2-pyridone derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to 2-pyridone compounds, represented by general formula [1], , where A represents benzene ring or pyridine ring, X represents structure, represented by general formula [3], V represents single bond or lower alkylene, W represents single bond, ether bond or lower alkylene, which can include ether bond, or their tautomers or stereoisomers.

EFFECT: obtaining pharmaceutically acceptable salts, which possess excellent activating activity with respect to GK and can be applied as medications.

27 cl, 23 tbl, 371 ex

 

The technical field to which the invention relates

The present invention relates to new derivatives of 2-pyridone with the activating glucokinase effect, and a drug containing these compounds as active component.

Background to the invention

Glucokinase (hereinafter referred to as GK) belongs to the family of hexokinase and catalyzes the phosphorylation of glucose contained in the cells such as beta cells of the pancreas or hepatocytes. GK in the liver and GK in beta-cells of the pancreas differ from each other in the sequence of the 15 N-terminal amino acids due to differences in splicing, but have the same enzymatic properties. GK has a high affinity to glucose S0,5about 10 mm and is not inhibited by the product, glucose 6-phosphate. Therefore the rate of reaction is sensitive to physiological changes in glucose levels in the blood. GK in beta-cells of the pancreas modulates dependent insulinotropic insulin secretion, and GK in the liver modulates glycolytically way or glycogenesis, which in turn ensures the maintenance and regulation of glucose levels in the blood. Therefore, it is assumed that GK acts as a glucose sensor, maintaining the homeostasis of glucose levels in the blood (see non-patent document 1).

Subjected� genetic engineering of the mouse and gene mutations found in humans, support the hypothesis that GK functions as in vivo glucose sensor. GK homozygous mice died from hyperglycemia immediately after birth, while heterozygous mice were observed hyperglycemia and impaired glucose tolerance (see non-patent document 2). Conversely, in mice with sverkhekspressiya GK confirmed the presence of hypoglycemia (see non-patent document 3). In addition, when human MODY2 (insulin-independent diabetes of the young), in which there is GK gene mutation in a person's youth develop diabetes (see non-patent document 4). It was confirmed that these gene mutations reduce the activity of GK. On the contrary, it was already reported families with gene mutations that increase the activity of GK (see non-patent document 5). As discovered, these gene mutations increase the affinity of GK for glucose and cause symptoms of fasting hypoglycemia associated with elevated concentrations of insulin in the blood.

Thus, it is shown that GK acts as a glucose sensor in mammals, including humans.

Substances that increase the activity of GK (hereinafter described as a GK-activating substances), can improve the symptoms of hyperglycemia, increasing metabolism of glucose and glycogenesis in the liver and/or caused by glucose insulin secretion from the beta cells of the pancreas. You can also expect coloccini symptoms of hyperglycemia led to the treatment and prevention of chronic diabetic complications, such as retinopathy, nephropathy, neurosis, ischemic heart disease and arteriosclerosis, and to cure and prevent diabetes-related diseases such as obesity, hyperlipidemia, hypertension and metabolic syndrome. It is therefore expected that compounds that increase the action of GK will be effective therapeutic agents against diabetes.

On the other hand, as previously reported, GK is expressed not only in the pancreas and liver, but also in the food centre and has an important function in antiedema effect on glucose (see non-patent document 6). Therefore, GK-activating substances can act on the food center and to provide antipixel effect and are expected to serve not only as a therapeutic agent against diabetes, but also as a therapeutic agent against obesity.

As a GK-activating substances known to some derivative of propionamide, picolylamine, benzamide derivative and benzimidazole, but the compounds of the present invention are not disclosed (see patent documents 1, 2, 3 and 4). It was reported also on derivatives of 2-pyridone structurally similar to the compounds of the present invention, but the compounds of the present invention were not disclosed; these compounds differ from the compounds of the present invention in that they described not in relation to the pharmaceutical industry�ski applications and in regard to the establishment of the method of synthesis of derivatives of 2-pyridone (see non-patent document 7). In addition, the known derivatives of 2-pyridone as therapeutic drugs against diabetes, but they differ from the compounds of the present invention relating to the structure, for example the substituent at position 3 of pyridone (see patent document 5). In addition, already known as GK-activating substances some derivatives of allodapini that may have pseudocyclic structure, but they are acyclic compounds and are different from the compounds of the present invention (see patent document 6).

[Documents of the prior art]

[Non-patent documents]

[Non-patent document 1] Matschinsky F. M., and Magnuson M. A., Frontiers in Diabetes, 16, 2004

[Non-patent document 2] A. Grupe et al. Cell, 83, 1, 69-78, 1995

[Non-patent document 3] Ferre T. et al. Proc. Natl. Acad. Sci., 93, 14, 7225-7230, 1996

[Non-patent document 4] Vionnet N. et al. Nature, 356, 6371, 721-722, 1992

[Non-patent document 5] Glaser B. et al. N. Engl. J. Med. 338, 4, 226-230, 1998

[Non-patent document 6] L. Kang et al. Diabetes, 55, 2, 412-420, 2006

[Non-patent document 7] R. Latif et al. J. Chem. Soc. C. Organic, 17, 2140-2144, 1968

[Patent documents]

[Patent document 1] WO 01/085707

[Patent document 2] WO 04/081001

[Patent document 3] WO 05/044801

[Patent document 4] WO 07/007910

[Patent document 5] US 4275069

[Patent document.�t 6] WO 01/44216

A brief summary of the invention

The problem solved by the invention

The aim of the present invention is to provide compounds having an excellent GK-activating effect and are useful as medicines.

Means for solving the problem

As a result of extensive research in the search for compounds having GK-activating effect, the authors present invention have found that this objective can be achieved by using derivatives of 2-pyridone represented by the General formula [1] or their pharmaceutically acceptable salts. This finding led to the creation of the present invention.

In particular, in accordance with the present invention it is proposed

(I) Derivative of 2-pyridone represented by the formula [1]:

[Formula 1]

{where in the formula [1]:

the ring is denoted by the symbol a represents a benzene ring or a pyridine ring,

R1is an RA-ZA-,

where-ZA- represents a single bond or represents any of the following formulas [2]:

[Formula 2]

when-ZA- represents any of the formulas [2],

RArepresents a lower alkyl group, lower cycloalkyl group, lower alkenyl�ing group, lower alkylamino group, aryl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower Alchemilla group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents); or

when-ZA- represents a single bond,

RArepresents a lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower alkenylphenol group, aryl group, heterocyclyl group (where lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower Alchemilla group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents), a hydrogen atom, a cyano group, a halogen atom, a nitro group, a formyl group, a hydroxy-group, amino group, carbamoyl group, formylamino, sulfamoyl group or raidgroup;

X is any one of structures represented by the formulas [3] shown below:

[Formula 3]

RXrepresents a hydrogen atom, a lower alkyl g�the SCP, lower cycloalkyl group, ORZ3, SRZ3or NRZ3RZ4,

RZ1, RZ2, RZ3and RZ4are the same or different and each represents a hydrogen atom or a lower alkyl group,

RY1and RY2are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, lower cycloalkyl group or hydroxy-group,

Y represents-O-, -S - or-NRZ5-,

RZ5represents a hydrogen atom or a lower alkyl group,

R4together with RY1form a saturated or unsaturated 3-8-membered ring which is formed together with the carbon atom to which is attached substituents and which may contain one or more nitrogen atoms, oxygen or sulfur, where the ring is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents),

or R4together with RZ5form a saturated or unsaturated 3-8-membered ring which is formed together with the nitrogen atom to which attached substituents and which may contain one or more nitrogen atoms, oxygen or sulfur, where the ring is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from follow�her group A1 substituents),

or R4is an RB-ZB-,

where-ZB- represents a single bond or represents any of the following formulas [4]:

[Formula 4]

when-ZB- represents any of the formulas [4],

RBrepresents a lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower alkenylphenol group, aryl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower Alchemilla group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents); or,

when-ZB- represents a single bond,

RBrepresents a lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower alkenylphenol group, aryl group, heterocyclyl group (where lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower Alchemilla group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 deputies), the atom of water�ode, a cyano group, a halogen atom, a nitro group, a formyl group, a hydroxy-group, amino group, carbamoyl group, formylamino, sulfamoyl group or raidgroup;

RZ6and RZ7are the same or different and each represents a hydrogen atom or a lower alkyl group,

RWrepresents ORCor NRCRZ8,

RCrepresents a lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower alkenylphenol group, aryl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower Alchemilla group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents),

RZ8represents a hydrogen atom or a lower alkyl group,

or RZ8together with RCmay form a saturated or unsaturated 3-8-membered ring which is formed together with the nitrogen atom to which attached substituents and which may contain one or more nitrogen atoms, oxygen or sulfur, where the ring is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from C�next group A1 substituents),

group A1 substituents represents a halogen atom, a nitro group, a cyano group, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom, nitro group, cyanide groups, lower cycloalkyl group, aryl group (where the aryl group is unsubstituted or substituted by 1 to 3 halogen atoms), heterocyclyl groups, hydroxyl groups, lower alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower cycloalkanes, aryloxy groups, aryl-lower alkoxygroup, geterotsiklicheskikh, heterocyclyl-lower alkoxygroup, lower allylthiourea, amino, mononessa of alkylamino, mononessa of cycloalkylation, denissa of alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, a lower alkanolamine and the carbonyl group), a lower cycloalkyl group, aryl group, heterocyclyl group (a low cycloalkyl group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A2 deputies), a hydroxy-group, a lower ALCO�syruppy (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), the lowest cycloalkanes, alloctype, aryl-lower alkoxygroup, geterotsiklicheskikh, heterocyclyl-lowest alkoxygroup, the lowest allylthiourea, an amino group, mononessa alkylamino, mononessa cycloalkylation, denissow alkylamino, lower alkanoyloxy group, lower cycloalkylcarbonyl group, geterotsiklicheskikh group, lower alkylsulfonyl group, lower alkoxycarbonyl group, the lowest alkanolamines or oxoprop,

group A2 deputies represents a lower alkyl group, lower alkoxygroup, the lowest allylthiourea, mononessa alkylamino, denissow alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, the lowest alkanolamine, a hydroxy-group, halogen atom, oxoprop or an amino group,

R2and R3are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, carbamoyl group, a lower alkyl group, lower alkylsulfonyl group, lower cycloalkyl group, the lowest alkoxygroup, the lowest cycloalkanes (where lower alkyl group, lower alkylsulfonyl group, lower cycloalkyl group, lower alkoxygroup or lower cicloergometria is unsubstituted or W�aligned 1-3 groups, which may be the same or different and selected from the group consisting of a halogen atom and hydroxy-group) or a hydroxy-group,

or adjacent R1and R2together form a C9-C12condensed bicyclic hydrocarbon ring, or a C6-C11condensed bicyclic heterokonta together with the benzene ring or pyridine ring, which is attached substituents (where C9-C12condensed bicyclic hydrocarbon ring, or a C6-C11condensed bicyclic heteroclita is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A4 substituents),

R5and the group A4 substituents are the same or different and each represents a halogen atom, carbamoyl group, lower alkanoyloxy group, an amino group, denissow alkylamino, a lower alkyl group, lower cycloalkyl group, the lowest alkoxygroup, the lowest cycloalkanes, aryl group, heteroaryl group, alloctype or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, lower alkoxygroup lowest cicloergometria, aryl group, heteroaryl group, alloctype or heterocyclyl group is irreplaceable�internal or substituted with 1-3 groups, which may be the same or different and selected from the following group A3 substituents),

group A3 substituents represents a halogen atom, a nitro group, a cyano group, a hydroxy-group, lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom, nitro group, cyanide groups, hydroxyl groups, lower cycloalkyl group, aryl group, heterocyclyl group, a lower alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower cycloalkanes, aryloxy groups, aryl-lower alkoxygroup, geterotsiklicheskikh, heterocyclyl-lower alkoxygroup, amino, mononessa of alkylamino, mononessa of cycloalkylation and denissa of alkylamino), lower cycloalkyl group, aryl group, heterocyclyl group, the lowest alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower cycloalkanes, alloctype, aryl-lower alkoxygroup, geterotsiklicheskikh, heterocyclyl-lowest alkoxygroup, an amino group, mononessa alkylamino, mononessa cycloalkylation, denissow alkylamino, lower alkoxycarbonyl group and�and carbamoyl group

V represents a single bond or lower alkylenes group and

W is a single bond, a simple ether bond or lower alkylenes group (a low Allenova group can contain simple ether bond},

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(II) In accordance with another variant of the present invention is proposed

the derived 2-pyridone under item (I) represented by the formula [1]:

[Formula 5]

{where in the formula [1]:

the ring is denoted by the symbol a represents a benzene ring or a pyridine ring,

R1is an RA-ZA-,

where-ZA- represents a single bond or represents any of the following formulas [2]:

[Formula 6]

when-ZA- represents any of the formulas [2],

RArepresents a lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower alkenylphenol group, aryl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower Alchemilla group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-3 g�uppada, which may be the same or different and selected from the following group A1 substituents); or,

when-ZA- represents a single bond,

RArepresents a lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower alkenylphenol group, aryl group, heterocyclyl group (where lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower Alchemilla group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents), a hydrogen atom, a cyano group, a halogen atom, a nitro group, a formyl group, a hydroxy-group, amino group, carbamoyl group, formylamino, sulfamoyl group or raidgroup;

X is any one of structures represented by the formulas [3] shown below:

[Formula 7]

RXrepresents a hydrogen atom, a lower alkyl group, lower cycloalkyl group, ORZ3, SRZ3or NRZ3RZ4,

RZ1, RZ2, RZ3and RZ4are the same or different and each represents a hydrogen atom or a lower alkyl group,

RY1and RY2are the same or RA�different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, lower cycloalkyl group or hydroxy-group,

Y represents-O-, -S - or-NRZ5-,

RZ5represents a hydrogen atom or a lower alkyl group,

R4together with RY1form a saturated or unsaturated 3-8-membered ring which is formed together with the carbon atom to which is attached substituents and which may contain one or more nitrogen atoms, oxygen or sulfur, where the ring is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents),

or R4together with RZ5form a saturated or unsaturated 3-8-membered ring which is formed together with the nitrogen atom to which attached substituents and which may contain one or more nitrogen atoms, oxygen or sulfur, where the ring is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents),

or R4is an RB-ZB-,

where-ZB- represents a single bond or represents any of the following formulas [4]:

[Formula 8]

when-ZB- represents any of the formulas [4],

RBis the FDS�th lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower alkenylphenol group, aryl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower Alchemilla group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents); or,

when-ZB- represents a single bond,

RBrepresents a lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower alkenylphenol group, aryl group, heterocyclyl group (where lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower Alchemilla group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents), a hydrogen atom, a cyano group, a halogen atom, a nitro group, a formyl group, a hydroxy-group, amino group, carbamoyl group, formylamino, sulfamoyl group or raidgroup;

RZ6and RZ7are the same or different and each represents a hydrogen atom or a lower alkyl group,

RWPR�dstanley a OR Cor NRCRZ8,

RCrepresents a lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower alkenylphenol group, aryl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, a lower alkenyl group, lower Alchemilla group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents),

RZ8represents a hydrogen atom or a lower alkyl group,

or RZ8together with RCmay form a saturated or unsaturated 3-8-membered ring which is formed together with the nitrogen atom to which attached substituents and which may contain one or more nitrogen atoms, oxygen or sulfur, where the ring is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A1 substituents),

group A1 substituents represents a halogen atom, a nitro group, a cyano group, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom, nitro group, zenegra�PY, lower cycloalkyl group, aryl group, heterocyclyl groups, hydroxyl groups, lower alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower cycloalkanes, aryloxy groups, aryl-lower alkoxygroup, geterotsiklicheskikh, heterocyclyl-lower alkoxygroup, lower allylthiourea, amino, mononessa of alkylamino, mononessa of cycloalkylation, denissa of alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, a lower alkanolamine and the carbonyl group), a lower cycloalkyl group, aryl group, heterocyclyl group (a low cycloalkyl group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A2 deputies), hydroxyl groups, lower alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower cycloalkanes, aryloxy groups, aryl-lower alkoxygroup, geterotsiklicheskikh, heterocyclyl-lower alkoxygroup, lower allylthiourea, amino, mononessa of alkylamino, mononessa of cycloalkylation, denissa of alkylamino, lower alkanoyloxy group, n�SSA alkylsulfonyl group, lower alkoxycarbonyl group, a lower alkanolamine or carbonyl group,

group A2 deputies represents a lower alkyl group, lower alkoxygroup, the lowest allylthiourea, mononessa alkylamino, denissow alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, the lowest alkanolamine, a hydroxy-group, halogen atom, oxoprop or an amino group,

R2and R3are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, lower cycloalkyl group, the lowest alkoxygroup or lower cycloalkanes (where lower alkyl group, lower cycloalkyl group, lower alkoxygroup or lower cicloergometria is unsubstituted or substituted by 1 to 3 halogen atoms),

or adjacent R1and R2together form a C9-C12condensed bicyclic hydrocarbon ring, or a C6-C11condensed bicyclic heterokonta together with the benzene ring or pyridine ring, which is attached substituents (where C9-C12condensed bicyclic hydrocarbon ring, or a C6-C11condensed bicyclic heteroclita is unsubstituted or substituted with 1-3 �the group, which may be the same or different and selected from the following group A4 substituents),

R5and the group A4 substituents are the same or different and each represents a halogen atom, a lower alkyl group, lower cycloalkyl group, the lowest alkoxygroup, the lowest cycloalkanes, aryl group, heteroaryl group, or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, lower alkoxygroup lowest cicloergometria, aryl group, heteroaryl group, or heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the following group A3 substituents),

group A3 substituents represents a halogen atom, a nitro group, a cyano group, a hydroxy-group, lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom, nitro group, cyanide groups, hydroxyl groups, lower cycloalkyl group, aryl group, heterocyclyl group, a lower alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower cycloalkanes, aryloxy groups, aryl-lower alkoxygroup, heterocyclics�the group, heterocyclyl-lower alkoxygroup, amino, mononessa of alkylamino, mononessa of cycloalkylation and denissa of alkylamino), lower cycloalkyl group, aryl group, heterocyclyl group, the lowest alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower cycloalkanes, alloctype, aryl-lower alkoxygroup, geterotsiklicheskikh, heterocyclyl-lowest alkoxygroup, an amino group, mononessa alkylamino, mononessa cycloalkylation, denissow alkylamino or lower alkoxycarbonyl group

V represents a single bond or lower alkylenes group and

W is a single bond, a simple ether bond or lower alkylenes group (a low Allenova group can contain simple ether bond)},

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(III) In accordance with another variant of the present invention is proposed

the derived 2-pyridone under item (I) or (II) represented by the formula [5]:

[Formula 9]

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(IV) In accordance with another variant of this every�retenu offered

the derived 2-pyridone under item (III) represented by the formula [6]:

[Formula 10]

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(V) In accordance with another variant of the present invention is proposed

the derived 2-pyridone under item (IV) represented by the formula [7]:

[Formula 11]

{where in the formula [7],

R4is an RB-ZB-,

where-ZB- represents a single bond or represents any of the following formulas [8]:

[Formula 12]

when-ZB- represents any of the formulas [8],

RBrepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A1 substituents); or,

when-ZB- represents a single bond,

RBrepresents a lower alkyl group, lower cycloalkyl group, aryl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same Il� different and selected from the following group A1 deputies);

group A1 substituents represents a halogen atom, a lower alkyl group, lower cycloalkyl group, aryl group, heterocyclyl group (a low cycloalkyl group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A2 deputies), a hydroxy-group, the lowest alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower allylthiourea, an amino group, mononessa alkylamino, denissow alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group the lowest alkanolamines or oxoprop and

group A2 deputies represents a lower alkyl group, lower alkoxygroup, the lowest allylthiourea, mononessa alkylamino, denissow alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, the lowest alkanolamine, a hydroxy-group, halogen atom, oxoprop or an amino group},

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(VI) according To another variant of the present invention is proposed

the derived 2-PI�idea under item (V), where

R1is an RA-ZA-,

where-ZA- represents a single bond or represents any of the following formulas [9]:

[Formula 13]

when-ZA- represents any of the formulas [9],

RArepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, mononessa of alkylamino and denissa of alkylamino), lower cycloalkyl group or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with one lower alkyl group); or,

when-ZA- represents a single bond,

RArepresents a hydrogen atom or a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, a lower alkoxygroup and denissa of alkylamino);

R2represents a hydrogen atom, a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or sameshe�Noah 1-3 halogen atoms) or lower alkoxygroup,

R4is an RB-ZB-,

where-ZB- is a single bond and

RBrepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by one group selected from the group consisting of lower cycloalkyl group, heterocyclyl groups, hydroxyl groups and lower alkanolamines), lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group and the carbonyl group), and

R5represents a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom and hydroxyl groups), lower cycloalkyl group or aryl group,

tautomer or stereoisomer this link�, its pharmaceutically acceptable salt, or its solvate.

(VII) In accordance with another variant of the present invention is proposed

the derived 2-pyridone under item (IV) represented by the formula [10]:

[Formula 14]

{where in the formula [10],

R4is an RB-ZB-,

where-ZB- represents a single bond or represents any of the following formulas [8]:

[Formula 15]

when-ZB- represents any of the formulas [8],

RBrepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A1 substituents); or,

when-ZB- represents a single bond,

RBrepresents a lower alkyl group, lower cycloalkyl group, aryl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A1 deputies);

group A1 substituents represents a halogen atom, a lower alkyl group, lower cycloalkyl� group aryl group, heterocyclyl group (a low cycloalkyl group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A2 deputies), a hydroxy-group, the lowest alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower allylthiourea, an amino group, mononessa alkylamino, denissow alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, the lowest alkanolamines or oxoprop and

group A2 deputies represents a lower alkyl group, lower alkoxygroup, the lowest allylthiourea, mononessa alkylamino, denissow alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, the lowest alkanolamine, a hydroxy-group, halogen atom, oxoprop or an amino group},

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(VIII) according To another variant of the present invention is proposed

the derived 2-pyridone under item (VII), where

R1is an RA-ZA-,

where-ZA- represents one�nary a bond or represents any of the following formulas [9]:

[Formula 16]

when-ZA- represents any of the formulas [9],

RArepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, mononessa of alkylamino and denissa of alkylamino), lower cycloalkyl group or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with one lower alkyl group); or

when-ZA- represents a single bond,

RArepresents a hydrogen atom, a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, a lower alkoxygroup and denissa of alkylamino), lower cycloalkyl group, aryl group or heterocyclyl group;

R2represents a hydrogen atom, a halogen atom, carbamoyl group, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or R�EIT and selected from the group consisting of a halogen atom and hydroxy-group) or lower alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms),

R3represents a hydrogen atom, a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms), lower alkoxygroup or a hydroxy-group,

R4is an RB-ZB-,

where-ZB- is a single bond and

RBrepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by one group selected from the group consisting of lower cycloalkyl group, aryl group, heterocyclyl groups (where heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a lower alkyl group and the carbonyl group), hydroxyl groups and lower alkanolamines), lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group, consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or heterocyclyl group (where heterocycl�price group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group, lower cycloalkylcarbonyl group, geterotsiklicheskikh group, lower alkylsulfonyl group and the carbonyl group), and

R5represents a halogen atom, carbamoyl group, lower alkanoyloxy group, an amino group, denissow alkylamino, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom and hydroxyl groups), lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted with one hydroxy-group), the lowest alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), aryl group, heteroaryl group, or alloctype (where alloctype is unsubstituted or substituted by one group, selected from the group consisting of a halogen atom and a lower alkyl group),

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(IX) according To another variant of the present invention is proposed

the derived 2-pyridone under item (VIII)

R1p�ecstasy an R A-ZA-,

where-ZA- represents a single bond or represents any of the following formulas [11]:

[Formula 17]

when-ZA- represents any of the formulas [11],

RArepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms), lower cycloalkyl group or heterocyclyl group; or,

when-ZA- represents a single bond,

RArepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or a halogen atom;

R2represents a hydrogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms), a halogen atom or a lower alkoxygroup,

R3represents a hydrogen atom or a halogen atom and

R5represents a chlorine atom or a cyclopropyl group,

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(X) In accordance with another variant of the present invention is proposed

the derived 2-pyridone under item (VI) or (IX), where RBis pyrrolidinyloxy group (where pyrrolidinyl GRU�PA is substituted with one exography or lower alkanoyloxy group),

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XI) according To another variant of the present invention is proposed

the derived 2-pyridone under item (X), where

RBis a group represented by the formula [12]:

[Formula 18]

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XII) according To another variant of the present invention is proposed

any of derivatives of 2-pyridone shown below:

6-{(E)-1-(3-chloro-4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

6-{(E)-1-(4-chlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

6-{(E)-1-[3-chloro-4-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

6-{(E)-1-(4-chloro-3-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

6-{(E)-1-(4-chloro-3-fluorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

3-cyclopropyl-6-{(E)-1-(4-fluoro-3-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

3-cyclopropyl-6-{(E)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

3-cyclopropyl-6-{(E)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(H)-it,

6-{(E)-1-(4-chloro-3-methoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

3-cyclopropyl-6-{(E)-1-[4-(deformity)-3-fluorophenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

3-cyclopropyl-6-{(E)-1-[4-methoxy-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

3-cyclopropyl-6-{(E)-1-[3-methyl-4-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

6-{(E)-1-(4-chloro-2-fluorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

3-cyclopropyl-6-{(E)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

6-{(E)-1-[3-chloro-4-(cyclopropylamino)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

6-{(E)-1-[3-chloro-4-(2,2,2-triptoreline)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

6-{(E)-1-(5-chloro-2-fluoro-4-methoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

6-{(E)-1-[3-chloro-4-(deformedarse)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

3-cyclopropyl-6-{(E)-1-(4-ethoxy-2,3-differenl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

3-cyclopropyl-6-{(E)-1-[4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

6-{(E)-1-(2-chloro-4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

3-dihydro-6-[(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-4-[(trifluoromethyl)sulfonyl]phenyl}ethenyl]pyridin-2(1H)-he,

3-chloro-6-{(E)-1-[4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

3-chloro-6-{(E)-1-[3-chloro-4-(ethylsulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

3-chloro-6-{(E)-1-[4-(cyclopentylmethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

3-cyclopropyl-6-{(E)-1-[4-(methyl-sulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

6-{(E)-1-[3-chloro-4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he,

3-cyclopropyl-6-{(E)-1-[4-(cyclopropanesulfonyl)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

3-chloro-6-{(E)-1-[4-(cyclopropanesulfonyl)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he and

3-chloro-6-{(E)-1-[3-chloro-4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he,

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XIII) according To another variant of the present invention is proposed

the derived 2-pyridone under item (III) represented by the formula [13]:

[Formula 19]

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XIV) according To another variant of the present invention is proposed

the derived 2-pyridone under item(XIII), represented by the formula [14]:

[Formula 20]

{where in the formula [14],

R4is an RB-ZB-,

where-ZB- represents a single bond or represents any of the following formulas [8]:

[Formula 21]

when-ZB- represents any of the formulas [8],

RBrepresents a lower alkyl group, lower cycloalkyl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A1 substituents); or,

when-ZB- represents a single bond,

RBrepresents a lower alkyl group, lower cycloalkyl group, aryl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A1 deputies);

group A1 substituents represents a halogen atom, a lower alkyl group, lower cycloalkyl group, aryl group, heterocyclyl group (denissa cycloalkyl group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A2 deputies), the lower alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower allylthiourea, an amino group, mononessa alkylamino, denissow alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, the lowest alkanolamines or oxoprop and

group A2 deputies represents a lower alkyl group, lower alkoxygroup, the lowest allylthiourea, mononessa alkylamino, denissow alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, the lowest alkanolamine, a hydroxy-group, halogen atom, oxoprop or an amino group},

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XV) according To another variant of the present invention is proposed

the derived 2-pyridone under item (XIV), where

R1is an RA-ZA-,

where-ZA- represents a single bond or represents any of the following formulas [9]:

[Formula 22]

when-ZA- represents any of the formulas [9],

RArepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, mononessa of alkylamino and denissa of alkylamino), lower cycloalkyl group or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with one lower alkyl group); or

when-ZA- represents a single bond,

RArepresents a hydrogen atom or a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, a lower alkoxygroup and denissa of alkylamino);

R2represents a hydrogen atom, a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower alkoxygroup,

R4is an RB-ZB-,

where-ZB- is a single bond and

RBrepresents a lower alkyl g�the SCP (where the lower alkyl group is unsubstituted or substituted by one group, selected from the group consisting of lower cycloalkyl group, heterocyclyl groups, hydroxyl groups and lower alkanolamines), lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group and the carbonyl group) and

R5represents a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom and hydroxyl groups), lower cycloalkyl group or aryl group,

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XVI) according To another variant of the present invention is proposed

the derived 2-pyridone under item (XIII) represented by the formula [15]:

[Formula 23]

{where in the formula [15]

R4is an RB-ZB-,

where-ZB- represents a single bond or represents any of the following formulas [8]:

[Formula 24]

when-ZB- represents any of the formulas [8],

RBrepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A1 substituents); or,

when-ZB- represents a single bond,

RBrepresents a lower alkyl group, lower cycloalkyl group, aryl group or heterocyclyl group (where lower alkyl group, lower cycloalkyl group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following group A1 deputies);

group A1 substituents represents a halogen atom, a lower alkyl group, lower cycloalkyl group, aryl group, heterocyclyl group (a low cycloalkyl group, aryl group or heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the following g�uppy Vice-A2), the hydroxy-group, the lowest alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), lower allylthiourea, an amino group, mononessa alkylamino, denissow alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, the lowest alkanolamines or oxoprop and

group A2 deputies represents a lower alkyl group, lower alkoxygroup, the lowest allylthiourea, mononessa alkylamino, denissow alkylamino, lower alkanoyloxy group, lower alkylsulfonyl group, lower alkoxycarbonyl group, the lowest alkanolamine, a hydroxy-group, halogen atom, oxoprop or an amino group},

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XVII) according To another variant of the present invention is proposed

the derived 2-pyridone under item (XVI), where

R1is an RA-ZA-,

where-ZA- represents a single bond or represents any of the following formulas [9]:

[Formula 25]

when-ZA- represents any of the formulas [9],

RArepresents a lower alkyl group (where the lower alkyl group is a m�is unsubstituted or substituted with 1-3 groups, which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, mononessa of alkylamino and denissa of alkylamino), lower cycloalkyl group or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with one lower alkyl group); or,

when-ZA- represents a single bond,

RArepresents a hydrogen atom, a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, a lower alkoxygroup and denissa of alkylamino), lower cycloalkyl group, aryl group or heterocyclyl group;

R2represents a hydrogen atom, a halogen atom, carbamoyl group, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom and hydroxy-group) or lower alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms),

R3represents a hydrogen atom, a halo atom�of Jena, lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms), lower alkoxygroup or a hydroxy-group,

R4is an RB-ZB-,

where-ZB- is a single bond and

RBrepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by one group selected from the group consisting of lower cycloalkyl group, aryl group, heterocyclyl groups (where heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a lower alkyl group and the carbonyl group), hydroxyl groups and lower alkanolamines), lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group, consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group, a lower C�Gloucestershire group, geterotsiklicheskikh group, lower alkylsulfonyl group and the carbonyl group), and

R5represents a halogen atom, carbamoyl group, lower alkanoyloxy group, an amino group, denissow alkylamino, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom and hydroxyl groups), lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted with one hydroxy-group), the lowest alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), aryl group, heteroaryl group, or alloctype (where alloctype is unsubstituted or substituted by one group, selected from the group consisting of a halogen atom and a lower alkyl group),

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XVIII) according To another variant of the present invention is proposed

the derived 2-pyridone under item (XVII), where

R1is an RA-ZA-,

where-ZA- represents a single bond or represents any of the following formulas [11]:

[Formula 26]

when-ZA- represents any of the formulas [11],

RArepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms), lower cycloalkyl group or heterocyclyl group; or,

when-ZA- represents a single bond,

RArepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or a halogen atom;

R2represents a hydrogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms), a halogen atom or a lower alkoxygroup,

R3represents a hydrogen atom or a halogen atom and

R5represents a chlorine atom or a cyclopropyl group,

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XIX) according To another variant of the present invention is proposed

the derived 2-pyridone under item (XV) or (XVIII), where RBis pyrrolidinyloxy group (where pyrrolidinyl group is substituted with one exography or lower alkanoyloxy group), a tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt or e�about the solvate.

(XX) according To another variant of the present invention is proposed

the derived 2-pyridone under item (XIX), where

RBis a group represented by the formula [12]:

[Formula 27]

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XXI) according To another variant of the present invention is proposed

any of derivatives of 2-pyridone shown below:

6-{1-(4-chloro-3-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he,

6-{1-[4-chloro-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he,

3-dihydro-6-{1-[4-(deformity)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he,

3-dihydro-6-{1-[4-(deformity)-3-fluorophenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he,

6-{1-[3-chloro-4-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he,

6-{1-[3-chloro-4-(propane-2-yloxy)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he,

3-cyclopropyl-6-{1-[3-methyl-4-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he,

6-{1-[3-chloro-4-(cyclopropylamino)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he,

6-{1-(5-chloro-2-fluoro-4-methoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylbenzene(1H)-he,

6-{1-[3-chloro-4-(deformedarse)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he,

3-dihydro-6-{1-[4-(cyclopropanesulfonyl)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he,

3-chloro-6-{1-[3-chloro-4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he and

6-{1-[3-chloro-4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he,

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XXII) In accordance with another variant of the present invention is proposed

the derived 2-pyridone under item (III) represented by the formula [16]:

[Formula 28]

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XXIII) according To another variant of the present invention is proposed

the derived 2-pyridone under item (III) represented by the formula [17]:

[Formula 29]

tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XXIV) In accordance with another variant of the present invention is proposed

the derived 2-pyridone under item (III) represented by the formula [18]:

[Formula 30]

Tau�Omer or a stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XXV) In accordance with another variant of the present invention is proposed

a medicament containing as an active ingredient a derivative of 2-pyridone according to any one of paragraphs (I) to(XXIV), a tautomer or stereoisomer of the compound, its pharmaceutically acceptable salt, or its solvate.

(XXVI) according To another variant of the present invention is proposed

medicament according to item (XXV), where the product is used for the prevention or treatment of a disease or condition that can be improved by activating glucokinase effect.

(XXVII) according To another variant of the present invention is proposed

medicament according to item (XXV), where the product is a prophylactic or therapeutic agent against diabetes or obesity.

[Advantages of the present invention]

The present invention may provide compounds having an excellent GK activating effect.

[Mode for carrying out the invention]

The present invention is described in more detail below, but is described as an example of variants of its implementation, particularly its limit.

In the present invention, "n" means normal, "i" means ISO, "s" means in�origny, the "t" means tertiary, "c" means cyclo, "o" means ortho, "m" means meta, "p" means a pair.

"Halogen atom" means a fluorine atom, chlorine atom, bromine atom and iodine atom.

The "lower alkyl group" means a straight or branched alkyl group containing 1-6 carbon atoms. Examples of the group include methyl group, ethyl group, n-propyl group, isopropylene group, n-butyl group, isobutylene group, sec-butyl group, tert-butyl group, n-pentelow group, isopentyl group, neopentyl group, n-hexoloy group and isohexyl group.

"Lower cycloalkyl group" means a cyclic alkyl group containing 3-8 carbon atoms. Examples of the group include cyclopropyl group, cyclobutyl group, cyclopentyl group, pirazinokarbazolovogo cyclohexyl group, cycloheptyl group and cyclooctyl group.

"4-6-membered lower cycloalkyl group" means a cyclic alkyl group containing 4-6 carbon atoms. Examples of the group include cyclobutyl group, cyclopentyl pirazinokarbazolovogo cyclohexyl group and the group.

"Aryl group" means a monocyclic aromatic hydrocarbon ring group or a condensed polycyclic aromatic hydrocarbon ring group containing 6-14 carbon atoms. �reamers groups include phenyl group, naftalina group and untilnow group.

"Heteroaryl group" means a 5-7-membered monocyclic aromatic heterocyclic group or condensed polycyclic aromatic heterocyclic group formed by 10 to 14 atoms, each of which consists of one or more identical or different atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and 1 to 9 carbon atoms. Examples of the group include imidazolidinyl group, pyrazolidine group, thiazolidine group, thiadiazolyl group, oxazolidinyl group, isoxazolyl group, pyrrolidino group, triazolyl group, pyridyloxy group, pyrimidinyl group, personilnya group, indolenine group, pinolillo group, pyridazinyl group and tetrazolyl group.

"Heterocyclyl group" means a 4 to 7-membered monocyclic saturated heterocyclic group, 4-7-membered partially saturated monocyclic heterocyclic group, or condensed polycyclic heterocyclic group formed by 10 to 14 atoms, each of which consists of one or more identical or different atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and 1 to 9 carbon atoms. Examples of the group include azetidinol group, pyrrolidinyl� group piperidinyl group, piperazinilnom group, morpholinyl group, tetrahydropyranyl group, tetrahydrofuryl group, tetrahydropyranyl group, dihydropyrazolo group, tetrahydropyranyloxy group, tetrahydrothiophene group, tetrahydropyranyloxy group, dihydrodipicolinate group, tetrahydropyranyloxy group, digidropiridinovykh group, thiomorpholine group, dioxinlike group, imidazolidinyl group, thiazolidine group, isothiazolinone group, casinonline group, diazepino group, DIOXOLANYL group, imidazolidinyl group, diazolidinyl group, 1,3-oxazolidinyl group, 1,4,5,6-tetrahydropyridine group, 1,2,3,4-tetrahydropyrimidines group, pyrazolidinone group, oxabicyclo[2,2,1]heptylene group tetrahydro-2H-tipirneni group and 1,1-digidropiridinovykh group.

"4-6-membered heterocyclyl group" means a 4-6-membered monocyclic saturated heterocyclic group or a 4-6-membered partially saturated monocyclic heterocyclic group, each of which consists of one or more identical or different atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and 1 to 5 carbon atoms. Examples of the group include azetidinol group, pyrrolidin�ilen group, piperidinyloxy group, tetrahydropyranyloxy group, tetrahydropyranyloxy group, 1,1-digidropiridinovykh group and morpholinyl group.

"C9-C12condensed bicyclic hydrocarbon ring" means an aromatic or partially saturated condensed bicyclic hydrocarbon ring which is formed from 9 to 12 carbon atoms and which contains in the structure of the benzene ring. Examples of the ring include indane ring and a naphthalene ring.

"C6-C11condensed bicyclic heteroclita" means an aromatic or partially saturated condensed bicyclic heterocycle, which consists of one or more identical or different atoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom, and 6-11 carbon atoms, and which contains in the structure of the benzene ring or pyridine ring. Examples of the heterocycle include Romanovy cycle, Romanovy cycle, 3,4-dihydro-2H-benzo[b][1,4]oxazinones cycle, benzofuranyl cycle, quinoline cycle, 1,3-dihydroisobenzofuran cycle, isoindoline cycle, 2,3-dihydrobenzo[b][1,4]occationaly cycle and 2,3-dihydrobenzo[d]isothiazolinones cycle.

"Saturated or unsaturated 3-8-membered ring which is formed together with the carbon atom that is joined by deputies, and �AutoRAE may contain one or more nitrogen atoms, oxygen or sulfur" means a 3-8-membered ring that may contain one or more identical or different atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and which contains 1-8 carbon atoms, where the ring may be partially unsaturated. Examples of the ring include cyclohexane cycle, pyrrolidinyl cycle, piperidinyl cycle, the piperazine cycle, moholynagy cycle, thiomorpholine cycle, 1,2,3,6-tetrahydropyridine cycle, isothiazolinones cycle, 1,3-oxazolidinyl cycle and 1,1-digidropiridinovym cycle.

"Saturated or unsaturated 3-8-membered ring which is formed together with the nitrogen atom to which attached substituents and which may contain one or more nitrogen atoms, oxygen or sulfur" means a 3-8-membered heterocycle containing one or more identical or different atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and 1 to 7 carbon atoms, where heterocycle may be partially unsaturated. Examples of the ring include pyrrolidinyl cycle, piperidinyl cycle, the piperazine cycle, moholynagy cycle, thiomorpholine cycle, 1,2,3,6-tetrahydropyridine cycle, isothiazolinones cycle, 1,3-oxazolidinyl cycle and 1,1-digidropiridinovym cycle.

The "lower alkenyl group" means a straight or razwell�nnow alkenyl group, containing 2-6 carbon atoms. Examples of the group include (E)-atenolol group, (Z)-atenolol group, (1E)-propenyloxy group, (2E)-propenyloxy group, (1E)-butenyloxy group, (1E)-pantanillo group, (1E)-hexenyl group, Isopropenyl group, isobutylene group, Deut-butenyloxy group, isopentenyl group, neopentylene group and tert-pantanillo group.

"Lower Alchemilla group" means a straight or branched alkenylphenol group containing 2-6 carbon atoms. Examples of the group include atenolol group, n-propenyloxy group, n-butenyloxy group, n-pantanillo group and n-hexylamino group.

"Lower alkoxygroup" means a straight or branched alkoxygroup containing 1-6 carbon atoms. Examples of the group include a methoxy group, an ethoxy group, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, n-pentyloxy, isopentylamine and n-hexyloxy.

"Lower cicloergometria" means a group in which the aforementioned "lower cycloalkyl group is connected to a hydroxy group. Examples of the group include cyclopropane, cyclobutanes, cyclopentyloxy and cyclohexyloxy.

"Alloctype" means a group in which the aforementioned "aryl groups�" is connected with a hydroxy group. Examples of the group include fenoxaprop and naphthyloxy.

"Geterotsiklicheskikh" means a group in which the above "heterocyclyl group is connected to a hydroxy group. Examples of the group include pyranyloxy and piperidinyloxy.

"Aryl-lower alkoxygroup" means "the lowest alkoxygroup", containing the above-mentioned "aryl group" as Deputy.

"Heterocyclyl is the lowest alkoxygroup" means "the lowest alkoxygroup" containing the above "heterocyclyl group as Deputy.

"Lower allylthiourea" means a straight or branched allylthiourea containing 1-6 carbon atoms. Examples of the group include metalcorp, ethylthiourea, n-PropertyGroup, isopropylthio, n-butylthiourea, isobutylthiazole, second-butylthiourea and tert-butylthiourea.

"Mononessa alkylamino" means an amino group containing one of the above-mentioned "lower alkyl group" as a substituent. Examples of the group include methylaminopropyl, ethylamino, n-propylamino, isopropylamino and n-butylamino.

"Mononessa cycloalkylation" means an amino group containing one of the above-mentioned "lower cycloalkyl group" as a substituent. Examples of the group include cyclopropylamino, cyclobutyl�nogroup, cyclopentylamine, cyclohexylamine, cycloheptylamine and cyclooctylamine.

"Denissa alkylamino" means an amino group with two identical or different above-mentioned "lower alkyl group" as substituents. Examples of the group include dimethylaminopropyl, di(n-propyl)amino group, di(isopropyl)amino group, ethylmethylamino and methyl(n-propyl)amino group.

"Lower alcoolica group" means a carbonyl group containing 2-7 carbon atoms and containing a straight or branched alkyl group. Examples of the group include acetyl group, propionyloxy group, n-butyryloxy group, isobutyryloxy group, n-valerino group, isovaleryl group and pivaloyl group.

"Lower cycloalkylcarbonyl group" means a carbonyl group containing the above-mentioned "lower cycloalkyl group" as a substituent. Examples of the group include cyclopropanecarbonyl group.

"Geterotsiklicheskikh group" means a carbonyl group containing the above "heterocyclyl group" as a substituent. Examples of the group include tetrahydro-2H-Piran-4-carbonyl group.

"Lower alkylsulfonyl group" means a group in which a straight or branched alkyl group containing 1-6 at�narodnih atoms, attached to sulfonyloxy group. Examples of the group include methylsulfonyl group, n-propylsulfonyl group, isobutylphenyl group and n-hexylaniline group.

"Lower alkoxycarbonyl group" means the group in which the aforementioned "lower alkoxygroup" attached to a carbonyl group. Examples of the group include methoxycarbonyl group and ethoxycarbonyl group.

"Lower alkanolamine" means a group in which the aforementioned "lower alcoolica group attached to the amino group. Examples of the group include acetylamino.

"Lower Allenova group" means a divalent hydrocarbon group containing 1-3 carbon atoms. Examples of the group include methylene group, ethylene group and propylene group. "Lower Allenova group which may contain a simple ether bond" means a group in which 1 or 2 simple essential connection inserted anywhere in the above-mentioned "lower alkalinous group".

"Xograph" means the substituent (=O), in which the oxygen atom replaces through the double bond. Consequently, oxoprop, which replaces the carbon atom forms a carbonyl group together with the carbon atom, one oxoprop, which replaces a sulfur atom, forms sulfonyloxy group together with the sulfur atom and two carbonyl group, cat�that replaces the sulfur atom, form sulfonyloxy group together with the sulfur atom. Specific examples oxazolidines heterocyclyl group, in which oxoprop replaces heterocyclyl group in the present invention include 2-oxopyrrolidin group, 2-oxopiperidine group, 1-oxalacetate-2H-tipirneni group, 1,1-dissidocerida-2H-tipirneni group, 1,1-dioxothiazolidine group, 2-oxo-1,3-oxazolidinyl group, and 6-oxo-1,1-digidropiridinovykh group.

