-NMR (CDCl 3, 400 MHz): δ 1.04 million-1,13 (21H, m)of 1.32 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,21 (1H, d, J=4.3 Hz), to 3.38 (1H, m), 3,42 (3H, c), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,60 (1H, DD, J=6,3, 10,2 Hz)to 3.67 (1H, DD, J=6,3, 9,8 Hz), to 3.73 (1H, m), 3,76 (1H, DD, J=5.0 and 9.8 Hz), 3,86 (1H, m), 4,58 (1H, m), to 6.43 (1H, OST, J=5,9 Hz), 6.48 in (1H, DD, J=2,8, 3,9 Hz), 6,56 (1H, t, J=2.0 Hz), is 6.61 (1H, DD, J=2,4, 3,9 Hz), 6,85 (1H, t, J=2.0 Hz), 7,00 (1H, t, J=2.0 Hz), 7,13 (2H, d, J=8.6 Hz), of 7.90 (2H, d, J=8.6 Hz), 9,80 (1H, USS).

(35c) (5S)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol

N-{(2S)-2-Hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide (177 mg, 0,262 mmol)synthesized in example (35b), dissolved in tetrahydrofuran (10 ml), to the solution was added anhydrous methansulfonate acid (70.0 mg, 0,402 mmol) and triethylamine (to 0.22 ml, was 1.58 mmol) and the resulting mixture was stirred at 70°C for 3 days under nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (10 ml) and extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-60%)to give the desired product (180 mg, yield ~100%) in the form of oil as the color.

1H-NMR (CDCl3, 400 MHz): δ 1,02-of 1.10 (21H, m)of 1.33 (3H, d, J=6.3 Hz), of 3.07 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=4,3, 10,2 Hz)and 3.59 (1H, DD, J=6,3, 10,2 Hz), 3,82-are 3.90 (3H, m)4,00 (1H, DD, J=9,8, 14.1 Hz), 4,58 (1H, m), 4.75 in (1H, m), of 6.49 (1H, d, J=3,9 Hz), 6,55 (1H, t, J=2.0 Hz), was 6.73 (1H, d, J=3,9 Hz), 6,83 (1H, t, J=2.0 Hz), 7,00 (1H, t, J=2.0 Hz), 7,13 (2H, d, J=9.0 Hz), of 7.90 (2H, d, J=9.0 Hz), 9,59 (1H, USS).

(35d) [(5R)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol-5-yl]methanol

(5S)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol (180 mg, 0,262 mmol)synthesized in example (35c), dissolved in tetrahydrofuran (10 ml), to the solution was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran, of 0.53 ml of 0.53 mmol) and the reaction mixture was stirred at room temperature for 30 minutes in nitrogen atmosphere. To the mixture is added water (10 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-100%)to give the target compound (103 mg, yield 79%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.27 (3H, d, J=6.3 Hz), of 3.07 (3H, c), 3,42 (3H, c), 3,49 (1H, DD, J=3,9, 0.2 Hz), to 3.58 (1H, DD, J=6,3, 10,2 Hz)to 3.67 (1H, DD, J=5,1, 12,5 Hz), 3,74 (1H, DD, J=7,4, 14,5 Hz), a-3.84 (1H, DD, J=3,1, 12,5 Hz), 4,00 (1H, DD, J=9,8, 14,5 Hz), of 4.54 (1H, m), 4,78 (1H, m), 6,46 (1H, d, J=3,9 Hz), 6,55 (1H, t, J=2.0 Hz), of 6.71 (1H, d, J=3,9 Hz), 6,85 (1H, t, J=2.0 Hz), 6,98 (1H, t, J=2.0 Hz), 7,14 (2H, d, J=8.6 Hz), of 7.90 (2H, d, J=9.0 Hz), 9,59 (1H, USS).

MS (ESI) m/z: 501,16898 (M+H)+.

Example 36

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5,5-dimethyl-4,5-dihydro-1,3-oxazol

(36a) of N-(2-Hydroxy-2-methylpropyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (300 mg, 0,673 mmol)synthesized in example (18a), dissolved in dichloromethane (10 ml), to the solution was added 1-amino-2-methyl-2-propanol (150 mg, 1,68 mmol), WSCI·HCl (185 mg, 0,965 mmol) and 4-dimethylaminopyridine (165 mg, 1.35 mmol) and the resulting mixture was stirred at room temperature for 17 hours under nitrogen atmosphere. To the reaction solution was added 1 N. hydrochloric acid (10 ml) and the solution share with dichloromethane (15 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-10%), receiving target product (307 mg, yield 88%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1.26 in (6H, c)of 1.32 (3H, d, J=6.3 Hz), of 3.07 (3H, c), is 3.41 (3H, c), is 3.41 (2H, m), 3,51 (1H, DD, J=3,9, 10,2 Hz)and 3.59 (1H, DD, J=6,3, 10,2 Hz), 4,58 (1H, m), 4,46 (1H, USS), 6,48 (1H, DD, J=2.7, and 3,9 Hz), 6,56 (1H, t, J=2.0 Hz), of 6.65 (1H, DD, J=2,4, 3,9 Hz)6,86 (1H, t, J=2.0 Hz), 7,00 (1H, t, J=2.0 Hz), 7,12 (2H, d, J=9.0 Hz), of 7.90 (2H, d, J=9.0 Hz), 9,86 (1H, USS).

(36b) of 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5,5-dimethyl-4,5-dihydro-1,3-oxazol

N-(2-Hydroxy-2-methylpropyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide (307 mg, 0,594 mmol)synthesized in example (36a), dissolved in tetrahydrofuran (10 ml), to the solution was added anhydrous methansulfonate acid (160 mg, 0,918 mmol) and triethylamine (0.25 ml, to 1.79 mmol) and the resulting mixture is stirred at room temperature for 4 days under nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (10 ml) and extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-70%), obtaining the target product (187 mg, yield 63%) as a solid washes the VA in white.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 1,47 (6H, c), of 3.07 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=3,9, 10,2 Hz)and 3.59 (1H, DD, J=6,3, 10,2 Hz), of 3.69 (1H, c), of 4.57 (1H, m), 6,50 (1H, d, J=3,9 Hz), 6,55 (1H, t, J=2.0 Hz), 6,74 (1H, d, J=3,9 Hz), 6,83 (1H, t, J=2.0 Hz), 7,00 (1H, t, J=2.0 Hz), 7,13 (2H, d, J=9.0 Hz), of 7.90 (2H, d, J=9.0 Hz).

MS (ESI) m/z: 499,18990 (M+H)+.

Example 37

2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5,6-dihydro-4H-1,3-oxazin

(37a) of N-(3-Hydroxypropyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (250 mg, 0,561 mmol)synthesized in example (18a), dissolved in dichloromethane (10 ml), to the solution was added 3-amino-1-propanol (90,0 μl, 1.18 mmol), WSCI-HCl (165 mg, 0.861 mmol) and 4-dimethylaminopyridine (140 mg, 1,15 mmol) and the resulting mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. To the reaction solution was added 1 N. hydrochloric acid (10 ml) and the solution separated dichloromethane (15 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-100%)to give the target product is (216 mg, yield 77%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 1.78 (2H, m), of 3.07 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,56-3,62 (3H, m), 3,71 (2H, m), 4,58 (1H, m), 6,32 (1H, USS), of 6.49 (1H, DD, J=2.7, and a 3.9 Hz), 6,56-6,60 (2H, m), at 6.84 (1H, t, J=2.0 Hz), of 6.99 (1H, t, J=2.0 Hz), 7,13 (2H, d, J=9.0 Hz), to $ 7.91 (2H, d, J=9.0 Hz), 9,63 (1H, USS).

(37b) 2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5,6-dihydro-4H-1,3-oxazin

N-(3-Hydroxypropyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulphonyl)phenoxy]phenyl}-1H-pyrrol-2-carboxamide (216 mg, 0,430 mmol)synthesized in example (37a), dissolved in tetrahydrofuran (10 ml), to the solution was added anhydrous methansulfonate acid (115 mg, 0,660 mmol) and triethylamine (of 0.18 ml, 1,29 mmol) and the resulting mixture was stirred at room temperature for 4 days, then at 80°C for 17 hours in a nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (10 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-90%), obtaining the target product (150 mg, yield 72%) as a solid pale brown color.

1/sup> H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), to 1.98 (2H, m), 3,06 (3H, c), is 3.41 (3H, c), 3,48-of 3.54 (3H, m)and 3.59 (1H, DD, J=6,3, 10,2 Hz), 4,32 (2H, OST, J=5.5 Hz), 4,56 (1H, m), 6,46 (1H, d, J=3,9 Hz), 6,53 (1H, t, J=2.0 Hz), 6,62 (1H, d, J=3,9 Hz), PC 6.82 (1H, t, J=2.0 Hz), of 6.99 (1H, t, J=2.0 Hz), 7,12 (2H, d, J=9.0 Hz), 7,89 (2H, d, J=9.0 Hz).

MS (ESI) m/z: 485,17572 (M+H)+.

Example 38

Methyl-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoate

(38a) 1-Bromo-3-methoxy-5-[(1S)-2-methoxy-1-methylethoxy]benzene

3-Bromo-5-methoxyphenol (7,60 g, or 37.4 mmol)synthesized in example (1a), dissolved in toluene (100 ml)solution was added R-(-)-1-methoxy-2-propanol (4,40 ml of 44.9 mmol) and triphenylphosphine (13.8 g, for 52.6 mmol)and then dropwise at 0°C add diethylazodicarboxylate (2.2 mol/l solution in toluene, 24 ml of 52.8 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours nitrogen atmosphere. The solvent is distilled off under reduced pressure, add diethyl ether (100 ml) and the precipitate removed by filtration. The mother liquor is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-20%)to give the target compound (which 9.22 g, yield 89%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ of 1.30 (3H, d, J=6.3 Hz), 3,40 (3H, c), 3,47 (1H, DD, J=10,6, a 4.3 Hz), 3,55 (1H, DD, J=10,4, 6,1 Hz), 3,76 (3H, c), 4,46-to 4.52 (1H, m), 6.42 per (1H, t, =2.2 Hz), of 6.65 (1H, DD, J=2,3, and 1.6 Hz), 6,69 (1H, t, J=2.0 Hz).

MS (EI) m/z: 274 (M)+.

(38b) 3-Bromo-5-[(1S)-2-methoxy-1-methylethoxy]phenol

1-Bromo-3-methoxy-5-[(1S)-2-methoxy-1-methylethoxy]benzene (of 9.21 g of 33.5 mmol)synthesized in example (38a), dissolved in 1-methyl-2-pyrrolidone (100 ml)to the solution add thiamethoxam sodium (2,75 g of 37.3 mmol) and the resulting mixture was stirred at 130°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add 2 N. hydrochloric acid (500 ml) and the mixture extracted with diethyl ether (300 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-25%), obtaining the target compound (8,30 g, yield 95%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), to 3.41 (3H, c), of 3.46 (1H, DD, J=10,2, a 4.3 Hz), 3,55 (1H, DD, J=10,6, 5,9 Hz), 4,45-4,51 (1H, m), 4,96 (1H, USS), 6,36 (1H, t, J=2.0 Hz), 6,59 (1H, t, J=2.0 Hz), of 6.68 (1H, t, J=2,0 Hz).

MS (EI) m/z: 260 (M)+.

(38c) 3-[(1S)-2-Methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

3-Bromo-5-[(1S)-2-methoxy-1-methylethoxy]phenol (8,30 g of 31.8 mmol)synthesized in example (38b), dissolved in N,N-dimethylformamide (100 ml)solution was added bis(pinacolato)LIBOR (10,50 g, a 41.3 mmol who), complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (810 mg, 0,992 mmol) and potassium acetate (15,50 g, 158 mmol) and the resulting mixture was stirred at 90°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, to the solution was added water (500 ml) and the mixture extracted with diethyl ether (300 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-30%)to give the target compound (8,75 g, yield 89%) as a brownish oil.

1H-NMR (CDCl3, 400 MHz): δ 1.26 in (3H, d, J=4,1 Hz)of 1.33 (12H, c)to 3.41 (1H, c), 3,47 (1H, DD, J=10,2, a 4.7 Hz), 3,57 (1H, DD, J=10,6, 5,9 Hz), to 4.52-4,58 (1H, m), 4,80 (1H, USS), 6,55 (1H, t, J=2.4 Hz), 6,83 (1H, d, J=2.4 Hz), to 6.95 (1H, d, J=2,4 Hz).

MS (FAB) m/z: 309 (M+H)+.

(38d) of tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate

3-[(1S)-2-Methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3,30 g of 10.7 mmol)synthesized in example (38c), and tert-butyl 2-bromo-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (4,10 g, 12.5 mmol)synthesized in example (1g), dissolved in a mixed solvent of 1,4-dioxane (100 ml) and water (25 ml), the solution add complex Dich orida [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (400 mg, 0,490 mmol) and potassium carbonate (7.20 g, to 52.1 mmol) and the reaction solution stirred at 50°C for 4 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, to the solution was added water (200 ml) and the mixture extracted with ethyl acetate (400 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=25%-40%), obtaining the target compound (3,72 g, yield 81%) as oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ 1,24-of 1.29 (12H, m), 3,40 (3H, c), 3,47 (1H, DD, J=4,4, 10,3 Hz), 3,57 (1H, DD, J=5,9, 10,3 Hz), 4,48-of 4.54 (1H, m), 5,74 (1H, OSS), to 6.19 (1H, USS), 6,39-6,44 (2H, USS), 6,55 (1H, USS), 6,60 (1H, d, J=3,9 Hz), 7,31 (1H, d, J=3.0 Hz), 7,81 (1H, d, J=3,4 Hz).

(38e) tert-Butyl 2-{3-[4-(methoxycarbonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (117 mg, 0,272 mmol)synthesized in example (38d), dissolved in dichloromethane (20 ml), to the solution was added 4-methoxycarbonylpropionyl acid (100 mg, 0,556 mmol), copper acetate(II) (80 mg, 0,440 mmol), triethylamine (0,20 ml, to 1.435 mmol) and molecular sieves 4Å (100 mg) and the resulting mixture was stirred at room temp is the temperature for 3 days under nitrogen atmosphere. The precipitate is removed by filtration through celite. Mother liquor is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=15%-25%), obtaining the target compound (70 mg, yield 46%) as a yellow oil.

1H-NMR (CDCl3, 400 MHz): δ 1,31 (12H, m), 3,40 (3H, c), of 3.48 (1H, DD, J=10,2, a 4.3 Hz), 3,57 (1H, DD, J=10,2, 5,9 Hz), 3,90 (3H, c), 4,48-4,58 (1H, m), and 6.25 (1H, d, J=3.5 Hz), to 6.58 (1H, d, J=3.5 Hz), 6,63 (1H, t, J=2.4 Hz), 6,70 (1H, DD, J=2,4, 1.2 Hz), at 6.84 (1H, DD, J=2,4, and 1.6 Hz),? 7.04 baby mortality (2H, d, J=9.0 Hz), 7,33 (1H, d, J=3.1 Hz), 7,80 (1H, d, J=3.5 Hz), 8,00 (2H, d, J=9.0 Hz).

(38f) Methyl-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoate

tert-Butyl 2-{3-[4-(methoxycarbonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70 mg, 0,124 mmol)synthesized in example (38e), dissolved in dichloromethane (1.0 ml). To the obtained solution under stirring in nitrogen atmosphere are added dropwise triperoxonane acid (2.0 ml) and the mixture is stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, then diluted with ethyl acetate (30 ml), add saturated aqueous solution of sodium bicarbonate (20 ml) and the solution separated. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure, and the scientists residue purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-50%)to give the target compound (65 mg, yield ~100%) liquid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 3,42 (3H, c), 3,52 (1H, DD, J=3,9, 10,2 Hz), 3,60 (1H, DD, J=5,9, 10,2 Hz), 3,91 (3H, c), 4,60-4,70 (1H, m), 6,56-6,59 (2H, m)6,86 (1H, USS), 6,93 (1H, USS), 7,05 (2H, d, J=9.0 Hz), to 7.15 (1H, USS), of 7.70 (1H, USS), 8,02 (2H, d, J=9.0 Hz).

MS (ESI) m/z: 465,19025 (M+H)+.

Example 39

1-(4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)alanon

(39a) of tert-butyl 2-{3-(4-acetylphenol)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (92 mg, 0,214 mmol)synthesized in example (38d), dissolved in dichloromethane (10 ml), to the solution was added 4-acetylphenylalanine acid (70 mg, 0,427 mmol), copper acetate(II) (60 mg, 0,330 mmol), triethylamine (0.15 ml, at 1.08 mmol) and molecular sieves 4Å (90 mg) and the resulting mixture was stirred at room temperature for 1 day under nitrogen atmosphere. The mixture caltrout through celite to remove the precipitate. Received the mother liquor is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=15%-25%), obtaining the target compound (73 mg, yield 62%) in the IDA butter yellow color.

1H-NMR (CDCl3, 400 MHz): δ 1.32 to (12H, m), to 2.57 (3H, c), 3,40 (3H, c), of 3.48 (1H, DD, J=10,2, a 4.3 Hz), 3,57 (1H, DD, J=10,2, 5,9 Hz), 4.53-in-of 4.54 (1H, m), of 6.26 (1H, d, J=3,9 Hz), 6,59 (1H, d, J=3.5 Hz), 6,63 (1H, t, J=2.3 Hz), of 6.71 (1H, t, J=1,8 Hz), 6,85 (1H, DD, J=2.2, while the 1.4 Hz), 7,06 (2H, dt, J=9,4, 2.4 Hz), 7,30 (1H, d, J=3.1 Hz), 7,80 (1H, d, J=3.1 Hz), 7,94 (2H, dt, J=9,4, 2,4 Hz).

(39b) 1-(4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)alanon

tert-Butyl 2-{3-(4-acetylphenol)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (73 mg, 0.133 mmol)synthesized in example (39a), dissolved in dichloromethane (1.0 ml). To the solution under stirring in nitrogen atmosphere are added dropwise triperoxonane acid (2.0 ml) and the mixture is stirred at room temperature for 2.5 hours. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-40%), obtaining the target compound (56 mg, yield 94%) liquid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 2,59 (3H, c), 3,42 (3H, c), 3,52 (1H, DD, J=10,3, 3,9 Hz)and 3.59 (1H, DD, J=10,3, 5,9 Hz), br4.61-and 4.68 (1H, m), 6,54-6,59 (2H, m), PC 6.82 (1H, d, J=2,9 Hz), 6,91 (1H, c), 7,06-7,11 (3H, USM), 7,18-7,20 (1H, USM), 7,68-of 7.70 (1H, USM), of 7.96 (2H, d, J=8,8 Hz), 10,51 (1H, USS).

MS (ESI) m/z: 449,15388 (M+H)+.

Example 40

1-(4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)ethanol

1-(4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)alanon (30 mg, 0,067 mmol)synthesized in example (39b), dissolved in a mixed solvent of tetrahydrofuran (3.0 ml) and methanol (1.0 ml), the solution add borohydride sodium (10 mg, 0,264 mmol) and the resulting mixture was stirred at room temperature for 3 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (10 ml) and the mixture extracted with ethyl acetate (10 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=40%-60%), obtaining the target compound (27.5 mg, yield 91%) as a solid white color.

1H-NMR (CDCl3, 400 Hz): δ of 1.33 (3H, d, J=6.3 Hz), of 1.53 (3H, d, J=6.3 Hz), 3,42 (3H, c), 3,49 (1H, DD, J=9,4, 5,1 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), to 4.52-4,59 (1H, m)to 4.92 (1H, q, J=6.3 Hz), 6,47-of 6.52 (2H, m), 6,72 (1H, t, J=2.7 Hz), 6,92 (1H, c),? 7.04 baby mortality (2H, d, J=8,2 Hz), 7,16 (1H, d, J=3.1 Hz), 7,37 (2H, d, J=9.0 Hz), to 7.67 (1H, d, J=3.1 Hz), 9,72 (1H, USS).

MS (ESI) m/z: 451,16915 (M+H)+.

Example 41

2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

(41a) 1-(3,4-Differentail)azetidin

Commercial the Eski available 3,4-differentyou acid (3.00 g, 19.0 mmol) dissolved in dichloromethane (50 ml), the solution is added N,N-dimethylformamide (0.10 ml)and then dropwise oxalicacid (1,98 ml of 22.8 mmol) and the resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The solvent is distilled off under reduced pressure, the obtained residue is dissolved in dichloromethane (100 ml), add the hydrochloride of azetidine of 2.27 g, and 24.2 mmol) and triethylamine (6,60 ml, with 47.4 mmol) and the resulting mixture was stirred at room temperature for 4.5 hours under nitrogen atmosphere. Add 0,5 N. hydrochloric acid (100 ml) and the mixture extracted with dichloromethane (100 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=40%-50%)to give the target compound (600 mg, yield 16%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ is 2.37 (2H, m)to 4.23 (2H, t, J=7.4 Hz), 4,32 (2H, t, J=7.4 Hz), 7,20 (1H, m), 7,40 (1H, m)to 7.50 (1H, m).

(41b) of 2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70 mg, 0,163 mmol)synthesized in example (38d)and 1-(3,4-differentail)azetidin (68 mg, 0.45 mmol), synthesized in example (41a), dissolved in dimethyl sulfoxide (3.0 ml), to the solution was added sodium hydride (60%, 25 mg, was 0.63 mmol) and the resulting mixture was stirred at 100°C for 5 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add 2 N. hydrochloric acid (30 ml) and the mixture extracted with diethyl ether (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-80%), obtaining the target compound (54 mg, yield 65%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), of 2.38 (2H, m)to 3.41 (3H, c), 3,50 (1H, DD, J=3,9, 10,2 Hz)to 3.58 (1H, DD, J=6,3, 10,2 Hz), 4,20-4.26 deaths (2H, USS), 4,33-and 4.40 (2H, USS), of 4.57 (1H, m), of 6.49-of 6.52 (2H, m), of 6.71 (1H, DD, J=2,4, 3,9 Hz), PC 6.82 (1H, DD, J=1,6, 2.4 Hz), 6,94 (1H, DD, J=1,6, 2.4 Hz), 7,07 (1H, t, J=8,2 Hz), 7,16 (1H, d, J=3.5 Hz), 7,40 (1H, DDD, J=1,2, 2,4, 8.6 Hz), 7,52 (1H, DD, J=2.0 a, and 11.0 Hz), to 7.68 (1H, d, J=3.2 Hz), 9,62 (1H, USS).

MS (ESI) m/z: 508,17094 (M+H)+.

Example 42

1-(3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoyl)azetidin-3-ol

(42a) 1-(3,4-differentail)-3-(tetrahydro-2H-Piran-2-yloxy)azetidin

Commercially available 3,4-differentyou acid (1,00 g, 6,33 mmol) p is straut in methanol (10 ml), add hydrochloride 3-hydroxyazetidine (830 mg, 7,58 mmol), n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (2.10 g, to 7.59 mmol) and N-methylmorpholin of 0.85 ml, and 2.83 mmol) and the resulting mixture was stirred at room temperature for 2.5 hours under nitrogen atmosphere. Insoluble substances are removed by filtration through celite and the solvent is distilled off under reduced pressure. The resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-70%).

The obtained product is dissolved in dichloromethane (20 ml)solution was added 3,4-dihydro-2H-Piran (1,00 ml, 11.1 mmol) and p-toluensulfonate pyridinium (250 mg, 0,99 mmol) and the resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. To the reaction solution add triethylamine (0.5 ml), the solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=35%-50%)to give the target compound (2.24 g, yield ~100%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ 1,48-of 1.65 (4H, USM), 1,68-1,89 (2H, USM), 3.46 in-3,55 (2H, USM), 3,83-3,88 (2H, USM), was 4.02-4,47 (2H, USM), 4,55-of 4.66 (2H, USM), 7,18-7,21 (1H, m), 7,38-7,42 (1H, m), 7,47-7,52 (1H, m).

(42b) of 2-(5-{3-(2-Fluoro-4-{[3-(tetrahydro-2H-Piran-2-yloxy)azetidin-1-yl]carbonyl}phenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-the l)-1,3-thiazole

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (150 mg, 0,348 mmol)synthesized in example (38d)and 1-(3,4-differentail)-3-(tetrahydro-2H-Piran-2-yloxy)azetidin (220 mg, 0,740 mmol)synthesized in example (42a), dissolved in dimethyl sulfoxide (5.0 ml)solution was added sodium hydride (60%, 70 mg, about 1.75 mmol) and the resulting mixture was stirred at 100°C for 1.5 hours in a nitrogen atmosphere. The reaction solution is cooled to room temperature, add a saturated solution of salt (30 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=65%-85%), obtaining the target compound (158 mg, 75%yield) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 1,48-1,90 (6H, m)to 3.41 (3H, c), 3.46 in-3,55 (2H, m), 3,50 (1H, DD, J=10,2, a 4.3 Hz)and 3.59 (1H, DD, J=10,4, 6,1 Hz), 3,80-to 3.89 (2H, m), 4,40 with 4.64 (4H, m), 6,51-of 6.52 (2H, m), 6,72 (1H, DD, J=3,5, 2.7 Hz), PC 6.82 (1H, USS), 6,94 (1H, USS), 7,06 (1H, t, J=8,4 Hz), 7,17 (1H, d, J=3.5 Hz), 7,34-7,44 (1H, m), 7,52 (1H, DD, J=10,0, 5.0 Hz), to 7.68 (1H, d, J=3.1 Hz), 9,52 (1H, USS).

MS (ESI) m/z: 608,22267 (M+H)+.

(42c) 1-(3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoyl)azetidin-3-ol

2-(5-{3-(2-Fluoro-4-{[3-(tetrahydro-2H-feast of the-2-yloxy)azetidin-1-yl]carbonyl}phenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole (110 mg, 0,181 mmol)synthesized in example (42b), dissolved in methanol (10 ml)and to the solution add 10-camphorsulfonic acid (20 mg, 0,086 mmol) and the resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. To the reaction solution add triethylamine (0.1 ml) and the solvent is distilled off under reduced pressure. The resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=90%-100%)to give the target compound (62 mg, yield 65%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 2,28 (1H, OSS), to 3.41 (3H, c), 3,50 (1H, DD, J=10,4, 4,1 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), 4,08 (1H, OSS), to 4.23 (1H, USS), 4,45-4,58 (2H, m), to 4.52-4,60 (1H, m), 4,71-4,80 (2H, m), 6,50-6,53 (2H, m), of 6.73 (1H, DD, J=3,5, 2.7 Hz), 6,83 (1H, t, J=1,8 Hz), 6,95-6,97 (1H, m), 7,06 (1H, t, J=8,2 Hz), 7,17 (1H, d, J=3.1 Hz), 7,37-7,40 (1H, m), 7,50-7,53 (1H, m), 7,68 (1H, d, J=3.1 Hz), being 9.61 (1H, USS).

MS (ESI) m/z: 524,16841 (M+H)+.

Example 43

Methyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoate

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (485 mg, 1,127 mmol)synthesized in example (38d)and commercially available methyl-3,4-differentat (540 mg, 3,137 mmol) dissolved in dimethyl sulfoxide (10 ml), to the solution was added sodium hydride (60%, 180 mg, mmol 4,50 and polucen the second mixture is stirred at 100°C for 2.5 hours in a nitrogen atmosphere. The reaction solution is cooled to room temperature, dobavlat water (50 ml) and the mixture extracted with diethyl ether (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-30%)to give the target compound (97 mg, yield 18%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), 3,39 (3H, c), of 3.48 (1H, DD, J=10,2, 3,9 Hz), 3,57 (1H, DD, J=10,2, 5,9 Hz), 3,91 (3H, c), 4,51-4,59 (1H, m), of 6.49-of 6.52 (2H, m), of 6.71 (1H, DD, J=3,9, and 2.3 Hz), 6,82-6,85 (1H, USM), 6,98 (1H, USS), 7,05 (1H, t, J=8,2 Hz), to 7.15 (1H, d, J=3.1 Hz), 7,66 (1H, d, J=3.1 Hz), 7,78 (1H, d, J=9.8 Hz), the 7.85 (1H, DD, J=11,1, 2.2 Hz), 9,78-9,87 (1H, m).

MS (ESI) m/z: 483,13782 (M+H)+.

Example 44

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}basamid

(44a) 3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid

Methyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoate (611 mg, of 1.42 mmol)synthesized in example (43), dissolved in methanol (18 ml)solution was added water (3 ml) and the monohydrate of lithium hydroxide (298 mg, 7,10 mmol) and the resulting mixture was stirred at 60°C for 4 hours in the atmosphere and the PTA. To the reaction solution was added water (50 ml), the mixture is extracted twice with ethyl acetate (40 ml) and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-75%), obtaining the target compound (519 mg, yield 88%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ to 1.38 (3H, d, J=6.3 Hz), of 3.45 (3H, c), 3,55 (1H, DD, J=10,2, a 4.3 Hz), to 3.64 (1H, DD, J=10,2, 5,9 Hz), 4,60-of 4.67 (1H, m), 6,63 (1H, DD, J=3,9, 2.7 Hz), 6,74 (1H, t, J=2.2 Hz), at 6.84 (1H, DD, J=3,9, 2,3 Hz), of 6.99 (1H, t, J=8,2 Hz), 7,16-7,14 (2H, m), 7,41 (1H, t, J=1,8 Hz), 7,55 (1H, dt, J=8,6, 1.0 Hz), to 7.61 (1H, d, J=3.1 Hz), 7,72 (1H, DD, J=10,6, 2.0 Hz), 11,85 (1H, c).

(44b) 3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}basamid

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (40,0 mg, 0,163 mmol)synthesized in example (44a), dissolved in dichloromethane (5 ml), to the solution was added 28% aqueous ammonia (0,50 ml), and WSCI·HCl (19.6 mg, is 0.102 mmol) and HOBt·H2O (13.1 mg, 0,086 mmol) and the resulting mixture was stirred at room temperature for 7 hours under nitrogen atmosphere. To the reaction solution was added water (10 ml) and the mixture extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled with igenom pressure, and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-75%), obtaining the target compound (11.3 mg, yield 28%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 3,42 (3H, c), 3,51 (1H, DD, J=10,3, 5,4 Hz)and 3.59 (1H, DD, J=10,3, 5,9 Hz), 4,54-br4.61 (1H, m), 6,51-is 6.54 (2H, m), of 6.73 (1H, DD, J=3,4, 2.4 Hz), at 6.84 (1H, c), 6,97 (1H, c), 7,09 (1H, t, J=8.1 Hz), 7,18 (1H, d, J=2,9 Hz), 7,53 (1H, d, J=8,8 Hz), to 7.67-7,73 (2H, m), 9,60 (1H, USS).

MS (ESI) m/z: 468,13800 (M+H)+.

Example 45

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-N-methylbenzamide

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (40,0 mg, 0,163 mmol)synthesized in example (44a), dissolved in tetrahydrofuran (5 ml)solution was added methylamine hydrochloride (17.3 mg, 0,256 mmol), HATU (64,5 mg, 0,170 mmol) and N,N-diisopropylethylamine (89 μl, 0.51 mmol) and the resulting mixture was stirred at room temperature for 4 hours in nitrogen atmosphere. To the reaction solution was added a saturated salt solution (15 ml), the mixture is extracted twice with ethyl acetate (15 ml), then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-55%), produces the target compound (41 mg, yield ~100%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), 3,03 (3H, d, J=4,7 Hz)to 3.41 (3H, c), 3,50 (1H, DD, J=10,2, 3,9 Hz)to 3.58 (1H, DD, J=10,2, 6.3 Hz), to 4.52-4,60 (1H, m), of 6.49-6,53 (2H, m), 6,72 (1H, DD, J=3,9, and 2.3 Hz), 6,79 (1H, t, J=2.0 Hz), 6,94 (1H, t, J=2.0 Hz), was 7.08 (1H, t, J=8.0 Hz), 7,17 (1H, d, J=3.5 Hz), 7,47 (1H, d, J=8.6 Hz), the 7.65 (1H, DD, J=10,9, 2.0 Hz), to 7.68 (1H, d, J=3,9 Hz), 9,48 (1H, USS).

MS (ESI) m/z: 482,15436 (M+H)+.

Example 46

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-N,N-dimethylbenzamide

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (40,0 mg, 0,163 mmol)synthesized in example (44a), dissolved in tetrahydrofuran (5 ml)solution was added dimethylamine hydrochloride (20,1 mg, 0,246 mmol), HATU (64,5 mg, 0,170 mmol) and N,N-diisopropylethylamine (89 μl, 0.51 mmol), the mixture is stirred at room temperature for 4 hours in nitrogen atmosphere. To the reaction solution was added a saturated salt solution (15 ml), the mixture is extracted twice with ethyl acetate (15 ml) and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-75%), obtaining the target compound (45 mg, yield 99%) as a solid pale yellow color.

1H-NMR(CDCl 3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), 3,02-3,14 (6H, USM), to 3.41 (3H, c), 3,50 (1H, DD, J=10,2, 3,9 Hz)to 3.58 (1H, DD, J=10,2, 5,9 Hz), to 4.52-br4.61 (1H, m), of 6.49-is 6.54 (2H, m), of 6.73 (1H, DD, J=3,7, 1.9 Hz), 6,85 (1H, t, J=1,6 Hz), to 6.95 (1H, t, J=1.6 Hz), was 7.08 (1H, t, J=8.0 Hz), 7,16-7,20 (2H, m), 7,29 (1H, DD, J=10,8, 1.8 Hz), to 7.68 (1H, d, J=3.1 Hz), 9,65 (1H, USS).

MS (ESI) m/z: 496,17025 (M+H)+.

Example 47

2-(5-{3-[2-Fluoro-4-(pyrrolidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (40,0 mg of 0.085 mmol)synthesized in example (44a), dissolved in tetrahydrofuran (5 ml), the solution add pyrrolidine (21 μl, 0.26 mmol), HATU (64,9 mg, 0,171 mmol) and N,N-diisopropylethylamine (89 μl, 0.51 mmol) and the resulting mixture was stirred at room temperature for 20 hours under nitrogen atmosphere. To the reaction solution was added a saturated salt solution (15 ml), the mixture is extracted twice with ethyl acetate (15 ml) and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-75%), obtaining the target compound (32 mg, yield 72%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), 1,84-to 1.98 (4H, m)to 3.38 (3H, c), 3,41-to 3.49 (3H, m), 3,55 (1H, DD, J=10,2, 5,9 Hz), 3,61 (2H, t, J=6.8 Hz), 4,8-4,56 (1H, m), 6,46-of 6.49 (2H, m), of 6.68 (1H, DD, J=3,9, 2.7 Hz), 6,78 (1H, t, J=1,8 Hz), 6.89 in (1H, t, J=2.0 Hz),? 7.04 baby mortality (1H, t, J=8,2 Hz), 7,13 (1H, d, J=3.1 Hz), 7,25-7,29 (1H, m), 7,38 (1H, DD, J=10,9, 2.0 Hz), to 7.64 (1H, d, J=3.5 Hz), of 9.51 (1H, USS).

MS (ESI) m/z: 522,18695 (M+H)+.

Example 48

4-(3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoyl)morpholine

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (49,0 mg, 0,105 mmol)synthesized in example (44a), dissolved in tetrahydrofuran (5 ml)solution was added morpholine (22 μl, 0.26 mmol), HATU (64,5 mg, 0,170 mmol) and N,N-diisopropylethylamine (89 μl, 0.51 mmol) and the mixture is stirred at room temperature for 4 hours in nitrogen atmosphere. To the reaction solution was added a saturated salt solution (15 ml), the mixture is extracted twice with ethyl acetate (15 ml) and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-75%), obtaining the target compound (39 mg, yield 70%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 3,42 (3H, c), 3,51 (1H, DD, J=10,2, a 4.3 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), and 3.72 (8H, OSS), to 4.52-br4.61 (1H, m), of 6.49-is 6.54 (2H, m), 6,72 (1H, DD, J=3,7, 2,5 Hz), PC 6.82 (1H, t, J=1,8 Hz), 6,93 (1H, t, J=1,8 Hz), to 7.09 (1H, t, J=8,2 Hz), 7,16-7,19 (2H, m), 7,30 (1H, DD, J10,6, 2.0 Hz), 7,69 (1H, d, J=3.1 Hz), to 9.45 (1H, USS).

MS (ESI) m/z: 538,18048 (M+H)+.

Example 49

2-(3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)-5-methyl-1,3,4-thiadiazole

(49a) N' -Acetyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzhydrazide

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (84 mg, 0,179 mmol)synthesized in example (44a), dissolved in dichloromethane (5.0 ml)solution was added acetohydrazide (40 mg, 0,540 mmol), HATU (200 mg, 0,526 mmol) and N,N-diisopropylethylamine (0.15 ml, 0,861 mmol) and the resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate)to give the target compound (110 mg, yield ~100%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1.44MB (3/2H, d, J=6.3 Hz), 1,49 (3/2H, d, J=6.3 Hz), was 2.05 (3H, c), of 3.46 (3H, c), 3,55 (1H, DD, J=10,8, 4,1 Hz), the 3.65 (1H, DD, J=10,0, 6,1 Hz), 4,58-4,69 (1H, m), 6,69 (1H, d, J=2.3 Hz), 6.73 x (1H c), 6,77 (1H, d, J=2.7 Hz), 7,12 (1H, USS), 7,16 (1H, USS), 7,29 (1H, USS), 7,34 (1H, USS), 7,37 (1H, OSS), was 7.45 (1H, d, J=8,2 Hz), a 7.62 (1H, USS), 11,51 (1H, OSS), to 11.79 (1H, USS), 12,56 (1H, USS).

MS (ESI) m/z: 547,14358 (M+Na)+.

(49b) 2-(3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-ti is evil-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)-5-methyl-1,3,4-thiadiazole

N' -Acetyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzhydrazide (40 mg, 0,076 mmol)synthesized in example (49a), dissolved in a mixed solvent of toluene (4.0 ml) and acetonitrile (2.0 ml)solution was added 2,4-disulfide 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphatase (45 mg, 0,111 mmol) and pyridine (0,03 ml, 0,372 mmol) and the resulting mixture was stirred at 100°C for 4 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, the solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-80%), obtaining the target compound (28 mg, yield 70%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), and 2.83 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=10,3, 4,4 Hz), 3,60 (1H, DD, J=10,3, 5,9 Hz), 4,57-4,63 (1H, m), 6,54-is 6.54 (2H, m), 6,77 (1H, c), 6,87 (1H, c), of 7.00 (1H, c), 7,14-7,17 (2H, m), of 7.64 (1H, DD, J=8,3, 1.0 Hz), to 7.68 (1H, d, J=3,4 Hz), to 7.84 (1H, DD, J=11,2, 2.0 Hz), 10,01 (1H, USS).

MS (ESI) m/z: 523,12785 (M+H)+.

Example 50

2-(3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)-5-methyl-1,3,4-oxadiazol

N' -Acetyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzhydrazide (45 mg, 0,086 mmol)synthesized in example (49a), dissolved in acetonitrile (3.0 ml), to the solution was added the hydrochloride (methoxycarbonylamino)triethylamine (50 mg, 0,210 mmol) and triethylamine (0.05 ml, 0,359 mmol) and the resulting mixture was stirred at 100°C for 1 day under nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=80%-100%)to give the target compound (26 mg, yield 60%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 2.63 in (3H, c), 3,42 (3H, c), 3,50 (1H, DD, J=10,2, a 4.3 Hz), 3,60 (1H, DD, J=10,2, 5,9 Hz), 4,54-to 4.62 (1H, m), 6,50-6,55 (2H, m), 6,72 (1H, DD, J=3,5, 2.0 Hz), 6,86 (1H, c), 6,99 (1H, c), 7,12-7,19 (2H, m), to 7.67 (1H, d, J=3.1 Hz), 7,78 (1H, d, J=9.0 Hz), 7,87 (1H, DD, J=10,8, and 1.4 Hz), 9,94 (1H, USS).

MS (ESI) m/z: 507,14909 (M+H)+.

Example 51

4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylbenzaldehyde

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (150 mg, 0,348 mmol)synthesized in example (38d)and commercially available 4-fluoro-3-methylbenzaldehyde (0,14 ml, 1,148 mmol) dissolved in dimethyl sulfoxide (5.0 ml)solution was added sodium hydride (60%, 40 mg, 1.00 mmol) and the resulting mixture was stirred at 100°C for 4 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add saturated aqueous races is the thief of ammonium chloride (30 ml) and the mixture extracted with diethyl ether (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=25%-30%)to give the target compound (84 mg, yield 54%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 2,39 (3H, c), 3,42 (3H, c), 3,50 (1H, DD, J=10,2, 3,9 Hz), 3,60 (1H, DD, J=10,4, 6,1 Hz), 4,55 with 4.64 (1H, m), 6,50 (1H, t, J=2.2 Hz), 6,53 (1H, DD, J=3,7, 2,9 Hz), 6,74 (1H, t, J=2.5 Hz), 6,83 (1H, t, J=2.0 Hz), of 6.96 (1H, d, J=8,2 Hz), 7,00-7,02 (1H, m), 7,17 (1H, d, J=3.1 Hz), the 7.65 (1H, d, J=2.3 Hz), to 7.68 (1H, d, J=3.1 Hz), 7,81 (1H, d, J=1.2 Hz), for 9.90 (1H, USS), 9,92 (1H, c).

MS (ESI) m/z: 449,15343 (M+H)+.

Example 52

(4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-were)methanol

4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylbenzaldehyde (32 mg, 0,071 mmol)synthesized in example 51, dissolved in methanol (3.0 ml), to the solution add borohydride sodium (5 mg, 0,132 mmol) and the resulting mixture was stirred at 0°C for 4 hours in nitrogen atmosphere. The reaction solution was allow to warm to room temperature, add saturated aqueous solution of ammonium chloride (10 ml) and the mixture extracted with ethyl acetate (10 ml). The organic layer is washed on Ishenim salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-75%), obtaining the target compound (26 mg, yield 81%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), and 2.26 (3H, c), is 3.41 (3H, c), 3,49 (1H, DD, J=10,2, a 4.3 Hz), to 3.58 (1H, DD, J=10,2, 5,9 Hz), 4,51-4,60 (1H, m), of 4.67 (2H, USS), 6,40 (1H, t, J=2.2 Hz), of 6.49 (1H, DD, J=3,5, 2.7 GHz), 6,70-6,72 (2H, m)6,86 (1H, DD, J=3,5, and 1.6 Hz), of 6.96 (1H, d, J=8,2 Hz), to 7.15 (1H, d, J=3.5 Hz), 7,19 (1H, DD, J=8,2, 2.0 Hz), 7,28 (1H, d, J=2.3 Hz), 7,66 (1H, d, J=3.5 Hz), 9,72 (1H, USS).

MS (ESI) m/z: 451,16757 (M+H)+.

Example 53

2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-methylphenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

(53a) 4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylbenzoic acid

4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylbenzaldehyde (50 mg, 0.11 mmol)synthesized in example 51, was dissolved in a mixed solvent of tert-butanol (5.0 ml) and water (2.0 ml), to the solution was added 2-methyl-2-butene (0.15 ml, of 1.42 mmol) and the dihydrate dihydrophosphate sodium (80 mg, 0.51 mmol)slowly at 0°C. add sodium chlorite (25 mg, 0.28 mmol) and the resulting mixture was stirred at 0°C for 2 hours in nitrogen atmosphere. To the mixture at 0°C add the Hydrosulphite solution soda is I (5 ml) and the mixture is stirred at room temperature for 10 minutes. To the mixture add water Hydrosulphite solution of sodium (15 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, obtaining the target compound (58 mg, yield ~100%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 2,33 (3H, c), is 3.41 (3H, c), 3,52 (1H, DD, J=10,6, a 4.3 Hz), 3,60 (1H, DD, J=10,2, 5,9 Hz), 4,62-4,71 (1H, m), 6,54-to 6.57 (2H, m), 6,85-6,87 (2H, m), 7,08-7,16 (2H, m), to 7.15 (1H, d, J=3.5 Hz), to 7.64 (1H, c), to 7.64 (1H, d, J=3.5 Hz), 7,87 (1H, c).

(53b) of 2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-methylphenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylbenzoic acid (58 mg, 0.125 mmol)synthesized in example (53a), and hydrochloride of azetidine (29 mg, 0,310 mmol) dissolved in dichloromethane (10.0 ml)solution was added HATU (95 mg, of 0.250 mmol) and N,N-diisopropylethylamine (0.15 ml, 0,861 mmol) and the resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=75%-90%), obtaining the target compound (58 mg, yield 92%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz) δ of 1.32 (3H, d, J=6.3 Hz), 2,30 (3H, c), 2,31-2,39 (2H, m)to 3.41 (3H, c), 3,49 (1H, DD, J=10,4, 4,1 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), 4,22-of 4.25 (2H, USM), 4,33 is 4.36 (2H, USM), to 4.52-4,60 (1H, m), to 6.43 (1H, t, J=2.3 Hz), 6,50 (1H, DD, J=3,7, 2,9 Hz), 6,72 (1H, DD, J=3,9, and 2.3 Hz), 6,76 (1H, t, J=1,8 Hz), make 6.90 (1H, c), 6,92-6,93 (1H, m), 7,16 (1H, d, J=3.1 Hz), 7,42 (1H, DD, J=8,2, 2.0 Hz), to 7.59 (1H, d, J=1.6 Hz), to 7.67 (1H, d, J=3.1 Hz), 9,73 (1H, USS).

MS (ESI) m/z: 504,19979 (M+H)+.

Example 54

2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-(trifluoromethyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

(54a) 1-[4-Fluoro-3-(trifluoromethyl)benzoyl]azetidin

Commercially available 4-fluoro-3-(trifluoromethyl)benzoic acid (230 mg, 1.10 mmol) dissolved in dichloromethane (50 ml), the solution was added the hydrochloride of azetidine (120 mg, 1.28 mmol), HATU (550 mg, 1,45 mmol) and N,N-diisopropylethylamine (0,50 ml, 2,87 mmol) and the resulting mixture is stirred for 4 hours at room temperature in a nitrogen atmosphere. To the mixture of 0.5 N. hydrochloric acid (100 ml) and the mixture extracted with dichloromethane (100 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-80%), obtaining the target compound (211 mg, yield 78%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ 2,35-2,4 (2H, m), 4,25 (2H, t, J=7,6 Hz)to 4.33 (2H, t, J=7.4 Hz), 7,83-7,87 (1H, m), to 7.93 (1H, DD, J=6,6, 2.0 Hz).