Preferred compounds of the present invention is as follows.

In particular:

preferred ring represented by the symbol A is a benzene ring,

preferred R1is an RA-ZA-,

one preferred ZA- in R1is any one of the following formulas [9]:

[Formula 31]

preferred RZ1in this case, represents a hydrogen atom or a lower alkyl group,

preferred RAin this case, represents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, mono�SSA of alkylamino and denissa of alkylamino), lower cycloalkyl group or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with one lower alkyl group),

more preferred ZA- has the following formula [19]:

[Formula 32]

more preferred RAin this case, represents a lower alkyl group or lower cycloalkyl group

another preferred ZA- represents a single bond,

preferred RAin this case, represents a hydrogen atom or a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, a lower alkoxygroup and denissa of alkylamino),

more preferred RArepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms),

preferred RXrepresents a hydrogen atom,

preferred RY1and RY2each represents a hydrogen atom,

preferred R4is an RB-ZB-,

preferred-ZB- represents a single tie�,

preferred RBrepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by one group selected from the group consisting of lower cycloalkyl group, heterocyclyl groups, hydroxyl groups and lower alkanolamines), lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group and the carbonyl group),

more preferred RBis a lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted by 1-2 �the group, which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group and the carbonyl group),

especially preferred RBis a 4-6-membered lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or 4-6-membered heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group and the carbonyl group),

preferred RWrepresents ORC,

preferred RCis a lower cycloalkyl group

preferred R2represents a hydrogen atom, a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower alkoxygroup,

more preferred R2represents a hydrogen atom, a halogen atom or a lower alkyl group (where the lower alkyl group �is unsubstituted or substituted by 1 to 3 halogen atoms),

preferred R3represents a hydrogen atom,

preferred R5represents a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups selected from the group consisting of a halogen atom and hydroxyl groups), lower cycloalkyl group or aryl group,

more preferred R5represents a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower cycloalkyl group

preferred V is a single bond and

preferred W is a single bond.

Another preferred embodiment is as follows.

Preferred ring represented by the symbol A is a benzene ring,

preferred R1is an RA-ZA-,

one preferred ZA- in R1is any one of the following formulas [9]:

[Formula 33]

preferred RZ1in this case, represents a hydrogen atom or a lower alkyl group,

preferred RAin this case, represents a lower alkyl group (where the lower alkyl group is resumesend�th or substituted with 1-3 groups, which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, mononessa of alkylamino and denissa of alkylamino), lower cycloalkyl group or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with one lower alkyl group),

more preferred ZA- has the following formula [11]:

[Formula 34]

more preferred RAin this case, represents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower cycloalkyl group

another preferred ZA- represents a single bond,

preferred RAin this case, represents a hydrogen atom, a halogen atom or a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of halogen atom, hydroxy-group, heterocyclyl group, a lower alkoxygroup and denissa of alkylamino),

more preferred RArepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 automaticlogin) or a halogen atom,

preferred RXrepresents a hydrogen atom,

preferred RY1and RY2each represents a hydrogen atom,

preferred R4is an RB-ZB-,

preferred-ZB- represents a single bond,

preferred RBrepresents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by one group selected from the group consisting of lower cycloalkyl group, aryl group, heterocyclyl groups (where heterocyclyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a lower alkyl group and the carbonyl group), hydroxyl groups and lower alkanolamines), lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group, consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl�PPI, lower alkanoyloxy group, lower cycloalkylcarbonyl group, geterotsiklicheskikh group, lower alkylsulfonyl group and the carbonyl group),

more preferred RBis a lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group, lower alkylsulfonyl group and the carbonyl group),

especially preferred RBis a 4-6-membered lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or 4-6-membered heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which can be�ü same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group, lower alkylsulfonyl group and the carbonyl group),

preferred RWrepresents ORC,

preferred RCis a lower cycloalkyl group

preferred R2represents a hydrogen atom, a halogen atom, carbamoyl group, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom and hydroxy-group) or lower alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms),

more preferred R2represents a hydrogen atom, a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower alkoxygroup,

preferred R3represents a hydrogen atom, a halogen atom, a lower alkyl group, lower alkoxygroup (where lower alkyl group or lower alkoxygroup is unsubstituted or substituted by 1-3 halogen atoms) or hydroxy-group,

more preferred R3represents a hydrogen atom or a halogen atom,

preferred R5pre�represents a halogen atom, carbamoyl group, lower alkanoyloxy group, an amino group, denissow alkylamino, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted with 1-3 groups which may be the same or different and selected from the group consisting of a halogen atom and hydroxyl groups), lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted with one hydroxy-group), the lowest alkoxygroup (where the lowest alkoxygroup is unsubstituted or substituted by 1 to 3 halogen atoms), aryl group, heteroaryl group, or alloctype (where alloctype is unsubstituted or substituted by one group selected from the group, consisting of a halogen atom and a lower alkyl group),

more preferred R5represents a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower cycloalkyl group

especially preferred R5represents a chlorine atom or a cyclopropyl group,

preferred V is a single bond and

preferred W is a single bond.

One of the preferred options is a structure represented by formula [7]:

[Formula 35]

(where in the formula [7]:

preferred R1is an RA-ZA-,

one preferred ZA- in R1has the following formula [19]:

[Formula 36]

preferred RAin this case, represents a lower alkyl group or lower cycloalkyl group

another preferred ZA- represents a single bond,

preferred RAin this case, represents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms),

preferred R2represents a hydrogen atom, a halogen atom or a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms),

preferred R4is an RB-ZB-,

preferred-ZB- represents a single bond,

preferred RBis a lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or heterocyclyl group (where g�teracycline group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group and the carbonyl group),

more preferred RBis a 4-6-membered lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or 4-6-membered heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group and the carbonyl group), and

preferred R5represents a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower cycloalkyl group).

Another preferred embodiment is a structure represented by formula [10]:

[Formula 37]

(where in formula [10]:

preferred R1is an RA-ZA-,

one preferred ZA- in R1has the following fo�mule [11]:

[Formula 38]

preferred RAin this case, represents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower cycloalkyl group

another preferred ZA- represents a single bond,

preferred RAin this case, represents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or a halogen atom,

preferred R2represents a hydrogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms), a halogen atom or a lower alkoxygroup,

preferred R3represents a hydrogen atom or a halogen atom,

preferred R4is an RB-ZB-,

preferred-ZB- represents a single bond,

preferred RBis a lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and ACS�group) or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group, lower alkylsulfonyl group and the carbonyl group),

more preferred RBis a 4-6-membered lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or 4-6-membered heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group, lower alkylsulfonyl group and the carbonyl group),

preferred R5represents a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower cycloalkyl group and

more preferred R5represents a chlorine atom or a cyclopropyl group).

Another preferred embodiment is a structure represented by formula [14]:

[Formula 39]

(where in the formula [14]:

preferred R1is an RA-ZA-,

one preferred ZA- in R1has the following formula [19]:

[Formula 40]

preferred RAin this case, represents a lower alkyl group or lower cycloalkyl group

another preferred ZA- represents a single bond,

preferred RAin this case, represents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms),

preferred R2represents a hydrogen atom, a halogen atom or a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms),

preferred R4is an RB-ZB-,

preferred-ZB- represents a single bond,

preferred RBis a lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or heterocyclyl group (where �heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group and the carbonyl group),

more preferred RBis a 4-6-membered lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or 4-6-membered heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group and the carbonyl group), and

preferred R5represents a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower cycloalkyl group).

Another preferred embodiment is a structure represented by formula [15]:

[Formula 41]

(where in the formula [15]:

preferred R1is an RA-ZA-,

one preferred ZA- in R1has the following fo�mule [11]:

[Formula 42]

preferred RAin this case, represents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower cycloalkyl group

another preferred ZA- represents a single bond,

preferred RAin this case, represents a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or a halogen atom,

preferred R2represents a hydrogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1 to 3 halogen atoms), a halogen atom or a lower alkoxygroup,

preferred R3represents a hydrogen atom or a halogen atom,

preferred R4is an RB-ZB-,

preferred-ZB- represents a single bond,

preferred RBis a lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and ACS�group) or heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group, lower alkylsulfonyl group and the carbonyl group),

more preferred RBis a 4-6-membered lower cycloalkyl group (a low cycloalkyl group is unsubstituted or substituted by one group selected from the group consisting of lower alkyl groups where lower alkyl group is unsubstituted or substituted with one hydroxy-group, hydroxy-group and the carbonyl group) or 4-6-membered heterocyclyl group (where heterocyclyl group is unsubstituted or substituted with 1-2 groups which may be the same or different and selected from the group consisting of lower alkyl groups, hydroxyl groups, lower alkanoyloxy group, lower alkylsulfonyl group and the carbonyl group),

preferred R5represents a halogen atom, a lower alkyl group (where the lower alkyl group is unsubstituted or substituted by 1-3 halogen atoms) or lower cycloalkyl group and

more preferred R5represents a chlorine atom or a cyclopropyl group).

Examples of pharmaceutically acceptable salts in the present invention include salts of mineral acids, such as hydrochloric�s, hydrobromide, hydroiodide, phosphates, sulphates and nitrates; sulfates, such as methansulfonate, econsultancy, benzolsulfonat and p-toluensulfonate; carboxylates such as oxalate, tartrate, citrate, maleate, succinates, acetates, benzoates, mandelate, ascorbates, lactates, gluconate and malate; salts of amino acids such as salts of glycine, lysine salt, arginine salt, ornithine salt, glutamate and aspartate; and mineral salts such as lithium salt, sodium salt, potassium salt, calcium salts and magnesium salts, and salts with organic bases, such as ammonium salts, salts of triethylamine, Diisopropylamine salt and salt cyclohexylamine. Preferred examples include hydrochloride, hydrobromide, phosphates, sulfates, methanesulfonates, p-toluensulfonate, oxalates, tartrates, citrates, acetates, lactates, glutamate, aspartate, sodium salt, potassium salt, ammonium salts and salts of triethylamine.

Solvates the present invention are pharmaceutically acceptable solvates of the compounds of the present invention or their salts. Compounds of the present invention and their salts can absorb, contain adsorbed water or form hydrates, exposed to the air, recrystallization or the like. Compounds of the present invention encompass such hydrates.

Connection really hard�the purchase may contain asymmetric centers, and in this case there will be a variety of optical isomers. Consequently, the compounds of the present invention may exist as (R)-isomers (individual), (S)-isomers (separate), racemates or (RS)-mixtures containing both optical isomers in any proportions. Such compounds containing two or more asymmetric centers have the diastereoisomers, resulting from optical isomerism for each asymmetric center. Compounds of the present invention also include compounds containing all of these forms in any ratio. For example, diastereoisomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and the optically active compounds can be obtained by methods of organic chemistry well known for this purpose. In this description, the symbol "*" at the asymmetric carbon atom the compounds in the schemes relates to stereoisomerism in asymmetric carbon atom with the established character and means a greater percentage of one enantiomer, however, it is preferred that the compound was essentially a single enantiomer. The absolute configuration of the asymmetric carbon atoms may also be unclear. Compounds of the present invention may contain Zh�electric isomers, such as (E)- and (Z)-isomers. Compounds of the present invention also include such isomers and compounds containing these isomers in any proportions.

Derivatives of 2-pyridone of the present invention may constitute their pharmaceutically acceptable salts, or may be a solvate data derivatives or salts. Further derivatives of 2-pyridone of the present invention, tautomers or stereoisomers derivatives or their pharmaceutically acceptable salts or solvates of the derivatives or the salts referred to also as "compounds of the present invention".

"Compounds of the present invention also include compounds, commonly called prodrugs, which contain chemically or metabolically degradable group and form the pharmacologically active compounds of the present invention as a result of solvolysis or in vivo under physiological conditions.

Compounds of the present invention have a GK activating effect. Therefore, the compounds of the present invention can improve the symptoms of hyperglycemia, increasing metabolism of glucose and glycogenesis in the liver and/or caused by glucose insulin secretion from the beta cells of the pancreas. Therefore, the compounds can be used as new drugs that are different from existing drugs about�Yves diabetes mechanism of action. The include diabetes mellitus type I, diabetes type II and other types of diabetes result from specific causes. Compounds of the present invention is also effective in the treatment and prevention of diabetic complications such as ketoacidosis, microangiopathy (retinopathy or nephropathy), arteriosclerosis (such as atherosclerosis, myocardial infarction, cerebral infarction or peripheral arterial occlusive disease), neuropathy (such as sensory neuropathy, motor neuropathy, or autonomic neuropathy, gangrene of the foot and infection.

Connections can also be used for the prevention and treatment of diabetes-related diseases such as obesity, hyperlipidemia, hypertension, metabolic syndrome, edema, hyperuricemia and gout.

Compounds of the present invention can also be used in combination with therapeutic agents against diabetes, therapeutic agents against diabetic complications, therapeutic agents against hyperlipidemia, therapeutic drugs against hypertension and the like, having a mechanism of action different from GK activating effect. We can expect that against the above mentioned diseases are combinations of compounds of the present invention with other agents will give additional effect to the�in effect, which provide the appropriate means separately.

Examples of therapeutic agents against diabetes, and therapeutic agents against diabetic complications, used in combination with compounds of the present invention include insulin preparations, insulinsensitizing (such as PPARγ agonists, agonists, PPARα/γ agonists, PPARδ agonists and PPARα/γ/δ) (e.g., pioglitazone, rosiglitazone, GW-501516, GW-590735, ABT-335, AZD-6610 and AVE-8133), inhibitors of α-glucosidase (e.g., voglibose, acarbose and miglitol), drug-based, biguanides (e.g., Metformin, buformin and phenformin), the promoters of insulin secretion (for example, glibenclamide, glimepiride, Repaglinide, nateglinide and mitiglinide), antagonists glucagonoma receptors, promoters of insulin receptor kinase, inhibitors of dipeptidyl peptidase IV (e.g., vildagliptin, alogliptin, sitagliptin, linagliptin and saxagliptin), an SGLT inhibitors (e.g., sergliflozin, canagliflozin, dapagliflozin, TS-071 and ASP-1941), PTP1b inhibitors (e.g., sodium Vanadate), inhibitors of glucose-6-phosphatase, glycogen phosphorylase inhibitors (for example, PSN-357 and FR-258900), the FBPase inhibitors (e.g., MB-07803), PEPCK inhibitors, inhibitors of privateheaders-kinase, D-Hiro-Inositol, GSK3 inhibitors, agonists of GLP-1 (e.g., liraglutide and ecstatic), agonists Amelina (e.g. praml�ntid), antagonists of glucocorticoid receptors, inhibitors of 11βHSD1 (e.g., AMG-221 and INCB-13739), inhibitors of protein kinase C (e.g., ruboxistaurin), β3 agonists adrenaline receptors (e.g., AJ-9677), inhibitors phosphatidylinositols, inhibitors phosphatidylinositols, ACC inhibitors, agonists of GPR40 receptor, agonists of GPR119 receptor (e.g., APD-597), agonists of GPR120 receptor agonists of TGR5 receptors, AMPK activators (e.g., DRL-16536), inhibitors algosaibi and AGE inhibitors.

Examples of agents against diabetes-related diseases, used in combination with compounds of the present invention include inhibitors of HMG-CoA reductase, inhibitors stvalentines, adsorbents, bile acids, IBAT inhibitors, CETP inhibitors, inhibitors of CPT, fibrates, ACAT inhibitors, MGAT inhibitors, DGAT inhibitors, inhibitors of absorption of cholesterol, inhibitors of pancreatic lipase, MTP inhibitors, derivatives of nicotinic acid, LXR agonists, the promoters of LDL receptors, inhibitors of angiotensin-converting enzyme, antagonists of angiotensin II, diuretics, calcium antagonists, inhibitors of endothelin-converting enzyme, antagonists endothelina receptors suppressant of appetite, inhibitors of production of uric acid and means of facilitating the excretion of uric acid.

Compounds of the present invention can� to be entered into individually or with a pharmaceutically or pharmacologically acceptable carriers or diluents. Compounds of the present invention, applied as a GK activating substances or the like, can be administered orally or parenterally as such. Compounds of the present invention can also be introduced orally or parenterally in the form of drugs containing the compounds as active ingredients. Examples of parenteral administration include intravenous, nasal introduction, trandermal introduction, subcutaneous administration, intramuscular administration, and sublingual administration.

The dose of a compound of the present invention change depending on subject of administration, route of administration, the particular disease, symptom and the like, and it is usually about 0.01 to 1000 mg and preferably 0.1 to 100 mg in a single dose, when injected, for example, orally to an adult patient with diabetes; it is desirable to introduce the indicated dose one to three times a day.

Compounds of the present invention can be synthesized by the methods shown below. The following methods of obtaining show General examples of ways to obtain and do not limit the means of obtaining.

Compounds of the present invention can be synthesized by means known per se in the field of chemistry, or process with one or more processes that resembles the JV�soba. Examples of such methods include the methods described in Organic Functional Group Preparations, 2nd ed., Academic Press, Inc., 1989, Comprehensive Organic Transformations, VCH Publishers Inc., 1989 and Fundamentals and Experiments of Peptide Synthesis, Maruzen Co., Ltd., 1985.

Suitable methods of protection and exemption from the protection of functional groups contained in the starting materials, intermediate compounds or the like, in the synthesis of compounds of the present invention can be carried out in accordance with methods well known to the person skilled in the art, such as methods described in Greene's Protective Groups in Organic Synthesis, John Wily and Sons, 2006.

General methods for obtaining compounds of the present invention is shown in schemes 1-13. The following methods of obtaining the demonstrate common examples of methods for obtaining compounds described most next, concrete examples and do not limit the means of obtaining. Compounds of the present invention can also be obtained by methods well known to the person skilled in the art, for example, with the change R1, R2, R3and R5within the scope of the present invention by changing the order of execution stages; the provision of protective groups for hydroxyl groups or amino groups, by promoting interaction and removing the protection on the subsequent stage or the addition of a new stage in the implementation of the respective stages.

Scheme 1: Method of synthesis of compounds (1-c) from compound (1-a)

[Formula 43]

In this diagram, R1, R2, R3and R5such as described above and G represents a protective group for hydroxyl groups.

Stage (1-1):

A method of producing compound (1-b): this method is a method of producing compound (1-b) through the reaction of accession" with the use of compound (1-a) and the lithium reagent, such as ability, a Grignard reagent, such as arellanobond, or the like.

Examples of the reactions of addition include a method of producing compound (1-b) formation of anion using arilbred as a matrix and an ORGANOMETALLIC reagent, such as n-butyllithium, sec-butyllithium or tert-butyllithium, or bases, such as hexamethyldisilazide lithium or hexamethyldisilazide potassium, in an inert solvent at temperatures from -78°C to 100°C and then the implementation of the interaction of the anion with the carbonyl compound, such as compound (1-a).

Stage (1-2):

A method of producing compound (1-c): this method is a method of producing compound (1-c) through the oxidation reaction of compound (1-b) containing a hydroxy-group, with an oxidizing agent.

Examples of the oxidation reaction include a method of producing compound (1-c)�umiestnenie interaction of the compound (1-b) with an oxidizing agent, such as manganese dioxide, in an inert solvent at temperatures from 0°C to 100°C.

Scheme 2: Method of synthesis of compound (2-a) from compound (1-b)

[Formula 44]

In this diagram, R1, R2, R3and R5such as described above and G represents a protective group for hydroxyl groups.

Stage (2-1):

A method of producing compound (2-a): this method is a method of obtaining compound (2-a) through the reaction of the restoration," the compound (1-b) containing a hydroxy-group, a reducing agent.

Examples of reduction reaction include a method of producing compound (2-a) the implementation of the interaction of the compound (1-b) with createlsserializer and trifluoroacetic acid at temperatures from 0°C to 100°C.

Scheme 3:

The method of synthesis of compound (3-b), (3-d) and (3-f) from compound (1-c) or method of synthesis of compound (3-d) from compound (2-a)

[Formula 45]

In this diagram, R1, R2, R3, R4, R5, RX, RY1and RY2such as described above, G represents a protective group for hydroxyl groups and L is a leaving group such as a halogen atom or mesilate, tosylate or triflic.

Used on stage (3-1) reagent of mittiga, such as salt triarylphosphine, Horner reagent-Ammo�sa, such as a phosphonate ester or reagent Julia set, such as arylalkylamine, is a commercially available compound, a known compound or a compound synthesized from readily available compounds using various methods of organic synthesis known to a person skilled in the technical field.

Alkylating reagent (3-g) used in stage (3-8), is a commercially available compound, a known compound or a compound synthesized from readily available compounds using various methods of organic synthesis known to a person skilled in the technical field.

Stage (3-1):

A method of producing compound (3-a): this method is a method of producing compound (3-a) the implementation of the "binding assays" using a carbonyl compound (1-c) and the reagent Wittig, such as salt triarylphosphine, reagent Horner-Emmons, such as a phosphonate ester, or reagent Julia set, such as arylalkylamine.

Examples of binding assays include a method of producing olefin compound (3-a) the formation of the anion with a salt triarylphosphine, phosphonate ester or arylalkylamine as a matrix and an ORGANOMETALLIC reagent, such as n-butyllithium, sec-butyllithium or tert-butyllithium, or based�I, such as hexamethyldisilazide lithium or hexamethyldisilazide potassium, in an inert solvent at temperatures from -78°C to 100°C and then the implementation of the interaction of the anion with the carbonyl compound (1-c). The obtained olefinic compound is usually an E/Z mixture, and each isomer can be isolated using column chromatography on silica gel, HPLC or the like.

Step (3-2):

A method of producing compound (3-b): compound (3-b) can be obtained by the implementation of the reaction of removing the protective group G, which contains the compound (3-a).

Examples of the reaction of removing the protective group" include (i) the reaction of removing the protective group, the protective group G represents an alkyl group or allyl group, such as a method of removing the protective group by hydrolysis in an inert solvent in the presence of an acid or a strong acid at a temperature from 0°C to 200°C, the method using trimethylsilylacetamide or the like and a method using aluminum chloride and alkylthiol, and (ii) the reaction of removing the protective group, the protective group G represents a benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group benzyloxycarbonyloxy group, benzhydryl (diphenylmethyl) group or the like, such as a method of removing the protective group, a hydrogen�frame of the analysis with the use of a catalytic amount of palladium-activated carbon or rhodium-activated carbon in an inert solvent in the presence or in the absence of acid at a temperature from 0°C to 80°C and method using an oxidizing agent such as ammonium nitrate-cerium(IV) or 2,3-dichloro-5,6-dicyano-p-benzoquinone.

Stage (3-3):

A method of producing compound (3-c): this method may be a method of recovery of the compound (3-a) as a matrix by catalytic hydrogenation using a catalytic amount of palladium-activated carbon, rhodium-activated carbon or platinum-activated carbon in an inert solvent in the presence or in the absence of acid at a temperature from 0°C to 80°C.

Stage (3-4):

A method of producing compound (3-d): compound (3-d) can be obtained by the reaction of removing the protective group G, which contains the compound (3-c).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group as described above in the process (3-2).

Stage (3-5):

A method of producing compound (3-e): cyclopropenone compound (3-e) can be obtained by the reaction of cyclopropylamine" olefin compound (3-a) as a matrix.

Examples of "response cyclopropylamine include the reaction of cyclopropylamine Simmons-Smith carried out through the implementation of the interaction of copper-zinc alloy or dialkylzinc with dehalogenation, such as diameter or chloridometer, in an inert solvent pritemperature from -78°C to 100°C.

Stage (3-6):

A method of producing compound (3-f): the compound (3-f) can be obtained through the reaction of removing the protective group G, which contains the compound (3-e).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Stage (3-7):

Another method of producing compound (3-f): cyclopropenone compound (3-f) can be obtained by the reaction of cyclopropylamine" olefin compound (3-b) as a matrix. Examples of "response cyclopropylamine" include the same "reaction cyclopropylamine", as described earlier in the process (3-5).

Another method of producing compound (3-c): this method is a method of producing compound (3-c) through alkylation reaction using methylene compound (2-a) and compounds (3-g).

Examples of "alkylation reaction" include a method of producing compound (3-c) formation of anion using methylene compound (2-a) as a matrix and an ORGANOMETALLIC reagent, such as n-butyllithium, sec-butyllithium or tert-butyllithium, or bases, such as hexamethyldisilazide lithium or hexamethyldisilazide potassium, in an inert solvent at temperatures from -78°C to 100°C and then the implementation of the interaction of the anion with the compound (3-g).

Scheme 4:

JV�GSS synthesis of compound (4-b), (4-d) and (4-g) from compound (1-c)

[Formula 46]

In this diagram, R1, R2, R3, R4, R5, RX, RY1, RY2and Y are as described above and G represents a protective group for hydroxyl groups.

Stage (4-1):

A method of producing compound (4-a): compound (4-a) can be obtained by the interaction of a carbonyl compound (1-c) as a matrix with a metal reagent such as an organolithium reagent, magnetogenesis reagent or zincirlerini reagent, in an inert solvent at temperatures from -78°C to 100°C.

Stage (4-2):

A method of producing compound (4-b): compound (4-b) can be obtained through the reaction of removing the protective group G, which contains the compound (4-a).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Stage (4-3):

A method of producing compound (4-c): when RXrepresents ORZ3, SRZ3or NRZ3RZ4that the compound (4-c) can be obtained by conversion of the hydroxyl groups of the compound (4-a) into a leaving group, such as mesilate, a tosylate or a halogen atom, in an inert solvent at temperatures from -78°C to 100°C and then the implementation of the interaction of compounds with the corresponding ness�m alkyl alcohol, lower alkylthio, kanonischen the alkyl amine or the like in the presence of base.

Stage (4-4):

A method of producing compound (4-d): the compound (4-d) can be obtained by the reaction of removing the protective group G, which contains the compound (4-c).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).Stage (4-5):

Another method of producing compound (4-c): when RXrepresents NRZ3RZ4that the compound (4-c) can be obtained by providing mononessa the alkyl amine or the like to act on the carbonyl compound (1-c) as a matrix in an inert solvent at temperatures from -78°C to 100°C, to obtain Yiming, and then the implementation of the interaction imina with a metal reagent such as an organolithium reagent, magnetogenesis reagent or zincirlerini reagent.

Stage (4-6):

A method of producing compound (4-e): when RXrepresents a lower alkyl group or lower cycloalkyl group, the compound (4-e) can be obtained by the interaction of a carbonyl compound (1-c) as a matrix with a metal reagent such as an organolithium reagent, magnetogenesis reagent or zincirlerini reagent, in an inert R�storytale at a temperature of from -78°C to 100°C.

Stage (4-7):

A method of producing compound (4-f): the compound (4-f) can be obtained by conversion of the hydroxyl groups of the compound (4-e) into a leaving group, such as mesilate, a tosylate or a halogen atom, in an inert solvent at temperatures from -78°C to 100°C and then the implementation of the interaction of the compound with an appropriate lower alkyl alcohol, lower alkylthio, kanonischen the alkyl amine or the like in the presence of base.

Stage (4-8):

A method of producing compound (4-g): the compound (4-g) can be obtained through the reaction of removing the protective group G, which contains the compound (4-f).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Scheme 5:

Method of synthesis of compound (5-b) from compound (1-b), or (1-c)

[Formula 47]

In this diagram, R1, R2, R3, R4, R5, RXand Y are as described above and G represents a protective group for hydroxyl groups.

Stage (5-1):

A method of producing compound (5-a): compound (5-a) can be obtained by conversion of the hydroxyl groups of the compound (1-b) into a leaving group, such as mesilate, a tosylate or a halogen atom, in an inert solvent at temperatures from -78°C to 100°C and then providing a corresponding bottom�him alkyl alcohol, lower alkylthiol, mononessa the alkyl amine or the like to act on the compound in the presence of base.

In accordance with another embodiment, when Y represents-O-, the compound (5-a) can be obtained by providing the lower alkyl alcohol to act on the hydroxy-group of compounds (1-b) in an inert solvent in the presence of a palladium catalyst at a temperature from 0°C to 100°C.

In accordance with another embodiment of the compound (5-a) can be obtained by nucleophilic substitution reactions of a mixture of compounds (1-b) and phenolic compounds with azosoedineniem, such as diethylazodicarboxylate and phosphine compound, such as triphenylphosphine, in an inert solvent at a temperature from room temperature to 100°C.

Stage (5-2):

A method of producing compound (5-b): compound (5-b) can be obtained through the reaction of removing the protective group G, which contains the compound (5-a).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Stage (5-3):

Another method of producing compound (5-a): when Y represents a-NRZ5-, the compound (5-a) can be obtained by way of the reductive amination reaction using the compound (1-c) as matric�and in an inert solvent at temperatures from -78°C to 100°C.

Examples of the reductive amination reaction include the reaction of reductive amination, carried out with the provision of appropriate mononessa the alkyl amine or the like to act on the compound (1-c) in an inert solvent at temperatures from -78°C to 100°C, to obtain Yiming, and then providing a metal remediation agent, such as triacetoxyborohydride sodium, cyanoborohydride sodium borohydride sodium hydride or, ability to act on the Institute of Mineralogy.

Scheme 6:

Method of synthesis of compound (6-b) from compound (1-c)

[Formula 48]

In this diagram, R1, R2, R3, R5and RWsuch as described above and G represents a protective group for hydroxyl groups.

Stage (6-1):

A method of producing compound (6-a): compound (6-a) can be obtained through the reaction of removing the protective group G, which contains the compound (1-c).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Stage (6-2):

A method of producing compound (6-b): compound (6-b) can be obtained by providing the lower alkylhydroxylamines, mononessa acylhydrazone or the like to act on the compound (6a) as a matrix in an inert solvent at temperatures from 0°C to 200°C.

Scheme 7: Method of synthesis of compounds (7-d), (7-e), (7-f), and (7-h) from compound (7-a) and the method of synthesis of compounds (7-k) and (7-l) from compound (7-i)

[Formula 49]

In this diagram, G is a protective group for hydroxyl groups.

Stage (7-1):

A method of producing compound (7-b): compound (7-b) can be obtained by boiling to reflux a mixture of iron chloride or tin and the compound (7-a) in a solvent such as ethanol, in the presence of acid, such as chloride or hydrochloric acid. In accordance with another variant, the compound (7-b) can be obtained by the reaction of catalytic reduction of the compound (7-a) as a matrix with a catalytic amount of palladium-activated carbon, rhodium-activated carbon or platinum-activated carbon in an inert solvent in the presence or in the absence of acid at a temperature from 0°C to 80°C in an atmosphere of hydrogen.

Stage (7-2):

A method of producing compound (7-c): compound (7-c) can be obtained by the interaction of the compound (7-b) in an inert solvent, such as N,N-dimethylformamide, in the presence brainwashes agent, such as N-bromosuccinimide or tetrabutylammonium, at a temperature from -30°C to 80°C.

Stage (7-3):

A method of producing compound (7-d): with�connection (7-d) can be obtained by the formation of salt diakonia from a mixture of the compound (7-c) and sodium nitrite or tert-nitrite in concentrated hydrochloric acid or concentrated sulfuric acid as solvent at a temperature of from -30°C to 80°C and then providing the copper chloride to act on the salt diakonia.

Stage (7-4):

A method of producing compound (7-e): the compound (7-e) can be obtained by the formation of salt diakonia from a mixture of the compound (7-c) and sodium nitrite or tert-nitrite in concentrated hydrochloric acid or concentrated sulfuric acid as solvent at a temperature from -30°C to 80°C and then the provision of potassium iodide to act on the salt diakonia.

Stage (7-5):

A method of producing compound (7-f): the compound (7-f) can be obtained by reaction of binding of the compound (7-e) as a matrix with cyclopropylboronic acid in an inert solvent in the presence of a palladium catalyst at a temperature from 0°C to 200°C.

Stage (7-6):

A method of producing compound (7-g): the compound (7-g) can be obtained by providing the sodium iodide to act on the compound (7-c) as a matrix in an inert solvent in the presence of copper iodide and DMEDA (N,N'-dimethylethylenediamine) at a temperature from 0°C to 200°C.

Stage (7-7):

A method of producing compound (7-h): the compound (7-h) can be obtained by the formation of salt diakonia from a mixture of the compound (7-g) and sodium nitrite or tert-nitrite in concentrated hydrochloric acid or concentreren�the auditors sulfuric acid as a solvent at a temperature from -30°C to 80°C and then providing the copper bromide ability to act on the salt diakonia.

Stage (7-8):

A method of producing compound (7-j): the compound (7-j) can be obtained by providing alkylhalogenide ability to act on the compound (7-i) as a matrix in an inert solvent in the presence of base at a temperature from 0°C to 200°C.

Stage (7-9):

A method of producing compound (7-k): the compound (7-k) can be obtained by providing the alcohol, such as methanol or 4-methoxybenzyloxy alcohol, the opportunity to act on the compound (7-j) in an inert solvent in the presence of base at a temperature from 0°C to 200°C.

Stage (7-10):

A method of producing compound (7-l): the compound (7-l) can be obtained by providing triisopropylsilane ability to act on the compound (7-k) in an inert solvent in the presence of acid, such as trifluoroacetic acid, at temperatures from 0°C to 200°C and remove protection from 4-methoxybenzyloxy group.

Stage (7-11):

Another method of producing compound (7-k): the compound (7-k) can be obtained by providing alkylhalogenide ability to act on the compound (7-l) as a matrix in an inert solvent in the presence of base at a temperature from 0°C to 200°C.

Scheme 8 synthesis of compound (8-i) from compound (8-a)

[Formula 50]

In this diagram, R1, R2, R3and R5such as described� above, G represents a protective group for hydroxyl groups, n is an integer from 1 to 3 and D is a group represented by the following formula (α):

[Formula 51]

(where the formula (α) is heterocyclyl group), aryl group or alloctype.

Stage (8-1):

A method of producing compound (8-b): compound (8-b) can be obtained by Pd(0)-Cu(I) binding compound (8-a) and 3-butyn-1-ol or 2-propyn-1-ol with a catalyst based on palladium(0), such as tetranitropentaerithrite(0), and a halide of copper(I), such as copper iodide(I), in an inert solvent in the presence of base at a temperature from 0°C to 80°C.

Stage (8-2):

A method of producing compound (8-c): compound (8-c) can be obtained by adding sodium hydride bis(2-methoxyethoxy)aluminum (Red-Al(R)) or hydride to the compound (8-b) as a matrix in an inert solvent at a temperature from -20°C to room temperature, and then adding jodorowski agent, such as N-jodatime, at temperatures from -78°C to -20°C. If the number of carbon atoms, represented by the symbol n is an integer of 1-2, may be Z-selective olefin obtained the connection.

Stage (8-3):

A method of producing compound (8-d): the compound (8-d) can be obtained by providing triphenylphosphine and t�tribromide carbon to act on the compound (8-c) as a matrix in an inert solvent at temperatures from 0°C to room temperature.

Stage (8-4):

A method of producing compound (8-f): the compound (8-f) can be obtained by nucleophilic substitution reactions of the mixture of compound (8-d) and compounds represented by formula (D-H, with a base in an inert solvent at a temperature from room temperature to 100°C.

Stage (8-5):

Another method of producing compound (8-f): the compound (8-f) can be obtained by nucleophilic substitution reactions of the mixture of compound (8-c) and compounds represented by formula (D-H, with azosoedineniem, such as diethylazodicarboxylate, and a phosphine compound, such as triphenylphosphine, in an inert solvent at a temperature from room temperature to 100°C.

Stage (8-6):

A method of producing compound (8-h): the compound (8-h) can be obtained by reaction of binding of the compound (8-f) as a matrix with the connection arivera or connection alloleva in the presence of palladium catalyst.

Examples of binding assays include the way that the interaction of the compound (8-f) with connection arivera or connection alloleva in an inert solvent, such as 1,2-dimethoxyethane, acetonitrile, toluene, tetrahydrofuran, dimethylsulfoxide, 1,4-dioxane or water, in the presence of a palladium catalyst and a base at a temperature from 20°C to 160°C. the Reaction can be carried out with used�eat microwaves.

Examples of the palladium catalyst used for the linking reaction include palladium catalysts are known to those skilled in the art, such as tetranitropentaerithrite(0), bis(dibenzylideneacetone)palladium(0), dichloride bis(triphenylphosphine)palladium(II) acetate bis(triphenylphosphine)palladium(II) and the complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro methane (1:1). Also possible the formation of a catalyst based on palladium(0) in the system with the use of palladium acetate(II) or palladium-activated carbon and triphenylphosphine in the presence of base and catalyst for the reaction.

Stage (8-7):

A method of producing compound (8-e): the compound (8-e) can be obtained by reaction of binding of the compound (8-c) as a matrix with the connection arivera or connection alloleva in the presence of palladium catalyst.

Examples of the "binding assays" include the same "binding reaction as described earlier in the process (8-6).

Stage (8-8):

A method of producing compound (8-g): the compound (8-g) can be obtained by providing triphenylphosphine and tetrabromide carbon to act on the compound (8-e) as a matrix in an inert solvent at temperatures from 0°C to room temperature.

Stage (8-9):

A method of producing a connection�t (8-h): the compound (8-h) can be obtained by nucleophilic substitution reactions of the mixture of compound (8-g) and compounds represented by the formula (D-H, with a base in an inert solvent at a temperature from room temperature to 100°C.

In accordance with another embodiment of the compound (8-h) can be obtained by reaction of binding of the compound (8-g) as a matrix with the connection arivera or connection alloleva in an inert solvent in the presence of palladium catalyst.

Examples of the "binding assays" include the same "binding reaction as described earlier in the process (8-6).

Stage (8-10):

Another method of producing compound (8-h): the compound (8-h) can be obtained by nucleophilic substitution reactions of the mixture of compound (8-e) and compounds represented by formula (D-H, with dialkyldithiocarbamate, such as diethylazodicarboxylate and triphenylphosphine, in an inert solvent at a temperature from room temperature to 100°C.

Stage (8-11):

A method of producing compound (8-i): compound (8-i) can be obtained through the reaction of removing the protective group G, which contains the compound (8-h).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Scheme 9: the Method of synthesis of compound (9-d) from compound (8-e)

[Formula 52]

In this diagram, R1, R2, R3, R4IR 5such as described above and G represents a protective group for hydroxyl groups.

Stage (9-1):

A method of producing compound (9-a): compound (9-a) can be obtained in two stages or one stage by providing a variety of oxidizing agents the opportunity to act on the compound (8-e) as a matrix. Examples of a method for producing a two-stage method include oxidation of the alcohol to the aldehyde with an oxidizing agent such as reagent dessa-Martin or manganese dioxide, or dimethyl sulfoxide, oxaliplatin or triethylamine, and oxidation of the aldehyde to the carboxylic acid chloride acid. Examples of a method for producing in one stage include the method of oxidation with potassium permanganate.

Stage (9-2):

A method of producing compound (9-b): compound (9-b) can be obtained by providing an N-bromosuccinimide ability to act on the compound (9-a) as a matrix with use of triethylamine, lithium acetate, Quaternary ammonium salt or the like as a catalyst.

Stage (9-3):

A method of producing compound (9-c): compound (9-c) can be obtained by reaction of binding of the compound (9-b) as a matrix with the connection arivera or reaction C-N binding compound (9-b) with a compound represented by a formula D'-H (where D' is heterocyclyl group performance�allenou shown above formula (α)), in the presence of palladium catalyst.

Examples of the reaction of C-N linking method include the implementation of the interaction of the compound (9-b) with a compound represented by a formula D'-H, in an inert solvent, such as 1,2-dimethoxyethane, acetonitrile, toluene, tetrahydrofuran, dimethylsulfoxide or 1,4-dioxane in the presence of a palladium catalyst and a base at a temperature from 20°C to 160°C. the Reaction can be carried out using microwaves. Examples of the palladium catalyst used for the reaction of C-N binding, include palladium catalysts are known to those skilled in the art, such as tetranitropentaerithrite(0), bis(dibenzylideneacetone)palladium(0), dichloride bis(triphenylphosphine)palladium(II) acetate bis(triphenylphosphine)palladium(II), Tris(dibenzylideneacetone)dipalladium(0) and the complex dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro methane (1:1). It is also possible the formation of a palladium catalyst in the system with the use of palladium acetate(II) or palladium-activated carbon, and monodentate or bidentate ligand, such as triphenylphosphine, dppf ([1,1'-bis(diphenylphosphino)ferrocene]) or BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), in the presence of base and catalyst for the reaction.

Examples of the method include a method of obtaining the compounds�of (9-c) by reaction of bonding with the amide compound in the presence of a metal catalyst. Examples of the metal catalyst include copper iodide and various palladium catalysts.

Stage (9-4):

A method of producing compound (9-d): compound (9-d) can be obtained by the reaction of removing the protective group G, which contains the compound (9-c).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Scheme 10: the Method of synthesis of compound (10-b) from compound (9-a)

[Formula 53]

In this diagram, R1, R2, R3and R5such as described above, G represents a protective group for the hydroxy-group and E represents a primary aliphatic amino group, such as methylaminopropan or atramentaria, secondary aliphatic amino group, such as dimethylaminopropyl or diethylaminopropyl, a cyclic amino group, such as piperidinyl group or morpholinyl group, or an aromatic amino group, such as inlinegroup.

Stage (10-1):

A method of producing compound (10-a): compound (10-a) can be obtained by the interaction of the compound (9-a) with an amine represented by the formula (E-H, in an inert solvent in the presence of a condensing agent for hydration, such as different carbodiimide, diphenylphosphoryl, salt �benzotriazol-1-electrogeneration hydrochloride or 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine, and in the presence or in the absence of a base, such as triethylamine or diisopropylethylamine, at a temperature from 0°C to 80°C.

Stage (10-2):

A method of producing compound (10-b): compound (10-b) can be obtained through the reaction of removing the protective group G, which contains the compound (10-a).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Scheme 11: the Method of synthesis of compound (11 g) from compound (11-a)

[Formula 54]

In this diagram, R1, R2, R3and R5such as described above and G represents a protective group for hydroxyl groups.

Stage (11-1):

A method of obtaining a compound (11-b): compound (11-b) can be obtained by Pd(0)-Cu(I) binding compound (11-a) and a derivative of 2-bromopyridine or derived 2-yodellin with a catalyst based on palladium(0), such as tetranitropentaerithrite(0), and a halide of copper(I), such as copper iodide(I), in an inert solvent in the presence of base at a temperature from room temperature to 100°C.

Stage (11-2):

A method of obtaining a compound (11-c): compound (11-c) can be obtained through the reaction of removing the protective group, 2,4-dimethoxybenzyl group that contains the compound (11-b), in an inert Sol�evaporator at a temperature of from room temperature to 100°C.

Examples of the reaction of removing the protective group include a method using an acid, such as trifluoroacetic acid, a method of removing the protective group by hydrogenolysis using catalytic amounts of palladium-activated carbon or rhodium-activated carbon and a method using an oxidizing agent such as ammonium nitrate-cerium(IV) or 2,3-dichloro-5,6-dicyano-p-benzoquinone.

Stage (11-3):

A method of obtaining a compound (11-d): the compound (11-d) can be obtained by reaction of catalytic hydrogenation of compound (11-c) as a matrix with a catalytic amount of Lindlar catalyst (palladium-calcium carbonate-lead acetate, palladium-barium carbonate, Nickel carbonate, barium or platinum-barium carbonate) in an inert solvent at a temperature from room temperature to 100°C.

Stage (11-4):

A method of obtaining a compound (11-e): the compound (11-e) can be obtained by bromination of compound (11-d) bromine in an inert solvent at a temperature from room temperature to 100°C and then securing the base to act on the connection.

Stage (11-5):

A method of obtaining a compound (11-f): the compound (11-f) can be obtained by reaction of binding of the compound (11-e) as a matrix with the connection arivera or connection alloleva in �nerton solvent in the presence of base and palladium catalyst at a temperature from room temperature to 100°C.

Examples of the "binding assays" include the same "binding reaction as described earlier in the process (8-6).

Stage (11-6):

A method of obtaining a compound (11-g): the compound (11-g) can be obtained through the reaction of removing the protective group G, which contains the compound (11-f).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Stage (11-7):

A method of obtaining a compound (11-h): the compound (11-h) can be obtained through the reaction of removing the protective group G, which contains the compound (11-e).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Stage (11-8):

Another method of obtaining the compound (11-g): the compound (11-g) can be obtained by reaction of binding of compounds (11-h) as a matrix with the connection arivera or connection alloleva in an inert solvent in the presence of base and palladium catalyst at a temperature from room temperature to 100°C.

Examples of the "binding assays" include the same "binding reaction as described earlier in the process (8-6).

Scheme 12: the Method of synthesis of compound (12-e) from compound (11-a)

[Formula 55]

In this diagram, R1, R2 , R3and R5such as described above and G represents a protective group for hydroxyl groups.

Stage (12-1):

A method of producing compound (12-a): compound (12-a) can be obtained by Pd(0)-Cu(I) binding compound (11-a) and helgaleena or kiltlifter compounds with a catalyst based on palladium(0), such as tetranitropentaerithrite(0), and a halide of copper(I), such as copper iodide(I), in an inert solvent in the presence of base at a temperature from room temperature to 100°C.