(54b) 2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-(trifluoromethyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (119 mg, 0.276 mmol)synthesized in example (38d)and 1-[4-fluoro-3-(trifluoromethyl)benzoyl]azetidine (145 mg, 0,587 mmol)synthesized in example (54a), dissolved in dimethyl sulfoxide (8,0 ml), to the solution was added sodium hydride (60%, 39 mg, 0.97 mmol) and the resulting mixture was stirred at 100°C for 2 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add saturated aqueous solution of ammonium chloride (30 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=45%-60%), obtaining the target compound (105 mg, yield 68%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 2,34-to 2.42 (2H, m), 3,42 (3H, c), 3,50 (1H, DD, J=10,2, a 4.3 Hz), 3,60 (1H, DD, J=10,2, 5,9 Hz), 4,25 (2H, t, J=6.8 Hz), 4,36 (2H, t, J=6.6 Hz), 4,56-4,60 (1H, m), 6,54-6,55 (2H,, m)of 6.73 (1H, DD, J=3,7, 2,5 Hz), 6.87 in (1H, t, J=1.6 Hz), of 6.99 (1H, d, J=8.6 Hz), 7,03 (1H, t, J=1.8 G is), 7,17 (1H, d, J=3.1 Hz), to 7.68 (1H, d, J=3.1 Hz), 7,74 (1H, DD, J=8,6, and 2.3 Hz), 8,00 (1H, d, J=2.0 Hz), 9,73 (1H, USS).

MS (ESI) m/z: 558,16727 (M+H)+.

Example 55

2-(5-{3-[4-(Azetidin-1-ylsulphonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

(55a) 1-[(4-Forfinal)sulfonyl]azetidin

Commercially available 4-forforstarkare (225 mg, 1.15 mmol) is suspended in water (8 ml), add the hydrochloride of azetidine (90,0 mg, 0.96 mmol) and potassium carbonate (293 mg, 2,12 mmol) and the resulting mixture was stirred at room temperature for 16 hours. To the reaction solution was added water (15 ml), the mixture was twice extracted with diethyl ether (15 ml), washed with saturated salt solution (15 ml) and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and dried in vacuum, obtaining the target compound (170 mg, yield 82%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 2,10-2,17 (2H, m), 3,82 (4H, t, J=7.8 Hz), 7,28-7,30 (2H, m), 7,88-a 7.92 (2H, m).

(55b) 2-(5-{3-[4-(Azetidin-1-ylsulphonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (60,0 mg, 0,139 mmol)synthesized in example (38d)and 1-[(4-forfinal)sulfonyl]azetidin (60,0 mg, 0,279 mmol)synthesized in example (55a), dissolved in N-metier is the Lydon (5.0 ml), to the solution was added sodium hydride (60%, 24 mg, of 0.60 mmol) and the resulting mixture was stirred at 100°C for 6 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (20 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-35%), obtaining the target compound (42 mg, yield 57%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.37 (3H, d, J=6.8 Hz), 2,12-to 2.18 (2H, m), of 3.45 (3H, c), of 3.54 (1H, DD, J=10,3, 4,4 Hz)to 3.64 (1H, DD, J=10,0, 6,1 Hz), 3,83 (4H, t, J=7,6 Hz), 4,59 with 4.65 (1H, m), to 6.57 (1H, t, J=3,4 Hz), 6,60 (1H, t, J=2.0 Hz), 6,76 (1H, t, J=3,7 Hz), 6,92 (1H, c), 7,07 (1H, c), 7,18 (2H, d, J=8,3 Hz), 7,21 (1H, d, J=2,9 Hz), 7,71 (1H, d, J=2,9 Hz), to 7.84 (2H, d, J=8,8 Hz), 9,76 (1H, USS).

MS (ESI) m/z: 526,14773 (M+H)+.

Example 56

2-(5-{3-[4-(Azetidin-1-ylsulphonyl)-2-fervency]-5-[(1S) -2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

(56a) 1-[(3,4-Differenl)sulfonyl]azetidin

Commercially available 3,4-differentialpressure (117 μl, 0.87 mmol) dissolved in dichloromethane (5 ml), to the solution was added the hydrochloride of azetidine (68 mg, 0.73 mmol) and triethylamine (203 μl, 1,45 mmol) and the resulting mixture plumage is eshivot at room temperature for 2 hours. To the reaction solution was added water (15 ml) and the mixture is twice extracted with dichloromethane (15 ml). The organic layer was washed with saturated salt solution (15 ml) and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-50%)to give the target compound (132 mg, yield 78%) as a colourless oil.

1H-NMR (CDCl3, 400 MHz): δ 2,10-to 2.18 (2H, m), 3,82 (4H, t, J=7,6 Hz), 7,35-7,41 (1H, m), 7,66 to 7.62 (1H, m), 7,72-to 7.68 (1H, m).

(56b) of 2-(5-{3-[4-(Azetidin-1-ylsulphonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (65,0 mg, 0,151 mmol)synthesized in example (38d)and 1-[(3,4-differenl)sulfonyl]azetidin (42,3 mg, 0,181 mmol)synthesized in example (56a), dissolved in N-organic (5.0 ml), to the solution was added sodium hydride (55%, 20 mg, 0.45 mmol) and the resulting mixture was stirred at 100°C for 4 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add saturated aqueous solution of ammonium chloride (20 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent banished is under reduced pressure, and the resulting residue is twice purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-35%), obtaining the target compound (35.6 mg, yield 43%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 2,11-of 2.20 (2H, m), 3,42 (3H, c), 3,51 (1H, DD, J=10,4, 4,1 Hz), 3,60 (1H, DD, J=10,4, 6,1 Hz), a-3.84 (4H, t, J=7,6 Hz), 4,55-4,63 (1H, m), 6,53-6,56 (2H, m), of 6.73 (1H, DD, J=3,9, and 2.3 Hz), 6.89 in (1H, t, J=2.0 Hz), 7,03 (1H, t, J=1,8 Hz), 7,14 (1H, t, J=8.0 Hz), 7,18 (1H, d, J=3.5 Hz), EUR 7.57 (1H, d, J=8.6 Hz), to 7.67-7,71 (2H, m), 9,79 (1H, USS).

MS (ESI) m/z: 544,13720 (M+H)+.

Example 57

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-N,N-dimethylbenzenesulfonamide

(57a) 3,4-Debtor-N,N-dimethylbenzenesulfonamide

Commercially available 3,4-differentialpressure (117 μl, 0.87 mmol) dissolved in dichloromethane (5 ml)solution was added dimethylamine hydrochloride (59 mg, 0.73 mmol) and triethylamine (203 μl, 1,45 mmol) and the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution was added water (15 ml), the mixture was twice extracted with dichloromethane (15 ml), then washed with saturated salt solution (15 ml), then dried over sodium sulfate. The solvent is distilled off under reduced pressure and then dried in vacuum, obtaining the target compound (41.0 mg, yield 26%) as a colourless oil.

1NMR (CDCl 3, 400 MHz): δ is 2.74 (6H, c), 7,32-7,38 (1H, m), to 7.59-of 7.55 (1H, m), to 7.61-7,66 (1H, m).

(57b) 3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-N,N-dimethylbenzenesulfonamide

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (65,0 mg, 0,151 mmol)synthesized in example (38d), and 3,4-debtor-N,N-dimethylbenzenesulfonamide (40,1 mg, 0,181 mmol)synthesized in example (57a), dissolved in N-organic (5.0 ml), the solution add sodium hydride (55%, 20 mg, 0.45 mmol) and the resulting mixture was stirred at 100°C for 4 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add saturated aqueous solution of ammonium chloride (20 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-35%), obtaining the target compound (31,0 mg, yield 39%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), was 2.76 (6H, c), 3,42 (3H, c), 3,51 (1H, DD, J=10,4, 4,1 Hz), 3,60 (1H, DD, J=10,4, 6,1 Hz), 4,55-to 4.62 (1H, m), 6,53-6,55 (2H, m), of 6.73 (1H, DD, J=3,7, 2,5 Hz), 6.87 in (1H, t, J=1,8 Hz), 7,02 (1H, t, J=1,8 Hz), 7,12 (1H, t, J=8.0 Hz), 7,18 (1H, d, J=3.5 Hz), 7,52-7,49 (1H, m), 7,63 (1H, DD, J=9,8, 2.0 Hz), 7.68 per 1H, d, J=3.1 Hz), 9,79 (1H, c).

MS (ESI) m/z: 532,13886 (M+H)+.

Example 58

3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-N-methylbenzenesulfonamide

(58a) 3,4-Debtor-N-methylbenzenesulfonamide

Commercially available 3,4-differentialpressure (117 μl, 0.87 mmol) dissolved in dichloromethane (5 ml)solution was added methylamine hydrochloride (49 mg, 0.73 mmol) and triethylamine (203 μl, 1,45 mmol) and the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution was added water (15 ml), the mixture was twice extracted with dichloromethane (15 ml), washed with saturated salt solution (15 ml) and then dried over sodium sulfate. The solvent is distilled off under reduced pressure, the residue is dried in vacuum, obtaining the target compound (44,7 mg, 30%yield) as a colorless oil.

1H-NMR (CDCl3, 400 MHz): δ 2,70 (3H, d, J=5.5 Hz), 4,43 (1H, OSS), was 7.36-7,30 (1H, m), of 7.64-7.68 per (1H, m), 7,69-7,74 (1H, m).

(58b) 3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-N-methylbenzenesulfonamide

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (60,0 mg, 0,139 mmol)synthesized in example (38d), and 3,4-debtor-N-methylbenzenesulfonamide (47,4 mg, 0,229 mmol)synthesized in example (58a), dissolved in N,N-dimethylformamide (5.0 ml), RAS the thief added potassium carbonate (77.0 mg, 0,557 mmol) and the resulting mixture was stirred at 100°C for 19 hours in a nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (20 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-25%), obtaining the target compound (21.1 mg, 30%yield) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (4H, d, J=5,9 Hz), 2,69 (3H, d, J=5.4 Hz), 3,42 (3H, c), 3,51 (1H, DD, J=10,3, 4,4 Hz), 3,60 (1H, DD, J=10,3, 5,9 Hz), 4,55-br4.61 (1H, m), with 5.22 (1H, c), 6,55 (2H, dt, J=8,3, 2.7 Hz), 6,74 (1H, t, J=2,9 Hz), 6.89 in (1H, c), 7,01 (1H, t, J=1.7 Hz), 7,12 (1H, t, J=8.1 Hz), 7,16-to 7.18 (1H, m), 7,56-to 7.61 (2H, m), of 7.69 (1H, d, J=9.8 Hz), 9,96 (1H, USS).

MS (ESI) m/z: 518,12006 (M+H)+.

Example 59

5-(Azetidin-1-ylcarbonyl)-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine

(59a) 5-(Azetidin-1-ylcarbonyl)-2-chloropyridin

Commercially available 6-chloronicotinic acid (160 mg, 1.01 mmol) was dissolved in dichloromethane (5 ml), to the solution was added the hydrochloride of azetidine (130 mg, of 1.39 mmol), HATU (420 mg, 1.10 mmol) and N,N-diisopropylethylamine (0,50 ml, 2,87 mmol) and the resulting mixture is stirred overnight at the room for the Noah temperature in a nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=40%-50%)to give the target compound (210 mg, yield ~100%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ 2.40 a (2H, m), 4,25 (2H, t, J=7,6 Hz), 4,35 (2H, t, J=7,6 Hz), 7,40 (1H, DD, J=0,8, 8.6 Hz), of 7.97 (1H, DD, J=2,4, and 8.2 Hz), to 8.62 (1H, DD, J=0.8, the 2,4 Hz).

(59b) 5-(Azetidin-1-ylcarbonyl)-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (84 mg, of € 0.195 mmol)synthesized in example (38d)and 5-(azetidin-1-ylcarbonyl)-2-chloropyridin (110 mg, 0,559 mmol)synthesized in example (59a), dissolved in dimethyl sulfoxide (3.0 ml), to the solution was added sodium hydride (60%, 30 mg, 0.75 mmol) and the resulting mixture was stirred at 100°C for 2 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add 2 N. hydrochloric acid (30 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=75%-90%), obtaining the target compound (56 m is, yield 59%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), of 2.38 (2H, m), 3,42 (3H, c), 3,50 (1H, DD, J=4,3, 10,2 Hz), 3,60 (1H, DD, J=5,9, 10,2 Hz), 4,24 (2H, t, J=7.4 Hz), 4,36 (2H, t, J=6.6 Hz), of 4.57 (1H, m), is 6.54 (1H, DD, J=2,7, 3,9 Hz), only 6.64 (1H, t, J=2.3 Hz), was 6.73 (1H, DD, J=2,4, 3,9 Hz), 6,97 (2H, m), 7,07 (1H, t, J=1,8 Hz), 7,16 (1H, d, J=3.5 Hz), to 7.67 (1H, d, J=3.1 Hz), 8,07 (1H, DD, J=2.7, and 8.6 Hz), to 8.45 (1H, d, J=2.4 Hz), 9,85 (1H, USS).

MS (ESI) m/z: 491,17450 (M+H)+.

Example 60

5-(Azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine

(60a) 5-(Azetidin-1-ylcarbonyl)-2,3-dichloropyridine

Commercially available 5,6-dichloronicotinic acid (200 mg, 1.04 mmol) dissolved in dichloromethane (5.0 ml)solution was added the hydrochloride of azetidine (125 mg, of 1.34 mmol), HATU (440 mg, of 1.16 mmol) and N,N-diisopropylethylamine (0.45 ml, 2.58 mmol) and the resulting mixture was stirred at room temperature for 5 hours in nitrogen atmosphere. To the mixture of 0.5 N. hydrochloric acid (30 ml) and the mixture extracted with dichloromethane (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-80%), obtaining the target compound (162 mg, yield 67%) as bescot the second liquid.

1H-NMR (CDCl3, 400 MHz): δ 2,38 is 2.46 (2H, m), 4,25 (2H, t, J=7,6 Hz), 4,37 (2H, t, J=7,6 Hz), 8,10 (1H, d, J=2.3 Hz), 8,51 (1H, d, J=2.3 Hz).

(60b) 5-(Azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70 mg, 0,163 mmol)synthesized in example (38d)and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (75 mg, 0,325 mmol)synthesized in example (60a), dissolved in dimethyl sulfoxide (5.0 ml), solution add sodium hydride (60%, 30 mg, 0.75 mmol) and the resulting mixture was stirred at 100°C for 3.5 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature, add saturated aqueous solution of ammonium chloride (30 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=85%-100%)to give the target compound (58 mg, yield 68%) as a solid yellow color.

lH-NMR (CDCl3, 400 MHz): δ of 1.35 (3H, d, J=5,9 Hz), 2,34-to 2.42 (2H, m), 3,42 (3H, c), 3,51 (1H, DD, J=10,6, a 4.7 Hz), 3,61 (1H, DD, J=10,4, 5.7 Hz), 4,21-4,27 (2H, m), 4,34-4,37 (2H, m), 4,56-4,59 (1H, m), is 6.54 (1H, t, J=2,9 Hz), of 6.66 (1H, t, J=1,8 Hz), 6,72 (1H, t, J=9 Hz), of 6.96 (1H, c), 7,05 (1H, c), 7,16 (1H, DD, J=3.3V, 0.6 Hz), to 7.68 (1H, DD, J=3.3V, 0.6 Hz), 8,16 (1H, DD, J=2.0 a, and 0.8 Hz), compared to 8.26 (1H, DD, J=1,8, 1.0 Hz), to 9.57 (1H, USS).

MS (ESI) m/z: 525,13929 (M+H)+.

Example 61

5-(Azetidin-1-ylcarbonyl)-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylpyridin

(61a) 5-(Azetidin-1-ylcarbonyl)-2-chloro-3-methylpyridin

Commercially available 6-chloro-5-methylnicotinic acid (200 mg, 1,29 mmol) dissolved in dichloromethane (7.0 ml), the resulting solution was added the hydrochloride of azetidine (160 mg, 1,71 mmol), HATU (1000 mg, 2,63 mmol) and N,N-diisopropylethylamine (0,69 ml of 3.96 mmol) and the mixture is then stirred at room temperature overnight under nitrogen atmosphere. To the mixture of 0.5 N. hydrochloric acid (30 ml) and the mixture extracted with dichloromethane (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-75%), obtaining the target compound (160 mg, yield 64%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ 2,32 (3H, c), a 2.36-to 2.42 (2H, m), 4,24 (2H, t, J=7,6 Hz), 4,35 (2H, t, J=7,6 Hz), 7,95 (1H, DD, J=9,3, 1.0 Hz), compared to 8.26 (1H, d, J=1.0 Hz).

(61b) 5-(Azetidin-1-ylcarbonyl)-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]Fe is oxy}-3-methylpyridin

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (59 mg, 0,137 mmol)synthesized in example (38d)and 5-(azetidin-1-ylcarbonyl)-2-chloro-3-methylpyridin (45 mg, 0,232 mmol)synthesized in example (61a), dissolved in dimethyl sulfoxide (3.0 ml), to the solution was added sodium hydride (60%, 25 mg, was 0.63 mmol) and the resulting mixture was stirred at 80°C for 4.5 hours under nitrogen atmosphere. The reaction solution is cooled to room temperature, add saturated aqueous solution of ammonium chloride (30 ml) and the mixture extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-80%), obtaining the target compound (50 mg, yield 72%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.35 (3H, d, J=6.3 Hz), 2,32-of 2.38 (2H, m), is 2.40 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=10,2, a 4.3 Hz), 3,60 (1H, DD, J=10,2, 5,9 Hz), to 4.23 (2H, t, J=7.2 Hz), 4,34 (2H, t, J=6.6 Hz), 4,56-4,58 (1H, m,), 6,53 (1H, DD, J=3,9, 2.7 Hz), 6,63 (1H, t, J=2.0 Hz), 6,72 (1H, DD, J=3,9, and 2.3 Hz), 6,92 (1H, t, J=1,8 Hz), 7,00 (1H, DD, J=3,9, and 1.6 Hz), 7,16 (1H, d, J=3.1 Hz), to 7.67 (1H, d, J=3.1 Hz), 7,94 (1H, DD, J=2,3, and 0.8 Hz), by 8.22 (1H, d, J=2.3 Hz), 9,46 (1H, USS).

MS (ESI) m/z: 505,19091 (M+H)+.

Example 62

Methyl 5-{3-[(1S)-2-methoxy-1-metile the oxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazin-2-carboxylate

(62a) Methyl-5-hydroxypyridine-2-carboxylate

Commercially available 5-hydroxypyridine-2-carboxylic acid (1,00 g, 7,14 mmol) dissolved in methanol (5 ml), to the solution was added 4 n hydrochloric acid in dioxane (25 ml), the mixture was stirred at 60°C for 1.5 hours and refluxed at 80°C for 2.5 hours. The reaction solution was allow to warm to room temperature, the solvent is distilled off under reduced pressure, and the obtained residue is added ethyl acetate (20 ml) to obtain a suspension. The formed precipitate is removed by filtration, washed with ethyl acetate and dried in vacuum, obtaining the target compound (673 mg, yield 61%) as a solid substance Orangevale brown.

1H-NMR (CD3OD, 400 MHz): δ of 3.31 (1H, c), 3,85 (3H, c), of 8.00 (1H, d, J=1.2 Hz), 8,13 (1H, d, J=1.2 Hz).

(62b) Methyl-5-chloropyrazine-2-carboxylate

Methyl-5-hydroxypyridine-2-carboxylate (673 mg, 4,37 mmol)synthesized in example (62a), dissolved in oxytrichloride phosphorus (6,1 ml) and add a few drops of N,N-dimethylformamide and the resulting mixture is refluxed for 2 hours in nitrogen atmosphere. The reaction solution was poured into ice water and the mixture extracted three times with chloroform (30 ml). The organic layer was washed with saturated aqueous bicarbonate is sodium and saturated salt solution (100 ml of each solution) and then dried over sodium sulfate. The solvent is distilled off under reduced pressure, obtaining the target compound (611 mg, yield 81%) as a solid gray color.

1H-NMR (CDCl3, 400 MHz): δ of 4.05 (3H, c)8,71 (1H, d, J=1.6 Hz), 9,10 (1H, d, J=1.2 Hz).

(62c) Methyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazin-2-carboxylate

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (200 mg, 0,464 mmol)synthesized in example (38d)and methyl-5-chloropyrazine-2-carboxylate (120 mg, 0,695 mmol)synthesized in example (62b), dissolved in N,N-dimethylformamide (10 ml), to the solution was added potassium carbonate (257 mg, of 1.86 mmol) and the resulting mixture was stirred at 80°C for 7 hours in a nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (40 ml) and the mixture extracted with ethyl acetate (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-50%). The obtained solid yellow product was dissolved in dichloromethane (2 ml)to the solution add triperoxonane acid (4 ml) and the mixture is stirred at room temperature for 1.5 hours. To the reaction solution add Aut saturated aqueous solution of sodium bicarbonate (40 ml) and the mixture is extracted twice with ethyl acetate (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-50%)to give the target compound (164 mg, yield 93%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.35 (3H, d, J=6.3 Hz), 3,42 (3H, c), 3,52 (1H, DD, J=10,2, a 4.3 Hz), 3,60 (1H, DD, J=10,2, 5,9 Hz), was 4.02 (3H, c), 4,56-4,63 (1H, m), 6,55 (1H, DD, J=3,9, 2.7 Hz), to 6.67 (1H, t, J=2.2 Hz), to 6.75 (1H, DD, J=3,9, and 2.3 Hz), 6,98 (1H, t, J=1,8 Hz), 7,10 (1H, t, J=1,8 Hz), 7,18 (1H, d, J=3.5 Hz), to 7.68 (1H, d, J=3.1 Hz), 8,51 (1H, d, J=1.2 Hz), 8,87 (1H, d, J=1.2 Hz), 9,74 (1H, USS).

MS (ESI) m/z: 467 (M+H)+.

Example 63

2-(Azetidin-1-ylcarbonyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazin

(63a) 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazin-2-carboxylic acid

Methyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazin-2-carboxylate (423 mg, 0,907 mmol)synthesized in example (62c), dissolved in methanol (10 ml), to the solution was added water (2 ml) and the monohydrate of lithium hydroxide (76,2 mg, 1.82 mmol) and the resulting mixture was stirred at 50°C for 1 hour in nitrogen atmosphere. To the reaction solution was added water (30 ml), the mixture is extracted twice utilized the volume (30 ml) and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: dichloromethane/methanol=0%-10%), obtaining the target compound (269 mg, yield 66%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ to 1.38 (3H, d, J=6.3 Hz), 3,44 (3H, c), of 3.54 (1H, DD, J=10,2, a 4.3 Hz), 3,63 (1H, DD, J=10,2, 5,9 Hz), 4,60 with 4.65 (1H, m), 6,62 (1H, DD, J=3,9, and 2.3 Hz), of 6.71 (1H, t, J=2.2 Hz), PC 6.82 (1H, DD, J=3,9, 2,3 Hz), 7,16-to 7.18 (2H, m), 7,37 (1H, c), to 7.67 (1H, d, J=3.5 Hz), 8,54 (1H, d, J=1.2 Hz), 8,81 (1H, c), 11,30 (1H, USS).

(63b) 2-(Azetidin-1-ylcarbonyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazin

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazin-2-carboxylic acid (28,0 mg, 0,062 mmol)synthesized in example (63a), dissolved in tetrahydrofuran (3 ml), to the solution was added the hydrochloride of azetidine a (17.4 mg, 0,186 mmol), HATU (35,3 mg, 0,093 mmol) and N,N-diisopropylethylamine (65 μl, of 0.37 mmol) and the resulting mixture was stirred at room temperature for 28 hours in a nitrogen atmosphere. To the reaction solution was added water (15 ml), the mixture is extracted with ethyl acetate (15 ml)then the organic layer is dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue purified preparative TLC (mobile phase: methanol/dichloromethane=15%), obtaining the target compound (29,1 mg, yield 96% in a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.35 (3H, d, J=5,9 Hz), 2,35-to 2.41 (2H, m), 3,42 (3H, c), 3,51 (1H, DD, J=10,3, 3,9 Hz), 3,60 (1H, DD, J=10,3, 5,9 Hz), 4.26 deaths (2H, t, J=7.8 Hz), 4,54-4,60 (1H, m), 4,69 (2H, t, J=7.8 Hz), is 6.54 (1H, t, J=3.2 Hz), of 6.65 (1H, c), of 6.73 (1H, t, J=2,9 Hz), to 6.95 (1H, c), 7,06 (1H, t, J=1.7 Hz), 7,17 (1H, d, J=2,9 Hz), to 7.67 (1H, d, J=3,4 Hz), 8,31 (1H, c), 8,88 (1H, c), RS 9.69 (1H, USS).

MS (ESI) m/z: 492,16821 (M+H)+.

Example 64

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazin-2-carboxylic acid (40,4 mg, 0,089 mmol)synthesized in example (63a), dissolved in tetrahydrofuran (5 ml), to the solution was added 1-methylpiperazine (30 μl, 0.27 mmol), HATU (67,9 mg, 0.18 mmol) and N,N-diisopropylethylamine (93 μl, 0.54 mmol) and the resulting mixture was stirred at room temperature for 12 hours under nitrogen atmosphere. To the reaction solution was added water (15 ml), the mixture is extracted with ethyl acetate (15 ml) and then the organic layer is dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/dichloromethane=0%-5%)to give the target compound (47 mg, yield 98%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.35 (3H, d, J=6.3 Hz), is 2.37 (3H, c), of 2.50 (2H, the sh), of 2.56 (2H, USS), 3,42 (3H, c), 3,52 (1H, DD, J=10,2, a 4.3 Hz), 3,61 (1H, DD, J=10,4, 6,1 Hz in), 3.75 (2H, USS), 3,85 (2H, USS), 4,54-to 4.62 (1H, m), is 6.54 (1H, t, J=3.3 Hz), of 6.65 (1H, t, J=2.0 Hz), was 6.73 (1H, DD, J=3,9, 2,3 Hz), to 6.95 (1H, t, J=1,8 Hz), 7,06 (1H, t, J=1,8 Hz), 7,17 (1H, d, J=3.1 Hz), to 7.68 (1H, d, J=3.1 Hz), 8,35 (1H, d, J=1.2 Hz), 8,56 (1H, d, J=1.2 Hz), 9,59 (1H, USS).

MS (ESI) m/z: 535,21022 (M+H)+.

Example 65

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-2-(methylsulphonyl)pyridine

(65a) 5-Bromo-2-(methylthio)pyridine

Commercially available 2,5-dibromopyridine (6,01 g, and 25.4 mmol) was dissolved in N,N-dimethylformamide(50 ml), the solution add thiamethoxam sodium (2.20 g, of 31.4 mmol) and the resulting mixture was stirred at 0°C for 3.5 hours under nitrogen atmosphere. The reaction solution was allow to warm to room temperature, add water (250 ml) and the mixture extracted with diethyl ether (250 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=3%-5%)to give the target compound (4,90 g, yield 94%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 2.54 (3H, c), was 7.08 (1H, d, J=8,2 Hz), 7,58 (1H, DD, J=8,6, and 2.3 Hz), 8,49 (1H, d, J=2.0 Hz).

(65b) 5-fluoro-2-(methylsulphonyl)pyridine

5-Br is m-2-(methylthio)pyridine (4,90 g, 24,0 mmol)synthesized in example (65a), dissolved in tetrahydrofuran (100 ml)to the solution dropwise at -78°C type n-utility (solution in hexane, 1.57 mol/l of 17.0 ml, or 26.7 mmol), the mixture was stirred at -78°C for 1 hour in nitrogen atmosphere. N-forbindelseshastighed (11,0 g, is 34.9 mmol) dissolved in tetrahydrofuran (25 ml), after which the resulting solution is added dropwise at -78°C is added to the reaction solution and the mixture was stirred at -78°C for 2 hours in nitrogen atmosphere. The reaction solution was allow to warm to room temperature and stirred for 1.5 hours. To the reaction mixture is added saturated aqueous solution of ammonium chloride (200 ml) and the mixture extracted with diethyl ether (300 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure.

The resulting residue is dissolved in methylene chloride (150 ml), the solution slowly at 0°C add m-chloroperbenzoic acid (65%, 16.5 g, 62,1 mmol) and the resulting mixture was stirred at 0°C for 1.5 hours in a nitrogen atmosphere. The mixture is filtered through celite to remove solids, add saturated aqueous solution of sodium bicarbonate (100 ml) and the mixture is extracted with methylene chloride (400 ml). The organic layer was washed with saturated aqueous solution of salt and for the eat dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=3%-5%)to give the target compound (1,95 g, yield 46%) as a solid, yellowish-white in color.

1H-NMR (CDCl3, 400 MHz): δ 3.24 in (3H, c), to 7.67 (1H, DDD, J=9,9, 6,9, 1.9 Hz), 8,16 (1H, DD, J=8,6, a 4.3 Hz), 8,59 (1H, d, J=2.7 Hz).

(65c) 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-2-(methylsulphonyl)pyridine

tert-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70.0 mg, 0.16 mmol)synthesized in example (38d)and 5-fluoro-2-(methylsulphonyl)pyridine (35,0 mg, 0.20 mmol)synthesized in example (65b), dissolved in N,N-dimethylformamide (5 ml) and the resulting mixture was stirred at 90°C for 3 days under nitrogen atmosphere. To the reaction solution was added water (15 ml), the mixture is extracted with ethyl acetate (30 ml), washed with saturated salt solution (30 ml) and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-40%), obtaining the target compound (28 mg, yield 35%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 3,24 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=10,4, 4,1 Hz)and 3.59 (1H, DD, J=10,2, 6.3 Hz), 4,58 (1H, DD, J=10,4, 6,1 Hz), 6,54-6,56 (2H, m), of 6.73 (1H, DD, J=3,7, 2,5 Hz)6,86 (1H, t, J=1,8 Hz),? 7.04 baby mortality (1H, t, J=2.0 Hz), 7,18 (1H, d, J=3.5 Hz), the 7.43 (1H, DD, J=8,6, 2.7 Hz), to 7.68 (1H, d, J=3,1 Hz), with 8.05 (1H, d, J=9.0 Hz), 8,49 (1H, d, J=2.7 Hz), 9,62 (1H, USS).

MS (ESI) m/z: 486,11507 (M+H)+.

Example 66

2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-oxadiazol

(66a) of tert-Butyl 2,5-dibromo-1H-pyrrole-1-carboxylate

Commercially available tert-butyl-1-errorcorrection (of 46.68 g, 279 mmol) was dissolved in tetrahydrofuran (500 ml) and the solution cooled to -78°C. To the solution in small portions during 1 hour add N-bromosuccinimide (100,48 g, 565 mmol). The reaction solution provide the ability to spontaneously warm to room temperature and the solution stirred at room temperature for 18 hours. The reaction solution is cooled to 0°C, add sodium sulfite (36,43 g), stirred the mixture for 30 minutes, then add hexane (200 ml), whereupon a precipitate, which is removed by filtration through celite. The filtrate is evaporated under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=1%-5%)to give the target compound (52,69 g, yield 58%) as a colourless oil.

1H-NMR (CDCl3, 500 MHz): δ of 1.65 (9H, c), and 6.25 (2H, c).

MS (EI)m/z: 323 (M +).

(66b) 2-Benzyl-1-tert-butyl-5-bromo-1H-pyrrole-1,2 -, in primary forms

tert-Butyl-2,5-dibromo-1H-pyrrole-1-carboxylate (10,98 g, 33.8 mmol)synthesized in example (66a), dissolved in diethyl ether (135 ml)and the solution cooled to -78°C. To the solution is slowly added dropwise n-utility (2,77M solution in hexane, to 12.8 ml, 35.5 mmol) and the resulting mixture is stirred for 1 hour. To the reaction solution is slowly added dropwise to benzylchloride (6.25 ml, to 44.0 mmol) and the mixture is stirred for 30 minutes. The reaction solution provide the ability to slowly warm to room temperature, after which the mixture is stirred for 1 hour. To the reaction solution was added saturated aqueous solution of ammonium chloride (200 ml) and diethyl ether (300 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=5%-45%), obtaining the target compound (8,80 g, yield 68%) as a brownish oil brown.

1H-NMR (CDCl3, 400 MHz): δ of 1.56 (9H, c), of 5.26 (2H, c), 6,21 (1H, d, J=3,9 Hz), 6,85 (1H, d, J=3,9 Hz), 7,28-7,39 (5H, m).

MS (FAB) m/z: 380 (M+H)+.

(66c) 2-Benzyl-1-tert-butyl-5-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-1,2 -, in primary forms

2-Benzyl-1-tre the-butyl-5-bromo-1H-pyrrole-1,2 -, in primary forms (8,75 g, 23,0 mmol)synthesized in example (66b), and 3-[(1S)-2-methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (7,11 g of 23.1 mmol)synthesized in example (38c), dissolved in a mixed solvent of 1,4-dioxane (92 ml) and water (23 ml), the solution add complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (570 mg, 0,698 mmol) and potassium carbonate (of 7.95 g, 57.5 mmol) and the resulting mixture was stirred at 55°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, to the solution was added water (200 ml) and the mixture extracted with ethyl acetate (200 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=15%-35%), obtaining the target compound (8,32 g, 75%yield) as a brown oil

1H-NMR (CDCl3, 500 MHz): δ of 1.29 (3H, d, J=6.3 Hz), of 1.41 (9H, c), 3,40 (3H, c), 3,47 (1H, DD, J=10,3, 4,4 Hz), 3,57 (1H, DD, J=10,3, 5,9 Hz), 4,48-of 4.54 (1H, m), 5,20 (1H, c), and 5.30 (2H, c), 6,17 (1H, d, J=3,4 Hz), 6,44 (1H, c), 6,48 (1H, c), to 6.57 (1H, c)6,94 (1H, d, J=3,4 Hz), 7,42-7,31 (5H, m).

MS (FAB) m/z: 481 (M+).

(66d) Benzyl-5-{3-(2-fluoro-4-formylphenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylate

2-Benzyl-1-tert-butyl-5-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]f the Nile}-1H-pyrrole-1,2 -, in primary forms (8,30 g, to 17.2 mmol)synthesized in example (66c), dissolved in N,N-dimethylformamide (86 ml)solution was added 3,4-differentally (2,85 ml of 25.9 mmol) and potassium carbonate (11,96 g, 86,5 mmol) and the resulting mixture was stirred at 90°C for 24 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (100 ml) and the mixture extracted with diethyl ether (300 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure, the obtained residue is dissolved in dichloromethane (20 ml), the solution add triperoxonane acid (10 ml) and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure, the obtained residue is dissolved in ethyl acetate (200 ml) and the solution washed with saturated aqueous sodium hydrogen carbonate (200 ml), then with saturated salt solution and the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled under reduced pressure to a residue, which was purified column chromatography (silica gel, elution solution: ethyl acetate/hexane=15%-35%), obtaining the target compound (6,34 g, yield 73%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), 3,40 (3H, c), 3,50 (1H, DD, J=10,2, 3,9 Hz)to 3.58 (1H, DD, J=10,4, 6,1 Hz), 4.53-in-4,60 (1H, m), 5,32 (2H, c), of 6.50 (1H, t, J=3.3 Hz), 6,59 (1H, c), 6,83 (1H, c), of 6.96-6,98 (2H, m), 7,12 (1H, t, J=8.0 Hz), 7,32-7,44 (5H, m), a 7.62 (1H, d, J=8,2 Hz), 7,72 (1H, DD, J=10,4, 1.8 Hz), 9,29 (1H, c), 9,92 (1H, d, J=2.0 Hz).

MS (FAB) m/z: 503 (M+).

(66e) 4-(3-{5-[(Benzyloxy)carbonyl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-3-Formentera acid

Benzyl-5-{3-(2-fluoro-4-formylphenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylate (6,33 g, 12.6 mmol)synthesized in example (66d), suspended in a mixed solvent of tert-butanol (120 ml) and water (40 ml) and the resulting suspension add the dihydrate of sodium dihydrophosphate (8,86 g of 56.8 mmol) and 2-methyl-2-butene (12,05 ml, 113 mmol). While cooling in an ice bath to the mixture is added slowly sodium chlorite (80%, of 2.93 g of 25.9 mmol) and the mixture is stirred at room temperature for 2 hours. To the mixture is added saturated aqueous salt solution (200 ml), the mixture is then extracted with dichloromethane (200 ml), the organic layer is dried over anhydrous magnesium sulfate, obtaining the target compound (7,17 g, yield ~100%) in the form of oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.36 (3H, d, J=6.3 Hz), 3.43 points (3H, c), 3,53 (1H, DD, J=10,2, 3,9 Hz), 3,62 (1H, DD, J=10,2, 5,9 Hz), 4,58 with 4.65 (1H, m), of 5.34 (2H, c), 6,55 (1H, DD, J=3,9, 2.7 Hz), 6,69 (1H, t, J=2.0 Hz), 7,02-7,06 (3H, m), 7,11 (1H, c), 7,34-7,44 (5H, m), 7,66 (1H, d, J=8.6 Hz), to 7.77 (1H, DD, J=10,9, 2.0 Hz), is 10.68 (1H, USS).

MS (FAB) m/z: 519 (M+).

(66f) Benzyl-5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-meth is latexi]phenyl}-1H-pyrrole-2-carboxylate

4-(3-{5-[(Benzyloxy)carbonyl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-3-fermenting acid (7,14 g, 13.7 mmol)synthesized in example (66e), dissolved in dichloromethane (120 ml). To the solution while cooling in an ice bath, add the hydrochloride of azetidine (1,772 g of 18.9 mmol), WSCI·HCl (3,62 g of 18.9 mmol), triethylamine (2.65 ml of 19.1 mmol) and 4-dimethylaminopyridine (464 mg, of 3.80 mmol) and the mixture is stirred at room temperature for 6 hours in nitrogen atmosphere. To the reaction solution was added to 0.5 N. hydrochloric acid (300 ml) and the mixture extracted with dichloromethane (300 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-85%), obtaining the target compound (4.12 g, yield 59%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), 2,34-to 2.41 (2H, m), 3,40 (3H, c), 3,49 (1H, DD, J=10,4, 4,1 Hz), 3,57 (1H, DD, J=10,4, 6,1 Hz), 4,21-4,27 (2H, USM), 4,33-4,39 (2H, USM), 4,51-of 4.57 (1H, m), 5,33 (2H, c), 6,48 (1H, DD, J=3,9, 2.7 Hz), 6,53 (1H, t, J=2.2 Hz), 6,78 (1H, t, J=1,8 Hz), 6.89 in (1H, t, J=1,8 Hz), 6,97 (1H, DD, J=3,9, and 2.3 Hz), 7,06 (1H, t, J=8.0 Hz), 7,34-7,44 (6H, m), 7,52 (1H, DD, J=10,9, 2.0 Hz), 9,19 (1H, USS).

MS (FAB) m/z: 558 (M+).

(66g) 5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-to robonova acid

Benzyl-5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylate (4,25 g, to 7.61 mmol)synthesized in example (66f), dissolved in ethanol (150 ml), the solution is added the catalyst, 10% palladium on carbon (804 mg) and the mixture is then stirred for 2 hours in hydrogen atmosphere. The catalyst was removed by filtering the mixture through celite, and the solvent is distilled off under reduced pressure, obtaining the target compound (3,45 g, yield 97%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), 2,32-to 2.40 (2H, m), 3,44 (3H, c), 3,52 (1H, DD, J=10,0, 4,1 Hz)to 3.64 (1H, DD, J=10,0, 6.3 Hz), 4,20-4.26 deaths (2H, USM), or 4.31-to 4.38 (2H, USM), of 4.66-4.72 in (1H, m), 6.48 in-6,50 (2H, m)6,86 (1H, c), of 7.00 (1H, c), 7,05 (1H, t, J=7,6 Hz), 7,16 (1H, c), 7,38 (1H, d, J=7.8 Hz), to 7.50 (1H, d, J=11.3 Hz), 10,17 (1H, USS).

MS (ESI) m/z: 469,17889 (M+H)+.

(66h) N' -Acetyl-5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-carbohydrazide

5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylic acid (126 mg, 0.27 mmol)synthesized in example (66g), and acetohydrazide (40 mg, 0.54 mmol) dissolved in dichloromethane (5 ml)solution was added HATU (153 mg, 0.40 mmol) and N,N-diisopropylethylamine (70 μl, 0.40 mmol) at room temperature and the mixture is stirred under nitrogen atmosphere for 1 hour. The reaction solution was diluted with dichloromethane (60 ml), washed with 1 N. hydrochloric acid, add saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/dichloromethane=5%)to give the desired product (87 mg, yield 62%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1.26 in (3H, d, J=6.3 Hz), at 1.91 (3H, c), 2,30-to 3.38 (2H, m), 3,37 (3H, c), of 3.46 (1H, DD, J=3,8, 10.1 Hz) to 3.58 (1H, DD, J=6,2, 10.1 Hz), 4,18-4,24 (2H, USM), 4,30 is 4.36 (2H, USM), 4,55-4,59 (1H, m), to 6.43 (1H, DD, J=2.7, and 4.0 Hz), 6,46 (1H, t, J=2.1 Hz), for 6.81 (1H, DD, J=2,4, 4,1 Hz), 6.87 in (1H, c), 7,01 (1H, t, J=8,2 Hz), 7,07 (1H, c), 7,35 (1H, d, J=8.6 Hz), 7,46 (1H, DD, J=2,0, up 10.9 Hz), 9,10 (1H, USS), 9,36 (1H, USS), to 10.62 (1H, USS).

(66i) 2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-oxadiazol

N' -Acetyl-5-{3-[4-(azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-carbohydrazide (86 mg, 0.16 mmol)synthesized in example (66h), dissolved in dichloromethane (5 ml), the resulting solution was added triethylamine (0.1 ml, to 0.72 mmol) and acid chloride p-toluensulfonate acid (69 mg, 0.36 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane (60 ml), washed with 1 N. hydrochloric acid, nasiman the m aqueous solution of sodium bicarbonate and a saturated solution of salt, and then the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-100%)to give the desired product (57 mg, yield 69%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 2,34-of 3.42 (2H, m), 2,58 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=3,9, 10.4 Hz) 3,59 (1H, DD, J=6,1, 10,3 Hz), 4,22-4,27 (2H, USM), 4,35-and 4.40 (2H, USM), 4,54-4,59 (1H, m), is 6.54 (1H, t, J=2.2 Hz), 6,55 (1H, DD, J=2,2, 2.7 Hz), to 6.80 (1H, t, J=1.7 Hz), 6,85 (1H, DD, J=1,9, 2.4 Hz), 6,93 (1H, DD, J=1,2, 1,6 Hz), was 7.08 (1H, t, J=8,2 Hz), 7,41 (1H, d, J=8.5 Hz), 7,52 (1H, DD, J=2,0 and 11.1 Hz), 9,49 (1H, USS).

MS (ESI) m/z: 507,20129 (M+H)+.

Example 67

(2S)-2-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}propan-1-ol

2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-1,3,4-oxadiazol (to 379.2 mg, 0,748 mmol)synthesized in example (66i), dissolved in dichloromethane (15 ml)to the solution at -78°C add tribromide boron in dichloromethane (1M, 750 μl, 0.75 mmol in nitrogen atmosphere and the resulting mixture was stirred at 0°C for 3 hours. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated R is the target salt and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/dichloromethane=2%-8%), obtaining the target compound (76,9 mg, yield 21%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), 2,34-to 2.42 (2H, m), 2,58 (3H, c), 2,80 (1H, t, J=6,1 Hz), 3,76-with 3.79 (2H, m), 4,22-4.26 deaths (2H, USM), 4,35-4,39 (2H, USM), to 4.52-4,59 (1H, m), of 6.45 (1H, t, J=2.2 Hz), 6,53 (1H, DD, J=3,9, 2.7 Hz), 6,79 (1H, t, J=1,8 Hz), at 6.84 (1H, DD, J=3,9, and 2.3 Hz), 6,91 (1H, t, J=1,8 Hz), 7,05 (1H, t, J=8,2 Hz), 7,38-7,41 (1H, m), 7,51 (1H, DD, J=10,9, 2.0 Hz), 9,92 (1H, USS).

MS (ESI) m/z: 493,18999 (M+H)+.

Example 68

2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol

(68a) 5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-N-(2-chloroethyl)-1H-pyrrol-2-carboxamide

5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylic acid (66 mg, 0.15 mmol)synthesized in example (66g), hydrochloride 2-chloroethylamine (34 mg, 0.30 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) dissolved in dichloromethane (10 ml)to the solution at room temperature add WSCI·HCl (31 mg, 0.16 mmol) and the resulting mixture is stirred for 1 hour in nitrogen atmosphere. The reaction solution was diluted with dichloromethane (60 ml), washed with the 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, and then the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-60%), obtaining the target product (56 mg, yield 79%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), 2,35-to 3.49 (2H, m)to 3.41 (3H, c), 3,50 (1H, DD, J=4,1 and 10.7 Hz) to 3.58 (1H, DD, J=6,1, 10,3 Hz), 3,71 (2H, t, J=5.4 Hz), of 3.77 (2H, t, J=5.6 Hz), 4,22-4,27 (2H, USM), 4,35-and 4.40 (2H, USM), 4,53-of 4.57 (1H, m), 6,24-6,28 (1H, m), 6,47 (1H, t, J=3.0 Hz), of 6.52 (1H, t, J=2.1 Hz), 6,62 (1H, DD, J=2.5 and a 4.1 Hz), 6,78 (1H, t, J=1.6 Hz), make 6.90 (1H, t, J=1.6 Hz), 7,06 (1H, t, J=8.0 Hz), 7,40 (1H, d, J=8.5 Hz), 7,52 (1H, DD, J=2.0 a, and 11.0 Hz), 9,43 (1H, USS).

(68b) 2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazol

5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-N-(2-chloroethyl)-1H-pyrrol-2-carboxamide (85 mg, 0.16 mmol)synthesized in example (68a), dissolved in tetrahydrofuran (3 ml)to the solution at 0°C. add sodium hydride (37 mg, 0.82 mmol) and the resulting mixture was stirred at room temperature for 20 hours. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate (50 ml). See the camping washed with saturated salt solution, the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate 100%-methanol/chloroform=2%)to give the desired product (33 mg, yield 41%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), 2,34-to 3.41 (2H, m)to 3.41 (3H, c), 3,49 (1H, DD, J=3,9, 10,5 Hz) to 3.58 (1H, DD, J=5,9, 10,2 Hz), of 4.00 (2H, t, J=9,3 Hz), 4,22-4.26 deaths (2H, USM), 4,35-4,39 (2H, USM), and 4.40 (2H, t, J=9,3 Hz), 4.53-in-of 4.57 (1H, m), 6.48 in (1H, d, J=3.8 Hz), 6,51 (1H, t, J=2.0 Hz), to 6.75 (1H, d, J=3.8 Hz), 6,78 (1H, t, J=1.6 Hz), 6,91 (1H, c), 7,06 (1H, t, J=8.1 Hz), 7,40 (1H, d, J=8.5 Hz), 7,52 (1H, DD, J=2,0, and 11.0 Hz).

MS (ESI) m/z: 494,20834 (M+H)+.