Stage (12-2):

A method of producing compound (12-b): compound (12-b) can be obtained by the provision of the tin hydride such as tributyltin hydride, to act on the compound (12-a) as a matrix in an inert solvent in the presence of a palladium catalyst at a temperature from 0°C to 100°C.

Stage (12-3):

A method of producing compound (12-c): compound (12-c) can be obtained by reaction of binding of the compound (12-b) as a matrix with derivatives of 2-bromopyridine or 2-yodellin in an inert solvent in the presence of base and palladium catalyst at a temperature from room temperature to 100°C.

Stage (12-4):

A method of producing compound (12-d): the compound (12-d) can be obtained by the reaction of removing the protective group G, which contains a link� (12-c).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Stage (12-5):

A method of producing compound (12-e): compound (12-e) can be obtained through the reaction of removing the protective group, 2,4-dimethoxybenzyl group that contains the compound (12-d), in an inert solvent at a temperature from room temperature to 100°C.

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (11-2).

Stage (12-6):

A method of producing compound (12-f): the compound (12-f) can be obtained through the reaction of removing the protective group, 2,4-dimethoxybenzyl group that contains the compound (12-c), in an inert solvent at a temperature from room temperature to 100°C.

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (11-2).

Stage (12-7):

Another method of obtaining the compound (12-e): compound (12-e) can be obtained through the reaction of removing the protective group G, which contains the compound (12-f).

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Figure 13: Method of synthesis of compound (13-e)from compound (13-a)

[Formula 56]

In this diagram, R1, R2, R3and R5such as described above and G represents a protective group for hydroxyl groups.

Stage (13-1):

A method of producing compound (13-b): compound (13-b) can be obtained by reaction of binding of compound (13-a) as a matrix with the connection arivera or pinivora, connection alloleva, connection Benzedrine or a phenol in an inert solvent in the presence of palladium catalyst or a copper catalyst at a temperature from room temperature to 100°C.

Examples of the "binding assays" include the same "binding reaction as described earlier in the process (8-6).

Stage (13-2):

A method of producing compound (13-d): compound (13-d) can be obtained by the reaction of removing the protective group, 2,4-dimethoxybenzyl group that contains the compound (13-b), in an inert solvent at a temperature from room temperature to 100°C.

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (11-2).

Stage (13-3):

A method of producing compound (13-e): compound (13-e) can be obtained through the reaction of removing the protective group G, which contains the compound (13-d).

Examples of the reaction of removing protection�Noah group" include the same "reaction of removing the protective group, as described earlier in the process (3-2).

Stage (13-4):

A method of producing compound (13-c): this method is a method of producing compound (13-c) through the reaction of removing the protective group, 2,4-dimethoxybenzyl group that contains the compound (13-a), in an inert solvent at a temperature from room temperature to 100°C.

Examples of the reaction of removing the protective group" include the same "reaction of removing the protective group, as described earlier in the process (11-2).

Stage (13-5):

Another method of obtaining the compound (13-d): compound (13-d) can be obtained by reaction of binding of compound (13-c) as a matrix with the connection arivera or pinivora, connection alloleva, connection Benzedrine or a phenol in an inert solvent in the presence of palladium catalyst or a copper catalyst at a temperature from room temperature to 100°C.

Examples of the "binding assays" include the same "binding reaction as described earlier in the process (8-6).

Reaction temperature in the General methods for obtaining compounds of the present invention is in the range from -78°C to 250°C, preferably from -20°C to 80°C. the reaction Time ranges from 5 minutes to 3 days, and preferably from 30 minutes to 18 hours. Methods of obtaining can be carried out at normal pressure, under pressure�m or under microwave irradiation, for example.

Base, acid and inert solvent in the description of the General methods for obtaining compounds of the present invention will be described more specifically, but not limited to subsequent illustrations. Suitable methods of allocation will be described specifically, but not limited to subsequent illustrations.

Examples of the "base" include inorganic bases such as hydrides of alkali metals or alkaline earth metals (such as lithium hydride, sodium hydride, potassium hydride and calcium hydride), amides of alkali metals or alkaline earth metals (such as lithium amide, sodium amide, diisopropylamide lithium, dicyclohexylamine lithium hexamethyldisilazide lithium and hexamethyldisilazide potassium), C1-C6alkoxides of alkali metals or alkaline earth metals (such as sodium methoxide, ethoxide sodium and tert-butoxide potassium), hydroxides of alkali metals or alkaline earth metals (such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide), carbonates of alkali metals or alkaline earth metals (such as sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate), bicarbonates of alkali metals (such as sodium bicarbonate and potassium bicarbonate) and phosphates of alkali metals or alkaline earth metals (such as triclofos�at), amines (such as triethylamine, diisopropylethylamine and N-methylmorpholine) and basic heterocyclic compounds (such as pyridine, 4-dimethylaminopyridine, DBU (1,8-diazabicyclo[5,4,0]undec-7-ene), DBN (1,5-diazabicyclo[4,3,0]non-5-ene), imidazole and 2,6-lutidine).

Examples of the acid include inorganic acids (such as hydrochloric acid, bromomethane acid, sulfuric acid, nitric acid and phosphoric acid), organic acids (such as p-toluensulfonate acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid and camphorsulfonic acid) and Lewis acids (such as boron TRIFLUORIDE, tribromide boron, aluminum chloride, triflic of scandium and triflic ytterbium).

Examples of the "inert solvent" include nitrile solvents, amide solvents, halogen-substituted hydrocarbon solvents, simple ether solvents, aromatic solvents, hydrocarbon solvents, ester solvents, alcohol solvents, sulfoxide solvents and water. These solvents may be used as mixtures of two or more solvents in an appropriate ratio.

The examples used nitrile solvents include acetonitrile and propionitrile. Examples of amide solvents include N,N-dimethylformamide (hereinafter sometimes reduce�enny abbreviated as DMF), N,N-dimethylacetamide and N-methylpyrrolidone. Examples of halogen-substituted hydrocarbon solvents include dichloro methane, chloroform, 1,2-dichloroethane and carbon tetrachloride. Some simple examples of the ether solvents include diethyl ether (hereinafter sometimes referred to as "ether"), tetrahydrofuran (hereinafter sometimes abbreviated as abbreviated as THF), 1,4-dioxane and 1,2-dimethoxyethan. Examples of aromatic solvents include benzene, toluene, xylene and pyridine. Examples of hydrocarbon solvents include hexane, pentane and cyclohexane. Examples of ester solvents include ethyl acetate and ethylformate. Examples of the alcoholic solvents include methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and ethylene glycol. Examples sulfoxide solvents include dimethylsulfoxide (hereinafter sometimes abbreviated as abbreviated as DMSO).

Compounds obtained by the above-described methods of preparation, can be isolated and purified by known methods such as solvent extraction, change of fluidity, transfer, crystallization, recrystallization and various chromatography methods.

Protective groups which can be used by connections in the General methods for obtaining compounds of the present invention, will be described below, but are not limited to such illustrations; can be librarycache and other suitable protective group.

Examples of protective groups for amino group include C1-C6the acyl group (such as formyl, acetyl and propionyl), C2-C12alkoxycarbonyl group (such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl), arylcarbamoyl group (such as benzoyl), trityloxy group, palolo group, N,N-dimethylaminomethylene group, substituted silyl group such as trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl and tert-butyldimethylsilyl) and C2-C6alkenyl group (such as 1-allyl), each of which is usually used in the synthesis of peptides. These groups may be substituted by one or more substituents selected from halogen atoms, C1-C6of the alkoxy groups (such as methoxy, ethoxy and propoxy) and nitro group.

Examples of protective groups for carboxypropyl include C1-C6alkyl group (such as methyl, ethyl and tert-butyl), C7-C20kalkilya group (such as benzyl and trityl), phenyl group, substituted silyl group such as trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl and tert-butyldimethylsilyl) and C2-C6alkenyl group (such as 1-allyl). These groups may be substituted with one �if several substituents, selected from halogen atoms, C1-C6of the alkoxy groups (such as methoxy, ethoxy and propoxy) and nitro group.

Examples of protective groups for hydroxyl groups include C1-C6alkyl group (such as methyl, ethyl and tert-butyl), C7-C20kalkilya group (such as benzyl and trityl), phenyl group, substituted silyl group such as trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl and tert-butyldimethylsilyl), C2-C6alkenyl group (such as 1-allyl), C1-C6the acyl group (such as formyl, acetyl and propionyl), C2-C12alkoxycarbonyl group (such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl), arylcarbamoyl group (such as benzoyl), 2-tetrahydropyranyloxy group and 2-tetrahydropyranyloxy group. These groups may be substituted by one or more substituents selected from halogen atoms, C1-C6of the alkoxy groups (such as methoxy, ethoxy and propoxy) and nitro group.

Examples of protective groups for carbonyl groups include cyclic acetals such as 1,3-dioxane and 1,3-dioxolan) and acyclic acetals (such as di-C1-C6allylacetate (dimethylacetal, diethylacetal and the like)).

Infusion�the invention is described in more detail in the following reference examples, examples, test example and examples, the manufacture of dosage forms. These examples do not limit the present invention and may be modified within the scope of the present invention.

The NMR spectra (nuclear magnetic resonance) measured at room temperature at 200 MHz (GEMINI 2000/200, Varian Instruments), 300 MHz (INOVA 300, Varian Instruments, JEOL JNM-ECP300, JEOL Ltd., JEOL JNM-ECX300, JEOL Ltd.), 500 MHz (JEOL ECA500, JEOL JNM-ECP500, JEOL Ltd.), 600 MHz (JEOL JNM-ECA600, JEOL Ltd.) and 700 MHz (JEOL JNM-ECA700, JEOL Ltd.). Chemical shifts in this description indicated in parts per million (δ) relative to internal standard (tetramethylsilane).

Mass spectra were measured using a Waters micromass ZQ (ESI: elektrorazpredelenie ionization), micromass Platform LC mass spectrometer (EI: electron ionization) or Shimadzu LCMS-2010EV (ESI: elektrorazpredelenie ionization/APCI: chemical Dual ionization at atmospheric pressure).

The progress of the reaction was monitored using TLC (silica gel 60, F254; production of Merck & Co., Inc.) or ortofoto HPLC.

For column chromatography silica gel is used Merck "Silica gel 60", Fuji Silysia Chemical "Silica gel PSQ60", Kanto Chemical Silica gel 60", "Silica gel 60N", Fuji Silysia Chemical Chromatorex NH" or a Packed column (YAMAZEN Hi-FlashTMColumn or MORITEX Purif Pack or biotage AB(R) SNAP Catridge KP-Sil). Unless otherwise noted, used Fuji Silysia Chemical "Silica gel PSQ60", Kanto Chemical Silica gel 60N" or a Packed column.

When the product was purified preparative TLC, used Merck Silia gel 60, 1 mm or 0.5 mm, F254 or Fuji Silysia Chemical CHROMATOREX NH-PLC 05 PLATE.

As columns for preparative HPLC was used SunFireTMPrep C18OBDTM5 μm (I. D. (inner diameter, EXT.d.) 30 mm, length, L) of 50 mm), Daicel Chemical Industries, LTD. CHIRALCEL OD-H 5 μm (EXT.d. 20 mm, length 250 mm, GL Science Inc. Inertsil ODS-3 5 ám (EXT.d. 20 mm, length 250 mm, Daicel Chemical Industries, LTD. CHIRALPAK IA, 5 µm (EXT.d. 10 mm, length 250 mm) or Daicel Chemical Industries, LTD. CHIRALPAK IB 5 µm (EXT.d. 20 mm, length 250 mm).

For reactions using microwaves in these reference examples and examples was used Initiator SixtyTMproduction AB biotage AB.

Referential example 1-1

(5-Chloro-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanon

[Formula 57]

(1) Solution methylpiperazine (2,31 g) in tetrahydrofuran (20 ml) was cooled to -78°C and n-butyllithium (2,64 M to 7.55 ml) was added dropwise in an atmosphere of gaseous argon. After stirring at the same temperature for 15 minutes, was added a solution of 6-methoxybenzaldehyde (2.5 g) in tetrahydrofuran and the mixture was stirred for 30 minutes. Was added to the reaction solution dropwise tert-butyllithium (1,59 M, 17,1 ml) and the mixture was stirred at the same temperature for one hour and at -40°C for 15 minutes. The reaction solution was cooled again to -78°C. a Solution of hexachloroethane (12.9 g) in tetrahydrofuran (20 ml) was slowly added dropwise and the mixture �eremetical at the same temperature for 30 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=20:1→10:1) to give 5-chloro-6-methoxypyridine-2-carbaldehyde in the form of a colorless powder (1.21 g).

(2) n-Butyllithium (2,64 M, 2.9 ml) was added to a solution of 4-bromothioanisole (1,61 g) in tetrahydrofuran (20 ml) at -78°C in a nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. Was added to the reaction solution, a solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (1.14 g) in tetrahydrofuran (10 ml), followed by stirring for one hour. The reaction solution was poured into a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=10:1→4:1) to give (5-chloro-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanol as a pale yellow oil (1.42 g).

(3) manganese Dioxide (of 8.34 g) d�ballali to a solution of (5-chloro-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanol (1.42 g) in chloroform (40 ml) and the mixture was stirred at 65°C for one hour. The reaction solution was filtered through celite and the filtrate concentrated. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:1) obtaining specified in the title compound as a yellow powder (1.02 g, 71%).

1H NMR (300 MHz, CDCl3) δ M. D. by 2.55 (s, 3H), was 4.02 (s, 3H), 7,29 (d, J=to 8.7 Hz, 2H), 7,56-to 7.68 (m, 1H), 7,82 (d, J=7.9 Hz, 1H), 8,09 (d, J=8,9 Hz, 2H).

MS(+): 294 [M+H]+.

The following compounds (reference examples 1-2 - 1-29) was obtained by reaction in the same manner as in reference example 1-1, using appropriate approach formulated above, respectively.

Referential example 1-2

(5-Chloro-6-methoxypyridine-2-yl)[4-(cyclopropanesulfonyl)phenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,61-0,83 (m, 2H), 1,07-1,22 (m, 2H), 2,23 (TT, J=7,3, 4,4 Hz, 1H), was 4.02 (s, 3H), 7,43 (d, J=to 8.7 Hz, 2H), 7,63 (d, J=7,8 Hz, 1H), 7,82 (d, J=7.9 Hz, 1H), 8,09 (d, J=to 8.7 Hz, 2H).

MS(+): 342 [M+Na]+.

Referential example 1-3

(5-Chloro-6-methoxypyridine-2-yl)[4-(cyclopentylmethyl)phenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 1,58-of 1.74 (m, 4H), 1,75-of 1.91 (m, 2H), 2,08-of 2.30 (m, 2H), 3,61-of 3.85 (m, 1H), was 4.02 (s, 3H), 7,34 (d, J=to 8.7 Hz, 2H), 7,63 (d, J=7,8 Hz, 1H), 7,81 (d, J=7,8 Hz, 1H), 8,07 (d, J=to 8.7 Hz, 2H).

MS(+): 348 [M+H]+.

Reference example 1-4

[3-Chloro-4-(ethylsulfanyl)phenyl](5-chloro-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 1.45 (t, J=7,4 Hz, 3H), 3,06 (sq, J=7,3 Hz, 2H), of 4.04 (s, 3H), 7,27 (d, J=8.4 Hz, 1H), 7,68 (d, J=7,8 Hz, 1H), 7,83 (d, J=7,9 Hz, 1H), And 8.04 (DD, J=8,4, and 1.9 Hz, 1H), 8,31 (d, J=1.9 Hz, 1H).

Reference example 1-5

(5-Chloro-6-methoxypyridine-2-yl)[3-(cyclopropylmethyl)phenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,68-0,75 (m, 2H), 1,06-to 1.14 (m, 2H), 2,17-of 2.27 (m, 1H), 4,01 (s, 3H), 7,35-the 7.43 (m, 1H), 7,56-7,61 (m, 1H), 7,65 (d, J=7,8 Hz, 1H), 7,82 (d, J=7,8 Hz, 1H), 7,86 (dt, J=7,7, 1.3 Hz, 1H), 8,10 (t, J=1.6 Hz, 1H).

MS(+): 320 [M+H]+.

Reference example 1-6

(5-Chloro-6-methoxypyridine-2-yl)[4-(cyclopropanesulfonyl)-3-methylphenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,70-0,80 (m, 2H), 1,12-1,23 (m, 2H), 2,10-2,22 (m, 1H), to 2.29 (s, 3H), 4,03 (s, 3H), 7,61 (d, J=7,7 Hz, 1H), 7.62 mm (d, J=8,3 Hz, 1H), 7,81 (d, J=8,0 Hz, 1H), 7,92-of 7.95 (m, 1H), 8,00 (DD, J=8,3, The 1.9 Hz, 1H).

MS(+): 334 [M+H]+.

Reference example 1-7

(4-tert-Butylphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), of 4.04 (s, 3H), 7,45-7,52 (m, 2H), 7.62 mm (d, J=8,0 Hz, 1H), 7,80 (d, J=7,7 Hz, 1H), 8,05-8,12 (m, 2H).

MS(+): 304 [M+H]+.

Reference example 1-8

(5-Chloro-6-methoxypyridine-2-yl)[4-methyl-3-(trifluoromethyl)phenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 2,58 (d, J=1.5 Hz, 3H), 4,01 (s, 3H), of 7.42 (d, J=7,1 Hz, 1H), 7,73 (d, J=7,7 Hz, 1H), 7,84 (d, J=8,3 Hz, 1H), 8,20 (DD, J=7,7, of 1.8 Hz, 1H), 8,63 (d, J=1.2 Hz, 1H).

MS(+): 330 [M+H]+.

Reference example 1-9

(5-Chloro-6-methoxypyridine-2-yl)(4-ethylphenyl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 1.29 (t, J=7,6 Hz, 3H), 2,74 (sq, J=7,6 Hz, 2H), was 4.02 (s, 3H), 7,30 (d, J=8,6 Hz, 2H), 7,61 (d, J=8,3 Hz, 1H), 7,80 (d, J=7,7 Hz, 1H), 8,07 (DD, J=6,6, a 1.8 Hz, 2H).

MS(+): 276 [M+H]+/sup> .

Reference example 1-10

(5-Chloro-6-methoxypyridine-2-yl){4-[(3-methylbutoxy)methyl]phenyl}methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.92 (d, J=6,6 Hz, 6H), 1,50-1,60 (m, 2H), 1,67-of 1.84 (m, 1H), 3,54 (t, J=6,7 Hz, 2H), 4,00 (s, 3H), 4,58 (s, 2H), 7,44 (d, J=8,3 Hz, 2H), of 7.64 (d, J=7,7 Hz, 1H), 7,81 (d, J=7,7 Hz, 1H), 8,10 (d, J=8,0 Hz, 2H).

MS(+): 348 [M+H]+.

Reference example 1-11

(5-Chloro-6-methoxypyridine-2-yl)[4-(propane-2-yl)phenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 1.29 (s, 3H), of 1.31 (s, 3H), 2,92-3,06 (m, 1H), 4,03 (s, 3H), of 7.33 (d, J=8.4 Hz, 2H), 7,61 (d, J=7,8 Hz, 1H), 7,80 (d, J=7,8 Hz, 1H), 8,09 (d, J=to 8.7 Hz, 2H).

Reference example 1-12

(5-Chloro-6-methoxypyridine-2-yl)[4-(methylsulfanyl)-3-(trifluoromethyl)phenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 2,60 (s, 3H), 4,03 (s, 3H), 7,41 (d, J=8,2 Hz, 1H), 7,74 (d, J=7,8 Hz, 1H), 7,84 (d, J=7,8 Hz, 1H), of 8.28 (DD, J=8,2 and 1.7 Hz, 1H), of 8.71 (d, J=the 1.7 Hz, 1H).

MS(+): 362 [M+H]+.

Reference example 1-13

(5-Chloro-6-methoxypyridine-2-yl){4-[2-(2-methylpropoxy)ethyl]phenyl}methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.88 (d, J=6,8 Hz, 6H), 1,75-1,95 (m, 1H), 2,96 (t, J=6,8 Hz, 2H), 3,20 (d, J=6,8 Hz, 2H), to 3.67 (t, J=6,8 Hz, 2H), 4,01 (s, 3H), 7,34 (d, J=8,2 Hz, 2H), 7,63 (d, J=7,8 Hz, 1H), 7,81 (d, J=7,8 Hz, 1H), 8,06 (d, J=8,2 Hz, 2H).

MS(+): 348 [M+H]+.

Reference example 1-14

(5-Chloro-6-methoxypyridine-2-yl)(3,4-dimethylphenyl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 2,33 (s, 3H), of 2.35 (s, 3H), 4,01 (s, 3H), 7.23 percent (d, J=7,8 Hz, 1H), 7,61 (d, J=8,2 Hz, 1H), 7,81 (d, J=7,8 Hz, 1H), a 7.87 (DD, J=8,0, a 1.4 Hz, 1H), 7,93 (s, 1H).

Reference example 1-15

(4-BU�ylphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. to 0.94 (t, J=7,4 Hz, 3H), 1,30-1,45 (m, 2H), 1,57-1,71 (m, 2H), 2,69 (t, J=7,8 Hz, 2H), was 4.02 (s, 3H), 7,28 (d, J=8,6 Hz, 2H), 7.62 mm (d, J=7,8 Hz, 1H), 7,81 (d, J=7,8 Hz, 1H), 8,07 (d, J=8,6 Hz, 2H).

MS(+): 304 [M+H]+.

Reference example 1-16

(5-Chloro-6-methoxypyridine-2-yl)(3-chloro-4-methylphenyl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 2,47 (s, 3H), 4,03 (s, 3H), 7,34 (d, J=7,8 Hz, 1H), 7,68 (d, J=8,2 Hz, 1H), 7,83 (d, J=8,2 Hz, 1H), 7,94 (DD, J=8,0, a 1.8 Hz, 1H), of 8.25 (d, J=1.6 Hz, 1H).

MS(+): 296 [M+H]+.

Reference example 1-17

(5-Chloro-6-methoxypyridine-2-yl)[4-(trifluoromethyl)phenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 3,98 (s, 3H), 7,68-7,78 (m, 3H), 7,86 (d, J=8,2 Hz, 1H), 8,22 (d, J=8,2 Hz, 2H).

MS(+): 316 [M+H]+.

Reference example 1-18

(5-Chloro-6-methoxypyridine-2-yl)(4-propylphenyl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,97 (t, J=7,4 Hz, 3H), 1,61-of 1.76 (m, 2H), 2,67 (t, J=7,8 Hz, 2H), was 4.02 (s, 3H), 7,28 (d, J=8,6 Hz, 2H), 7.62 mm (d, J=7,8 Hz, 1H), 7,81 (d, J=7,8 Hz, 1H), 8,07 (d, J=8,2 Hz, 2H).

MS(+): 290 [M+H]+.

Referential example 1-19

(5-Chloro-6-methoxypyridine-2-yl)[4-(2-methylpropyl") phenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,92 (s, 3H), were 0.94 (s, 3H), 1,84-2,00 (m, 1H), 2,56 (d, J=7,4 Hz, 2H), was 4.02 (s, 3H), 7,21-7,28 (m, 2H), 7,61 (d, J=7,7 Hz, 1H), 7,80 (d, J=7,7 Hz, 1H), 8,06 (d, J=8,3 Hz, 2H).

Referential example 1-20

(5-Chloro-6-methoxypyridine-2-yl)(2,4-dimethylphenyl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. is 2.37 (s, 3H), 2,39 (s, 3H), 3,89 (s, 3H), 7,02 (d, J=7,7 Hz, 1H), was 7.08 (s, 1H), of 7.42 (d, J=7,7 Hz, 1H), members, 7.59 (d, J=7,7 Hz, 1H), 7,76 (d, J=7,7 Hz,1H).

MS(+): 276 [M+H]+.

Reference example 1-21

[4-(4-{[tert-Butyl(dimethyl)silyl]oxy}butyl)phenyl](5-chloro-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,00 (s, 6H), of 0.85 (s, 9H), 1,46-of 1.75 (m, 4H), 2,67 (t, J=7,4 Hz, 2H) and 3.59 (t, J=6.3 Hz, 2H), 3,97 (s, 3H), 7.23 percent (d, J=8,6 Hz, 2H), EUR 7.57 (d, J=7,7 Hz, 1H), of 7.75 (d, J=7,7 Hz, 1H), 8,01 (d, J=8,3 Hz, 2H).

MS(+): 434 [M+H]+.

Referential example 1-22

[3-Chloro-4-(cyclopropanesulfonyl)phenyl](5-chloro-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.74 to 0.82 (m, 2H), 1,15-of 1.27 (m, 2H), 2,13-2,22 (m, 1H), of 4.05 (s, 3H), 7,67 (d, J=8,3 Hz, 1H), 7,68 (d, J=8,0 Hz, 1H), 7,83 (d, J=7,7 Hz, 1H), 8,07 (DD, J=8,3, a 1.9 Hz, 1H), 8,28 (d, J=1.9 Hz, 1H).

MS(+): 354 [M+H]+.

Reference example 1-23

tert-Butyl 4-({4-[(5-chloro-6-methoxypyridine-2-yl)carbonyl]phenyl}sulfonyl)piperazine-1-carboxylate

1H NMR (300 MHz, CDCl3) δ M. D. of 1.41 (s, 9H), 3,03 (t, J=5.1 Hz, 4H), 3,53 (t, J=5.1 Hz, 4H), 3,98 (s, 3H), 7,73-7,78 (m, 1H), 7,82-7,90 (m, 3H), 8,23-8,31 (m, 2H).

MS(+): 518 [M+Na]+.

Referential example 1-24

(3-Chloro-4-ethoxyphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 1,42-to 1.61 (m, 3H), of 4.05 (s, 3H), 4,22 (sq, J=7,0 Hz, 2H), 6,98 (d, J=to 8.7 Hz, 1H), 7,65 (d, J=7.9 Hz, 1H), 7,83 (s, 1H), 8,11 (DD, J=to 8.7, 2.2 Hz, 1H), of 8.39 (s, 1H).

MS(+): 326 [M+H]+.

Reference example 1-25

(4-{[tert-Butyl(dimethyl)silyl]oxy}-3-methylphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.28 (s, 6H), of 1.03 (s, 9H), and 2.26 (s, 3H), 4,03 (s, 3H), is 6.81 (d, J=8.4 Hz, 1H) 7,58 (d, J=7.9 Hz, 1H), 7,80 (d, J=7.9 Hz, 1H), 7,91-7,96 (m, 1H), 8,01-with 8.05 (m, 1H).

MS(+): 392 [M+H]+.

Referential example 1-26

(4-{[tert-Butyl(dimethyl)silyl]oxy}-3-fluorophenyl)(5-chloro-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,23-0,26 (m, 6H), of 1.02 (s, 9H), of 4.04 (s, 3H), 6,98 (t, J=8.4 Hz, 1H), of 7.64 (d, J=7.9 Hz, 1H), 7,82 (d, J=7.9 Hz, 1H), 7,92 (DDD, J=8,5, 2,1, 1.0 Hz, 1H), 8,03 (DD, J=11,8, and 2.2 Hz, 1H).

MS(+): 396 [M+H]+.

Referential example 1-27

[4-{[tert-Butyl(dimethyl)silyl]oxy}-3-(trifluoromethyl)phenyl](5-chloro-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,34 (s, 6H), of 1.03 (s, 9H), of 4.04 (s, 3H), of 6.99 (d, J=8.4 Hz, 1H), 7,71 (d, J=7.9 Hz, 1H), 7,83 (d, J=7,8 Hz, 1H), 8,27 (DD, J=8,9, and 2.1 Hz, 1H), is 8.74 (d, J=2,3 Hz, 1H).

MS(+): 446 [M+H]+.

Referential example 1-28

(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)(5-chloro-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.25 (s, 6H), of 1.00 (s, 9H), 4,03 (s, 3H), 6,78-6,97 (m, 2H), 7,60 (d, J=7.9 Hz, 1H), 7,80 (d, J=7,8 Hz, 1H), 8,04-to 8.19 (m, 2H).

MS(+): 378 [M+H]+.

Referential example 1-29

(5-Chloro-6-methoxypyridine-2-yl)[4-(triptoreline)phenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 4,01 (s, 3H), 7,30 (d, J=7,8 Hz, 2H), 7,68 (d, J=7,8 Hz, 1H), 7,83 (d, J=7,8 Hz, 1H), 8,18-of 8.25 (m, 2H).

MS(+): 332 [M+H]+.

Patterns reference examples 1-2 - 1-29 shown below.

Table 1-1

Table 1-2

Reference example 1-30

(5-Chloro-6-methoxypyridine-2-yl)[3-chloro-4-(propane-2-yloxy)phenyl]methanon

[Formula 58]

(1) (4-{[tert-Butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-chloro-6-methoxypyridine-2-yl)methanon was obtained as an orange oil (3.94 g, 55% (two steps)) by carrying out essentially the same reaction as in reference example 1-1(2)(3), except that used the (4-bromo-2-chlorphenoxy)(tert-butyl)dimethylsilane.

(2) 1 M solution of tetrabutylammonium in tetrahydrofuran (3,39 ml) was added to a solution of (4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-chloro-6-methoxypyridine-2-yl)methanone (700 mg) in tetrahydrofuran (10 ml) at room temperature and the mixture was stirred at room temperature for two hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (10 ml) and�eat was added 2-jumprope (333 μl) and potassium carbonate (464 mg) at room temperature, followed by stirring at 65°C for three hours. The reaction solution was adjusted again to room temperature and was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=30:1) obtaining specified in the header connection in the form of a colorless oil (538 mg, 93%).

1H NMR (300 MHz, CDCl3) δ M. D., of 1.42 (s, 3H), of 1.44 (s, 3H), 4,03 (s, 3H), 4,60-4,80 (m, 1H), 6,98 (d, J=8,6 Hz, 1H), 7.62 mm (d, J=7,7 Hz, 1H), 7,78 (d, J=7,7 Hz, 1H), 8,08 (DD, J=8,6, and 2.1 Hz, 1H), to 8.38 (d, J=2.7 Hz, 1H).

MS(+): 340 [M+H]+.

The following compounds (reference examples 1-31 - 1-33) were obtained by conducting the reaction in the same manner as in reference example 1-30, using appropriate alkylhalogenide, respectively.

Referential example 1-31

(5-Chloro-6-methoxypyridine-2-yl)[3-chloro-4-(3-methylbutoxy)phenyl]methanon

[Formula 59]

1H NMR (300 MHz, CDCl3) δ M. D. 0,99 (s, 3H), 1,01 (s, 3H), 1,79 (TD, J=6,5 Hz, 6.5 Hz, 2H), 1,82-of 1.98 (m, 1H), of 4.05 (s, 3H), of 4.16 (t, J=6,6 Hz, 2H), 6,99 (d, J=8.4 Hz, 1H), 7,65 (d, J=7,8 Hz, 1H), 7,82 (d, J=7.5 Hz, 1H), 8,11 (DD, J=8,7, and 2.1 Hz, 1H), to 8.38 (d, J=2.4 Hz, 1H).

Reference example 1-32

(5-Chloro-6-methoxypyridine-2-yl)[3-chloro-4-(2-methylpropoxy)phenyl]methanon

[Formula 60]

1H NMR (300 MHz, CDCl3) δ M. D. of 1.09 (d, J=6,8 Hz, 6H), 2,12-of 2.30 (m, 1H), 3,88 (d, J=6,8 Hz, 2H), of 4.04 (s, 3H), 6,97 (d, J=to 8.7 Hz, 1H), 7,65 (d, J=7,8 Hz, 1H), 7,81 (d, J=7,8 Hz, 1H), 8,10 (DD, J=to 8.7, 2.2 Hz, 1H), to 8.38 (d, J=2,2 Hz, 1H).

MS(+): 354 [M+H]+.

Referential example 1-33

(5-Chloro-6-methoxypyridine-2-yl){3-chloro-4-[(4-methylpentyl)oxy]phenyl}methanon

[Formula 61]

1H NMR (300 MHz, CDCl3) δ M. D. of 0.93 (d, J=6,8 Hz, 6H), 1,32-of 1.43 (m, 2H), 1,55-1,72 (m, 1H), 1,82-of 1.97 (m, 2H), of 4.04 (d, J=1,7 Hz, 3H), 4,11 (t, J=6,0 Hz, 2H), 6,97 (d, J=to 8.7 Hz, 1H), 7,65 (d, J=7,8 Hz, 1H), 7,81 (d, J=7,8 Hz, 1H), 8,10 (DD, J=to 8.7, 2.2 Hz, 1H), to 8.38 (d, J=2,2 Hz, 1H).

MS(+): 382 [M+H]+.

Reference example 1-34

[4-(4-{[tert-Butyl(dimethyl)silyl]oxy}butoxy)-3-chlorophenyl](5-chloro-6-methoxypyridine-2-yl)methanon

[Formula 62]

(1) [3-Chloro-4-(4-hydroxyethoxy)phenyl](5-chloro-6-methoxypyridine-2-yl)methanon (759 mg, 54%) was obtained by carrying out essentially the same reaction as in reference example 1-30(2), except that used 4-bromo-1-butanol instead of 2-jumprope.

(2) tert-Butyldimethylchlorosilane (240 mg) and imidazole (108 mg) was then added to a solution of [3-chloro-4-(4-hydroxyethoxy)phenyl](5-chloro-6-methoxypyridine-2-yl)methanone (391 mg) in N,N-dimethylformamide (10 ml) under cooling with ice and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was cooled with ice and added a saturated solution of ammonium chloride followed by extraction with ethyl acetate. �organicheski layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:0→10:1) obtaining specified in the title compound (389 mg, 76%).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.06 (s, 6H), to 0.89 (s, 9H), 1,69-of 1.80 (m, 2H), 1,89-2,00 (m, 2H), 3,71 (t, J=6,1 Hz, 2H), of 4.04 (s, 3H), 4,17 (t, J=6.3 Hz, 2H), 6,97 (d, J=8,9 Hz, 1H), 7,65 (d, J=7,7 Hz, 1H), 7,81 (d, J=7,7 Hz, 1H), 8,09 (DD, J=8,5, and 2.2 Hz, 1H), 8,37 (d, J=2.4 Hz, 1H).

Referential example 1-35

4-{2-Chloro-4-[(5-chloro-6-methoxypyridine-2-yl)carbonyl]phenoxy}butyl 4-methylbenzenesulfonate

[Formula 63]

Triethylamine (830 ml), trimethylamine hydrochloride (188 mg) and 4-methylbenzenesulfonamide (555 mg) was then added to a solution of [3-chloro-4-(4-hydroxyethoxy)phenyl](5-chloro-6-methoxypyridine-2-yl)methanone obtained in reference example 1-34(1) (360 mg) in chloroform (8 ml) under cooling with ice and the mixture was stirred at room temperature for 4.5 hours. Triethylamine (150 μl) and 4-methylbenzenesulfonamide (185 mg) was then added under cooling with ice and the mixture was stirred at room temperature for another 1.5 hours. Was added to the reaction solution with water followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column � silica gel (hexane:ethyl acetate=3:1) obtaining specified in the title compound (357 mg, 70%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,90-2,00 (m, 4H), 2,44 (s, 3H), of 4.04 (s, 3H), 4,06-4,22 (m, 4H), 6,93 (d, J=8,9 Hz, 1H), 7,34 (d, J=8,6 Hz, 2H), 7,66 (d, J=7.9 Hz, 1H), 7,76-a 7.85 (m, 3H), 8,10 (DD, J=8,8, and 2.1 Hz, 1H), to 8.36 (d, J=2,0 Hz, 1H).

MS(+): 524 [M+H]+.

Referential example 1-36

(6-Methoxy-5-methylpyridine-2-yl)[4-(methylsulfanyl)phenyl]methanon

[Formula 64]

(1) 6-Methoxy-5-methylpyridine-2-carbaldehyde (14,8 g, 67%) was obtained by carrying out essentially the same reaction as in reference example 1-1(1), except that used methyliodide.

(2) (6-Methoxy-5-methylpyridine-2-yl)[4-(methylsulfanyl)phenyl]methanol (15.0 g, 74%) was obtained by carrying out essentially the same reaction as in reference example 1-1(2), except that used 6-methoxy-5-methylpyridine-2-carbaldehyde.

(3) (6-Methoxy-5-methylpyridine-2-yl)[4-(methylsulfanyl)phenyl]methanon (400 mg, 81%) was obtained by carrying out essentially the same reaction as in reference example 1-1(3), except that used 6-methoxy-5-methylpyridine-2-yl)[4-(methylsulfanyl)phenyl]methanol.

1H NMR (300 MHz, CDCl3) δ M. D. 2,28 (s, 3H), of 2.54 (s, 3H), 3,95 (s, 3H), 7,28 (d, J=9,8 Hz, 2H), 7,49-7,66 (m, 2H), 8,14 (d, J=to 8.7 Hz, 2H).

The following compounds (reference examples 1-37 - 1-50) were obtained by conducting the reaction in the same manner as in reference example 1-36 using methyliodide or, according to another variant, atili�Dida and using appropriate approach formulated above, respectively.

Referential example 1-37

[4-(Cyclopropanesulfonyl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,67-0,78 (m, 2H), 1,10-1,21 (m, 2H), 2,18 and 2.26 (m, 1H), 2,28 (s, 3H), 3,96 (s, 3H), of 7.42 (d, J=8,9 Hz, 2H), 7,51-7,66 (m, 2H), 8,14 (d, J=8,9 Hz, 2H).

MS(+): 300 [M+H]+.

Referential example 1-38

4-[(6-Methoxy-5-methylpyridine-2-yl)carbonyl]-N,N-dimethylbenzenesulfonamide

1H NMR (300 MHz, CDCl3) δ M. D. 2,30 (s, 3H), to 2.76 (s, 6H), 3,90 (s, 3H), 7,56-7,65 (m, 1H), 7,73 (d, J=7,3 Hz, 1H), a 7.87 (d, J=to 8.7 Hz, 2H), 8,30 (d, J=8,9 Hz, 2H).

MS(+): 335 [M+H]+.

Referential example 1-39

N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-[(6-methoxy-5-methylpyridine-2-yl)carbonyl]-N-methylbenzenesulfonamide

1H NMR (300 MHz, CDCl3) δ M. D. of 0.06 (s, 6H), 0.88 to (s, 9H), 2,30 (s, 3H), of 2.91 (s, 3H), 3,20 (t, J=5.8 Hz, 2H), 3,76-3,84 (m, 2H), 3,90 (s, 3H), 7,56-7,63 (m, 1H), 7,72 (d, J=7.5 Hz, 1H), of 7.88 (d, J=to 8.7 Hz, 2H), 8,23-of 8.34 (m, 2H).

MS(+): 479 [M+H]+.

Referential example 1-40

[3-Chloro-4-(methylsulfanyl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. to 2.29 (s, 3H), by 2.55 (s, 3H), 3,97 (s, 3H), 7,21 (d, J=8.4 Hz, 1H), 7,54-7,61 (m, 1H), 7,63-7,69 (m, 1H), 8,12 (DD, J=8,4, and 1.9 Hz, 1H), to 8.38 (d, J=1.9 Hz, 1H).

MS(+): 308 [M+H]+.

Referential example 1-41

{4-[(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}(6-methoxy-5-methylpyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.08 (s, 6H), 0,92 (s, 9H), 1,90-of 2.01 (m, 2H), to 2.29 (s, 3H), of 3.12 (t, J=7,4 Hz, 2H), of 3.77 (t, J=5.8 Hz, 2H), 397 (, 3H), 7,32 (d, J=8.4 Hz, 1H), 7,54-to 7.60 (m, 1H), 7,63-to 7.68 (m, 1H), 8,08 (DD, J=8,4, and 1.9 Hz, 1H), to 8.38 (d, J=1,87 Hz, 1H).

MS(+): 466 [M+H]+.

Referential example 1-42

tert-Butyl 3-({4-[(6-methoxy-5-methylpyridine-2-yl)carbonyl]phenyl}sulfanyl)azetidin-1-carboxylate

1H NMR (300 MHz, CDCl3) δ M. D. of 1.44 (s, 9H), 2,28 (s, 3H), 3,85-3,97 (m, 5H), 4,06-is 4.21 (m, 1H), 4,37-a 4.53 (m, 2H), of 7.19 (d, J=8,9 Hz, 2H), 7,50-of 7.70 (m, 2H), 8,14 (d, J=8,9 Hz, 2H).

MS(+): 414 [M+H]+.

Referential example 1-43

[4-(Ethylsulfanyl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 1,39 (t, J=7,4 Hz, 3H), 2,28 (s, 3H), 3,05 (sq, J=7,4 Hz, 2H), 3,95 (s, 3H), 7,32 (d, J=8,9 Hz, 2H), 7,51-7,66 (m, 2H), 8,13 (d, J=to 8.7 Hz, 2H).

MS(+): 288 [M+H]+.

Referential example 1-44

[4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 1.41 (s, 6H), 2,28 (s, 3H), 3,90 (s, 3H), 4,15 (s, 2H), 7,51-7,61 (m, 1H), of 7.64-7,71 (m, 1H), 7,98-8,07 (m, 2H), 8,13-8,23 (m, 2H).

MS(+): 325 [M+H]+.

Referential example 1-45

(6-Methoxy-5-methylpyridine-2-yl)[6-(methylsulfanyl)pyridin-3-yl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. to 2.29 (s, 3H), 2,63 (s, 3H), 3,97 (s, 3H), 7,18-value of 7, 37 (m, 1H), 7,49-7,63 (m, 1H), 7,65-7,74 (m, 1H), 8,24-to 8.41 (m, 1H), 9,29-9,41 (m, 1H).

MS(+): 275 [M+H]+.

Referential example 1-46

[3-Chloro-4-(methylsulfanyl)phenyl](5-ethyl-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 1,25 (t, J=7.5 Hz, 3H), by 2.55 (s, 3H), 2,68 (sq, J=7,7 Hz, 2H), 3,97 (s, 3H), 7,21 (d, J=8.4 Hz, 1H), 7,56-of 7.62 (m, 1H), 7,66-7,72 (�, 1H), 8,12 (DD, J=8,4, a 1.8 Hz, 1H), of 8.39 (d, J=the 1.7 Hz, 1H).

MS(+): 322 [M+H]+.

Referential example 1-47

{4-[(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)sulfanyl]phenyl}(5-ethyl-6-methoxypyridine-2-yl)methanon

1H NMR (200 MHz, CDCl3) δ M. D. of 0.07 (s, 6H), of 0.91 (s, 9H), 1,14-of 1.37 (m, 3H), 1,78-2,05 (m, 2H), 2,55-of 2.81 (m, 2H), 2,99-3,21 (m, 2H), 3,65-3,82 (m, 2H), 3,94 (s, 3H), 7,28-the 7.43 (m, 2H), 7,51-7,72 (m, 2H), 8,03-of 8.25 (m, 2H).

MS(+): 446 [M+H]+.

Referential example 1-48

{4-[(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}(5-ethyl-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.08 (s, 6H), 0,92 (s, 9H), 1,20-1,30 (m, 3H), 1,89-2,02 (m, 2H), 2,68 (sq, J=7,7 Hz, 2H), 3,03-3,17 (m, 2H), of 3.77 (t, J=5.8 Hz, 2H), 3,96 (s, 3H), 7,32 (d, J=8.4 Hz, 1H), 7,58 (d, J=6,7 Hz, 1H), Of 7.70 (s, 1H), 8,08 (DD, J=8,4, of 1.7 Hz, 1H), of 8.39 (s, 1H).

MS(+): 480 [M+H]+.

Referential example 1-49

[4-(Cyclopropanesulfonyl)phenyl](5-ethyl-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,66-0,80 (m, 2H), 1,08-1,20 (m, 2H), 1,24 (t, J=7.5 Hz, 3H), 2,16-of 2.30 (m, 1H), 2,68 (sq, J=7,7 Hz, 2H), 3,95 (s, 3H), of 7.42 (d, J=8,9 Hz, 2H), 7,53-to 7.60 (m, 1H), 7,61-7,66 (m, 1H), 8,15 (d, J=to 8.7 Hz, 2H).

MS(+): 314 [M+H]+.

Referential example 1-50

(4-{[tert-Butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-ethyl-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.28 (s, 6H), of 1.05 (s, 9H), 1,25 (t, J=7.5 Hz, 3H), 2,68 (sq, J=7,7 Hz, 2H), 3,97 (s, 3H), 6,94 (d, J=8,6 Hz, 1H), 7,53-to 7.60 (m, 1H), 7,63-of 7.70 (m, 1H), with 8.05 (DD, J=8,6, and 2.2 Hz, 1H), 8,45 (d, J=2,2 Hz, 1H).

MS(+): 406 [M+H]+.

The structure of a reference when�'erov 1-37 - 1-50 is shown below.

Table 2

Reference example 1-51

(5-Cyclopropyl-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanon

[Formula 65]

(1) a Suspension of zinc chloride (27 g) in tetrahydrofuran (300 ml) was cooled to 0°C in the presence of gaseous nitrogen was added a 1 M solution of cyclopropanemethylamine in tetrahydrofuran (186 ml) followed by stirring at room temperature for 30 minutes. The reaction solution was cooled to 0°C. Then was added dichlorobis(triphenylphosphine)palladium(II) (3,26 g) and a solution of ethyl 5-bromopyridin-2-carboxylate (21.4 g) in tetrahydrofuran (100 ml) and the mixture was stirred at 0°C for 30 minutes and at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:1) to give ethyl 5-cyclopropylidene-2-carboxylate (15.5 g, 87%) as bled�about brown butter.

(2) m-Chloroperbenzoic acid (55 g) was added to a solution of ethyl 5-cyclopropylidene-2-carboxylate (15.5 g) in chloroform (300 ml) under cooling with ice and the mixture was stirred at room temperature for four hours. The reaction solution was poured into a mixed solvent of a saturated aqueous solution of sodium bicarbonate and a saturated solution of sodium thiosulfate, and the mixture was stirred at room temperature for 30 minutes. After extraction with chloroform, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→9:1) to give 1-oxide ethyl 5-cyclopropylidene-2-carboxylate (15.4 g) as a pale yellow oil.

(3) Trifluoroacetic anhydride (23 ml) was added to a solution of 1-oxide ethyl 5-cyclopropylidene-2-carboxylate (15.4 g) in N,N-dimethylformamide (45 ml) and the mixture was stirred at 50°C for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The rest of acidaliaplanitia on a column of silica gel (chloroform:methanol=10:0→9:1) to give ethyl 5-cyclopropyl-6-hydroxypyridine-2-carboxylate (12.4 g, 78%) as colorless powder.

(4) silver Carbonate (70 g) and methyliodide (11,2 ml) was added to a solution of ethyl 5-cyclopropyl-6-hydroxypyridine-2-carboxylate (12.4 g) in chloroform (250 ml) and the mixture was stirred at 60°C for eight hours. The reaction solution was filtered through celite and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→4:1) to give ethyl 5-cyclopropyl-6-methoxypyridine-2-carboxylate (13,05 g, 99%) as a colorless oil.

(5) the Hydride (4,44 g) was added in small portions to a solution of ethyl 5-cyclopropyl-6-methoxypyridine-2-carboxylate (17.3 g) in tetrahydrofuran (300 ml) under cooling with ice and the mixture was stirred at the same temperature for one hour. The reaction solution was poured into a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure to obtain (5-cyclopropyl-6-methoxypyridine-2-yl)methanol (14.1 g).

(6) manganese Dioxide (67 g) was added to a solution of (5-cyclopropyl-6-methoxypyridine-2-yl)methanol (14.1 g) in chloroform (200 ml) and the mixture was stirred at 65°C for one hour. The reaction solution was filtered� through celite and the filtrate concentrated to give 5-cyclopropyl-6-methoxypyridine-2-carbaldehyde (11 g, 85%).

(7) (5-Cyclopropyl-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanol (2,93 g, 93%) was obtained by carrying out essentially the same reaction as in reference example 1-1(2) except that used 5-cyclopropyl-6-methoxypyridine-2-carbaldehyde (1.53 g).

(8) Specified in the title compound was obtained as a pale yellow oil (2,38 g, 99%) by carrying out essentially the same reaction as in reference example 1-1(3), except that used the (5-cyclopropyl-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanol.

1H NMR (300 MHz, CDCl3) δ M. D. 0,71-0,81 (m, 2H), 0,99-of 1.12 (m, 2H), 2,11-of 2.24 (m, 1H), by 2.55 (s, 3H), 3,97 (s, 3H), 7,20-7,32 (m, 3H), 7.62 mm (d, J=7,6 Hz, 1H), 8,11-to 8.19 (m, 2H).

MS(+): 300 [M+H]+.

The following compounds (reference examples 1-52 - 1-59) were obtained by conducting the reaction in the same manner as in reference example 1-51, using appropriate approach formulated above, respectively.

Referential example 1-52

[3-Chloro-4-(methylsulfanyl)phenyl](5-cyclopropyl-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,72-0,83 (m, 2H), 0,98-of 1.16 (m, 2H), of 2.09 and 2.26 (m, 1H), by 2.55 (s, 3H), 3,99 (s, 3H), 7,15-7,31 (m, 2H), 7,66 (d, J=7,6 Hz, 1H), 8,12 (DD, J=8,3, of 1.8 Hz, 1H), of 8.39 (d, J=the 1.7 Hz, 1H).

MS(+): 334 [M+H]+.

Referential example 1-53

(5-Cyclopropyl-6-methoxypyridine-2-yl)(4-ethylphenyl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.67 to 0.82 (m, 2H), 0,97-of 1.15 (m, 2H), of 1.29 (t, J=7,6 Hz, 3H), 2,10-of 2.27 (m, 1H), 2,73 (sq J=7,6 Hz, 2H), 3,98 (s, 3H), 7,15-value of 7, 37 (m, 3H), 7,60 (d, J=8,1 Hz, 1H), 8,13 (d, J=8,2 Hz, 2H).

MS(+): 282 [M+H]+.

Referential example 1-54

(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.25 (s, 6H), of 0.65-0.84 (m, 2H), 0,93-1,12 (m, 11H), 2,05-2,32 (m, 1H), 3,98 (s, 3H), of 6.79-of 6.96 (m, 2H), 7.23 percent (d, J=7,6 Hz, 1H), 7,58 (d, J=7,6 Hz, 1H), with 8.05 to 8.35 (m, 2H).

MS(+): 384 [M+H]+.

Reference example 1-55

(4-{[tert-Butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.28 (s, 6H), of 0.65-0,83 (m, 2H), of 0.95 to 1.31 (m, 11H), 2,05-to 2.29 (m, 1H), 4,00 (s, 3H), 6,94 (d, J=8,6 Hz, 1H), 7,24 (d, J=7,6 Hz, 1H), 7,63 (d, J=8,1 Hz, 1H), with 8.05 (DD, J=8,5, and 2.1 Hz, 1H), 8,45 (d, J=2,2 Hz, 1H).

MS(+): 418 [M+H]+.

Referential example 1-56

[4-(3-{[tert-Butyl(dimethyl)silyl]oxy}propoxy)phenyl](5-cyclopropyl-6-methoxypyridine-2-yl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,00 (s, 6H), 0,66-0,75 (m, 2H), from 0.84 (s, 9H), 0,94-of 1.03 (m, 2H), 1,89-2,03 (m, 2H), 2,06-to 2.18 (m, 1H), 3,76 (t, J=6,0 Hz, 2H), 3,93 (s, 3H), 4,11 (t, J=6,4 Hz, 2H), 6,86-at 6.92 (m, 2H), 7,17 (d, J=7,4 Hz, 1H), 7,53 (d, J=8,3 Hz, 1H), 8,13-8,20 (m, 2H).

MS(+): 442 [M+H]+.

Referential example 1-57

(5-Cyclopropyl-6-methoxypyridine-2-yl)[4-(cyclopropanesulfonyl)-3-methylphenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,70-0,80 (m, 4H), 1,00-1,09 (m, 2H), 1,13-1,22 (m, 2H), 2,12-2,22 (m, 2H), to 2.29 (s, 3H), 3,99 (s, 3H), 7.23 percent (d, J=7,4 Hz, 1H), 7,60 (d, J=7,7 Hz, 1H), 7,61 (d, J=8,3 Hz, 1H), 7,98-8,02 (m, 1H), With 8.05 (DD, J=8,3, a 1.9 Hz, 1H).

MS(+): 340 [M+H]+.

Saloon�th example 1-58

(5-Cyclopropyl-6-methoxypyridine-2-yl)(4-methylphenyl)methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,70-0,80 (m, 2H), 0,95-1,11 (m, 2H), 2,08-of 2.25 (m, 1H), 2,44 (s, 3H), 3,97 (s, 3H), 7.23 percent (d, J=7,7 Hz, 1H), 7,27 (d, J=8,0 Hz, 2H), 7,60 (d, J=7,4 Hz, 1H), 8,09 (d, J=8,3 Hz, 2H).

MS(+): 268 [M+H]+.

Referential example 1-59

(5-Cyclopropyl-6-methoxypyridine-2-yl)[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 0,71-0,80 (m, 2H), 1,00-1,09 (m, 2H), 1,41 (s, 6H), 2,10-2,22 (m, 1H), 3,92 (s, 3H), 4,15 (s, 2H), 7,24 (d, J=7,7 Hz, 1H), 7,66 (d, J=7,7 Hz, 1H), 8,02 (d, J=8,9 Hz, 2H), 8,17 (DD, J=7,1, 2,1 Hz, 2H).

MS(+): 351 [M+H]+.

The structure of a reference of examples 1-52 - 1-59 shown below.

Table 3

Referential example 1-60

(5-Cyclopropyl-6-methoxypyridine-2-yl)(4-ethoxyphenyl)methanon

[Formula 66]

(1) a Small amount of iodine was added to a suspension of 1-bromo-4-ethoxybenzene (484 μl), and magnesium (to 82.3 mg) in THF at room temperature in a nitrogen atmosphere and the mixture was stirred at 50°C for one hour. The reaction solution was adjusted again to room temperature and added to a solution of 5-cyclopropyl-6-methoxypyridine-2-carbaldehyde (300 mg) in tetrahydrofuran (1 ml) with subsequent change�ywaniem at 50°C for one hour. The tetrahydrofuran was concentrated under reduced pressure and was added a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was filtered through diatomaceous earth and then the solvent was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1→9:1) to give (5-cyclopropyl-6-methoxypyridine-2-yl)(4-ethoxyphenyl)methanol as a yellow oil (438 mg, 86%).

(2) Specified in the title compound was obtained as a pale yellow oil (441 mg, 99%) by carrying out essentially the same reaction as in reference example 1-1(3), except that used the (5-cyclopropyl-6-methoxypyridine-2-yl)(4-ethoxyphenyl)methanol.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.71-0.79 in (m, 2H), 0,99-1,08 (m, 2H), 1,45 (t, J=7,2 Hz, 3H), 2,10-of 2.23 (m, 1H), 3,98 (s, 3H), 4,12 (sq, J=7.2 Hz, 2H), 6,94 (d, J=8,9 Hz, 2H), 7,22 (d, J=7,6 Hz, 1H), 7,58 (d, J=7,6 Hz, 1H), 8,22 (d, J=8,9 Hz, 2H).

MS(+): 298 [M+H]+.

Referential example 1-61

(5-Cyclopropyl-6-methoxypyridine-2-yl)(3-ethoxyphenyl)methanon

[Formula 67]

(1) (3-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon was obtained as a brown oil (1,193 g, 84% (two steps)) by carrying out essentially the same reaction as in reference example 1-51(7)(8), except that used 3-brave�oxy)(tert-butyl)dimethylsilane.

(2) Specified in the title compound was obtained as a colorless oil (270 mg, 75%) by carrying out essentially the same reaction as in reference example 1-30(2), except that used (3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon and used ethyliodide instead of 2-jumprope.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.71 to 0.82 (m, 2H), 0,99-1,11 (m, 2H), 1,43 (t, J=6,9 Hz, 3H), 2,11-of 2.24 (m, 1H), 3,97 (s, 3H), 4,10 (sq, J=6,9 Hz, 2H), 7,07-made 7.16 interest (m, 1H), 7.23 percent (d, J=7,6 Hz, 1H), 7,35 (t, J=8,1 Hz, 1H), 7,60 (d, J=7,6 Hz, 1H), of 7.64-of 7.70 (m, 1H), 7,74 (DD, J=8,1, 2,0 Hz, 1H).

MS(+): 298 [M+H]+.

Referential example 1-62

(3-Chloro-4-ethoxyphenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon

[Formula 68]

Specified in the title compound was obtained as white solid (1,77 g, 94%) by carrying out essentially the same reaction as in reference example 1-61(2), except that used 4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-55.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.73-0.79 in (m, 2H), 1,01-1,09 (m, 2H), of 1.52 (t, J=7,2 Hz, 3H), 2,12-2,22 (m, 1H), 4,00 (s, 3H), is 4.21 (q, J=7,2 Hz, 2H), 6,97 (d, J=to 8.7 Hz, 1H), 7.23 percent (d, J=7,8 Hz, 1H), 7,63 (d, J=7,8 Hz, 1H), 8,15 (DD, J=8,7 Hz and 1.8 Hz, 1H), is 8.46-8,49 (m, 1H).

MS(+): 332 [M+H]+.

Referential example 1-63

[3-(4-{[tert-Butyl(dimethyl)silyl]oxy}butoxy)phenyl](5-cyclopropyl-6-methox�pyridin-2-yl)methanon

[Formula 69]

Specified in the title compound was obtained as a pale yellow oil (291 mg, 59% (two steps)) by carrying out essentially the same reaction as in reference example 1-34, except that used (3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-61(1).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.06 (s, 6H), 0,73-0,80 (m, 2H), of 0.90 (s, 9H), 1,00-1,11 (m, 2H), 1,64-of 1.75 (m, 2H), 1,80-of 1.92 (m, 2H), 2,11-of 2.23 (m, 1H), 3,69 (t, J=6.3 Hz, 2H), 3,97 (s, 3H), of 4.04 (t, J=6.3 Hz, 2H), 7,11 (DDD, J=8,3, of 2.8, and 1.1 Hz, 1H), 7.23 percent (d, J=7,7 Hz, 1H), 7,35 (t, J=8,0 Hz, 1H), 7,60 (d, J=7,4 Hz, 1H), 7,67 (DD, J=2,8, the 1.7 Hz, 1H), 7,73 (dt, J=8,0, 1,1 Hz, 1H).

MS(+): 456 [M+H]+.

Referential example 1-64

[3-(3-{[tert-Butyl(dimethyl)silyl]oxy}propoxy)phenyl](5-cyclopropyl-6-methoxypyridine-2-yl)methanon

[Formula 70]

Specified in the title compound was obtained as a colorless oil (349 mg, 72% (two steps)) by carrying out essentially the same reaction as in reference example 1-63, except that used 3-bromo-1-propanol instead of 4-bromo-1-butanol.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.04 (s, 6H), 0,72-0,81 (m, 2H), of 0.88 (s, 9H), 1,01-1,11 (m, 2H), 1,95-2,04 (m, 2H), 2,07-of 2.23 (m, 1H), 3,81 (t, J=6,1 Hz, 2H), 3,97 (s, 3H), 4,12 (t, J=6,1 Hz, 2H), 7,11 (DDD, J=8,3, of 2.5, 0.8 Hz, 1H), 7.23 percent (d, J=7,4 Hz, 1H), of 7.36 (t, J=7,7 Hz, 1H), 7,60 (d, J=7,7 Hz, 1H), 7,68 (DD, J=2,8, a 1.4 Hz, 1H), 7,73 (dt, J=7,7, and 1.1 Hz, 1H).

MS(+): 442 [M+H +.

Referential example 1-65

4-{2-Chloro-4-[(5-cyclopropyl-6-methoxypyridine-2-yl)carbonyl]phenoxy}butyl 4-methylbenzenesulfonate

[Formula 71]

Specified in the title compound (440 mg, 52% (two steps)) was obtained by carrying out essentially the same reaction as in reference examples 1-34(1) and 1-35, sequentially, except that used 4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-55.

1H NMR (300 MHz, CDCl3) δ M. D. 0,68-0,81 (m, 2H), 1,00-1,10 (m, 2H), 1,83-of 1.98 (m, 4H), 2,10-of 2.23 (m, 1H), 2,44 (s, 3H), 3,99 (s, 3H), 4,01-4,20 (m, 4H), 6,91 (d, J=to 8.7 Hz, 1H), 7.23 percent (d, J=7.5 Hz, 1H), to 7.33 (d, J=8.4 Hz, 2H), 7,63 (d, J=7.5 Hz, 1H), 7,79 (d, J=8.4 Hz, 2H), to 8.14 (DD, J=8,7, and 2.1 Hz, 1H), 8,43 (d, J=2.4 Hz, 1H).

MS(+): 530 [M+H]+.

Referential example 1-66

[4-(4-{[tert-Butyl(dimethyl)silyl]oxy}butoxy)-3-chlorophenyl](5-cyclopropyl-6-methoxypyridine-2-yl)methanon

[Formula 72]

Specified in the title compound (277 mg, 57% (two steps)) was obtained by carrying out essentially the same reaction as in reference example 1-34, except that used 4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-55.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.06 (s, 6H), of 0.72 to 0.82 (m, 2H), of 0.90 (s, 9H), 0.98 m-1,12 (m, 2H), 1,68-of 1.81 (m, 2H), 1,88-2,02 (m, 2H, 2,12-of 2.23 (m, 1H), and 3.72 (t, J=6,1 Hz, 2H), 4,00 (s, 3H), of 4.16 (t, J=6.3 Hz, 2H), 6,97 (d, J=8,6 Hz, 1H), 7,24 (d, J=7,8 Hz, 1H), 7,63 (d, J=7,8 Hz, 1H), 8,15 (DD, J=8,8, 2,3 Hz, 1H), is 8.46 (d, J=2.5 Hz, 1H).

Reference example 1-67

[6-Methoxy-5-(trifluoromethyl)pyridin-2-yl][4-(methylsulfanyl)phenyl]methanon

[Formula 73]

(1) sodium Borohydride (405 mg) was added to a solution of ethyl 6-methoxy-5-(trifluoromethyl)pyridine-2-carboxylate (670 mg, described in WO 2005058830) in methanol (20 ml) under cooling with ice and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure to obtain [6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanol (540 mg).

(2) 6-Methoxy-5-(trifluoromethyl)pyridin-2-carbaldehyde (405 mg) was obtained by carrying out essentially the same reaction as in reference example 1-51(6), except that used [6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanol.

(3) Specified in the title compound was obtained as a colorless oil (305 mg) by carrying out the reaction essentially in the same manner as in reference example 1-1(2)(3), except that used 6-methoxy-5-(trifluoromethyl)pyridin-2-carbaldehyde.

1H �Mr (300 MHz, CDCl3) δ M. D. by 2.55 (s, 3H), of 4.04 (s, 3H), 7,30 (d, J=8,9 Hz, 2H), 7,63-of 7.70 (m, 1H), 8,01-to 8.14 (m, 3H).

MS(+): 328 [M+H]+.

The following compounds (reference examples 1-68 - 1-75) were obtained by conducting the reaction in the same manner as in reference example 1-67, using appropriate approach formulated above, respectively.

Referential example 1-68

[4-(Cyclopropanesulfonyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.68-0.79 in (m, 2H), 1,12-1,22 (m, 2H), 2,23 (TT, J=7,4, 4,4 Hz, 1H), of 4.04 (s, 3H), of 7.36-7,50 (m, 2H), 7,60-of 7.70 (m, 1H), 7,99-8,13 (m, 3H).

MS(+): 354 [M+H]+.

Referential example 1-69

(4-{[tert-Butyl(dimethyl)silyl]oxy}-3-chlorophenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.29 (s, 6H), of 1.05 (s, 9H), 4,06 (s, 3H), of 6.96 (d, J=8,5 Hz, 1H), 7,68 (DD, J=7,7, 0.8 Hz, 1H), 8,00 (DD, J=8,5, and 2.2 Hz, 1H), with 8.05 (DD, J=7,7, 0.6 Hz, 1H), 8,35 (d, J=2,2 Hz, 1H).

MS(+): 446 [M+H]+.

Referential example 1-70

{4-[(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.08 (s, 6H), of 0.91 (s, 9H), 1,90-2,02 (m, 2H), 3,12 (t, J=7,2 Hz, 2H), of 3.77 (t, J=5.4 Hz, 2H), of 4.05 (s, 3H), of 7.33 (d, J=8,2 Hz, 1H), 7,71 (DD, J=7,5, 0.7 Hz, 1H), 8,02 (DD, J=8,2 and 1.7 Hz, 1H), 8,06 (DD, J=7,8, 0.7 Hz, 1H), 8,27 (d, J=the 1.7 Hz, 1H).

MS(+): 520 [M+H]+.

Referential example 1 to 71

{4-[(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)sulfanyl]phenyl}[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methano�

1H NMR (300 MHz, CDCl3) δ M. D. of 0.07 (s, 6H), of 0.91 (s, 9H), 1,85-2,00 (m, 2H), 3,05-3,18 (t, J=7,4 Hz, 2H), of 3.75 (t, J=6.3 Hz, 2H), 4,03 (s, 3H), 7,34 (d, J=8,6 Hz, 2H), 7,65 (d, J=7,7 Hz, 1H), 8,00-8,10 (m, 3H).

MS(+): 486 [M+H]+.

Referential example 1-72

[4-(4-{[tert-Butyl(dimethyl)silyl]oxy}butyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.05 (s, 6H), to 0.89 (s, 9H), 1,50-1,80 (m, 4H), of 2.72 (t, J=7,7 Hz, 2H), to 3.64 (t, J=6.3 Hz, 2H), of 4.04 (s, 3H), 7,30 (d, J=8.4 Hz, 2H), of 7.64 (DD, J=7,8, 0.6 Hz, 1H), 8,00-8,10 (m, 3H).

MS(+): 468 [M+H]+.

Referential example 1-73

(3-Chloro-4-methoxyphenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. 4,01 (s, 3H), 4,06 (s, 3H), 7,02 (d, J=8,5 Hz, 1H), of 7.70 (DD, J=7,7, 0.8 Hz, 1H), 8,06 (DD, J=7,7, 0.6 Hz, 1H), 8,13 (DD, J=8,5, and 2.2 Hz, 1H), 8,37 (d, J=2,2 Hz, 1H).

Referential example 1-74

(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.26 (s, 6H), of 1.00 (s, 9H), of 4.04 (s, 3H), 6,91 (d, J=9,0 Hz, 2H), 7.62 mm (d, J=9,0 Hz, 1H), 7,95-8,11 (m, 3H).

MS(+): 412 [M+H]+.

Referential example 1-75

(4-{2-[3-(Diethylamino)propyl]-1,3-dioxolan-2-yl}phenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon

1H NMR (300 MHz, CDCl3) δ M. D. of 0.98 (t, J=7,1 Hz, 6H), 1,45-1,65 (m, 2H), 1,86-of 1.95 (m, 2H), is 2.40 (t, J=7,6 Hz, 2H), 2,47 (sq, J=7,0 Hz, 4H), 3.75 to 3,82 (m, 2H), 4,01-4,07 (m, 5H), EUR 7.57 (d, J=8,6 Hz, 2H), 7,66 (d, J=7,7 Hz, 1H), With 8.05 (d, J=7,7 Hz, 1H), 8,10 (d, J=8,6 Hz, 2H).

MS(+): 467 [M+H]+.

Patterns reference examples -68 - 1-75 shown below.

Table 4

Referential example 1-76

[6-Methoxy-5-(propan-2-yl)pyridin-2-yl][4-(methylsulfanyl)phenyl]methanon

[Formula 74]

(1) Ethyl 5-(prop-1-EN-2-yl)pyridine-2-carboxylate was obtained as yellow oil (10 g, 71%) by carrying out essentially the same reaction as in reference example 1-51(1), except that used the prop-1-EN-2-imagebased.

(2) 10% palladium-activated carbon (5.8 g) was added to a solution of ethyl 5-(prop-1-EN-2-yl)pyridine-2-carboxylate (10 g) in ethanol (100 ml) and the mixture was stirred in a stream of hydrogen gas at room temperature over night. The reaction solution was filtered through celite and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→0:1) to give ethyl 5-isopropylpyridine-2-carboxylate as a colorless oil (10 g, 95%).

(3) Specified in the title compound was obtained as yellow oil (1.88 g) carrying out the reaction essentially in the same manner as in reference example 1-51(2) to(7), except that used ethyl 5-isopropylpyridine-2-�arboxylic.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.26 (d, J=7,0 Hz, 6H), of 2.54 (s, 3H), 3,12-3,35 (m, 1H), 3,95 (s, 3H), 7,28 (d, J=to 8.7 Hz, 2H), 7,52-of 7.75 (m, 2H), 8,16 (d, J=to 8.7 Hz, 2H).

MS(+): 302 [M+H]+.

Referential example 1-77

[5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-6-methoxypyridine-2-yl][4-(cyclopropanesulfonyl)phenyl]methanon

[Formula 75]

(1) 6-(Dimethoxymethyl)-2-methoxypyridine-3-carbonitrile was obtained as a pale yellow oil (4,17 g, 86%) by carrying out essentially the same reaction as in reference example 1-51(4), except that used 6-(dimethoxymethyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (4,47 g, described in J. Hetero. Chem., 1994, 31, p. 297).

(2) Water (10 ml) and sodium hydroxide (3,96 g) was added to a solution of 6-(dimethoxymethyl)-2-methoxypyridine-3-carbonitrile (4,17 g) in a mixture of tetrahydrofuran-methanol (30 ml) and the mixture was stirred at 90°C for 15 hours. The reaction solution was poured into water and weakly acidified with 1 M hydrochloric acid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent to obtain crude product containing 6-(dimethoxymethyl)-2-methoxypyridine-3-carboxylic acid (4.1 g).

(3) Diisopropylethylamine (4,56 ml) and Bop reagent (registered trade Zn�K) (10 g) was added to a solution of 6-(dimethoxymethyl)-2-methoxypyridine-3-carboxylic acid (4.1 g) in tetrahydrofuran (40 ml) under cooling with ice and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0°C and added sodium borohydride (2.72 g), followed by stirring at room temperature over night. The reaction solution was poured into a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=5:1→1:1) to give [6-(dimethoxymethyl)-2-methoxypyridine-3-yl]methanol (2.3 g, 60%) as a colorless oil.

(5) Imidazole (1.47 g) and tert-butyldiphenylchlorosilane (3,54 g) was added to a solution of [6-(dimethoxymethyl)-2-methoxypyridine-3-yl]methanol (2.3 g) in N,N-dimethylformamide (23 ml) and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1→10:1) to give 3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(dimethoxymethyl)-2-methoxypyridine (5,47 g, 99%) as a colorless oil.

(6) 1 M hydrochloric Ki�lot (40 ml) was added to a solution of 3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(dimethoxymethyl)-2-methoxypyridine (5,47 g) in tetrahydrofuran (40 ml) and the mixture was stirred at 60°C for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=5:1→1:1) to give 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxypyridine-2-carbaldehyde (3.2 g, 73%) as a colorless oil.

(7) Specified in the title compound was obtained as a colorless oil (2.3 g, 51%) by carrying out essentially the same reaction as in reference example 1-1(2)(3), except that used 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxypyridine-2-carbaldehyde and used 1-bromo-4-(cyclopropanesulfonyl)benzene instead of 4-bromothioanisole.

1H NMR (300 MHz, CDCl3) δ M. D. 0,67-0,80 (m, 2H), 1,08-of 1.20 (m, 11H), 2,22 (TT, J=7,4, 4,4 Hz, 1H), 3,85 (s, 3H), 4,80 (s, 2H), 7,34-7,53 (m, 8H), of 7.64-7,78 (m, 5H), 8,04-8,17 (m, 3H).

MS(+): 554 [M+H]+.

Referential example 1-78

[4-(Cyclopropanesulfonyl)phenyl](6-methoxy-5-vinylpyridin-2-yl)methanon

[Formula 76]

(1) 5-Bromo-6-methoxypyridine-2-carbaldehyde (754 mg, 42%) was obtained by carrying out essentially the same reaction as in reference example 1-1(1), except that used tetrabromide of carbon.

(2) Tetranitroaniline�alladi (403 mg), phenylboronic acid (510 mg) and 2 M sodium carbonate solution (3.5 ml) was then added to a solution of 5-bromo-6-methoxypyridine-2-carbaldehyde (753 mg) in 1,2-dimethoxyethane (23 ml) in a nitrogen atmosphere and the mixture was stirred at 80°C for three hours. Was added to the reaction solution with water at room temperature followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. Then evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1→1:1) and then purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1) to give 6-methoxy-5-vinylpyridin-2-carbaldehyde (445 mg, 60%).

(3) Specified in the title compound was obtained (360 mg, 53% (two steps)) by carrying out essentially the same reaction as in reference example 1-1(2)(3), except that used 6-methoxy-5-vinylpyridin-2-carbaldehyde and used 1-bromo-4-(cyclopropanesulfonyl)benzene instead of 4-bromothioanisole.

1H NMR (300 MHz, CDCl3) δ M. D. 0,70-0,85 (m, 2H), 1,10-1,25 (m, 2H), 2,15-2,35 (m, 1H), 3,97 (s, 3H), 7,40-of 7.50 (m, 5H), 7,60-7,65 (m, 2H), 7,76 (d, J=7,8 Hz, 1H), 7,81 (d, J=7,8 Hz, 1H), 8,15-of 8.25 (m, 2H).

MS(+): 362 [M+H]+

Referential example 1-79

(5-Cyclopropyl-6-methoxypyridine-2-yl)[4-(propane-2-yl)phenyl]methanon

[Form�and 77]

Specified in the title compound (352 mg, 76% (two steps)) was obtained by carrying out essentially the same reaction as in reference example 1-51(7)(8) sequentially, except that used 1-bromo-4-(propan-2-yl)benzene.

1H NMR (300 MHz, CDCl3) δ M. D. 0,73-0,80 (m, 2H), 1,00-1,08 (m, 2H), 1,28 (s, 3H), of 1.31 (s, 3H), 2,12-of 2.23 (m, 1H), 2,91-3,06 (m, 1H), 3,97 (s, 3H), 7,22 (d, J=7,4 Hz, 1H), 7,31 (d, J=8,0 Hz, 2H), EUR 7.57-7.62 mm (m, 1H), 8,14 (d, J=8,3 Hz, 2H).

Referential example 1-80

(4-tert-Butyl-3-chlorophenyl)(5-chloro-6-methoxypyridine-2-yl)methanon

[Formula 78]

(1) a Mixture of 4-bromo-1-tert-butyl-2-chlorobenzene and 4-bromo-2-chloro-1-(prop-1-EN-2-yl)benzene (1:1) was obtained as a colorless oil (166 mg) by carrying out reaction according to the method described in WO 2006013048, using 4-bromo-2-chlorobenzoic acid (2 g).

(2) a Mixture specified in the title compound and (5-chloro-6-methoxypyridine-2-yl)[3-chloro-4-(prop-1-EN-2-yl)phenyl]methanone (1:1) were obtained by carrying out essentially the same reaction as in reference example 1-1(2)(3), consecutively, except that used a mixture of 4-bromo-1-tert-butyl-2-chlorobenzene and 4-bromo-2-chloro-1-(prop-1-EN-2-yl)benzene (1:1).

MS(+): 338 [M+H]+.

Referential example 1 to 81

(5-Chloro-6-methoxypyridine-2-yl)[4-(4-methoxybutyl)phenyl]methanon

[Formula 79]

Specified in the header�e compound (625 mg, 66% (two steps)) was obtained by carrying out essentially the same reaction as in reference example 1-1(2)(3), consecutively, except that used 1-bromo-4-(4-methoxybutyl)benzene.

1H NMR (300 MHz, CDCl3) δ M. D. 1,55-of 1.81 (m, 4H), of 2.72 (t, J=7,4 Hz, 2H), of 3.33 (s, 3H), 3,40 (t, J=6,4 Hz, 2H), 4,01 (s, 3H), 7,28 (d, J=8,6 Hz, 2H), 7,61 (d, J=7,7 Hz, 1H), 7,80 (d, J=8,0 Hz, 1H), 8,06 (d, J=8,3 Hz, 2H).

MS(+): 334 [M+H]+.

Referential example 1-82

(4-tert-Butylphenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon

[Formula 80]

Specified in the title compound (694 mg, 54% (two steps)) was obtained by carrying out essentially the same reaction as in reference example 1-67(3), except that used 1-bromo-4-tert-butylbenzoyl.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 4,06 (s, 3H), 7,51 (d, J=to 8.7 Hz, 2H), 7,65 (d, J=8,1 Hz, 1H), with 8.05 (d, J=7.5 Hz, 1H), 8,10 (d, J=8,1 Hz, 2H).

MS(+): 338 [M+H]+.

Referential example 1-83

(5-Chloro-6-methoxypyridine-2-yl)(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanon

[Formula 81]

(1) (5-Chloro-6-methoxypyridine-2-yl)(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanol was obtained as yellow crystals (413 mg, 72%) by carrying out essentially the same reaction as in reference example 1-1(2), except that used 7-bromo-4-methyl-3,4-dihydro-2H-1,4-benzoxazin.

(2) sodium Hydride (purity: 63%, 75 mg) is added to�and to a solution of (5-chloro-6-methoxypyridine-2-yl)(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanol (302 mg) in tetrahydrofuran (2 ml) under cooling with ice and the mixture was stirred with heating to room temperature over night. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=2:1→1:1) obtaining specified in the title compound as a yellow solid (231 mg).

1H NMR (300 MHz, CDCl3) δ M. D. 3,02 (s, 3H), 3,40-3,45 (m, 2H), of 4.05 (s, 3H), 4,23-to 4.28 (m, 2H), 6,63 (d, J=8,6 Hz, 1H), 7,51 (d, J=7,7 Hz, 1H), 7,69 (d, J=2.1 Hz, 1H), 7,76 (d, J=7,7 Hz, 1H), 7,80 (DD, J=8,6, and 2.1 Hz, 1H).

MS(+): 319 [M+H]+.

Referential example 1-84

[3-Chloro-4-(propan-2-yl)phenyl](5-cyclopropyl-6-methoxypyridine-2-yl)methanon

[Formula 82]

Specified in the title compound (160 mg, 54% (two steps)) was obtained by carrying out essentially the same reaction as in reference example 1-51(7)(8) sequentially, except that used 4-bromo-2-chloro-1-(propane-2-yl)benzene.

1H NMR (300 MHz, CDCl3) δ M. D. 0,68-0,81 (m, 2H), and 0.98-1,10 (m, 2H), 1,28 (s, 3H), of 1.31 (s, 3H), of 2.08 and 2.26 (m, 1H), 3,41-of 3.53 (m, 1H), 4,00 (s, 3H), 7,20-7,29 (m, 1H), 7,40 (d, J=8,1 Hz, 1H), 7,66 (d, J=7,8 Hz, 1H), 8,07 (DD, J=8,1, 1.5 Hz, 1H), 8,35 (d, J=1,8 Hz, 1H).

MS(+): 330 [M+H]+.

Referential example 1-85

(4-tert-Butylphenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon

[Formula 83]

Specified in for�over the head of the compound was obtained as a colorless oil (405 mg, 71% (two steps)) by carrying out essentially the same reaction as in reference example 1-51(7)(8) sequentially, except that used 1-bromo-4-tert-butylbenzoyl.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.73-0.79 in (m, 2H), 1,00-1,08 (m, 2H), of 1.33 (s, 9H), 2,12-of 2.23 (m, 1H), 4,00 (s, 3H), 7.23 percent (d, J=7.5 Hz, 1H), of 7.48 (d, J=to 8.7 Hz, 2H), 7,61 (d, J=7.5 Hz, 1H), 8,17 (d, J=to 8.7 Hz, 2H).

Referential example 1-86

(5-Chloro-6-methoxypyridine-2-yl)[3-chloro-4-(propan-2-yl)phenyl]methanon

[Formula 84]

Specified in the title compound was obtained as a pale yellow oil (240 mg, 23% (two steps)) by carrying out essentially the same reaction as in reference example 1-1(2)(3) sequentially, except that used 4-bromo-2-chloro-1-(propane-2-yl)benzene.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.28 (s, 3H), of 1.31 (s, 3H), 3,40-to 3.56 (m, 1H), of 4.05 (s, 3H), 7,41 (d, J=8,1 Hz, 1H), 7,68 (d, J=7.5 Hz, 1H), 7,83 (d, J=7,8 Hz, 1H), 8,03 (d, J=9.8 Hz, 1H), 8,28 (s, 1H).

Referential example 1-87

(5-Chloro-6-methoxypyridine-2-yl)(4-cyclopropylmethyl)methanon

[Formula 85]

(1) a Solution of bromine (0.65 ml) in acetic acid (3 ml) was added dropwise to a solution of cyclopropylbenzene (1,59 ml) and sodium acetate (1.14 g) in acetic acid (16 ml) under cooling with ice and the mixture was stirred at room temperature over night. Was added to the reaction solution, hexane and water and a saturated solution of sodium bisulphite�I with subsequent extraction. The organic layer was washed with saturated sodium carbonate solution, dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (only hexane) to give a mixture of 4-bromo-1-cyclopropylbenzene and cyclopropylbenzene in the form of a colorless oil (851 mg).

(2) n-Butyllithium (1.65 M, 3 ml) was added dropwise to a solution mixture of 4-bromo-1-cyclopropylbenzene and cyclopropylbenzene (976 mg) in tetrahydrofuran (20 ml) at -78°C in a nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. A solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (732 mg) in tetrahydrofuran (9 ml) was added to the reaction solution at -78°C and the mixture was stirred at the same temperature for three hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:0→1:10) to give (5-chloro-6-methoxypyridine-2-yl)(4-cyclopropylmethyl)methanol (765 mg).

(3) Specified in the title compound (732 mg, 96%) was obtained by carrying out essentially the�th same reaction as in reference example 1-1(3), except that used the (5-chloro-6-methoxypyridine-2-yl)(4-cyclopropylmethyl)methanol.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.74-0.87 (m, 2H), 1,01-to 1.14 (m, 2H), 1,90-2,05 (m, 1H), was 4.02 (s, 3H), 7,14 (d, J=8.4 Hz, 2H), 7.62 mm (d, J=7,2 Hz, 1H), 7,81 (d, J=8,1 Hz, 1H), with 8.05 (d, J=8.4 Hz, 2H).

MS(+): 288 [M+H]+.

Referential example 1 to 88

(5-Chloro-6-methoxypyridine-2-yl)[4-(cyclopropylamino)phenyl]methanon

[Formula 86]

Specified in the title compound (813 mg, 46% (two steps)) was obtained by carrying out essentially the same reaction as in reference example 1-1(2)(3) sequentially, except that used 1-bromo-4-cyclopropylamines.

1H NMR (300 MHz, CDCl3) δ M. D. 0,70-0,79 (m, 2H), 1,12-to 1.21 (m, 2H), 2,18-of 2.28 (m, 1H), 4,03 (s, 3H), 7,43 (d, J=8,9 Hz, 2H), 7,63 (d, J=7,8 Hz, 1H), 7,82 (d, J=7,8 Hz, 1H), 8,09 (d, J=8,9 Hz, 2H).

MS(+): 304 [M+H]+.

Referential example 1-89

tert-Butyl {4-[(5-chloro-6-methoxypyridine-2-yl)carbonyl]phenyl}carbamate

[Formula 87]

Specified in the title compound (2.15 g) was obtained by carrying out essentially the same reaction as in reference example 1-1(2)(3), consecutively, except that used tert-butyl 4-brompheniramine.

1H NMR (300 MHz, CDCl3) δ M. D. a 1.54 (s, 9H), 4,01 (s, 3H), 6,67-6,72 (user.s, 1H), of 7.48 (d, J=8,9 Hz, 2H), 7,63 (d, J=7.9 Hz, 1H), 7,81 (d, J=7,8 Hz, 1H), 8,16 (d, J=8,9 Hz, 2H).

MS(+): 363 [MH] +.

Referential example 1-90

(3-Chloro-4-ethylphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon

Specified in the title compound was obtained as a pale yellow oil (385 mg, 66% (two steps)) by carrying out essentially the same reaction as in reference example 1-1(2)(3), except that used 4-bromo-2-chloro-1-ethylbenzene.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.28 (t, J=7.5 Hz, 3H), 2,84 (sq, J=7.5 Hz, 2H), of 4.04 (s, 3H), 7,35 (d, J=7.5 Hz, 1H), 7,68 (DD, J=9,2, 0.8 Hz, 1H), 7,83 (DD, J=7,8, 0.6 Hz, 1H), 7,98 (DD, J=to 7.5, 1.5 Hz, 1H), of 8.26 (d, J=1.5 Hz, 1H).

Referential example 1-91

(5-Chloro-6-methoxypyridine-2-yl)(4-methylphenyl)methanon

Specified in the title compound was obtained as a white amorphous substance (584 mg, 77% (two steps)) by carrying out essentially the same reaction as in reference example 1-1(2)(3), except that used 4-bromthymol.

1H NMR (300 MHz, CDCl3) δ M. D. 2,44 (s, 3H), of 4.00 (s, 3H), 7,27 (d, J=7,8 Hz, 2H), 7.62 mm (d, J=7,8 Hz, 1H), of 7.75 (d, J=7,8 Hz, 1H), 8,03 (d, J=8,2 Hz, 2H).

MS(+): 262 [M+H]+.

Referential example 1-92

[3-Chloro-4-(propane-2-yloxy)phenyl](5-cyclopropyl-6-methoxypyridine-2-yl)methanon

Specified in the title compound was obtained as a colorless amorphous substance (643 mg, 78% (two steps)) by carrying out essentially the same reaction as in reference example 1-30(2), except that used 4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-cyclopropyl-6-methox�pyridin-2-yl)methanon, obtained in reference example 1-55.

1H NMR (300 MHz, CDCl3) δ M. D. 0,72-0,80 (m, 2H), 1,00-1,10 (m, 2H), 1,43 (s, 3H), 1,45 (s, 3H), 2,10-of 2.25 (m, 1H), 4,00 (s, 3H), 4,60-4,80 (m, 1H), 6,98 (d, J=8,9 Hz, 1H), 7.23 percent (d, J=7,4 Hz, 1H), 7.62 mm (d, J=7,4 Hz, 1H), Of 8.13 (DD, J=8,3, and 2.1 Hz, 1H), of 8.47 (d, J=2.1 Hz, 1H).

Referential example 1-93

[6-Methoxy-5-(trifluoromethyl)pyridin-2-yl][4-(trifluoromethyl)phenyl]methanon

Specified in the title compound was obtained as a colorless oil (201 mg, 16% (two steps)) by carrying out essentially the same reaction as in reference example 1-67(3), except that used 4-bromobenzonitrile.

1H NMR (300 MHz, CDCl3) δ M. D. 4,01 (s, 3H), 7,76 (d, J=to 8.7 Hz, 2H), to 7.77 (d, J=7,8 Hz, 1H), 8,10 (d, J=7,8 Hz, 1H), 8,23 (d, J=8,1 Hz, 2H).

MS(+): 350 [M+H]+.

Referential example 1-94

(3-Chloro-4-methoxyphenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon

Specified in the title compound was obtained as a colorless amorphous substance (772 mg, quantitative (two steps)) by carrying out essentially the same reaction as in reference example 1-30(2), except that used 4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-55, and used methyliodide instead of 2-jumprope.

1H NMR (300 MHz, CDCl3) δ M. D. 0,73-0,80 (m, 2H), 1,00-1,10 (m, 2H), 2,10-of 2.25 (m, 1H), 3,99 (s, 3H), of 4.00 (s, 3H), 7,00 (d, J=8,6 Hz, 1H), 7.23 percent (d, J=7,7 Hz, 1H), 7,63 (d, J=8,3 Hz, 1H), 8,18 (DD, J=8,6, 21 Hz, 1H), of 8.47 (d, J=2.1 Hz, 1H).

Referential example 1 to 95

(4-Chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon

Specified in the title compound was obtained as white solid (1.04 g, 69% (two steps)) by carrying out essentially the same reaction as in reference example 1-51(7)(8), except that used 4-brotherbear.

1H NMR (300 MHz, CDCl3) δ M. D. 0,71-0,81 (m, 2H), 1,01-1,10 (m, 2H), 2,11-of 2.23 (m, 1H), 3,95 (s, 3H), 7,24 (d, J=7,6 Hz, 1H), 7,44 (d, J=8,3 Hz, 2H), 7,65 (d, J=7,6 Hz, 1H), 8,14 (d, J=8,3 Hz, 2H).

The structure of a reference of examples 1-90 - 1 to 95 is shown below.

Table 5

Referential example 2-1

2-Methoxy-3-methyl-6-[4-(methylsulfanyl)benzyl]pyridin

[Formula 88]

Triethylsilane (5 ml) and trifluoroacetic acid (5 ml) were added sequentially to (6-methoxy-5-methylpyridine-2-yl)[4-(methylsulfanyl)phenyl]methanol obtained in reference example 1-36(2) (2.13 g) and the mixture was stirred at 60°C for four hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sulfate MAGN�I and was filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→4:1→2:1) with obtaining specified in the header connection in the form of a colorless oil (1,69 g).

1H NMR (300 MHz, CDCl3) δ M. D. to 2.13 (s, 3H), 2,46 (s, 3H), 3,93 (s, 3H), 3,95 (s, 2H), 6,55 (d, J=7,6 Hz, 1H), 7,15-7,28 (m, 5H).

MS(+): 260 [M+H]+.

Compounds of reference examples 2-2 and 2-4 were obtained by carrying out essentially the same reaction as in reference example 2-1, except that used the corresponding pyridine-2-carbaldehyde, respectively.

Reference example 2-2

3-Ethyl-2-methoxy-6-[4-(methylsulfanyl)benzyl]pyridin

[Formula 89]

1H NMR (300 MHz, CDCl3) δ M. D. of 1.15 (t, J=7.5 Hz, 3H), 2,46 (s, 3H), 2,53 (sq, J=7,4 Hz, 2H), 3,93 (s, 3H), 3,95 (s, 2H), to 6.58 (d, J=7,3 Hz, 1H), 7,17-7,29 (m, 5H).