Example 69

(5S)-2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol

(69a) 5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-N-[(2R)-2-hydroxypropyl]-1H-pyrrol-2-carboxamide

5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylic acid (580 mg, 1,24 mmol)synthesized in example (66g), dissolved in dichloromethane (15 ml)solution was added (R)-(-)-1-amino-2-propanol (196 μl, 2.48 mmol), WSCI·HCl (366 mg, at 1.91 mmol) and 4-dimethylaminopyridine (228 mg, of 1.87 mmol) and the mixture is stirred at room temperature techenie hours in nitrogen atmosphere. To the reaction solution was added to 0.25 N. hydrochloric acid (100 ml) and the mixture extracted with ethyl acetate (100 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/dichloromethane=3%-9%), obtaining the target compound (486 mg, 75%yield) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1,22 (3H, d, J=6.3 Hz), of 1.30 (3H, d, J=6.3 Hz), 2,33-to 2.41 (2H, m), 2,77 (1H, d, J=3,9 Hz), 3,22-3,29 (1H, m)to 3.41 (3H, c), 3,50 (1H, DD, J=10,2, 3,9 Hz), 3,55-3,62 (2H, m), 3,94-4,01 (1H, USM), 4,20-4.26 deaths (2H, USM), 4,33-4,39 (2H, USM), 4,51-4,59 (1H, m), to 6.43-6,46 (2H, m), 6,51 (1H, t, J=2.2 Hz), 6,62 (1H, DD, J=3,9, and 2.3 Hz), to 6.80 (1H, t, J=1,8 Hz), 6,91 (1H, t, J=1,8 Hz),? 7.04 baby mortality (1H, t, J=8,2 Hz), 7,37 (1H, d, J=8.6 Hz), to 7.50 (1H, DD, J=11,3, 2.0 Hz), 9,80 (1H, USS).

MS (FAB) m/z: 526 (M+H)+.

(69b) (5S)-2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol

5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-N-[(2R)-2-hydroxypropyl]-1H-pyrrol-2-carboxamide (464 mg, 0,883 mmol)synthesized in example (69a), dissolved in tetrahydrofuran (17 ml), to the solution was added anhydrous methansulfonate acid (558 mg, 3,20 mmol) and triethylamine (860 μl, of 6.20 mmol) and the resulting mixture was stirred at room temperature for 3 days the th in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/dichloromethane=3%-9%), obtaining the target compound (228 mg, 51%yield) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=6.3 Hz), 2,34-to 2.41 (2H, m)to 3.41 (3H, c), 3,50 (1H, DD, J=10,2, 3,9 Hz), 3,52-3,59 (2H, m), 4,08 (1H, DD, J=13,9, 9,2 Hz), 4,22-4.26 deaths (2H, USM), 4,35-to 4.38 (2H, USM), 4,53-4,60 (1H, m), 4.80 to 4,89 (1H, m), 6.48 in (1H, d, J=3,9 Hz), 6,51 (1H, t, J=2.2 Hz), 6,77 (1H, d, J=3,9 Hz), 6,79 (1H, t, J=1,8 Hz), 6,93 (1H, c), 7,05 (1H, t, J=8,2 Hz), 7,37-7,40 (1H, m), 7,51 (1H, DD, J=10,9, 2.0 Hz).

MS (ESI) m/z: 508,22382 (M+H)+.

Example 70

(2S)-2-(3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)propan-1-ol

(5S)-2-(5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fervency]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol (337,8 mg, 0,666 mmol)synthesized in example (69b), dissolved in dichloromethane (10 ml)to the resulting solution at -78°C is added a solution of boron tribromide in dichloromethane (1M, 1 ml, 1 mmol) under nitrogen atmosphere and the mixture is stirred at room is the temperature for 1 hour. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/dichloromethane=2%-8%), obtaining the target compound (93,7 mg, yield 29%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ 1.26 in (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=6.3 Hz), 2,33-to 2.41 (2H, m), 3,55 (1H, DD, J=13,7, 7,4 Hz), to 3.73-3,81 (2H, m), 4,08 (1H, DD, J=13,7, 9.4 Hz), 4,22-4.26 deaths (2H, USM), 4,33-4,37 (2H, USM), 4,56 with 4.64 (1H, m), 4,81-of 4.90 (1H, m), 6,30 (1H, t, J=2.2 Hz), 6,44 (1H, d, J=3,9 Hz), 6,74-6,76 (2H, m)6,86 (1H, c), of 7.00 (1H, t, J=8,2 Hz), 7,34-7,37 (1H, m), 7,49 (1H, DD, J=10,9, 2.0 Hz).

MS (ESI) m/z: 494,20864 (M+H)+.

Example 71

5-(Azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine

(71a) 5-(3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-1H-pyrrole-2-carboxylic acid

2-Benzyl-1-tert-butyl-5-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-1,2 -, in primary forms (a total of 5.21 g, was 10.82 mmol)synthesized in example (66c), and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (2.55 g, 11,04 mmol)synthesized in example (60a), dissolved in AOC is onitrile (100 ml), to the resulting solution was added potassium carbonate (4,30 g, 31,11 mmol) and the mixture refluxed with stirring for 1 day under nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (200 ml) and the mixture extracted with ethyl acetate (200 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=75%-90%).

The obtained product is dissolved in triperoxonane acid (15 ml) and the solution stirred at room temperature for 1.5 hours under nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=75%-90%).

The obtained product is dissolved in tetrahydrofuran (20 ml), to the solution was added palladium on carbon (800 mg) and the mixture is stirred at room temperature for 4 hours in hydrogen atmosphere. The mixture is filtered through celite, the solvent is distilled off. To the obtained residue is added saturated aqueous sodium hydrogen carbonate solution (30 ml) and the mixture extracted with diethyl ether. To the aqueous layer add 2 N. hydrochloric acid (50 ml) and the mixture extrag the shape with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, obtaining the target compound (3,52 g, yield 67%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.35 (3H, d, J=6.3 Hz), 2,35-to 2.42 (2H, m), of 3.45 (3H, c), of 3.54 (1H, DD, J=10,0, 4,1 Hz), the 3.65 (1H, DD, J=10,4, 6,1 Hz), 4,24 (2H, t, J=7,6 Hz), 4,35 (2H, t, J=6.3 Hz), 4,65-4,71 (1H, m), 6,53 (1H, DD, J=3,5, 2.7 Hz), 6,70 (1H, t, J=2.2 Hz), 7,01-7,02 (2H, USM), 7,21 (1H, c), 8,16 (1H, d, J=2.3 Hz), of 8.27 (1H, d, J=2.0 Hz), becomes 9.97 (1H, USS).

(71b) 5-(Azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine

5-(3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-1H-pyrrole-2-carboxylic acid (600 mg, of 1.23 mmol)synthesized in example (71a), dissolved in dichloromethane (15 ml), the resulting solution was added acetohydrazide (200 mg, 2,70 mmol), WSCI·HCl (510 mg, of 2.66 mmol) and 4-dimethylaminopyridine (300 mg, of 2.46 mmol), the mixture is stirred at room temperature for 1 day under nitrogen atmosphere. Add saturated aqueous solution of ammonium chloride (100 ml) and the mixture extracted with dichloromethane (100 ml). The organic layer was washed with saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

The residue is dissolved in dichloromethane (15 ml)to dissolve the add the p-toluensulfonate (500 mg, 2,62 mmol) and triethylamine (1.0 ml, 7,17 mmol), the mixture is stirred at room temperature for 5 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture extracted with dichloromethane (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate)to give the target compound (520 mg, yield 81%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.35 (3H, d, J=6.3 Hz), 2,35 is 2.43 (1H, m), 2,59 (3H, c), 3,42 (3H, c), 3,52 (1H, DD, J=10,2, a 4.3 Hz), 3,61 (1H, DD, J=10,2, 5,9 Hz), 4,24 (2H, t, J=7.4 Hz), 4,37 (2H, t, J=7,6 Hz), 4,56-to 4.62 (1H, m,), to 6.58 (1H, DD, J=3,9, 2.7 Hz), 6,70 (1H, t, J=2.2 Hz), 6,85 (1H, DD, J=3,9, and 2.3 Hz), of 6.96 (1H, t, J=1.6 Hz), 7,05 (1H, t, J=2.0 Hz), 8,17 (1H, d, J=2.0 Hz), of 8.27 (1H, d, J=2.0 Hz), to 9.57 (1H, USS).

MS (ESI) m/z: 524,17210 (M+H)+.

Example 72

(2S)-2-(3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy)propan-1-ol

5-(Azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine (370 mg, 0,706 mmol)synthesized in example (71b), dissolved in dichloromethane (10 ml), the resulting solution was added dropwise at -78°C EXT is make the boron tribromide (solution in dichloromethane, 1.0 mol/l of 1.10 ml, 1.10 mmol) and the resulting mixture was stirred at room temperature for 1 hour in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (20 ml) and the mixture extracted with dichloromethane (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/dichloromethane=1%-3%), obtaining the target compound (205 mg, yield 57%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.30 (3H, d, J=6.3 Hz), 1,78 (1H, d, J=7.8 Hz), 2,34-to 2.42 (2H, m), to 2.57 (3H, c), 2,71-2,87 (1H, m), of 3.73-of 3.80 (2H, m)to 4.23 (2H, t, J=7,6 Hz), 4,35 (2H, t, J=7.4 Hz), to 4.52-4,58 (1H, m), 6,56 (1H, t, J=2,9 Hz), only 6.64 (1H, d, J=1.6 Hz), at 6.84 (1H, DD, J=3,9, and 2.3 Hz), of 6.96 (1H, t, J=1,8 Hz), 7,01 (1H, t, J=1,8 Hz), 8,16 (1H, d, J=2.0 Hz), compared to 8.26 (1H, d, J=2.3 Hz), 9,92 (1H, c).

MS (ESI) m/z: 510,15468 (M+H)+.

Example 73

5-(Azetidin-1-ylcarbonyl)-3-chloro-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}pyridine

(73a) 5-(3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-N-(2-chloroethyl)-1H-pyrrol-2-carboxamide

5-(3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-1H-pyrrole-2-carboxylic acid (800 mg,of 1.65 mmol), synthesized in example (71a), dissolved in dichloromethane (10.0 ml)solution was added the hydrochloride of 2-chloroethylamine (300 mg, at 2.59 mmol), WSCI·HCl (630 mg, 3,29 mmol) and 4-dimethylaminopyridine (400 mg, with 3.27 mmol), the mixture was stirred at room temperature under nitrogen atmosphere for 2.5 days. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture extracted with dichloromethane (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate)to give the target compound (210 mg, yield 23%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 2,35-to 2.42 (2H, m), 3,42 (3H, c), 3,51 (1H, DD, J=10,6, a 4.7 Hz), 3,60 (1H, DD, J=10,2, 5,9 Hz), 3,68-to 3.73 (2H, m), 3.75 to of 3.80 (2H, m), 4,24 (2H, t, J=7.8 Hz), 4,36 (2H, t, J=7,0 Hz), 4,55-4,60 (1H, m), 6,27 (1H, t, J=5.7 Hz), 6,50 (1H, DD, J=3,9, 2.7 Hz), 6,63 (1H, DD, J=3,7, 2,5 Hz), of 6.68 (1H, t, J=2.2 Hz), to 6.95 (1H, t, J=1,8 Hz), 7,03 (1H, t, J=1,8 Hz), 8,16 (1H, d, J=2.3 Hz), compared to 8.26 (1H, d, J=2.0 Hz), of 9.55 (1H, USS).

(73b) 5-(Azetidin-1-ylcarbonyl)-3-chloro-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}pyridine

5-(3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-N-(2-chloroethyl)-1H-pyrrol-2-carboxamide (210 mg ,384 mmol), synthesized in example (73a), dissolved in tetrahydrofuran (10.0 ml)solution was added sodium hydride (60%, 80 mg, 2.00 mmol) and the mixture is stirred at room temperature for 7.5 hours under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture extracted with dichloromethane (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate)to give the target compound (120 mg, yield 62%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 2,35-to 2.42 (2H, m)to 3.41 (3H, c), 3,50 (1H, DD, J=10,3, 4,4 Hz), 3,60 (1H, DD, J=10,3, 5,9 Hz), of 4.00 (2H, t, J=9,3 Hz), 4,24 (2H, t, J=6.8 Hz), 4,36 (2H, t, J=6.3 Hz), 4,40 (2H, t, J=9,3 Hz), 4,55-br4.61 (1H, m), 6,50 (1H, d, J=3,9 Hz), 6,66 (1H, t, J=2.0 Hz), to 6.75 (1H, d, J=3,9 Hz)6,94 (1H, c),? 7.04 baby mortality (1H, t, J=5,1 Hz), 8,15 (1H, d, J=2.0 Hz), compared to 8.26 (1H, d, J=2.0 Hz).

MS (ESI) m/z: 511,17658 (M+H)+.

Example 74

5-(Azetidin-1-ylcarbonyl)-3-chloro-2-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine

5-(3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-1H-pyrrole-2-carboxylic acid (800 mg, of 1.65 mmol)synthesized in p is the iMER (71a), dissolved in dichloromethane (15 ml)solution was added (R)-(-)-1-amino-2-propanol (0.35 ml, of 4.45 mmol), WSCI·HCl (630 mg, 3,29 mmol) and 4-dimethylaminopyridine (800 mg, 6,55 mmol), the mixture is stirred at room temperature for 8 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture extracted with dichloromethane (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/dichloromethane=3%-8%), and receiving the product in a solid yellow color.

The product is dissolved in tetrahydrofuran (15 ml), to the solution was added anhydrous methansulfonate acid (500 mg, 2,87 mmol) and triethylamine (0,80 ml, 5,74 mmol) and then stirred the mixture at room temperature overnight under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture extracted with dichloromethane (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate), p is the best target compound (520 mg, yield 60%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=6.3 Hz), 2,35-to 2.42 (2H, m)to 3.41 (3H, c), 3,45-of 3.64 (3H, m), 4,08-of 4.12 (1H, m)to 4.23 (2H, t, J=7.0 Hz), 4,36 (2H, t, J=8,4 Hz), 4,54-to 4.62 (1H, m), 4,84-4,87 (1H, m), 6,51 (1H, d, J=3.5 Hz), 6,66 (1H, t, J=2.2 Hz), 6.75 in-is 6.78 (1H, m)6,94 (1H, c), 7,02-to 7.09 (1H, m), 8,16 (1H, d, J=2.0 Hz), compared to 8.26 (1H, d, J=2.0 Hz).

MS (ESI) m/z: 525,19126 (M+H)+.

Example 75

(2S)-2-(3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)propan-1-ol

5-(Azetidin-1-ylcarbonyl)-3-chloro-2-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine (320 mg, 0,610 mmol)synthesized in example (74), dissolved in dichloromethane (10 ml)to the solution dropwise at -78°C add tribromide boron (solution in dichloromethane, 1.0 mol/l to 0.92 ml, of 0.92 mmol) and the resulting mixture was stirred at room temperature for 1 hour in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (20 ml) and the mixture extracted with dichloromethane (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/dichloromethane=1%-3%), Paul is the tea of the target compound (165 mg, yield 53%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.28 (3H, d, J=6.3 Hz), of 1.40 (3H, d, J=5,9 Hz), 2,34-to 2.42 (2H, m), 3,52 (1H, DD, J=13,7, 7,4 Hz), 3,76 (2H, d, J=5.5 Hz), 4,06 (1H, DD, J=13,9, 9,2 Hz), to 4.23 (2H, t, J=7.8 Hz), 4,34 (2H, t, J=7,4 Hz), 4,51-4,60 (1H, m), 4,76-a 4.86 (1H, m), 6,44 (1H, d, J=3.1 Hz), 6,53 (1H, c), 6,72 (1H, d, J=3.5 Hz), 6.87 in-6,92 (2H, m), 8,15 (1H, d, J=2.0 Hz), 8,23 (1H, d, J=1.2 Hz), of 10.05 (1H, USS).

MS (ESI) m/z: 511,17339 (M+H)+.

Example 76

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine

(76a) Benzyl-5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylate

2-Benzyl-1-tert-butyl-5-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-1,2 -, in primary forms (of 5.05 g, 10,49 mmol)synthesized in example (66c), and 5-fluoro-2-(methylsulphonyl)pyridine (2,05 g, 11,70 mmol)synthesized in example (65b), dissolved in N,N-dimethylformamide (30 ml), to the solution was added potassium carbonate (4,50 g, 32,56 mmol), the mixture was stirred at 80°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (150 ml) and the mixture extracted with diethyl ether (150 ml). The organic layer was washed with saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

Received about the SPS dissolved in triperoxonane acid (10 ml) and the mixture is stirred at room temperature for 1 hour in nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=35%-50%)to give the target compound (5,08 g, yield 90%) as a white oil color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 3,23 (3H, c), is 3.41 (3H, c), 3,51 (1H, DD, J=10,3, 3,9 Hz)to 3.58 (1H, DD, J=10,3, 6.3 Hz), 4,54-br4.61 (1H, m), 5,33 (2H, c), 6,51 (1H, t, J=3.2 Hz), 6,59 (1H, c)6,86 (1H, c), of 6.99 (1H, t, J=2,9 Hz), 7,02 (1H, c), 7,32 was 7.45 (7H, m), of 8.04 (1H, d, J=8,8 Hz), 8,48 (1H, c), 9,36 (1H, USS).

(76b) 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid

Benzyl-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylate (5,08 g, 9.47 mmol)synthesized in example (76a), dissolved in ethyl acetate (30 ml), the solution is added the catalyst, 10% palladium on carbon (1.10 g) and the resulting mixture was stirred at room temperature for 3 hours in hydrogen atmosphere. The mixture is filtered through celite, the solvent is distilled off under reduced pressure, obtaining the target compound in the form of solid white (4,30 g, yield ~100%).

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=5,9 Hz), 3,23 (3H, c), 3,47 (3H, c), of 3.57 (1H, DD, J=9,8, 3,9 Hz)to 3.67 (1H, DD, J=10,0, and 6.6 Hz), 4.72 in-4,80 (1H, m), of 6.52 (1H, c), 6,59 (1H, c), 6,92 (1H, c), 7,03 (1H, c), 7,32 (1H c), was 7.45 (1H, DD, J=8,5) and 1.7 Hz), with 8.05 (1H, d, J=8,8 Hz), 8,49 (1H, d, J=2.4 Hz), 10,31 (1H, USS).

(76c) 5-(3-[(1S)-2-Methoxy-1-meth is latexi]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1000 mg, 2,24 mmol)synthesized in example (76b), dissolved in methanol (20 ml)solution was added (R)-(-)-1-amino-2-propanol (0,40 ml, 5.08 mmol) and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (1000 mg, 3.61 mmol) and the mixture is then stirred at room temperature overnight under nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=1%-3%), and receiving the product in a solid yellow color.

The product is dissolved in tetrahydrofuran (20 ml), to the solution was added anhydrous methansulfonate acid (600 mg, 3,44 mmol) and triethylamine (0.70 to ml, 5,02 mmol) and the mixture is stirred at room temperature overnight under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=1%-3%), obtaining the target compound (450 mg, yield 41) in the form of a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=6.3 Hz), 3,23 (3H, c), 3,42 (3H, c), 3,49-3,61 (4H, m), 4.09 to (1H, DD, J=13,9, 8,8 Hz), 4.53-in-4,63 (1H, m), 4,79-4,88 (1H, m), 6,51 (1H, d, J=3,9 Hz), to 6.57 (1H, d, J=1.6 Hz), 6,76 (1H, d, J=3,9 Hz), 6,83 (1H, c), 7,02 (1H, c), 7,44 (1H, DD, J=8,6, and 2.3 Hz), with 8.05 (1H, d, J=8.6 Hz), 8,49 (1H, c).

MS (ESI) m/z: 486,17067 (M+H)+.

Example 77

(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine (310 mg, 0,638 mmol)synthesized in example (76c), dissolved in methylene chloride (7.0 ml)to the solution at -78°C is added dropwise tribromide boron (solution of 1.0 mol/l in dichloromethane, and 1.00 ml, 1.0 mmol) and the resulting mixture was stirred in nitrogen atmosphere at room temperature for 1 hour. To the reaction solution was added saturated aqueous solution of ammonium chloride (20 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=1%-3%), obtaining the target compound (245 mg, yield 81%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=6.3 Hz), 3,23 (3H, c), 3,55 (1H, DD, J=13,9, 7,2 Hz), with 3.79 (2H, d, J=5,1 Hz), 4.09 to (1H, DD, J=14,1, and 9.4 Hz), 4,56-4,63 (1H, m), 4,81-4,88 (1H, m), 6,38 (1H, USS), 6,48 (1H, t, J=3.3 Hz), to 6.75 (1H, d, J=3.5 Hz), to 6.80 (1H, USS), of 6.96 (1H, USS), 7,39 (1H, USS), 8,03 (1H, d, J=8,2 Hz), to 8.45 (1H, c).

MS (ESI) m/z: 472,15208 (M+H)+.

Example 78

5-{3-[5-(4,5-Dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}-2-(methylsulphonyl)pyridine

(78a) 3-Bromo-5-methoxyphenol

Commercially available 1-bromo-3,5-dimethoxybenzene (18,74 g, 86,3 mmol) dissolved in 1-methyl-2-pyrrolidone (100 ml)to the solution add thiamethoxam sodium (6,74 g of 96.2 mmol) and the resulting mixture was stirred at 100°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add 1 N. hydrochloric acid (200 ml) and the mixture extracted with diethyl ether (500 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-25%), obtaining the target compound (15,03 g, yield 86%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 3.77 (3H, c), 4,82 (1H, c), 6,33 (1H, t, J=2.4 Hz), is 6.61 (1H, t, J=2.0 Hz), 6,66 (1H, t, J=2.0 Hz).

(78b) 1-Bromo-3-methoxy-5-[(1S)-2-methoxy-1-IU is ylethoxy]benzene

3-Bromo-5-methoxyphenol (7,60 g, or 37.4 mmol)synthesized in example (78a), dissolved in toluene (100 ml)solution was added R-(-)-1-methoxy-2-propanol (4,40 ml of 44.9 mmol) and triphenylphosphine (13.8 g,for 52.6 mmol) and then at 0°C dropwise diethylazodicarboxylate (solution of 2.2 mol/l in toluene, 24 ml of 52.8 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours under nitrogen atmosphere. The solvent is distilled off under reduced pressure, add diethyl ether (100 ml) and the precipitate removed by filtration. The mother liquor is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-20%)to give the target compound (which 9.22 g, yield 89%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ of 1.30 (3H, d, J=6.3 Hz), 3,40 (3H, c), 3,47 (1H, DD, J=10,6, a 4.3 Hz), 3,55 (1H, DD, J=10,4, 6,1 Hz), 3,76 (3H, c), 4,46-to 4.52 (1H, m), 6.42 per (1H, t, J=2.2 Hz), of 6.65 (1H, DD, J=2,3, and 1.6 Hz), 6,69 (1H, t, J=2.0 Hz).

MS (EI) m/z: 274 (M)+.

(78c) 3-Bromo-5-[(1S)-2-methoxy-1-methylethoxy]phenol

1-Bromo-3-methoxy-5-[(1S)-2-methoxy-1-methylethoxy]benzene (of 9.21 g of 33.5 mmol)synthesized in example (78b), dissolved in 1-methyl-2-pyrrolidone (100 ml)to the solution add thiamethoxam sodium (2,75 g of 37.3 mmol) and the resulting mixture was stirred at 130°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add 2 N. hydrochloric acid (500 ml) and the mixture extracted with diethyl ether (300 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-25%), obtaining the target compound (8,30 g, yield 95%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), to 3.41 (3H, c), of 3.46 (1H, DD, J=10,2, a 4.3 Hz), 3,55 (1H, DD, J=10,6, 5,9 Hz), 4,45-4,51 (1H, m), 4,96 (1H, USS), 6,36 (1H, t, J=2.0 Hz), 6,59 (1H, t, J=2.0 Hz), of 6.68 (1H, t, J=2,0 Hz).

MS (EI) m/z: 260 (M)+.

(78d) 3-[(1S)-2-Methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

3-Bromo-5-[(1S)-2-methoxy-1-methylethoxy]phenol (8,30 g of 31.8 mmol)synthesized in example (78c), dissolved in N,N-dimethylformamide (100 ml)solution was added bis(pinacolato)LIBOR (10,50 g, a 41.3 mmol), complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (810 mg, 0,992 mmol) and potassium acetate (15,50 g, 158 mmol) and the resulting the mixture was stirred at 90°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, to the solution was added water (500 ml) and the mixture extracted with diethyl ether (300 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solution is tel distilled off under reduced pressure, and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-30%)to give the target compound (8,75 g, yield 89%) as a brown oil.

1H-NMR (CDCl3, 400 MHz): δ 1.26 in (3H, d, J=4,1 Hz)of 1.33 (12H, c)to 3.41 (1H, c), 3,47 (1H, DD, J=10,2, a 4.7 Hz), 3,57 (1H, DD, J=10,6, 5,9 Hz), to 4.52-4,58 (1H, m), 4,80 (1H, USS), 6,55 (1H, t, J=2.4 Hz), 6,83 (1H, d, J=2.4 Hz), to 6.95 (1H, d, J=2,4 Hz).

MS (FAB) m/z: 309 (M+H)+.

(78e) tert-Butyl-2,5-dibromo-1H-pyrrole-1-carboxylate

Commercially available tert-butyl-1-errorcorrection (of 46.68 g, 279 mmol) was dissolved in tetrahydrofuran (500 ml) and the resulting solution was cooled to -78°C. To the solution in small portions during one hour add N-bromosuccinimide (100,48 g, 565 mmol). The reaction solution provide the ability to spontaneously warm to room temperature and the mixture is stirred at room temperature for 18 hours. The reaction solution is cooled to 0°C, the solution was added sodium sulfite (36,43 g), the mixture is stirred for 30 minutes, then add hexane (200 ml) and the resulting precipitate removed by filtration through celite. The solvent is distilled off from the filtrate under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=1%-5%)to give the target compound (52,69 g, yield 58%) as a colourless oil.

1H-NMR (CDCl 3, 500 MHz): δ of 1.65 (9H, c), and 6.25 (2H, c).

MS (EI) m/z: 323 (M+).

(78f) 2-Benzyl-1-tert-butyl-5-bromo-1H-pyrrole-1,2 -, in primary forms

tert-Butyl-2,5-dibromo-1H-pyrrole-1-carboxylate (10,98 g, 33.8 mmol)synthesized in example (78e), dissolved in diethyl ether (135 ml) and the resulting solution was cooled to -78°C. To the solution is slowly added dropwise n-utility (solution 2.77 mol/l in hexane, to 12.8 ml, 35.5 mmol) and the resulting mixture is stirred for 1 hour. To the reaction solution was slowly added dropwise benzylchloride (6.25 ml, to 44.0 mmol) and the resulting mixture is stirred for 30 minutes. The reaction mixture is allowed the opportunity to slowly warm to room temperature and the mixture is stirred for 1 hour. To the reaction solution was added saturated aqueous solution of ammonium chloride (200 ml) and diethyl ether (300 ml). The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=5%-45%), obtaining the target compound (8,80 g, yield 68%) as a reddish brown oil.

1H-NMR (CDCl3, 400 MHz): δ of 1.56 (9H, c), of 5.26 (2H, c), 6,21 (1H, d, J=3,9 Hz), 6,85 (1H, d, J=3,9 Hz), 7,28-7,39 (5H, m).

MS (FAB) m/z: 380 (M+H)+.

(78g) 2-Benzyl-tert-butyl-5-{3-hydroxy-5-[(1S)-2-methoxy-1-IU is ylethoxy]phenyl}-1H-pyrrole-1,2 -, in primary forms

2-Benzyl-1-tert-butyl-5-bromo-1H-pyrrole-1,2 -, in primary forms (8,75 g, 23,0 mmol)synthesized in example (78f), and 3-[(1S)-2-methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (7,11 g of 23.1 mmol)synthesized in example (78d), dissolved in a mixed solvent of 1,4-dioxane (92 ml) and water (23 ml), the solution add complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (570 mg, 0,698 mmol) and potassium carbonate (of 7.95 g, 57.5 mmol) and the resulting mixture was stirred at 55°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, to the solution was added water (200 ml) and the mixture extracted with ethyl acetate (200 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=15%-35%), obtaining the target compound (8,32 g, 75%yield) as a brown oil.

1H-NMR (CDCl3, 500 MHz): δ of 1.29 (3H, d, J=6.3 Hz), of 1.41 (9H, c), 3,40 (3H, c), 3,47 (1H, DD, J=10,3, 4,4 Hz), 3,57 (1H, DD, J=10,3, 5,9 Hz), 4,48-of 4.54 (1H, m), 5,20 (1H, c), and 5.30 (2H, c), 6,17 (1H, d, J=3,4 Hz), 6,44 (1H, c), 6,48 (1H, c), to 6.57 (1H, c)6,94 (1H, d, J=3,4 Hz), 7,42-7,31 (5H, m).

MS (FAB) m/z: 481 (M+).

(78h) 5-Bromo-2-(methylthio)pyridine

Commercially available 2,5-dibromopyridine (6,01 g, and 25.4 mmol) dissolve the N,N-dimethylformamide (50 ml), to the solution add thiamethoxam sodium (2.20 g, of 31.4 mmol) and the resulting mixture was stirred at 0°C for 3.5 hours under nitrogen atmosphere. The reaction solution was allow to warm to room temperature, then add water (250 ml) and the mixture extracted with diethyl ether (250 ml). The organic layer was washed with saturated aqueous salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=3%-5%)to give the target compound (4,90 g, yield 94%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 2.54 (3H, c), was 7.08 (1H, d, J=8,2 Hz), 7,58 (1H, DD, J=8,6, and 2.3 Hz), 8,49 (1H, d, J=2.0 Hz).

(78i) 5-fluoro-2-(methylsulphonyl)pyridine

5-Bromo-2-(methylthio)pyridine (4,90 g, 24,0 mmol)synthesized in example (78h), dissolved in tetrahydrofuran (100 ml)to the solution at -78°C is added dropwise n-utility (solution of 1.57 mol/l in hexane, of 17.0 ml, or 26.7 mmol), the mixture was stirred at -78°C for 1 hour in nitrogen atmosphere. N-Forbindelsesfaneblad (11,0 g, is 34.9 mmol) dissolved in tetrahydrofuran (25 ml), then added dropwise to the reaction solution at -78°C and the mixture was stirred at -78°C for 2 hours in nitrogen atmosphere. The reaction solution was allow to warm decanates temperature and then it is stirred for 1.5 hours. To the mixture is added saturated aqueous solution of ammonium chloride (200 ml) and the mixture extracted with diethyl ether (300 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure.

The resulting residue is dissolved in methylene chloride (150 ml)to the resulting solution at 0°C, slowly add m-chloroperbenzoic acid (65%, 16.5 g, 62,1 mmol) and the resulting mixture was stirred at 0°C for 1.5 hours in a nitrogen atmosphere. The solid white precipitate is removed by filtration through celite, the filtrate is added a saturated aqueous solution of sodium bicarbonate (100 ml) and the mixture is extracted with methylene chloride (400 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=3%-5%)to give the target compound (1,95 g, yield 46%) as a solid, yellowish-white in color.

1H-NMR (CDCl3, 400 MHz): δ 3.24 in (3H, c), to 7.67 (1H, DDD, J=9,9, 6,9, 1.9 Hz), 8,16 (1H, DD, J=8,6, a 4.3 Hz), 8,59 (1H, d, J=2.7 Hz).

(78j) Benzyl-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylate

2-Benzyl-1-tert-butyl-5-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-H-pyrrole-1,2 -, in primary forms (of 5.05 g, 10,49 mmol)synthesized in example (78g), and 5-fluoro-2-(methylsulphonyl)pyridine (2,05 g, 11,70 mmol)synthesized in example (78i), dissolved in N,N-dimethylformamide (30 ml), to the solution was added potassium carbonate (4,50 g, 32,56 mmol) and the resulting mixture was stirred at 80°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (150 ml) and the mixture extracted with diethyl ether (150 ml). The organic layer was washed with saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

The obtained product is dissolved in triperoxonane acid (10 ml) and the solution stirred at room temperature for 1 hour in nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=35%-50%)to give the target compound (5,08 g, yield 90%) as a white oil color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 3,23 (3H, c), is 3.41 (3H, c), 3,51 (1H, DD, J=10,3, 3,9 Hz)to 3.58 (1H, DD, J=10,3, 6.3 Hz), 4,54-br4.61 (1H, m), 5,33 (2H, c), 6,51 (1H, t, J=3.2 Hz), 6,59 (1H, c)6,86 (1H, c), of 6.99 (1H, t, J=2,9 Hz), 7,02 (1H, c), 7,32 was 7.45 (7H, m), of 8.04 (1H, d, J=8,8 Hz), 8,48 (1H, c), 9,36 (1H, USS).

(78k) 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid

Benzyl-5-(3-[(1S)-2-methoxy-1-IU is ylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylate (5,08 g, 9.47 mmol)synthesized in example (78j), dissolved in ethyl acetate (30 ml), the solution is added the catalyst, 10% palladium on carbon (1.10 g) and the mixture is stirred at room temperature for 3 hours in hydrogen atmosphere. The mixture is filtered through celite, and the solvent is distilled off under reduced pressure, obtaining the target compound (4,30 g, yield ~100%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=5,9 Hz), 3,23 (3H, c), 3,47 (3H, c), of 3.57 (1H, DD, J=9,8, 3,9 Hz)to 3.67 (1H, DD, J=10,0, and 6.6 Hz), 4.72 in-4,80 (1H, m), of 6.52 (1H, c), 6,59 (1H, c), 6,92 (1H, c), 7,03 (1H, c), 7,32 (1H c), was 7.45 (1H, DD, J=8,5) and 1.7 Hz), with 8.05 (1H, d, J=8,8 Hz), 8,49 (1H, d, J=2.4 Hz), 10,31 (1H, USS).

(78l) 5-{3-[5-(4,5-Dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}-2-(methylsulphonyl)pyridine

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1,00 g, 2,24 mmol)synthesized in example (78k), dissolved in methanol (20 ml), the resulting solution was added ethanolamine (0,30 ml, equal to 4.97 mmol) and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (1,00 g, 3.61 mmol) and the mixture is stirred at room temperature for 1 day under nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=1%-3%), and receiving the product in the form of TV is Gogo substance of white color.

The product is dissolved in tetrahydrofuran (20 ml), to the solution was added anhydrous methansulfonate acid (700 mg, 4.02 mmol) and triethylamine (0,85 ml, 6,10 mmol) and the resulting mixture was stirred at 50°C for 5 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture is extracted with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=1%-3%), obtaining the target compound (410 mg, yield 39%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 3,23 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=10,2, 3,9 Hz)and 3.59 (1H, DD, J=10,6, 6.3 Hz), of 4.00 (2H, t, J=9,2 Hz), 4,43 (2H, t, J=9.4 Hz), 4,55-br4.61 (1H, m), 6,51 (1H, d, J=3.5 Hz), to 6.57 (1H, t, J=2.2 Hz), 6,77 (1H, d, J=3,9 Hz), at 6.84 (1H, t, J=1,8 Hz), 7,03 (1H, t, J=1.6 Hz), 7,44 (1H, DD, J=8,6, 2.7 GHz), with 8.05 (1H, d, J=8.6 Hz), 8,49 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 472,15408 (M+H)+.

Example 79

(2S)-2-(3-[5-(4,5-Dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

5-{3-[5-(4,5-Dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}-2-(methylsulphonyl)pyridine (230 mg, 0.49 mmol)synthesized in example is e (78l) is dissolved in methylene chloride (10 ml), to the solution at-78ºC added dropwise tribromide (boron solution in methylene chloride, 1.0 mol/l, 0.75 ml, 0.75 mmol) and the mixture is stirred at room temperature for 1.5 hours under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (20 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-4%), obtaining the target compound (170 mg, yield 76%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.30 (3H, d, J=6.3 Hz), 3,23 (3H, c), with 3.79 (2H, d, J=5,9 Hz), to 4.01 (2H, t, J=9.4 Hz), 4,43 (2H, t, J=9.4 Hz), 4,55-br4.61 (1H, m), 6,44 (1H, t, J=2.2 Hz), of 6.49 (1H, d, J=3,9 Hz), 6,76 (1H, d, J=3.5 Hz), for 6.81 (1H, t, J=2.0 Hz), of 6.96 (1H, c), 7,40 (1H, DD, J=8,6, and 2.3 Hz), of 8.04 (1H, d, J=8.6 Hz), 8,46 (1H, d, J=2.3 Hz).

MS (ESI) m/z: 458,13852 (M+H)+.

Example 80

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-2-(methylsulphonyl)pyridine

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3--yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (600 mg, of 1.34 mmol)synthesized in example (78k), dissolved in methylene chloride (20 ml), the solution add acetogen the Zid (220 mg, of 2.97 mmol), WSCI·HCl (580 mg, 3.03 mmol) and 4-dimethylaminopyridine (150 mg, of 1.23 mmol) and the resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (100 ml) and the mixture is extracted with methylene chloride (100 ml). The organic layer was washed with saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

The resulting residue is dissolved in methylene chloride (20 ml), the resulting solution was added and p-toluensulfonate (510 mg, 2.68 mmol) and triethylamine (0.75 ml, 5,38 mmol) and the mixture is stirred at room temperature for 4 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60-80%), obtaining the target compound (450 mg, yield 69%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.35 (3H, d, J=6.3 Hz), 2,59 (3H, c), 3,24 (3H, c), 3,42 (3H, c), 3,52 (1H, DD, J=10,6, 3.5 Hz), 3,61 (1H, DD, J=11,3, 5,5 Hz), 4,51-4,72 (1H, m), 6,59-of 6.61 (2H, USM), 6,87-6,90 (H, USM), 7,06 (1H, USS), 7,46 (1H, d, J=8.6 Hz), of 8.06 (1H, d, J=8.6 Hz), and 8.50 (1H, d, J=1.6 Hz), to 9.66 (1H, USS).

MS (ESI) m/z: 485,14739 (M+H)+.

Example 81

(2S)-2-(3-[5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-2-(methylsulphonyl)pyridine (320 mg, 0,660 mmol)synthesized in example 80, dissolved in methylene chloride (10 ml)to the solution at -78°C is added dropwise tribromide (boron solution in methylene chloride, 1.0 mol/l 1,00 ml, 1.00 mmol) and the mixture is stirred at room temperature for 1 hour in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (20 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=1%-3%), obtaining the target compound (190 mg, yield 61%) as a solid yellow color.

lH-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), 2,34 (1H, OSS), to 2.55 (3H, c), 3,21 (3H, c), 3,76 (2H, USS), 4,49-4,58 (1H, m), of 6.52 (1H, c), 6,55 (1H, DD, J=3,9, 2.7 GHz), for 6.81-6,84 (2H, m), 7,00 (1H, t, J=2.0 Hz), 7,42 (1H, DD, J=8,6, 2.7 Hz), 8,03 (1H, d, J=8.6 Hz), to 8.45 (1H, is, J=2.7 Hz), 9,76 (1H, USS).

MS (ESI) m/z: 471,13599 (M+H)+.

Example 82

{(5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

(82a) 5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(5R)-5-{[(tryptophan-2-ililil)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.70 g, 3,81 mmol)synthesized in example (78k), dissolved in methanol (30 ml)solution was added (S)-(-)-3-amino-1,2-propandiol (0,80 g, 8,78 mmol) and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (1.70 g, 6,14 mmol) and the resulting mixture was stirred at room temperature for 3 days under nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=7%-10%), and receiving the product in a solid yellow color.

The product is dissolved in methylene chloride (40 ml)to the resulting solution add triisopropylchlorosilane (1,32 ml of 6.17 mmol), 4-dimethylaminopyridine (0.75 g, 6,14 mmol) and triethylamine (2.87 in ml, 20,59 mmol) and the resulting mixture was stirred at room temperature for 1 day under nitrogen atmosphere. To react the traditional solution was added a saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=1%), and receiving the product in a solid yellow color.

The product is dissolved in tetrahydrofuran (30 ml), the resulting solution was added anhydrous methansulfonate acid (1,05 g, 6,03 mmol) and triethylamine (1.70 ml, 12.20 mmol), the mixture was stirred at 50°C for 4.5 hours under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-70%), obtaining the target compound (1.18 g, yield 47%) as a solid pale yellow color.

1H-NMR (CDCl3, 500 MHz): δ 0,99-1,16 (21H, m)of 1.32 (3H, d, J=6.3 Hz), 3,23 (3H, c), 3,40 (3H, c), 3,50 (1H, DD, J=10,3, 3,9 Hz)to 3.58 (1H, DD, J=10,3, 5,9 Hz), 3,81-are 3.90 (2H, m), 3,92-4,01 (2H, m), 4,51-to 4.62 (1H, USS), 4,70-4,78 (1H, USS), of 6.49 (1H, d, J=3,9 Hz), 6,56 (1H, c), 6,72 (1H, t, J=2.0 Hz), 6,83 (1H, c), 7,01 (1H, c), the 7.43 (1H, DD, J=7,6, 1.7 Hz), of 8.04 (1H, d, J=8,3 Hz), 8,48 (1H, is, J=2,4 Hz).

(82b) {(5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(5R)-5-{[(tryptophan-2-ililil)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine (1.18 g, to 1.79 mmol)synthesized in example (82a), dissolved in tetrahydrofuran (10 ml), to the solution at room temperature add tetrabutylammonium fluoride (solution 1.0 mol/l in tetrahydrofuran, 2.00 ml, 2.00 mmol) and the mixture is stirred at room temperature for 30 minutes in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (20 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-3%), obtaining the target compound (680 mg, yield 76%) as a solid white color.

lH-NMR (CDCl3, 400 MHz): δ of 1.27 (3H, d, J=6.3 Hz), 3,21 (3H, c), 3,40 (3H, c), of 3.48 (1H, DD, J=10,2, 3,9 Hz), of 3.56 (1H, DD, J=10,2, 6.3 Hz), 3,68 (1H, DD, J=12,1, 5,1 Hz in), 3.75 (1H, DD, J=14,5, 7,4 Hz), 3,85 (1H, d, J=9.4 Hz), of 4.00 (1H, DD, J=14,1, 9.8 Hz), a 4.53 (1H, USS), 4,78 (1H, USS), 6,46 (1H, d, J=3,9 Hz), 6,55 (1H, t, J=2.2 Hz), 6,72 (1H, d, J=3,9 Hz), for 6.81 (1H, is, J=2.0 Hz), 6,97 (1H, c), 7,42 (1H, DD, J=8,6, 2.7 Hz), 8,03 (1H, d, J=8.6 Hz), 8,46 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 502,16243 (M+H)+.

Example 83

(2S)-2-(3-{5-[(5R)-5-(Hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

{(5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol (520 mg, 1.04 mmol)synthesized in example (82b), dissolved in methylene chloride (10 ml)to the solution at-78ºC added dropwise tribromide boron (solution in methylene chloride, 1.0 mol/l, 2.00 ml, 2.00 mmol) and the resulting mixture was stirred at room temperature for 4 hours in nitrogen atmosphere. To the reaction solution was added 1 N. aqueous sodium hydroxide solution (20 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=3%-5%)to give the target compound (148 mg, yield 29%) as a solid white color.

lH-NMR (CDCl3, 400 MHz): δ of 1.30 (3H, d, J=5,9 Hz), 3,23 (3H, c), 3,70-3,82 (3H, m), 3,90-3,99 (2H, m), 4,07 (1H, t, J=11.5 Hz), to 4.62 (1H, USS), of 4.95 (1H, USS), 6,47 (2H, d, J=3,9 Hz)6,86 (2H, d, J=3,9 Hz), to 7.15 (1H, c), 7,0 (1H, DD, J=8,8, 2.4 Hz), 8,03 (1H, d, J=8,8 Hz), to 8.45 (1H, d, J=2.4 Hz), of 11.26 (1H, USS).

MS (ESI) m/z: 488,14896 (M+H)+.

Example 84

(2S)-2-(3-{5-[(4R)-4-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

(84a) N-[(1R)-2-Hydroxy-1-methylethyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (2.00 g, 4,48 mmol)synthesized in example (78k), D-alaninol (0,52 ml, 6,72 mmol), HOBT.H2O (0.73 g, 5,38 mmol) and N-methylmorpholin (0,99 ml, 8,96 mmol) dissolved in methylene chloride (40 ml)to the solution at room temperature add WSCI·HCl (0,94 g is 4.93 mmol) and the mixture is then stirred for 30 hours under nitrogen atmosphere. The reaction solution is diluted with methylene chloride (100 ml), washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-90%), obtaining the target compound (1,94 g, 86%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ of 1.27 (3H, d, J=6,8 Hz)of 1.33 (3H, d, J=6.3 for the TS) of 3.23 (3H, c), is 3.41 (3H, c), 3,51 (1H, DD, J=3,9, 10,3 Hz), 3,57-of 3.64 (2H, m), 3,76 (1H, DD, J=3,5, and 11.0 Hz), 4,21-4,27 (1H, USM), 4,55-4,60 (1H, m), the 6.06 (1H, d, J=7,3 Hz), 6.48 in (1H, DD, J=2.7, and 4.0 Hz), to 6.57 (1H, t, J=2.1 Hz), 6,60 (1H, DD, J=2.0 a, and 2.3 Hz), at 6.84 (1H, t, J=1.7 Hz), 7,01 (1H, t, J=1.7 Hz), 7,44 (1H, DD, J=2.7, and 8.7 Hz), of 8.04 (1H, d, J=8.7 Hz), of 8.47 (1H, d, J=2.7 Hz), 9,71 (1H, USS).

(84b) 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine

N-[(1R)-2-Hydroxy-1-methylethyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide (1,94 g of 3.85 mmol)synthesized in example (84a), dissolved in tetrahydrofuran (35 ml), the resulting solution was added anhydrous methansulfonate acid (1,38 g of 7.70 mmol) and the triethylamine (2,15 ml, 15,41 mmol) and the resulting mixture was stirred at 50°C for 1.5 hours in a nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (30 ml) and the mixture extracted with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-75%), obtaining the target compound (1,59 g, yield 85%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (6H, d, J=6.3 Hz), 3,23 (3H, c), 3,41 3H, c)a 3.50 (1H, DD, J=3,9, 10,2 Hz)and 3.59 (1H, DD, J=6,1, 10.4 Hz), 3,93 (1H, t, J=7.8 Hz), 4,30 is 4.36 (1H, m), 4,50 (1H, DD, J=8,2, 9,2 Hz), 4,56-4,60 (1H, m), 6,51 (1H, d, J=3,9 Hz), to 6.57 (1H, t, J=2.2 Hz), 6.75 in (1H, d, J=3.8 Hz), at 6.84 (1H, t, J=1,8 Hz),? 7.04 baby mortality (1H, t, J=1,8 Hz), 7,44 (1H, DD, J=2,8, and 8.7 Hz), with 8.05 (1H, d, J=8,8 Hz), to 8.45 (1H, d, J=2.7 Hz).