MS(+): 274 [M+H]+

Reference example 2-3

2-Methoxy-6-[4-(methylsulfanyl)benzyl]-3-propylpyridine

[Formula 90]

1H NMR (300 MHz, CDCl3) δ M. D. 0,92 (t, J=7,4 Hz, 3H), 1,48-to 1.67 (m, 2H), 2,47 (DD, J=8,5, 6,8 Hz, 5H), 3,92 (s, 3H), 3,95 (s, 2H), to 6.57 (d, J=7,3 Hz, 1H), 7,11-7,32 (m, 5H).

MS(+): 288 [M+H]+

Reference example 2-4

6-[3-Chloro-4-(methylsulfanyl)benzyl]-2-methoxy-3-methylpyridine

[Formula 91]

1H NMR (300 MHz, CDCl3) δ M. D. to 2.13 (s, 3H), of 2.45 (s, 3H), 3,92 (s, 2H), 3,93 (s, 3H), and 57 (d, J=7,2 Hz, 1H), 7,04-7,13 (m, 1H), made 7.16 interest-7,21 (m, 1H), 7.23 percent-7,29 (m, 1H), to 7.33 (d, J=the 1.7 Hz, 1H).

MS(+): 294 [M+H]+

Referential example 3-1

5-({[(2R,3R,7S)-2,3-Diphenyl-1,4-dioxaspiro[4,4]non-7-yl]methyl}sulfonyl)-1-phenyl-1H-tetrazol

[Formula 92]

(1) Sodium salt of 1-phenyl-1H-tetrazol-5-thiol (25 g) was added to a solution of (2R,3R,7S)-7-(iodomethyl)-2,3-diphenyl-1,4-dioxaspiro[4,4]nonane (48,3 g, described in WO 2003095438) in acetone (500 ml) and the mixture was stirred at 60°C for three hours. Evaporated from the reaction solution under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:1) to give 5-({[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]methyl}sulfanyl)-1-phenyl-1H-tetrazole (39.5 g) as a pale yellow oil.

(2) m-Chloroperbenzoic acid was added to a solution of 5-({[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]methyl}sulfanyl)-1-phenyl-1H-tetrazole (39.5 g) in chloroform (395 ml) under cooling with ice and the mixture was stirred at room temperature over night. The reaction solution was poured into a mixed solvent of a saturated aqueous solution of sodium bicarbonate and a saturated solution of sodium thiosulfate, and the mixture was stirred at room temperature for 30 minutes. After extraction with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sulph�including magnesium and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=10:1→4:1→1:1) obtaining 5-({[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]methyl}sulfonyl)-1-phenyl-1H-tetrazole (41 g) as a pale yellow oil.

1H NMR (300 MHz, CDCl3) δ M. D. 1,69-to 1.86 (m, 1H), 1,99-is 2.37 (m, 4H), 2,46-2,59 (m, 1H), 2,83-3,05 (m, 1H), 3,82-was 4.02 (m, 2H), 4,70 (s, 2H), 7,15-7,24 (m, 4H), 7,28-of 7.36 (m, 6H), 7,56-7,65 (m, 3H), 7,66-7,73 (m, 2H).

Referential example 3-2

(5R)-5-{[(1-Phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-2-he

[Formula 93]

(1) 1-Phenyl-1H-tetrazol-5-thiol (9.0 g) and triphenylphosphine (13.2 g) was added to a solution of (R)-(-)-5-(gidroximetil)-2-pyrrolidinone (4.5 g) in tetrahydrofuran (90 ml) and then cooled with ice. To this mixture was added dropwise a solution of 2.2 M of diethylazodicarboxylate in toluene (23 ml) and the mixture was stirred at room temperature over night. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column with NH silica gel (hexane:ethyl acetate=4:1→1:1→0:1) obtaining (R)-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfanyl]methyl}pyrrolidin-2-one (1.98 g) as priceless as a whole.�ethno oil.

(2) Specified in the title compound (5.8 g, 87%) was obtained as colorless powder by carrying out essentially the same reaction as in reference example 3-1(2), except that used the (R)-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfanyl]methyl}pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. 1,88-2,03 (m, 1H), 2,32-of 2.44 (m, 2H), 2,46-of 2.64 (m, 1H), 3,73-3,93 (m, 1H), of 4.09-4,20 (m, 1H), 4,32-4,48 (m, 1H), 6,41-6,54 (m, 1H), 7,55-7,74 (m, 5H).

Reference example 3-3

(5R)-1-Methyl-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-2-he

[Formula 94]

(1) Triethylamine (5,26 ml), trimethylamine hydrochloride (1,07 g) and 4-methylbenzenesulfonamide (5.6 g) were added sequentially to a solution of (R)-5-(gidroximetil)-1-methylpyrrolidine-2-she (2,93 g, 48,3 g, described in J. Med. Chem., 34(3), 1991, 887-900) in chloroform (40 ml) under cooling with ice and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure solvent obtaining (R)-(1-methyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate as a yellow amorphous substance (6.6 g).

(2) (R)-1-Methyl-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfanyl]methyl}pyrrolidin-2-it was obtained as colorless at�osca (4,9 g) the carrying out essentially the same reaction, as in reference example 3-1(1), except that used the (R)-(1-methyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate.

(3) Specified in the title compound was obtained as colorless powder (2.2 g) by carrying out essentially the same reaction as in reference example 3-1(2), except that used the (R)-1-methyl-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfanyl]methyl}pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. 2,09-of 2.28 (m, 1H), 2,31-of 2.57 (m, 3H), 2,95 (s, 3H), 3,61-3,84 (m, 1H), 4,15-to 4.36 (m, 2H), 7,53-of 7.82 (m, 5H).

MS(+): 321 [M+H]+.

The following compounds (reference examples 3-4 - 3-21) were obtained by conducting the reaction and purification in the same manner as described above in reference examples 3-1 - 3-3, using the corresponding alcohols.

Reference example 3-4

5-{[(CIS-4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)methyl]sulfonyl}-1-phenyl-1H-tetrazol

1H NMR (300 MHz, CDCl3) δ M. D. of 0.03 (s, 6H), to 0.89 (s, 9H), 1,40-of 1.57 (m, 2H), 1,60-to 1.77 (m, 6H), 2,11-of 2.30 (m, 1H), of 3.69 (d, J=6,2 Hz, 2H), a 3.87-of 4.05 (m, 1H), 7,55-7,65 (m, 3H), 7,66-7,74 (m, 2H).

MS(+): 437 [M+H]+.

Reference example 3-5

5-{[(TRANS-4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)methyl]sulfonyl}-1-phenyl-1H-tetrazol

1H NMR (300 MHz, CDCl3) δ M. D. of 0.05 (s, 6H), of 0.87 (s, 9H), 1,10-of 1.44 (m, 4H), 1,79-of 2.06 (m, 4H), 2,07-of 2.23 (m, 1H), 3,44-of 3.60 (m, 1H), of 3.69 (d, J=6,4 Hz, 2H), 7,54-of 7.75 (m, 5H).

MS(+): 437 [M+H]+.

Reference example 3-6

1-Phenyl-5-[(tetrahydrofuran-3-ilmet�l)sulfonyl]-1H-tetrazol

1H NMR (300 MHz, CDCl3) δ M. D. 1,74-1,94 (m, 1H), of 2.21-of 2.38 (m, 1H), 2,81-of 3.07 (m, 1H), 3,65 (DD, J=9,1, 6.3 Hz, 1H), 3,73-4,06 (m, 5H), 7,56-7,66 (m, 3H), 7,66-7,74 (m, 2H).

MS(+): 295 [M+H]+.

Reference example 3-7

1-Phenyl-5-{[2-(tetrahydrofuran-2-yl)ethyl]sulfonyl}-1H-tetrazol

1H NMR (300 MHz, CDCl3) δ M. D. 1,47-1,62 (m, 1H), 1,84-of 1.98 (m, 2H), 2,00-of 2.27 (m, 3H), 3,66 is 4.03 (m, 5H), 7,53-7,65 (m, 3H), 7,65-7,73 (m, 2H).

MS(+): 309 [M+H]+.

Reference example 3-8

1-Phenyl-5-{[2-(tetrahydrofuran-3-yl)ethyl]sulfonyl}-1H-tetrazol

1H NMR (300 MHz, CDCl3) δ M. D. 1,48-of 1.74 (m, 1H), 1,92-2,22 (m, 3H), 2,30-of 2.50 (m, 1H), of 3.45 (DD, J=8,6, 6,4 Hz, 1H), 3,66-3,84 (m, 3H), 3,84-3,99 (m, 2H), 7,52-7,66 (m, 3H), 7,67-the 7.75 (m, 2H).

MS(+): 309 [M+H]+.

Reference example 3-9

1-(4-{[(1-Phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}piperidine-1-yl)alanon

1H NMR (300 MHz, CDCl3) δ M. D. 1,33-1,49 (m, 2H), 1,94 is 2.01 (m, 1H), 2,09 (s, 3H), 2,13 (s, 1H), 2,35-2,52 (m, 1H), 2,53-of 2.67 (m, 1H), 3,03-3,17 (m, 1H), 3,74 (d, J=6,2 Hz, 2H), 3,78-3,88 (m, 1H), 4,58-4,69 (m, 1H), 7,54-7,73 (m, 5H).

MS(+): 372 [M+Na]+.

Reference example 3-10

1-[(3S)-3-{[(1-Phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-1-yl]alanon

1H NMR (300 MHz, CDCl3) δ M. D. 1,69-2,00 (m, 1H), 2,02 (s, 3H), 2,20-of 2.54 (m, 1H), 2,74-3,11 (m, 1H), 3,15-4,13 (m, 6H), 7,53-7,79 (m, 5H).

MS(+): 358 [M+Na]+.

Reference example 3-11

1-(3-{[(1-Phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}azetidin-1-yl)alanon

1H NMR (300 MHz, CDCl3) δ M. D. to 1.87 (s, 3H), 3,32-of 3.46 (m, 1H), of 3.91 (DD, J=10,6, 6,0 Hz, 1H), 4,06-4,17 (m, 3H), 4,23-of 4.44 (m, 2H), 7,56-7,73 (m, 5H).

<> MS(+): 344 [M+Na]+.

Reference example 3-12

(5R)-5-[(1,3-Benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-2-he

1H NMR (300 MHz, CDCl3) δ M. D. 1,79-1,98 (m, 1H), 2,31-by 2.55 (m, 3H) and 3.59 (DD, J=14,5, 9.9 Hz, 1H), 3,73-3,85 (m, 1H), 4,26-4,42 (m, 1H), 6,36-is 6.51 (user.s, 1H), 7,58-7,74 (m, 2H), 7,99-8,07 (m, 1H), 8,20-8,29 (m, 1H).

MS(+): 297 [M+H]+.

Referential example 3-13

5-({[1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}sulfonyl)-1-phenyl-1H-tetrazol

LC-Mass: retention time 5,20 min

column SunFire C18 3.5 µm 2.1 x 20 mm: temperature 40°C

H2O:CH3CN (0,1% HCO2H added) =

90:10-15:about 85./about. 0.4 ml/min (0-3 min)

15:85 vol./about. 0.4 ml/min (3-5 min)

15:85 to 90:10 vol./about. 0.5 ml/min (5-5,5 min)

MS(+): 409 [M+H]+

Reference example 3-14

5-{[(2R)-3-{[tert-Butyl(diphenyl)silyl]oxy}-2-methylpropyl"] sulfonyl}-1-phenyl-1H-tetrazol

1H NMR (300 MHz, CDCl3) δ M. D. of 1.06 (s, 9H), of 1.16 (d, J=6,8 Hz, 3H), 2,41-2,60 (m, 1H), 3,45-3,65 (m, 2H), 3,67-of 3.80 (m, 1H), 4,05-4,20 (m, 1H), 7,30-7,49 (m, 6H), 7,52-7,73 (m, 9H).

MS(+): 543 [M+Na]+.

Reference example 3-15

5-{[(2S)-3-{[tert-Butyl(diphenyl)silyl]oxy}-2-methylpropyl"] sulfonyl}-1-phenyl-1H-tetrazol

1H NMR (300 MHz, CDCl3) δ M. D. of 1.08 (s, 9H), of 1.17 (d, J=6,8 Hz, 3H), 2,45-2,60 (m, 1H), 3,50-3,65 (m, 2H), of 3.75 (DD, J=10,4, 4,8 Hz, 1H), 4,16 (DD, J=14,6, and 4.5 Hz, 1H), 7,30-of 7.50 (m, 6H), 7,55-of 7.75 (m, 9H).

MS(+): 543 [M+Na]+.

Reference example 3-16

tert-Butyl (3S)-3-[(1,3-benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-1-carboxylate

1H NMR (300 �Hz, CDCl3) δ M. D. of 1.43 (s, 9H), 1.65 V-1,89 (m, 1H), 2,11-2,32 (m, 1H), 2,73-to 2.94 (m, 1H), 3,09 (DD, J=11,0, 8,0 Hz, 1H), 3,21-3,36 (m, 1H), 3,40-of 3.77 (m, 4H), EUR 7.57-of 7.70 (m, 2H), 8,00-8,06 (m, 1H), to 8.19 to 8.25 (m, 1H).

Referential example 3-17

1-{(3S)-3-[(1,3-Benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-1-yl}alanon

1H NMR (300 MHz, CDCl3) δ M. D. 1,64-2,00 (m, 1H), of 2.05 (s, 3H), of 2.15-2.49 USD (m, 1H), 2,78-of 3.04 (m, 1H), 3,09-3,96 (m, 6H), members, 7.59-7,71 (m, 2H), 8,01-8,08 (m, 1H), 8,23 (d, J=7.5 Hz, 1H).

Referential example 3-18

tert-Butyl (2R)-2-[(1,3-benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-1-carboxylate

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 1,79-of 1.99 (m, 2H), 2,09-of 2.30 (m, 2H), 3,27-3,61 (m, 3H), 3,90-to 4.28 (m, 1H), 4,28-4,48 (m, 1H), 7,50-of 7.70 (m, 2H), 8,01 (d, J=7.5 Hz, 1H), 8,22 (DD, J=to 7.5 and 1.8 Hz, 1H).

MS(+): 405 [M+Na]+.

Reference example 3-19

1-{(3S)-3-[(1,3-Benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-1-yl}propane-1-he

1H NMR (300 MHz, CDCl3) δ M. D. 1,14 (TT, J=7,4, 1.6 Hz, 3H), 1,64-of 1.99 (m, 1H), 2,16-2,42 (m, 3H), 2,74-3,01 (m, 1H), 3,32-3,92 (m, 6H), members, 7.59-7,71 (m, 2H), 8,03-with 8.05 (m, 1H), 8,21-8,24 (m, 1H).

Reference example 3-20

2-({[(3S)-1-(Ethylsulfonyl)pyrrolidin-3-yl]methyl}sulfonyl)-1,3-benzothiazol

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (t, J=7,4 Hz, 3H), of 1.87 (DDD, J=19,4, 10,6, 6,8 Hz, 1H), 2,27-is 2.37 (m, 1H), of 2.91 (DD, J=15,3, 8,0 Hz, 1H), 3,02 (sq, J=7,4 Hz, 2H), 3,24 (DD, J=10,0, 8,0 Hz, 1H), 3,32-to 3.41 (m, 1H), 3,56 (TT, J=9,0, Of 3.1 Hz, 1H), 3,61-with 3.79 (m, 3H), 7,60-of 7.70 (m, 2H), 8,04 (DD, J=7,0, 1.6 Hz, 1H), 8,23 (DD, J=to 7.6 and 1.8 Hz, 1H).

MS(+): 375 [M+H]+.

Referential example 3-21

(5S)-5-[(1,3-Benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-2-he

1H I�R (300 MHz, CDCl3) δ M. D. 1,80-1,99 (m, 1H), 2,30-2,52 (m, 3H), 3,50-3,68 (m, 1H), 3,74-a 3.87 (m, 1H), 4,26-4,42 (m, 1H), 6.32 per-6,54 (user.s, 1H), 7,58-7,73 (m, 2H), 8,00-8,10 (m, 1H), 8,20-8,30 (m, 1H).

MS(+): 297 [M+H]+.

Patterns reference examples 3-4 - 3-21 shown below.

Table 6-1

Table 6-2

Reference example 4-1

6-Bromo-3-chloro-2-methoxypyridine

[Formula 95]

(1) 10% palladium-activated carbon (2.5 g) was added to a solution of commercially available 2-methoxy-3-nitropyridine (50.5 g) in methanol (500 ml) and the mixture was stirred for four hours under a hydrogen atmosphere. The reaction solution was filtered through celite and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=8:1) to give 2-methoxypyridine-3-amine as a yellow powder (37.2 g, 92%).

1H NMR (300 MHz, CDCl3) δ M. D. 3,64-3,88 (m, 2H), 3,92-of 4.05 (m, 3H), 6,67-6,76 (m, 1H), 6,84-at 6.92 (m, 1H), 7,54-of 7.62 (m, 1H).

MS(+): 125 [M+H]+ .

(2) a Solution of 2-methoxypyridine-3-amine (39,4 g) in N,N-dimethylformamide (200 ml) was cooled to -30°C and a solution of N-bromosuccinimide (62.1 g) in N,N-dimethylformamide (100 ml) was added dropwise. After stirring for 30 minutes, the reaction solution was poured into water and was extracted with chloroform. The organic layer was sequentially washed with a saturated solution of sodium sulfite, water and saturated brine, and dried over sodium sulfate. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→4:1) to give 6-bromo-2-methoxypyridine-3-amine as a yellow powder (51,9 g, 80%).

1H NMR (300 MHz, CDCl3) δ M. D. 3,64-3,84 (m, 2H), 3,98 (s, 3H), 6,78 (DD, J=7,9, 1.0 Hz, 1H), of 6.87 (d, J=7.9 Hz, 1H).

MS(+): 203 [M+H]+.

(3) a Solution of sodium nitrite (7.04 g) in water (10 ml) was added dropwise to a suspension of 6-bromo-2-methoxypyridine-3-amine (10.4 g) in concentrated hydrochloric acid (35 ml) under cooling with ice. After stirring for 10 minutes, the reaction system was added dropwise to a suspension of copper chloride (12.7 g) in concentrated hydrochloric acid (15 ml) under cooling with ice and the mixture was stirred at 65°C for one hour and 15 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer is washed�and saturated brine, and dried over anhydrous magnesium sulfate. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→7:3) with obtaining specified in the title compound as a yellow powder (9,69 g, 85%).

1H NMR (300 MHz, CDCl3) δ M. D. is 4.03 (s, 3H), 7,03 (d, J=7.9 Hz, 1H), 7,47 (d, J=7.9 Hz, 1H).

Reference example 4-2

3-(5-Chloro-6-methoxypyridine-2-yl)prop-2-yn-1-ol

[Formula 96]

Triethylamine (70 ml) and dichloride bestlifeinsurance(II) (756 mg) was added to 6-bromo-3-chloro-2-methoxypyridine (12.1 g), 2-propyn-1-Ola (4.0 g) and copper iodide (210 mg) in a nitrogen atmosphere and the mixture was stirred at room temperature for four hours. Water and ethyl acetate was added to the reaction solution, followed by filtration. The aqueous layer was adjusted to pH 3 or less than 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=7:3→5:5) with obtaining specified in the header connection in the form of light brown powder (at 8.60 g, 80%).

1H NMR (300 MHz, CDCl3) δ M. D. is 4.03 (s, 3H), 4,52 (s, 2H), 7,01 (d, J=7.9 Hz, 1H), 7,58 (d, J=7,8 Hz, 1H).

MS(+): 198 [M+H]+.

(2Z)-3-(5-Chloro-6-methoxypyridine-2-yl)-3-hotprop-2-EN-1-ol

[Formula 97]

A solution of 3-(5-chloro-6-methoxypyridine-2-yl)prop-2-yn-1-ol (3.0 g) in tetrahydrofuran (50 ml) was stirred under cooling with ice in a nitrogen atmosphere, adding thereto dropwise a solution of bis(2-methoxyethoxy)case of sodium (Red-Al(R)) in toluene (3.6 M, 7 ml). The mixture was stirred at room temperature for one hour. The reaction solution was cooled to ambient temperature -78°C. was Added dropwise a solution of N-jodatime (6.2 g) in tetrahydrofuran (30 ml) and the mixture is then stirred at an outside temperature of -78°C for one hour. Was added to the reaction solution of 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed successively with 10% sodium thiosulfate solution and saturated brine, and dried over sodium sulfate. After filtration evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→5:5) with obtaining specified in the header connection in the form of a brown powder (3,79 g, 76%).

1H NMR (300 MHz, CDCl3) δ M. D. 4,07 (s, 3H), 4,47 (t, J=5.8 Hz, 2H), 7,11 (t, J=5.6 Hz, 1H), 7,24 (d, J=7.9 Hz, 1H), 7,60 (d, J=7.9 Hz, 1H).

MS(+): 326 [M+H]+.

Reference example 4-4

(2E)-3-(4-tert-Butylphenyl)-3-(5-chloro-6-methoxy�of iridin-2-yl)prop-2-EN-1-ol

[Formula 98]

4-tert-Butylphenylmethyl acid (3.5 g), Tris(dibenzylideneacetone)dipalladium(0) (183 mg), three(2-furyl)phosphine (280 mg) and cesium carbonate (1.98 g) was added to a solution of (2Z)-3-(5-chloro-6-methoxypyridine-2-yl)-3-hotprop-2-EN-1-ol (881 mg) in a mixture of 1,4-dioxane (20 ml)-water (10 ml) in a nitrogen atmosphere and the mixture was stirred at an ambient temperature of 65°C for 1.5 hours. The reaction solution was allowed to cool, was diluted with ethyl acetate and filtered. The filtrate was washed with saturated brine and dried over sodium sulfate. After filtration evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=19:1→1:1) obtaining specified in the header connection in the form of a light yellow powder (912 mg, 91%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), of 4.09 (s, 3H), 4,18-4,24 (m, 2H), to 6.42 (d, J=7.9 Hz, 1H), 7,09-7,17 (m, 3H), 7,39-of 7.46 (m, 3H).

MS(+): 332 [M+H]+.

Reference example 4-5

6-[(1E)-3-Bromo-1-(4-tert-butylphenyl)prop-1-EN-1-yl]-3-chloro-2-methoxypyridine

[Formula 99]

Triphenylphosphine (1.10 g) and tetrabromide carbon (1,81 g) were successively added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridine-2-yl)prop-2-EN-1-ol (912 mg) in tetrahydrofuran (30 ml) under cooling with ice and the mixture was stirred under cooling with ice over�ie 1.5 hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1) obtaining specified in the header connection in the form of black powder (1.28 g).

1H NMR (300 MHz, CDCl3) δ M. D. 1,38 (s, 9H), 4,03 (d, J=8,9 Hz, 2H), 4,11 (s, 3H), to 6.42 (d, J=7.9 Hz, 1H), 7,17-7,24 (m, 3H), of 7.42-7,50 (m, 3H).

Reference example 4-6

(2E)-3-(4-tert-Butylphenyl)-3-(5-chloro-6-methoxypyridine-2-yl)prop-2-ANOVA acid

[Formula 100]

Reagent dessa-Martin (770 mg) was added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridine-2-yl)prop-2-EN-1-ol (601 mg) in chloroform (20 ml) and the mixture was stirred at room temperature for 30 minutes. Was added to the reaction solution of 10% sodium thiosulfate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration evaporated under reduced pressure the solvent. The sodium dihydrogen phosphate (1.0 g) and acid chloride (1.6 g) was added to a solution of the obtained residue and 2-methyl-2-butene (2.3 g) in a mixture of tert-butanol (15 ml)-water (5 ml) and the mixture was stirred at to�room temperature for one hour. The reaction solution was cooled with ice and then brought to pH below 2 by adding 1 M hydrochloric acid, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=9:1). Thereafter, the resulting solid substance was washed with hexane and then dried with obtaining specified in the title compound as colorless powder (434 mg, 69%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 4,10 (s, 3H), 6,50 (d, J=7.9 Hz, 1H), 7,13-of 7.19 (m, 2H), 7,22 (s, 1H), 7,43 (d, J=8,2 Hz, 2H), 7,50 (d, J=7.9 Hz, 1H).

MS(+): 368 [M+Na]+.

Reference example 4-7

6-[(E)-2-Bromo-1-(4-tert-butylphenyl)ethenyl]-3-chloro-2-methoxypyridine

[Formula 101]

97% acetonitrile solution (52 ml) containing triethylamine (26 μl) was added to (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridine-2-yl)prop-2-envoy acid (1.3 g). To the mixture was added N-bromosuccinimide (806 mg) and the mixture was stirred at room temperature for 15 minutes. From the reaction solution was evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=19:1) obtaining specified in the header connection in the form of bescot�th powder (363 mg, 25%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 4,07 (s, 3H), 6,39 (d, J=7.9 Hz, 1H), of 7.19 (d, J=8,2 Hz, 2H), of 7.42-7,49 (m, 3H), 7,72 (s, 1H).

MS(+): 380 [M+H]+.

Reference example 4-8

4-(5-Chloro-6-methoxypyridine-2-yl)but-3-yn-1-ol

[Formula 102]

Specified in the title compound was obtained as a pale brown solid (4.10 g, 85%) by carrying out essentially the same reaction as in reference example 4-2, except that used 3-Butin-1-ol instead of 2-propyn-1-ol.

1H NMR (300 MHz, CDCl3) δ M. D. is 2.73 (t, J=6.3 Hz, 2H), 3,86 (t, J=6.3 Hz, 2H), 4,03 (s, 3H), 6,97 (d, J=7.9 Hz, 1H), 7,55 (d, J=7,8 Hz, 1H).

MS(+): 212 [M+H]+.

Reference example 4-9

(3Z)-4-(5-Chloro-6-methoxypyridine-2-yl)-4-godbout-3-EN-1-ol

[Formula 103]

Specified in the title compound was obtained as brown solid (2,26 g, 47%) by carrying out essentially the same reaction as in reference example 4-3, except that used 4-(5-chloro-6-methoxypyridine-2-yl)but-3-yn-1-ol instead of 3-(5-chloro-6-methoxypyridine-2-yl)prop-2-yn-1-ol.

1H NMR (300 MHz, CDCl3) δ M. D. 2,69 (sq, J=6,5 Hz, 2H), a 3.87 (t, J=6,5 Hz, 2H), 4,06 (s, 3H), to 6.88 (t, J=6,9 Hz, 1H), 7,22 (d, J=7.9 Hz, 1H), 7,58 (d, J=7.9 Hz, 1H).

MS(+): 340 [M+H]+.

Reference example 4-10

(3E)-4-(4-tert-Butylphenyl)-4-(5-chloro-6-methoxypyridine-2-yl)but-3-EN-1-ol

[Formula 104]

Specified in the title compound was obtained as orange powder (2,39 g, quantitative) by carrying out essentially the same reaction as in reference example 4-4, except that used the (3Z)-4-(5-chloro-6-methoxypyridine-2-yl)-4-godbout-3-EN-1-ol instead of (2Z)-3-(5-chloro-6-methoxypyridine-2-yl)-3-hotprop-2-EN-1-ol.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 2,33-of 2.43 (m, 2H), 3,69-of 3.80 (m, 2H), 4,08 (s, 3H), 6,36 (d, J=7.9 Hz, 1H), to 7.04 (t, J=7,7 Hz, 1H), 7,12 (d, J=8.4 Hz, 2H), 7,41 (d, J=7,3 Hz, 3H).

MS(+): 346 [M+H]+.

Referential example 4-11

5-Chloro-6-methoxypyridine-2-carbaldehyde

[Formula 105]

(1) Concentrated sulfuric acid (4 ml) was added to a solution of 5-chloropyridin-2-carboxylic acid (25,3 g) in ethanol (500 ml) under cooling with ice and the mixture was stirred while boiling to reflux for four hours. The reaction solution was cooled to room temperature and was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform→hexane:ethyl acetate=1:1) and evaporated under reduced pressure the solvent from fractions containing ethyl 5-chloropyridin-2-carboxylate. Peroxide urea (30,2 g) was added to a solution of �of STATCOM in chloroform (300 ml) under cooling with ice. Was added dropwise within 30 minutes a mixture of trifluoroacetic anhydride (44,7 ml) and chloroform (300 ml) and the mixture was stirred and gradually come to room temperature for two hours. Was added to the reaction solution dropwise a saturated solution of sodium thiosulfate, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1) to give 1-oxide ethyl 5-chloropyridin-2-carboxylate as a yellow oil (36,8 g, quantitative).

(2) Trifluoroacetic anhydride (147 ml) was added dropwise during 20 minutes to a solution of 1-oxide ethyl 5-chloropyridin-2-carboxylate (36,8 g) in N,N-dimethylformamide (220 ml) under cooling with ice and the mixture was stirred at 50°C for one hour. The reaction solution was cooled with ice and added water. Was slowly added sodium bicarbonate for the implementation of neutralization, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was suspended with ethyl acetate, stirred and then filtered. The filtrate was concentrated under reduced pressure. The same operation was repeated another �VA times. The resulting solids were combined and dried under reduced pressure to obtain ethyl 5-chloro-6-hydroxypyridine-2-carboxylate as a white solid (2.42 g, 75%). The filtrate was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1) to give ethyl 5-chloro-6-hydroxypyridine-2-carboxylate as a white solid (1.84 g, 6%).

(3) silver Carbonate ('s 142.4 g) and methyliodide (25 ml) was added to a solution of ethyl 5-chloro-6-hydroxypyridine-2-carboxylate (26,0 g) in chloroform (500 ml) and the mixture was stirred at 70°C for seven hours. The reaction solution was filtered through celite and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=30:1) and purified again by chromatography on a column of silica gel (hexane:ethyl acetate=20:1) to give ethyl 5-chloro-6-methoxypyridine-2-carboxylate as a white solid (22,3 g, 80%).

(4) Hydride (2,54 g) was added in small portions to a solution of ethyl 5-chloro-6-methoxypyridine-2-carboxylate (22,3 g) in tetrahydrofuran (223 ml) under cooling with ice and the mixture was stirred at the same temperature for 10 minutes. Was added to the reaction solution of water while cooling with ice. After filtration through celite the filtrate was concentrated under reduced pressure. To the residue was added saturated �Astor salt, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure. Manganese dioxide (116,4 g) was added to a solution of the residue in chloroform (223 ml) and the mixture was stirred at 60°C for one hour. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was suspended with hexane, stirred and then filtered. The filtrate was concentrated under reduced pressure. The same operation was repeated three more times. The resulting solids were combined and dried under reduced pressure obtaining specified in the title compound as a white solid (14.7 g, 83%).

1H NMR (300 MHz, CDCl3) δ M. D. of 4.13 (s, 3H), 7,54 (d, J=7,7 Hz, 1H), 7,80 (DD, J=7,7, 0.8 Hz, 1H), 9,94 (d, J=0.8 Hz, 1H).

MS(+): 172 [M+H]+.

Referential example 4-12

6-{(1E)-3-Bromo-1-[4-(cyclopropanesulfonyl)phenyl]prop-1-EN-1-yl}-3-chloro-2-methoxypyridine

Specified in the title compound was obtained as a black oil (1.2 g) by carrying out essentially the same reaction as in reference examples 4-4 and 4-5, except that used [4-(cyclopropanesulfonyl)phenyl]Bronevoy acid instead of 4-tert-butylaniline acid.

1H NMR (300 MHz, CDCl3) δ M. D. 0.70 to 0,81 (m, 2H), 1,07-of 1.18 (m, 2H), 2,16-to 2.29 (m, 1H), 4,01 (d, J=to 8.7 Hz, 2H), of 4.09 (s, 3H), gold 6.43 (d, J=7.9 Hz, 1H), 7,17-of 7.25(m, 3H), 7,44 (d, J=5.8 Hz, 2H), of 7.46 (d, J=5.1 Hz, 1H).

Referential example 4-13

(3E)-4-(4-tert-Butylphenyl)-4-(5-chloro-6-methoxypyridine-2-yl)but-3-enitel

Sodium cyanide (137 mg) was added to a solution of 6-[(1E)-3-bromo-1-(4-tert-butylphenyl)prop-1-EN-1-yl]-3-chloro-2-methoxypyridine (500 mg) in ethanol (10 ml) and the mixture was stirred at room temperature for 22 hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with 2 M sodium hydroxide solution and saturated brine, dried over sodium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=19:1→4:1) obtaining specified in the title compound as a yellow oil (230 mg, 53%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 3,11 (d, J=7.5 Hz, 2H), 4,10 (s, 3H), 6,38 (d, J=7.9 Hz, 1H), of 6.96 (t, J=7.5 Hz, 1H), 7,12 (d, J=8.4 Hz, 2H), 7,43-of 7.50 (m, 3H).

MS(+): 341 [M+H]+.

Referential example 4-14

6-Methoxy-5-propylpyridine-2-carbaldehyde

Specified in the title compound was obtained by carrying out essentially the same reaction as in reference example 1-1(1), except that used 1-jumprope instead of hexachlorethane.

1H NMR (300 MHz, CDCl3) δ M. D. 0,83-of 1.10 (m, 3H), of 1.53-1,78 (m, 2H), 2,46-2,69 (m, 2H), of 4.04 (s, 3H), 7,43-7,61 (m, 2H), 9,87-10,02 (m, 1H).

MS(+): 180 [M+H]+.

SS�dairy example 4-15

(5R)-5-[(5-Chloro-6-methoxypyridine-2-yl)ethinyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he

(5R)-1-(2,4-Dimethoxybenzyl)-5-ethynylpyridine-2-he (600 mg, synthesized according to Tetrahedron Asymmetry, 1995, 239 using dimethyl (R)-glutamatergic as starting material) in acetonitrile (6 ml) was added to a solution of 6-bromo-3-chloro-2-methoxypyridine (667 mg), dichloride bis(triphenylphosphine)palladium(II) (81 mg) and copper iodide (22 mg) in triethylamine (12 ml) in a stream of nitrogen gas at 40°C for 30 minutes. The mixture was stirred at room temperature for four hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→0:1) obtaining specified in the header connection in the form of a colorless oil (452 mg, 52%).

1H NMR (300 MHz, CDCl3) δ M. D. 2,12-2,48 (m, 3H), 2,53-2,70 (m, 1H), 3,79 (s, 3H), of 3.80 (s, 3H), of 4.04 (s, 3H), of 4.26 (d, J=15 Hz, 1H), 4,37-to 4.46 (m, 1H), 4,89 (d, J=15 Hz, 1H), 6,38-of 6.49 (m, 2H), 6,94 (d, J=7,8 Hz, 1H), 7,18-7,25 (m, 1H), EUR 7.57 (d, J=7,8 Hz, 1H).

Referential example 4-16

(5R)-5-[(5-Chloro-6-methoxypyridine-2-yl)ethinyl]pyrrolidin-2-he

Trifluoroacetic acid (4 ml) and anisole (2 ml) was added to (5R)-5-[(5-chloro-6-methoxy�of iridin-2-yl)ethinyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-ONU (457 mg) and the mixture was stirred at 80°C for two hours. The reaction solution was concentrated and the residue was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→0:1) obtaining specified in the header connection in the form of a colorless oil (234 mg, 82%).

1H NMR (300 MHz, CDCl3) δ M. D. of 2.27 to 2.45 (m, 2H), 2,46-to 2.65 (m, 2H), of 4.04 (s, 3H), of 4.54-4.72 in (m, 1H), 5,64-5,80 (m, 1H), 6,99 (d, J=7,8 Hz, 1H), members, 7.59 (d, J=7,8 Hz, 1H).

MS(+): 251 [M+H]+.

Referential example 4-17

(5R)-5-[(Z)-2-(5-Chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he

The Lindlar catalyst (50 mg) was added to a solution of (5R)-5-[(5-chloro-6-methoxypyridine-2-yl)ethinyl]pyrrolidin-2-one (232 mg) in methanol (5 ml) and the mixture was stirred at room temperature for eight hours under a hydrogen atmosphere. The reaction solution was filtered through celite and then evaporated the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→0:1) obtaining specified in the header connection in the form of a colorless oil (166 mg, 71%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,85 is 2.01 (m, 1H), 2,25-of 2.64 (m, 3H), was 4.02 (s, 3H), 5,43-of 5.60 (m, 1H), 5,72-to 5.85 (m, 1H), 5,86-of 6.04 (m, 1H), 6,28-of 6.45 (m, 1H), was 6.77 (d, J=7,8 Hz, 1H), 7,60 (d, J=7,8 Hz, 1H).

Reference example 4-18

(5R)-5-[(Z)-2-Bromo-2-(chlor-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he

Bromine (80 ml) was added to a solution of (5R)-5-[(Z)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (200 mg) in carbon tetrachloride (2 ml) under cooling with ice and the mixture was stirred at the same temperature (0°C) for 15 minutes. The reaction solution was concentrated and the residue was dissolved in chloroform. 1,8-Diazabicyclo[5,4,0]undec-7-ene (238 ml) was added under cooling with ice and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→0:1) obtaining specified in the title compound as colorless powder (164 mg, 62%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,90-2,10 (m, 1H), 2,38-2,48 (m, 2H), 2,50-2,70 (m, 1H), of 4.05 (s, 3H), 4,70-is 4.85 (m, 1H), 5,67-5,84 (m, 1H), of 7.19 (d, J=7.9 Hz, 1H), 7,31 (d, J=8,1 Hz, 1H), 7,65 (d, J=7.9 Hz, 1H).

MS(+): 331 [M+H]+.

Referential example 4-19

6-{(Z)-1-Bromo-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he

48% bromoethanol acid (2 ml) was added to a solution of (5R)-5-[(Z)-2-bromo-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (115 mg) in 1,4-dioxane (3 ml) and the mixture was stirred at 65°C for one hour. Rea�; the solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→4:1) obtaining specified in the title compound as colorless powder (40 mg, 37%).

1H NMR (600 MHz, CDCl3) δ M. D. of 2.05 to 2.14 (m, 1H), 2,32-2,41 (m, 1H), 2,44-by 2.55 (m, 2H), 4,67-to 4.76 (m, 1H), 6,59 (d, J=7,3 Hz, 1H), to 7.04 (d, J=7,8 Hz, 1H), of 7.48-to 7.55 (user.s, 1H), EUR 7.57 (d, J=7,8 Hz, 1H), 12.84 per-13,24 (user.s, 1H).

MS(+): 317 [M+H]+.

Referential example 4-20

6-Bromo-3-cyclopropyl-2-methoxypyridine

(1) a Solution of sodium nitrite (5.44 g) in water (15 ml) was added dropwise to a suspension of 6-bromo-2-methoxypyridine-3-amine (16.0 g) in concentrated hydrochloric acid (130 ml) and water (175 ml) at an internal temperature of 5°C or below and the mixture was stirred in this form for 20 minutes. The resulting suspension was added dropwise to a solution of potassium iodide (39,2 g) in water (760 ml) at an internal temperature of 5°C or below. The mixture was brought to room temperature and then stirred at 60°C for two hours. The reaction solution was adjusted to room temperature and then was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and filter�Lee, then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=95:5→85:15) to give 6-bromo-3-iodo-2-methoxypyridine in the form of a pale orange powder (21,1 g).

1H NMR (600 MHz, CDCl3) δ M. D. 3,99 (s, 3H), of 6.85 (d, J=7,8 Hz, 1H), 7,82 (d, J=7,8 Hz, 1H).

MS(+): 314 [M+H]+.

(2) palladium Acetate (36 mg) was added to a suspension of 6-bromo-3-iodo-2-methoxypyridine (1.0 g), cyclopropylboronic acid (547 mg), triphenylphosphine (84 mg) and potassium carbonate (1,32 g) in toluene (20 ml) and water (1 ml) and the mixture was stirred at 110°C for 4.5 hours. Was added to the reaction solution, water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=99:1→96:4) with obtaining specified in the header connection in the form of a colorless oil (782 mg).

1H NMR (600 MHz, CDCl3) δ M. D. 0,60-0,63 (m, 2H), 0,92-0,96 (m, 2H), 1,95 is 2.01 (m, 1H), 3,98 (s, 3H), 6,95 (s, 2H).

MS(+): 228 [M+H]+.

Referential example 4-21

(5R)-5-[(5-Cyclopropyl-6-methoxypyridine-2-yl)ethinyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he

Specified in the title compound was obtained as a pale brown resin (6,84 g) the holding of existing�have the same reaction, as in the reference example 4-15, except that used 6-bromo-3-cyclopropyl-2-methoxypyridine instead of 6-bromo-3-chloro-2-methoxypyridine.

1H NMR (600 MHz, CDCl3) δ M. D. of 0.64 to 0.69 (m, 2H), 0,94-1,00 (m, 2H), 2,03-2,10 (m, 1H), 2,18-of 2.24 (m, 1H), 2,27-of 2.35 (m, 1H), 2,37 is 2.44 (m, 1H), 2,57-of 2.64 (m, 1H), 3,79 (s, 3H), of 3.80 (s, 3H), of 4.00 (s, 3H), of 4.26 (d, J=15.1 Hz, 1H), However, 4.40 (DD, J=8,3, 4,1 Hz, 1H), 4,90 (d, J=14,7 Hz, 1H), 6,41-of 6.45 (m, 2H), 6,91 (d, J=7,3 Hz, 1H), 7,02 (d, J=7,3 Hz, 1H), 7,21-of 7.24 (m, 1H).

MS(+): 407 [M+H]+.

Referential example 4-22

(5R)-5-[(5-Cyclopropyl-6-methoxypyridine-2-yl)ethinyl]pyrrolidin-2-he

Specified in the title compound was obtained as a pale brown resin (14,6 g) the carrying out essentially the same reaction as in reference example 4-16, except that used the (5R)-5-[(5-cyclopropyl-6-methoxypyridine-2-yl)ethinyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-it.

1H NMR (600 MHz, CDCl3) δ M. D. of 0.63 to 0.68 (m, 2H), 0,95-1,00 (m, 2H), 2,05-2,10 (m, 1H), 2,31-2,39 (m, 2H), 2,49-of 2.58 (m, 2H), 3,99 (s, 3H), 4,63 (DD, J=7,6, 4,8 Hz, 1H), 5,73 (user.s, 1H), 6,94 (d, J=7,3 Hz, 1H), 7,02 (d, J=7,3 Hz, 1H).

Referential example 4-23

(5R)-5-[(Z)-2-(5-Cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he

Specified in the title compound was obtained as pale brown powder (10.2 g) the carrying out essentially the same reaction as in reference example 4-17, except that used the (5R)-5-[(5-cyclopropyl-6-methoxypyridine-2-yl)ethinyl]pyrrolidin-2-it.

1H NMR (600 MHz, CCl 3) δ M. D. 0,62-0,68 (m, 2H), from 0.92 to 0.99 (m, 2H), 1,88-of 1.96 (m, 1H), 2,04-of 2.09 (m, 1H), 2,33-by 2.55 (m, 3H), 3,98 (s, 3H), 5,53-to 5.58 (m, 1H), 5,70 (DD, J=11,7, 8,0 Hz, 1H), 6,05 (user.s, 1H), 6,33 (DD, J=11,7, a 1.2 Hz, 1H), 6,70 (d, J=7,3 Hz, 1H), 7,07 (d, J=7,3 Hz, 1H).

MS(+): 259 [M+H]+.

Referential example 4-24

(5R)-5-[(Z)-2-Bromo-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he

Specified in the title compound was obtained as pale brown powder (11.3 g) the carrying out essentially the same reaction as in reference example 4-18, except that used the (5R)-5-[(Z)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. 0,61-0,71 (m, 2H), of 0.91-of 1.07 (m, 2H), 1,91-of 2.15 (m, 2H), 2,35-2,69 (m, 3H), of 4.00 (s, 3H), 4,71-of 4.90 (m, 1H), 5,59-5,71 (m, 1H), 7,06-to 7.18 (m, 2H), 7,24 (d, J=7,6 Hz, 1H).

MS(+): 337 [M+H]+.

Referential example 4-25

6-[(Z)-1-Bromo-2-(tetrahydro-2H-Piran-4-yl)ethenyl]-3-chloro-2-methoxypyridine

(1) Solution hexamethyldisilazide lithium in tetrahydrofuran (1 M, 10 ml) was added to a solution of triphenyl(tetrahydro-2H-Piran-4-ylmethyl)phosphonite (5,51 g) in tetrahydrofuran (20 ml) under cooling with ice and the mixture was stirred at room temperature for one hour. A solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (1.3 g) in tetrahydrofuran (20 ml) was slowly added to the reaction solution and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water with subsequent�slip by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The filtrate was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1) to give 3-chloro-2-methoxy-6-[(Z)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridine as a colorless powder (1.62 g, 60%).

(2) Specified in the title compound was obtained as colorless powder (1,97 g, 93%) by carrying out essentially the same reaction as in reference example 4-18, except that used 3-chloro-2-methoxy-6-[(Z)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 1,57-1,70 (m, 2H), 1,71-to 1.82 (m, 2H), 2,80-of 3.04 (m, 1H), 3,41-3,61 (m, 2H), 3,94-4,07 (m, 5H), of 6.99 (d, J=8,9 Hz, 1H), 7,28 (d, J=8,1 Hz, 1H), 7,61 (d, J=8,1 Hz, 1H).