(84c) (2S)-2-(3-{5-[(4R)-4-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine (1.20 g, 2,47 mmol)synthesized in example (84b), dissolved in methylene chloride (25 ml), the resulting solution was cooled to -78°C, and then to the solution dropwise in nitrogen atmosphere add tribromide (boron solution in methylene chloride, 1.0 mol/l, 2,72 ml of 2.72 mmol). The mixture should be allowed the opportunity to spontaneously warm to room temperature, then the mixture is stirred at room temperature for 30 minutes to neutralize the added saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride (80 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=70%-100%)to give the target compound (895 mg, 77%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.2 Hz), of 1.34 (1H, d, J=6.6 Hz), 3,23 (3H, c), 3,79-3,81 (2H, m), 3,95 (1H, t, J=7.9 Hz), 4,32-to 4.38 (1H, m)to 4.52 (1H, DD, J=8,1, and 9.3 Hz), br4.61 with 4.65 (1H, m), 6.35mm (1H, t, J=2.2 Hz), 6,47 (1H, d, J=3,9 Hz), to 6.75 (1H, d, J=3.8 Hz), to 6.80 (1H, DD, J=1,4, 2,4 Hz), 6,97 (1H, t, J=1,8 Hz), 7,37 (1H, DD, J=2.7, and an 8.8 Hz), 8,02 (1H, d, J=8,8 Hz), 8,43 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 472,15382 (M+H)+.

Example 85

(2S)-2-(3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

(85a) N-[(1R)-1-(Hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2,69 mmol)synthesized in example (78k), (R)-(-)-2-amino-1-butanol (0,38 ml, a 4.03 mmol), HOBT·H2O (0,44 g of 3.23 mmol) and N-methylmorpholin (0,59 ml, 5,38 mmol) dissolved in methylene chloride (30 ml)to the solution at room temperature add WSCI·HCl (0,62 g of 3.23 mmol) and the mixture is then stirred for 6 hours in nitrogen atmosphere. The reaction solution is diluted with methylene chloride (50 ml), washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography the raffia (silica gel, eluting solvent: ethyl acetate/hexane=50%-90%), obtaining the target compound (1.18 g, 85%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.01 (3H, t, J=7.4 Hz), of 1.33 (3H, d, J=6.3 Hz), 1,67-of 1.74 (2H, m), 3,23 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=3,9, 10.4 Hz)and 3.59 (1H, DD, J=6,2, 10.4 Hz), of 3.69 (1H, DD, J=5,7, up 10.9 Hz), with 3.79 (1H, DD, J=3,4, and 11.0 Hz), 4,01-4,06 (1H, USM), 4,56-4,60 (1H, m), of 6.02 (1H, d, J=8,3 Hz), of 6.49 (1H, DD, J=2,9, 3,9 Hz), to 6.58 (1H, t, J=2.3 Hz), is 6.61 (1H, DD, J=2.5 and a 4.1 Hz), at 6.84 (1H, t, J=1,8 Hz), 7,02 (1H, t, J=1,8 Hz), was 7.45 (1H, DD, J=2,8, and 8.7 Hz), with 8.05 (1H, d, J=8.7 Hz), to 8.45 (1H, DD, J=0.8, the 2,8 Hz), 9,60 (1H, USS).

(85b) 5-(3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-2-(methylsulphonyl)pyridine

N-[(1R)-1-(Hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide (1.18 g, 2.28 mmol)synthesized in example (85a), dissolved in tetrahydrofuran (20 ml), to the solution was added anhydrous methansulfonate acid (0,82 g, 4,56 mmol) and triethylamine (of 1.27 ml, 9,12 mmol) and the resulting mixture was stirred at 50°C for 1.5 hours in a nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (30 ml) and extracted with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromate what graphy (silica gel, eluting solvent: ethyl acetate/hexane=40%-70%), obtaining the target compound (1.06 g, yield 93%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 0,99 (3H, t, J=7.4 Hz), of 1.34 (3H, d, J=6.4 Hz), 1.56 to of 1.65 (1H, m), 1,66-of 1.74 (1H, m), 3,23 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=4,0, 10,2 Hz), 3,60 (1H, DD, J=6,1, 10,3 Hz), was 4.02 (1H, t, J=7,8 Hz), 4,16-4,20 (1H, m), 4,46 (1H, t, J=8.7 Hz), 4,56-4,60 (1H, m), 6,51 (1H, d, J=3,9 Hz), 6,56 (1H, t, J=2.2 Hz), 6,74 (1H, d, J=3.8 Hz), 6,85 (1H, t, J=1.7 Hz), 7,05 (1H, t, J=1.7 Hz), 7,44 (1H, DD, J=of 2.7, 8.7 Hz), with 8.05 (1H, DD, J=0,8, 8.5 Hz), to 8.45 (1H, DD, J=0.8, the 2.7 GHz).

(85c) (2S)-2-(3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

5-(3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-2-(methylsulphonyl)pyridine (1.06 g, 2,12 mmol)synthesized in example (85b), dissolved in methylene chloride (20 ml), the resulting solution was cooled to -78°C and add tribromide boron (solution in the methylene chloride, 1.0 mol/l of 2.33 ml, of 2.33 mmol) under nitrogen atmosphere. The mixture should be allowed the opportunity to spontaneously warm to room temperature and then the mixture is stirred at room temperature for 30 minutes, then to neutralize the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride (80 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate is. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=70%-100%)to give the target compound (738 mg, 71%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.02 (3H, t, J=7.4 Hz), of 1.28 (3H, d, J=6.2 Hz), 1,58-of 1.66 (1H, m), 1,67-of 1.74 (1H, m), up 3.22 (3H, c), 3,80-3,82 (2H, m), a 4.03 (1H, t, J=8.0 Hz), 4,16-to 4.23 (1H, m), of 4.49 (1H, t, J=8.7 Hz), 4,62-4,68 (1H, m), of 6.29 (1H, d, J=2.2 Hz), 6,45 (1H, t, J=3,7 Hz), 6,74 (1H, d, J=3,9 Hz), 6,79 (1H, t, J=1,8 Hz), to 6.95 (1H, t, J=1.7 Hz), 7,35 (1H, DD, J=2.7, and 8.7 Hz), 8,01 (1H, d, 8.7 Hz), 8,42 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 486,16955 (M+H)+.

Example 86

{(4R)-2-[5-(3-[(lS)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol

(86a) Methyl-N-{[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]carbonyl}-L-serinate

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.60 g, 3.58 mmol)synthesized in example (78k), the hydrochloride of the methyl ester of L-serine (0,61 g of 3.94 mmol), HOBT·H2O (0,53 g of 3.94 mmol) and N-methylmorpholin (0,79 ml, 7,17 mmol) was dissolved in a mixed solvent of methylene chloride (30 ml) and N,N-dimethylformamide (7 ml)to the solution at room temperature add WSCI·HCl (0,82 g, 4.30 mmol) and the mixture is then stirred for 5 hours in nitrogen atmosphere. The reaction solution is diluted with methylene chloride (100 ml), washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-80%), obtaining the target compound (1,91 g, 97%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ of 1.33 (3H, d, J=6.4 Hz), up 3.22 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=3,8, 10,3 Hz)to 3.58 (1H, DD, J=6,3, 10,3 Hz), of 3.78 (3H, c), 3,98 (1H, DD, J=3,4, 11.3 Hz), Android 4.04 (1H, DD, J=3,9, 11.3 Hz), 4,56-4,59 (1H, USM), 4,80 of 4.83 (1H, m), 6.48 in (1H, DD, J=2.7, and 3.8 Hz), 6,56 (1H, t, J=2.0 Hz), 6,74 (1H, DD, J=2.0 a, 2,4 Hz), to 6.88 (1H, t, J=1.7 Hz), 6,97 (1H, d, J=7.5 Hz),? 7.04 baby mortality (1H, t, J=1.9 Hz), the 7.43 (1H, DD, J=2,8, 8,8 Hz), 8,03 (1H, d, J=8,8 Hz), 8,46 (1H, d, J=2,8 Hz), and 10.5 (1H, USS).

(86b) Methyl-(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-carboxylate

Methyl-N-{[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]carbonyl}-L-serinate (1,91 g of 3.57 mmol)synthesized in example (86a), dissolved in methylene chloride (40 ml)to the solution at-78ºC added dropwise TRIFLUORIDE bis(2-methoxyethyl)aminocore (0,85 ml, with 4.64 mmol). The mixture is stirred for 30 minutes in a nitrogen atmosphere, and then to the mixture is added potassium carbonate(0.74 g, to 5.35 mmol) and the mixture was stirred at 0°C for 10 minutes, and then for 3 hours at room temperature. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (30 ml), the mixture is extracted with methylene chloride (100 ml), the organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-70%), obtaining the target compound (1,76 g, 93%) as white powder.

1H-NMR (CDCl3, 500 MHz): δ of 1.34 (3H, d, J=6.2 Hz), 3,23 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=4,1, 10,3 Hz)and 3.59 (1H, DD, J=6,3, 10,3 Hz), 3,82 (1H, c), 4,56-4,60 (2H, m), of 4.67 (1H, t, J=8,2 Hz), the 4.90 (1H, DD, J=5,2, 7,8 Hz), of 6.50 (1H, d, J=3.8 Hz), 6,59 (1H, t, J=2.2 Hz), for 6.81 (1H, d, J=3,9 Hz), at 6.84 (1H, t, J=1.7 Hz), 7,03 (1H, c), was 7.45 (1H, DD, J=2.7, and 8.6 Hz), of 8.06 (1H, d, J=8.7 Hz), 8,48 (1H, d, J=2.7 Hz).

(86c) {(4R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol

Methyl(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-carboxylate (1,76 g of 3.32 mmol)synthesized in example (86b), dissolved in tetrahydrofuran (30 ml) and the solution at 0ºC add alumoweld lithium (0.25 g, of 6.65 mmol). The mixture is stirred for 30 minutes in nitrogen atmosphere, the m successively added water (0.25 ml), 5 N. aqueous sodium hydroxide solution (0.25 ml) and again water (0.75 ml) and the mixture is stirred for 10 minutes. To the reaction solution was added ethyl acetate (100 ml), then the mixture is stirred for 5 minutes and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (1,15 g, 69%) as white powder.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 3,23 (3H, c), is 3.41 (3H, c), 3,51 (1H, DD, J=4,1, 10.4 Hz), to 3.58-3,62 (2H, m), of 3.97 (1H, d, J=and 12.2 Hz), 4,10-to 4.15 (2H, m), or 4.31-4,39 (2H, m), 4,56-4,60 (1H, m), 6,37 (1H, d, J=3.8 Hz), 6,47 (1H, d, J=3, 9 Hz), to 6.57 (1H, t, J=2.2 Hz), 6.87 in (1H, DD, J=1,2, 1,4 Hz), 7,05 (1H, t, J=1,8 Hz), 7,46 (1H, DD, J=2,8, 8,8 Hz), with 8.05 (1H, DD, J=0,7, 8,8 Hz)and 8.50 (1H, DD, J=0.7 and 2.8 Hz).

Example 87

(2S)-2-(3-{5-[(4R)-4-(Hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

{(4R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol (200 mg, 0.40 mmol)synthesized in example (86c), dissolved in methylene chloride (5 ml), the solution cooled to -78°C and the solution in an atmosphere of nitrogen was added dropwise tribromide (boron solution in methylene chloride, 1.0 mol/l to 0.80 ml, 0.80 mmol). After samoproizvol the aqueous heating to room temperature, the mixture was stirred at room temperature for 30 minutes, add saturated aqueous solution of sodium bicarbonate to neutralize the reaction solution and then the resulting mixture was extracted with methylene chloride (80 ml). The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-4%), obtaining the target compound (143 mg, 74%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), 3,23 (3H, c), the 3.65 (1H, DD, J=3,5, 12.1 Hz), 3,74-of 3.80 (2H, m), of 3.95 (1H, DD, J=2,7, and 12.2 Hz), 4,20 (1H, t, J=6.8 Hz), 4,34-to 4.41 (1H, m)to 4.41 (1H, t, J=9.8 Hz), 4,57-br4.61 (1H, m), 6,37 (1H, d, J=3,9 Hz), 6.48 in (1H, t, J=2.2 Hz), 6,53 (1H, d, J=3,9 Hz), 6,85 (1H, t, J=1,8 Hz), 7,01 (1H, t, J=1,8 Hz), 7,42 (1H, DD, J=2.7, and an 8.8 Hz), of 8.04 (1H, d, J=8,8 Hz), of 8.47 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 488,14910 (M+H)+.

Example 88

(2S)-2-(3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

(88a) (2R,3R)-3-Aminobutane-2-ol

(2R,3R)-3-(Dibenzylamino)butane-2-ol ([a]23D-82°c: 1,60, a solution in chloroform (2.70 g, 10.0 mmol)synthesized in accordance with the known method (J. Org. Chem., 2006, 71, 6420), dissolved in methanol (20 ml), to the solution was added palladium hydroxide on plastics technology : turning & the de (0.85 grams), the resulting mixture was stirred at 60 psi (413,7 kPa) at room temperature for 4 hours in hydrogen atmosphere. The mixture is filtered through celite, the solvent is distilled off under reduced pressure, obtaining the target compound (0.73 g, yield 82%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ of 1.10 (3H, d, J=6.6 Hz), of 1.17 (3H, d, J=6.3 Hz), 2,60-to 2.67 (1H, m), 3,31-3,37 (1H, m).

(88b) N-[(1R,2R)-2-Hydroxy-1-methylpropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (2.00 g, 4,48 mmol)synthesized in example (78k), and (2R,3R)-3-aminobutane-2-ol (0,94 g, 8,96 mmol)synthesized in example (88a), dissolved in methanol (30 ml), to the solution is added n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (2,84 g, 8,96 mmol) at room temperature and then the mixture is stirred for 3 days under nitrogen atmosphere. The solvent is distilled off under reduced pressure, add water (30 ml) and extracted with ethyl acetate (70 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-90%), poluchatelej connection (1,33 g, 57%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.23 (3H, t, J=6.3 Hz), of 1.27 (3H, d, J=6,6 Hz)of 1.33 (3H, d, J=6.3 Hz), 3,23 (3H, c), is 3.41 (3H, c), 3,52 (1H, DD, J=3,9, 10,3 Hz)and 3.59 (1H, DD, J=6,2, 10,3 Hz), 3,82-3,86 (1H, m), of 4.05-4.09 to (1H, m,), 4,58-to 4.62 (1H, m), 6,17 (1H, d, J=8.7 Hz), of 6.49 (1H, DD, J=2,9, 3,9 Hz), to 6.57 (1H, t, J=2.2 Hz), 6,63 (1H, DD, J=2,3, 3,9 Hz)6,86 (1H, t, J=1,8 Hz), 7,05 (1H, t, J=1,8 Hz), 7,44 (1H, DD, J=2,8, 8,7 Hz), of 8.04 (1H, d, J=8.7 Hz), 8,48 (1H, d, J=2,8 Hz), 9,83 (1H, USS).

(88c) 5-(3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-2-(methylsulphonyl)pyridine

N-[(1R,2R)-2-Hydroxy-1-methylpropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide (1,33 g, 2.57 mmol)synthesized in example (88b), dissolved in tetrahydrofuran (25 ml), the solution was added anhydrous methansulfonate acid (0,92 g, 5,14 mmol) and triethylamine (1,43 ml, 10,28 mmol) and the resulting mixture was stirred at 50°C for 5 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (40 ml) and the mixture extracted with ethyl acetate (80 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=40%-70%), receiving the target link is (0.95 g, yield 74%) as a solid white color.

lH-NMR (CDCl3, 500 MHz): δ of 1.20 (3H, t, J=6.9 Hz), of 1.33 (3H, d, J=6.3 Hz), of 1.33 (3H, d, J=6.6 Hz), 3,23 (3H, c), is 3.41 (3H, c), 3,50 (1H, DD, J=4,0, 10.4 Hz), to 3.58 (1H, DD, J=6,1, 10.4 Hz), 4,24-the 4.29 (1H, m), 4,55-4,58 (1H, m,), 4,79-4,84 (1H, m), 6,50 (1H, d, J=3.8 Hz), 6,56 (1H, t, J=2.2 Hz), 6,74 (1H, d, J=3.8 Hz), 6,83 (1H, t, J=1,8 Hz), 7,01 (1H, t, J=1,8 Hz), the 7.43 (1H, DD, J=2,8, 8.6 Hz), with 8.05 (1H, d, J=8.6 Hz), 8,48 (1H, d, J=2,8 Hz).

(88d) (2S)-2-(3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

5-(3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-2-(methylsulphonyl)pyridine (0.95 g, a 1.96 mmol)synthesized in example (88c), dissolved in methylene chloride (20 ml), the solution cooled to -78°C, to a solution under nitrogen atmosphere add tribromide (boron solution in methylene chloride, 1.0 mol/l of 2.15 ml of 2.15 mmol). After spontaneous heating the reaction solution to room temperature, it was stirred at room temperature for 30 minutes, then add saturated aqueous solution of sodium bicarbonate to neutralize the reaction solution, and extracted with a mixture of methylene chloride (80 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica compound is spruce, eluting solvent: ethyl acetate/hexane=70%-100%)to give the target compound (617 mg, 67%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.23 (3H, t, J=7,0 Hz)of 1.27 (3H, d, J=6.2 Hz), of 1.34 (3H, d, J=6.6 Hz), 3,23 (3H, c), 3,81-a 3.83 (2H, m), 4,27 is 4.35 (1H, m), 4,65-4,70 (1H, m), 4,81-4,89 (1H, m), 6,24 (1H, t, J=2.2 Hz), 6,44 (1H, d, J=3.8 Hz), was 6.73 (1H, d, J=3.8 Hz), 6,76 (1H, DD, J=1,2, 2,2 Hz), 6,92 (1H, t, J=1.7 Hz), 7,32 (1H, DD, J=2,8, 8,8 Hz), 8,00 (1H, d, J=8,8 Hz), to 8.41 (1H, d, J=2,8 Hz).

MS (ESI) m/z: 486,17002 (M+H)+.

Example 89

{(4R,5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-5-yl}methanol

(89a) (2R,3R)-3-[(Diphenylmethyl)amino]-1-[(tryptophan-2-ililil)oxy]butane-2-ol

Molecular sieves 4A (10 g) is added to digidratirovannogo to methylene chloride (200 ml). In this system add tetraisopropoxide titanium (8,8 ml, 30 mmol) and diethyl ester of L-(+)-tartaric acid (6.2 ml, 36 mmol) at -20°C and the mixture is stirred at the same temperature for 15 minutes. (2E)-2-Butene-1-ol (25 ml, 295 mmol)dissolved in digidrirovanne the methylene chloride (50 ml), added dropwise at -20°C and the mixture is stirred at the same temperature for 15 minutes. After that, the system adds tert-butylhydroperoxide (add methylene chloride for extraction followed by the addition of molecular sieves 4A (5 g) and stirring for 20 minutes) (p is the target in the Deccan, 5-6 mol/l, 100 ml, 0.5 to 0.6 mmol) at -20°C, the mixture was stirred at -20°C for 8.5 hours in a nitrogen atmosphere, and the solution is stored overnight at -30°C.

In the resulting system at room temperature is added n-tributylphosphine (75 ml, 300 mmol), tetraisopropoxide titanium (135 ml, 460 mmol) and 1,1-diphenylethane (75 ml, 440 mmol) and the mixture is stirred at room temperature for 1 week. To the reaction solution was added water (30 ml) and the formed precipitate is removed by filtration. To the stock solution add water (400 ml) and the mixture is extracted with methylene chloride (1 liter). The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=15%-40%), and receiving the product in liquid form is dark brown.

The obtained liquid product was dissolved in methylene chloride (300 ml)to the solution at room temperature is added triethylamine (85 ml, 610 mmol) and chloride triisopropylsilyl (50 ml, 234 mmol) and the resulting mixture was stirred at room temperature for 1.5 days. To the reaction solution was added saturated aqueous solution of ammonium chloride (500 ml) and the mixture is extracted with methylene chloride (500 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-5%)to give the target compound (80,5 g, yield 64%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 0,96-1,07 (21H, m), 1,10 (3H, d, J=6.3 Hz), 2,72-of 2.81 (1H, m), or 3.28 (1H, USS), 3,56-3,63 (1H, m), and 3.72 (1H, DD, J=10,2, 5,9 Hz), 3,80 (1H, DD, J=10,2, 3,9 Hz), to 4.98 (1H, c), 7,15-7,20 (2H, m), 7.23 percent-7,29 (4H, m), 7,34-7,40 (4H, m).

(89b) Benzyl{(2R,3R)-3-hydroxy-4-[(tryptophan-2-ililil)oxy]butane-2-yl}carbamate

(2R,3R)-3-[(Diphenylmethyl)amino]-1-[(triisopropyl-2-ililil)oxy]butane-2-ol (10.3 g, 24,1 mmol)synthesized in example (89a), dissolved in ethanol (40 ml), to the solution was added palladium on carbon (3,20 g) and the resulting mixture was stirred at room temperature for 6 hours in an atmosphere of hydrogen. The reaction solution is filtered through celite and the solvent is distilled off under reduced pressure, obtaining the product as a colourless liquid.

The obtained product is dissolved in water (40 ml), heated to 50°C., to the solution was added sodium bicarbonate (4,50 g, 53.6 mmol) and benzylchloride (3,50 ml, 24.5 mmol) at room temperature and the resulting mixture was stirred at room temperature for 5 hours. The reaction solution is extracted with methylene chloride (100 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue Colo cleanse the face-to-face chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-15%), obtaining the target compound (7,00 g, yield 73%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ 1.04 million-1,09 (21H, m)of 1.18 (3H, d, J=6,8 Hz)to 2.67 (1H, USS), 3,65-to 3.73 (2H, m), of 3.77 (1H, DD, J=10,0, and 3.7 Hz), 3,86 (1H, USS), 5,10 (2H, c), 5,27 (1H, USS), 7,30-7,38 (5H, m).

(89c) (5R,6S)-5,10-Dimethyl-3-oxo-1-phenyl-9,9-di(propan-2-yl)-2,8-dioxa-4-Aza-9-silundika-6-yl-4-nitrobenzoate

Benzyl{(2R,3R)-3-hydroxy-4-[(tryptophan-2-ililil)oxy]butane-2-yl}carbamate (7,00 g of 17.7 mmol)synthesized in example (89b), dissolved in toluene (80 ml), to the solution was added 4-nitrobenzoic acid (6,10 g of 36.5 mmol) and triphenylphosphine (11.85 g, 45,2 mmol) and the resulting mixture is cooled to 0°C. In nitrogen atmosphere to a mixture dropwise over 10 minutes add diethylazodicarboxylate (40% solution in toluene of 20.3 ml of 44.7 mmol) and the mixture is stirred at room temperature for 4 hours. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-15%), obtaining the target compound (of 7.90 g, yield 82%) as a yellow liquid.

1H-NMR (CDCl3, 400 MHz): δ 0,96-1,09 (21H, m)of 1.29 (3H, d, J=7,0 Hz), 3,90-4,01 (1H, m), 4,25-4,32 (1H, m), 4,95-5,10 (3H, m), 5,13-5,20 (1H, m), 7.24 to 7,39 (5H, m), 8,14-8,21 (2H, m), 8,23-8,30 (2H, m).

(89d) Benzyl{(2R,3S)-3-hydroxy-4-[(tryptophan-2-ililil)oxy]butane-2-yl}carbamate

(5R,6S)-5,10-Dimethyl-3-oxo-1-f the Nile-9,9-di(propan-2-yl)-2,8-dioxa-4-Aza-9-silundika-6-yl-4-nitrobenzoate (of 7.90 g, 14.5 mmol)synthesized in example (89c), dissolved in methylene chloride (150 ml), the solution add hydride diisobutylaluminum (solution 1.0 mol/l in hexane, and 30.0 ml, 30.0 mmol) and the resulting mixture was stirred at -40°C for 8 hours in nitrogen atmosphere. The reaction solution was allow to warm to 0°C, the solution was added methanol (5.0 ml), then 5 N. aqueous sodium hydroxide solution (150 ml) and the mixture is extracted with methylene chloride (200 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-15%), obtaining the target compound (3,70 g, yield 65%) as a colourless liquid.

1H-NMR (CDCl3, 400 MHz): δ 1,01-1,13 (21H, m)of 1.26 (3H, d, J=6.6 Hz), of 2.72 (1H, USS), 3,55-to 3.67 (2H, m), of 3.73 (2H, USS), 5,10 (2H, c), 5,13 (1H, USS), 7,31 and 7.36 (5H, m).

(89e) (2S,3R)-3-amino-1-[(tryptophan-2-ililil)oxy]butane-2-ol

Benzyl{(2R,3S)-3-hydroxy-4-[(tryptophan-2-ililil)oxy]butane-2-yl}carbamate (3,70 g, 9,35 mmol)synthesized in example (89d), dissolved in ethanol (30 ml), to the solution was added palladium on carbon (1,00 g) and the resulting mixture was stirred at room temperature for 8 hours in an atmosphere of hydrogen. The reaction solution is filtered through celite, and the solvent is distilled the ri reduced pressure, receiving the target compound (2.65 g, yield ~100%) liquid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ 1.04 million-1,14 (24H, m), 2.95 and-to 3.02 (1H, m), 3,30-to 3.35 (1H, m), 3,66 (1H, DD, J=9,8, and 6.3 Hz), 3,76 (1H, DD, J=9,8, a 4.3 Hz).

(89f) N-{(1R,2S)-2-Hydroxy-1-methyl-3-[(triisopropylsilyl)oxy]propyl}-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2,69 mmol)synthesized in example (78k), (2S,3R)-3-amino-1-[(tryptophan-2-ililil)oxy]butane-2-ol (1.08 g, 4,11 mmol)synthesized in example (89e), HOBT·H20 (0,44 g of 3.23 mmol) and N-methylmorpholin (0,59 ml, 5,38 mmol) is dissolved in N,N-dimethylformamide (20 ml), the solution add WSCI·HCl (0,62 g of 3.23 mmol) at room temperature and then the mixture is stirred for 18 hours under nitrogen atmosphere. To the reaction solution was added a saturated salt solution (30 ml) and the mixture extracted with ethyl acetate (60 ml). The mixture was washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-50%)to give the target compound (1,69 g, 91%) as a powder be the CSOs color.

1H-NMR (CDCl3, 400 MHz): δ 1,03-1,13 (21H, m)of 1.34 (3H, d, J=6.3 Hz), of 1.35 (3H, d, J=6.8 Hz), 3,23 (3H, c), 3,42 (3H, c), 3,51 (1H, DD, J=4.0 a, 10,3 Hz), 3,54-3,61 (2H, m), of 3.73-of 3.78 (2H, m), 4,14-4,18 (1H, m), 4,56-4,60 (1H, m)of 6.31 (1H, USM), of 6.49 (1H, DD, J=2,9, 3,9 Hz), 6,57-6,60 (2H, m), at 6.84 (1H, DD, J=1.5 and 2.3 Hz), 7,02 (1H, t, J=1,8 Hz), was 7.45 (1H, DD, J=2,8, 8,8 Hz), of 8.09 (1H, d, J=8.7 Hz), 8,49 (1H, d, J=2.7 Hz), 9,52 (1H, USS).

(89g) 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(4R,5R)-4-methyl-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine

N-[(1R,2S)-2-Hydroxy-1-methyl-3-[(triisopropylsilyl)oxy]propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide (1,69 g, 2.45 mmol)synthesized in example (89f), dissolved in tetrahydrofuran (25 ml), the resulting solution was add anhydrous methansulfonate acid (0.88 g, of 4.90 mmol) and triethylamine (1,37 ml of 9.80 mmol) and the resulting mixture was stirred at 50°C for 5 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (40 ml) and the solution extracted with ethyl acetate (60 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-50%)to give the target compound (1.23 g, Ihad 75%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1.04 million-1,14 (21H, m)of 1.34 (6H, d, J=6.3 Hz), 3,23 (3H, c), 3,42 (3H, c), 3,50 (1H, DD, J=4.0 a, 10,3 Hz)and 3.59 (1H, DD, J=6,1, 10,3 Hz), of 3.94 (2H, d, J=5.3 Hz), 4,37-to 4.41 (1H, m), 4,56-4,60 (1H, m), 4,65-4,69 (1H, m), of 6.49 (1H, d, J=3,9 Hz), 6,56 (1H, t, J=2.1 Hz), 6,74 (1H, d, J=3.8 Hz), 6,85 (1H, c),? 7.04 baby mortality (1H, c), 7,44 (1H, DD, J=2,8, 8.6 Hz), with 8.05 (1H, d, J=8.6 Hz), 8,48 (1H, d, J=2,8 Hz).

(89h) {(4R,5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-5-yl}methanol

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(4R,5R)-4-methyl-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine (1.23 g, to 1.83 mmol)synthesized in example (89g), dissolved in tetrahydrofuran (20 ml), to to the solution was added tetrabutylammonium fluoride (solution 1.0 mol/l in tetrahydrofuran, 2,11 ml, 2,11 mmol) is added at room temperature and then the mixture was stirred at room temperature for 1 hour in nitrogen atmosphere. To the reaction solution was added water (20 ml) and the mixture extracted with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=90%-100%)to give the target compound (715 mg, yield 76%) as a solid substance be the CSOs color.

1H-NMR (CDCl3, 400 MHz): δ 1.26 in (3H, d, J=7,1 Hz)is 1.31 (3H, d, J=6.3 Hz), 3,23 (3H, s), 3,42 (3H, s), 3,50 (1H, DD, J=3,9, 10,3 Hz)and 3.59 (1H, DD, J=6,3, 10,3 Hz), 3,85 (2H, d, J=5.4 Hz), 4,36 was 4.42 (1H, m), 4.53-in-4,48 (1H, m,), 4,70 was 4.76 (1H, m), 6,50 (1H, d, J=3.8 Hz), to 6.57 (1H, t, J=2.1 Hz), 6,77 (1H, d, J=3.8 Hz), at 6.84 (1H, t, 1.8 Hz), 7,00 (1H, t, 1.8 Hz), the 7.43 (1H, DD, J=2,8, 8,8 Hz), of 8.04 (1H, d, J=8,8 Hz), 8,48 (1H, d, J=2,8 Hz).

MS (ESI) m/z: 516,17829 (M+H)+.

Example 90

(2S)-2-(3-{5-[(4R,5R)-5-(Hydroxymethyl)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

{(4R,5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-2-yl}methanol (200 mg, 0,39 mmol)synthesized in example (89h), dissolved in methylene chloride (5 ml), the solution at-78ºC under nitrogen atmosphere add tribromide (boron solution in methylene chloride, 1.0 mol/l to 0.78 ml, 0.78 mmol), the mixture is allowed the opportunity to warm to room temperature and stirred the mixture at room temperature for 45 minutes. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting RA is the solvent: methanol/methylene chloride=0%-4%), receiving the target compound (87 mg, yield 45%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (6H, t, J=5,9 Hz), 3,23 (3H, s), with 3.79 (2H, d, J=4.9 Hz), 3,85 (2H, d, J=6.3 Hz), to 4.41 (1H, dt, J=16,3, 7,1 Hz), 4,59 (1H, DD, J=11,5, 5.6 Hz), 4,73-of 4.77 (1H, m), 6,38 (1H, s), 6,46 (1H, d, J=3,4 Hz), 6,77 (1H, d, J=3,9 Hz), for 6.81 (1H, s), 6,98 (1H, s), 7,35 (1H, d, J=8,8 Hz), 8,01 (1H, d, J=8,8 Hz), 8,44 (1H, s).

MS (ESI) m/z: 502,16510 (M+H)+.

Example 91

{(4R,5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol

(91a) N-[(1R,2R)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2,69 mmol)synthesized in example (78k), and commercially available L-threonine (0,57 g, 5,38 mmol) dissolved in methanol (25 ml)to the solution at room temperature add n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (1.70 g, 5,38 mmol) and the resulting mixture was stirred in nitrogen atmosphere for 3.5 hours. The solvent is distilled off under reduced pressure and the obtained residue was diluted with ethyl acetate (100 ml). The mixture was washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate and a saturated solution of the m salt, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-6%), obtaining the target compound (883 mg, 62%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.23 (3H, d, J=6.4 Hz), of 1.30 (3H, d, J=6.3 Hz), 3,23 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=3,9, 10,2 Hz)to 3.58 (1H, DD, J=6,4, 10.4 Hz), a 3.87 (2H, d, J=4.0 Hz), 3,97-a 4.03 (1H, USM), 4,22-4.26 deaths (1H, m,), 4,55-4,58 (1H, m), of 6.49 (1H, DD, J=2,8, 3,9 Hz), to 6.57 (1H, t, J=2.2 Hz), 6,68-of 6.71 (2H, m)6,86 (1H, t, J=1.7 Hz), 7,02 (1H, t, J=1,8 Hz), 7,44 (1H, DD, J=2.7, and 8.7 Hz), of 8.04 (1H, d, J=8,8 Hz), of 8.47 (1H, d, J=2.7 Hz), of 10.05 (1H, USS).

(91b) N-[(1R,2R)-2-Hydroxy-1-{[(triisopropylsilyl)oxy]methyl}propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide

N-[(1R,2R)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide (883 mg, of 1.65 mmol)synthesized in example (91a), triethylamine (1,15 ml of 8.27 mmol) and 4-dimethylaminopyridine (404 mg, of 3.31 mmol) dissolved in methylene chloride (20 ml)to the resulting solution at room temperature add chloride triisopropylsilyl (0,60 ml of 2.81 mmol) and the resulting mixture is stirred for 20 hours under nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatograph is her (silica gel, eluting solvent: ethyl acetate/hexane=30%-60%), obtaining the target compound (1,03 g, 90%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1,05-a 1.08 (18H, m), 1,09 is 1.16 (3H, m)of 1.23 (3H, d, J=6,4 Hz)of 1.34 (3H, d, J=6.3 Hz), 3,24 (3H, s), 3,42 (3H, s), 3,52 (1H, DD, J=4,0, 10,2 Hz), 3,60 (1H, DD, J=6,2, 10.4 Hz), 3,99-Android 4.04 (1H, m), 4,03-4,06 (2H, m), 4,30 is 4.35 (1H, m), 4,56-br4.61 (1H, m), 6,51 (1H, t, J=3,4 Hz), 6,59 (1H, t, J=2.2 Hz), 6,62 of 6.66 (2H, m), 6,85 (1H, t, J=1,8 Hz), 7,03 (1H, t, J=1.7 Hz), 7,46 (1H, DD, J=2.7, and an 8.8 Hz), of 8.06 (1H, d, J=8,8 Hz), 8,49 (1H, d, J=2.7 Hz), 9,49 (1H, USS).

(91c) 5-(3-[(lS)-2-Methoxy-1-methylethoxy]-5-{5-[(4R,5S)-5-methyl-4-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine

N-[(1R,2R)-2-Hydroxy-1-{[(triisopropylsilyl)oxy]methyl}propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide (1,03 g, 1,49 mmol)synthesized in example (91b), dissolved in tetrahydrofuran (20 ml), to the solution was added anhydrous methansulfonate acid (0.54 g, 2,99 mmol) and triethylamine (0,83 ml, 5,97 mmol) and the resulting mixture was stirred at 50°C for 4.5 hours under nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (30 ml) and the solution extracted with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and polucen the th residue purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=20%-50%)to give the target compound (901 mg, yield 90%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ 1,03-1,13 (21H, m)of 1.33 (3H, d, J=6.3 Hz), of 1.52 (3H, d, J=6.6 Hz), 3,23 (3H, s)to 3.41 (3H, s), 3,50 (1H, DD, J=3,9, 10.4 Hz), to 3.58 (1H, DD, J=6,2, 10.5 Hz), 3,81 (1H, t, J=9.5 Hz), 3,95 (1H, DD, J=3,9, 10.4 Hz), 4,21-of 4.25 (2H, m), 4,56-4,59 (1H, m), 4,89-is 4.93 (1H, m), 6,50 (1H, d, J=3,9 Hz), 6,56 (1H, t, J=2.2 Hz), 6,76 (1H, d, J=3,9 Hz), at 6.84 (1H, s), 7,02 (1H, s), 7,44 (1H, DD, J=2.7, and an 8.8 Hz), 8,05 (1H, d, J=8,8 Hz), 8,48 (1H, d, J=2.7 Hz).

(91d) {(4R,5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(4R,5S)-5-methyl-4-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulphonyl)pyridine (901 mg, of 1.34 mmol)synthesized in example (91c), dissolved in tetrahydrofuran (15 ml), to the solution at 0ºC add tetrabutylammonium fluoride (solution in tetrahydrofuran, 1 mol/l, and 1.54 ml, 1.54 mmol) and the resulting mixture was stirred at room temperature for 1 hour in nitrogen atmosphere. To the mixture is added water (20 ml) and the mixture extracted with ethyl acetate (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, elwer the store solvent: ethyl acetate/hexane=80%-100%), receiving the target compound (578 mg, yield 84%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 1.39 (3H, d, J=6.8 Hz), 3,23 (3H, s)to 3.41 (3H, s), 3,50 (1H, DD, J=4,1, 10.4 Hz)and 3.59 (1H, DD, J=6,1, 10.4 Hz), of 3.77 (1H, DD, J=6,2, 11.2 Hz), a-3.84 (1H, DD, J=3,7, and 11.8 Hz), 4,22-4,27 (1H, m), 4,54-br4.61 (1H, m), a 4.83-of 4.90 (1H, m), of 6.45 (1H, d, J=3.8 Hz), 6,55 (1H, t, J=2.2 Hz), of 6.68 (1H, d, J=3,9 Hz), make 6.90 (1H, t, 1.8 Hz), 7,07 (1H, t, 1.8 Hz), the 7.43 (1H, DD, J=2,8, and 8.7 Hz), of 8.04 (1H, d, J=8.7 Hz), 8,49 (1H, d, J=2,8 Hz).

MS (ESI) m/z: 516,17933 (M+H)+.

Example 92

(2S)-2-(3-{5-[(4R,5S)-4-(Hydroxymethyl)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol

{(4R,5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol (178 mg, 0.35 mmol)synthesized in example (91d), dissolved in methylene chloride (5 ml), obtained the solution at-78ºC add tribromide (boron solution in methylene chloride, 1.0 mol/l to 0.70 ml, 0.70 mmol), then the mixture allow to warm to room temperature and the mixture is stirred for 45 minutes. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride. The organic layer was washed with saturated salt solution and dried over sodium sulfate. The solvent is distilled off under reduced pressure, and receiving the hydrated residue purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-4%), obtaining the target compound (142 mg, yield 83%) as a white solid.

1H-NMR (CDCl3, 400 MHz): δ of 1.30 (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=6.6 Hz), 3,23 (3H, s), 3,76-a 3.87 (4H, m), 4,22-4,27 (1H, m), 4.53-in-4,60 (1H, m), 4.92 in-4,84 (1H, m), of 6.45 (1H, d, J=3,9 Hz), 6.48 in (1H, s), 6,69 (1H, d, J=3,9 Hz), 6.87 in (1H, t, J=1,8 Hz), 7,02 (1H, s), 7,41 (1H, DD, J=8,6, 2.7 Hz), 8,03 (1H, d, J=8.6 Hz), of 8.47 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 502,16583 (M+H)+.

Example 93

(1S)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(93A) N-[(1S,2S)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2,69 mmol)synthesized in example (78k), commercially available D-threonine (0.34 g, 3,23 mmol), NOT·H2Oh (0.40 g, 3,23 mmol) and N-methylmorpholin (0,59 ml, 5,38 mmol) is dissolved in N,N-dimethylformamide (20 ml)to the resulting solution at room temperature add WSCI·HCl (0,62 g of 3.23 mmol) and the resulting mixture was stirred in nitrogen atmosphere for 20 hours. To the reaction solution was added a saturated salt solution (30 ml) and the mixture extracted with ethyl acetate (60 ml). The organic layer was washed with 1 N. hydrochloric acid, asystem aqueous solution of sodium bicarbonate and a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-7%), obtaining the target compound (1.24 g, 86%) as a white solid.

1H-NMR (CDCl3, 400 MHz): δ 1,25 (3H, d, J=6.3 Hz), of 1.33 (3H, d, J=6.3 Hz), 3,23 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=3,9, 10,3 Hz)and 3.59 (1H, DD, J=6,3, 10.4 Hz), 3,90-3,91 (2H, m), 3,98-a 4.03 (1H, USM), 4,23-the 4.29 (1H, m), 4,56-4,60 (1H, m), 6,50 (1H, t, J=3.2 Hz), to 6.58 (1H, t, J=2.2 Hz), 6,66 (1H, USM), 6,69-6,70 (1H, m), 6,85 (1H, t, J=1.7 Hz), 7,03 (1H, t, J=1.7 Hz), 7,44 (1H, DD, J=2.7, and 8.7 Hz), of 8.04 (1H, d, J=8,7 Hz), 8,48 (1H, d, J=2.7 Hz), 9,77 (1H, USS).

(93b) (1S)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

N-[(1S,2S)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide (1.24 g, 2.32 mmol)synthesized in example (93A), dissolved in tetrahydrofuran (20 ml)to the resulting solution at 0ºC add anhydrous methansulfonate acid (0,63 g, 3,49 mmol) and triethylamine (0,97 ml, 6,97 mmol) and the resulting mixture was stirred in nitrogen atmosphere for 1 hour. The mixture should be allowed the opportunity to spontaneously warm to room temperature, after which the mixture is stirred for 2 hours at room temperature and for 2 hours at a temperature of 50ºC. To the mixture is added saturated odny solution of sodium bicarbonate (30 ml) and the solution divided by ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-100%)to give the target compound (800 mg, yield 67%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ 1,24 (3H, d, J=6.3 Hz), of 1.33 (3H, d, J=6.3 Hz), 3,23 (3H, s), 3,40 (3H, s), 3,50 (1H, DD, J=4.0 a, 10,3 Hz)to 3.58 (1H, DD, J=6,3, 10,3 Hz), 3,71 (1H, t, J=6.2 Hz), 4,08-to 4.14 (2H, m), to 4.41-of 4.44 (1H, m), 4,54-4,59 (1H, m), 6,50 (1H, d, J=3,9 Hz), 6,56 (1H, t, J=2.1 Hz), 6,74 (1H, q, j 3.9 Hz), 6,86 (1H, t, 2.0 Hz), 7,05 (1H, t, 1.9 Hz), 7,42 (1H, DD, J=2.7, and an 8.8 Hz), 8,03 (1H, d, J=8,8 Hz), of 8.47 (1H, d, J=2,8 Hz),

MS (ESI) m/z: 516,17981 (M+H)+.

Example 94

(2S)-2-[3-(5-{(4S)-4-[(1S)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy]propane-1-ol

(1S)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (187 mg, 0.36 mmol)synthesized in example (93b), dissolved in methylene chloride (5 ml), the resulting solution is cooled to-78ºC and to the solution under nitrogen atmosphere add tribromide (boron solution in methylene chloride, 1.0 mol/l to 0.73 ml, 0.73 mmol). The mixture should be allowed the opportunity to spontaneously warm to room temperature, the mixture is stirred at room temperature is round within 30 minutes, then to neutralize the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride (70 ml). The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-4%), obtaining the target compound (134 mg, 78%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ 1.28 (in the 6N, d, J=6.6 Hz), up 3.22 (3H, s), 3.72 points-3,81 (3H, m), 4,13-4,19 (2H, m), 4,42 is 4.45 (1H, m), 4,59 with 4.65 (1H, m), 6,41 (1H, t, J=2.2 Hz), of 6.45 (1H, d, J=3,9 Hz), 6,72 (1H, d, J=3,9 Hz), 6,83 (1H, s), of 6.99 (1H, s), 7,37 (1H, DD, J=2.7, and an 8.8 Hz), 8,02 (1H, d, J=8,8 Hz), 8,44 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 502,16521 (M+H)+.

Example 95

(1R)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(95a) of N-[(1S,2R)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.47 g, 3,29 mmol)synthesized in example (78k), commercially available D-ALLO-threonine (0.52 g, 4,94 mmol), HOBT·H 2O (0,49 g, 3.62 mmol) and N-methylmorpholin (to 0.72 ml, to 6.58 mmol) was dissolved in N,N-dimethylformamide (10 ml)to the solution at room temperature add WSCI·HCl (0,76 g, 3.95 mmol) and the mixture is then stirred for 5.5 hours under nitrogen atmosphere. To the reaction solution was added a saturated salt solution (40 ml) and the mixture extracted with ethyl acetate (70 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-6%), obtaining the target compound (1.42 g, 81%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ is 1.31 (3H, d, J=6.2 Hz), 1,32 (3H, d, J=6.6 Hz), 2,84-of 2.86 (1H, m), 2,89 (1H, d, J=6.2 Hz), 3,23 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=3,9, 10,3 Hz)and 3.59 (1H, DD, J=6,3, 10,3 Hz), 3,80-a-3.84 (1H, USM), 3,92-of 3.96 (1H, m), 4,07-4,11 (2H, USM), 4,54-4,59 (1H, m), of 6.49 (1H, DD, J=2,9, 3,9 Hz), to 6.57 (1H, t, J=2.2 Hz), to 6.67 (1H, DD, J=2,3, 3,9 Hz), to 6.80 (1H, d, J=8.0 Hz), 6,86 (1H, t, J=1,8 Hz), 7,01 (1H, t, J=1,8 Hz), the 7.43 (1H, DD, J=2,8, and 8.7 Hz), 8,03 (1H, d, J=8.7 Hz), of 8.47 (1H, d, J=2,8 Hz), 9,94 (1H, USS).

(95b) (1R)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

N-[(1S,2R)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide (1.42 g, of 2.66 mmol), sintezirovannyi in (95a), dissolved in tetrahydrofuran (25 ml)to the solution at 0 ° C add anhydrous methansulfonate acid (0,72 g, 3,99 mmol) and triethylamine (1,11 ml, 7,98 mmol) and then stirred for 1 hour in nitrogen atmosphere. The mixture allow to warm to room temperature, the mixture is stirred at room temperature for 1 hour and then stirred at 50°C for 2 hours. To the mixture is added saturated aqueous sodium hydrogen carbonate solution (30 ml) and the solution extracted with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-100%)to give the target compound (758 mg, yield 55%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.15 (3H, d, J=6.3 Hz), of 1.35 (3H, d, J=6.3 Hz), 3,23 (3H, s)to 3.41 (3H, s), 3,51 (1H, DD, J=4,0, 10.4 Hz)and 3.59 (1H, DD, J=6,2, 10.4 Hz), 4,20-4,27 (4H, m), 4,56-to 4.62 (1H, m), 6,36 (1H, d, J=3.8 Hz), 6,41 (1H, d, J=3.8 Hz), to 6.57 (1H, t, J=2.1 Hz), make 6.90 (1H, t, 1.8 Hz), 7,07 (1H, t, 1.8 Hz), was 7.45 (1H, DD, J=2,8, and 8.7 Hz), with 8.05 (1H, d, J=8.7 Hz), and 8.50 (1H, d, J=2,8 Hz).

MS (ESI) m/z: 516,17893 (M+H)+.

Example 96

(2S)-2-[3-(5-{(4S)-4-[(1R)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy]propane-1-ol

(1R)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (178 mg, 0.35 mmol)synthesized in example (95b), dissolved in methylene chloride (5 ml), then the solution is cooled to -78°C, to a solution under nitrogen atmosphere add tribromide (boron solution in methylene chloride, 1.0 mol/l to 0.69 ml, 0.69 mmol). The mixture allow to warm to room temperature, then stirred at room temperature for 30 minutes, then add saturated aqueous solution of sodium bicarbonate to neutralize the reaction solution and extracted with methylene chloride (70 ml). The organic layer was washed with 1 N. aqueous sodium hydroxide solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-4%), obtaining the target compound (132 mg, 76%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1,19 (3H, d, 6.3 Hz), is 1.31 (3H, d, J=6.3 Hz), 3,23 (3H, s), of 3.73-3,81 (2H, m), 4,17-of 4.25 (2H, m), 4,32 (1H, s), 4,34 (1H, d, J=1.5 Hz), 4,57-br4.61 (1H, m), to 6.39 (1H, d, J=3,9 Hz), of 6.49 (1H, d, J=2.1 Hz), is 6.54 (1H, d, J=3,9 Hz), 6.87 in (1H, t, J=1,8 Hz), 7,02 (1H, t, J=1,8 Hz), 7,42 (1H, DD, J=2,8, 8.6 Hz), of 8.04 (1H, d, J=8.6 Hz), of 8.47 (1H, d, J=2,8 Hz).

MS (ESI) m/z: 502,16427 (M+H)+.

Example 97

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-5-(methylsulphonyl)pyrazin

(97a) 5-(Methylsulfanyl)pyrazin-2-amine

2-Aminopyrazine (50,8 g of 0.53 mol) is dissolved in methylene chloride (1.0 l), to the solution at 0ºC for 30 minutes add N-bromosuccinimide (97.9 g, 0.55 mol) and then stirred at 0°C for 2.5 hours in a nitrogen atmosphere. The reaction solution is heated to room temperature and the formed precipitate is removed by filtration. The obtained filter cake washed with ethyl acetate. Uterine fluid collected, and the solvent is distilled off under reduced pressure. This procedure is repeated twice to obtain the mother liquor, from which the solvent is distilled off under reduced pressure, obtaining the product in a solid yellow color.

The product is dissolved in N,N-dimethylformamide (300 ml), the solution add thiamethoxam sodium (75,0 g, 1.07 mol) and the resulting mixture was stirred at 100°C for 3 hours in nitrogen atmosphere. The reaction solution is heated to room temperature, add water (1.5 l) and the mixture extracted with ethyl acetate (1.0 l). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue purified speakers chromatog what afia (silica gel, eluting solvent: ethyl acetate/hexane=20%-30%)to give the target compound (42.5 g, yield 56%) as a solid orange color.

1H-NMR (CDCl3, 400 MHz): δ 2,52 (3H, s)to 4.41 (2H, USS), 7,92 (1H, d, J=1.6 Hz), 7,98 (1H, d, J=1.6 Hz).

(97b) of 2-Chloro-5-(methylsulfanyl)pyrazin

Sodium nitrite (of 50.9 g of 0.74 mol) dissolved in water (150 ml)and then dropwise the resulting solution was added to 5 N. aqueous hydrochloric acid (1.0 l) at 0°C for 1 hour.

Next, to the obtained solution at 0ºC for 40 minutes add 5-(methylsulfanyl)pyrazin-2-amine (40,4 g, 0.28 mol)synthesized in example (97a), and the mixture was stirred at 0°C for 1 hour. The reaction solution was allow to warm to room temperature, and then to the solution was added water (500 ml) and the resulting mixture extracted with ethyl acetate (1.0 l). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-20%)to give the target compound (11.9 g, yield 26%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ to 2.57 (3H, s), 8,24 (1H, d, J=1.2 Hz), 8,39 (1H, d, J=1.2 Hz).

(97c) of 2-Chloro-5-(methylsulphonyl)pyrazin

2-Chloro-5-(methylsulfanyl)pyrazin (10,82 g of 67.4 mmol), sinisiraan the second example (97b), dissolved in methylene chloride (200 ml), the solution slowly at 0°C add m-chloroperbenzoic acid (approximately 65%, or 37.4 g, 140 mmol) and then stirred at 0°C for 1.5 hours in a nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (300 ml) and the mixture is extracted with methylene chloride (400 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-50%)to give the target compound (10.1 g, yield 78%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 3.27 (3H, s), to 8.70 (1H, d, J=1.2 Hz), which is 9.09 (1H, d, J=1.2 Hz).

(97d) Benzyl-5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylate

2-Benzyl-1-tert-butyl-5-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-1,2 -, in primary forms (3,40 g, 7,06 mmol)synthesized in example (78g), and 2-chloro-5-(methylsulphonyl)pyrazin (1.92 g, 7,06 mmol)synthesized in example (97c), dissolved in acetonitrile (35 ml), the resulting solution was added potassium carbonate (2,93 g and 21.2 mmol) and the resulting mixture is refluxed for 11 hours in a nitrogen atmosphere. The reaction solution is cooled to anatoy temperature, then to the solution was added water (100 ml) and extracted twice with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-50%).

The resulting product (solid brown) (3,85 g) dissolved in methylene chloride (5 ml)solution was added triperoxonane acid (5 ml) and then stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (50 ml) and the resulting mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-60%), obtaining the target compound (3.58 g, yield 88%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.35 (3H, d, J=6.3 Hz), 3,24 (3H, s), 3,42 (3H, s), 3,52 (1H, DD, J=10,3, 3,9 Hz), 3,60 (1H, DD, J=10,3, 5,9 Hz), 4,57-br4.61 (1H, m), of 5.34 (2H, s), 6,53 (1H, DD, J=3,9, 2,9 Hz), 6,70 (1H, t, J=2.2 Hz), 6,93 (1H, t, J=1.5 Hz), of 6.99 (1H, DD, J=3,9, 2.4 Hz), 7,06 (1H, t, J=1.7 Hz), 7,34 was 7.45 (5H, m), and 8.50 (1H, d, J=1.5 Hz), 8,81 (1H, d, J1,5 Hz), 9,18 (1H, s).

(97e) 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid

Benzyl-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylate (3.58 g, of 6.66 mmol)synthesized in example (97d), dissolved in methanol (100 ml), the solution is added catalytic 10% palladium on carbon (2.00 g) and the resulting mixture was stirred at room temperature for 3 hours in hydrogen atmosphere. Catalytic palladium on carbon is removed by filtration through celite and washed with tetrahydrofuran. The solvent is distilled off under reduced pressure, obtaining the target compound (2,56 g, 86%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), up 3.22 (3H, s), of 3.45 (3H, s), 3,55 (1H, DD, J=10,2, 3,9 Hz), 3,66 (1H, DD, J=9,4, 5,9 Hz), 4.72 in (1H, s), of 6.49 (1H, s), of 6.66 (1H, s), 6,99 (2H, s), 7,29 (1H, s), of 8.47 (1H, ), 8,79 (1H, s), 10,23 (1H, USS).

(97f) 2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-5-(methylsulphonyl)pyrazin

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (700 mg, 1.56 mmol)synthesized in example (97e), and 4-dimethylaminopyridine (172 mg, of 1.41 mmol) dissolved in methylene chloride (15 ml)to the solution at room temperature add WSCI·HCl (689 mg, of 3.60 mmol) and acetohydrazide (255 mg, 3,44 mmol) and the floor is i.i.d. mixture is stirred for 14 hours under nitrogen atmosphere. The reaction solution is diluted with methylene chloride (50 ml) and washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

Received the product in a solid yellow color (788 mg) is dissolved in methylene chloride (10 ml), to the solution was added p-toluensulfonate (597 mg, of 3.13 mmol) and triethylamine (of 0.87 ml, 6.26 mmol) and the resulting mixture was stirred at room temperature for 6 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (30 ml) and the mixture is extracted twice with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (456 mg, yield 60%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.36 (3H, d, J=6.3 Hz), at 2.59 (3H, s), 3,24 (3H, s), 3,42 (3H, s), 3,53 (1H, DD, J=10,4, 4,1 Hz), 3,61 (1H, DD, J=10,2, 5,9 Hz), 4,56-4,63 (1H, m), 6,59 (1H, t, J=3.1 Hz), 6,69 (1H, t, J=2.0 Hz), 6,86 (1H, DD, J=3,7, 2,5 Hz), to 6.95 (1H, t, J=1.6 Hz), was 7.08 (1H, t, J=1,8 Hz), 8,51 (1H, d, J=1.2 Hz), 8,81 (1H, d, J=1.2 Hz), 9,43 (1H, s).

MS (ESI) m/z: 486,14274 (M+H)+.

<> Example 98

(2S)-2-(3-[5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol

2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(5-methyl-l,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-5-(methylsulphonyl)pyrazin (382 mg, 0.79, which mmol)synthesized in example (97f), dissolved in methylene chloride (10 ml)to the solution at-78ºC under nitrogen atmosphere add tribromide (boron solution in methylene chloride, 1.0 mol/l that was 1.58 ml, was 1.58 mmol). Next, the mixture allow to warm to room temperature and the mixture is stirred for 1.5 hours under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (219 mg, yield 59%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), at 2.59 (3H, s), 2,70 (1H, USS)at 3.25 (3H, s), 3,79-3,82 (2H, m), 4,54-br4.61 (1H, m), to 6.57 (1H, t, J=3.1 Hz), 6,63 (1H, t, J=2.0 Hz), 6,86 (1H, DD, J=3,7, 2,5 Hz), of 6.96 (1H, t, J=1,8 Hz), 7,07 (1H, t, J=1,8 Hz)and 8.50 (1H, d, J=1.6 Hz), 8,80 (1H, d, J=1.2 Hz), 9,84 (1H, USS).

MS (ESI) m/z: 472,12965 (M+H)+.

Example 99

2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-(methylsulphonyl)pyrazin

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (700 mg, 1.56 mmol)synthesized in example (97e), and 4-dimethylaminopyridine (96 mg, 0.78 mmol) dissolved in methylene chloride (20 ml)to the solution at room temperature add WSCI·HCl (480 mg, of 2.50 mmol) and (R)-1-amino-2-propanol (283 μl, of 3.60 mmol) and the mixture is then stirred for 14 hours under nitrogen atmosphere. The reaction solution is diluted with methylene chloride (60 ml), washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-8%).

Received the product in a solid white color (546 mg) was dissolved in tetrahydrofuran (15 ml), to the solution was added anhydrous methansulfonate acid (377 mg, of 2.16 mmol) and triethylamine (0.45 ml, 3.25 mmol) and the resulting mixture was stirred at 50°C for 4 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (30 ml) and the resulting mixture twice ek is tracerout with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (509 mg, yield 67%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), of 1.42 (3H, d, J=6.3 Hz), 3,24 (3H, s), 3,42 (3H, s), 3,49-3,62 (3H, m), 4,07 (1H, DD, J=13,5, 8,8 Hz), 4.53-in-br4.61 (1H, m), 4,79-to 4.87 (1H, m), 6,51 (1H, d, J=3,9 Hz), of 6.65 (1H, t, J=2.0 Hz), to 6.75 (1H, d, J=3,9 Hz)6,91 (1H, t, J=1.6 Hz), 7,06 (1H, t, J=1,8 Hz), 8,49 (1H, s), 8,81 (1H, s).

MS (ESI) m/z: 487,16506 (M+H)+.

Example 100

(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol

2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-(methylsulphonyl)pyrazin (426 mg, 0.88 mmol)synthesized in example 99, dissolved in methylene chloride (10 ml)to the solution in a nitrogen atmosphere at -78°C add tribromide (boron solution in methylene chloride, 1.0 mol/l of 1.76 ml of 1.76 mmol). The mixture allow to warm to room temperature and the mixture is stirred for 1.5 hours. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with Meiling what oredom. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (243 mg, yield 59%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), the 1.44 (3H, d, J=6.3 Hz)at 3.25 (3H, s), of 3.56 (1H, DD, J=13,9, 7,2 Hz), 3,80 (2H, d, J=5.5 Hz), 4,10 (1H, DD, J=14,1, and 9.4 Hz), br4.61 (1H, q, J=5.6 Hz), a 4.86 (1H, dt, J=11,6, 4,5 Hz), 6,47 (1H, d, J=3.5 Hz), 6,50 (1H, s), of 6.75 (1H, d, J=3.5 Hz), 6.89 in (1H, s), of 6.99 (1H, s), of 8.47 (1H, d, J=1.2 Hz), 8,80 (1H, d, J=1.2 Hz).

MS (ESI) m/z: 473,14774 (M+H)+.

Example 101

{(5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

(101a) of N-[(2S)-2,3-dihydroxypropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.07 g, 2,39 mmol)synthesized in example (97e), dissolved in methylene chloride (20 ml)to the solution at room temperature add WSCI·HCl (732 mg, 3,82 mmol), (S)-(-)-3-amino-1,2-propandiol (500 mg, 5,49 mmol) and 4-dimethylaminopyridine (146 mg, 1,19 mmol) and the resulting mixture is stirred for 25 hours is in nitrogen atmosphere. The reaction solution was diluted with ethyl acetate (50 ml), washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target product (666 mg, 54%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.35 (4H, d, J=6,1 Hz), 3,24 (4H, s), 3,42 (3H, s), 3,53 (1H, DD, J=10,3, 3,9 Hz), 3,59-3,63 (5H, m), 3,84-a 3.87 (1H, m), 4,58 (1H, dt, J=11,7, 5,2 Hz), 6,41 (1H, s), 6,50 (1H, t, J=3.2 Hz), only 6.64 (1H, DD, J=3,7, 2.7 Hz), of 6.68 (1H, d, J=2.0 Hz), to 6.95 (1H, s), was 7.08 (1H, s), and 8.50 (1H, s), 8,81 (1H, s), 9,79 (1H, s).

(101b) N-{(2S)-2-Hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide

N-[(2S)-2,3-Dihydroxypropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide (666 mg, 1.28 mmol)synthesized in example (101a), dissolved in methylene chloride (20 ml), the solution is added triethylamine (0,89 ml, 6,40 mmol), chloride triisopropylsilyl (410 μl, 1.92 mmol 4-dimethylaminopyridine (234 mg, 1.92 mmol) and the resulting mixture is stirred for 14 hours under nitrogen atmosphere. The reaction solution is diluted with methylene chloride (50 ml), washed with water and saturated concrete is salt and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-60%), obtaining the target product (558 mg, 64%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1.06 a-1,15 (21H, m)of 1.35 (3H, d, J=6.3 Hz), 3,13 (1H, d, J=3,9 Hz), 3,24 (3H, s), 3,42 (3H, s), 3,52 (1H, DD, J=10,3, 3,9 Hz), 3,60 (1H, DD, J=10,3, 6,8 Hz), 3,68 (1H, DD, J=10,0, 6,1 Hz), to 3.73 (1H, TD, J=7,0, 3.1 Hz), of 3.77 (1H, DD, J=10,0, 4.6 Hz), a 3.87 (1H, s), 4,58 (1H, DD, J=10,3, 6.3 Hz), 6,33 (1H, t, J=5.6 Hz), 6,50 (1H, t, J=3.2 Hz), 6,60 (1H, t, J=3.2 Hz), to 6.67 (1H, s), 6,92 (1H, s), 7,06 (1H, s), and 8.50 (1H, d, J=1.0 Hz), 8,81 (1H, d, J=1.0 Hz), 9,44 (1H, s).

(101c) 2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5R)-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-(methylsulphonyl)pyrazin

N-{(2S)-2-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-carboxamide (558 mg, 0.82 mmol)synthesized in example (101b), dissolved in tetrahydrofuran (20 ml), to the solution was added anhydrous methansulfonate acid (287 mg, of 1.65 mmol) and triethylamine (0,34 ml, 2,47 mmol) and the resulting mixture was stirred at 50°C for 6 hours in nitrogen atmosphere. To the reaction solution was added water (40 ml) and the resulting mixture is extracted twice with methylene chloride (40 ml). The organic layer was washed with saturated salt solution and then dried over besod the first magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (496 mg, yield 94%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1,00-1,13 (21H, m)of 1.34 (3H, d, J=6.3 Hz), 3,24 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=10,6, 3,9 Hz), 3,60 (1H, DD, J=10,4, 6,1 Hz), 3,83-Android 4.04 (4H, m), of 4.57 (1H, dt, J=6.3, in the 4.3 Hz), 4,72-rate 4.79 (1H, m), of 6.50 (1H, d, J=3,9 Hz), of 6.65 (1H, t, J=2.0 Hz), was 6.73 (1H, d, J=3,9 Hz), make 6.90 (1H, t, J=1,8 Hz), 7,05 (1H, t, J=1,8 Hz), 8,49 (1H, d, J=1.2 Hz), 8,81 (1H, d, J=1.2 Hz).

(101d) {(5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5R)-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-(methylsulphonyl)pyrazin (496 mg, 0.82 mmol)synthesized in example (101c), dissolved in tetrahydrofuran (20 ml), the resulting solution was added tetrabutylammonium fluoride (a solution of 1.0 mol/l in tetrahydrofuran, of 0.82 ml, 0.82 mmol) and the resulting mixture is stirred for 2 hours in nitrogen atmosphere. To the reaction solution was added water (40 ml) and the resulting mixture was extracted twice with ethyl acetate (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (133 mg, yield 35%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), 3,24 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=10,4, 4,1 Hz), 3,60 (1H, DD, J=10,2, 5,9 Hz), 3,71 (1H, DD, J=12,5, 5,5 Hz), with 3.79 (1H, DD, J=14,3 and 7.6 Hz), 3,88 (1H, DD, J=12,5, 3,1 Hz), Android 4.04 (1H, DD, J=14,3, 10,0 Hz), of 4.57 (1H, DD, J=10,0, 5.7 Hz), 4,85-4,78 (1H, m), 6,50 (1H, d, J=3,9 Hz), 6,66 (1H, t, J=2.2 Hz), 6,77 (1H, d, J=3,9 Hz), 6,93 (1H, s), 7,06 (1H, s), 8,49 (1H, d, J=1.2 Hz), 8,81 (1H, d, J=1.6 Hz).

MS (ESI) m/z: 503,15918 (M+H)+.

Example 102

(2S)-2-(3-{5-[(5R)-5-(Hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl[oxy}phenoxy)propan-1-ol

{(5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol (105 mg, 0.21 mmol)synthesized in example (101d), dissolved in methylene chloride (10 ml)to the solution at -78°C under nitrogen atmosphere add tribromide (boron solution in methylene chloride, 1.0 mol/l, 315 μl, 0,315 mmol), the mixture allow to warm to room temperature and the mixture is stirred for 1 hour. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled with igenom pressure, and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-7,5%), obtaining the target compound (67 mg, yield 66%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), 3,24 (3H, s), 3,70-3,91 (5H, m), a 4.03 (1H, DD, J=14,1, 9.8 Hz), 4,55 (1H, DD, J=10,6, 5,9 Hz), 4,85-4,78 (1H, m), 6,47 (1H, d, J=3,9 Hz), to 6.58 (1H, t, J=2.0 Hz), to 6.75 (1H, d, J=3.5 Hz), 6,92 (1H, t, J=1,8 Hz), 7,01 (1H, t, J=1.6 Hz), 8,48 (1H, d, J=1.2 Hz), 8,80 (1H, d, J=1.2 Hz).

MS (ESI) m/z: 489,14448 (M+H)+.

Example 103

(5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-ol

(103a) Benzyl-L-threonine

L-threonic of 21.2 g (178 mmol) dissolved in toluene (100 ml), to the solution was added benzyl alcohol (100 ml, 966 mmol) and monohydrate p-toluensulfonate acid (35,0 g, 194 mmol) and the resulting mixture is refluxed for 17 hours under nitrogen atmosphere. After cooling the mixture to room temperature, to the mixture is added water (200 ml), the mixture is washed three times with ethyl acetate (100 ml). To the aqueous layer add a saturated aqueous solution of sodium bicarbonate and the mixture extracted three times with ethyl acetate (100 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate, and the resulting residue purified speaker chromatogra the Oia (silica gel, eluting solvent: methanol/methylene chloride=0%-15%), obtaining the target product (10.6 g, yield 28%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1,22 (3H, d, J=6.3 Hz), 3,30 (1H, d, J=6.3 Hz), 3,49 (1H, USS), 5,19 (2H, s), 7,34-7,39 (5H, m).

(103b) Benzyl-N-{[5-(3-[(1S)-2-methoxy-1-methoxyethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1-pyrrol-2-yl]carbonyl}-L-threonine

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-[5-(methylsulphonyl)pyrazin-2-yl]oxy)phenyl}-1H-pyrrole-2-carboxylic acid (9,49 g of 21.2 mmol)synthesized in example (97e), dissolved in N,N-dimethylformamide (200 ml), to the solution was added benzyl-L-threonine (4.44 g, of 21.2 mmol)synthesized in example (103a), WSCI·HCl (4,88 g, 25.5 mmol), HOBT·H2O (3,15 g, with 23.3 mmol) and N-methylmorpholin (of 4.66 ml, 42,4 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours under nitrogen atmosphere. To the reaction solution was added water (200 ml) and the resulting mixture was extracted twice with ethyl acetate (200 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=70%-100%)to give the target product (13.5 g, yield ~100%) in the form of oil pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.27 (3H, d, J=6.3 Hz, of 1.35 (3H, d, J=6.3 Hz), 3,24 (3H, s), 3,42 (3H, s), 3,52 (1H, DD, J=4,3, 10,2 Hz), 3,61 (1H, DD, J=5,9, 10,2 Hz), of 4.44 (1H, m), 4,59 (1H, m), to 4.81 (1H, DD, J=2.7, and 8.6 Hz), total of 5.21 (1H, d, J=12,5 Hz in), 5.25 (1H, d, J=12,5 Hz), of 6.52 (1H, t, J=3,9 Hz), to 6.67 (1H, t, J=2.0 Hz), of 6.71 (1H, OSD, J=8.6 Hz), 6.75 in (1H, DD, J=2,4, 3,9 Hz)6,94 (1H, t, J=1.9 Hz), was 7.08 (1H, t, J=1.9 Hz), 7,33-7,38 (5H, m), 8,49 (2H, m), 8,81 (2H, m), 9,63 (1H, USS).

(103c) Benzyl(4S,5S)-2-[5-(3-[(1S)-2-methoxy-1-methoxyethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-carboxylate

Benzyl-N-{[5-(3-[(1S)-2-methoxy-1-methoxyethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]carbonyl}-L-threonine (13.5 g, of 21.2 mmol)synthesized in example (103b), dissolved in methylene chloride (150 ml) and the solution cooled to -78°C. To the solution is added dropwise TRIFLUORIDE bis(2-methoxyethyl)aminocore (vs. 5.47 ml, 29.7 mmol) and the mixture was stirred at -78°C for 40 minutes. To the reaction solution was added potassium carbonate (5,86 g, 42,4 mmol) and the mixture is stirred for 1.5 hours, during which the temperature of the mixture is slowly increased to room temperature. To the mixture at 0°C is added a saturated aqueous solution of sodium bicarbonate (100 ml) and the resulting mixture is extracted twice with methylene chloride (100 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography the raffia (silica gel, eluting solvent: ethyl acetate/hexane=40%-70%), obtaining the target product (9,68 g, yield 74%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), of 1.35 (3H, d, J=6.3 Hz), 3,23 (3H, s)to 3.41 (3H, s), 3,51 (1H, DD, J=3,9, 10,2 Hz), 3,60 (1H, DD, J=5,9, 10,2 Hz), 4,58 (1H, m), 4,94 (1H, d, J=9.8 Hz), 5,02 (1H, m), 5,19 (1H, d, J=12.1 Hz), 5,24 (1H, d, J=12.1 Hz), 6,51 (1H, t, J=3,9 Hz), 6,66 (1H, t, J=2.4 Hz), 6,78 (1H, t, J=3,9 Hz)6,94 (1H, t, J=2.0 Hz), was 7.08 (1H, t, J=2.4 Hz), 7,35-7,39 (5H, m), 8,48 (2H, d, J=1,2 Hz), 8,81 (2H, d, J=1.2 Hz).

(103d) (5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-ol

Benzyl(4S,5S)-2-[5-(3-[(1S)-2-methoxy-1-methoxyethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-carboxylate (1,53 g, 2,47 mmol)synthesized in example (103c), dissolved in tetrahydrofuran (50 ml), the solution add catalytic 10% palladium on carbon (600 mg) and the resulting mixture was stirred at room temperature for 2.5 hours in an atmosphere of hydrogen. Catalytic palladium on carbon is removed by filtration and washed with ethyl acetate. The solvent is distilled off under reduced pressure.

The resulting residue is dissolved in acetonitrile (60 ml) and to the solution dropwise at 0°C is added dropwise a solution of giammarinaro cerium(IV) (2,03 g, 3,70 mmol) in water (30 ml). The mixture is stirred at room temperature for 17 hours in the atmosphere is fere nitrogen, then add saturated aqueous solution of sodium bicarbonate (30 ml) and the resulting mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=70%-100%)to give the target product (645 mg, yield 52%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), 1,37 (6/3H, d, J=6,7 Hz), 1,47 (3/3H, d, J=6,7 Hz), 3,23 (3H, s)to 3.41 (3H, s), 3,50 (1H, DD, J=4,3, 10,2 Hz), 3,60 (1H, DD, J=5,9, 10,2 Hz), 4,50-of 4.66 (2H, m), 5,39 (2/3H, d, J=3.1 Hz), 5,66 (1/3H, d, J=6,7 Hz), 6,50 (1H, OSD, J=3,9 Hz), of 6.65 (1H, t, J=2.4 Hz), PC 6.82 (1H, OSD, J=3,9 Hz)6,94 (1H, t, J=2.0 Hz), was 7.08 (1H, t, J=2.0 Hz), 8,48 (2H, d, J=1.2 Hz), 8,80 (2H,, d, J=1.2 Hz).

MS (ESI) m/z: 503,16004 (M+H)+.

Example 104

(5S)-2-[5-(3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-ol

(5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-ol (410 mg, 0,816 mmol)synthesized in example (103d), dissolved in methylene chloride (20 ml)and the solution cooled to -78°C. To the solution add tribromide (boron solution in methylene chloride, 1.0 mol/l, 2,04 ml, 2.04 mmol) and polucen the second mixture is stirred for 2 hours with a gradual temperature increase to room temperature. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (20 ml) and the resulting mixture is extracted twice with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-10%), obtaining the target product (362 mg, yield 91%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.30 (3H, d, J=6.3 Hz), 1,38 (6/3H, d, J=6,7 Hz), 1,49 (3/3H, d, J=6,7 Hz), 3,23 (3H, s), 3,76 (2H, OSD, J=5.5 Hz), 4,51-of 4.57 (2H, m), 5,39 (2/3H, d, J=3.5 Hz), 5,66 (1/3H, d, J=6,7 Hz), of 6.49 (1H, d, J=3,9 Hz), is 6.61 (1H, t, J=2.4 Hz), for 6.81 (1H, d, J=3,9 Hz)6,94 (1H, t, J=2.0 Hz), 7,06 (1H, t, J=2.0 Hz), of 8.47 (2H, d, J=1.2 Hz), 8,78 (2H, d, J=1.2 Hz).

MS (ESI) m/z: 489,14439 (M+H)+.

Example 105

(5S)-2-[5-(3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4(5H)-he

(105a) (5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4(5H)-he

(5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-ol (80.0 mg, strength of 0.159 mmol)synthesized in example (103d), dissolved in methylene chloride (10 ml), the solution was added pyridinium dichromate (240 mg, 0,638 mmol) and molecular sieves 4A (200 mg) and the resulting mixture was stirred at room temperature for 2 hours in nitrogen atmosphere. The mixture is filtered through celite, the solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-70%), obtaining the target product (to 44.1 mg, yield 55%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.36 (3H, d, J=6.3 Hz), of 1.62 (3H, d, J=7,0 Hz)at 3.25 (3H, s), 3,42 (3H, s), 3,52 (1H, DD, J=3,9, 10,2 Hz), 3,62 (1H, DD, J=5,9, 10,2 Hz), to 4.62 (1H, m), to 4.81 (1H, q, J=7.0 Hz), of 6.68 (1H, d, J=3,9 Hz), 6,76 (1H, t, J=2.4 Hz), 7,03 (1H, t, J=2.0 Hz), 7,17 (1H, t, J=2.0 Hz), 7,26 (1H, d, J=3,9 Hz), charged 8.52 (2H, d, J=1.2 Hz), 8,82 (2H, d, J=1.2 Hz).

(105b) (5S)-2-[5-(3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4(5H)-he

(5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4(5H)-on (100 mg, 0,200 mmol)synthesized in example (105a), dissolved in methylene chloride (10 ml) and the solution cooled to -78°C. To the solution add tribromide (boron solution in methylene chloride, 1.0 mol/l, is 0.260 ml, is 0.260 mmol) and the resulting mixture is stirred for 2 hours while slowly raising the temperature to room temperature. To the reaction solution was added saturated aqueous bicarbonate NAT the Oia (10 ml) and the resulting mixture is extracted twice with methylene chloride (10 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-10%), obtaining the target product (98,0 mg, yield ~100%) as a solid white color.

lH-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), and 1.63 (3H, DD, J=2.7, and a 7.0 Hz), 3,26 (3H, s), 3,80-a-3.84 (2H, m), to 4.62 (1H, m), 4,84 (1H, square, J=7,0 Hz), of 6.66 (1H, d, J=3,9 Hz), 6,69 (1H, m), 7,03 (1H, m), 7,20 (1H, m), 7,26 (1H, OSD, J=3,9 Hz), 8,51 (2H, d, J=1.2 Hz), 8,81 (2H, d, J=1.2 Hz).

MS (ESI) m/z: 487,12874 (M+H)+.

Example 106

(2S)-2-(3-{5-[(5S)-5-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol

(106a) Benzyl-5-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylate

3-[(1S)-2-Methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (26,79 g of 86.9 mmol)synthesized in example (78d), and 2-benzyl-1-tert-butyl-5-bromo-1H-pyrrole-l,2, in primary forms (32,32 g, 85,0 mmol)synthesized in example (78f), dissolved in 1,4-dioxane (360 ml) and water (90 ml), to the solution add complex dichloride [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (2,34 g, 2,87 mmol) and potassium carbonate (30,40 g, 220 mmol) and the resulting mixture was stirred at 60°C for 3 hours in the atmosphere is ore of nitrogen. The reaction solution is cooled to room temperature, to the solution was added water (1000 ml) and the mixture extracted with ethyl acetate (700 ml). The organic layer was washed with saturated salt solution, then dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure.

The resulting residue is dissolved in methylene chloride (100 ml)to the solution add triperoxonane acid (120 ml) and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, then diluted with ethyl acetate (500 ml), washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, then dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-50%)to give the target compound (17,40 g, yield 54%) as a brown oil.

1H-NMR (CDCl3, 400 Hz): δ is 1.31 (3H, d, J=6.3 Hz), 3,42 (3H, s), 3,49 (1H, DD, J=9,8, a 4.3 Hz)and 3.59 (1H, DD, J=10,2, 6.3 Hz), to 4.52-4,59 (1H, m), to 5.35 (2H, s), 6.42 per (1H, t, J=2.0 Hz), 6,47 (1H, DD, J=3,9, 2.7 Hz), 6,72 (1H, ), 6,77 (1H, OSS), to 6.80 (1H, s), 6,98 (1H, DD, J=3,9, 2.7 Hz), 7,45-7,33 (5H, m), 9,94 (1H, USS).

MS (FAB) m/z: 382 (M+H)+.

(106b) Benzyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylate

Benzyl-5-{3-hydroxy--[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylate (27,35 g, 71,7 mmol)synthesized in example (106a), dissolved in methylene chloride (350 ml), the resulting solution was added chloride triisopropylsilyl (18,4 ml, 86,0 mmol), triethylamine (30,0 ml, 215 mmol) and 4-dimethylaminopyridine (10,53 g, 86,2 mmol) and the resulting mixture was stirred at room temperature for 4 hours in nitrogen atmosphere. To the reaction solution was added water (400 ml), the organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=3%-20%)to give the target product (34,41 g, yield 89%) as oil pale yellow color.

1H-NMR (CDCl3, 400 Hz): δ is 1.11 (18H, d, J=7,0 Hz), 1,22-of 1.30 (3H, m)of 1.32 (3H, d, J=6.3 Hz), to 3.41 (3H, s), 3,49 (1H, DD, J=10,2, a 4.3 Hz), to 3.58 (1H, DD, J=10,2, 5,9 Hz), 4,49-4,56 (1H, m), 5,33 (2H, s), to 6.43 (1H, t, J=2.3 Hz), 6,47 (1H, DD, J=3,9, 2.7 Hz), 6,66 (1H, t, J=2.0 Hz), of 6.71 (1H, t, J=1,8 Hz), 6,98 (1H, DD, J=3,9, 2.7 Hz), 7,32 was 7.45 (5H, m), 9,19 (1H, USS).

MS (FAB) m/z: 538 (M+H)+.

(106c) 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid

Benzyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylate (of 34.40 g, 64,0 mmol)synthesized in example (106b), dissolved in ethanol (320 ml), the solution is added catalytic 10% palladium on carbon (3,54 g), the scientists, the mixture is stirred for 2 hours in hydrogen atmosphere. Catalytic palladium on carbon is removed by filtration through celite and the solvent is distilled off under reduced pressure, obtaining the target compound (27,31 g, yield 95%) as a solid white color.

1H-NMR (CDCl3, 400 Hz): δ is 1.11 (18H, d, J=7,4 Hz), 1,22-of 1.30 (3H, m)of 1.33 (3H, d, J=6.3 Hz), of 3.46 (1H, s), 3,51 (1H, DD, J=10,2, a 4.7 Hz), 3,66 (1H, DD, J=10,2, 5,9 Hz), br4.61-4,69 (1H, m), to 6.43 (1H, t, J=2.0 Hz), 6,51 (1H, DD, J=3,7, 2.2 Hz), 6,74 (1H, t, J=1.6 Hz), 6,98 (1H, t, J=1.6 Hz), 7,05 (1H, DD, J=3,9, and 2.3 Hz), 10,02 (1H, USS).

MS (FAB) m/z: 448 (M+H)+.

(106d) N-[(2R)-2-Hydroxybutyl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1,03 g, 2,30 mmol)synthesized in example (106c), dissolved in methylene chloride (20 ml), the resulting solution was added (2R)-1-aminobutane-2-ol (0.40 g,of 4.49 mmol)synthesized in accordance with the known method (Angew. Chem. Int. Ed. 2007, 46, 2245), WSC-HCl (1,15 g, 6,00 mmol), and 4-dimethylaminopyridine (280 mg, to 2.29 mmol) and the resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture is extracted with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled at ponie nom pressure, and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-80%), obtaining the target compound (1.01 g, yield 85%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 0,99 (3H, t, J=7.4 Hz), is 1.11 (18H, d, J=7,0 Hz), 1,23-of 1.30 (3H, m)is 1.31 (3H, d, J=6.3 Hz), 1,49 is 1.60 (2H, m), 3.27 to the 3.35 (1H, m), 3,42 (3H, s), 3,49 (1H, DD, J=10,2, a 4.3 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), 3,62 at 3.69 (1H, m), 3,70 is 3.76 (1H, m), 4,49-4,56 (1H, m), 6,33 (1H, t, J=5.7 Hz), 6,41 (1H, t, J=2.2 Hz), 6,45 (1H, DD, J=3,5, 3.1 Hz), is 6.61 (1H, DD, J=3,7, 2,5 Hz), to 6.67 (1H, t, J=1,8 Hz), was 6.73 (1H, t, J=1,8 Hz), 9,58 (1H, s).

(106e) (5S)-5-Ethyl-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol

N-[(2R)-2-Hydroxybutyl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide (1.01 g, 1,95 mmol)synthesized in example (106d), dissolved in tetrahydrofuran (40 ml), to the solution was added anhydrous methansulfonate acid (600 mg, 3,44 mmol) and triethylamine (1.60 ml, mmol 11,48) and the resulting mixture was stirred at 50°C for 8 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (80 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column x is matography (silica gel, eluting solvent: ethyl acetate/hexane=50%-70%), obtaining the target compound (980 mg, yield 100%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.01 (3H, t, J=7.4 Hz), 1,09-to 1.14 (18H, m), 1,24-of 1.30 (3H, m)of 1.32 (3H, d, J=6.3 Hz), 1,71-to 1.82 (2H, m), 3,42 (3H, s), 3,49 (1H, DD, J=10,2, a 4.3 Hz), 3,57-3,63 (2H, m), Android 4.04 (2H, DD, J=14,1, and 9.4 Hz), 4,51-4,56 (1H, m), 4,62-and 4.68 (1H, m), to 6.39 (1H, t, J=2.2 Hz), 6,46 (1H, d, J=3,9 Hz), of 6.71 (1H, s), of 6.75 (1H, s)6,76 (1H, s).

(106f) 2-(3-{5-[(5S)-5-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenoxy)-5-(methylsulphonyl)pyrazin

(5S)-5-Ethyl-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol (980 mg, of 1.95 mmol)synthesized in example (106e), dissolved in tetrahydrofuran (20 ml)to the solution at room temperature add tetrabutylammonium fluoride (solution in tetrahydrofuran, 1.0 to mol/l of 4.00 ml, 4.00 mmol) and then stirred at room temperature for 1.5 hours under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture is extracted with methylene chloride (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, obtaining the product in a solid yellow color.

The product is dissolved in acetonitrile (20 ml)at room temperature for RA is Toru add 2-chloro-5-(methylsulphonyl)pyrazin (420 mg, to 2.18 mmol)synthesized in example (97c), and cesium carbonate (1.42 g, 4,36 mmol) and the resulting mixture was stirred at room temperature for 2 hours in nitrogen atmosphere. To the reaction solution was added water (30 ml) and the mixture is extracted with methylene chloride (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate=100%), obtaining the target compound (860 mg, yield 88%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ a 1.08 (3H, t, J=7.4 Hz), to 1.38 (3H, d, J=6.3 Hz), 1,81-of 1.94 (2H, m), 3,24 (3H, s), 3,42 (3H, s), of 3.56 (1H, DD, J=10,6, 3,9 Hz), 3,62 (1H, DD, J=10,6, 5,9 Hz), 3,74 (1H, DD, J=12,7, a 7.6 Hz), 4,17 (1H, DD, J=12,1, 9.8 Hz), 4,74 (1H, USS), 4,99 (1H, USS), is 6.61 (1H, d, J=4.3 Hz), 6,74 (1H, s), 7,06 (1H, s), 7,20 (1H, s), 7,40 (1H, s), and 8.50 (1H, d, J=1.2 Hz), 8,82 (1H, d, J=1.2 Hz).

(106g) (2S)-2-(3-{5-[(5S)-5-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol

2-(3-{5-[(5S)-5-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenoxy)-5-(methylsulphonyl)pyrazin (860 mg, 1,72 mmol)synthesized in example (106f), dissolved in methylene chloride (20 ml), the solution in a nitrogen atmosphere at -78°C is added dropwise add tribromide (boron solution in methylene chloride, 1.0 mol/l, 2,50 ml of 2.50 mmol who) and the mixture is then stirred at room temperature for 2 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (20 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-4%), obtaining the target compound (764 mg, yield 91%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.02 (3H, t, J=7.4 Hz), of 1.33 (3H, d, J=6.3 Hz), 1,67-of 1.85 (2H, m), 3,23 (3H, s), 3,63 (1H, DD, J=13,7, 7,8 Hz), to 3.73-a 3.83 (2H, m), 4,07 (1H, DD, J=13,7, 9.4 Hz), 4,60 (1H, USS), 4,72 (1H, USS), 6,51 (1H, d, J=3,9 Hz), 6,60 (1H, s), for 6.81 (1H, d, J=3.5 Hz), of 6.96 (1H, s), 7,12 (1H, s), 8,48 (1H, d, J=1.2 Hz), 8,80 (1H, d, J=1.2 Hz).

MS (ESI) m/z: 487,16397 (M+H)+.

Example 107

(2S)-2-(3-{5-[(4R)-4-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol

(107a) N-[(2R)-1-Hydroxypropan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (2.25 g, of 5.03 mmol)synthesized in example (106c), dissolved in methanol (50 ml), the solution dobavlyayte D-alaninol (0,70 ml, 8,97 mmol) and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-yl)-4-methylmorpholine (3,05 g, 11,02 mmol) and the resulting mixture was stirred at room temperature for 1 day under nitrogen atmosphere. After that, the solvent is distilled off under reduced pressure, add saturated aqueous solution of ammonium chloride (50 ml) and the mixture extracted with ethyl acetate (80 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=80%-100%)to give the target compound (1,95 g, 75%yield) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.11 (18H, d, J=7,4 Hz), 1,23 of 1.28 (3H, m)of 1.28 (3H, d, J=7,0 Hz)of 1.32 (3H, d, J=5,9 Hz), 3,42 (3H, s), 3,49 (1H, DD, J=10,2, a 4.3 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), to 3.64 (1H, DD, J=11,1, 6,1 Hz), of 3.77 (1H, DD, J=10,9, 3.5 Hz), 4,24 (1H, USS), a 4.53 (1H, USS), equal to 6.05 (1H, s)6,41 (1H, t, J=2.0 Hz), 6,45 (1H, t, J=3.3 Hz), 6,60 (1H, DD, J=3,7, 2,5 Hz), to 6.67 (1H, t, J=1,8 Hz), 6,74 (1H, t, J=1,8 Hz), 9,60 (1H with).

(107b) (4R)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol

N-[(2R)-1-Hydroxypropan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide (1,95 g, 3,76 mmol)synthesized in example (107a), dissolved in tetrahydrofuran (30 ml), to the solution was added anhydrous methansulfonate acid (1.25 g, 7,18 mmol) and triethylamine (2,80 ml, 20,09 mmol) and the resulting mixture is stirred is at 50°C for 1 day under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (80 ml) and the mixture is extracted with methylene chloride (120 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-80%), obtaining the target compound (1.18 g, yield 64%) as a solid yellow color.

lH-NMR (CDCl3, 400 MHz): δ 1.12 in (18H, d, J=7,4 Hz), of 1.23 to 1.31 (3H, m), is 1.31 and 1.35 (6H, m), 3,42 (3H, s), 3,49 (1H, DD, J=10,2, 4,7 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), 3,93 (1H, t, J=7.8 Hz), 4,33 (1H, USS), of 4.49 (1H, DD, J=9,0, 8,2 Hz), of 4.54 (1H, USS), 6,40 (1H, t, J=2.2 Hz), 6,46 (1H, d, J=3.5 Hz), 6,72 (1H, t, J=1,8 Hz), 6,74 (1H, d, J=3,9 Hz), 6,77 (1H, t, J=1,8 Hz).

(107c) 3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol

(4R)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol (1.18 g, 2,42 mmol)synthesized in example (107b), dissolved in tetrahydrofuran (10 ml)to the solution at room temperature add tetrabutylammonium fluoride (solution 1.0 mol/l in tetrahydrofuran, to 3.00 ml, 3.00 mmol) and the resulting mixture was stirred at room temperature for 30 minutes in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of chlorine is IDA ammonia (30 ml) and the mixture is extracted with methylene chloride (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=1%-3%), obtaining the target compound (720 mg, yield 90%) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), for 1.49 (3H, d, J=6.3 Hz), 3,42 (3H, s), of 3.48 (1H, DD, J=10,2, 4,7 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), was 4.02 (1H, t, J=7,6 Hz), 4,47-br4.61 (3H, m), 6,38 (1H, t, J=2.2 Hz), 6.48 in (1H, d, J=3,9 Hz), was 6.73 (1H, t, J=1,8 Hz), 6,76 (1H, d, J=3,9 Hz), to 7.09 (1H, s), 11,09 (1H, s).

(107d) of 2-Bromo-5-(methylsulphonyl)pyrazin

2.5-Dibromopyrazine (270 mg, to 1.14 mmol) dissolved in tetrahydrofuran (10 ml)to the solution at room temperature add thiamethoxam sodium (320 mg, of 4.57 mmol) and the resulting mixture was stirred at room temperature for 2.5 hours under nitrogen atmosphere. To the reaction solution was added water (10 ml) and the mixture extracted with diethyl ether (10 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=5%-10%), and receiving the product in a solid yellow color.

The resulting product of restore the t in methylene chloride (10 ml) and to the solution was added m-chloroperbenzoic acid (approximately 65%, 580 mg, approximately 2.2 mmol) at room temperature and then stirred at room temperature for 1 hour in nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (10 ml) and the mixture is extracted with methylene chloride (10 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=15%-25%), obtaining the target compound (190 mg, yield 70%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 3,26 (3H, s), 8,80 (1H, d, J=1.2 Hz), 9,06 (1H, d, J=1.2 Hz).

(107e) 2-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-(methylsulphonyl)pyrazin

3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (340 mg, 1,03 mmol)synthesized in example (107c), dissolved in acetonitrile (10 ml)to the solution at room temperature is added 2-bromo-5-(methylsulphonyl)pyrazin (300 mg, of 1.27 mmol)synthesized in example (107d), and cesium carbonate (850 mg, 2,61 mmol) and the resulting mixture was stirred at room temperature for 4.5 hours under nitrogen atmosphere. To the reaction solution was added water (20 ml) and the mixture extrag the shape with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate=100%), obtaining the target compound (456 mg, yield 91%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=4.3 Hz), of 1.35 (3H, d, J=3,9 Hz), 3,24 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=10,2, 3,9 Hz), 3,60 (1H, DD, J=10,4, 6,1 Hz), 3,93 (1H, t, J=7.8 Hz), 4,33 (1H, USS), 4,51 (1H, t, J=8,6 Hz), 4,58 (1H, USS), of 6.52 (1H, d, J=3,9 Hz), 6,66 (1H, t, J=2.2 Hz), 6,76 (1H, d, J=3,9 Hz), 6,92 (1H, t, J=1,8 Hz), 7,07 (1H, d, J=1.6 Hz), 8,49 (1H, d, J=1.2 Hz), 8,81 (1H, d, J=1.6 Hz).

(107f) (2S)-2-(3-{5-[(4R)-4-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol

2-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-(methylsulphonyl)pyrazin (456 mg, of 0.94 mmol)synthesized in example (107e), dissolved in methylene chloride (5.0 ml)to the resulting solution was cooled to -78°C, drops add tribromide (boron solution in methylene chloride, 1.0 mol/l, 1.50 ml, 1.50 mmol) and the resulting mixture was stirred at room temperature for 3 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (10 ml) and the mixture is extracted with methylene chloride (20 ml). Organic is the cue layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=4%-6%), obtaining the target compound (330 mg, yield 74%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 1.40 (3H, d, J=6.6 Hz), up 3.22 (3H, s), 3,71 (1H, DD, J=11,7, a 4.3 Hz), 3,81 (1H, DD, J=11,7, and 6.6 Hz), 4,05-to 4.14 (1H, m), of 4.38 is 4.45 (1H, m), 4,59-of 4.67 (2H, m), 6,53 (1H, d, J=3,9 Hz), 6,62 (1H, t, J=2.2 Hz), 6.87 in (1H, d, J=3,9 Hz), 6,98 (1H, s), 7,27 (1H, s), of 8.47 (1H, d, J 1.2 Hz), 8,79 (1H, d, J=1.2 Hz).

MS (ESI) m/z: 473,14930 (M+H)+.