Reference example 4-26

(5R)-5-[(E)-2-(4-tert-Butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he

(1) copper Iodide (74 mg) and dichloride bis(triphenylphosphine)palladium(II) (135 mg) was added to a solution of 4-tert-butylidene (3.0 g) in triethylamine (10 ml) and the mixture was stirred at room temperature for 15 minutes. Was added thereto over one hour (5R)-1-(2,4-dimethoxybenzyl)-5-ethynylpyridine-2-he (1.0 g) and the mixture was stirred at room temperature for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:0→1:1) to give (5R)-5-[(4-tert-butylphenyl)ethinyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as colorless powder (1.25 g, 84%).

(2) Dichloride bis(tricyclohexylphosphine)palladium(II) (230 mg) and tributylammonium (1.0 ml) were successively added to a solution of (5R)-5-[(4-tert-butylphenyl)ethinyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (1.24 g) in tetrahydrofuran (15 ml) in a stream of gaseous nitrogen and the mixture was stirred at room temperature for two hours. The reaction solution was filtered through celite and then the filtrate was concentrated. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→2:1) obtaining specified in the title compound as colorless powder (2,16 g, 96%).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.65-1,49 (m, 33H), 1,68-to 1.87 (m, 1H), 1,99-of 2.21 (m, 1H), 2.26 and-of 2.58 (m, 3H), 3,66 (s, 3H), 3,76 (s, 3H), 4,00-of 4.26 (m, 3H), of 4.66 (d, J=16 Hz, 2H), to 5.58 (s, 1H), 6,23 of 6.31 (m, 1H), 6,36 (s, 1H), 6,62 (d, J=8,5 Hz, 2H), to 6.88 (s, 1H), 7,12 (d, J=8,5 Hz, 2H).

MS(+): 684 [M+H]+.

The compounds of examples 4-27 - 4-30 synthesized by carrying out essentially the same reaction as in reference example 4-26, using appropriate arylalkenes (1-iodo-4-isopropylbenzene, 1-chloro-4-iadanza, 1-iodine-4-(Tr�permitil)benzene and 2-bromo-5-(trifluoromethyl)pyridine instead of 4-tert-butyl-1-yogashala, respectively.

Referential example 4-27

(5R)-1-(2,4-Dimethoxybenzyl)-5-[(E)-2-[4-(propane-2-yl)phenyl]-2-(tributylstannyl)ethenyl]pyrrolidin-2-he

Specified in the title compound was obtained as a colorless oil (4.7 g).

1H NMR (300 MHz, CDCl3) δ M. D. 0,72-0,93 (m, 15H), of 1.13 to 1.31 (m, 12H), 1,32-1,48 (m, 6H), 1,68-of 1.88 (m, 1H), 2,04-to 2.18 (m, 1H), 2.26 and-2,60 (m, 2H), 2,71-of 2.93 (m, 1H), to 3.67 (s, 3H), 3,76 (s, 3H), 4,03-4,22 (m, 2H), of 4.66 (d, J=16 Hz, 1H), to 5.56 (d, J=9,0 Hz, 1H), for 6.24-6,33 (m, 1H), 6,33 is 6.41 (m, 1H), 6,55-6,69 (m, 2H), to 6.88 (d, J=8,2 Hz, 1H), 6,93-7,03 (m, 2H).

MS(+): 670 [M+H]+.

Reference example 4-28

(5R)-5-[(E)-2-(4-Chlorophenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he

Specified in the title compound was obtained as a pale brown oil (12.8 g).

1H NMR (300 MHz, CDCl3) δ M. D. 0,71-0,97 (m, 15H), 1,19-of 1.48 (m, 12H), 1,65-of 1.81 (m, 1H), 1,98-to 2.13 (m, 1H), 2,27-by 2.55 (m, 2H), 3,71 (s, 3H), 3,79 (s, 3H), 3,97-4,15 (m, 2H), 4,71 (d, J=15.2 Hz, 1H), of 5.60 (d, J=9,0 Hz, 1H), 6.32 per (DD, J=8,3, 2.4 Hz, 1H), 6,39 (d, J=2,3 Hz, 1H), is 6.51-6,61 (m, 2H), at 6.84 (d, J=8,2 Hz, 1H), was 7.08 (d, J=8,5 Hz, 2H).

MS(+): 662 [M+H]+.

Reference example 4-29

(5R)-1-(2,4-Dimethoxybenzyl)-5-{(E)-2-(tributylstannyl)-2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-2-he

Specified in the title compound was obtained as a pale orange oil (8.9 g).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.83 and 0.90 (m, 15H), 1,18-1,48 (m, 12H), 1,62-of 1.84 (m, 1H), 1,99-to 2.13 (m, 1H), 2,28-of 2.57 (m, 2H), 3,71 (s, 3H), 3,76 (user.s, 3H), of 3.91 is 4.03 (m, 1H), 4,08 (d, J=15,7 Hz, 1H), 4,73 (d, J=to 15.4 Hz, 1H), 5,63 (l, J=9,2 Hz, 1H), 6,29 (DD, J=8,3, 2.4 Hz, H), 6,39 (d, J=2,3 Hz, 1H), 6,71 (d, J=7.9 Hz, 2H), 6,80 (d, J=8,2 Hz, 1H), 7,35 (d, J=7.9 Hz, 2H).

MS(+): 696 [M+H]+.

Referential example 4-30

(5R)-1-(2,4-Dimethoxybenzyl)-5-{(E)-2-(tributylstannyl)-2-[5-(trifluoromethyl)pyridin-2-yl]ethenyl}pyrrolidin-2-he

Specified in the title compound was obtained as colorless powder (800 mg).

1H NMR (300 MHz, CDCl3) δ M. D. 0,70-of 1.07 (m, 15H), 1,14-of 1.34 (m, 6H), 1,35-is 1.51 (m, 6H), 1,69-of 1.96 (m, 1H), 2,08-2,71 (m, 3H), 3,66 (s, 3H), 3,74 (s, 3H), 3,93-of 4.38 (m, 2H), 4,71 is 5.07 (m, 1H), 5,69-of 5.91 (m, 1H), 6,13-6,44 (m, 2H), 6,59-6,76 (m, 1H), 6,78-of 6.96 (m, 1H), of 7.48-7,76 (m, 1H), 8,65-8,83 (m, 1H).

MS(+): 697 [M+H]+.

Referential example 4-31

3-Bromo-6-iodo-2-methoxypyridine

(1) sodium Iodide (40 g), copper iodide (6.0 g) and N,N'-dimethylethylenediamine (7 ml) was added to a solution of 6-bromo-2-methoxypyridine-3-amine (26 g) in 1,4-dioxane (250 ml) in a stream of gaseous nitrogen and the mixture was stirred at 120°C for 14 hours. The reaction solution was allowed to cool, after which was added water and ethyl acetate. After filtration through celite was followed by extraction. The organic layer was washed with 20% sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=85:15→70:30) to give 6-iodo-2-methoxypyridine-3-amine as a colorless powder (25 g, 75%).

1H NMR (300 �Hz, CDCl3) δ M. D. 3,66-3,83 (user.s, 2H), 3,96 (s, 3H), to 6.58 (d, J=7,6 Hz, 1H), to 7.09 (d, J=7,8 Hz, 1H).

MS(+): 251 [M+H]+.

(2) tert-butyl Nitrite (6.2 ml), copper bromide(I) (5.0 g) and copper bromide(II) (6.5 g) were successively added to a solution of 6-iodo-2-methoxypyridine-3-amine (25 g) in acetonitrile (400 ml) under cooling with ice and the mixture was stirred at 65°C for two hours. The reaction solution was poured into 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=70:30→0:100) with obtaining specified in the title compound (3.7 g) as colorless powder.

1H NMR (300 MHz, CDCl3) δ M. D. 4,00 (s, 3H), of 7.19 (d, J=7,8 Hz, 1H), 7,40 (d, J=7,8 Hz, 1H).

MS(+): 313 [M+H]+.

Referential example 4-32

6-iodo-2-[(4-methoxybenzyl)oxy]-3-propoxyphene

(1) potassium Carbonate (1,38 g) and n-propylitic (1.13 g) was added to a solution of 2-bromo-6-yodellin-3-ol (1.0 g, described in WO 2007088996) in N,N-dimethylformamide (10 ml) and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous �Ulfat magnesium and filtered, then evaporated under reduced pressure solvent obtaining 2-bromo-6-iodine-3-propoxybenzene in the form of a crude product.

(2) 4-Methoxybenzyloxy alcohol (689 mg) was added to a solution of sodium hydride (200 mg) in N,N-dimethylformamide (4 ml) under cooling with ice and the mixture was stirred at room temperature for 15 minutes. Added to it a solution of 2-bromo-6-iodine-3-propoxybenzene in N,N-dimethylformamide (2 ml) and the mixture was stirred at 85°C for six hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=10:1→1:1) obtaining specified in the title compound as colorless powder (670 mg).

1H NMR (300 MHz, CDCl3) δ M. D. from 0.87 to 1.11 (m, 3H), 1,69-of 1.91 (m, 2H), 3,81 (s, 3H), 3,85-3,98 (m, 2H), to 5.35 (s, 2H), 6,72 (d, J=8,1 Hz, 1H), 6,83-to 6.95 (m, 2H), 7,18 (d, J=7.9 Hz, 1H), of 7.36-7,52 (m, 2H).

MS(+): 400 [M+H]+.

Compounds of reference examples 4-33 - 4-35 synthesized by carrying out essentially the same reaction as in reference example 4-32, except that used methyliodide, methylchloroform and 2-jumprope instead of 1-jumprope.

Referential example 4-33

6-iodine-3-methods�si-2-[(4-methoxybenzyl)oxy]pyridin

Specified in the title compound was obtained as a colorless oil (660 mg, 29% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 3.80 (s, 6H), and 5.36 (s, 2H), 6,72 (d, J=8,1 Hz, 1H), 6,89 (d, J=to 8.7 Hz, 2H), 7,21 (d, J=8,1 Hz, 1H), 7,45 (d, J=to 8.7 Hz, 2H).

MS(+): 372 [M+H]+.

Referential example 4-34

3-(Deformedarse)-6-iodo-2-[(4-methoxybenzyl)oxy]pyridin

Specified in the title compound (1.53 g, 23% (two steps)) was obtained as a colorless oil by carrying out the reaction at 90°C.

1H NMR (300 MHz, CDCl3) δ M. D. 3,82 (s, 3H), and 5.36 (s, 2H), from 6.22 is 6.81 (m, 1H), 6,86-to 6.95 (m, 2H), was 7.08 (d, J=7.9 Hz, 1H), 7,29 (d, J=7.9 Hz, 1H), 7,41 (d, J=to 8.7 Hz, 2H).

Referential example 4-35

6-iodo-2-[(4-methoxybenzyl)oxy]-3-(propane-2-yloxy)pyridine

Specified in the title compound was obtained as colorless powder (430 mg).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.30 (d, J=6.1 Hz, 6H), 3,81 (s, 3H), 4,33-a 4.53 (m, 1H), of 5.34 (s, 2H), 6,76 (d, J=7.9 Hz, 1H), of 6.85-of 6.96 (m, 2H), 7,18 (d, J=7.9 Hz, 1H), 7,38-7,47 (m, 2H).

MS(+): 400 [M+H]+.

Referential example 4-36

6-iodo-2-methoxypyridine-3-ol

(1) potassium Carbonate (12 g) and 4-methoxybenzylamine (8,8 ml) was added to a solution of 2-bromo-6-yodellin-3-ol (12 g) in N,N-dimethylformamide (130 ml) and the mixture was stirred at room temperature for six hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sulfate MAGN�I and was filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=90:1→0:100) to give 2-bromo-6-iodo-3-[(4-methoxybenzyl)oxy]pyridine as a colorless powder (18 g, 100%).

(2) sodium Methoxide (11 g) was added to a solution of 2-bromo-6-iodo-3-[(4-methoxybenzyl)oxy]pyridine (17 g) in dimethylsulfoxide (90 ml) and the mixture was stirred at 90°C for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=95:5→70:30) to give 6-iodo-2-methoxy-3-[(4-methoxybenzyl)oxy]pyridine as a colorless powder (10 g, 71%).

(3) Triisopropylsilane (2.1 g) and trifluoroacetic acid (4.0 ml) was added to a solution of 6-iodo-2-methoxy-3-[(4-methoxybenzyl)oxy]pyridine (1 g) in chloroform (10 ml) and the mixture was stirred at 0°C for one hour. Evaporated from the reaction solution under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=90:10→50:50) with obtaining specified in the title compound as colorless powder (604 mg, 96%).

1H NMR (300 MHz, CDCl3 ) δ M. D. 4,01 (s, 3H), about 6,82 (d, J=7.9 Hz, 1H), 7,20 (d, J=7,8 Hz, 1H).

MS(+): 252 [M+H]+.

Compounds of reference examples 4-37 - 4-39 synthesized by carrying out essentially the same reaction as in reference example 4-36(1), except that used 6-iodo-2-methoxypyridine-3-ol obtained in reference example 4-36 using sodium hydride instead of potassium carbonate, and used appropriate alkylhalogenide (cyclopentylmethyl, 3-bromopropane-tert-butyldimethylsilyl and 3-bromo-2,2-DIMETHYLPROPANE-tert-butyldiphenylsilyl) instead of 4-methoxybenzylamine, respectively.

Referential example 4-37

3-(Cyclopentyloxy)-6-iodo-2-methoxypyridine

Specified in the title compound was obtained as a light red oil (169 mg, 66%).

1H NMR (300 MHz, CDCl3) δ M. D. 1.56 to to 1.69 (m, 2H), 1,73-of 1.97 (m, 6H), 3,96 (s, 3H), 4,66-to 4.76 (m, 1H), 6,72 (d, J=8.4 Hz, 1H), 7,18 (d, J=7.9 Hz, 1H).

MS(+): 320 [M+H]+.

Referential example 4-38

3-(3-{[tert-Butyl(dimethyl)silyl]oxy}propoxy)-6-iodo-2-methoxypyridine

Specified in the title compound was obtained as a colorless oil (638 mg, 100%).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.08 (s, 6H), 0.88 to (s, 9H), 2,02-of 2.09 (m, 2H), 3,79 (t, J=5.8 Hz, 2H), 3,98 (s, 3H), of 4.09 (t, J=6,5 Hz, 2H), 6,78 (d, J=7.9 Hz, 1H), 7,21 (d, J=7.9 Hz, 1H).

MS(+): 424 [M+H]+.

Referential example 4-39

3-(3-{[tert-Butyl(diphenyl)silyl]oxy}-2,2-DIMETHYLPROPANE)-6-iodo-2-methoxypyridine

Specified in the header� compound was obtained as a colorless oil (37 mg, 7%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.01 (s, 9H), of 1.02 (s, 6H), 3,53 (s, 2H), 3,76 (s, 2H), 3,92 (s, 3H), 6,70 (d, J=7.9 Hz, 1H), made 7.16 interest (d, J=7.9 Hz, 1H), 7,28-7,40 (m, 6H), EUR 7.57-7.62 mm (m, 4H).

MS(+): 576 [M+H]+.

Referential example 4-40

1-(6-Bromo-2-methoxypyridine-3-yl)alanon

A solution of 6-bromo-3-iodo-2-methoxypyridine (500 mg) in diethyl ether (15 ml) was cooled to -80°C in a nitrogen atmosphere was added dropwise n-butyllithium (2.6 M, 0,735 ml). After stirring at the same temperature for one hour, was added dropwise N,N-dimethylacetamide (0,37 ml). The mixture was warmed up to -40°C for 1.5 hours to complete the reaction. Was added to the reaction system of water and ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→4:1) obtaining specified in the title compound as colorless powder (284 mg, 78%).

1H NMR (300 MHz, CDCl3) δ M. D. 2,62 (s, 3H), 4,08 (s, 3H), made 7.16 interest (d, J=7,8 Hz, 1H), 7,97 (d, J=7,8 Hz, 1H).

MS(+): 230 [M+H]+.

Referential example 4-41

tert-Butyl 3-(6-bromo-2-methoxypyridine-3-yl)propanoate

(1) a Solution of 6-bromo-3-iodo-2-methoxypyridine (1.0 g) in diethyl ether (38 ml) was cooled to -80°C in a nitrogen atmosphere was added dropwise n-butyllithium (2.6 M, 0,735 ml). After premesis�tion at the same temperature for one hour, was added dropwise N,N-dimethylformamide (0,62 ml). The mixture was stirred at the same temperature for one hour and added to the reaction system with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=94:6→9:1) to give 6-bromo-2-methoxynicotinate in the form of a colorless powder (618 mg, 90%).

(2) (tert-Butoxycarbonylmethylene)triphenylphosphorane (1.74 g) was added to a solution of 6-bromo-2-methoxynicotinate (500 mg) in chloroform (5 ml) under cooling with ice, followed by stirring for one hour. Evaporated from the reaction solution under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1) to give tert-butyl 3-(6-bromo-2-methoxypyridine-3-yl)acrylate as a colorless oil (726 mg, 100%).

(3) 10% platinum-activated carbon was added to a solution of tert-butyl 3-(6-bromo-2-methoxypyridine-3-yl)acrylate (727 mg) in ethyl acetate (7.3 ml) and the mixture was stirred for four hours under a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate concentrated. The residue was purified by chromatography�th on a column of silica gel (hexane:ethyl acetate=8:1) obtaining specified in the header connection in the form of a colorless oil (657 mg, 90%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.41 (s, 9H), 2,42-2,56 (m, 2H), 2,72-2,84 (m, 2H), 3,96 (s, 3H), 6,98 (d, J=7,6 Hz, 1H), 7,27 (d, J=7,6 Hz, 1H).

MS(+): 316 [M+H]+.

Reference example 4-42

(5R)-5-[(E)-2-(5-Bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-he

(1) (5R)-5-[(E)-2-(4-tert-Butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he (4.0 g), 3-bromo-6-iodo-2-methoxypyridine (3.7 g), cesium fluoride (1.8 g) and copper iodide (1.3 g) was subjected to replacement with nitrogen was added N,N-dimethylformamide (40 ml) followed by degassing. Was added to a mixture of tetrakis(triphenylphosphine)palladium(0) (693 mg) and the mixture was stirred at 65°C for two hours. After bringing back to room temperature was added water and ethyl acetate and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:1) to give (5R)-5-[(E)-2-(5-bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as brown powder (2.6 g, 77%).

1H NMR (300 MHz, CDCl3) δ M. D. to 1.32 (s, 9H), 1,80-of 1.95 (m, 1H), 2,06-of 2.20 (m, 1H), 2,32-of 2.46 (m, 1H), 2,48-2,61 (m, 1H) and 3.59 (s, 3H), 3,76 (s, 3H) 3,98 (s, 3H), 4,01-4,11 (m, 1H), 4,17 (d, J=15.1 Hz, H), 4,63 (d, J=to 15.4 Hz, 1H), 6,23 (d, J=7.9 Hz, 1H), 6,27-system 6.34 (m, 2H), of 6.79 (d, J=9.8 Hz, 1H), 6,87-6,98 (m, 3H), 7,26-7,32 (m, 2H), 7,80 (d, J=7,8 Hz, 1H).

MS(+): 579 [M+H]+.

(2) Trifluoroacetic acid (10 ml) and anisole (5 ml) was added to (5R)-5-[(E)-2-(5-bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-ONU (950 mg) and the mixture was stirred at 70°C for five hours. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:4) with obtaining specified in the title compound as a yellow amorphous substance (460 mg, 66%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 2,20-2,51 (m, 4H), 4,07 (s, 3H), 4,14-to 4.23 (m, 1H), 5,48-5,63 (user.s, 1H), 6,29 (d, J=7.9 Hz, 1H), 6,89 (d, J=9,5 Hz, 1H), was 7.08 (d, J=8,5 Hz, 2H), 7,44 (d, J=8,5 Hz, 2H), 7,61 (d, J=7.9 Hz, 1H).

MS(+): 429 [M+H]+.

Compounds of reference examples 4 to 43 and 4-44 synthesized by carrying out essentially the same reaction as in reference example 4-42(1), except that used the (5R)-5-[(E)-2-(4-chlorophenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he (reference example 4-28) and (5R)-1-(2,4-dimethoxybenzyl)-5-{(E)-2-(tributylstannyl)-2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-2-he (reference example 4-29) instead of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one.

Referential example 4 to 43

(5R)-5-[(E)-2-(5-Bromo-6-methoxypyridine-2-yl)-2-(chlorphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he

Specified in the title compound was obtained as a light yellow amorphous substance (2,37 g, 80%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,77-of 1.92 (m, 1H), 2,02-of 2.15 (m, 1H), 2,31-of 2.45 (m, 1H), 2,47-2,62 (m, 1H), 3,62 (s, 3H), of 3.78 (s, 3H), 3,92 is 4.03 (m, 4H), 4,15 (d, J=15.1 Hz, 1H), 4,69 (d, J=15.2 Hz, 1H), 6,19 (d, J=7.9 Hz, 1H), 6,31-of 6.37 (m, 2H), of 6.79 (d, J=9.8 Hz, 1H), of 6.87 (d, J=8,5 Hz, 2H), at 6.92 (d, J=8,9 Hz, 1H), 7,25 (d, J=9,5 Hz, 2H), 7,61 (d, J=7.9 Hz, 1H).

MS(+): 557 [M+H]+.

Referential example 4-44

(5R)-5-{(E)-2-(5-Bromo-6-methoxypyridine-2-yl)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he

Specified in the title compound was obtained as a light yellow amorphous substance (2,47 g, 82%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,79-1,94 (m, 1H), 2,05-2,17 (m, 1H), 2,33-of 2.46 (m, 1H), 2,49-2,62 (m, 1H), 3,62 (s, 3H), of 3.77 (s, 3H), 3,89-was 4.02 (m, 4H), 4,15 (d, J=to 15.4 Hz, 1H), 4,70 (d, J=15.2 Hz, 1H), 6,16 (d, J=7.9 Hz, 1H), 6,28-6,36 (m, 2H), about 6,82 (d, J=10.1 Hz, 1H), 6,89 (d, J=8,1 Hz, 1H), 7,05 (d, J=7,8 Hz, 2H), 7,52 (d, J=8.4 Hz, 2H), 7,61 (d, J=7.9 Hz, 1H).

MS(+): 591 [M+H]+.

Referential example 4-45

1-Propan-2-yl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

Specified in the title compound was obtained as yellow oil (2.2 g, 79% (two steps)) by carrying out essentially the same reaction as in reference example 4-26, except that used 1-(cyclopropanesulfonyl)-4-iadanza (reference example 5-55) instead of 1-tert-butyl-4-yogashala.

1H NMR (300 MHz, CDCl3) δ M. D. 0,82-of 0.91 (m, 15H), 0,97-1,06 (m, 2H), 1,19-1,49 (m, 14H), ,68-1,83 (m, 1H), from 2.00 to 2.14 (m, 1H), 2,30-of 2.57 (m, 3H), 3,74 (s, 3H), 3,79 (s, 3H), 3,86-3,98 (m, 1H), 4,08 (d, J=15,7 Hz, 1H), 4,74 (d, J=15,7 Hz, 1H), 5,65 (d, J=9,2 Hz, 1H), between 6.30 (DD, J=8,3, 2.4 Hz, 1H), 6,39 (d, J=2,3 Hz, 1H), 6,73-6,83 (m, 3H), 7,61 (d, J=8,5 Hz, 2H).

MS(+): 732 [M+H]+.

The structure of a reference of examples 4-12 - 4-45 shown below.

Table 7-1

Table 7-2

Table 7-3

Referential example 5-1

(4-Chloro-3-methoxyphenyl)baronova acid

n-Butyllithium (2.76 M, 2.5 ml) was added dropwise to a solution of commercially available 4-bromo-2-chloroanisole (1.0 g) in toluene (8 ml) and tetrahydrofuran (3 ml) at -78°C and the mixture was stirred in this form for 30 minutes. Then added trimethylboron (1.0 ml) and the mixture was stirred at room temperature for 15 minutes. Added diluted hydrochloric acid and ethyl�cetat, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:0→98:2) to obtain specified in the title compound as colorless powder (535 mg).

1H NMR (600 MHz, METHANOL-d4) δ M. D. 3,88 (s, 3H), 7,15 (d, J=7,8 Hz, 1H) 7,24 (s, 1H) 7,34 (d, J=7,8 Hz, 1H).

Referential example 5-2

[3-Chloro-4-(triptoreline)phenyl]baronova acid

Specified in the title compound was obtained by carrying out essentially the same reaction as in reference example 5-1, except that used 4-bromo-2-chloro-1-(triptoreline)benzene instead of 4-bromo-2-chloroanisole.

1H NMR (600 MHz, METHANOL-d4) δ M. D. 7,34-7,44 (m, 1H), 7,58-of 7.82 (m, 2H).

MS(-): 239 [M-H]-.

Reference example 5-3

[4-Chloro-3-(triptoreline)phenyl]baronova acid

Specified in the title compound was obtained by carrying out essentially the same reaction as in reference example 5-1, except that used 4-bromo-1-chloro-2-(triptoreline)benzene instead of 4-bromo-2-chloroanisole.

1H NMR (600 MHz, CDCl3) δ M. D. 4,60 (s, 2H), 7,63-7,66 (m, 1H), 8,02-and 8.04 (m, 1H), 8,05-8,08 (m, 1H).

MS(-): 239 [M-H]-.

Reference example 5-4

[4-Chloro-3-(deformedarse)phenyl]baronova acid

(1) a Suspension of 5-bromo-2-chloro-1-(deformedarse)benzene (1.0 g), complex �of lore 1,1'-bis(diphenylphosphino)ferienparadies-dichloro methane (317 mg), bis(pinacolato)DIBORANE mixtures (1,48 g) and potassium acetate (1.14 g) in 1,4-dioxane (20 ml) was stirred at 80°C for 14 hours. Ethyl acetate and a saturated solution of ammonium chloride was added to the reaction solution and was filtered through celite, the insoluble material and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:0→99:1) to give crude 2-(4-chloro-3-deformational)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.14 g).

(2) 2 M hydrochloric acid (10 ml) was added to the crude 2-(4-chloro-3-deformational)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.14 g) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for four hours. Was added to the reaction solution, water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was extracted with 2 M sodium hydroxide solution. The resulting solution was acidified with concentrated hydrochloric acid and then was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of forces�by Kagel (hexane:ethyl acetate=99:1→50:50) with obtaining specified in the title compound (93 mg).

1H NMR (600 MHz, CDCl3) δ M. D. at 6.64 (t, J=73,0 Hz, 1H), 7,60-7,63 (m, 1H), 7,96-8,01 (m, 2H).

Reference example 5-5

2-[3-Chloro-4-(deformity)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

(1) Deoxo-fluorine(R) (5,63 ml) and ethanol (few drops) was added to a solution of 4-bromo-2-chlorobenzaldehyde (3.2 g) in chloroform (30 ml) under cooling with ice and the mixture was stirred at 80°C for two hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:0→90:10) to give 4-bromo-2-chloro-1-(deformity)benzene (3.0 g) as a colorless oil.

(2) Bis(pinacolato)DIBORANE mixtures (2.1 g), complex dichloride 1,1'-bis(diphenylphosphino)ferienparadies(II), dichloro methane (346 mg) and potassium acetate (812 mg) was added to a solution of 4-bromo-2-chloro-1-(deformity)benzene (1.0 g) in 1,4-dioxane (10 ml) and the mixture was stirred at 65°C for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solution�tel. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:0→90:10) with obtaining specified in the title compound (780 mg, 65%) as a colorless oil.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.35 (s, 12H), 6,71-7,17 (m, 1H), 7,58-7,69 (m, 1H), 7,73-7,80 (m, 1H), 7,81-of 7.88 (m, 1H).

Compounds of reference examples 5-6 - 5-9 synthesized by carrying out essentially the same reaction as in reference example 5-5, except that used the corresponding aldehydes (4-bromo-2-forbindelse, 4-bromo-2-methylbenzaldehyde, 4-bromo-2-methoxybenzaldehyde and 4-bromo-2-(methyl-sulfonyl)benzaldehyde instead of 4-bromo-2-chlorobenzaldehyde, respectively.

Reference example 5-6

2-[4-(Deformity)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

Specified in the title compound was obtained as a colorless oil (540 mg).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.35 (s, 12H), 6,61-7,18 (m, 1H), 7,41-7,73 (m, 3H).

Reference example 5-7

2-[4-(Deformity)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

Specified in the title compound was obtained as colorless powder (1.0 g).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.35 (s, 12H), 2,43 (s, 3H), 6,50-7,07 (m, 1H), 7,41-7,56 (m, 1H), 7,62-7,83 (m, 2H).

Reference example 5-8

2-[4-(Deformity)-3-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

Specified in the title compound was obtained as a colorless oil (400 mg).

1H �Mr (300 MHz, CDCl3) δ M. D. of 1.36 (s, 12H), of 3.91 (s, 3H), 6,74-7,17 (m, 1H), 7,30-value of 7, 37 (m, 1H), 7,44-7,51 (m, 1H), 7,53-7,61 (m, 1H).

Referential example 5-9

2-[4-(Deformity)-3-(methyl-sulfonyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

Specified in the title compound was obtained as colorless powder (982 mg).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 12H), 3,13 (s, 3H), 7,65 (s, 1H), to 7.89 (d, J=7,6 Hz, 1H), 8,16 (d, J=7,1 Hz, 1H), 8,52 (d, J=0.8 Hz, 1H).

Referential example 5-10

N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzolsulfonat

(1) a Solution of 4-bromobenzaldehyde (1.10 g) in chloroform (10 ml) was stirred in an ice bath while slowly adding dropwise N-methylethanolamine (5 ml). The mixture was brought again to room temperature and stirred for about 2.5 hours. The reaction solution was quenched with concentrated hydrochloric acid, again with stirring in an ice bath. The mixed solution was poured into 6 M hydrochloric acid (10 ml) as such, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure to obtain crude 4-bromo-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide in the form of a colorless oil (1,339 g, quantitative).

(2) a Solution of 4-bromo-N-(2-hydroxyethyl)-N-methylbenzofuran�Meade (1,339 g) in chloroform (15 ml) was stirred on an ice bath, while adding tert-butyldimethylchlorosilane (1.04 g) and N,N-dimethyl-4-aminopyridin (84 mg). Was added dropwise triethylamine and the mixture was brought again to room temperature and stirred for 16 hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=95:5→60:40) to give 4-bromo-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-N-methylbenzenesulfonamide in the form of a colorless powder (1,77 g, 100%).

1H NMR (600 MHz, CDCl3) δ M. D. of 0.05 (s, 6H), of 0.87 (s, 9H), 2,87 (s, 3H), 3,16 (t, J=5.7 Hz, 2H), of 3.77 (t, J=5.7 Hz, 2H), 7,66 (s, 4H).

MS(+): 408 [M+H]+.

(3) Deborah of bisphenola (2,21 g), a complex chloride 1,1'-bis(diphenylphosphino)ferienparadies-dichloro methane (355 mg) and potassium acetate (853 mg) was added to a solution of 4-bromo-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-N-methylbenzenesulfonamide (1,77 g) in 1,4-dioxane (18 ml) and the mixture was stirred at 84°C for 2.5 hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of forces�by Kagel (hexane:ethyl acetate=95:5→60:40) with obtaining specified in the title compound as colorless powder (2,461 g, quantitative).

1H NMR (600 MHz, CDCl3) δ M. D. of 0.05 (s, 6H), of 0.87 (s, 9H), of 1.36 (s, 12H), 2,85 (s, 3H), 3,13 (t, J=5.7 Hz, 2H), of 3.77 (t, J=5.7 Hz, 2H), to 7.77 (d, J=8,3 Hz, 2H), 7,94 (d, J=8,3 Hz, 2H).

MS(+): 456 [M+H]+.

Patterns reference examples 5-1 - 5-10 shown below.

Table 8

Reference example 5-11

5,5-Dimethyl-2-[3-methyl-4-(trifluoromethyl)phenyl]-1,3,2-dioxaborinane

A solution of 4-bromo-2-methylbenzonitrile (500 mg) in tetrahydrofuran (5 ml) was cooled to ambient temperature -78°C under an atmosphere of nitrogen was added dropwise a solution of n-utility in hexane (1,57 M, 2.0 ml). After stirring at -78°C for 30 minutes, was added dropwise triisopropylsilyl (0,72 ml) and the mixture was stirred at room temperature over night. Was added acetic acid (0,18 ml) and 2,2-dimethyl-1,3-propandiol (240 mg), followed by stirring at room temperature for three hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatographie� on a column of silica gel (hexane:ethyl acetate=10:1) obtaining specified in the title compound as colorless solid (353 mg, 62%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.03 (s, 6H), 2,48 (d, J=1,8 Hz, 3H), of 3.78 (s, 4H), 7,56 (d, J=7,7 Hz, 1H), 7,67 (d, J=8,9 Hz, 1H), 7,69 (s, 1H).

Referential example 5-12

6-(5,5-Dimethyl-1,3,2-dioxaborinane-2-yl)-2,2-dimethyl-3,4-dihydro-2H-chromen

Specified in the title compound was obtained as white solid (72 mg, 13%) by carrying out essentially the same reaction as in reference example 5-11, except that used 6-bromo-2,2-dimethyl-3,4-dihydro-2H-chromen instead of 4-bromo-2-methylbenzonitrile and used trimethylboron instead of triisopropylsilane.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.01 (s, 6H), 1,32 (s, 6H), to 1.79 (t, J=6,8 Hz, 2H), 2,77 (t, J=6,9 Hz, 2H), 3,73 (s, 4H), 6.75 in (d, J=8.4 Hz, 1H), of 7.46-7,58 (m, 2H).

Referential example 5-13

2-(4-Cyclopropylmethyl)-5,5-dimethyl-1,3,2-dioxaborinane

Specified in the title compound was obtained as a colorless solid (721 mg, 63%) by carrying out essentially the same reaction as in reference example 5-11, except that used 4-bromo-1-cyclopropylbenzene instead of 4-bromo-2-methylbenzonitrile.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.65-0,78 (m, 2H), 0,92-of 1.16 (m, 2H), 1,01 (s, 6H), 1,80-of 1.95 (m, 1H), of 3.77 (s, 4H), to 7.04 (d, J=7,7 Hz, 2H), 7,67 (d, J=8,3 Hz, 2H).

Referential example 5-14

2-[3-Chloro-4-(cyclopropylamino)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane

Specified in the title compound (834 mg, 74%) was obtained by carrying out essentially the same reaction as in Ref�full-time example 5-11, except that used 4-bromo-2-chloro-1-(cyclopropylamino)benzene instead of 4-bromo-2-methylbenzonitrile.

1H NMR (300 MHz, CDCl3) δ M. D. 0,78-of 0.91 (m, 4H), 1,01 (s, 6H), 3,74 (s, 4H), 3,78-3,86 (m, 1H), 7,25 (d, J=8,0 Hz, 1H), of 7.64 (DD, J=8,3, a 1.2 Hz, 1H), 7,76 (d, J=1.5 Hz, 1H).

Referential example 5-15

2-[3-Chloro-4-(2,2,2-triptoreline)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane

(1) 2,2,2-Triptoreline (15.2 g) and potassium carbonate (10.0 g) was added to a solution of 4-bromo-2-chlorophenol (5.0 g) in N,N-dimethylformamide (20 ml) and the mixture was stirred at 80°C for 20 hours. The reaction solution was cooled to room temperature and was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (only hexane) to give 4-bromo-2-chloro-1-(2,2,2-triptoreline)benzene as a colorless oil (3.0 g, 43%).

(2) Specified in the title compound was obtained as crude product (236 mg, 21%) by carrying out essentially the same reaction as in reference example 5-11, except that used 4-bromo-2-chloro-1-(2,2,2-triptoreline)benzene instead of 4-bromo-2-methylbenzonitrile.

Referential example 5-16

4-Bromo-2-chloro-1-ethylbenzene

A solution of 4-bromo-2-chloro-1-attilan�OLM (883 mg), iron acetate(II) (7 mg) and 5% rhodium-activated carbon (167 mg) in tetrahydrofuran (17 ml) was stirred at room temperature for three hours in hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (only hexane) obtaining specified in the header connection in the form of a colorless oil (414 mg, 46%).

1H NMR (300 MHz, CDCl3) δ M. D. to 1.21 (t, J=7,4 Hz, 3H), 2,70 (sq, J=7.9 Hz, 2H), to 7.09 (d, J=8,9 Hz, 1H), 7,31 (DD, J=8,9, and 3.0 Hz, 1H), 7,49 (d, J=3.0 Hz, 1H).

Referential example 5-17

2-(3-Chloro-4-ethylphenyl)-5,5-dimethyl-1,3,2-dioxaborinane

Specified in the title compound was obtained as a colorless oil (148 mg, 27%) by carrying out essentially the same reaction as in reference example 5-11, except that used 4-bromo-2-chloro-1-ethylbenzene, obtained in reference example 5-16, instead of 4-bromo-2-methylbenzonitrile.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.01 (s, 6H), 1,23 (t, J=7,4 Hz, 3H), 2,76 (sq, J=7,4 Hz, 2H), of 3.75 (s, 4H), 7,21 (d, J=7,4 Hz, 1H), members, 7.59 (d, J=7,4 Hz, 1H), 7,74 (s, 1H).

Referential example 5-18

4-Bromo-1-(cyclopropylmethyl)-2-methylbenzol

(1) Tert-butoxide potassium (994 mg) and bromocyclopropane (2,92 g) was added to a solution of 2-methylbenzothiazole (1.05 g) in dimethylsulfoxide (10 ml) and the mixture was stirred at 100°C for 9.5 hours. The reaction solution was cooled �about room temperature and added to a saturated salt solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=10:1) to give 1-(cyclopropylmethyl)-2-methylbenzol in the form of an orange oil (1.41 g, quantitative).

(2) Bromine (0.42 ml) was added to a solution of 1-(cyclopropylmethyl)-2-methylbenzol (1.35 g) in acetic acid (10 ml) under cooling with ice and the mixture was stirred at room temperature for 17 hours. The reaction solution was cooled with ice and added saturated sodium thiosulfate solution and saturated salt solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (only hexane) and evaporated under reduced pressure the solvent. The precipitated solid was filtered and washed with hexane, after which the filtrate evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (only hexane) obtaining specified in the header connection in the form of a pale yellow oil (1.59 g, 80%).

1H NMR (300 MHz, CDCl3) δ M. D. 0,62-0,73 (m, 2H), of 1.03-1.14 in (m, 2H), 2,04-to 2.14 (m, 1H), 2,22 (s, 3H), 7,25 (d, J=1.1 Hz, 1H), 7,29 (DD, J=8,3, 1.9 G�, 1H), value of 7, 37 (d, J=8,3 Hz, 1H).

Referential example 5-19

1-Bromo-4-[(3-methylbutoxy)methyl]benzene

The sodium hydride (purity: 55%, 700 mg) and 1-bromo-3-methylbutan (2,56 ml) was added to a solution of 4-bromobenzylamine alcohol (2.0 g) in N,N-dimethylformamide (40 ml) under cooling with ice and the mixture was stirred at room temperature for five hours. Was added to the reaction solution, a saturated solution of ammonium chloride followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:1→50:1→30:1) with obtaining specified in the header connection (2,31 g, 85%).

LC-Mass: retention time 4,24 min

column SunFire C18 3.5 µm 2.1 x 20 mm, 40°C

H2O:CH3CN (0,1% HCO2H added) =

60:40-0:100 Rev./about. 0.4 ml/min (0-3 min)

0:100 Rev./about. 0.4 ml/min (3-5 min)

Referential example 5-20

1-Bromo-4-[2-(2-methylpropoxy)ethyl]benzene

Potassium hydroxide (1,32 g) and 1-bromo-2-methylpropan (1,04 ml) was added to a solution of 2-(4-bromophenyl)ethanol (140 ml) in dimethylsulfoxide (2 ml) and the mixture was stirred at room temperature over night. Was added to the reaction solution with water followed by extraction with dichloromethane. The organic layer was filtered through diato�new earth and the filtrate evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (only hexane) obtaining specified in the header connection in the form of a colorless oil (180 mg, 70%).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.88 (d, J=6,8 Hz, 6H), of 1.84 (sq t, J=6,8, 6,5 Hz, 1H), 2,83 (t, J=6,8 Hz, 2H), 3,18 (d, J=6,5 Hz, 2H) and 3.59 (t, J=6,8 Hz, 2H), 7,11 (d, J=8,2 Hz, 2H), 7,39 (d, J=8,2 Hz, 2H).

Referential example 5-21

[4-(4-Bromophenyl)butoxy](tert-butyl)dimethylsilane

(1) Hydride (759 mg) was added to a solution of 4-(4-bromophenyl)butyric acid (3.12 g) in tetrahydrofuran (90 ml) under cooling with ice and the mixture was stirred under cooling with ice for one hour. Was added to the reaction solution of acetone and water, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=30:1→10:1→7:1→5:1) obtaining 4-(4-bromophenyl)butan-1-ol (to 2.29 g, quantitative).

(2) tert-Butyldimethylchlorosilane (1.13 g) and imidazole (513 mg) was added to a solution of 4-(4-bromophenyl)butan-1-ol (1.15 g) in N,N-dimethylformamide (35 ml) under cooling with ice and the mixture was stirred at room temperature for one hour. Was added to the reaction solution with water followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over contraindicated�ohms sodium and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:1→50:1→20:1) with obtaining specified in the title compound (1.78 g, quantitative).

1H NMR (300 MHz, CDCl3) δ M. D. 0,00 (s, 6H), of 0.85 (s, 9H), 1,40-1,70 (m, 4H), of 2.54 (t, J=7,3 Hz, 2H), only 3.57 (t, J=6,1 Hz, 2H), 7,00 (d, J=8,6 Hz, 2H), 7,34 (d, J=8,0 Hz, 2H).

Referential example 5-22

4-Bromo-2-chloro-1-(cyclopropylmethyl)benzene

Specified in the title compound was obtained as yellow oil (2.18 g, 34% (two steps)) by carrying out essentially the same reaction as in reference example 5-18, except that used 2-chlorbenzoyl instead of 2-methylbenzoyl.

1H NMR (300 MHz, CDCl3) δ M. D. 0,66-0,79 (m, 2H), 1,08-1,19 (m, 2H), 2,03-2,19 (m, 1H), of 7.36 (DD, J=8,5, and 1.9 Hz, 1H), 7,41 (d, J=8,5 Hz, 1H), 7,47 (d, J=1.9 Hz, 1H).

Referential example 5-23

[3-(4-Bromophenoxy)propoxy](tert-butyl)dimethylsilane

(1) potassium Carbonate (12.0 g) and 3-bromo-1-propanol (5,1 ml) was added to a solution of 4-bromophenol (5.0 g) in N,N-dimethylformamide (200 ml) under cooling with ice and the mixture was stirred at room temperature for 8.5 hours. The reaction solution was cooled with ice and added a saturated solution of ammonium chloride and water, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. Then evaporated under reduced giving�starting solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=7:1→4:1→3:1) obtaining 3-(4-bromophenoxy)propan-1-ol in the form of a crude product.

(2) tert-Butyldimethylchlorosilane (8.7 g) and imidazole (3.9 g) was added to a solution of 3-(4-bromophenoxy)propan-1-ol in N,N-dimethylformamide (193 ml) under cooling with ice and the mixture was stirred at room temperature for 40 minutes. The reaction solution was cooled with ice and added water and a saturated solution of ammonium chloride followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:1). Pyrrolidin (4,82 ml) and triethylamine (8,86 ml) was added to a solution of the obtained crude product in tetrahydrofuran (145 ml) under cooling with ice and the mixture was stirred at room temperature for 27 hours. The reaction solution was cooled with ice and added a saturated solution of ammonium chloride followed by extraction with a mixture of hexane-chloroform (1:1). The organic layer was dried over sodium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:1→80:1) obtaining specified in �agolove connection (of 7.88 g, 79% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.05 (s, 6H), to 0.89 (s, 9H), 1,90-2,05 (m, 2H), 3,79 (t, J=6,0 Hz, 2H), 4,03 (t, J=6,1 Hz, 2H), 6,78 (DD, J=6,8, 2.4 Hz, 2H), of 7.36 (DD, J=6,8, and 2.1 Hz, 2H).

Referential example 5-24

3-[2-(4-Bromophenyl)-1,3-dioxolan-2-yl]-N,N-diethylpropane-1-amine

(1) Diethylamine (180 ml) and triethylamine (90 ml) was added to a solution of 4'-bromo-4-chlorobutyrophenone (18,13 g) in acetonitrile (90 ml) and the mixture was stirred at 100°C for one hour. The reaction solution was cooled to room temperature and was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=5:1→ethyl acetate:methanol:triethylamine=40:4:1) to give 1-(4-bromophenyl)-4-(diethylamino)butane-1-one as brown oil (9,02 g, 44%).

(2) ethylene Glycol (10 ml) and the monohydrate p-toluensulfonate acid (128 mg) was added to a solution of 1-(4-bromophenyl)-4-(diethylamino)butane-1-one (2.0 g) in toluene (80 ml) and the mixture was stirred at 150°C for one hour. The reaction solution was cooled to room temperature and was added monohydrate p-toluensulfonate acid (1.28 g), after which the mixture was stirred at 150°C for one hour. The reaction solution was cooled to room temperature and naturalisatiedienst aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:1) obtaining specified in the header connection in the form of a brown oil (2.09 g, 91%).