Example 108

(2S)-2-(3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol

(108a) (4R)-4-Ethyl-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.40 g, 3,13 mmol)synthesized in example (106c), dissolved in methanol (20 ml), the resulting solution was added (R)-(-)-2-amino-1-butanol (0.65 g, 7,29 mmol) and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (1,75 g,6,32 mmol) and then stirred at room temperature under nitrogen atmosphere for 2 days. After that, the solvent is distilled off under reduced pressure, add saturated aqueous solution of chlorine is Yes ammonium (50 ml) and the mixture is extracted with methylene chloride (100 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-80%)to give the product as a white foam.

The obtained product is dissolved in tetrahydrofuran (20 ml), add anhydrous methansulfonate acid (0,80 g, 4,59 mmol) and triethylamine (1.20 ml, 8,61 mmol) and the resulting mixture was stirred in nitrogen atmosphere at 50°C during the night. To the reaction solution was added saturated aqueous solution of ammonium chloride (60 ml) and the mixture is extracted with methylene chloride (100 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=70%-90%), obtaining the target compound (965 mg, yield 62%) as a solid white color.

1H-NMR (CDCl3,400 MHz): δ of 1.00 (3H, t, J=7,6 Hz), 1,07-to 1.14 (18H, m), of 1.23 to 1.31 (3H, m)of 1.32 (3H, d, J=6.3 Hz), 1.56 to of 1.65 (1H, m), 1,68-to 1.77 (1H, m)to 3.41 (3H, s), of 3.48 (1H, DD, J=10,0, 4,6 Hz)and 3.59 (1H, DD, J=10,0, 5.6 Hz), to 4.01 (1H, t, J=7.8 Hz), 4,15-is 4.21 (1H, m), of 4.44 (1H, t, J=8,8 Hz), 4,49-of 4.54 (1H, m), to 6.39 (1H, t, J=2.0 Hz), 6,46 (1H, d, J=3,9 Hz), of 6.71 (1H, t, J=1.7 Hz), 6,74 (1H, d, J=3,4 Hz), 6,76 (1H, t, J=1.7 Hz).

(108b) 3-{-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol

(4R)-4-Ethyl-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol (965 mg, of 1.93 mmol)synthesized in example (108a), dissolved in tetrahydrofuran (10 ml)to the solution at room temperature add tetrabutylammonium fluoride (solution 1.0 mol/l in tetrahydrofuran, 2,50 ml of 2.50 mmol) and the resulting mixture was stirred at room temperature for 1 hour in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture is extracted with methylene chloride (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-4%), obtaining the target compound (550 mg, yield 83%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.10 (3H, t, J=7.4 Hz), 1,32 (3H, d, J=6.3 Hz), 1,73 (1H, TD, J=14,1, 7,0 Hz), of 1.85 (1H, TD, J=14,0, 7,0 Hz)to 3.41 (3H, s), of 3.48 (1H, DD, J=10,2, 4,7 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), 4.09 to to 4.15 (1H, m,), 4,32-and 4.40 (1H, m), 4,48-of 4.57 (2H, m), 6,36 (1H, t, J=2.2 Hz), 6,47 (1H, d, J=3.5 Hz), 6,72 (1H, t, J=1,8 Hz), 6,76 (1H, d, J=3,9 Hz), 7,10 (1H, t, J=1,8 Hz), 11,12 (1H, USS).

(108c) 2-(3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenoxy)-5-(methylsulphonyl)pyrazin

3-{5-[(4R)-4-Ethyl-4,5-is hydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (272 mg, 0,79 mmol)synthesized in example (108b), dissolved in acetonitrile (5.0 ml)to the solution at room temperature is added 2-chloro-5-(methylsulphonyl)pyrazin (220 mg, 1,14 mmol)synthesized in example (97c), and cesium carbonate (640 mg, a 1.96 mmol) and the resulting mixture was stirred at room temperature for 3.5 hours under nitrogen atmosphere. To the reaction solution was added water (20 ml) and the mixture is extracted with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-3%), obtaining the target compound (417 mg, yield ~100%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 0.96 (3H, t, J=7.4 Hz), of 1.34 (3H, d, J=6.3 Hz), 1,53 is 1.60 (1H, m), 1,65-1,72 (1H, m), 3,23 (3H, s)to 3.41 (3H, s), 3,50 (1H, DD, J=10,2, a 4.3 Hz)and 3.59 (1H, DD, J=10,6, 5,9 Hz), 4,01 (1H, t, J=7,8 Hz), 4,11-4,19 (1H, m), to 4.41-to 4.46 (1H, m), of 4.57 (1H, USS), of 6.50 (1H, d, J=3,9 Hz), only 6.64 (1H, t, J=2.2 Hz), was 6.73 (1H, d, J=3.5 Hz), 6,94 (1H, d, J=1.6 Hz), to 7.09 (1H, d, J=1.6 Hz), of 8.47 (1H, d, J=0.8 Hz), 8,80 (1H, d, J=0.8 Hz).

(108d) (2S)-2-(3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol

2-(3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenoxy)-5-(methylsulphonyl)Piras is n (417 mg, 0.83 mmol)synthesized in example (108c), dissolved in methylene chloride (10 ml), the resulting solution was cooled to-78ºC, added dropwise tribromide (boron solution in methylene chloride, 1.0 mol/l of 1.00 ml, 1.00 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for one hour. To the reaction solution was added 1 N. aqueous sodium hydroxide solution (20 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=3%-4%), obtaining the target compound (325 mg, yield 80%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.01 (3H, t, J=7.4 Hz), of 1.30 (3H, d, J=6.3 Hz), 1,57-of 1.64 (1H, m), 1,68 is 1.75 (1H, m), 3,23 (3H, s), 3,78-of 3.80 (2H, m), was 4.02 (1H, t, J=8.0 Hz), 4,16-4,22 (1H, m), 4,47 (1H, t, J=8,8 Hz), 4,57-4,63 (1H, m), of 6.45 (1H, d, J=3.5 Hz), of 6.49 (1H, s), of 6.73 (1H, d, J=3,9 Hz), make 6.90 (1H, s), 7,01 (1H, s), 8,44 (1H, s), 8,79 (1H, s).

MS (ESI) m/z: 487,16468 (M+H)+.

Example 109

(2S)-2-(3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl[oxy}phenoxy)propan-1-ol

(109a) of N-[(2R,3R)-3-Hydroxybutane-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-feast of the ol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (0,89 g, 1,99 mmol)synthesized in example (106c), dissolved in methanol (20 ml), the solution is added (2R,3R)-3-aminobutane-2-ol (0,41 g, 4,60 mmol)synthesized in example (88a), and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (1.20 g, 4,34 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 days. After that, the solvent is distilled off under reduced pressure, add saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (80 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=60%-80%), obtaining the target compound (722 mg, yield 70%) as a white foam.

1H-NMR (CDCl3, 400 MHz): δ is 1.11 (18H, d, J=7,0 Hz), 1,22-of 1.29 (3H, m)of 1.24 (3H, d, J=6.3 Hz), of 1.28 (3H, d, J=7,0 Hz)of 1.32 (3H, d, J=6.3 Hz), 2,34 (1H, USS), 3,42 (3H, s), 3,49 (1H, DD, J=10,2, a 4.3 Hz)and 3.59 (1H, DD, J=10,2, 5,5 Hz), a-3.84 (1H, USS), a 4.03-4,13 (1H, m), 4,49-4,56 (1H, m), the 6.06 (1H, d, J=8.6 Hz), 6,41 (1H, t, J=2.2 Hz), 6,45 (1H, DD, J=3,7, 2,9 Hz), is 6.61 (1H, DD, J=3,9, and 2.3 Hz), to 6.67 (1H, t, J=1,8 Hz), was 6.73 (1H, t, J=2.0 Hz), 9,49 (1H, USS).

(109b) (4R,5S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dimethyl-4,5-dihydro-1,3-oxazol

N-[(2R,3R)-3-Hydroxybutane-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide (722 mg, of 1.39 mmol)synthesized in example (109a), dissolved in tetrahydrofuran (30 ml), to the solution was added anhydrous methansulfonate acid (430 mg, 2,47 mmol) and triethylamine (1.20 ml, 8,61 mmol) and the mixture was stirred at 50°C in nitrogen atmosphere overnight. The reaction solution allow to cool to room temperature, to the solution was added a saturated aqueous solution of ammonium chloride (50 ml) and the resulting mixture extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=40%-70%), obtaining the target compound (700 mg, yield 100%) as a yellow liquid.

1H-NMR (CDCl3, 400 MHz): δ is 1.11 (18H, d, J=7,0 Hz)to 1.21 (3H, d, J=7,0 Hz), 1,23-of 1.30 (3H, m)is 1.31 (3H, d, J=6.3 Hz), of 1.33 (3H, d, J=6.6 Hz), 3,42 (3H, s), of 3.48 (1H, DD, J=10,2, a 4.3 Hz), to 3.58 (1H, DD, J=10,2, 5,9 Hz), 4,24-4,32 (1H, m), 4,48-4,56 (1H, m), 4,78-is 4.85 (1H, m), to 6.39 (1H, t, J=2.2 Hz), 6,46 (1H, d, J=3.5 Hz), 6,70 (1H, s), 6.73 x to 6.75 (2H, m).

(109c) 3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol

(4R,5S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)is XI]phenyl)-1H-pyrrol-2-yl]-4,5-dimethyl-4,5-dihydro-1,3-oxazol (700 mg, of 1.39 mmol)synthesized in example (109b), dissolved in tetrahydrofuran (10 ml)to the solution at room temperature add tetrabutylammonium fluoride (solution 1.0 mol/l in tetrahydrofuran, 2.00 ml, 2.00 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture is extracted with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-3%), obtaining the target compound (420 mg, yield 88%) as a yellow liquid.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 1,35-1,40 (6H, m)to 3.41 (3H, s), of 3.48 (1H, DD, J=10,0, 4.5 Hz)and 3.59 (1H, DD, J=10,2, 5,5 Hz), 4,40-4,48 (1H, m), 4,48-4,56 (1H, m), 4,86-4,94 (1H, m), 6,38 (1H, t, J=2.0 Hz), 6,47 (1H, d, J=3,9 Hz), 6,72 (1H, s), of 6.75 (1H, d, J=3,9 Hz), to 7.09 (1H, s).

(109d) 2-(3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenoxy)-5-(methylsulphonyl)pyrazin

3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (420 mg, 1,22 mmol)synthesized in example (109c), dissolved in acetonitrile (20 ml)to the solution at room is temperature add 2-chloro-5-(methylsulphonyl)pyrazin (345 mg, of 1.46 mmol)synthesized in example (97c), and cesium carbonate (1,02 g of 3.13 mmol) and the resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. To the reaction solution was added water (30 ml) and the mixture is extracted with methylene chloride (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-3%), obtaining the target compound (513 mg, yield 84%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1,19 of 1.28 (6H, m)of 1.35 (3H, d, J=6.6 Hz), 3,24 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=10,2, a 4.3 Hz), 3,61 (1H, DD, J=10,4, 5.7 Hz), 4,25 is 4.35 (1H, m), 4,57-4,63 (1H, m), 4,81-4,91 (1H, m), of 6.52 (1H, d, J=3,9 Hz), 6,76 (1H, s), of 6.96 (1H, s), 7,12 (1H, s), 8,49 (1H, d, J=1.2 Hz), 8,81 (1H, d, J=1.6 Hz).

(109e) ((2S)-2-(3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol

2-(3-{5-[(4R,5S)-4,5-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenoxy)-5-(methylsulphonyl)pyrazin (513 mg, of 1.02 mmol)synthesized in example (109d), dissolved in methylene chloride (10 ml), the resulting solution was cooled to -78°C, added dropwise tribromide (boron solution in methylene chloride, 1.0 mol/l, 1.50 ml, 1.50 mmol) and the resulting semipermissive at room temperature for 2 hours in nitrogen atmosphere. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (20 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=4%-5%)to give the target compound (390 mg, yield 79%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ 1,22 (3H, d, J=7,0 Hz)of 1.32 (3H, d, J=6.3 Hz), of 1.34 (3H, d, J=6.6 Hz), 3,23 (3H, s), 3,76-with 3.79 (2H, m), 4,25-to 4.33 (1H, m), 4,54-4,60 (1H, m), 4,81-4,88 (1H, m), of 6.49 (1H, d, J=3,9 Hz), 6,59 (1H with), to 6.75 (1H, d, J=3,9 Hz), to 6.95 (1H, s), to 7.09 (1H, s), of 8.47 (1H, s), 8,80 (1H, d, J=1.2 Hz). MS (ESI) m/z: 487,16580 (M+H)+.

Example 110

{(4R,5S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol

(110a) N-[(2R,3R)-1,3-Dihydroxybutyl-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (2,05 g, 4,58 mmol)synthesized in example (106c), dissolved in methanol (20 ml)solution was added commercially available L-threonine (1.50 g, 14,27 mmol) and n-hydrate chloride 4-(4,6-is metoxi-1,3,5-triazine-2-yl)-4-methylmorpholine (2.85 g, 10,30 mmol) and the resulting mixture was stirred in nitrogen atmosphere at room temperature for 3 days. After that, the solvent is distilled off under reduced pressure, add saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (80 ml). The organic layer was washed with saturated aqueous salt solution and then dried over anhydrous magnesium sulfate. The resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=3%-7%), obtaining the target compound (2.10 g, yield 86%) as a white foam.

1H-NMR (CDCl3, 400 MHz): δ is 1.11 (18H, d, J=7,4 Hz), to 1.21 and 1.33 (6H, m)to 1.22 (3H, d, J=6.3 Hz), 3,44 (3H, s), 3,49 (1H, DD, J=10,2, 3,9 Hz), 3,57 (1H, DD, J=10,2, 6.3 Hz), 3,83 (2H, USS), of 3.96 (1H, USS), 4.26 deaths (1H, DDD, J=12,5, 6,3, 2.0 Hz), 4,45-a 4.53 (1H, m), 6,41 (1H, t, J=2.2 Hz), 6,44 (1H, DD, J=3,5, 2.7 Hz), 6,68-6,72 (3H, m), 6,72-6,77 (1H, m), 10,36 (1H, s).

(110b) N-{(2R,3R)-3-Hydroxy-1-[(tryptophan-2-ililil)oxy]butane-2-yl}-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide

N-[(2R,3R)-1,3-Dihydroxybutyl-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide (2.10 g, 3.93 mmol)synthesized in example (110a), dissolved in methylene chloride (50 ml), the solution add triisopropylchlorosilane (1.50 ml, 7,01 mmol), 4-dimethylaminopyridine (1.50 g, 12,27 mmol) and triethylamine (5,00 ml, 35,87 mmol) and the resulting mixture is PE is amerivault at room temperature for 1 day under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=25-40%), obtaining the target compound (2,52 g, yield 93%) as a solid white color.

1H-NMR (CDCl3, 500 MHz): δ of 1.07 (18H, d, J=6.8 Hz), 1,12 (18H, d, J=7,3 Hz), to 1.21 to 1.31 (9H, m)of 1.32 (3H, d, J=6.3 Hz), 3,42 (3H, s), 3,49 (1H, DD, J=10,3, 4,4 Hz), 3,55 (1H, USS)and 3.59 (1H, DD, J=10,3, 5,9 Hz), 4,00-Android 4.04 (1H, m,), Android 4.04-4,06 (2H, m), 4,29-4,34 (1H, m), 4,49-4,55 (1H, m), 6,41 (1H, t, J=2.2 Hz), 6,46 (1H, DD, J=3,9, 2,9 Hz), 6,60 (1H, s), is 6.61 (1H, DD, J=3,4, 2.4 Hz), to 6.67 (1H, t, J=2.0 Hz), 6,72 (1H, t, J=2.0 Hz), 9,34 (1H, s).

(110c) (4R,5S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-5-methyl-4-{[(tryptophan-2-ililil)oxy]methyl}-4,5-dihydro-1,3-oxazol

N-{(2R,3R)-3-Hydroxy-1-[(tryptophan-2-ililil)oxy]butane-2-yl}-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide (2,52 g, 3.65 mmol)synthesized in example (110b), dissolved in tetrahydrofuran (20 ml), to to the solution was added anhydrous methansulfonate acid (1,05 g, 6,03 mmol) and triethylamine (2.00 ml, 14,35 mmol) and the resulting mixture was stirred at 50°C in an atmosphere of azo is but within 1 day. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-30%)to give the target compound (2.30 g, yield 94%) liquid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ 1.06 a (18H, d, J=5,1 Hz)of 1.11 (18H, d, J=7,4 Hz), 1,22-of 1.30 (6H, m)is 1.31 (3H, d, J=6.3 Hz), of 1.52 (3H, d, J=6.3 Hz), 3,42 (3H, s), of 3.48 (1H, DD, J=10,2, 4,7 Hz)and 3.59 (1H, DD, J=10,4, 5.7 Hz), 3,82 (1H, DD, J-10,2, 9.0 Hz), 3,98 (1H, DD, J=10,2, 3,9 Hz), 4,24 (1H, TD, J=8,7, 3,9 Hz), 4,48-4,55 (1H, m), 4,86-4,96 (1H, m), to 6.39 (1H, t, J=2.2 Hz), of 6.45 (1H, d, J=3,9 Hz), to 6.67 (1H, s)of 6.71 (1H, s), of 6.75 (1H, d, J=3,9 Hz).

(110d) {(4R,5S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol

(4R,5S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-5-methyl-4-{[(tryptophan-2-ililil)oxy]methyl}-4,5-dihydro-1,3-oxazol (2.30 g, of 3.42 mmol)synthesized in example (110c), dissolved in tetrahydrofuran (20 ml)to the resulting solution at room temperature add tetrabutylammonium fluoride (solution 1.0 mol/l in tetrahydrofuran, 8,00 ml of 8.00 mmol) and the resulting mixture was AC who're asked at room temperature in nitrogen atmosphere for 30 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride (60 ml) and the mixture is extracted with methylene chloride (80 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/ethyl acetate=5%-10%), and receiving the product in a solid white color (2.10 g).

The resulting product (1.20 g) was dissolved in acetonitrile (15 ml)to the solution at 0°C for 5 hours in nitrogen atmosphere is added 2-chloro-5-(methylsulphonyl)pyrazin (410 mg, 2,13 mmol)synthesized in example (97c), and potassium carbonate (0.85 grams, 6,15 mmol), the mixture was stirred in nitrogen atmosphere at 0°C for 5 hours and then at room temperature for 3 hours. To the reaction solution was added water (30 ml) and the mixture is extracted with methylene chloride (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/ethyl acetate=4%-6%), obtaining the target compound (964 mg, yield 95%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.35 (3H, d, J=6.3 Hz), 1,4 (3H, d, J=6.3 Hz), 3,23 (3H, s)to 3.41 (3H, s), 3,50 (1H, DD, J=10,2, a 4.3 Hz), 3,60 (1H, DD, J=10,2, 5,9 Hz), of 3.77 (1H, DD, J=11,5, 6,1 Hz), 3,85 (1H, DD, J=11,7, 3.5 Hz), 4,22-to 4.28 (1H, m), 4,54-4,60 (1H, m), 4,82-4,88 (1H, m), of 6.45 (1H, d, J=3.5 Hz), of 6.65 (1H, t, J=2.2 Hz), to 6.67 (1H, d, J=2.3 Hz), 6,94 (1H, t, J=1,8 Hz), 7,10 (1H, t, J=1,8 Hz), 8,48 (1H, d, J=1.2 Hz), 8,80 (1H, d, J=1.2 Hz).

MS (ESI) m/z: 517,17452 (M+H)+.

Example 111

(2S)-2-(3-{5-[(4R,5S)-4-(Hydroxymethyl)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl)]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol

{(4R,5S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol (209 mg, 0.40 mmol)synthesized in example (110d), dissolved in methylene chloride (5.0 ml)to the solution at-78ºC added dropwise tribromide (boron solution in methylene chloride, 1.0 mol/l to 0.80 ml, 0.80 mmol) and the resulting mixture was stirred at room temperature for 40 minutes under nitrogen atmosphere. To the reaction solution was added 1 N. aqueous sodium hydroxide solution (10 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=4%-6%), obtaining the target compound (169 mg, yield 8%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=6.3 Hz), of 1.41 (3H, d, J=6.6 Hz), 3,23 (3H, s), 3,76 (2H, d, J=4,7 Hz), 3,70-of 3.80 (1H, m), 3,85 (1H, DD, J=11,7, 3,9 Hz), 4,21-of 4.25 (1H, m), 4,49-4,60 (1H, m), 4,82-4,89 (1H, m), to 6.43 (1H, d, J=2.7 Hz), 6,59 (1H, s), to 6.67 (1H, d, J=2.7 Hz), to 6.95 (1H, s), 7,07 (1H, s), of 8.47 (1H, s), 8,78 (1H, s).

MS (ESI) m/z: 503,15957 (M+H)+.

Example 112

(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(112a) of N-[(2S,3S)-1,3-Dihydroxybutyl-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.75 g, 3,91 mmol)synthesized in example (106c), dissolved in methanol (30 ml), the resulting solution was added D-threonine (1,00 g of 9.51 mmol) and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (2.85 g, 10,30 mmol) and then stirred at room temperature under nitrogen atmosphere for 5 days. After that, the solvent is distilled off under reduced pressure, add saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (80 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The resulting residue is purified column chromatography (silica gel, eluting solvent is: methanol/methylene chloride=3%-7%), receiving the target connection (1,76 g, yield 84%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1,08 (18H, d, J=7,4 Hz), 1.18 to 1,25 (6H, m)of 1.27 (3H, d, J=6.3 Hz), and 2.83 (2H, OSS), to 3.38 (3H, s), of 3.45 (1H, DD, J=10,2, a 4.3 Hz), 3,55 (1H, DD, J=10,2, 5,9 Hz), a 3.87 (2H, s), 3,94-4,01 (2H, m), 4,22 (1H, USS), 4,46-to 4.52 (1H, m), 6,37 (1H, USS), 6,40-to 6.43 (1H, m), 6,59 of 6.66 (3H, m), 6,70 (1H, s), 9,78 (1H, USS).

(112b) (lS)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

N-[(2S,3S)-1,3-Dihydroxybutyl-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide (1,76 g, 3,29 mmol)synthesized in example (112a), dissolved in tetrahydrofuran (20 ml)to the resulting solution at -40°C add anhydrous methansulfonate acid (0.54 g, 3,10 mmol) and triethylamine (1,00 ml, 7,17 mmol) and the resulting mixture was stirred in nitrogen atmosphere at the same temperature for 4 hours and then at 50°C during the night. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-5%), receiving targeted of the giving (880 mg, yield 52%) as a white foam.

1H-NMR (CDCl3, 400 MHz): δ 1.12 in (18H, d, J=7,0 Hz), 1,22-of 1.30 (6H, m)of 1.32 (3H, d, J=6.3 Hz), 3,42 (3H, s), of 3.48 (1H, DD, J=10,2, a 4.3 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), 3,69 of 3.75 (1H, m), 4,10-4,20 (2H, m), of 4.45 (1H, USS), 4,53 (1H, USS), 6,40 (1H, t, J=1.6 Hz), 6,47 (1H, d, J=3,9 Hz), 6,70 (1H, s), of 6.75 (1H, s), 6,77 (1H, d, J=3,9 Hz).

(112c) 3-(5-{(4S)-4-[(1S)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol

(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (1.48 g, is 2.88 mmol)synthesized in example (112b), dissolved in tetrahydrofuran (20 ml)to the resulting solution at room temperature add tetrabutylammonium fluoride (solution 1.0 mol/l in tetrahydrofuran, of 3.50 ml, 3.50 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=3%-6%), obtaining the target compound (880 mg, yield 85%) as a solid white color.

1H-NMR(CDCl 3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), of 1.37 (3H, d, J=6.3 Hz), 3,42 (3H, s), of 3.46 (1H, DD, J=10,2, a 4.7 Hz), 3,61 (1H, DD, J=10,0, 5.7 Hz), 3,85-to 3.92 (1H, m), 4,25 is 4.36 (2H, m), 4,49-4,56 (2H, m), 6.48 in (1H, d, J=3,9 Hz), is 6.54 (1H, t, J=2.0 Hz), was 6.73 (1H, t, J=1,8 Hz), 6,79 (1H, d, J=3.5 Hz), 7,06 (1H, s).

(112d) (1S)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

3-(5-{(4S)-4-[(1S)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (880 mg, 2,44 mmol)synthesized in example (112c), dissolved in acetonitrile (20 ml), to the solution was added 2-chloro-5-(methylsulphonyl)pyrazin (630 mg of 3.27 mmol)synthesized in example (97c), and potassium carbonate (1.20 g, 8,68 mmol) and the resulting mixture was stirred at room temperature for 4 hours in nitrogen atmosphere. To the reaction solution was added water (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=1%-3%), obtaining the target compound (1,00 g, yield 79%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.28 (3H, d, J=6.3 Hz), of 1.35 (3H, d, J=6.3 Hz), 3,23 (3H, s)to 3.41 (3H, s), 3,51 (1H, DD, J=10,2, a 4.3 Hz), 3,60 (1H, DD, J=10,2, 6.3 Hz), to 3.73 (1H, USS),4,11-4,22 (2H, m)to 4.46 (1H, USS), 4,60 (1H, USS), of 6.52 (1H, d, J=3,9 Hz), to 6.67 (1H, t, J=2.0 Hz), 6,78 (1H, d, J=3,9 Hz), of 6.96 (1H, s), 7,12 (1H, s), 8,49 (1H, s), 8,81 (1H, s).

MS (ESI) m/z: 517,17608 (M+H)+.

Example 113

(2S)-2-[3-(5-{(4S)-4-[(1S)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy]propane-1-ol

(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (204 mg, 0,395 mmol)synthesized in example (112d), dissolved in methylene chloride (5.0 ml), to the resulting solution at -78°C is added dropwise tribromide (boron solution in methylene chloride, 1.0 mol/l to 0.80 ml, 0.80 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1.5 hours. To the reaction solution was added 1 N. aqueous sodium hydroxide solution (10 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=3%-5%)to give the target compound (159 mg, yield 80%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.28 (3H, d, J=6.3 Hz), 1,32 (3H, d, J=6.3 Hz), 3,24 (3H, s), of 3.73-of 3.78 (3H, m), 4,12-to 4.23 (2H, m, to 4.46 (1H, OSS), to 4.52-4,59 (1H, m), 6,50 (1H, d, J=3,9 Hz), 6,62 (1H, t, J=2.0 Hz), 6,76 (1H, d, J=3,9 Hz)6,94 (1H, t, J=1,8 Hz), was 7.08 (1H, s), 8,49 (1H, d, J=1.2 Hz), 8,80 (1H, d, J=1.2 Hz).

MS (ESI) m/z: 503,15930 (M+H)+.

Example 114

(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

(114a) N-[(2S,3R)-1,3-Dihydroxybutyl-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.63 g, of 3.64 mmol)synthesized in example (106c), dissolved in methanol (20 ml), the resulting solution was added D-ALLO-threonine (1,05 g of 9.99 mmol) and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (2.00 g, of 7.23 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 day. After that, the solvent is distilled off under reduced pressure, add saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (80 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=3%-7%), obtaining the target compound (1.70 g, yield 87%) as a white foam is about color.

1H-NMR (CDCl3, 400 MHz): δ of 1.07 (18H, d, J=7,0 Hz), 1,17-of 1.27 (9H, m), a 2.01 (1H, USS), 3,37 (3H, s), 3,44 (1H, DD, J=10,0, 4,1 Hz), 3,44 (1H, s), 3,53 (1H, DD, J=10,4, 6,1 Hz), 3.72 points-of 3.78 (1H, m), 3,88-3,93 (1H, m), 3,93-of 3.95 (1H, m), 3.96 points-Android 4.04 (2H, m), of 4.44-to 4.52 (1H, m), 6.35mm (1H, t, J=2.0 Hz), to 6.39 (1H, t, J=3.1 Hz), to 6.67 (1H, t, J=1,8 Hz), 6,70 (1H, s), 6,72 (1H, s), of 6.99 (1H, d, J=7.8 Hz), 10,34 (1H, USS).

(114b) (1R)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

N-[(2S,3R)-1,3-Dihydroxybutyl-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-carboxamide (1.70 g, 3,18 mmol)synthesized in example (114a), dissolved in tetrahydrofuran (20 ml)to the resulting solution at 0ºC add anhydrous methansulfonate acid (0,78 g, 4,48 mmol) and triethylamine (1.50 ml, of 10.76 mmol) and the resulting mixture was stirred at the same temperature under nitrogen atmosphere for 1.5 hours and then at 50°C during the night. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-4%), obtaining the target compound (1,30 g, yield 79%) as a white foam is the same.

1H-NMR (CDCl3, 400 MHz): δ 1.10 is to 1.14 (18H, m)of 1.20 (3H, d, J=6.6 Hz), 1,23-of 1.32 (3H, m)of 1.34 (3H, d, J=6.3 Hz), to 3.41 (3H, s), of 3.48 (1H, DD, J=10,2, a 4.3 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), 4,20-4,34 (4H, m), a 4.53 (1H, USS), 6,33 (1H, d, J=3,9 Hz), 6,40 (1H, t, J=2.0 Hz), 6,44 (1H, USS), 6,74 (1H, t, J=1,8 Hz), 6,78 (1H, t, J=1,8 Hz).

(114c) 3-(5-{(4S)-4-[(lR)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol

(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tryptophan-2-ililil)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (1.30 grams, 2,52 mmol)synthesized in example (114b), dissolved in tetrahydrofuran (15 ml)to the solution at room temperature add tetrabutylammonium fluoride (solution 1.0 mol/l in tetrahydrofuran, of 4.00 ml, 4.00 mmol) and the resulting mixture for 1 hour and stirred at room temperature under nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/ethyl acetate=8%-12%), obtaining the target compound (766 mg, yield 85%) as a white foam.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (6H, d, J=6.3 Hz), or 3.28 (1H, USS), 3,42 (3H, s), 3,47 (1H, DD, J=10,2, 43 Hz), 3,61 (1H, DD, J=10,2, 5,9 Hz), 4,23 (1H, USS), 4,35-4,43 (1H, m), 4,47-4,56 (3H, m), 6,46-of 6.49 (2H, m), 6,72 (1H, s), is 6.78 (1H, d, J=3.5 Hz),? 7.04 baby mortality (1H, t, J=1,8 Hz), 11,07 (1H, s).

(114d) (1R)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol

3-(5-{(4S)-4-[(1R)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (766 mg, 2,13 mmol)synthesized in example (114c), dissolved in acetonitrile (15 ml), to the solution was added 2-chloro-5-(methylsulphonyl)pyrazin (590 mg, a 3.06 mmol)synthesized in example (97c), and potassium carbonate (870 mg, of 6.29 mmol) and the resulting mixture for 4 hours, stirred at room temperature under nitrogen atmosphere. To the reaction solution was added water (50 ml) and the mixture is extracted with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/ethyl acetate=5%-8%), obtaining the target compound (890 mg, yield 81%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.17 (3H, d, J=6.6 Hz), of 1.36 (3H, d, J=6.3 Hz), 3,23 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=10,4, 4,1 Hz), 3,60 (1H, DD, J=10,2, 5,9 Hz), 4,10-4.26 deaths (2H, m), 4,28 is 4.35 (2H, m), 4,58 (1H, USS), 6.42 per (1H, d, J=3,9 Hz), 6,56 (1H, d, J=3.5 Hz), 6,66 (1H, t, J=2.2 Hz), of 6.96 (1H, d, J=1.6 Hz), 7,11(1H, C)8,49 (1H, d, J=1.2 Hz), 8,81 (1H, d, J=1.2 Hz).

MS (ESI) m/z: 517,17565 (M+H)+.

Example 115

(2S)-2-[3-(5-{(4S)-4-[(1R)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy]propane-1-ol

(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (213 mg, 0,412 mmol)synthesized in example (114d), dissolved in methylene chloride (5.0 ml), to the solution at -78°C is added dropwise tribromide (boron solution in methylene chloride, 1.0 mol/l to 0.80 ml, 0.80 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1.5 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (10 ml) and the mixture is extracted with methylene chloride (20 ml). The organic layer was washed with 1 N. aqueous sodium hydroxide solution (10 ml) and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=4%-5%)to give the target compound (147 mg, 71%yield) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.18 (3H, d, J=6.3 Hz), of 1.33 (3H, d, J=6.3 Hz), to 1.61 (2H, USS), 3,23 (3H, s), of 3.73-3,82 (2H, m), 4,16-4.26 deaths (2H, m), 4,30 is 4.36 (2H, m), 4,54-br4.61 (1H, m), to 6.39 (1H, d, J=3,9 Hz), 6,53(1H, d, J=3.5 Hz), is 6.61 (1H, s), to 6.95 (1H, s), 7,07 (1H, s), 8,48 (1H, d, J=1.2 Hz), 8,80 (1H, d, J=1.6 Hz).

MS (ESI) m/z: 503,15973 (M+H)+.

Example 116

1-{[4-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)phenyl]sulfonyl}-4-methylpiperazin

(116a) 1-[(4-Forfinal)sulfonyl]-4-methylpiperazin

Commercially available 4-forbindelsesfaneblad (1,00 g, 5,14 mmol) suspended in water (15 ml)suspension type N-methylpiperazine (0.68 ml of 6.17 mmol) and potassium carbonate (1.56 g, 11.3 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 14 hours. To the reaction solution was added water (50 ml), the mixture is extracted with ethyl acetate (50 ml), the organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=50%-90%), obtaining the target compound (491 mg, yield 37%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 2.28 (3H, s), 2.49 USD (4H, t, J=4.9 Hz), 3.04 from (4H, USS), 7,21 (2H, DD, J=9,4, 7,8 Hz), 7,76-7,79 (2H, m).

(116b) N-[(2R)-2-Hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]the dryer is l}-1H-pyrrole-2-carboxylic acid (51,4 g, 115 mmol)synthesized in example (106c), dissolved in methanol (600 ml)solution was added (R)-(-)-1-amino-2-propanol (19.9 ml, 253 mmol) and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (63.7 g, 230 mmol) and the resulting mixture is stirred for 15 hours under nitrogen atmosphere. The solvent is distilled off under reduced pressure, add water (500 ml), the mixture is extracted twice with ethyl acetate (500 ml). Then the organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=25%-67%), obtaining the target compound (48,7 g, yield 84%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1.12 in (18H, d, J=7.8 Hz), 1.27mm (3H, q, J=8,3 Hz)of 1.32 (3H, d, J=6.3 Hz), 2,60 (1H, s), 3.27 to to 3.33 (1H, m), 3,42 (3H, s), 3,49 (1H, DD, J=10,3, 4,4 Hz), 3,56-the 3.65 (2H, m), a 4.03 (1H, s), a 4.53 (1H, TD, J=6,1, 4,4 Hz), of 6.31 (1H, USS), 6,41 (1H, t, J=2.2 Hz), 6,46 (1H, t, J=3.2 Hz), is 6.61 (1H, t, J=3.2 Hz), to 6.67 (1H, t, J=1.7 Hz), was 6.73 (1H, t, J=2.0 Hz), of 9.51 (1H, USS).

(116c) (5S) -2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol

N-[(2R)-2-hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-carboxamide (48.7 per g of 96.5 mmol)synthesized in example (116b), dissolved in tetrahydrofuran (600 ml), to the solution was added anhydrous methansulfonate acid (33.6 g, 193 mmol) and triethylamine (40,4 ml, 289 mmol) and the resulting mixture is stirred for 3 hours at 50°C in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (500 ml) and the resulting mixture was extracted twice with ethyl acetate (500 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, to the obtained residue, add diisopropylate (300 ml) and the resulting suspension is stirred, during which a precipitate of white color, which is removed by filtration. From the mother liquor under reduced pressure, the solvent is distilled off and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-50%). The product is dried in vacuum together with the filtered product, obtaining the target compound (34.8 g, yield 74%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.11 (18H, d, J=7.8 Hz), of 1.25 to 1.34 (3H, m)to 1.38 (3H, d, J=6.3 Hz), of 1.65 (3H, d, J=5,9 Hz), 3.43 points (3H, s), to 3.58-the 3.65 (2H, m), 3,76 (1H, DD, J=10,9, and 7.8 Hz), 4,28 (1H, DD, J=11,3, 9.8 Hz), 4,81-to 4.87 (1H, m), 5,28 lower than the 5.37 (1H, m), 6,51 (1H, t, J=2.2 Hz), 6,62 (1H, d, J=2.0 Hz), 6,91 (1H, s), 7,19 (1H, s), 7,35 (1H, s).

(116d) 3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol

(5S)-2-(5-{3-[(15)-2-Methox is-1 methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazol (29.5 g, 60,7 mmol)synthesized in example (116c), dissolved in tetrahydrofuran (400 ml), to the solution was added tetrabutylammonium fluoride (solution in tetrahydrofuran, 1.0 mol/l, 66 ml, 66 mmol) and the resulting mixture is stirred for 1 hour in nitrogen atmosphere. The solvent is distilled off under reduced pressure, to the residue water is added (400 ml) and the resulting mixture was extracted twice with ethyl acetate (400 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-50%)to give the target compound (16.7 g, yield 83%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), 1,49 (4H, d, J=6.3 Hz), 3,42 (3H, s), 3,49 (1H, DD, J=10,2, 4,7 Hz)and 3.59 (1H, DD, J=10,2, 5,5 Hz), 3,68 (1H, DD, J=13.3-inch, 7,4 Hz), 4,22 (1H, DD, J=13,5, 9,2 Hz), to 4.52-of 4.57 (1H, m,), equal to 4.97-4,88 (1H, m), 6,34 (1H, t, J=2.0 Hz), 6,47 (1H, d, J=3.5 Hz), 6,72 (1H, s)6,76 (1H, d, J=3.5 Hz), 7,10 (1H, s).

(116e) 1-{[4-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)phenyl]sulfonyl}-4-methylpiperazin

3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (40 mg, 0.12 mmol)synthesized in example (116d), and 1-[(4-forfinal)sulfonyl]-4-methylpiperazine (25 mg, 0.15 mmol), synthesized the example (116a), dissolved in N,N-dimethylformamide (2 ml), the resulting solution was added potassium carbonate (51 mg, and 0.37 mmol) and the mixture for 1 hour and stirred at 100°C in nitrogen atmosphere. To the mixture again, add 1-[(4-Forfinal)sulfonyl]-4-methylpiperazine (30 mg) and the mixture was stirred at 90°C during the night. The reaction solution is cooled to room temperature, to the solution was added water (10 ml) and the resulting mixture was extracted twice with ethyl acetate (10 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (25 mg, yield 35%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=5,9 Hz), USD 1.43 (3H, d, J=6.3 Hz), to 2.29 (3H, s)of 2.50 (4H, USS), 3,06 (4H, USS), of 3.43 (3H, d, J=2.4 Hz), 3,50-3,61 (3H, m, 4,10 (1H, DD, J=14,2, and 9.3 Hz), 4,58 (1H, DD, J=10,5, 6,1 Hz), 4,82-a 4.86 (1H, m), of 6.52 (1H, d, J=3,4 Hz), 6,55 (1H, t, J=2.2 Hz), 6,77 (1H, d, J=3,9 Hz), at 6.84 (1H, d, J=2.0 Hz), 6,98 (1H, s), to 7.09 (2H, d, J=6.8 Hz), 7,71 (2H, d, J=9,3 Hz).

MS (FAB) m/z: 569,2418 (M+H)+.

Example 117

(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenoxy}phenoxy)propan-1-ol

(117a) 3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-Digi the ro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol

3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (60 mg, 0.18 mmol)synthesized in example (116d), dissolved in methylene chloride (4 ml)to the solution at-78ºC under nitrogen atmosphere add tribromide (boron solution in methylene chloride, 1.0 mol/l to 0.38 ml, 0,38 mmol). After this mixture is allowed to warm to room temperature and the resulting mixture is stirred for 1 hour. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: hexane/ethyl acetate=50%-70%), obtaining the target compound (41 mg, yield 72%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), for 1.49 (3H, d, J=5,9 Hz), 3,66-of 3.78 (3H, m)to 4.23 (1H, DD, J=13,7, 9,3 Hz)to 4.52 (1H, DDD, J=14,4, 8,1, 4.6 Hz), is 4.93 (1H, DQC, J=17,7, 5.0 Hz), 6,32 (1H, t, J=2.0 Hz), 6.48 in (1H, d, J=3,9 Hz), of 6.71 (1H, s), 6,77 (1H, d, J=3,4 Hz), 7,11 (1H, s), 11,09 (1H, s).

(117b) (2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenoxy}phenoxy)propan-1-ol

3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (40 mg, 0.13 mmol)synthesized in p is the iMER (117a), and 1-[(4-forfinal)sulfonyl]-4-methylpiperazine (49 mg, 0,19 mmol)synthesized in example (116a), dissolved in N,N-dimethylformamide (2 ml), the resulting solution was added potassium carbonate (52 mg, 0.38 mmol) and the mixture is stirred for 4 hours at 100°C in nitrogen atmosphere. The reaction solution is cooled to room temperature, to the solution was added water (10 ml) and the resulting mixture was extracted twice with ethyl acetate (10 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (17 mg, yield 25%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=6.3 Hz), 2,28 (3H, s), 2,48 is 2.51 (4H, USM), 3,03 (4H, USS), 3,55 (1H, DD, J=13,9, 7,2 Hz), of 3.77 (2H, d, J=5,1 Hz), 4.09 to (1H, DD, J=14,1, and 9.4 Hz), 4,55-4,60 (1H, m,), 4,87-to 4.81 (1H, m), 6.42 per (1H, s), of 6.50 (1H, d, J=3,9 Hz), 6,76 (1H, d, J=3.5 Hz), 6,83 (1H, s), to 6.95 (1H, s), 7,07 (2H, d, J=8.6 Hz), of 7.70 (2H, d, J=8.6 Hz).

MS (FAB) m/z: 555,2271 (M+H)+.

Example 118

(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridazin-3-yl]oxy}phenoxy)propan-1-ol

(118a) 6-Chloropyridazine-3-thiol

In nitrogen atmosphere dichloropyridazin (1,00 g of 6.71 mmol) dissolved the methanol (20 ml), to the solution add 10-20% aqueous solution of potassium hydrosulfide (20 ml) and the resulting mixture is refluxed for 2 hours. The solvent is distilled off under reduced pressure, the residue diluted with water and the mixture is neutralized 1 N. hydrochloric acid. The resulting yellow precipitate is removed by filtration, washed with water and hexane, then dried in vacuum, obtaining the target compound (500 mg, 51%yield) as a solid yellow color.

1H-NMR (CDCl3, 400 MHz): δ 7,00 (1H, d, J=9.4 Hz), 7,60 (1H, d, J=9.4 Hz), 11,68 (1H, USS).

(118b) 3-Chloro-6-(methylthio)pyridazine

6-Chloropyridazine-3-thiol (500 mg, 3,41 mmol)synthesized in example (118a), dissolved in methanol (20 ml), add sodium methoxide (203 mg, 3.75 mmol) and jodean (234 ml, 3.75 mmol) and the resulting mixture was stirred at 60°C for 30 minutes in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (50 ml) and the resulting mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-50%)to give the target compound (515 mg, yield 94%) as a solid yellow color.

1H-NMR (CDCl 3, 400 MHz): δ a 2.71 (3H, s), 7,25 (1H, d, J=9.6 Hz), 7,30 (1H, d, J=9.0 Hz).

(118c) 3-Chloro-6-(methylsulphonyl)pyridazin

3-Chloro-6-(methylthio)pyridazine (90 mg, 0.50 mmol)synthesized in example (118b), dissolved in methylene chloride (10 ml), the resulting solution was added m-chloroperbenzoic acid (220 mg, 1.00 mmol) and the resulting mixture was stirred at 0°C for 30 minutes. To the reaction solution was added water (20 ml) and the resulting mixture is extracted twice with methylene chloride (10 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-100%)to give the target compound (77 mg, 71%yield) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 3.45 (3H, s), 7,81 (1H, d, J=8,2 Hz), 8,16 (1H, d, J=8,4 Hz).

(118d) 3-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-6-(methylsulphonyl)pyridazin

3-Chloro-6-(methylsulphonyl)pyridazin (41 mg, 0.27 mmol)synthesized in example (118c), and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (80 mg, 0.24 mmol)synthesized in example (116d), dissolved in acetonitrile (2 ml)to the resulting solution was added cesium carbonate (158 mg, 0,48 IMO the b) and the resulting mixture is stirred for 1 hour in nitrogen atmosphere. To the reaction solution was added water (10 ml) and the mixture extracted with ethyl acetate (10 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-4%), obtaining the target compound (116 mg, yield 98%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), of 1.42 (3H, d, J=6.3 Hz), 3,40 (3H, s), 3,42 (3H, s), 3,48-3,62 (3H, m), 4,07 (1H, DD, J=13,9, 9,2 Hz), 4,58 (1H, TD, J=6,2, 4,4 Hz), 4,82 (1H, dt, J=11,7, 4.6 Hz), 6,50 (1H, d, J=3.5 Hz), 6,69 (1H, t, J=2.2 Hz), 6,74 (1H, d, J=3,9 Hz), 6,99 (1H, q, J=2.0 Hz), to 7.09 (1H, t, J=1,8 Hz), 7,40 (1H, d, J=9.0 Hz), 8,17 (1H, d, J=9.0 Hz).

(118e) (2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridazin-3-yl]oxy}phenoxy)propan-1-ol

3-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-6-(methylsulphonyl)pyridazin (116 mg, 0.24 mmol)synthesized in example (118d), dissolved in methylene chloride (5 ml)to the resulting solution at-78ºC under nitrogen atmosphere add tribromide boron (solution in methylene chloride, 1.0 mol/l of 0.26 ml, 0.26 mmol). After this mixture allow to warm to room temperature, then stirred for 4 hours. To the reaction solution was added saturated aqueous RA is solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (100 mg, yield 89%) as a solid white color.

1H-NMR (CDCl3, 400 MHz) δ of 1.30 (3H, d, J=6.3 Hz), of 1.41 (3H, d, J=6.3 Hz), 3,39 (3H, s), 3,53 (1H, DD, J=13,7, 7,4 Hz), 3,76-of 3.77 (2H, m), 4,07 (1H, DD, J=13,9, 9,2 Hz), 4,56 (1H, DD, J=10,8, 6,1 Hz), 4,82 (1H, dt, J=12,0, 4.6 Hz), 6,47 (1H, d, J=3.5 Hz), is 6.61 (1H, t, J=2.2 Hz), 6,74 (1H, d, J=3,9 Hz), of 6.99 (1H, t, J=1.6 Hz), 7,03 (1H, t, J=1.6 Hz), 7,39 (1H, d, J=9.4 Hz), 8,16 (1H, d, J=9.4 Hz).

MS (ESI) m/z: 473,15056 (M+H)+.

Example 119

2-(Azetidin-1-ylsulphonyl)-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine

(119a) 5-Chloropyridin-2-thiol

In nitrogen atmosphere for 2.5-dichloropyridine (5,00 g, 33.8 mmol) was dissolved in dimethyl sulfoxide (35 ml), the solution add nonahydrate disulfide sodium (9.00 g, is 37.2 mmol) and the resulting mixture was stirred at 120°C for 2 hours. The reaction solution is cooled to room temperature, add water (50 ml) and the reaction solution is neutralized 5 N. hydrochloric acid. The resulting precipitate is collected by filtration, washed with water and hexane, and then the obtained solid product was then purified to lodochnoy chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-10%), obtaining the target compound (2.28 g, yield 46%) as a solid yellow color.

1H NMR (CDCl3, 400 MHz) δ 2,63 (1H, s), 7,34 (1H, DD, J=9,0, 2.2 Hz), 7,41 (1H, d, J=9.3 Hz), of 7.70 (1H, s).

(119b) 2-(Azetidin-1-ylsulphonyl)-5-chloropyridin

5-Chloropyridin-2-thiol (1,00 g, 6,87 mmol)synthesized in example (119a), dissolved in methylene chloride (30 ml) and 1 N. hydrochloric acid (30 ml) and the resulting solution was cooled to -5°C. To the reaction solution was cooled in an ice bath to 0°C, are added dropwise 7% aqueous solution of sodium perchlorate (30 ml), maintaining the temperature at 0°C or below, and the resulting Smeg stirred for 15 minutes. The organic layer is extracted with pre-cooled by the ice separating funnel and cooled to -78°C, add a solution in methylene chloride (10 ml) of commercially available hydrochloride of azetidine (2,24 mg of 17.7 mmol) and triethylamine (1.8 ml, 12.9 mmol), the mixture allow to warm to 0°C and the resulting mixture is stirred for 30 minutes. To the reaction solution was added water (50 ml) and the resulting mixture was extracted twice with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column of chromatographie is (silica gel, eluting solvent: ethyl acetate/hexane=5%-60%), obtaining the target compound (735 mg, yield 46%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 2,19 was 2.25 (2H, m), 4,10 (4H, t, J=7.8 Hz), to $ 7.91 (1H, DD, J=8,3, 2.0 Hz), 7,95 (1H, d, J=7.8 Hz), 8,72 (1H, d, J=2.0 Hz).

(119c) 2-(Azetidin-1-ylsulphonyl)-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine

2-(Azetidin-1-ylsulphonyl)-5-chloropyridin (170 mg, 0.73 mmol)synthesized in example (119b), and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (230 mg, 0.70 mmol)synthesized in example (116d), dissolved in N,N-dimethylformamide (3.5 ml)solution was added cesium carbonate (454 mg, of 1.39 mmol) and the resulting mixture for 2 hours, stirred at 100°C in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (20 ml) and the resulting mixture was extracted twice with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=5%-50%)to give the target compound (273 mg, 75%yield) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), USD 1.43 (3H,d, J=6.3 Hz), 2,18-of 2.24 (2H, m), 3,42 (3H, s), 3,49-3,61 (3H, m, 4,10 (4H, t, J=7,6 Hz), 4,56-to 4.62 (1H, m), 4,82-a 4.86 (1H, m), 6,51 (1H, d, J=3,9 Hz), to 6.58 (1H, t, J=2.0 Hz), 6,76 (1H, d, J=3,9 Hz), to 6.88 (1H with),? 7.04 baby mortality (1H, s), the 7.43 (1H, DD, J=8,8, 2,9 Hz), 7,94 (1H, d, J=8,8 Hz), 8,53 (1H, d, J=2,9 Hz).

MS (ESI) m/z: 527,20527 (M+H)+.

Example 120

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-sulfonamide

(120a) 5-Chloro-N-(4-methoxybenzyl)pyridine-2-sulfonamide

5-Chloropyridin-2-thiol (1,00 g, 6,87 mmol)synthesized in example (119a), dissolved in a mixture of methylene chloride (30 ml)/1 N. hydrochloric acid (30 ml) and the resulting solution was cooled to -5°C. To the reaction solution are added dropwise cooled in an ice bath 7% aqueous solution of sodium perchlorate (35 ml), maintaining the temperature of the mixture at 0°C or below, and the resulting mixture is stirred for 15 minutes. The organic layer is extracted with pre-cooled by the ice separating funnel and cooled to -78°C, add commercially available 4-methoxybenzylamine (2,24 ml of 17.7 mmol), the mixture allow to warm to 0°C and stirred for 30 minutes. To the reaction solution was added 0.1 G. of hydrochloric acid (30 ml) and the resulting mixture is extracted twice with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. Races shall foretell distilled off under reduced pressure, and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=5%-100%)to give the target compound (983 mg, yield 46%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 3.78 (3H, s), 4,20 (2H, d, J=6.3 Hz), 5,07 (1H, s), 6,79 (2H, dt, J=9,4, 2,5 Hz), 7,14 (2H, d, J=8.6 Hz), 7,83 (1H, DD, J=8,6, and 2.3 Hz), of 7.90 (1H, d, J=7.8 Hz), at 8.60 (1H, DD, J=2,3, 0.8 Hz).

(120b) of 5-Chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide

5-Chloro-N-(4-methoxybenzyl)pyridine-2-sulfonamide (983 mg, 3.14 mmol)synthesized in example (120a), dissolved in N,N-dimethylformamide (5 ml) and to the solution was added sodium hydride (132 mg, 3,30 mmol). After cooling with ice add p-methoxybenzylamine (of 1.02 ml, 3,37 mmol), the mixture allow to warm to room temperature and stirred the mixture for 2 hours. To the reaction solution was added water (20 ml) and the resulting mixture was extracted twice with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-100%)to give the target compound (1,14 g, yield 84%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 3.78 (6H, s), and 4.40 (4H, s), 6.75 in (4H, dt, J=9,3/2,5 Hz), 7,05 (4H, dt, J=8,2, 20 Hz), for 7.78 (1H, DD, J=8,2, 2.3 Hz), to 7.84 (1H, d, J=7.8 Hz), 8,55 (1H, d, J=2.7 Hz).

(120c) N,N-Bis(4-methoxybenzyl)-5-(3-[(1S)-2-methoxy-l-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-sulfonamide

5-Chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (288 mg, 0.67 mmol)synthesized in example (120b), and 3-[(lS)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (220 mg, 0.67 mmol)synthesized in example (116d), dissolved in N,N-dimethylformamide (3 ml)solution was added cesium carbonate (434 mg, of 1.33 mmol) and the resulting mixture for 1 hour and stirred at 100°C in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (20 ml) and the resulting mixture was extracted twice with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0,5%-5%)to give the target compound (160 mg, yield 33%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=5,9 Hz), USD 1.43 (3H, d, J=6.3 Hz), 3,42 (3H, s), 3,50-3,62 (3H, m), of 3.77 (6H, s), 4.09 to (1H, DD, J=13,9, 9,0 Hz)to 4.41 (4H, s), 4,56-4,63 (1H, m), 4,81-a 4.86 (1H, m), of 6.52 (1H, d, J=3,9 Hz), 6,56 (1H, t, J=2.0 Hz), 6,76 (4H, d, J=8,8 Hz), 7,07 (4H, d, J=8,8 Hz), 7,33 (1H, DD, J=8,5, 2.7 Hz), 7,88 (1H, d, J=88 Hz), 8,39 (1H, d, J=2,9 Hz).

(120d) 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-sulfonamide

N,N-Bis(4-methoxybenzyl)-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-sulfonamide (160 mg, 0.24 mmol)synthesized in example (120c), dissolved in triperoxonane acid (2 ml) and the mixture was stirred at 40°C for 8 hours. The solvent is distilled off under reduced pressure, to the residue in small portions, add methylene chloride and triethylamine and the solvent again removed under reduced pressure. The resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (106 mg, yield 99%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 1.42 (3H, d, J=5,9 Hz), 3,42 (3H, s), 3,49-of 3.53 (2H, m)and 3.59 (1H, DD, J=10,3, 5,9 Hz), of 4.05 (1H, DD, J=14,2, and 9.3 Hz), 4,55-br4.61 (1H, m), 4,79-a 4.86 (1H, m), and 5.30 (2H, USS), 6,50 (1H, d, J=3,9 Hz), 6,56 (1H, t, J=2.2 Hz), to 6.75 (1H, d, J=3,9 Hz), 6,85 (1H, t, J=1.7 Hz), 7,03 (1H, t, J=1.7 Hz), 7,42 (1H, DD, J=8,5, 2.7 Hz), 7,95 (1H, d, J=8,8 Hz), 8,42 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 487,16619 (M+H)+.

Example 121

5-(3-[(1S)-2-Methoxy-l-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-sulfonamide

(121a) 5-Chloro-N-methylpyridine-2-sulfonamide

5-lipiridy-2-thiol (1,00 g, 6,87 mmol)synthesized in example (119a), dissolved in a mixture of methylene chloride (30 ml)/1 N. hydrochloric acid (30 ml) and the resulting solution was cooled to -5°C. To the reaction solution are added dropwise ice 7% aqueous solution of sodium perchlorate (30 ml)maintaining the temperature of the mixture at 0°C or below, and the resulting mixture is stirred for 15 minutes. The organic layer is extracted in a separating funnel, pre-cooled with ice, and cooled to -78°C, add methylenechloride solution (10 ml) of a commercially available solution of 40% methylamine/methanol (1,33 ml, and 17.2 mmol) and the mixture allow to warm to 0°C, and the resulting mixture is stirred for 2 hours. To the reaction solution was added water (50 ml) and the resulting mixture was extracted twice with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=30%-80%), obtaining the target compound (889 mg, yield 63%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 2,77 (3H, d, J=4.9 Hz), to 4.81 (1H, s), of 7.90 (1H, DD, J=8,3, 2.4 Hz), of 7.97 (1H, d, J=8,3 Hz), 8,65 (1H, d, J=2,4 Hz).

(121b) 5-Chloro-N-(4-methoxybenzyl)-N-methylpyridin-2-sulfonamide

5-Chloro-N-methylpyridin-2-Sul is foamed (889 mg, 4.30 mmol)synthesized in example (121a), dissolved in N,N-dimethylformamide (15 ml) and to the solution was added sodium hydride (172 mg, 4.30 mmol). After cooling in an ice bath, the solution was added p-methoxybenzylamine (0,70 ml, 5,16 mmol), the mixture allow to warm to room temperature and then stirred the mixture for 3 hours. To the reaction solution was added water (20 ml) and the resulting mixture was extracted twice with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-20%)to give the target compound (817 mg, yield 58%) as a colourless oil.

1H-NMR (CDCl3, 400 MHz): δ and 2.79 (3H, s), 3,81 (3H, s), 4,36 (2H, s), 6.87 in (2H, dt, J=9,4, 2.4 Hz), 7,25 (2H, d, J=7,3 Hz), 7,88 (1H, DD, J=8,3, 2.4 Hz), 7,94 (1H, d, J=8,3 Hz), 8,66 (1H, d, J=2,4 Hz).

(121c) N-(4-Methoxybenzyl)-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-sulfonamide

5-Chloro-N-(4-methoxybenzyl)-N-methylpyridin-2-sulfonamide (228 mg, 0.70 mmol)synthesized in example (121b), and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-lH-pyrrol-2-yl}phenol (220 mg, 0.67 mmol)synthesized in example (116d), dissolved in N,N (3 ml), to the solution was added cesium carbonate (434 mg, of 1.33 mmol) and the resulting mixture was stirred at 100°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (20 ml) and the resulting mixture was extracted twice with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0,5%-5%)to give the target compound (293 mg, 71%yield) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=5,9 Hz), and 2.79 (3H, s), 3,42 (3H, s), 3,49-3,61 (3H, m), 3,81 (3H, s)4,08 (1H, DD, J=13,7, and 9.3 Hz), 4,37 (2H, s), 4,55-to 4.62 (1H, m), 4.80 to to 4.87 (1H, m), 6,51 (1H, d, J=3,9 Hz), to 6.57 (1H, t, J=2.2 Hz), to 6.75 (1H, d, J=3,9 Hz), 6.87 in-6,89 (3H, m), 7,03 (1H, s), 7,28 (2H, d, J=8,8 Hz), 7,41 (1H, DD, J=8,5, 2.7 Hz), 7,94 (1H, d, J=8,3 Hz), of 8.47 (1H, d, J=2.4 Hz).

(121d) 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-sulfonamide

N-(4-Methoxybenzyl)-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-sulfonamide (292 mg, 0.47 mmol)synthesized in example (121c), dissolved in triperoxonane acid (2 ml) and the resulting solution was stirred at 45°C for 1 casabalance distilled off under reduced pressure, to the residue in small portions, add methylene chloride and triethylamine, and the solvent is again distilled off under reduced pressure. The resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-4%), obtaining the target compound (208 mg, yield 88%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=5,9 Hz), USD 1.43 (3H, d, J=6.3 Hz), was 2.76 (3H, s)to 3.41 (3H, s), 3,49-3,61 (3H, m), 4,08 (1H, DD, J=a 13.9, 9.0 Hz), br4.61-4,55 (1H, m), 4,84 (1H, DD, J=15,1, 7,3 Hz), 6,50 (1H, d, J=3,9 Hz), 6,56 (1H, t, J=2.2 Hz), 6,76 (1H, d, J=3,9 Hz)6,86 (1H, s),? 7.04 baby mortality (1H, s), 7,41 (1H, DD, J=8,5, 2.7 Hz), of 7.96 (1H, d, J=8,8 Hz), to 8.45 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 501,18090 (M+H)+.

Example 122

5-(3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-sulfonamide

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-sulfonamide (166 mg, 0.32 mmol)synthesized in example (121d), dissolved in methylene chloride (5 ml)to the resulting solution at-78ºC under nitrogen atmosphere add tribromide boron (solution in methylene chloride, 1.0 mol/l to 0.34 ml, 0.34 mmol). The mixture allow to warm to room temperature, and the mixture is then stirred for 1.5 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and the mixture is extracted with methylene chloride. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-4%), obtaining the target compound (119 mg, yield 78%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.30 (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=6.8 Hz), a 2.75 (3H, s), of 3.54 (1H, DD, J=13,7, 7,3 Hz), 3.75 to of 3.77 (2H, m), 4,08 (1H, DD, J=9,3, of 13.7 Hz), to 4.52-4,58 (1H, m), 4,81-4,88 (1H, m), to 6.43 (1H, s), 6,47 (1H, d, J=3,9 Hz), to 6.75 (1H, d, J=4.4 Hz), 6,83 (1H, s), 7,00 (1H, s), 7,39 (1H, DD, J=8,8, 2.0 Hz), 7,95 (1H, d, J=8,8 Hz), 8,39 (1H, s).

MS (ESI) m/z: 487,16369 (M+H)+.

Example 123

5-(3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-carboxamide

(123a) 5-fluoro-N-methylpyridin-2-carboxamide

5-Herperidin-2-carboxylic acid (495 mg, 3,51 mmol) dissolved in methylene chloride (10 ml)solution was added HOBt·H2O (591 mg, 3,86 mmol), WSCI·HCl (1.35 g, 7,02 mmol), triethylamine (2,44 ml, 17.5 mmol) and a solution of 40% methylamine/methanol (0,82 ml, 10.5 mmol) and the resulting mixture is stirred for 15 hours. To the reaction solution was added water (30 ml) and the resulting mixture is extracted twice with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous Sul is blockhead magnesium. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-50%)to give the target compound (490 mg, yield 91%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 3,03 (3H, d, J=5.5 Hz), 7,53 (1H, dt, J=2.7, and 8.6 Hz), the 7.85 (1H, USS), 8,24 (1H, DD, J=8,2, a 4.7 Hz), scored 8.38 (1H, d, J=2.7 Hz).

(123b) 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[ (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-carboxamide

5-fluoro-N-methylpyridin-2-carboxamide (122 mg, 0.79, which mmol)synthesized in example (123a), and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (275 mg, 0.83 mmol)synthesized in example (116d), dissolved in N,N-dimethylformamide (3 ml), to the solution was added potassium carbonate (219 mg, was 1.58 mmol) and the resulting mixture was stirred at 100°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (30 ml) and the resulting mixture was extracted twice with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%), receiving the target link is (283 mg, yield 77%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 1.42 (3H, d, J=6.3 Hz), 3,03 (3H, d, J=5,1 Hz)to 3.41 (3H, s), 3,48-3,61 (3H, m), 4,08 (1H, DD, J=13,9, 9,2 Hz), 4.53-in-4,60 (1H, m), 4.80 to a 4.86 (1H, m), of 6.49 (1H, d, J=3,9 Hz), 6,53 (1H, t, J=2.2 Hz), 6,74 (1H, d, J=3.5 Hz), 6,83 (1H, d, J=1.6 Hz), 7,00 (1H, s), 7,41 (1H, DD, J=8,6, 2.7 Hz), 7,86 (1H, USS), 8,17 (1H, d, J=8.6 Hz), 8,31 (1H, d, J=2.7 Hz).

(123c) 5-(3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-carboxamide

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridin-2-carboxamide (176 mg, 0.38 mmol)synthesized in example (123b), dissolved in methylene chloride (5 ml)to the resulting solution at-78ºC add tribromide (boron solution in methylene chloride, 1.0 mol/l and 0.50 ml, 0.50 mmol). After this mixture allow to warm to room temperature and the mixture is stirred for 1 hour. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (118 mg, yield 69%) in the form of solid substances is TBA white.

1H-NMR (CDCl3, 400 MHz): δ of 1.28 (3H, d, J=5,9 Hz), of 1.42 (3H, d, J=6.3 Hz), 3,03 (3H, d, J=5,1 Hz), of 3.54 (1H, DD, J=13,9, 7,2 Hz), 3,76 (2H, d, J=4,7 Hz), 4,07 (1H, DD, J=13,9, 9,2 Hz), of 4.57 (1H, DD, J=ll,l and 6.1 Hz), a 4.83 (1H, dt, J=11,7, 4.6 Hz), 6,38 (1H, s), of 6.45 (1H, d, J=3.5 Hz), was 6.73 (1H, d, J=3,9 Hz), to 6.80 (1H, s), 6,93 (1H, s), 7,35 (1H, DD, J=8,6, 2.7 Hz), 7,87 (1H, d, J=5.5 Hz), 8,15 (1H, d, J=8.6 Hz), of 8.27 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 451,19720 (M+H)+.

Example 124

5-(3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyrazine-2-carboxamide

(124a) 5-Chloro-N-methylpyrazine-2-carboxamide

5-Chloropyrazine-2-carboxylic acid (1,99 g, 12.6 mmol) was dissolved in N,N-dimethylformamide (10 ml)solution was added HOBt·H2(591 mg, 3,86 mmol), WSCI·HCl (1.35 g, 7,02 mmol), N-methylmorpholin (2.76 ml of 25.1 mmol) and 40% methylamine/methanol (2,92 ml of 37.6 mmol) and the resulting mixture stirred for 18 hours. To the reaction solution was added water (50 ml) and the resulting mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-75%), obtaining the target compound (585 mg, yield 27%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 303 (3H, d, J=4.9 Hz), 7,60 (1H, USS), of 8.09 (1H, d, J=1.5 Hz), 8,93 (1H, d, J=1.0 Hz).

(124b) 5-(3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyrazine-2-carboxamide

5-Chloro-N-methylpyrazine-2-carboxamide (171 mg, 1.00 mmol)synthesized in example (124a) and 3-[(1S)-2-methoxy-l-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (300 mg, of 0.91 mmol)synthesized in example (116d), dissolved in N,N-dimethylformamide (3 ml), to the solution was added potassium carbonate (376 mg, of 2.72 mmol) and the resulting mixture was stirred at 100°C for 5 hours in nitrogen atmosphere. To the reaction solution was added 5-chloro-N-methylpyrazine-2-carboxamide (110 mg, 0.64 mmol) and the mixture is stirred for 3 hours. The reaction solution is cooled to room temperature, add water (30 ml) and the resulting mixture was extracted twice with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give product as a solid white (206 mg).

The obtained product is dissolved in methylene chloride (5 ml) and to the resulting solution at -78°C add tribromide (boron solution in methylene chloride, 1.0 mol/l, 0,57 is l, of 0.57 mmol). After this mixture allow to warm to room temperature and the resulting mixture is stirred for 1.5 hours. The reaction solution was again cooled to -78°C, to a solution add tribromide (boron solution in methylene chloride, 1.0 mol/l of 1.00 ml, 1.00 mmol), then the mixture allow to warm to room temperature and the mixture is then stirred for 3 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with methylene chloride. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (87,8 mg, yield 21%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=5,9 Hz), USD 1.43 (3H, d, J=6.3 Hz), 3,05 (3H, d, J=5.4 Hz), 3,55 (1H, DD, J=13,9, a 7.6 Hz), of 3.77 (2H, d, J=5.4 Hz), 4.09 to (1H, DD, J=a 13.9, 9.0 Hz), 4,56 (1H, DD, J=11,2, 5,9 Hz), 4,87-4,80 (1H, m), of 6.49 (1H, d, J=3,4 Hz), 6,60 (1H, s), of 6.75 (1H, d, J=3,9 Hz), 6,93 (1H, s), 7,00 (1H, s), a 7.62 (1H, d, J=4.9 Hz), 8,29 (1H, s), 8,93 (1H, d, J=1.0 Hz).

MS (ESI) m/z: 452,19252 (M+H)+.

Example 125

{(5R)-2-[5-(3-{[6-(Cyclopropanesulfonyl)pyridine-3-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

(125a) 5-Chloro-2-[(3-chloropropyl)thio]pyridine

5-Chloropyridin-2-thiol (600 mg, 4,12 mmol)synthesized in example (119a), dissolved in methanol (15 ml), to the solution was added 28% solution of sodium methoxide in methanol (0.95 ml, 4,94 mmol) and 1-bromo-3-chloropropane (and 0.61 ml, 6,18 mmol) and the resulting mixture was stirred at 60°C for 1.5 hours. The reaction solution is cooled to room temperature, add water (40 ml) and the resulting mixture was extracted twice with ethyl acetate (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and dried in vacuum, obtaining the target compound (849 mg, yield 92%) as a colourless oil.

1H-NMR (CDCl3, 400 MHz): δ 2.26 and-2,31 (2H, m), 3,55-to 3.58 (2H, m)to 3.67 (2H, t, J=6.3 Hz), of 7.96 (1H, DD, J=8,3, 2.0 Hz), of 8.06 (1H, d, J=7.8 Hz), to 8.70 (1H, d, J=2,4 Hz).

(125b) 5-Chloro-2-[(3-chlorpropyl)sulfonyl]pyridine

5-Chloro-2-[(3-chloropropyl)thio]pyridine (846 mg, of 3.80 mmol)synthesized in example (125a), dissolved in methylene chloride (20 ml), the resulting solution was cooled in an ice bath, the solution was added m-chloroperbenzoic acid (2,02 g, 7.62 mmol) and the resulting mixture is stirred for 1 hour. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (40 ml) and the resulting mixture is extracted twice with methylene chloride (40 ml). The organic layer washed the Ute saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-20%)to give the target compound (733 mg, yield 76%) as a colourless oil.

1H-NMR (CDCl3, 400 MHz): δ 2.21 are to 2.14 (2H, m), 3,30 (2H, t, J=6.8 Hz), to 3.67 (2H, t, J=6.3 Hz), 7,13 (1H, DD, J=8,6, and 0.8 Hz), was 7.45 (1H, DD, J=8,6, and 2.3 Hz), of 8.37 (1H, DD, J=5,1, 3.1 Hz).

(125c) 5-Chloro-2-(cyclopropanesulfonyl)pyridine

5-Chloro-2-[(3-chlorpropyl)sulfonyl]pyridine (732 mg, of 3.05 mmol)synthesized in example (125b), dissolved in tetrahydrofuran (10 ml), the solution is cooled to -30°C, the solution was added tert-piperonyl potassium (582 mg, 5.18 mmol) and the resulting mixture is stirred for 30 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride (40 ml) and the resulting mixture is extracted twice with methylene chloride (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-25%), obtaining the target compound (397 mg, yield 60%).

1H-NMR (CDCl3, 400 MHz): δ 1,07 by 1.12 (2H, m), 1,37-of 1.41 (2H, m), was 2.76-and 2.83 (1H, m), to $ 7.91 (1H, DD, J=8,2, 2.3 Hz), 7,98 (1H, d, J=8,2 Hz), 8,71 (1H, DD, J=2,3, 0.8 Hz).

(125d) N-[(2S)-2,3-Dihydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methyl is toxi]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-carboxamide

5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (to 9.32 g of 20.8 mmol)synthesized in example (106c), dissolved in methanol (200 ml)solution was added (S)-(-)-3-amino-1,2-propandiol (5,01 g, 55,0 mmol) and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-the triazine-2-yl)-4-methylmorpholine (10,13 g, and 32.3 mmol) and the resulting mixture during the night stirred at room temperature under nitrogen atmosphere. The solvent is distilled off under reduced pressure, to the obtained residue, add water (300 ml) and ethyl acetate (200 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=70%-100%)to give the target product (to 9.32 g, yield 86%) as a colourless oil.

1H-NMR (CDCl3, 400 Hz): δ is 1.11 (18H, d, J=7,0 Hz), 1,22-of 1.29 (3H, m)is 1.31 (3H, d, J=6.3 Hz), 3,07-3,14 (2H, m), 3,42 (3H, s), 3,50 (1H, DD, J=10,2, a 4.3 Hz), 3,54-3,66 (5H, m), 3,83-are 3.90 (1H, m), 4,49-of 4.57 (1H, m), 6,34 (1H, t, J=6.5 Hz), 6.42 per (1H, t, J=2.3 Hz), 6,46 (1H, DD, J-3,9, 2.7 Hz), 6,63 (1H, DD, J=3,9, and 2.3 Hz), to 6.67 (1H, t, J=1.6 Hz), was 6.73 (1H, t, J=1.6 Hz), of 9.55 (1H, USS).

(125e) of N-{(2S)-2-Hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-carboxamide

N-[(2S)-2,3-Dihydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(carisopro ililil)oxy]phenyl}-1H-pyrrol-2-carboxamide (of 9.30 g, of 17.9 mmol)synthesized in example (125d), dissolved in methylene chloride (180 ml)to the solution add triisopropylsilane (4,25 ml, to 19.9 mmol), triethylamine (7,45 ml of 53.5 mmol) and 4-dimethylaminopyridine (2.20 g, 18.0 mmol) and the resulting mixture was stirred at room temperature for 2.5 hours under nitrogen atmosphere. To the reaction solution was added water (300 ml), the organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=10%-35%), obtaining the target compound (10,56 g, yield 87%) as a colourless oil.

1H-NMR (CDCl3, 400 Hz): δ 1.18 to 1,06 (39H, m), 1,22-of 1.30 (3H, m)of 1.32 (3H, d, J=6.3 Hz), 3,20 (1H, d, J=4.3 Hz), 3,38-3,44 (1H, m), 3,42 (3H, s), 3,49 (1H, DD, J=10,2, a 4.3 Hz)and 3.59 (1H, DD, J=10,2, 5,5 Hz), 3,66-with 3.79 (3H, m), 3,85-3,91 (1H, m), 4,49-4,56 (1H, m), 6,30 (1H, t, J=5,9 Hz), 6,41 (1H, t, J=2.0 Hz), 6,45 (1H, DD, J=3,9, 2.7 Hz), 6,59 (1H, DD, J-3,9, and 2.3 Hz), 6,66 (1H, t, J=2.0 Hz), 6,72 (1H, t, J=2.0 Hz), 9,34 (1H, USS).

(125f) (5R)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-yl)-5{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol

N-{(2S)-2-Hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-carboxamide (10,54 g, 15.6 mmol)synthesized in example (125e), dissolved in whom tetrahydrofurane (160 ml), to the solution was added anhydrous methansulfonate acid (5,51 g of 31.6 mmol) and triethylamine (8,70 ml of 62.4 mmol) and the resulting mixture for 3 hours, stirred at room temperature under nitrogen atmosphere, then the mixture is heated to 60°C and then stirred for 3 hours. To the reaction solution was added water (200 ml) and the mixture extracted with ethyl acetate (300 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=5%-30%)to give the target compound (9,72 g, yield 95%) as a brown oil.

1H-NMR (CDCl3, 400 Hz): δ 1.04 million-1,14 (39H, m), 1,22-of 1.29 (3H, m)of 1.32 (3H, d, J=6.3 Hz), 3,42 (3H, s), of 3.48 (1H, DD, J=10,2, a 4.3 Hz)and 3.59 (1H, DD, J=10,2, 5,9 Hz), 3,85-are 3.90 (3H, m), was 4.02 (1H, DD, J=14,1, 9.8 Hz), 4,48-of 4.54 (1H, m), 4,72-4,78 (1H, m), to 6.39 (1H, t, J=2.0 Hz), of 6.45 (1H, d, J=3,9 Hz), to 6.67 (1H, t, J=2.0 Hz), of 6.71 (1H, t, J=2.0 Hz), was 6.73 (1H, d, J=3,9 Hz).

(125g) 3-{5-[(5R)-5-(Hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol

(5R)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-yl)-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol (RS 9.69 g, 14.7 mmol)synthesized in example (125f), dissolved in tetrahydrofuran (150 ml)to the solution at 0°C is added dropwise ft the reed tetrabutylammonium (solution in tetrahydrofuran, 1 mol/l, and 30.0 ml, 30 mmol) and the resulting mixture was stirred at 0°C for 30 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride (200 ml) and the mixture extracted with ethyl acetate (200 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=3%-7%), obtaining the target compound (6.50 g, yield ~100%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 Hz): δ is 1.31 (3H, d, J=6.3 Hz), to 3.41 (3H, s), of 3.48 (1H, DD, J=10,2, a 4.3 Hz), to 3.58 (1H, DD, J=10,2, 5,9 Hz), of 3.78 (1H, DD, J=12,5, 5,5 Hz), 3,92-of 3.97 (2H, m), of 4.12 (1H, DD, J=13,7, 9.8 Hz), 4,51-4,59 (1H, m), 4,88-4,94 (1H, m), to 6.39 (1H, t, J=2.0 Hz), 6,47 (1H, d, J=3.5 Hz), 6,72 (1H, s), PC 6.82 (1H, d, J=3,9 Hz), 7,06 (1H, s)11,05 (1H, USS).

(125h) {(5R)-2-[5-(3-{[6-(Cyclopropanesulfonyl)pyridine-3-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol

5-Chloro-2-(cyclopropanesulfonyl)pyridine (168 mg, 0.77 mmol)synthesized in example (125c), and 3-{5-[(5R)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (401 mg, of 1.16 mmol)synthesized in example (125g), dissolved in N,N-dimethylformamide (2 ml), to the solution was added potassium carbonate (213 mg, 154 mmol) and the resulting mixture for 3 hours AC who're asked at 100°C in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (30 ml) and the resulting mixture was extracted twice with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0,5%-5%)to give the target compound (139 mg, yield 34%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1.06 a-1,11 (2H, m)is 1.31 (3H, d, J=6.3 Hz), 1,37-of 1.41 (2H, m), was 2.76-and 2.83 (1H, m), 3,42 (3H, d, J=2.3 Hz), 3,50 (1H, DD, J=10,2, 3,9 Hz)and 3.59 (1H, DD, J=10,2, 6.3 Hz), 3,68-with 3.79 (2H, m), a 3.87 (1H, DD, J=12,3, 2,9 Hz), a 4.03 (1H, DD, J=14,1, 9.8 Hz), 4,60-a 4.53 (1H, m), 4,84-of 4.77 (1H, m), of 6.49 (1H, d, J=3,9 Hz), to 6.57 (1H, t, J=2.2 Hz), to 6.75 (1H, d, J=3,9 Hz)6,86 (1H, t, J=1,8 Hz), 7,03 (1H, s), 7,42 (1H, DD, J=8,6, 2.7 Hz), of 7.97 (1H, d, J=8.6 Hz), 8,51 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 528,17975 (M+H)+.

Example 126

5-(3-{5-[(5R)-5-(Hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-N-methylpyridin-2-carboxamide

5-fluoro-N-methylpyridin-2-carboxamide (150 mg, 0.97 mmol)synthesized in example (123a), and 3-{5-[(5R)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (438 mg, of 1.27 mmol)synthesized in example (125g), dissolved in N,N-dimethylformamide (3 ml)to a solution of EXT the keys potassium carbonate (269 mg, 1,95 mmol) and the resulting mixture is stirred for 3 hours at 100°C in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (30 ml) and the resulting mixture was extracted twice with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (281 mg, yield 60%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.30 (3H, d, J=6.3 Hz), 3,03 (3H, d, J=4,9 Hz)to 3.41 (3H, s), 3,49 (1H, DD, J=10,3, 3,9 Hz)to 3.58 (1H, DD, J=10,3, 6.3 Hz), of 3.69 (1H, DD, J=11,7, a 5.4 Hz), 3,76 (1H, DD, J=13,9, 7,1 Hz), 3,85 (1H, d, J=and 12.2 Hz), was 4.02 (1H, DD, J=14,2, and 9.3 Hz), 4,58-to 4.52 (1H, m), 4,78 (1H, s), 6,47 (1H, d, J=3,9 Hz), is 6.54 (1H, t, J=2.2 Hz), was 6.73 (1H, d, J=3,4 Hz), 6,83 (1H, t, J=1.7 Hz), 6,98 (1H, s), 7,40 (1H, DD, J=8,8, 2,9 Hz), 7,86 (1H, d, J=4.4 Hz), 8,16 (1H, d, J=8,3 Hz), 8,30 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 481,20954 (M+H)+.

Example 127

5-(3-{5-[(5R)-5-(Hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-N-methylpyridin-2-sulfonamide

(127a) 5-(3-{5-[(5R)-5-Hydroxymethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-N-(4-methoxybenzyl)-N-methylpyridin-2-sulfonamide

5-Chloro-N-(4-methoxybenzyl)-N-methyl is iridin-2-sulfonamide (427 mg, 1,31 mmol)synthesized in example (121b), and 3-{5-[(5R)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (568 mg, of 1.64 mmol)synthesized in example (125g), dissolved in N,N-dimethylformamide (5 ml), to the solution was added potassium carbonate (361 mg, 2,61 mmol) and the resulting mixture was stirred at 100°C for 2 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (40 ml) and the resulting mixture was extracted twice with ethyl acetate (40 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%is 3.5%), obtaining the target compound (228 mg, yield 27%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ is 1.31 (3H, d, J=5,9 Hz), and 2.79 (3H, s), 3.43 points (3H, s), 3,51 (1H, DD, J=10,3, 3,9 Hz)and 3.59 (1H, DD, J=10,3, 6.3 Hz), 3,69-to 3.73 (1H, m), 3.75 to-3,81 (4H, m), a 3.87 (1H, d, J=and 12.2 Hz), Android 4.04 (1H, DD, J=14,2, 9.8 Hz), 4,37 (2H, s), 4,55-4,58 (1H, m), 4,79-4,84 (1H, m), 6,50 (1H, d, J=3,9 Hz), to 6.58 (1H, t, J=2.2 Hz), 6,76 (1H, d, J=3,9 Hz), 6,85 (1H, s), to 6.88 (2H, d, J=8,8 Hz), of 6.99 (1H, s), 7,28 (3H, d, J=8,8 Hz), 7,42 (1H, DD, J=8,8, 2,9 Hz), 7,94 (1H, d, J=8,8 Hz), of 8.47 (1H, d, J=2,4 Hz).

(127b) 5-(3-{5-[(5R)-5-(Hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-N-methylpyridin-2-sulfonamide

5-(3-{5-[(5R)-5-Hydroxymethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-N-(4-methoxybenzyl)-N-methylpyridin-2-sulfonamide (292 mg, 0.47 mmol)synthesized in example (127a), dissolved in triperoxonane acid (2 ml) and the resulting solution was stirred at 45°C for 6 hours. The solvent is distilled off under reduced pressure, to the residue in small portions, add methylene chloride and triethylamine, and then the solvent is again distilled off under reduced pressure. The resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-4%), obtaining the target compound (184 mg, yield 100%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=5,9 Hz), USD 1.43 (3H, d, J=6.3 Hz), was 2.76 (3H, s)to 3.41 (3H, s), 3,49-3,61 (3H, m), 4,08 (1H, DD, J=a 13.9, 9.0 Hz), br4.61-4,55 (1H, m), 4,84 (1H, DD, J=15,1, 7,3 Hz), 6,50 (1H, d, J=3,9 Hz), 6,56 (1H, t, J=2.2 Hz), 6,76 (1H, d, J=3,9 Hz)6,86 (1H, s),? 7.04 baby mortality (1H, s), 7,41 (1H, DD, J=8,5, 2.7 Hz), of 7.96 (1H, d, J=8,8 Hz), to 8.45 (1H, d, J=2,4 Hz).

MS (ESI) m/z: 517,17549 (M+H)+.

Example 128

5-(3-{5-[(5R)-5-(Hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-N-methylpyrazine-2-sulfonamide

(128a) 5-Bromopyrazine-2-thiol

In nitrogen atmosphere for 2.5-dibromopyrazine (300 mg, of 1.26 mmol) dissolved in dimethyl sulfoxide (3 ml)to the solution add nonahydrate disulfi the sodium (454 mg, 1,89 mmol) and the resulting mixture was stirred at 100°C for 1.5 hours. The reaction solution is cooled to room temperature, to the solution was added water (30 ml) and the solution neutralized 5 N. hydrochloric acid. The resulting precipitate is collected by filtration and washed with water, then dissolved in a mixture of diethyl ether/tetrahydrofuran and the insoluble matter is removed by filtration. The solvent is distilled off under reduced pressure, and the residue is dried in vacuum, obtaining the target compound (163 mg, yield 68%) as a solid orange color.

1H-NMR (CDCl3, 400 MHz): δ 3,19 (1H, s), of 7.97 (1H, d, J=1.0 Hz), a 8.34 (1H, d, J=1.0 Hz).

(128b) 5-Bromo-N-methylpyrazine-2-sulfonamide

5-Bromopyrazine-2-thiol (988 mg, 5.17 mmol)synthesized in example (128a), dissolved in a mixture of methylene chloride (15 ml)/1 N. hydrochloric acid (15 ml) and the resulting solution was cooled to -10°C. To the reaction solution are added dropwise 7% aqueous solution of sodium perchlorate (15 ml), cooled in an ice bath, keeping the temperature of the mixture at the level of -5°C or below, and the resulting mixture is stirred for 1 hour. The organic layer is extracted with the help of separating funnel, pre-cooled with ice, cool it to 0°C, add a commercially available 40% solution of methylamine in methanol (1,00 ml, 12.9 mmol), the mixture is allowed to warm to room temperature, and then mix premesis the Ute for 17 hours. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the resulting mixture is extracted twice with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-30%)to give the target compound (147 mg, yield 11%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ and 2.83 (3H, d, J=5.5 Hz), 4,80 (1H, s), 8,76 (1H, d, J=1.6 Hz), 8,96 (1H, d, J=1.2 Hz).

(128c) 5-(3-{5-[(5R)-5-(Hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)-N-methylpyrazine-2-sulfonamide

5-Bromo-N-methylpyrazine-2-sulfonamide (147 mg, of 0.58 mmol)synthesized in example (128b), and 3-{5-[(5R)-5-(hydroxymethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (262 mg, from 0.76 mmol)synthesized in example (125g), dissolved in acetonitrile (6 ml), the solution was added potassium carbonate (161 mg, 1,17 mmol) and the resulting mixture is stirred for 4 hours under nitrogen atmosphere. To the reaction solution was added water (20 ml) and the resulting mixture was extracted twice with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. RA the solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%is 3.5%), obtaining the target compound (161 mg, yield 54%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), of 2.81 (3H, s), 3,42 (3H, s), 3,51 (1H, DD, J=10,3, 3,9 Hz), 3,60 (1H, DD, J=10,3, 5,9 Hz), 3,68 is 3.76 (2H, m), 3,85 (1H, DD, J=12,2, 3,4 Hz), 4,00 (1H, DD, J=14,2, 9.8 Hz), 4,60-4,54 (1H, m), 4,76-4,82 (1H, m), 5,23 (1H, s), of 6.49 (1H, d, J=3,9 Hz), 6,66 (1H, t, J=2.0 Hz), to 6.75 (1H, d, J=3,4 Hz), of 6.96 (1H, t, J=1.7 Hz), 7,06 (1H, t, J=2.0 Hz), 8,44 (1H, d, J=1.5 Hz), to 8.70 (1H, d, J=1.0 Hz).

MS (ESI) m/z: 518,17036 (M+H)+.

Example 129

1-{[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-yl]carbonyl}-4-methylpiperazin

(129a) Methyl-5-herperidin-2-carboxylate

Commercially available 2-bromo-5-herperidin (3.80 g, 21.6 mmol) was dissolved in methanol (50 ml) and N,N-dimethylformamide (50 ml), the solution was added palladium acetate (484 mg, of 2.16 mmol), 1,1-bis(diphenylphosphino)ferrocene (2,39 g, 4,32 mmol) and triethylamine (6.0 ml, 43.2 mmol) and the resulting mixture for 3 days was stirred at room temperature in an atmosphere of carbon monoxide, and then the insoluble matter is removed by filtration. To the solution was added water (100 ml), the mixture is extracted with ethyl acetate (100 ml), the organic layer was washed with saturated salt solution and dried over besod the first magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-50%)to give the target compound (2,87 g, yield 86%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ 4,01 (3H, s), 7,54 (1H, dt, J=8,6, 3,9 Hz), to 8.20 (1H, DD, J=8,6, a 4.7 Hz), 8,59 (1H, d, J=2.7 Hz).

(129b) Methyl-5-(3-{5-[(benzyloxy)carbonyl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)pyridine-2-carboxylate

2-Benzyl-1-tert-butyl-5-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-1,2 -, in primary forms (4,08 g of 8.47 mmol)synthesized in example (78g), and methyl-5-herperidin-2-carboxylate (1.45 g, to 9.32 mmol)synthesized in example (129a), dissolved in N,N-dimethylformamide (30 ml), to the solution was added potassium carbonate (3.51 g, and 25.4 mmol) and the resulting mixture was stirred at 100°C for 3 hours in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (100 ml) and the mixture extracted with ethyl acetate (100 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: ethyl acetate/hexane=0%-35%).

Received the product in a solid yellow color rastv the accelerate in methylene chloride (5 ml), to the solution add triperoxonane acid (7.5 ml) and the resulting mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (50 ml) and the resulting mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (3,26 g, 75%yield) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), 3,40 (3H, s), 3,50 (1H, DD, J=10,2, 3,9 Hz)to 3.58 (1H, DD, J=10,4, 6.5 Hz), of 4.00 (3H, s), to 4.52-4,59 (1H, m), 5,32 (2H, s), 6,50 (1H, t, J=2,9 Hz), 6,59 (1H, s), 6,83 (1H, ), 6,99-6,97 (2H, m), 7,34-7,44 (5H, m)to 8.12 (1H, d, J=8.6 Hz), charged 8.52 (1H, d, J=2.7 Hz), which 9.22 (1H, s).

(129c) 5-(3-{[6-(Methoxycarbonyl)]pyridin-3-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-1H-pyrrole-2-carboxylic acid

Methyl-5-(3-{5-[(benzyloxy)carbonyl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy)pyridine-2-carboxylate (3,18 g, 6,16 mmol)synthesized in example (129b), dissolved in 5% formic acid/ethanol (200 ml), the solution is added catalytic 10% palladium on carbon (2.00 g), then stirred for 2 hours in hydrogen atmosphere. The catalyst (PAL who ADI on carbon) is removed by filtration through celite and then washed with tetrahydrofuran. The solvent is distilled off under reduced pressure, the residue diluted with methylene chloride (100 ml), washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, obtaining the target compound (2,41 g, yield 92%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (3H, d, J=6.3 Hz), of 3.46 (3H, s), of 3.54 (1H, DD, J=10,2, 3,9 Hz), 3,66 (1H, DD, J=10,2, and 6.6 Hz), of 4.00 (3H, s), 4,71 (1H, TD, J=6.3, in the 4.3 Hz), of 6.49 (1H, DD, J=3,9, 2.7 Hz), 6,59 (1H, d, J=2.0 Hz), 6,92 (1H, t, J=1.6 Hz), 7,02 (1H, DD, J=3,9, and 2.3 Hz), 7,39 (1H, DD, J=8,8, 2,9 Hz), 8,13 (1H, d, J=8.6 Hz), to 8.57 (1H, d, J=2.7 Hz), 10,46 (1H, s).

(129d) Methyl-5-(3-{[(2R)-2-hydroxypropyl]carbarnoyl}-1H-pyrrol-2-yl)-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}pyridine-2-carboxylate

5-(3-{[6-(Methoxycarbonyl)]pyridin-3-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-1H-pyrrole-2-carboxylic acid (800 mg, of 1.87 mmol)synthesized in example (129c), dissolved in methanol (20 ml)solution was added (R)-(-)-1-amino-2-propanol (339 μl, 4.30 mol) and n-hydrate chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (829 mg, 2,99 mmol) and the resulting mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (726 mg, yield 80%) as a solid white color is the same.

1H-NMR (CDCl3, 400 MHz): δ 1,25 (3H, d, J=6.6 Hz), 1,32 (3H, d, J=6.3 Hz), 3.25 to of 3.32 (1H, m)to 3.41 (3H, s), 3,51 (1H, DD, J=10,2, 3,9 Hz), 3,57-the 3.65 (2H, m), of 4.05 (3H, s), 4,58 (1H, TD, J=6,3, 4.0 Hz), 6.35mm (1H, s), 6.48 in (1H, DD, J=3,9, 3.1 Hz), to 6.57 (1H, t, J=2.2 Hz), is 6.61 (1H, DD, J=3,9, and 2.3 Hz), 6,85 (1H, t, J=1,8 Hz), 7,00 (1H, t, J=1,8 Hz), was 7.36 (1H, DD, J=8,8, 2,9 Hz)to 8.12 (1H, d, J=9.0 Hz), 8,53 (1H, d, J=2.7 Hz), 9,66 (1H, s).

(129e) Methyl-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-carboxylate

Methyl-5-(3-{[(2R)-2-hydroxypropyl]carbarnoyl}-1H-pyrrol-2-yl)-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}pyridine-2-carboxylate (726 mg, 1.50 mmol)synthesized in example (129d), dissolved in tetrahydrofuran (20 ml), to the solution was added anhydrous methansulfonate acid (523 mg, 3.00 mmol) and triethylamine (0.63 ml, 4,50 mmol) and the resulting mixture 5 hours is stirred at 50°C in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the mixture is extracted with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-7,5%), obtaining the target compound (264 mg, yield 38%) as a solid pale yellow color.

1H-NMR (CDCl3that 400 is Hz): δ of 1.32 (3H, d, J=6.3 Hz), of 1.42 (3H, d, J=6.3 Hz), to 3.41 (3H, d, J=3.1 Hz), 3,54 (3H, DDT, J=26,4, 11,3, 4,4 Hz)to 4.01 (3H, s), 4.04 the-4,11 (1H, m), 4,60-a 4.53 (1H, m), 4,87-4,78 (1H, m), of 6.49 (1H, d, J=3,9 Hz), 6,55 (1H, t, J=2.0 Hz), to 6.75 (1H, d, J=3,9 Hz), 6,83 (1H, t, J=1,8 Hz), of 6.99 (1H, t, J=2.0 Hz), 7,35 (1H, DD, J=8,6, 2.7 Hz), to 8.12 (1H, d, J=9.0 Hz), 8,53 (1H, d, J=2.7 Hz).