1H NMR (300 MHz, CDCl3) δ M. D. 0,99 (t, J=7,2 Hz, 6H), 1.41 to to 1.58 (m, 2H), 1,58 (t, J=7,8 Hz, 2H), is 2.40 (t, J=7,8 Hz, 2H), 2,50 (sq, J=7.2 Hz, 4H), 3,67-3,81 (m, 2H), 3,93-4,07 (m, 2H), 7,27-7,34 (m, 2H), 7,39-of 7.48 (m, 2H).

Referential example 5-25

1-Bromo-4-(4-methoxybutyl)benzene

The sodium hydride (purity: 55%, 434 mg) and methyliodide (0,62 ml) was added to a solution of 4-(4-bromophenyl)butan-1-ol obtained in reference example 5-21(1), N,N-dimethylformamide (30 ml) under cooling with ice and the mixture was stirred at room temperature for 7.5 hours. Was added to the reaction solution with water followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1→20:1→10:1) with obtaining specified in the header connection (1,06 g, 88%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,51-of 1.73 (m, 4H), of 2.06 (t, J=7,4 Hz, 2H), 3,32 (s, 3H), 3,37 (t, J=6,1 Hz, 2H), 7,00-was 7.08 (m, 2H), to 7.33-of 7.42 (m, 2H).

Referential example 5-26

4-Bromo-2-chloro-1-(propane-2-yl)benzene

Triathlete� (1.8 ml) and trifluoroacetic acid (5,8 ml) was added to a solution of 2-(4-bromo-2-chlorophenyl)propan-2-ol (1.9 g) in dichloromethane (76 ml) and the mixture stirred at room temperature for one day. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (only hexane) obtaining specified in the header connection in the form of a colorless oil (1.74 g, 98%).

LC-Mass: retention time 5,82 min

Column SunFire C18 3.5 µm 2.1 x 20 mm: temperature 40°C

H2O:CH3CN (0,1% HCO2H added) =

90:10 vol./about. 0.3 ml/min (0-1 min)

90:10 to 40:60 vol./about. 0.3 ml/min (1-4 min)

40:60 vol./about. 0.4 ml/min (4-5 minutes)

40:60 to 10:90./about. 0.4 ml/min (5-5,1 min)

10:90 vol./about. 0.5 ml/min (5,1-5,3 min)

10:90 - 90:10 vol./about. 0.5 ml/min (5,3-5,5 min)

90:10 vol./about. 0.5 ml/min (5,5-8 min)

MS(+): 233 [M+H]+.

Referential example 5-27

4,4,5,5-Tetramethyl-2-[4-(2,2,2-trifluoroethyl)phenyl]-1,3,2-dioxaborolan

A solution of 1-bromo-4-(2,2,2-trifluoroethyl)benzene (510 mg), bis(pinacolato)DIBORANE mixtures (1,08 g), complex chloride 1,1'-bis(diphenylphosphino)ferienparadies-dichloro methane (70 mg) and triethylamine (1.2 ml) in 1,4-dioxane (10 ml) was stirred at 80°C for 7.5 hours in a nitrogen atmosphere. The reaction solution was cooled to room temperature and was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sulfate� magnesium and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=10:0→10:1) obtaining specified in the title compound as a colorless solid (68 mg, 12%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.34 (s, 12H), 3,37 (sq, J=10,9 Hz, 2H), 7,29 (d, J=7,2 Hz, 2H), 7,80 (d, J=8,1 Hz, 2H).

Referential example 5-28

2-[4-(3-Methoxypropyl)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane

(1) 1-Bromo-4-(3-methoxypropyl)benzene was obtained as a colorless oil (2,07 g, 84%) by carrying out essentially the same reaction as in reference example 5-25, except that used 3-(4-bromophenyl)propan-1-ol instead of 4-(4-bromophenyl)butan-1-ol.

(2) Specified in the title compound was obtained as white solid (of 116.8 mg, 51%) by carrying out essentially the same reaction as in reference example 5-11, except that used 1-bromo-4-(3-methoxypropyl)benzene instead of 4-bromo-2-methylbenzonitrile.

1H NMR (300 MHz, CDCl3) δ M. D. and 1.02 (s, 6H), 1,82-of 1.96 (m, 2H), 2,69 (t, J=7,2 Hz, 2H), of 3.33 (d, J=0.8 Hz, 3H), 3,37 (t, J=6,6 Hz, 2H), 3,76 (s, 4H), of 7.19 (d, J=7,7 Hz, 2H), 7,72 (d, J=7,7 Hz, 2H).

Referential example 5-29

2-[4-(Deformity)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

Specified in the title compound was obtained as a pale yellow oil (238 mg, 36%) by carrying out essentially the same reaction as in reference example 5-27, except�the increase in I used 1-bromo-4-(deformity)benzene instead of 1-bromo-4-(2,2,2-trifluoroethyl)benzene.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.34 (s, 12H), 6,63 (t, J=56.4 Hz, 1H), 7,49 (d, J=7,8 Hz, 2H), to 7.89 (d, J=7.5 Hz, 2H).

Referential example 5-30

4-Bromo-2-chloro-1-(cyclopropanesulfonyl)benzene

Oxon(R) (20,3 g) was added to a solution of 4-bromo-2-chloro-1-(cyclopropylmethyl)benzene obtained in reference example 5-22 (964 mg) in a mixture of tetrahydrofuran (20 ml)-methanol (20 ml)-water (10 ml) and the mixture stirred at room temperature for one day. Another added Oxon(R) (6.8 g) and the mixture stirred at room temperature for 18 hours. Was added to the reaction solution with water followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform), to obtain specified in the header connection in the form of a pale yellow amorphous substance (597 mg, 55%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,00-of 1.18 (m, 2H), 1,28-of 1.42 (m, 2H), 2,92-3,11 (m, 1H), 7,58 (DD, J=8,5, and 1.9 Hz, 1H), 7,74 (d, J=1.9 Hz, 1H), of 7.88 (d, J=8,3 Hz, 1H).

MS(+): 295 [M+H]+.

Referential example 5-31

2-[3-Chloro-4-(cyclopentyloxy)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane

(1) potassium Carbonate (2.0 g) and bromocyclopentane (0,775 ml) was added to a solution of 4-bromo-2-chlorophenol (1,0 �) in N,N-dimethylformamide (10 ml) and the mixture was stirred at room temperature for four days. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with a saturated solution of ammonium chloride and water, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=10:1) to give 4-bromo-2-chloro-1-(cyclopentyloxy)benzene as a colorless oil (1.31 g, 98%).

(2) Specified in the title compound was obtained as a pale yellow solid (1.24 g, 86%) by carrying out essentially the same reaction as in reference example 5-11, except that used 4-bromo-2-chloro-1-(cyclopentyloxy)benzene instead of 4-bromo-2-methylbenzonitrile.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.01 (s, 6H), 1,50-1,75 (m, 2H), 1,75-2,00 (m, 6H), 3,74 (s, 4H), 4,75-is 4.93 (m, 1H), 6,89 (d, J=8.4 Hz, 1H), 7,61 (DD, J=7,8, a 1.8 Hz, 1H), of 7.70 (d, J=1.2 Hz, 1H).

Referential example 5-32

2-[3-Chloro-4-(deformedarse)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

(1) a Solution of 4-bromo-2-chlorophenol (830 mg) and 30% potassium hydroxide solution (16 ml) in acetonitrile (16 ml) was cooled to -78°C. was Added 2-chloro-2,2-defloration (2.95 ml) and the mixture was stirred at 80°C for 40 hours. The reaction solution was cooled to room temperature and was extracted with diethyl ether. The organic layer was washed with water and saturated brine, su�or over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=10:1→10:1) to give 4-bromo-2-chloro-1-(deformedarse)benzene as a colorless oil (533 mg, 52%).

(2) a Solution of 4-bromo-2-chloro-1-(deformedarse)benzene (100 mg), potassium acetate (114 mg), bis(pinacolato)DIBORANE mixtures (108 mg) and the complex chloride 1,1'-bis(diphenylphosphino)ferienparadies-dichloro methane (15,8 mg) in 1,4-dioxane (1 ml) was stirred under a nitrogen atmosphere at 100°C for 19 hours. The reaction solution was cooled to room temperature and filtered through celite. After washing with ethyl acetate the filtrate is evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1→2:1) obtaining specified in the header connection in the form of a pale yellow oil (104 mg, 88%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.34 (s, 12H), 6,56 (t, J=73,3 Hz, 1H), 7,21 (d, J=7,8 Hz, 1H), 7,68 (DD, J=8,1, 1.5 Hz, 1H), of 7.88 (d, J=1,8 Hz, 1H).

Referential example 5-33

2-[4-(Cyclopentyloxy)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane

Specified in the title compound was obtained as colorless solids (1,27 g, 96%) by carrying out essentially the same reaction as in reference example 5-11, except that used 1-bromo-4-(cyclopentyloxy)benzene instead of 4-bromo-2-methylbenzonitrile.

1H NMR (300 MHz, CDCl3 ) δ M. D. of 1.01 (s, 6H), 1,50-1,70 (m, 2H), 1,70-2,00 (m, 6H), of 3.75 (s, 4H), 4,71-is 4.85 (m, 1H), of 6.85 (d, J=8.4 Hz, 2H), 7,71 (d, J=to 8.7 Hz, 2H).

Referential example 5-34

2-(3-Chloro-4-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaborinane

Specified in the title compound (738 mg, 72%) was obtained by carrying out essentially the same reaction as in reference example 5-11, except that used 4-bromo-2-chloro-1-methoxybenzoyl instead of 4-bromo-2-methylbenzonitrile.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.01 (s, 6H), of 3.75 (s, 4H), 3,92 (s, 3H), 6,90 (d, J=8,3 Hz, 1H), 7,66 (DD, J=8,2, 1.6 Hz, 1H), 7,79 (d, J=1.2 Hz, 1H).

Referential example 5-35

1-(Benzylmethyl)-4-bromo-2-chlorobenzene

A solution of 4-bromo-2-chlorobenzenesulfonamide (1.16 g), sodium sulfite (1.01 g) and sodium bicarbonate (672 mg) in water (8 ml) was stirred at 100°C for 1.5 hours. The reaction solution was cooled to 50°C and added tetrabutylammonium (1.29 g) and the bromide (1,43 ml), after which the mixture was stirred at 70°C for three more hours. The reaction solution was cooled to room temperature and was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1) obtaining specified in the title compound as a white solid (1.29 g, 94%).

1H NMR (300 MHz, CDCl3) δ M. D. 4,63 (s, 2H), made 7.16 interest-7,22 (m, 2H), 7,22-value of 7, 37 (m, 3H), 7,38-of 7.46 (m, 1H), 7,58 (d, J=8,5 Hz, 1H), 7,71-to 7.77 (m, 1H).

Referential example 5-36

4,4,5,5-Tetramethyl-2-[4-(2,2,2-triptoreline)phenyl]-1,3,2-dioxaborolan

Specified in the title compound was obtained as a colorless oil (303 mg, 17%) by carrying out essentially the same reaction as in reference example 5-32, except that used 1-bromo-4-(2,2,2-triptoreline)benzene instead of 1-bromo-4-(2,2,2-trifluoroethyl)benzene.

1H NMR (300 MHz, CDCl3) δ M. D. 1,30-1,40 (m, 12H), 4,25-of 4.44 (m, 2H), of 6.85-6,97 (m, 2H), 7,69-7,84 (m, 2H).

Structures of reference examples 5 to 11 - 5-36 shown below.

Table 9-1

Table 9-2

Referential example 5-37

4-Bromo-2-chloro-1-(ethylsulfonyl)benzene

Attentional sodium (2.0 g) was added to a solution of 4-bromo-2-chloro-1-fervently (5.0 g) in N,N-dimethylformamide (20 ml) and the mixture was stirred at 65°C for two hours. The reaction solution was poured into water, followed by extraction e�ilaclama. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=90:1→0:100) with obtaining specified in the header connection in the form of a colorless oil (4.8 g).

1H NMR (300 MHz, CDCl3) δ M. D. 1,22-of 1.41 (m, 3H), 2,83-of 3.07 (m, 2H), 7,01-to 7.18 (m, 1H), 7,31-7,40 (m, 1H), of 7.48-7,61 (m, 1H).

Referential example 5-38

1-Bromo-3-(cyclopropylmethyl)benzene

Tert-butoxide potassium (4 g) and cyclopropylboronic (7,6 ml) was added to a solution of 3-bromothiophene (6 g) in dimethylsulfoxide (30 ml) and the mixture was stirred at 80°C for five hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→7:3) with obtaining specified in the title compound as a light yellow oil (1.6 g, 23%).

1H NMR (300 MHz, CDCl3) δ M. D. 0,63-0,77 (m, 2H), 1,04-of 1.18 (m, 2H), 2,11-of 2.25 (m, 1H), 7,09-7,17 (m, 1H), 7,22-7,29 (m, 2H), of 7.48-7,53 (m, 1H).

MS(+): 229 [M+H]+.

Referential example 5-39

[4-Bromo-2-(trifluoromethyl)phenoxy](tert-butyl)dimethylsilane

(1) Tetra-n-butylammonium (37 g) was added in small portions to a solution of 2-hydroxybenzonitrile (10 g) in chloroform (350 ml) and the mixture was stirred at room temperature for eight hours. Evaporated from the reaction solution under reduced pressure solvent and then added to the residue 0.5 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium thiosulfate, water and saturated brine, and dried over sodium sulfate. Evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=8:2→6:4) to give a mixture of 2-hydroxybenzonitrile and 4-bromo-2-(trifluoromethyl)phenol (16 g).

(2) Imidazole (6.8 g) and tert-butyldimethylsilyl (12 g) was added to a solution mixture of 2-hydroxybenzonitrile and 4-bromo-2-(trifluoromethyl)phenol (16 g) in N,N-dimethylformamide (60 ml) and the mixture stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hex�n:ethyl acetate=8:2→7:3) to give a mixture of [4-bromo-2-(trifluoromethyl)phenoxy](tert-butyl)dimethylsilane and [2-(trifluoromethyl)phenoxy](tert-butyl)dimethylsilane (17 g).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.26 (s, 6H), of 1.00 (s, 9H), of 6.79 (d, J=9,0 Hz, 1H), 7,45-7,51 (m, 1H), 7,65 (d, J=2,8 Hz, 1H).

MS(+): 299 [M-tBu]+.

Referential example 5-40

{3-[(4-Bromo-2-chlorophenyl)sulfanyl]propoxy}(tert-butyl)dimethylsilane

Specified in the title compound was obtained as a colorless oil (4.0 g) by carrying out essentially the same reaction as in reference examples 5-37 and 5-39(2) sequentially, except that used 3-hydroxy-1-propanethiol instead ethanolate sodium.

1H NMR (200 MHz, CDCl3) δ M. D. of 0.06 (s, 6H), of 0.90 (s, 9H), 1,77-of 1.97 (m, 2H), 2,91-3,09 (m, 2H), 3,63-3,82 (m, 2H), 7,10-7,21 (m, 1H), 7,28-value of 7, 37 (m, 1H), 7,44-EUR 7.57 (m, 1H).

Referential example 5-41

tert-Butyl 3-[(4-bromophenyl)sulfanyl]azetidin-1-carboxylate

Specified in the title compound was obtained as a colorless oil (9.2 g) the carrying out essentially the same reaction as in reference example 5-38, except that used tert-butyl 3-[(phenylsulfonyl)oxy]azetidin-1-carboxylate instead of cyclopropylamine and used 4-brominethiophenol.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.43 (s, 9H), 3,78-3,89 (m, 2H), 3,92-of 4.04 (m, 1H), 4,25-4,45 (m, 2H), 7,03-7,14 (m, 2H), 7,38-7,49 (m, 2H).

MS(+): 366 [M+Na]+.

Referential example 5-42

{3-[(4-Bromophenyl)sulfanyl]propoxy}(tert-butyl)dimethylsilane

Potassium carbonate (4.1 g) and (3 bromopropane)-tert-butyldimethylsilyl (4.1 g) was added to a solution of 4-bromothiophene (3.0 g) � N,N-dimethylformamide and the mixture was stirred at room temperature over night. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1→20:1) obtaining specified in the header connection in the form of a colorless oil (5.5 g).

1H NMR (200 MHz, CDCl3) δ M. D. of 0.05 (s, 6H), of 0.90 (s, 9H), 1,64-of 1.95 (m, 2H), 2,81-3,13 (m, 2H), 3,60-with 3.79 (m, 2H), 7,09-7,24 (m, 2H), 7,34-7,49 (m, 2H).

Referential example 5-43

(4-Bromo-2-pertenece)(tert-butyl)dimethylsilane

Specified in the title compound was obtained as a colorless oil (16 g) by carrying out essentially the same reaction as in reference example 5-39(2), except that used 4-bromo-2-forfinal instead of 4-bromo-2-(trifluoromethyl)phenol.

1H NMR (300 MHz, CDCl3) δ M. D. 0,18 (d, J=1.1 Hz, 6H), 0,99 (s, 9H), of 6.79 (t, J=to 8.7 Hz, 1H), 7,08-7,13 (m, 1H), 7,21 (DD, J=10,1, 2,3 Hz, 1H).

Referential example 5-44

The diamide N,N-dimethyl-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfuric acid

Dimethylsulphamoyl (492 mg) and triethylamine (0,95 ml) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg) in chloroform (5 ml) and the mixture was stirred at room temperature over night. The reaction solution was concentrated and the residues�it was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:0→2:1) obtaining specified in the header connection in the form of a pale orange powder (427 mg).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.34 (s, 12H), 2,84 (s, 6H), 6,47-6,54 (m, 1H), 7,14 (d, J=8,5 Hz, 2H), 7,76 (d, J=8,5 Hz, 2H).

MS(+): 327 [M+H]+.

Referential example 5-45

1-Propan-2-yl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

Specified in the title compound was obtained as colorless powder (514 mg) by carrying out essentially the same reaction as in reference example 5-44, except that used 2-isocyanatopropyl instead of dimethylsulfoxide.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.16 (s, 3H), 1,19 (s, 3H), of 1.33 (s, 12H), of 3.91-4,07 (m, 1H), 4,49-USD 4.61 (m, 1H), 6,23 is 6.35 (m, 1H), 7,29 (d, J=8,5 Hz, 2H), of 7.75 (d, J=8.4 Hz, 2H).

MS(+): 305 [M+H]+.

Patterns reference examples 5-37 - 5-45 shown below.

Table 10

Referential example 5-46

4-(5,5-Dimethyl-1,3,2-dioxaborinane-2-yl)-2-methylbenzonitrile

A solution of 4-bromo-2-methylbenzonitrile (1.0 g) in tetrahydrofuran (16 ml) was cooled to ambient temperature -78°C under an atmosphere of nitrogen was added dropwise a solution of n-utility in hexane (1,57 M, 3.5 ml). After stirring at -78°C for 40 minutes, was added dropwise triisopropylsilyl (1.5 ml) and the mixture was stirred at room temperature for 1.5 hours. EXT�ulali to the reaction solution of 1 M hydrochloric acid (10 ml) followed by diethyl ether extraction. The organic layer was washed with water and saturated brine, dried over sodium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was dissolved in toluene (4 ml) and tetrahydrofuran (3 ml) was added 2,2-dimethyl-1,3-propandiol (531 mg) and anhydrous magnesium sulfate (catalytic amount), after which the mixture was stirred at room temperature for five minutes. The insoluble material in the reaction solution was filtered and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1→20:1) obtaining specified in the title compound as colorless solid (778 mg, 67%).

1H NMR (300 MHz, CDCl3) δ M. D. and 1.02 (s, 6H), of 2.54 (s, 3H), of 3.78 (s, 4H), 7,56 (d, J=7,7 Hz, 1H), 7,66 (d, J=7,4 Hz, 1H), 7,73 (s, 1H).

Referential example 5-47

4-Bromo-2-chloro-1-(propane-2-ylsulphonyl)benzene

Specified in the title compound was obtained as a colorless oil (432 mg, 36%) by carrying out essentially the same reaction as in reference example 5-35, except that used 2-bromopropane bromide instead.

1H NMR (300 MHz, CDCl3) δ M. D. 1,32 (d, J=6,9 Hz, 6H), 3,68-3,83 (m, 1H), 7,61 (DD, J=8,5, and 1.9 Hz, 1H), 7,73 (d, J=1.9 Hz, 1H), 7,96 (d, J=8,3 Hz, 1H).

MS(+): 319 [M+Na]+.

Referential example 5-48

{3-[(4-Bromophenyl)sulfonyl]propoxy}(tert-butyl)l�methylsilane

(1) 3-(4-Brompheniramine)propan-1-ol was obtained as a colorless oil (784 mg, 70%) by carrying out essentially the same reaction as in reference example 5-35, except that used 3-bromo-1-propanol instead of bromide and used 4-bromobenzonitrile instead of 4-bromo-2-chlorobenzenesulfonamide.

(2) tert-Butyldimethylchlorosilane (508 mg) and diisopropylethylamine (587 μl) was added to a solution of 3-(4-brompheniramine)propan-1-ol (784 mg) in N,N-dimethylformamide (4 ml) and the mixture was stirred at room temperature for 2.5 hours. Was added to the reaction solution of tert-butyldimethylchlorosilane (127 mg) and diisopropylethylamine (147 μl) and the mixture was stirred at room temperature for another two hours. Was added to the reaction solution of tert-butyldimethylchlorosilane (254 mg) and diisopropylethylamine (1,17 ml) and the mixture stirred at room temperature for another 30 minutes. Was added to the reaction solution with water followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1→33:1→19:1→9:1) with obtaining specified in the title compound as a white solid (720 mg, 65%).

1H NMR (300 MHz, CDCl3) δ M. D. 0,00 (s, 6H), from 0.84 (s, 9H), 1,82-of 1.96 (m, 2H), 3,14-3,26 (m, 2H), to 3.64 (t, J=5.8 Hz, 2H), of 7.64-7,83 (m, 4H).

MS(+): 393 [M+H]+.

Referential example 5-49

4-Bromo-2-chloro-1-(cyclopentylmethyl)benzene

Specified in the title compound was obtained as a white amorphous substance (308 mg, 24%) by carrying out essentially the same reaction as in reference example 5-35, except that used bromocyclopentane bromide instead.

1H NMR (300 MHz, CDCl3) δ M. D. 1,51-of 2.20 (m, 8H), 3,99-4,16 (m, 1H), 7,60 (DD, J=8,5, and 1.9 Hz, 1H), 7,73 (d, J=1.9 Hz, 1H), 7,97 (d, J=8,3 Hz, 1H).

MS(+): 345 [M+Na]+.

Referential example 5-50

2-Chloro-5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)benzonitrile

Specified in the title compound was obtained as yellow solid (454 mg, 39%) by carrying out essentially the same reaction as in reference example 5-11, except that used 5-bromo-2-chlorobenzonitrile instead of 4-bromo-2-methylbenzonitrile.

1H NMR (300 MHz, CDCl3) δ M. D. and 1.02 (s, 6H), of 3.77 (s, 4H), of 7.48 (d, J=7,7 Hz, 1H), 7,91 (DD, J=7,9, 1.3 Hz, 1H), 8,09 (d, J=1.5 Hz, 1H).

Referential example 5-51

2-[4-(Deformedarse)-3-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

(1) Ethyldichloroarsine (1,87 ml) and potassium carbonate (2.72 g) was added to a solution of 4-bromo-2-methoxyphenol (2.0 g) in N,N-dimethylformamide (20 ml) and the mixture was stirred at 70°C for 23 hours. The reaction solution was cooled to room temperature and to�aslali with water followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=20:1) and then was purified column chromatography on NH-silica gel (hexane:ethyl acetate=30:1→20:1) to give 4-bromo-1-(deformedarse)-2-methoxybenzene in the form of a white solid (636 g, 26%).

(2) Specified in the title compound was obtained as white solid (357 mg, 47%) by carrying out essentially the same reaction as in reference example 5-32, except that used 4-bromo-1-(deformedarse)-2-methoxybenzoyl instead of 4-bromo-2-chloro-1-(deformedarse)benzene.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.34 (s, 12H), 3,92 (s, 3H), 6,56 (t, J=75,1 Hz, 1H), 7,14 (d, J=8,0 Hz, 1H), 7,39 (s, 1H), 7,40 (d, J=7,4 Hz, 1H).

Referential example 5-52

2-[4-(Deformedarse)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

Specified in the title compound was obtained as a pale yellow oil (1.21 g, 40% (two steps)) by carrying out essentially the same reaction as in reference example 5-51, except that used 4-bromo-2-METHYLPHENOL instead of 4-bromo-2-methoxyphenol.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.34 (s, 12H), of 2.28 (d, J=6,6 Hz, 3H), of 6.52 (t, J=74,0 Hz, 1H), to 7.04 (d, J=8,0 Hz, 1H), 7,63 (d, J=8,0 Hz, 1H), 7,68 (s, 1H).

Referential example 5-53

2-[4-(Deformedarse)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

Specified in the title compound was obtained as a colorless oil (0,67 g, 24% (two steps)) by carrying out essentially the same reaction as in reference example 5-51, except that used 4-bromo-2-forfinal instead of 4-bromo-2-methoxyphenol.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.34 (s, 12H), to 6.57 (t, J=73,4 Hz, 1H), 7,15-7,24 (m, 1H), of 7.48-7,63 (m, 2H).

Referential example 5-54

4-Bromo-2-chloro-1-[(cyclopropylmethyl)sulfonyl]benzene

Specified in the title compound was obtained as a pale brown oil (444 mg, 36%) by carrying out essentially the same reaction as in reference example 5-35, except that was used (methyl bromide)cyclopropane bromide instead.

1H NMR (300 MHz, CDCl3) δ M. D. 0,14-0,37 (m, 2H), 0,44-0,70 (m, 2H), 0,90-1,15 (m, 1H), of 3.33 (d, J=7,2 Hz, 2H), of 7.64 (DD, J=8,5, and 1.9 Hz, 1H), 7,73 (d, J=1.9 Hz, 1H), 8,02 (d, J=8,5 Hz, 1H).

MS(+): 331 [M+Na]+.

Referential example 5-55

1-(Cyclopropanesulfonyl)-4-idental

Specified in the title compound was obtained as colorless powder (2,19 g, 93%) by carrying out essentially the same reaction as in reference example 4-31(1), except that used 1-bromo-4-(cyclopropanesulfonyl)benzene (described in WO 2004009086).

1H NMR (300 MHz, CDCl3) δ M. D. 0,98-1,11 (m, 2H), 1,29-of 1.41 (m, 2H), 2,36-2,53 (m, 1H), 7,61 (d, J=8,5 Hz, 2H), 7,92 (d, J=8,2 Hz, 2H).

MS(+): 309 [M+H] +.

Patterns reference examples 5-46 - 5-55 shown below.

Table 11

Example 1-1

3-Chloro-6-{(E)-2-Cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}pyridin-2(1H)-he

[Formula 106]

(1) Solution litigationrelated in tetrahydrofuran (1 M, with 5.22 ml) was added to a solution of (cyclopentylmethyl)triphenylphosphite (described in WO 2001044216) (2,46 g) in tetrahydrofuran (20 ml) in a nitrogen atmosphere under cooling with ice and the mixture was stirred at room temperature for one hour. The reaction solution was again cooled with ice and added a solution of (5-chloro-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanone obtained in reference example 1-1 (1.0 g) in tetrahydrofuran (10 ml), after which the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:hexane=1:1) to obtain� 3-chloro-6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-2-methoxypyridine (710 mg, 58%) as a colorless oil.

(2) 48% bromoethanol acid (1.5 ml) was added to a solution of 3-chloro-6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-2-methoxypyridine (250 mg) in 1,4-dioxane (1.5 ml) and the mixture was stirred at 85°C for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol=9:1) to give a pale brown oil. The resulting oil was converted into a powder using hexane/ethylacetate solution, and the process of filtering gave specified in the title compound as a pale brown powder (230 mg, 71%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.40 to 1.63 (m, 4H), 1,68-1,90 (m, 4H), 2,32-of 2.58 (m, 4H), of 5.81 (d, J=7,8 Hz, 1H), 6,47 (d, J=10.1 Hz, 1H), 7,10 (d, J=8,5 Hz, 2H), 7.23 percent-to 7.33 (m, 2H), 7,44 (d, J=7,8 Hz, 1H), 10,91-at 11.23 (user.s, 1H).

MS(+): 345 [M+H]+.

Example 1-2

3-Chloro-6-{(E)-2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethenyl}pyridin-2(1H)-he

[Formula 107]

Water (3 ml) and Oxon(R) (853 mg) were successively added to a solution of 3-chloro-6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}pyridin-2(1H)-she obtained in example 1-1 (160 mg) in a mixture of TG�-methanol (1:1, 6 ml) and the mixture stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (chloroform:hexane=10:0→9:1). The obtained crude product is recrystallized from smeshannogo solution of chloroform:ethyl acetate:hexane (1:1:1, 6 ml) with obtaining specified in the title compound as colorless powder (130 mg, 74%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,40-of 1.64 (m, 4H), 1,67-of 1.92 (m, 4H), 2,22-2,52 (m, 1H), 3,14 (s, 3H), for 5.66 (d, J=7,6 Hz, 1H), 6,63 (d, J=10.1 Hz, 1H), value of 7, 37-EUR 7.57 (m, 3H), 8,00 (d, J=8,5 Hz, 2H), 11,40-11,73 (user.s, 1H).

MS(+): 378 [M+H]+.

Example 1-3

6-{(E)-2-Cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-(propane-2-yl)pyridin-2(1H)-he

[Formula 108]

Specified in the title compound was obtained as colorless powder (135 mg, 23% (two steps)) by carrying out essentially the same reaction as in example 1-1, except that used [6-methoxy-5-(propan-2-yl)pyridin-2-yl][4-(methylsulfanyl)phenyl]methanon obtained in reference example 1-76.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.17 (d, J=7,0 Hz, 6H), 1,32-of 1.81 (m, 8H), 2,35-2,51 (m, 1H), 2,3 (s, 3H), is 3.08-or 3.28 (m, 1H), 5,86 (d, J=7,1 Hz, 1H), 6,19 (d, J=9.9 Hz, 1H), 7,03-to 7.18 (m, 3H), 7.23 percent-7,32 (m, 2H), 9,34-9,59 (user.s, 1H).

MS(+): 354 [M+H]+.

Example 1-4

6-{(E)-2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethenyl}-3-(propane-2-yl)pyridin-2(1H)-he

[Formula 109]

Specified in the title compound was obtained as colorless powder (60 mg, 50%) by carrying out essentially the same reaction as in example 1-2, except that used 6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-(propane-2-yl)pyridin-2(1H)-he obtained in example 1-3.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.17 (d, J=6,8 Hz, 6H), 1,40-1,60 (m, 4H), 1,64-1,89 (m, 4H), of 2.21 is 2.44 (m, 1H), 3,13 (s, 3H), 3,15-3,26 (m, 1H), 5,63 (l, J=7,3 Hz, 1H), a 6.53 (d, J=10.1 Hz, 1H), 7,05-to 7.18 (m, 1H), of 7.42 (d, J=8,5 Hz, 2H), 7,92-with 8.05 (m, 2H), 10,91 is 11.05 (user.s, 1H).

MS(+): 386 [M+H]+.

Example 1-5

6-{(E)-2-Cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 110]

(1) 6-{(E)-2-Cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-cyclopropyl-2-methoxypyridine was obtained as a colorless oil (480 mg, 33%) by carrying out essentially the same reaction as in example 1-1(1), except that used the (5-cyclopropyl-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanon obtained in reference example 1-51.

(2) 4 M hydrogen chloride-1,4-dioxane solution (4.5 ml) was added to a suspension of 6-{(E)-2-cyclopentyl-1-[4(methylsulfanyl)phenyl]ethenyl}-3-cyclopropyl-2-methoxypyridine (150 mg) in water (1.5 ml) and the mixture was stirred at 90°C for 1.5 hours. The reaction solution was cooled to room temperature and was extracted with chloroform twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in hexane-ethylacetate solution by heating and then recrystallization by cooling to room temperature gave specified in the title compound as colorless powder (111 mg, 77%).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.54 to 0.63 (m, 2H), from 0.87 to 0.98 (m, 2H), 1,29-to 1.82 (m, 8H), 2,03-of 2.15 (m, 1H), 2,36-2,51 (m, 1H), 2,51 (s, 3H), 5,80 (d, J=7,2 Hz, 1H), 6.18 of (d, J=10.0 Hz, 1H), 6,80 (DD, J=7,3, 0.6 Hz, 1H), 7,05-7,13 (m, 2H), 7.23 percent-7,30 (m, 2H), 9,34-9,65 (user.s, 1H).

MS(+): 352 [M+H]+.

Example 1-6

6-{(E)-2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 111]

(1) the Crude product containing 6-{(E)-2-cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethenyl}-2-methoxy-3-cyclopropylidene, were obtained by carrying out essentially the same reaction as in example 1-2, except that used 6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-cyclopropyl-2-methoxypyridine obtained in example 1-5(1).

(2) Specified in the title compound was obtained as colorless powder (132 mg, 84% (two steps)) by carrying out essentially the same R�shares, as in example 1-5(2), except that used 6-{(E)-2-cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethenyl}-2-methoxy-3-cyclopropylidene.

1H NMR (300 MHz, CDCl3) δ M. D. 0,52-0,66 (m, 2H), with 0.83 to 1.01 (m, 2H), 1,36-of 1.84 (m, 8H), 2,05-of 2.20 (m, 1H), 2,23-2,43 (m, 1H), 3,13 (s, 3H), to 5.58 (d, J=7,2 Hz, 1H), is 6.51 (d, J=10.1 Hz, 1H), 6,78 (d, J=7,2 Hz, 1H), 7,35-of 7.48 (m, 2H)That 7,91 and 8.04 (m, 2H), 10,82-11,14 (user.s, 1H).

MS(+): 384 [M+H]+.

Example 1-7

6-{(E)-2-Cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 112]

Specified in the title compound was obtained as a colorless amorphous substance (174 mg, 29% (two steps)) by carrying out essentially the same reaction as in example 1-1, except that used 6-methoxy-5-methylpyridine-2-yl)[4-(methylsulfanyl)phenyl]methanon obtained in reference example 1-36.

1H NMR (300 MHz, CDCl3) δ M. D. 1,10-of 1.85 (m, 8H), 2,12 (s, 3H), 2,35-by 2.55 (m, 1H), 2,53 (s, 3H), of 5.85 (d, J=7,3 Hz, 1H), 6,12 (d, J=9.9 Hz, 1H), 7,00-7,30 (m, 5H), 8,90-9,35 (user.s, 1H).

MS(+): 326 [M+H]+.

Example 1-8

6-{(E)-2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 113]

Specified in the title compound was obtained as colorless powder (375 mg, 88% (two steps)) by carrying out essentially the same reaction as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(E)-2-cyclopent�l-1-[4-(methylsulfanyl)phenyl]ethenyl}-2-methoxy-3-methylpyridine, obtained in example 1-7.

1H NMR (300 MHz, CDCl3) δ M. D. 1,31-1,62 (m, 4H), 1,67-to 1.87 (m, 4H), 2,12 (s, 3H), 2,23-2,48 (m, 1H), 3,14 (s, 3H), 5,64 (d, J=7,0 Hz, 1H), 6,39 (d, J=10.1 Hz, 1H), 7,14 (d, J=8,2 Hz, 1H), 7,43 (d, J=8.4 Hz, 2H), 7,99 (d, J=8.4 Hz, 2H), 10,12-10,48 (user.s, 1H).

MS(+): 358 [M+H]+.

Example 1-9

6-{(E)-2-Cyclopentyl-1-[4-(ethylsulfanyl)phenyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 114]

(1) 6-{(E)-2-Cyclopentyl-1-[4-(ethylsulfanyl)phenyl]ethenyl}-2-methoxy-3-methylpyridine was obtained as a colorless oil (470 mg, 31%) by carrying out essentially the same reaction as in example 1-1(1), except that used [4-(ethylsulfanyl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon obtained in referential example 1 to 43.

(2) Specified in the title compound was obtained as colorless powder (180 mg, 76%) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-{(E)-2-cyclopentyl-1-[4-(ethylsulfanyl)phenyl]ethenyl}-2-methoxy-3-methylpyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 1,28-to 1.86 (m, 8H), 1,38 (t, J=7,3, 3H), 2,12 (s, 3H), 2,34-2,63 (m, 1H), 3,00 (sq, J=7,3 Hz, 2H), 5,82 (d, J=7,0 Hz, 1H), of 6.20 (d, J=9.9 Hz, 1H), to 7.09 (d, J=8,5 Hz, 2H), 7,14 (d, J=5,9 Hz, 1H), 7,32 (d, J=8,5 Hz, 2H), 9,52-9,80 (user.s, 1H).

MS(+): 340 [M+H]+.

Example 1-10

6-{(E)-2-Cyclopentyl-1-[4-(ethylsulfonyl)phenyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 115]

Specified in the header� compound was obtained as colorless powder (118 mg, 46% (two steps)) by carrying out essentially the same reaction as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(E)-2-cyclopentyl-1-[4-(ethylsulfanyl)phenyl]ethenyl}-2-methoxy-3-methylpyridine obtained in example 1-9(1).

1H NMR (300 MHz, CDCl3) δ M. D. 1,27-of 1.42 (m, 3H), 1,42-of 1.64 (m, 4H), 1,66-of 1.83 (m, 4H), 2,12 (s, 3H), 2,25-2,48 (m, 1H), 3,19 (sq, J=7.5 Hz, 2H), of 5.60 (d, J=7,0 Hz, 1H), 6,36-to 6.57 (m, 1H), 7,08-to 7.18 (m, 1H), 7,35-7,52 (m, 2H), Of 7.88-8,08 (m, 2H), 10,56-10,85 (m, 1H).

MS(+): 372 [M+H]+.

Example 1-11

6-{(E)-2-Cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 116]

Specified in the title compound was obtained as colorless powder (105 mg, 5.3 per cent (three stages)) by carrying out essentially the same reaction as in examples 1-1(1), 1-2 and 1-1(2) sequentially except that used [4-(cyclopropanesulfonyl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon obtained in reference example 1-37.

1H NMR (300 MHz, CDCl3) δ M. D. 0,99-to 1.21 (m, 2H), 1,36-of 1.64 (m, 6H), 1,67-1,89 (m, 4H), to 2.13 (s, 3H), 2,27-of 2.44 (m, 1H), 2,48-of 2.67 (m, 1H), 5,69 (d, J=7,0 Hz, 1H), 6,38 (d, J=10.1 Hz, 1H), made 7.16 interest (d, J=6,9 Hz, 1H), 7,39 (d, J=8.4 Hz, 2H), 7,94 (d, J=8,5 Hz, 2H), for 10.08-10,25 (user.s, 1H).

MS(+): 384 [M+H]+.

Example 1-12

6-[(E)-2-Cyclopentyl-1-{4-[(3-hydroxypropyl)sulfanyl]phenyl}ethenyl]-3-ethylpyridine-2(1H)-he

[Formula 117]

(1) 6-[1-{4-[(3-{[tert-Butyl(dimethyl)silyl]about�si}propyl)sulfanyl]phenyl}-2-cyclopentylacetyl]-3-ethyl-2-methoxypyridine (E:Z=1:1 mixture) was obtained as a colorless oil (800 mg) by carrying out essentially the same reaction, as in example 1-1(1), except that used{[4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]phenyl}(5-ethyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-47.

(2) Specified in the title compound was obtained as a colorless oil (50 mg, 33%) by carrying out essentially the same reaction as in example 1-1(2) except that used 6-[1-{4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]phenyl}-2-cyclopentylacetyl]-3-ethyl-2-methoxypyridine (E:Z=1:1 mixture).

1H NMR (200 MHz, CDCl3) δ M. D. of 1.17 (t, J=7.5 Hz, 3H), of 1.30-of 1.85 (m, 8H), 1,90-2,07 (m, 2H), 2,33-2,62 (m, 3H), 3,01-3,20 (m, 2H), 3,71-of 3.91 (m, 2H), 5,88 (d, J=7,0 Hz, 1H), 6,13 (d, J=9,7 Hz, 1H), 6,99-7,20 (m, 3H), value of 7, 37 (s, 2H).

MS(+): 384 [M+H]+.

Example 1-13

6-[(E)-2-Cyclopentyl-1-{4-[(3-hydroxypropyl)sulfonyl]phenyl}ethenyl]-3-ethylpyridine-2(1H)-he

[Formula 118]

Specified in the title compound was obtained as colorless powder (86 mg, 17% (two steps)) by carrying out essentially the same reaction as in examples 1-2 and 1-1(2) sequentially except that used 6-[1-{4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]phenyl}-2-cyclopentylacetyl]-3-ethyl-2-methoxypyridine (E:Z=1:1 mixture), obtained in example 1-12(1).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.17 (t, J=7.5 Hz, 3H), of 1.35 to 1.63 (m, 4H), 1,67-of 1.88 (m, 4H), of 1.98 to 2.14 (m, 2H), 2,25-2,43 (m, 1H), 2,54 (sq, J=7.5 Hz, 2H), 3,22-of 3.42 (m, 2H), 3,71-of 3.85 (m, 2H),5,69 (d, J=7,1 Hz, 1H), 6,41 (d, J=10.1 Hz, 1H), 7,13 (d, J=9,0 Hz, 1H), of 7.42 (d, J=8,5 Hz, 2H), 7,97 (d, J=8,5 Hz, 2H).

MS(+): 416 [M+H]+.

Example 1-14

4-[(E)-2-Cyclopentyl-1-(5-methyl-6-oxo-1,6-dihydropyridine-2-yl)ethenyl]-N,N-dimethylbenzenesulfonamide

[Formula 119]

Specified in the title compound was obtained as colorless powder (135 mg, 5,1% (two steps)) by carrying out essentially the same reaction as in example 1-1, except that used 4-[(6-methoxy-5-methylpyridine-2-yl)carbonyl]-N,N-dimethylbenzenesulfonamide obtained in reference example 1-38.

1H NMR (300 MHz, CDCl3) δ M. D. 1,34-1,59 (m, 4H), 1,64-to 1.87 (m, 4H), to 2.13 (s, 3H), 2,27-2,48 (m, 1H), 2,80 (s, 6H), for 5.66 (d, J=7,0 Hz, 1H), 6,37 (d, J=10.1 Hz, 1H), 7,15 (d, J=7,0 Hz, 1H), 7,38 (d, J=8.4 Hz, 2H), 7,82 (d, J=8.4 Hz, 2H), 10,12-10,37 (user.s, 1H).

MS(+): 387 [M+H]+.

Example 1-15

4-[(E)-2-Cyclopentyl-1-(5-methyl-6-oxo-1,6-dihydropyridine-2-yl)ethenyl]-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide

[Formula 120]

Specified in the title compound was obtained as colorless powder (132 mg, 16% (two steps)) by carrying out essentially the same reaction as in example 1-1, except that used N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-[(6-methoxy-5-methylpyridine-2-yl)carbonyl]-N-methylbenzenesulfonamide obtained in reference example 1-39.

1H NMR (300 MHz, CDCl3) δ M. D. 1,33-to 1.61 (m, 6H), 1,65-to 1.86 (�, 2H), 2,12 (s, 3H), 2,23-2,52 (m, 1H), equal to 2.94 (s, 3H), 3,21-3,39 (m, 2H), 3,69-3,94 (m, 2H), of 5.72 (d, J=7,0 Hz, 1H), 6,38 (d, J=10.1 Hz, 1H), 7,10-7,20 (m, 1H), value of 7, 37 (d, J=8,5 Hz, 2H), a 7.85 (d, J=8,5 Hz, 2H).

MS(+): 417 [M+H]+.

Example 1-16

6-[(E)-1-(3-Chloro-4-methoxyphenyl)-2-cyclopentylacetyl]-3-ethylpyridine-2(1H)-he

[Formula 121]

(1) 6-[(E)-1-(4-{[tert-Butyl(dimethyl)silyl]oxy}-3-chlorophenyl)-2-cyclopentylacetyl]-3-ethyl-2-methoxypyridine was obtained as a colorless amorphous substance (409 mg, 43%) by carrying out essentially the same reaction as in example 1-1(1), except that used 4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-ethyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-50.

(2) 1 M solution of tetrabutylammonium in tetrahydrofuran (1,73 ml) was added to a solution of 6-[(E)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)-2-cyclopentylacetyl]-3-ethyl-2-methoxypyridine (409 mg) in tetrahydrofuran (3 ml) under cooling with ice and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water and made acidic with 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hex�n:ethyl acetate=10:1→1:1) to give 2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenol as a yellow oil (306 mg, 99%).

(3) potassium Carbonate (188 mg) and methyliodide (73 μl) were successively added to a solution of 2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenol (163 mg) in N,N-dimethylformamide (3 ml) and the mixture was stirred at room temperature for four hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=10:0→2:1) to give 6-[(E)-1-(3-chloro-4-methoxyphenyl)-2-cyclopentylacetyl]-3-ethyl-2-methoxypyridine in the form of a yellow oil (131 mg, 77%).