(129f) 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-carboxylic acid

Methyl-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-carboxylate (264 mg, or 0.57 mmol)synthesized in example (129e), dissolved in methanol (20 ml)solution was added and water (3 ml) and the monohydrate of lithium hydroxide (71 mg, 1.70 mmol) and the resulting mixture for 1 hour and stirred at 50°C in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (50 ml), then extracted twice with methylene chloride (40 ml), washed with saturated salt solution and dried over sodium sulfate. The solvent is distilled off under reduced pressure, the residue is dried in vacuum, obtaining the target compound (256 mg, yield 100%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.40 (3H, d, J=6.3 Hz), 1,67 (3H, d, J=6.3 Hz), 3.43 points (3H, s), to 3.58-the 3.65 (2H, m), of 3.78 (1H, DD, J=11,2, 7,8 Hz), the 4.29 (1H, t, J=10.3 Hz), 4,84-of 4.90 (1H, m), and 5.30 and 5.36 (1H, m), of 6.65 (1H, d, J=3,9 Hz), 6,69 (1H, t, J=2.2 Hz), 7,21 (2H, s)to 7.50 (1H, DD, J=7,3, 3,4 Hz), 7,56 (1H, s), 8,18 (1H, s), 8,39 (1H, d, J=2,4 Hz).

(129g) 1-{[5-(3-[(1S)-2-M is toxi-1 methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-yl]carbonyl}-4-methylpiperazin

5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-carboxylic acid (270 mg, of 0.60 mmol)synthesized in example (129f), dissolved in tetrahydrofuran (5 ml), the resulting solution was added N-methylpiperazine (199 μl, to 1.79 mmol), HATU (454 mg, 1,19 mmol) and N,N-diisopropylethylamine (624 μl, 3.58 mmol) and the resulting mixture for 3 days was stirred at room temperature under nitrogen atmosphere. To the reaction solution was added a saturated salt solution (15 ml), the mixture was extracted twice with ethyl acetate (15 ml) and dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (208 mg, yield 65%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.32 (3H, d, J=6.3 Hz), of 1.42 (3H, d, J=5,9 Hz), of 2.33 (3H, s), is 2.44 (2H, t, J=4.9 Hz), 2,52 (2H, t, J=4,9 Hz)to 3.41 (3H, d, J=0.8 Hz), 3,48-of 3.60 (3H, m), of 3.73 (2H, USS), a-3.84 (2H, USS), 4,08 (1H, DD, J=14,3, 9,2 Hz), 4,56 (1H, DD, J=10,2, 6.3 Hz), a 4.83 (1H, DD, J=the 15.6, 6.6 Hz), of 6.49 (1H, d, J=4.3 Hz), is 6.54 (1H, t, J=2.0 Hz), to 6.75 (1H, d, J=3,9 Hz), for 6.81 (1H, t, J=1,8 Hz), to 6.95 (1H, t, J=1,8 Hz), 7,38 (1H, DD, J=8,6, 2.7 Hz), 7,69 (1H, d, J=8.6 Hz), at 8.36 (1H, d, J=2.7 Hz).

MS (ESI) m/z: 534,27234 (M+H)+.

Example 130

(2S)-2-[3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-({6-[(4-methylpiperazin-1-yl)carbonitriding-3-yl}oxy)phenoxy]propane-1-ol

1-{[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-l,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-yl]carbonyl}-4-methylpiperazine (185 mg, 0.35 mmol)synthesized in example (129g), dissolved in methylene chloride (10 ml), the resulting solution was at -78°C add tribromide (boron solution in methylene chloride, 1.0 mol/l, 694 μl, 0,694 mmol). After this mixture allow to warm to room temperature, and the mixture is then stirred for 50 minutes. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-10%), obtaining the target compound (51 mg, yield 28%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.28 (3H, d, J=6.3 Hz), USD 1.43 (3H, d, J=6.3 Hz), was 2.34 (3H, s), is 2.44 (2H, t, J=4.9 Hz), 2,53 (2H, t, J=4.9 Hz), 3,55 (1H, DD, J=13,9, 7,2 Hz), and 3.72 (2H, t, J=4,7 Hz), of 3.78 (2H, d, J=5.5 Hz), 3,84 (2H, s), 4.09 to (1H, DD, J=13,9, 9,2 Hz), 4,60 (1H, DD, J=11,3, 5,5 Hz), is 4.85 (1H, dt, J=11,6, 4.5 Hz), 6.35mm (1H, s), 6,46 (1H, d, J=3,9 Hz), to 6.75 (1H, d, J=3,9 Hz), 6,79 (1H, t, J=1,8 Hz), make 6.90 (1H, s), 7,33 (1H, DD, J=8,6, 2.7 Hz), to 7.67 (1H, DD, J=8,6, and 0.8 Hz), with 8.33 (1H, t, J=1,8 Hz).

MS (ESI) m/z: 520,25784 (M+H)+.

Primer

2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin

(131a) of 2-Chloro-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin

Commercially available 5-hydroxypyridine-2-carboxylic acid (5,00 g of 39.0 mmol) was dissolved in thionyl chloride (64 ml), the solution add a few drops of N,N-dimethylformamide and the resulting mixture is refluxed for 5 hours in nitrogen atmosphere. The solvent is distilled off under reduced pressure and the resulting residue diluted with methylene chloride (50 ml). The mixture is cooled in an ice bath and add diisopropylethylamine (18.7 ml, 107 mmol) and 1-methylpiperazine (4,37 ml of 39.2 mmol) and the mixture for 3 days was stirred at room temperature under nitrogen atmosphere. To the reaction solution was added water (100 ml) and the mixture is extracted with methylene chloride (100 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=3%-5%)to give the target compound (5.32 g, yield 62%) as a solid brown color.

1H-NMR (CDCl3, 400 MHz): δ was 2.34 (3H, s), is 2.44 (2H, t, J=5,1 Hz), 2,53 (2H, t, J=5,1 Hz)to 3.64(2H, t, J=5,1 Hz), a-3.84 (2H, t, J=4.9 Hz), 8,55 (1H, d, J=1.2 Hz), 8,76 (1H, d, J=1.6 Hz).

(131b) Benzyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}oxy)phenyl}-1H-pyrrole-2-carboxylate

2-Benzyl-1-tert-butyl-5-{3-hydroxy-5-[(1S)-2-methoxy-l-methylethoxy]phenyl}-1H-pyrrole-1,2 -, in primary forms (2.00 g, 4,15 mmol)synthesized in example (78g), and 2-chloro-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin (1.10 g, of 4.57 mmol)synthesized in example (131a), dissolved in N,N-dimethylformamide (20 ml)to the mixture is added potassium carbonate (1,72 g, 12.5 mmol)and the resulting mixture is stirred for 4 hours at 80°C in nitrogen atmosphere. The reaction solution is cooled to room temperature, add water (80 ml) and the resulting mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-7,5%), and receiving the product (2,88 g) as a brown oil.

The obtained product is dissolved in methylene chloride (5 ml)solution was added triperoxonane acid (5 ml) and then stirred at room temperature for 2 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (50 ml) and p is obtained mixture is extracted twice with methylene chloride (50 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-7,5%), obtaining the target compound (1,96 g, yield 81%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), was 2.34 (3H, s), a 2.45 (2H, t, J=4.5 Hz), 2,53 (2H, t, J=4,9 Hz)to 3.41 (3H, s), 3,51 (1H, DD, J=10,9, and 3.7 Hz)and 3.59 (1H, DD, J=9,8, 5,5 Hz), 3,71 (2H, USS), a-3.84 (2H, USS), 4,53-4,60 (1H, m), 5,33 (2H, s), 6,51 (1H, DD, J=3,9, 2.7 Hz), 6,69 (1H, t, J=2.0 Hz), 6,93 (1H, s), 6,98 (1H, DD, J=3,7, 2,5 Hz), 7,02 (1H, s), 7,34-7,44 (5H, m), 8,35 (1H, t, J=1.4 Hz), 8,54 (1H, d, J=0.8 Hz), of 9.21 (1H, USS).

(131c) N-[(2R)-2-Hydroxypropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}oxy)phenyl}-1H-pyrrol-2-carboxamide

Benzyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}oxy)phenyl}-1H-pyrrole-2-carboxylate (1,94 g of 3.32 mmol)synthesized in example (131b), dissolved in methanol (100 ml), the solution is added the catalyst, 10% palladium on carbon (1.20 g) and the resulting mixture was stirred at room temperature for 2.5 hours in an atmosphere of hydrogen. The catalyst was removed by filtration through celite and washed his tetrahydrofuran. The solvent is distilled off under reduced pressure, obtaining the product in the form of TV is Gogo substance white (1.45 g).

The resulting product (700 mg, of 1.41 mmol) and 4-dimethylaminopyridine (86 mg, 0.71 mmol) dissolved in methylene chloride (30 ml)to the solution at room temperature add WSCI·HCl (625 mg, and 2.26 mmol) and (R)-1-amino-2-propanol (256 μl, 3.25 mmol) and the resulting mixture is stirred for 3 days under nitrogen atmosphere. The reaction solution is diluted with methylene chloride (60 ml), washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-10%), obtaining the target product (447 mg, 50%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ of 1.23 (3H, d, J=6.3 Hz), of 1.33 (3H, d, J=8.0 Hz), was 2.34 (3H, s), a 2.45 (2H, t, J=4,7 Hz), 2,53 (2H, t, J=4,7 Hz), 3,23-3,30 (1H, m), 3,42 (3H, s), 3,51 (1H, DD, J=10,2, a 4.3 Hz), to 3.58-3,63 (2H, m), 3,71 (2H, t, J=4,7 Hz), a-3.84 (2H, t, J=5.5 Hz), 4,00 (1H, USS), 4,53-4,60 (1H, m), 6,37 (1H, s), of 6.49 (1H, t, J=3.3 Hz), is 6.61 (1H, DD, J=3,9, and 2.3 Hz), of 6.66 (1H, s), 6,93 (1H, t, J=1,8 Hz), 7,02 (1H, t, J=2.0 Hz), a 8.34 (1H, s), 8,53 (1H, s), to 9.66 (1H, USS).

(131d) 2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin

N-[(2R)-2-Hydroxypropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}oxy)phenyl}-1H-pyrrol-2-carboxamide (447 mg ,81 mmol), synthesized in example (131c), dissolved in tetrahydrofuran (20 ml), to the solution was added anhydrous methansulfonate acid (282 mg, of 1.62 mmol) and triethylamine (0,34 ml, 2,43 mmol) and the resulting mixture for 4 hours, stirred at 50°C in nitrogen atmosphere. To the reaction solution was added saturated aqueous solution of ammonium chloride (30 ml) and the resulting mixture is extracted twice with methylene chloride (30 ml). The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=0%-5%)to give the target compound (279 mg, yield 65%) as a solid pale yellow color.

1H-NMR (CDCl3, 400 MHz): δ of 1.34 (3H, d, J=6.3 Hz), of 1.42 (3H, d, J=6.3 Hz), was 2.34 (3H, s)to 2.46 (2H, t, J=4,7 Hz), 2,53 (2H, t, J=4,7 Hz), 3,42 (3H, s), 3,49-3,62 (3H, m), and 3.72 (2H, t, J=4.3 Hz), a-3.84 (2H, t, J=5,1 Hz), 4,08 (1H, DD, J=14,1, 9.0 Hz), 4.53-in-4,60 (1H, m), 4,87-4,78 (1H, m), 6,50 (1H, d, J=3,9 Hz), of 6.65 (1H, t, J=2.2 Hz), to 6.75 (1H, d, J=3,9 Hz)6,91 (1H, t, J=1,8 Hz), 7,02 (1H, t, J=2.0 Hz), a 8.34 (1H, d, J=1.2 Hz), 8,54 (1H, d, J=1.2 Hz).

MS (ESI) m/z: 535,26585 (M+H)+.

Example 132

(2S)-2-[3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}oxy)phenoxy]propane-1-ol

2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-45-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin (259 mg, 0.48 mmol)synthesized in example (131d), dissolved in methylene chloride (15 ml)to the solution at -78°C add tribromide (boron solution in methylene chloride, 1.0 mol/l, 0,81 ml, 0.81 mmol). After this mixture is allowed to warm to room temperature, and the mixture is stirred for 3 hours. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography (silica gel, eluting solvent: methanol/methylene chloride=2%-8%), obtaining the target compound (62,4 mg, yield 25%) as a solid white color.

1H-NMR (CDCl3, 400 MHz): δ 1.28 (in 4H, d, J=6.3 Hz), of 1.41 (3H, d, J=6.3 Hz), was 2.34 (3H, s), a 2.45 (2H, t, J=4.5 Hz), 2,52 (2H, t, J=4,7 Hz), 3,53 (1H, DD, J=13,7, 7,4 Hz), 3,71 (2H, t, J=4,7 Hz), of 3.77-with 3.79 (2H, m), 3,83 (2H, t, J=4,7 Hz), 4,07 (1H, DD, J=13,7, 9.4 Hz), 4,59 (1H, TD, J=11,5, 5.7 Hz), a 4.83 (1H, DQC, J=17,8, 5,1 Hz), 6,44 (1H, d, J=3,9 Hz), 6,47 (1H, s), 6,72 (1H, d, J=3,9 Hz), to 6.88 (1H, s)6,94 (1H, s), 8,30 (1H, ), charged 8.52 (1H, d, J=0.8 Hz).

MS (ESI) m/z: 521,25002 (M+H)+.

An example of biological test 1

(1) CC drug

cDNA encoding pancreatic GK polypeptide human (GenBank Accession No. NM_000162, a variant of human glucokinase 1) clone from a cDNA library through polymerase chain reactions is (PCR) and introducing the expression vector of the protein, fused with glutathione-S-transferase (glutathione S-transferase - GST) (GEX4T, GE Healthcare Bioscience). The vector is introduced into Escherichia coli (such as BL21 or JM109, Invitrogen) and transformed E. coli grown overnight at 37 degrees C followed by separation of the cells. After freezing and thawing of the selected cells cells suspended in phosphate buffer containing Triton-X at a final concentration of 1% followed by destruction of the cells by means of an ultrasonic homogenizer. The supernatant obtained by using a low-speed processing in the centrifuge homogenate (10000×g, 30 minutes), optionally subjected to high speed centrifugation (100000×g, 10 minutes) followed by separation of the supernatant and purified fused protein using the cleaning system of GST-fused protein (Bulk GST Purification Module, GE Healthcare Bioscience). GK-fused protein is divided into two smaller aliquots and stored at -80°C.

(2) Test definition Ledger activity.

GK activity determined using purified Ledger, as described in (1) above. More precisely, the enzyme solution obtained by adding purified Ledger obtained in (1)described above, and glucose-6-phosphate dehydrogenase (Sigma) to a solution of 1 set for analysis of glucose (D-Glucose UV Method, Roche Diagnostics). The enzyme solution, the diluent of the test compounds and glucose (final concentration: 5 mm) are mixed in a 96-hole tablet ELISA and provide an opportunity to respond during the 30 minutes at room temperature. After completion of the reaction determine the spectral absorption capacity at a wavelength of 340 nm using a SpectraMax Plus (Molecular Probe). In addition, the spectral absorption ability of unreacted solution (without added glucose) is used as the background.

The speed of activation of GC presents the values calculated by the formula: (absorbance after interaction within 30 minutes with the addition of test compound)/(absorbance after interaction within 30 minutes without addition of test compound). The results of the speed of activation of GC obtained when the concentration of the test compounds 1 μm, are presented in table 1.

Table 1
ExampleActivation speed GK
12,0
21,9
31,9
151,6
202,0
212,0
252,0
262,3
292,0
312,0
322,0
331,7
352,1
412,1
472,0
602,0
641,9
652,4
671,7
682,0
692,2
701,9
732,0
742,0
751,8
763,0
772,6
812,2
822,7
842,7
852,9
862,5
882,4
892,3
912,6
932,4
952,5
981,9
1001,9
1011,9
1032,1
1072,0
1082,0
1092,2
1102,4
1122,4
1142,2
1222,5
1232,6
1262,6
1272,4

Based on the results, the compounds of the present invention have excellent activity activation of GC and applicable as a therapeutic and/or prophylactic agents for diseases selected from the group including diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macroangioapthy) and metabolic syndrome.

Example 1 drug: capsule

The compound of example 1 or 7850 mg
Lactose128 mg
Corn starch70 mg
Magnesium stearate2 mg
250 mg

Powders of the above drug mixed and passed through a sieve of 60 mesh with the subsequent introduction of 250 mg of powder in a gelatin capsule to obtain a capsule.

Example of preparation 2: tabled the

The compound of example 1 or 7850 mg
Lactose126 mg
Corn starch23 mg
Magnesium stearate1 mg
200 mg

Powders of the above drug mixed, granularit using a paste of cornstarch and dried, is then formed into tablets using the apparatus for tableting with obtaining tablets weighing 200 mg. This tablet can be coated with a coating of sugar when you need it.

The POSSIBILITY of APPLICATION IN INDUSTRIAL environments

The compound of General formula (I) according to the present invention or its pharmaceutically acceptable salt has excellent activity activation of GC and applicable as a therapeutic and/or prophylactic drugs (especially as a therapeutic drug for diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinop the party and diabetic macroangioapthy) or metabolic syndrome (especially diabetes or impaired glucose tolerance) to apply to warm-blooded animals (particularly humans).

1. The compound of General formula (I)

where A represents a group of formula=NOR4or an oxygen atom,
R4represents a hydrogen atom or a C1-C6alkyl group,
R1represents a C1-C6alkyl group, a C1-C6alkoxygroup, halogenated C1-C6alkyl group, halogenated C1-C6alkoxygroup, amino, mono-C1-C6-alkylamino, halogenated mono-C1-C6-alkylamino, di(C1-C6alkyl)amino group or halogenated di(C1-C6alkyl)amino group, or
A and R1together with the carbon atom to which they are attached, form a 5 - or 6-membered heterocyclic aromatic group or heterocyclic group is partially or fully restored saturation, which can be benzododecinium containing 1-3 heteroatoms selected from N, O, and S, which may be substituted and may contain 1 or 2 substituent, independently selected from the group of substituents α,
R2represents a phenyl group which may be substituted and may contain 1 or 2 substituent, independently selected who's from a group of substituents α, or 6-membered heteroaryl group containing 1 or 2 N atom which may be substituted and may contain 1 or 2 substituent, independently selected from the group of substituents α,
R3represents a hydroxyl group or a C1-C6alkoxygroup, and
the group of the substituents is a group of substituents selected from a halogen atom, a C1-C6alkyl groups, halogenated C1-C6alkyl group, a hydroxyl group, a C1-C6alkyl group substituted by 1 or 2 hydroxyl groups, C1-C6alkoxygroup, halogenated C1-C6alkoxygroup, formyl group, carboxyl group, With2-C7alkylcarboxylic group2-C7alkoxycarbonyl group2-C7alkylcarboxylic, C1-C6alkylsulfonyl group, C3-C6cycloalkylcarbonyl groups, groups of formula-V-NR5R6where V represents a carbonyl group or sulfonyloxy group, R5and R6may be the same or may be different and respectively represent a hydrogen atom or a C1-C6alkyl group, or R5and R6together with the nitrogen atom to which they are attached, form a 4-6-membered saturated, a heterocycle which may be substituted is a diversified and contain 1 or 2 substituent, independently selected from C1-C6alkyl group and hydroxyl group, and a 4-6-membered saturated the heterocycle may optionally contain one oxygen atom or one nitrogen atom, 1,3,4-oxadiazol-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group, 1,3,4-thiadiazole-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group, and carbonyl group, or its pharmaceutically acceptable salt.

2. The compound or its pharmaceutically acceptable salt according to claim 1, where the General formula (I) represents a General formula (Ia)

3. The compound or its pharmaceutically acceptable salt according to claim 1, where A represents an oxygen atom.

4. The compound or its pharmaceutically acceptable salt according to claim 1, where R1represents a C1-C6alkyl group, a C1-C6alkoxygroup or halogenated mono-C1-C6alkylamino.

5. The compound or its pharmaceutically acceptable salt according to claim 4, where R1represents a methyl group or 2-chloroethylamino.

6. The compound or its pharmaceutically acceptable salt according to claim 1, where the 5 - or 6-membered heterocyclic aromatic group or heterocyclic group is partially or fully restored saturation, formed by A and R 1together with the carbon atom to which they are attached, can be substituted and can contain 1 or 2 substituent, independently selected from the group of substituents α, and is a 2-pyridyloxy group, 5,6-dihydro-4H-1,3-oxazin-2-ilen group, 1,3-thiazol-2-ilen group, 1,3-oxazol-2-ilen group, 1,3,4-oxadiazol-2-ilen group, 1,3,4-thiadiazole-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-ilen group, or 1,3-benzothiazol-2-strong group which may be substituted and may contain 1 or 2 substituent, independently selected from the group of substituents γ, and the group of substituents γ is a group of substituents comprising halogen atom, a C1-C6alkyl group, halogenated C1-C6alkyl group, a C1-C6alkyl group, substituted by 1 or 2 hydroxyl groups, C1-C6alkoxygroup, carboxyl group, mono-C1-C6alkyl aminocarbonyl group, di-C1-C6alkylaminocarbonyl group and hydroxyl group.

7. The compound or its pharmaceutically acceptable salt according to claim 1, where the 5 - or 6-membered heterocyclic aromatic group or heterocyclic group is partially or fully restored saturation, formed by A and R1together with the carbon atom to which they are attached, may shall be substituted and can contain 1 or 2 substituent, independently selected from the group of substituents α, and represents 1,3-thiazol-2-ilen group, 5-methyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group, 4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 5-hydroxymethyl-4, 5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-4-hydroxy-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 5-carboxy-1,3-thiazol-2-ilen group, 5-dimethylaminoethyl-1,3-thiazol-2-ilen group 5-methyl-1,3,4-thiadiazole-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-ilen group.

8. The compound or its pharmaceutically acceptable salt according to claim 1, where the 5 - or 6-membered heterocyclic aromatic group or heterocyclic group is partially or fully restored saturation is, formed by A and R1together with the carbon atom to which they are attached, can be substituted and can contain 1 or 2 substituent, independently selected from the group of substituents α, and represents a 4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-strong group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, 1,3-thiazol-2-ilen group, 5-carboxy-1,3-thiazol-2-ilen group, 5-dimethylaminoethyl-1,3-thiazol-2-ilen group, 5-methyl-1,3,4-thiadiazole-2-ilen group, 5-methyl-1,3,4-oxadiazol-2-ilen group, 4,5-dihydro-1,3-thiazol-2-ilen group or 5,6-dihydro-4H-1,3-oxazin-2-ilen group.

9. The compound or its pharmaceutically acceptable salt according to claim 1, where the 5 - or 6-membered heterocyclic aromatic group or heterocyclic group is partially or fully restored saturation, formed by A and R1together with the carbon atom, to the which they are attached, can be substituted and can contain 1 or 2 groups independently selected from the group of substituents α, and represents a 4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R)-4-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (5R)-5-hydroxymethyl-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1R)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, (4S)-4-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-ilen group, a (4R,5S)-4-hydroxymethyl-5-methyl-4,5-dihydro-1,3-oxazol-2-ilen group or (4R, 5R)-5-hydroxymethyl-4-methyl-4,5-dihydro-1,3-oxazol-2-ilen group.

10. The compound or its pharmaceutically acceptable salt according to claim 1, where R2represents a phenyl group which may be substituted and may contain 1 or 2 substituent, independently selected from the group of substituents δ, or 2-pyridyloxy group, 3-pyridyloxy group or 2-personilnya group which may be substituted and may contain 1 or 2 substituent, independently selected from the group of substituents δ, and the group of substituents δ is a group of substituents comprising halogen atom, a C1-C6alkyl group, halogenated C1-C6alkyl group, a C1-C6Ala is the function group, substituted by 1 or 2 hydroxyl groups, C2-C7alkylcarboxylic group, C2-C7alkoxycarbonyl group, C1-C6alkylsulfonyl group, a group of the formula-V-NR5R6(where V represents a carbonyl group or sulfonyloxy group, and R5and R6may be the same or may be different and respectively represent a hydrogen atom or a C1-C6alkyl group, or R5and R6together with the nitrogen atom to which they are attached, form a 4-6-membered saturated, a heterocycle which may be substituted and may contain 1 or 2 substituent, independently selected from C1-C6alkyl group and hydroxyl group, and a 4-6-membered saturated the heterocycle may optionally contain one oxygen atom or nitrogen atom), 1,3,4-oxadiazol-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group, and 1,3,4-thiadiazole-2-ilen group, optionally substituted in the 5-position of the C1-C6alkyl group.

11. The compound or its pharmaceutically acceptable salt according to claim 1, where R2is a 4-methylsulfinylphenyl group, 4-(1-azetidine)carbonyl-2-florfenicol group, 2-fluoro-4-(1-pyrrolidinyl)Carboniferous group, 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group, 2-matilal is of IMT-5-pyridyloxy group, 5-(4-methyl-1-piperazinil)carbonyl-2-personilnya group, 2-methylaminomethyl-5-pyridyloxy group, 2-methylaminomethyl-5-pyridyloxy group or 5-methylsulphonyl-2-personilnya group.

12. The compound or its pharmaceutically acceptable salt according to claim 1, where R2is a 4-methylsulfinylphenyl group, 2-methylsulphonyl-5-pyridyloxy group, 5-methylsulphonyl-2-personilnya group or 5-(1-azetidine)carbonyl-3-chloro-2-pyridyloxy group.

13. The compound or its pharmaceutically acceptable salt according to claim 1, where R3represents a hydroxyl group or a methoxy group.

14. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound of formula (I) is a
(2S)-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,
(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,
(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,
{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,
(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,
(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,
{(4R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol,
(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[b-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,
{(4R,5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-5-yl}methanol,
{(4R,5S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,
(1S)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol,
(1R)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol,
(2S)-2-(3-{5-[(58)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,
{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,
(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,
(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,
(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-and the}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,
{[4R,5S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,
(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol or
(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol.

15. The compound according to claim 1, where the compound of General formula (I) is a
(2S)-2-{3-[5-(4,5-dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[4-(methylsulphonyl)phenoxy]phenoxy}propan-1-ol,
(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[4-(methylsulphonyl)phenoxy]phenoxy)propan-1-ol,
(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,
{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,
(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,
(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,
{(4R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol,
(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dig the draw-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol,
{(4R,5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazol-5-yl}methanol,
{(4R,5S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,
(1S)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol,
(1R)-1-{(4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol,
(2S)-2-(3-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,
{(5R)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{1[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol,
(2S)-2-(3-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,
(2S)-2-(3-{5-[(4R)-4-ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,
(2S)-2-(3-{5-[(4R,5S)-4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol,
{(4R,5S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol,
(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(meth sulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol or
(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol.

16. The compound according to claim 1, which represents the
(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol, or its pharmaceutically acceptable salt.

17. The compound according to claim 1, which represents the
{(5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol, or its pharmaceutically acceptable salt.

18. The compound according to claim 1, which represents the
(2S)-2-(3-{5-[(4R)-4-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol, or its pharmaceutically acceptable salt.

19. The compound according to claim 1, which represents the
{(4R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol, or its pharmaceutically acceptable salt.

20. The compound according to claim 1, which represents the
(1S)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol, or its pharmaceutically acceptable salt.

21. The compound according to claim 1, which represents the
(1R)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol or its pharmaceutically acceptable salt.

22. The compound according to claim 1, which represents the
(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol, or its pharmaceutically acceptable salt.

23. The compound according to claim 1, which represents the
(2S)-2-(3-{5-[(4R)-4-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol, or its pharmaceutically acceptable salt.

24. The compound according to claim 1, which represents the
(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridazin-3-yl]oxy}phenoxy)propan-1-ol, or its pharmaceutically acceptable salt.

25. The compound according to claim 1, which represents the
(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol.

26. The compound according to claim 1, which represents the
{(5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol.

27. The compound according to claim 1, which represents the
(2S)-2-(3-{5-[(4R)-4-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenoxy)propan-1-ol.

28. The compound according to claim 1, which represents the
{(4R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-ylmethanol.

29. The compound according to claim 1, which represents the
(1S)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol.

30. The compound according to claim 1, which represents the
(1R)-1-{(4S)-2-[5-(3-[(18)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulphonyl)pyridine-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol.

31. The compound according to claim 1, which represents the
(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol.

32. The compound according to claim 1, which represents the
(2S)-2-(3-{5-[(4R)-4-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[5-(methylsulphonyl)pyrazin-2-yl]oxy}phenoxy)propan-1-ol.

33. The compound according to claim 1, which represents the
(2S)-2-(3-{5-[(5S)-5-Methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[6-(methylsulphonyl)pyridazin-3-yl]oxy}phenoxy)propan-1-ol.

34. The pharmaceutical composition exhibiting activating activity of glucokinase (GK), containing as active ingredient the compound or pharmaceutically acceptable salt according to any one of claims 1 to 33 and the media.

35. The pharmaceutical composition according to clause 34 for use in the treatment and/or prophylaxis of diseases which can be treated and/or prevented by activating glucokinase.

36. The pharmaceutical composition according to clause 34 for use in the treatment and/or prevention of illness is evania, the symptoms are treated, reduced, attenuated and/or warned by the activation of glucokinase and maintain glucose homeostasis or regulation of glucose levels in the blood.

37. The pharmaceutical composition according to clause 34 for use in the treatment and/or prophylaxis of diabetes impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic retinopathy and diabetic macroangioapthy) or metabolic syndrome.

38. The pharmaceutical composition according to clause 34 for use in the treatment and/or prevention of diabetes or disorders of glucose tolerance.

39. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 33 for use in the treatment and/or prophylaxis of diseases which can be treated and/or prevented by activating glucokinase.

40. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 33 for use in the treatment and/or prevention of the disease, the symptoms are treated, reduced, attenuated and/or preventing activation of glucokinase and the maintenance of glucose homeostasis or regulation of glucose levels in the blood.

41. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 33 for use in the treatment and/or prophylaxis of diabetes, is arsenia glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macroangioapthy) or metabolic syndrome.

42. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 33 for use in the treatment and/or prevention of diabetes or disorders of glucose tolerance.

43. The use of compound or its pharmaceutically acceptable salt according to any one of claims 1 to 33 for obtaining a pharmaceutical composition exhibiting activating activity of glucokinase (GK).

44. The use of compound or its pharmaceutically acceptable salt according to any one of claims 1 to 33 for obtaining a pharmaceutical composition for the treatment and/or prevention of disease, symptoms of which are treated, reduced, attenuated and/or preventing activation of glucokinase and the maintenance of glucose homeostasis or regulation of glucose levels in the blood.

45. The use of compound or its pharmaceutically acceptable salt according to any one of claims 1 to 33 for obtaining a pharmaceutical composition for the treatment and/or prevention of diabetes impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetes is ical retinopathy and diabetic macroangioapthy) or metabolic syndrome.

46. The use of compound or its pharmaceutically acceptable salt according to any one of claims 1 to 33 for obtaining a pharmaceutical composition for the treatment and/or prevention of diabetes or disorders of glucose tolerance.

47. Method for activating glucokinase including the introduction of a warm-blooded animal a pharmaceutically effective amount of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 33.

48. The method of treatment and/or prevention of disease, symptoms of which are treated, reduced, attenuated and/or preventing activation of glucokinase and maintaining glucose homeostasis or regulation of glucose levels in the blood, the method includes the introduction of a warm-blooded animal a pharmaceutically effective amount of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 33.

49. The method according to p, where the disease is a diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macroangioapthy) or metabolic syndrome.

50. The method according to § 49, where the disease is a diabetes mellitus or impaired glucose tolerance.

51. The method according to any of PP-50, gameprogrammer animal is man.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes, which can be applied as antibacterial, antifungal and antiviral agents, as biologically active complexing agents, selective sorbents and extractants of precious metals, special reagents for suppression of vital activity of bacteria in various technical media (from light industry to oil). Essence of method lies in interaction of α,ω-alkanediamine with 1,3,6-oxadithiapinane in presence of catalyst SmCl3·6H2O with mole ratio α,ω-alkanediamine : 1,3,6-oxadithiapinane : SmCl3·6H2O=10:20:(0.3-0.7) at temperature ~20°C and atmospheric pressure for 2.5-3.5 h. Output of α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes (1) constitutes 72-85%.

EFFECT: increase of compound application efficiency.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, in which R1 denotes hydrogen or C1-6alkyl; R2 denotes isooxazolyl group, substituted with C1-6alkyl; RB denotes -CF3, -CHF2, -CH2F, or C1-6alkyl. The invention also relates to pharmaceutical compositions for treating cancer which contain the disclosed compounds.

EFFECT: obtaining novel compounds and a pharmaceutical compositions based on said compounds, which can be used in medicine for treating cancerous diseases.

15 cl, 77 dwg, 10 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted heteroaryl derivatives of general formula I: , wherein: A means N, CR7-10, with A at the most twice meaning N; W means O, S or NR4, the values B, C, R7-10 are presented in clause 1 of the patent claim. The method for preparing the compound I is described.

EFFECT: compounds show analgesic activity that enables using them for a variety of diseases, especially acute pain, neuropathic, chronic or inflammatory pain.

16 cl, 2 tbl, 307 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I),

, where groups and radicals R1, R2 independently denote H, C1-8-alkyl or C3-7-cycloalkyl, where the alkyl or cycloalkyl group can be mono- or poly-substituted with identical or different groups R11; or R2 denotes a -CH2- or -CH2-CH2- bridge which is bonded with a group Y, and R1 is as defined above, or denotes a group selected from C1-4-alkyl-CO-, C1-4-alkyl-O-CO-, (C1-4-alkyl)NH-CO- or (C1-4-alkyl)2N-CO-, where the alkyl groups can be mono- or polyfluorinated; or R1 and R2 form an alkylene bridge such that R1R2N- denotes a group selected from: azetidine, pyrrolidine, piperdine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free amino group is substituted with R13, piperidin-4-one, morpholine, thiomorpholine, 4-C1-4-alkoxy iminopiperidin-1-yl and 4-hydroxy iminopiperidin-1-yl. Wherein, when R1 and R2 form an alkylene bridge, one or more H atoms in the alkylene bridge can be substituted with identical or different groups R14, and X denotes a C1-3-alkylene bridge which can contain one, two or three identical or different C1-3-alkyl substitutes; and Y denotes a group of subformula selected from: and , where the group can be mono-substituted with a substitute R20; Z denotes -CH2-CH2- or -C(=O)-CH2-; U, V both denote CH, one of groups U, V denotes N, and the other of U, V denotes CH, where CH can be substituted with L; and L independently denotes halogen, cyano or C1-3-alkyl; and k equals 0, 1 or 2; W is selected from a group consisting of -CH2-O- and -O-CH2-; B is selected from a group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thiophenyl and thiazolyl; each of which can be mono- or poly-substituted with identical or different substitutes R20; radicals R11, R13, R14, R20 assume values given in claim 1. The invention also relates to a pharmaceutical composition containing at least one compound of formula I and having action on MCH receptor.

EFFECT: disclosed pharmaceutical compositions are useful in treating metabolic disorders or eating disorders, especially obesity, bulimia, anorexia, hyperphagia and diabetes.

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing mono-(di-, tetra-)methyl-1,2-bis-(1,3,5-dithiazinan-5-yl)ethanes of general formula (1-3): , (1) R1=CH3, R2, R3, R4=H (2) R1, R3=CH3, R2, R4=H (3) R1, R2, R3, R4=CH3, which involves reaction of hydrogen sulphide-saturated aqueous solution of (37%) formaldehyde and acetaldehyde with 1,2-diaminoethane with molar ratio of initial reagents 1,2-diaminoethane: formaldehyde: acetaldehyde: hydrogen sulphide equal to 10:50:10:40 to obtain (1), 10:40:20:40 to obtain (2), 10:20:40:40 to obtain (3), at temperature 40°C and atmospheric pressure for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as selective sorbents and extraction agents of precious metals, agents for protecting leather, fur and textile from biodeterioration, biologically active substances with respect to different microorganisms and sulphate-reducing bacteria.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1,2-bis-(2,4,6-trialkyl-1,3,5-dithiazinan-5-yl)ethanes of general formula (1): . The method involves reaction of a hydrogen sulphide-saturated aldehyde of formula RCHO, where R=CH3, C2H5, n-C3H7, n-C4H9, n-C5H11, with 1,2-diaminoethane with molar ratio of initial reagents 1,2-diaminoethane: aldehyde: hydrogen sulphide equal to 10:60:40 at temperature 40°C and atmospheric pressure for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as selective sorbents and extraction agents of precious metals, agents for protecting leather, fur and textile from biodeterioration, biologically active substances with respect to different microorganisms and sulphate-reducing bacteria.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2(3H)-benzothiazolone. The method is realised by boiling bis-(2,2'-dimethoxycarboxamido)-phenyl disulphide with zinc dust for 7,5 hours in glacial acetic acid, followed by separating zinc salts, diluting the filtrate with ice water, filtering the crystalline product and washing said product with diluted HCl (1:1) and water and then drying on air and recrystallising from ethanol. The invention also relates to a method of producing 3-2-[2-oxo-1,3-benzothiazol-3(2H)-yl]ethyl-1,3-benzothiazol-2(3H)-one. The method is realised by boiling 2(3H)-benzothiazolone with 1,2-dibromoethane in acetone in the presence of K2CO3. Water is then added and the mixture is treated with diethyl ether, followed by washing the organic phase with 10% aqueous NaOH solution and water, drying with anhydrous potassium carbonate, removing the solvent and recrystallising from methanol. The invention relates to a method of producing 3-(2-chloroacetyl)-1,3-benzothiazol-2(3H)-one. The method is realised by boiling 2(3H)-benzothiazolone in anhydrous benzene with chloroacetyl chloride for 10 hours, then washing the cooled reaction mass with 2% aqueous NaOH solution, extracting with benzene, washing the merged extracts with water, drying with anhydrous calcium chloride and removing the solvent, followed by recrystallisation from chloroform.

EFFECT: improved method of producing 2(3H)-benzothiazolone derivatives.

3 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel carbostyril compounds of general formula (1) or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds, having activity on promotion of TFF2 production, a pharmaceutical composition based on said compounds, an agent based on disclosed compounds used in case of a disorder where up-regulation of TFF has a prophylactic and/or therapeutic effect, use of disclosed compounds to prepare said agent and a method of producing disclosed compounds. The invention also relates to novel specific carbostyril compounds or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds. In structural formula (1), A is a direct bond, a lower alkylene group or lower alkylidene group, X is an oxygen or sulphur atom, the bond between positions 3 and 4 of the carbostyril backbone is a single bond or a double bond, R4 and R5 each denotes a hydrogen atom provided that, when the bond between positions 3 and 4 of the carbostyril backbone is a double bond, R4 and R5 can instead be bonded to each other in form of a -CH=CH-CH=CH- group, and R1, R2 and R3 assume values given in the claims.

EFFECT: high efficiency of compositions based on said compounds.

32 cl, 23 dwg, 184 tbl, 1535 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, in which R1 denotes hydrogen or C1-6alkyl; R2 denotes isooxazolyl group, substituted with C1-6alkyl; RB denotes -CF3, -CHF2, -CH2F, or C1-6alkyl. The invention also relates to pharmaceutical compositions for treating cancer which contain the disclosed compounds.

EFFECT: obtaining novel compounds and a pharmaceutical compositions based on said compounds, which can be used in medicine for treating cancerous diseases.

15 cl, 77 dwg, 10 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: in general formula 1 , a cyclic ring can be selectively formed; each of R1 and R2 is independently selected from a group consisting of hydrogen, with a straight or branched alkyl chain having 1-6 carbon atoms and phenetyl or R1 and R2 together form a 5- or 6-member heterocyclic ring or R1 and R2 together with Ar1 form a bicyclic ring; Ar1 is selected from a group consisting of furanyl, thionyl, methylene dioxyphenyl and phenyl, which can be substituted with at least one identical or different substitutes selected from a group consisting of hydrogen, with a straight or branched alkyl chain having 1-6 carbon atoms, a halogen such as F, O and Br, with a straight or branched alkoxy chain, having 1-6 carbon atoms, nitro and trifluoromethyl; Z is hydrogen or fluorine, or taken together with Ar1 forms a bicyclic ring; Ar2 is selected from a group consisting of phenyl, methylene dioxyphenyl, pyridine pyrimidine, naphthyl, bis(fluorophenyl)methyl and quinoxaline, which can be substituted with at least one identical or different substitutes selected from a group consisting of hydrogen, with a straight or branched alkyl chain, having 1-6 carbon atoms, hydroxy, halogen, with a straight or branched alkoxy chain having 1-6 carbon atoms, nitro, acetyl, tert-butyl acetate, trifluoromethyl, amino and acetate; n is equal to 1 or 2; m is an integer from 0 to 2.

EFFECT: improved method.

26 cl, 2 dwg, 2 tbl, 87 ex

FIELD: chemistry.

SUBSTANCE: invention is a 6-10-member aryl selected from phenyl, naphthyl, tetrahydronaphthalenyl, indanyl or a 6-member heteroaryl containing 1-2 N atoms, selected from pyridyl or pyrimidinyl, where the aryl and heteroaryl groups can be unsubstituted or substituted with 1-3 substitutes selected from a group consisting of C3-6-cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, halogen atom, C1-7-alkyl, C1-7-alkoxy, oxazolyl, piperidin-1-yl, or C1-7-alkyl, substituted with a halogen atom, or represents phenyl, where at least one hydrogen atom is substituted with deuterium or tritium; R2 is a hydrogen atom, C1-7-alkyl or is benzyl, unsubstituted or substituted C1-7-alkoxy or halogen atom; or R1 and R2 together with a N atom with which they are bonded form 2,3-dihydroindol-1-yl or 3,4-dihydro-1quinolin-1-yl. The invention also relates to a method of producing compounds of formula and to a pharmaceutical composition having high affinity for the TAAR1 receptor.

EFFECT: compounds of formula (I), having high affinity for the TAAR1 receptor.

29 cl, 4 dwg, 1 tbl, 183 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted heteroaryl derivatives of general formula I: , wherein: A means N, CR7-10, with A at the most twice meaning N; W means O, S or NR4, the values B, C, R7-10 are presented in clause 1 of the patent claim. The method for preparing the compound I is described.

EFFECT: compounds show analgesic activity that enables using them for a variety of diseases, especially acute pain, neuropathic, chronic or inflammatory pain.

16 cl, 2 tbl, 307 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazole derivatives of formula I wherein R1 represents a hydrogen atom or C1-7alkyl; R2 represents C1-7alkyl; R3 represents C1-7alkyl, C1-7alkoxy, phenyloxy, benzyloxy, a halogen atom or C1-7alkyl substituted by a halogen atom; R4 represents a hydrogen atom or C1-7alkyl; X represents -CH2-, -CHR2 - or -O; Y represents -CH2-, -CH2CH2- or a bond; provided X represents -O-, Y represents -CH2-; Z represents -CH2- or -CHR2-; provided R2 is found twice, simultaneously for X and Z which are CHR2 , then R2 can be identical alkyls or different; n has the value 0, 1 or 2; provided n has the value 2, R3 can be identical or different; and its pharmaceutically acceptable acid addition salts, except for the following compounds: 1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline and 1-(3H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole. Also, the invention refers to a method for preparing the compounds of formula I, to a drug based on the compound of formula I and applying the compound of formula I in preparing the drug.

EFFECT: there are prepared new imidazole derivatives effective in treating such pathological conditions, as bipolar disorder, stress-induced disorder, psychotic disorders, schizophrenia, neurological conditions, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease.

13 cl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (II)

or to its pharmaceutically acceptable salt wherein the ring A represents a group presented by formula 2 R1 represents hydrogen or C1-6alkyl; R2 represents -SR5, halogen, halogenated C1-6alkyl, etc., R3 represents a group presented by formula: -CH=CH-C(RaRb)-Rc-Rd, or a group presented by formula: -(CReRf)m-C(RaRb)-Rc-Rd wherein radicals and symbols have the values presented in the patent claim, R4 represents -OR6, -CONR7R8, -NR9CONR7R8, -(CR10R11)POH, -(CR10R11)pOCONR7R8, -NR9COR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9CONR7R8, -CN, halogen or NR9(C=O)OR12; R5 represents C1-6alkyl; R6 represents -CONR7R8; each of R7 and R8 independently represents hydrogen or etc., R10 and R11 independently represents hydrogen; R12 represents C1-6alkyl; each of m and p independently represents an integer 1 to 3. This compound is applicable as a type 1 11β-hydroxysteroiddehydrogenase inhibitor.

EFFECT: invention also refers to single compounds, pharmaceutical compositions on the basis of the declared compounds, to a method for preventing and treating diabetes and the use of the compound of formula (II).

21 cl, 289 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel clathrate complex of β-cyclodextrin with 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine of formula : with molar ratio 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine: β-cyclodextrin from 1:1 to 1:10, synthesis method and use thereof as an antiviral agent for treating influenza. The disclosed method involves mixing solutions of β-cyclodextrin and 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine in molar ratio from 1:1 to 1:10 while stirring and heating to temperature not higher than 70°C and then maintaining said conditions until a homogeneous solution is obtained and extraction of the obtained complex.

EFFECT: clathrate complex is a novel effective anti-influenza virus agent which is obtained using a novel efficient method.

13 cl, 2 ex, 3 tbl, 11 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of 2-substituted azole

compounds of formula , (a) reaction of an aldehyde of formula

with an azole of formula in the presence of a carbonylating agent of formula to obtain an oxazolidone of formula , reaction of the oxazolidone of formula (Ia) so as to perform hydrolysis of a triarylmethyl group, splitting the O-(C=Q) bond and opening the oxazolidone, followed by reaction of the obtained intermediate compound with Prot-Z, where Prot-Z is an agent which protects an amino group, to obtain an azole-containing intermediate compound of formula (lb) and and oxidation of the intermediate compound of formula (Ib) to obtain a 2-substituted azole derivative of formula (I). The invention also relates to azole compounds of formulae (I), (la), (lb), (Ic) and (II).

EFFECT: novel method of obtaining azoles of formula (I), as well as obtaining novel compounds of formulae (I), (la), (lb), (Ic) and (II), having useful biological properties.

41 cl, 5 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel dihydroindolone derivatives of formula I or its pharmaceutically acceptable salts: Formula I, where values of R1-R9,R16,R17,n1,n2,n3, m, are given in 1 of the formula. Described are methods of obtaining compounds.

EFFECT: compounds demonstrate anti-tumour activity, which makes it possible to use them in pharmaceutical compositions for treatment and/or prevention of diseases, associated with protein tyrosine kinases in organism, in particular for treatment and/or prevention of tumours and diseases, associated with proliferation of fibroblasts.

13 cl, 1 dwg, 5 tbl, 37 ex

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