(4) Specified in the title compound was obtained as colorless powder (50 mg, 39%) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-[(E)-1-(3-chloro-4-methoxyphenyl)-2-cyclopentylacetyl]-3-ethyl-2-methoxypyridine.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.17 (t, J=7.5 Hz, 3H), 1,32-1,89 (m, 8H), 2,30-2,61 (m, 3H), 3,95 (s, 3H), of 5.81 (d, J=7,0 Hz, 1H), for 6.24 (d, J=10.0 Hz, 1H), 6,91-of 6.99 (m, 1H), 7,02-to 7.09 (m, 1H), 7,13 (d, J=7,2 Hz, 1H), 7,20 (s, 1H), 9,70-9,86 (user.s, 1H).

MS(+): 358 [M+H]+.

Example 1-17

6-[(E)-1-(3-Chloro-4-ethoxyphenyl)-2-cyclopentylacetyl]-3-ethylpyridine-2(1H)-he

[Formula 122]

Specified in for�over the head of the compound was obtained as colorless powder (50 mg, 11% (four stages)) by carrying out essentially the same reaction as in example 1-16, except that used ethyliodide instead of methyliodide.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.17 (t, J=7.5 Hz, 3H), 1,29-of 1.85 (m, 11H), 2,31-of 2.67 (m, 3H), 4,15 (sq, J=7,0 Hz, 2H), 5,82 (d, J=7,0 Hz, 1H), from 6.22 (d, J=10.0 Hz, 1H), to 6.88-6,97 (m, 1H), 6,99-7,06 (m, 1H), 7,12 (d, J=7,2 Hz, 1H), Of 7.19 (d, J=2,0 Hz, 1H), 9,61-9,79 (user.s, 1H).

MS(+): 372 [M+H]+.

Example 1-18

6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylacetyl}-3-methylpyridine-2(1H)-he

[Formula 123]

(1) 6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylacetyl}-2-methoxy-3-methylpyridine (196 mg, 25%) was obtained by carrying out essentially the same reaction as in example 1-1(1), except that used [3-chloro-4-(methylsulfanyl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon obtained in reference example 1-40.

(2) Specified in the title compound was obtained as a colorless solid (162 mg, 89%) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylacetyl}-2-methoxy-3-methylpyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 1,35-1,60 (m, 4H), 1,60-of 1.85 (m, 4H), 2,14 (s, 3H), 2,35-of 2.50 (m, 1H), 2,52 (s, 3H), of 5.85 (d, J=6,9 Hz, 1H), of 6.26 (d, J=9.9 Hz, 1H), 7,07 (DD, J=8,1, of 1.8 Hz, 1H), 7,15-of 7.25 (m, 3H), 9,80-10,00 (user.s, 1H).

MS(+): 360 [M+H]+.

Example 1-19

6-{(E)-1-[3-Chloro-4-(methyls�Lionel)phenyl]-2-cyclopentylacetyl}-3-methylpyridine-2(1H)-he

[Formula 124]

Specified in the title compound was obtained as a colorless solid (91 mg, 22% (two steps)) by carrying out essentially the same reaction as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylacetyl}-2-methoxy-3-methylpyridine obtained in example 1-18(1).

1H NMR (300 MHz, CDCl3) δ M. D. 1,40-1,55 (m, 4H), 1,68-of 1.83 (m, 4H), 2,14 (s, 3H), 2,24-2,43 (m, 1H), 3,35 (s, 3H), 5,65 (d, J=7,2 Hz, 1H), 6.35 mm (d, J=10.5 Hz, 1H), made 7.16 interest (DD, J=6,9, 0.9 Hz, 1H), 7,32 (DD, J=8,1, 1.5 Hz, 1H), 7,40 (d, J=1.5 Hz, 1H), to 8.19 (d, J=8,1 Hz, 1H), 9,90-10,15 (user.s, 1H).

MS(+): 392 [M+H]+.

Example 1-20

6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylacetyl}-3-ethylpyridine-2(1H)-he

[Formula 125]

(1) 6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylacetyl}-3-ethyl-2-methoxypyridine was obtained as a pale yellow oil (60 mg, 10%) by carrying out essentially the same reaction as in example 1-1(1), except that used [3-chloro-4-(methylsulfanyl)phenyl](5-ethyl-6-methoxypyridine-2-yl)methanon, obtained in reference example 1-46.

(2) Specified in the title compound was obtained as colorless powder (15 mg, 26%) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-cyclopentyl�Tennille}-3-ethyl-2-methoxypyridine.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.17 (d, J=7.5 Hz, 3H), 1,33-of 1.84 (m, 8H), 2,52 (s, 3H), 2,33-2,61 (m, 3H), 5,77 (d, J=7,1 Hz, 1H), of 6.26 (d, J=10.1 Hz, 1H), 6,98-7.23 percent (m, 4H), 10,25-10,42 (user.s, 1H).

MS(+): 374 [M+H]+.

Example 1-21

6-{(E)-1-[3-Chloro-4-(methyl-sulfonyl)phenyl]-2-cyclopentylacetyl}-3-ethylpyridine-2(1H)-he

[Formula 126]

Specified in the title compound was obtained as colorless powder (25 mg) by carrying out essentially the same reaction as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylacetyl}-3-ethyl-2-methoxypyridine obtained in example 1-20(1).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.17 (t, J=7.5 Hz, 3H), 1,39-of 1.64 (m, 4H), 1,67-to 1.87 (m, 4H), 2,20-2,42 (m, 1H), 2,46-2,71 (m, 2H), 3,35 (s, 3H), to 5.62 (d, J=7,1 Hz, 1H), is 6.51 (d, J=10.3 Hz, 1H), 7,12 (d, J=7,3 Hz, 1H), to 7.33 (DD, J=8,1, 1.6 Hz, 1H), 7,41 (d, J=1.6 Hz, 1H), to 8.19 (d, J=8,1 Hz, 1H), 10,82-to 11.11 (user.s, 1H).

MS(+): 406 [M+H]+.

Example 1-22

6-[(E)-1-{3-Chloro-4-[(3-hydroxypropyl)sulfanyl]phenyl}-2-cyclopentylacetyl]-3-methylpyridine-2(1H)-he

[Formula 127]

(1) 6-[(E)-1-{4-[(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-cyclopentylacetyl]-2-methoxy-3-methylpyridine was obtained as a colorless oil (1.24 g, 42%) by carrying out essentially the same reaction as in example 1-1(1), except use {4-[(3-{[tert-butyl(dimethyl)silyl]oxy}prop�l)sulfanyl]-3-chlorophenyl}(6-methoxy-5-methylpyridine-2-yl)methanon, obtained in reference example 1-41.

(2) Specified in the title compound was obtained as colorless powder (77 mg, 40% (two steps)) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-[(E)-1-{4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-cyclopentylacetyl]-2-methoxy-3-methylpyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 1,38-to 1.61 (m, 4H), 1,63-of 1.84 (m, 4H), 1.93 and-of 2.06 (m, 2H), 2,11 (s, 3H), 2,32-2,53 (m, 1H), 3,11 (t, J=7,2 Hz, 2H), 3,84 (t, J=6,0 Hz, 2H), 5,70 (d, J=7,2 Hz, 1H), 6,41 (d, J=10.0 Hz, 1H), 7,06 (DD, J=8,1, a 1.9 Hz, 1H), 7,14 (DD, J=7,0, 1,1 Hz, 1H), 7,21 (d, J=1.9 Hz, 1H), 7,30 (d, J=8,1 Hz, 1H).

MS(+): 404 [M+H]+.

Example 1-23

6-[(E)-1-{3-Chloro-4-[(3-hydroxypropyl)sulfonyl]phenyl}-2-cyclopentylacetyl]-3-methylpyridine-2(1H)-he

[Formula 128]

(1) 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(6-methoxy-5-methylpyridine-2-yl)ethenyl]phenyl}sulfonyl)propan-1-ol was obtained as a colorless oil (148 mg, 88%) by carrying out essentially the same reaction as in example 1-2, except that used 6-[(E)-1-{4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-cyclopentylacetyl]-2-methoxy-3-methylpyridine obtained in example 1-22(1).

(2) Specified in the title compound was obtained as a colorless amorphous substance (31 mg, 72%) by carrying out essentially the same reaction as in example 1-1(2) except that the use�Ali 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(6-methoxy-5-methylpyridine-2-yl)ethenyl]phenyl}sulfonyl)propan-1-ol.

1H NMR (300 MHz, CDCl3) δ M. D. 1,38-of 1.88 (m, 8H), 2,01-of 2.16 (m, 5H), 2,25-of 2.44 (m, 1H), 3,58-3,66 (m, 2H), 3,81 (t, J=5,9 Hz, 2H), to 5.62 (d, J=7,0 Hz, 1H), 6,47 (d, J=10.3 Hz, 1H), 7,13-of 7.19 (m, 1H), 7,32 (DD, J=8,1, 1.6 Hz, 1H), 7,41 (d, J=1.6 Hz, 1H), 8,16 (d, J=8,1 Hz, 1H).

MS(+): 436 [M+H]+.

Example 1-24

6-[(E)-1-(3-Chloro-4-{[3-(diethylamino)propyl]sulfanyl}phenyl)-2-cyclopentylacetyl]-3-methylpyridine-2(1H)-he

[Formula 129]

(1) Triethylamine (148 ml), trimethylamine hydrochloride (50 mg) and 4-methylbenzenesulfonate (74 mg) were successively added to a solution of 6-[(E)-1-{3-chloro-4-[(3-hydroxypropyl)sulfanyl]phenyl}-2-cyclopentylacetyl]-3-methylpyridine-2(1H)-she obtained in example 1-22 (143 mg) in chloroform (5 ml) under cooling with ice and the mixture was stirred at room temperature for one hour. Was added to the reaction solution of water and N,N-dimethylethylenediamine, followed by extraction with chloroform. The organic layer was washed sequentially with 1 M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=9:1→1:1) to give 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-methyl-6-oxo-1,6-dihydropyridine-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (33 mg, 18%) as a colorless amorphous substance.

(2) potassium Carbonate (290 mg) and diethylamine (219 μl) were successively added to a solution of 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-methyl-6-oxo-1,6-dihydropyridine-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (33 mg) in acetonitrile (3 ml) and the mixture was stirred at 90°C for two hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→9:1) obtaining specified in the title compound (18 mg, 66%) as a colorless amorphous substance.

1H NMR (300 MHz, CDCl3) δ M. D. was 1.04 (t, J=7,2 Hz, 6H), 1,37-to 1.82 (m, 8H), 1,81-of 1.95 (m, 2H), 2,12 (d, J=0.9 Hz, 3H), 2,37-of 2.64 (m, 7H), 3,02 (t, J=7,3 Hz, 2H), 5,70 (d, J=7,0 Hz, 1H), 6,38 (d, J=10.0 Hz, 1H), 7,05 (DD, J=8,1, The 1.7 Hz, 1H), 7,11-7,17 (m, 1H), 7,20 (d, J=1.9 Hz, 1H), 7,29 (d, J=8,2 Hz, 1H).

MS(+): 459 [M+H]+.

Example 1-25

6-[(E)-1-(3-Chloro-4-{[3-(diethylamino)propyl]sulfonyl}phenyl)-2-cyclopentylacetyl]-3-methylpyridine-2(1H)-he

[Formula 130]

Specified in the title compound was obtained as a colorless amorphous substance (19 mg, 16% (three stages)) by carrying out essentially the same reaction as in examples 1-24(1)(2) and 1-1(2) sequentially, except that the ISP�litovali 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(6-methoxy-5-methylpyridine-2-yl)ethenyl]phenyl}sulfonyl)propan-1-ol, obtained in example 1-23(1).

1H NMR (300 MHz, CDCl3) δ M. D. 1,34-1,89 (m, 14H), 2,13 (d, J=0.8 Hz, 3H), 2,27-2,71 (m, 3H), 3,09-of 3.43 (m, 6H), 3,62 (t, J=6,2 Hz, 2H), 5,63-of 5.72 (m, 1H), 6,38 (d, J=10.1 Hz, 1H), made 7.16 interest-7,22 (m, 1H), 7,35 (DD, J=8,1, 1.6 Hz, 1H), The 7.43 (d, J=1.6 Hz, 1H), 8,14 (d, J=8,1 Hz, 1H).

MS(+): 491 [M+H]+.

Example 1-26

6-[(E)-1-(3-Chloro-4-{[3-(diethylamino)propyl]sulfanyl}phenyl)- 2-cyclopentylacetyl]-3-ethylpyridine-2(1H)-he

[Formula 131]

(1) 6-[(E)-1-{4-[(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-cyclopentylacetyl]-3-ethyl-2-methoxypyridine was obtained as a colorless oil (273 mg, 37%) by carrying out essentially the same reaction as in example 1-1(1), except use {4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}(5-ethyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-48.

(2) 3-({2-Chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfanyl)propan-1-ol was obtained as a colorless oil (195 mg, 86%) by carrying out essentially the same reaction as in example 1-16(2), except that used 6-[(E)-1-{4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-cyclopentylacetyl]-3-ethyl-2-methoxypyridine.

(3) Triethylamine (87 ml), trimethylamine hydrochloride (20 mg) and 4-methylbenzenesulfonamide (60 mg) were successively added to a solution of 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-FL�l-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfanyl)propan-1-ol (95 mg) in chloroform (2 ml) under cooling with ice and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure solvent obtaining 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (120 mg) as a yellow amorphous substance.

(4) potassium Carbonate (290 mg) and diethylamine (219 μl) were successively added to a solution of 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (120 mg) in acetonitrile (3 ml) and the mixture was stirred at 90°C for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→9:1) to give 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfanyl)-N,N-diethylpropane-1-amine (110 mg, 80%) as a colorless oil.

(5) Specified in the title compound was obtained as colorless powder (45 mg) by carrying out essentially the same reaction as in example 1-1(2), W� except that used 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfanyl)-N,N-diethylpropane-1-amine.

1H NMR (300 MHz, CDCl3) δ M. D. was 1.04 (t, J=7,2 Hz, 6H), 1.14 in-1,23 (m, 3H), 1,33-of 1.97 (m, 12H), 2,31-of 2.68 (m, 7H), 2,93-3,13 (m, 2H), 5.78% was established (d, J=7,2 Hz, 1H), for 6.24 (d, J=10.1 Hz, 1H), to 7.04 (DD, J=8,1, a 1.9 Hz, 1H), 7,10-7,15 (m, 1H), Of 7.19 (d, J=the 1.7 Hz, 1H), 7,29 (d, J=8,1 Hz, 1H), 9,67-of 9.89 (user.s, 1H).

MS(+): 473 [M+H]+.

Example 1-27

6-[(E)-1-(3-Chloro-4-{[3-(diethylamino)propyl]sulfonyl}phenyl)-2-cyclopentylacetyl]-3-ethylpyridine-2(1H)-he

[Formula 132]

(1) 3-({2-Chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfonyl)propan-1-ol was obtained as a colorless amorphous substance (82 mg, 66%) by carrying out essentially the same reaction as in example 1-2, except that used 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfanyl)propan-1-ol obtained in example 1-26(2).

(2) Specified in the title compound was obtained as a colorless amorphous substance (40 mg) by carrying out essentially the same reaction as in example 1-26(3) to(5), except that used 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfonyl)propan-1-ol.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.91 and 1.05 (m, 6H), of 1.18 (t, J=7.5 Hz, 3H), 1,37-of 2.06 (m, 10H), 2,22-2,63 (m, 9H), 3,40-3,62 (m, 2H), 5,61 (d, J=7,0 Hz, 1H), gold 6.43 (d, J=10.3 Hz, 1H), 7,12 (d, J=7,8 Hz, 1H), 7,31 (DD, J=8,1, 1.6 Hz,1H), 7,40 (d, J=1.6 Hz, 1H), 8,16 (d, J=8,1 Hz, 1H).

MS(+): 505 [M+H]+.

Example 1-28

6-{(E)-2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 133]

Specified in the title compound was obtained as colorless powder (57 mg, 14% (three stages)) by carrying out essentially the same reaction as in examples 1-1(1), 1-2 and 1-1(2) sequentially except that used [6-methoxy-5-(trifluoromethyl)pyridin-2-yl][4-(methylsulfanyl)phenyl]methanon obtained in reference example 1-67.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.43 to 1.63 (m, 4H), 1,67-to 1.87 (m, 4H), 2,16-of 2.45 (m, 1H), 3,14 (s, 3H), 5,73 (d, J=7.5 Hz, 1H), about 6,82 (d, J=10.1 Hz, 1H), of 7.42 (d, J=8,5 Hz, 2H), 7,65 (d, J=7.5 Hz, 1H), 8,02 (d, J=8,5 Hz, 2H), 11,89-12,21 (user.s, 1H).

MS(+): 412 [M+H]+.

Example 1-29

6-{(E)-2-Cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]ethenyl}-3-vinylpyridin-2(1H)-he

[Formula 134]

Specified in the title compound was obtained as colorless powder (130 mg, 38% (two steps)) by carrying out essentially the same reaction as in example 1-1, except that used [4-(cyclopropanesulfonyl)phenyl](6-methoxy-5-vinylpyridin-2-yl)methanon obtained in reference example 1-78.

1H NMR (300 MHz, CDCl3) δ M. D. 0,70-0,80 (m, 2H), 1,05-1,20 (m, 2H), 1,20-of 1.84 (m, 8H), 2,15-of 2.30 (m, 1H), 2,36-of 2.54 (m, 1H), 6,01 (d, J=7,3 Hz, 1H), 6,29 (d, J=9.9 Hz, 1H), 7,12 (d, J=7.9 Hz, 2H), 7,32 (d, J=6,6 Hz, 1H, 7,35-7,50 (m, 5H), of 7.70 (d, J=8,3 Hz, 2H), 9,70-10,00 (user.s, 1H).

MS(+): 414 [M+H]+.

Example 1-30

6-{(E)-2-Cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]ethenyl}-3-(gidroximetil)pyridin-2(1H)-he

[Formula 135]

Specified in the title compound was obtained as colorless powder (18 mg) by carrying out essentially the same reaction as in examples 1-1(1), 1-16(2), 1-2 and 1-1(2) sequentially except that used [5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxypyridine-2-yl][4-(cyclopropanesulfonyl)phenyl]methanon obtained in reference example 1-77.

1H NMR (300 MHz, CDCl3) δ M. D. 0,98-1,22 (m, 2H), 1,34-of 1.64 (m, 6H), 1,68-1,90 (m, 4H), 2,29-2,47 (m, 1H), 2,49-of 2.64 (m, 1H), 3,20-3,47 (user.s, 1H), of 4.44-4,65 (m, 2H), of 5.83 (d, J=7,0 Hz, 1H), 6,40 (d, J=10.1 Hz, 1H), 7,21-7,32 (m, 1H), 7,35-of 7.42 (m, 2H), 7,96 (d, J=8,6 Hz, 2H), 10,43-of 10.67 (user.s, 1H).

MS(+): 400 [M+H]+.

Example 1-31

6-[(E)-2-Cyclopentyl-1-{4-[(1-utilization-3-yl)sulfanyl]phenyl}ethenyl]-3-methylpyridine-2(1H)-he

[Formula 136]

(1) tert-Butyl 3-({4-[(E)-2-cyclopentyl-1-(6-methoxy-5-methylpyridine-2-yl)ethenyl]phenyl}sulfanyl)azetidin-1-carboxylate was obtained as a colorless amorphous substance (505 mg, 33%) by carrying out essentially the same reaction as in example 1-1(1), except that used tert-butyl 3-({4-[(6-methoxy-5-methylpyridine-2-yl)carbonyl]phenyl}sulfanyl)azetidin-1-carboxylate, obtained�tion in reference example 1-42.

(2) 4 M hydrochloric acid (4 ml, solution in 1,4-dioxane) was added to a solution of tert-butyl 3-({4-[(E)-2-cyclopentyl-1-(6-methoxy-5-methylpyridine-2-yl)ethenyl]phenyl}sulfanyl)azetidin-1-carboxylate (156 mg) in diethyl ether (4 ml) and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to obtain crude product containing 6-{(E)-1-[4-(azetidin-3-ylsulphonyl)phenyl]-2-cyclopentylacetyl}-2-methoxy-3-methylpyridine.

(3) 90% acetaldehyde (31 μl) and acetic acid was added to a solution of 6-{(E)-1-[4-(azetidin-3-ylsulphonyl)phenyl]-2-cyclopentylacetyl}-2-methoxy-3-methylpyridine in chloroform (2 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled and triacetoxyborohydride sodium (206 mg) was added, after which the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=100:0→93:7) to give 6-[(E)-2-cyclopentyl-1-{4-[(1-utilization-3-yl)sulfanyl]phenyl}ethenyl]-2-methoxy-3-methylpyridine in view� colorless oil (78 mg, 58%).

(4) Specified in the title compound was obtained as a colorless powder (28 mg) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-[(E)-2-cyclopentyl-1-{4-[(1-utilization-3-yl)sulfanyl]phenyl}ethenyl]-2-methoxy-3-methylpyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 0,97 (t, J=7,2 Hz, 3H), 1,25-of 1.57 (m, 4H), 1,60-of 1.85 (m, 4H), 2,12 (s, 3H), 2,32-of 2.58 (m, 3H), 3,02-3,18 (m, 2H), 3,70-a 3.87 (m, 2H), 3,95-4,10 (m, 1H), 5,82 (d, J=7,0 Hz, 1H), 6,16 (d, J=10.1 Hz, 1H), 7,06-7,11 (m, 2H), 7,12-7,17 (m, 1H), of 7.19-7,24 (m, 2H), 9,31-9,47 (user.s, 1H).

MS(+): 395 [M+H]+.

Example 1-32

6-[(E)-2-Cyclopentyl-1-{4-[(1-utilization-3-yl)sulfonyl]phenyl}ethenyl]-3-methylpyridine-2(1H)-he

[Formula 137]

(1) tert-Butyl 3-({4-[(E)-2-cyclopentyl-1-(6-methoxy-5-methylpyridine-2-yl)ethenyl]phenyl}sulfonyl)azetidin-1-carboxylate was obtained as a colorless amorphous substance (240 mg, 68%) by carrying out essentially the same reaction as in example 1-2, except that used tert-butyl 3-({4-[(E)-2-cyclopentyl-1-(6-methoxy-5-methylpyridine-2-yl)ethenyl]phenyl}sulfanyl)azetidin-1-carboxylate obtained in example 1-31(1).

(2) Specified in the title compound was obtained as a colorless amorphous substance (103 mg, 48% (three stages)) by carrying out essentially the same reaction as in example 1-31(2) to(4), except that used tert-butyl 3-({4-[(E)-2-cyclopentyl-1-(6-methoxy-5-meth�pyridin-2-yl)ethenyl]phenyl}sulfonyl)azetidin-1-carboxylate.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.95 (t, J=7,2 Hz, 3H), 1,38-1,59 (m, 4H), 1,62-of 1.84 (m, 4H), 2,12 (s, 3H), 2,23-of 2.42 (m, 1H), 2,47-2,61 (m, 2H), 3,41-3,68 (m, 4H), of 3.91-4,19 (m, 1H), 5,59 (d, J=7,2 Hz, 1H), 6,44 (d, J=10.1 Hz, 1H), 7,08-7,20 (m, 1H), 7,34-of 7.48 (m, 2H), 7,82-7,98 (m, 2H), 10,54-10,81 (user.s, 1H).

MS(+): 427 [M+H]+.

Example 1-33

Methyl 4-[(E)-2-cyclopentyl-1-(5-methyl-6-oxo-1,6-dihydropyridine-2-yl)ethenyl]benzoate

[Formula 138]

(1) 6-{(E)-2-Cyclopentyl-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]ethenyl}-2-methoxy-3-methylpyridine was obtained as a colorless oil (400 mg, 67%) by carrying out essentially the same reaction as in example 1-1(1), except that used [4-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon obtained in reference example 1-44.

(2) 48% bromoethanol acid (1 ml) was added to a solution of 6-{(E)-2-cyclopentyl-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]ethenyl}-2-methoxy-3-methylpyridine (80 mg) in acetonitrile (1 ml) and the mixture was stirred at 100°C for two hours and concentrated under reduced pressure. The residue was dissolved in methanol (1 ml) was added 4 M hydrochloric acid (2 ml), after which the mixture was stirred at 90°C for four hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous alpacamania and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:1) obtaining specified in the title compound as colorless powder (15 mg, 21%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,31-1,62 (m, 4H), 1,64-of 1.86 (m, 4H), 2,12 (s, 3H), 2,28-2,52 (m, 1H), 3,95 (s, 3H), of 5.68 (d, J=7,0 Hz, 1H), of 6.26 (d, J=10.0 Hz, 1H), 7,13 (DD, J=7,0, 1,1 Hz, 1H), 7,22-7,38 (m, 2H), 8,00-8,13 (m, 2H)That 9,49-for 9.88 (user.s, 1H).

MS(+): 338 [M+H]+.

Example 1-34

6-{(E)-2-Cyclopentyl-1-[6-(methylsulfanyl)pyridin-3-yl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 139]

Specified in the title compound was obtained as colorless powder (110 mg, 16% (two steps)) by carrying out essentially the same reaction as in example 1-1, except that used 6-methoxy-5-methylpyridine-2-yl)[6-(methylsulfanyl)pyridin-3-yl]methanon obtained in reference example 1-45.

1H NMR (300 MHz, CDCl3) δ M. D. 1,29-of 1.64 (m, 4H), 1,67-1,89 (m, 4H), 2,12 (s, 3H), 2,30-of 2.54 (m, 1H), 2,61 (s, 3H), of 5.68 (d, J=7,0 Hz, 1H), 6,36 (d, J=9.9 Hz, 1H), 7,13 (d, J=8,2 Hz, 1H), of 7.19-7,25 (m, 1H), 7,28-value of 7, 37 (m, 1H), 8,30 (d, J=3.0 Hz, 1H), 10,24-10,55 (user.s, 1H).

MS(+): 327 [M+H]+.

Example 1-35

6-{(E)-2-Cyclopentyl-1-[6-(methyl-sulfonyl)pyridin-3-yl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 140]

Specified in the title compound was obtained as colorless powder (52 mg, 50%) holding p� basically the same reaction as in example 1-2, except that used 6-{(E)-2-cyclopentyl-1-[6-(methylsulfanyl)pyridin-3-yl]ethenyl}-3-methylpyridine-2(1H)-he obtained in example 1-34.

1H NMR (300 MHz, CDCl3) δ M. D. 1,44-of 1.64 (m, 4H), 1,67-to 1.86 (m, 4H), 2,12 (s, 3H), 2,23-of 2.45 (m, 1H), 3,30 (s, 3H), 5,52 (d, J=7,1 Hz, 1H), to 6.67 (d, J=10.3 Hz, 1H), 7,14 (DD, J=7,1, of 1.2 Hz, 1H), 7,82 (DD, J=8,0, and 2.1 Hz, 1H), 8,08-8,18 (m, 1H), of 8.56 is 8.62 (m, 1H), 11,65-11,82 (user.s, 1H).

MS(+): 359 [M+H]+.

Example 1-36

6-{(1E)-3-Cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]prop-1-EN-1-yl}-3-methylpyridine-2(1H)-he

[Formula 141]

(1) 6-{(1E)-3-Cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]prop-1-EN-1-yl}-2-methoxy-3-methylpyridine was obtained as a colorless oil (564 mg, 44%) by carrying out essentially the same reaction as in example 1-1(1), except that used the (2-cyclopentylmethyl)(triphenyl)phosphonium iodide instead (cyclopentylmethyl)triphenylphosphite and used [4-(cyclopropanesulfonyl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon obtained in reference example 1-37.

(2) Specified in the title compound was obtained as colorless powder (81 mg, 84%) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-{(1E)-3-cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]prop-1-EN-1-yl}-2-methoxy-3-methylpyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 0,70-0,78 (m, 2H), 1,01-1,19 (m, 4H), 1.41 to 1.65 m, 4H), 1,71-to 1.86 (m, 2H), 1,87 is 2.01 (m, 1H), 2,04 and 2.26 (m, 6H), 5,79 (d, J=7,2 Hz, 1H), 6,48 (t, J=7,3 Hz, 1H), 7,03-7,11 (m, 2H), 7,14-7,20 (m, 1H), to 7.33-7,41 (m, 2H).

MS(+): 366 [M+H]+.

Example 1-37

6-{(1E)-3-Cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]prop-1-EN-1-yl}-3-methylpyridine-2(1H)-he

[Formula 142]

Specified in the title compound was obtained as colorless powder (52 mg, 50%) by carrying out essentially the same reaction as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(1E)-3-cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]prop-1-EN-1-yl}-2-methoxy-3-methylpyridine obtained in example 1-36(1).

1H NMR (300 MHz, CDCl3) δ M. D. 0,99-of 1.16 (m, 4H) 1,37-of 1.46 (m, 2H) 1,47-1,59 (m, 4H) 1,69-of 1.85 (m, 2H) 1,92-1,98 (m, 1H) 2,03-2,11 (m, 2H) 2,12 (s, 3H) 2,54 (TT, J=8,0, 4,8 Hz, 1H) 5,69 (d, J=7,0 Hz, 1H) 6,55 (t, J=7.5 Hz, 1H) 7,15 (DD, J=7,1, of 1.2 Hz, 1H) 7,32-the 7.43 (m, 2H) 7,90-7,99 (m, 2H) 10,35-10,56 (user.s, 1H).

Example 1-38

6-{(E)-2-Cyclopentyl-1-[4-(4-hydroxybutyl)phenyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 143]

Specified in the title compound was obtained as white solid (212 mg, 54% (two steps)) by carrying out essentially the same reaction as in example 1-1, except that used [4-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-72.

1H NMR (300 MHz, CDCl3) δ m l 1,20-of 1.95 (m, 12H), 2,36-of 2.58 (m, 1H), 2,70 (t, J=7,4 Hz, 2H), 3,70 (t, J=6.3 Hz, 2H), 5,94 (d, J=7,4 Hz, 1H), 6,56 (d, J=10.1 Hz, 1H), was 7.08 (DD, J=6,6, a 1.8 Hz, 2H), 7,24 (d, J=8,0 Hz, 2H), 7,65 (d, J=7,4 Hz, 1H).

MS(+): 406 [M+H]+.

Example 1-39

6-[(E)-2-Cyclopentyl-1-{4-[4-(diethylamino)butyl]phenyl}ethenyl]-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 144]

Specified in the title compound was obtained as white solid (7.0 mg, 14% (two steps)) by carrying out essentially the same reaction as in example 1-24, except that used 6-{(E)-2-cyclopentyl-1-[4-(4-hydroxybutyl)phenyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he obtained in example 1-38.

1H NMR (300 MHz, CDCl3) δ M. D. 1,19 (t, J=7,0 Hz, 6H), 1,30-of 1.88 (m, 14H), 2,36 is 2.55 (m, 1H), 2,56-2,90 (m, 6H), of 6.06 (d, J=7,4 Hz, 1H), to 6.42 (d, J=10.1 Hz, 1H), was 7.08 (d, J=8,0 Hz, 2H), 7,24 (d, J=11.3 Hz, 2H), 7,67 (d, J=8,0 Hz, 1H).

MS(+): 461 [M+H]+.

Example 1-40

6-[(E)-2-Cyclopentyl-1-{4-[(3-hydroxypropyl)sulfonyl]phenyl}ethenyl]-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 145]

Specified in the title compound was obtained as white solid (17 mg, 17% (three stages)) by carrying out essentially the same reaction as in examples 1-1(1), 1-2 and 1-1(2) sequentially except that used {4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]phenyl}[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in referential example 1 to 71.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.40 to 1.63 (m, 4H), 1,65-of 1.85 (m, 4H), 2,01 to 2.14 (m, 2H), 2,25-2,45 (m, 1H), 3,32 (t, J=7,1 Hz, 2H), of 3.78 (t, J=6.3 Hz, 2H), of 5.85 (q, j 7,1 Hz, 1H), 6,61 (d, J=8,6 Hz, 1H), 7,41 (d, J=8,0 Hz, 2H), 7,67 (d, J=8,0 Hz, 1H), 8,00 (d, J=8,3 Hz, 2H).

MS(+): 456 [M+H]+.

Example 1-41

6-[(E)-2-Cyclopentyl-1-(4-{[3-(diethylamino)propyl]sulfonyl}phenyl)ethenyl]-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 146]

Specified in the title compound was obtained as white solid (51 mg, 15% (five stages)) by carrying out essentially the same reaction as in examples 1-1(1), 1-2, 1-24 and 1-1(2) sequentially except that used {4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]phenyl}[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon, obtained in reference example 1 to 71.

1H NMR (300 MHz, CDCl3) δ M. D. 0,85-1,15 (m, 6H), 1,30-of 1.74 (m, 8H), 1,75-2,10 (m, 2H), 2,21-2,70 (m, 7H), 3,25 (t, J=7,7 Hz, 2H), 5,73 (d, J=7,4 Hz, 1H), 6,76 (d, J=10.1 Hz, 1H), 7,40 (d, J=8,3 Hz, 2H), 7,65 (d, J=8,3 Hz, 1H), 7,98 (d, J=8,3 Hz, 2H).

MS(+): 511 [M+H]+.

Example 1-42

6-[(E)-2-Cyclopentyl-1-{4-[4-(diethylamino)butanoyl]phenyl}ethenyl]-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 147]

Specified in the title compound was obtained as a colorless solid (28 mg, 11% (two steps)) by carrying out essentially the same reaction as in example 1-1, except that used(4-{2-[3-(diethylamino)propyl]-,3-dioxolan-2-yl}phenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon, obtained in reference example 1-75.

1H NMR (300 MHz, CDCl3) δ M. D. 1,40-1,80 (m, 14H) 2,25-2,46 (m, 3H) 3,07-3,26 (m, 6H) 3,30 (t, J=6,6 Hz, 2H) 5,85 (d, J=7,7 Hz, 1H) to 6.57 (d, J=10.1 Hz, 1H) 7,31 (d, J=8,0 Hz, 2H) of 7.64 (d, J=7,7 Hz, 1H) 8,04 (d, J=8,0 Hz, 2H) 10,28-10,81 (user.s, 1H)

MS(+): 475 [M+H]+.

Example 1-43

6-[(E)-2-Cyclopentyl-1-(4-{[3-(diethylamino)propyl]amino}phenyl)ethenyl]-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 148]

(1) 4-{(E)-2-Cyclopentyl-1-[6-methoxy-5-(triptoreline)-2-yl]ethenyl}phenol (256 mg, 63% (two steps)) was obtained by carrying out essentially the same reaction as in example 1-16(1) and (2), except that used 4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-74.

(2) Triftormetilfullerenov anhydride (0,035 ml) and pyridine (0,017 ml) were successively added to a solution of 4-{(E)-2-cyclopentyl-1-[6-methoxy-5-(triptoreline)-2-yl]ethenyl}phenol (50 mg) in methylene chloride (4 ml) under cooling with ice, followed by stirring at room temperature. Another added triftormetilfullerenov anhydride (0.07 ml) and pyridine (0,034 ml). The mixture was stirred for 90 minutes total. Separately sequentially added triftormetilfullerenov anhydride (0,241 ml) and pyridine (0,115 ml) to a solution of 4-{(E)-2-cyclopentyl-1-[6-methoxy-5-(triptoreline)-2-yl]ethenyl}phenol (130 mg) in methylene�loride (made 7.16 interest ml) under cooling with ice and the mixture was stirred under cooling with ice for five minutes. Another added triftormetilfullerenov anhydride (0.6 ml) under cooling with ice and the mixture was stirred at room temperature for another four hours. Added water corresponding to the reaction solution, followed by extraction with chloroform. The organic layers were dried over anhydrous sodium sulfate and filtered. Then evaporated under reduced pressure the solvent. The resulting residue were combined and purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1→30:1) to give 4-{(E)-2-cyclopentyl-1-[6-methoxy-5-(triptoreline)-2-yl]ethenyl}phenyl triftormetilfullerenov (243 mg, 99%).

(3) cesium Carbonate (30 mg), (2-biphenyl)dicyclohexylphosphino (4.3 mg) and palladium acetate (3 mg) were successively added to a solution of 4-{(E)-2-cyclopentyl-1-[6-methoxy-5-(triptoreline)-2-yl]ethenyl}phenyl triftormetilfullerenov (30 mg) and 3-(diethylamino)Propylamine (0,012 ml) in toluene (3 ml) at room temperature in an argon atmosphere and the mixture was stirred at 110°C for three hours. The reaction solution was adjusted again to room temperature and was added tert-butoxide sodium (3.0 mg) in an argon atmosphere, after which the mixture was stirred at 110°C for one hour. The reaction solution was adjusted again to room temperature and evaporated under reduced pressure the solvent. The obtained residue was purified chromatog�afia on a column of silica gel (chloroform:methanol=100:0→10:1) to give N'-(4-{(E)-2-cyclopentyl-1-[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]ethenyl}phenyl)-N,N-diethylpropane-1,3-diamine (16 mg, 57%).

(4) Specified in the title compound was obtained as white solid (9.2 mg, 40%) by carrying out essentially the same reaction as in example 1-1(2) except that used N'-(4-{(E)-2-cyclopentyl-1-[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]ethenyl}phenyl)-N,N-diethylpropane-1,3-diamine.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.31 (t, J=7,2 Hz, 6H), 1,35-of 2.16 (m, 10H), 2,48-of 2.64 (m, 1H), 2,90-3,10 (m, 6H), of 3.32 (t, J=6,2 Hz, 2H), 6,15 (d, J=7.5 Hz, 1H), 6,37 (d, J=9.9 Hz, 1H), only 6.64 (DD, J=6,8, 1,8 Hz, 2H), 6,95 (DD, J=6,6, a 1.8 Hz, 2H), 7,67 (d, J=7.5 Hz, 1H).

MS(+): 462 [M+H]+.

Example 1-44

6-[(E)-1-{3-Chloro-4-[3-(ethylamino)propoxy]phenyl}-2-cyclopentylacetyl]-3-cyclopropylidene-2(1H)-he

[Formula 149]

(1) 6-{(E)-1-[3-Chloro-4-(3-hydroxypropoxy)phenyl]-2-cyclopentylacetyl}-3-cyclopropyl-2-methoxypyridine was obtained as a colorless oil (140 mg, 46% (three stages)) by carrying out essentially the same reaction as in example 1-16(1) to(3), except that used 4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-55, and used 3-bromo-1-propanol instead of methyliodide.

(2) Specified in the title compound was obtained as white solid (66 mg, 46% (three stages)) by carrying out essentially the same reaction as in example 1-26(3) to(5), except that used 6-{(E)-1-[3-chloro-4-(3-hydroxyprop�oxy)phenyl]-2-cyclopentylacetyl}-3-cyclopropyl-2-methoxypyridine and 2 M ethylamine-methanol solution.

1H NMR (300 MHz, DMSO-d6) δ M. D. of 0.50 to 0.61 (m, 2H), 0,72-0,89 (m, 2H), 1,19 (t, J=7,7 Hz, 3H), 1,32-of 1.52 (m, 4H), 1,55-of 1.73 (m, 4H), 1,89-2,02 (m, 1H), 2,10 (t, J=6,0 Hz, 2H), 2,22-to 2.40 (m, 1H), 3,00 (sq, J=7,7 Hz, 2H), 3,11 (t, J=7,4 Hz, 2H), 4,18 (t, J=6,0 Hz, 2H), and 5.30-of 5.45 (m, 1H), 6,41 (d, J=9,2 Hz, 1H), is 6.81 (d, J=7,1 Hz, 1H), was 7.08 (DD, J=8,6, 1.5 Hz, 1H), 7,10-7,22 (m, 2H), to 8.19-8,40 (user.s, 1H), 11,22-11,38 (user.s, 1H).

MS(+): 441 [M+H]+.

Example 1-45

4-[(E)-2-Cyclopentyl-1-(5-cyclopropyl-6-oxo-1,6-dihydropyridine-2-yl)ethenyl]-N-[2-(diethylamino)ethyl]benzamide

[Formula 150]

(1) 6-{(E)-2-Cyclopentyl-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]ethenyl}-3-cyclopropyl-2-methoxypyridine was obtained as yellow oil (136 mg, 46%) by carrying out essentially the same reaction as in example 1-1(1), except that used the (5-cyclopropyl-6-methoxypyridine-2-yl)[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]methanon obtained in reference example 1-59.

(2) 48% bromoethanol acid (4 ml) was added to a solution of 6-{(E)-2-cyclopentyl-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]ethenyl}-3-cyclopropyl-2-methoxypyridine (136 mg) in acetonitrile (4 ml) at room temperature. The mixture was stirred at room temperature for three hours and then stirred at 90°C for three hours. The reaction solution was concentrated under reduced pressure. Was added methanol (2 ml) and 35% hydrochloric acid (2 ml) at room Tempe�the atur and the mixture was stirred at room temperature over night. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. To the obtained crude product was added at room temperature ethanol (6.5 ml) and 1 M sodium hydroxide solution (1.2 ml) and the mixture was stirred at room temperature for another three days. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol=100:0→10:1) to give 4-[(E)-2-cyclopentyl-1-(5-cyclopropyl-6-oxo-1,6-dihydropyridine-2-yl)ethenyl]benzoic acid (100 mg, 88%).

(3) 1-hydroxy-benzotriazole (39 mg), triethylamine (0.04 ml), N,N-diethylethylenediamine (0,061 ml) and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (55 mg) were successively added to a solution of 4-[(E)-2-cyclopentyl-1-(5-cyclopropyl-6-oxo-1,6-dihydropyridine-2-yl)ethenyl]benzoic acid (50 mg) in N,N-dimethylformamide at room temperature and the mixture was stirred at room temperature over night. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The remainder of�imali preparative TLC (chloroform:methanol=20:1) and the obtained solid substance was washed with diethyl ether obtaining specified in the title compound as a white solid (17 mg, 26%).

HPLC: retention time 3,815 min

L-column ODS-a 4.6×250 mm

0.01 M acetate buffer:MeCN=40:60 vol./vol., 40°C, 1.0 ml/min

MS(+): 448 [M+H]+.

Example 1-46

3-Chloro-6-[(E)-2-cyclopentyl-1-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}ethenyl]pyridin-2(1H)-he

[Formula 151]

(1) tert-Butyl 4-({4-[(E)-1-(5-chloro-6-methoxypyridine-2-yl)-2-cyclopentylacetyl]phenyl}sulfonyl)piperazine-1-carboxylate was obtained as a colorless amorphous substance (178 mg, 17%) by carrying out essentially the same reaction as in example 1-1(1), except that used tert-butyl 4-({4-[(5-chloro-6-methoxypyridine-2-yl)carbonyl]phenyl}sulfonyl)piperazine-1-carboxylate obtained in reference example 1-23.

(2) Trifluoroacetic acid (0.2 ml) was added to a solution of tert-butyl 4-({4-[(E)-1-(5-chloro-6-methoxypyridine-2-yl)-2-cyclopentylacetyl]phenyl}sulfonyl)piperazine-1-carboxylate (178 mg) in chloroform (3 ml) and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure to obtain 1-({4-[(E)-1-(5-chloro-6-methoxypyridine-2-yl)-2-cyclopentylacetyl]phenyl}sulfonyl)piperazine in the form of a crude product.

(3) 1-({4-[((E)-1-(5-Chloro-6-methoxypyridine-2-yl)-2-cyclopentylacetyl]phenyl}sulfonyl)-4-methylpiperazine was obtained as a colorless amorphous substance (154 mg, 99%) by carrying out essentially the same �eacli, as in example 1-31(3), except that used a 37% solution of formaldehyde instead of acetaldehyde and used 1-({4-[(E)-1-(5-chloro-6-methoxypyridine-2-yl)-2-cyclopentylacetyl]phenyl}sulfonyl)piperazine.

(4) Specified in the title compound was obtained as colorless powder (66 mg, 44%) by carrying out essentially the same reaction as in example 1-1(2), except that used 1-({4-[(E)-1-(5-chloro-6-methoxypyridine-2-yl)-2-cyclopentylacetyl]phenyl}sulfonyl)-4-methylpiperazine.

1H NMR (300 MHz, CDCl3) δ M. D. 1,40-of 1.66 (m, 4H), 1,69-of 1.88 (m, 4H), 2,23-of 2.42 (m, 4H), 2,47-2,60 (m, 4H), 2,99-3,26 (m, 4H), 5,59 (d, J=7,6 Hz, 1H), 6,47 (d, J=10.3 Hz, 1H), 7,32-7,41 (m, 2H), 7,45 (d, J=7,6 Hz, 1H), 7,71-7,86 (m, 2H), at 10.64-10,98 (user.s, 1H)

MS(+): 462 [M+H]+.

Example 1-47

3-Dihydro-6-[(E)-1-[4-(methylsulfanyl)phenyl]-2-(tetrahydrofuran-3-yl)ethenyl]pyridin-2(1H)-he

[Formula 152]

(1) 1 M solution hexamethyldisilazide lithium in tetrahydrofuran (5,14 ml) was added to a solution of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole obtained in reference example 3-6 (1.51 g) in tetrahydrofuran (15 ml) in a stream of gaseous nitrogen at -78°C and the mixture was stirred at -78°C for one hour. Added a solution of (5-cyclopropyl-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanone obtained in reference example 1-51 (700 mg) in tetrahydrofuran (10 ml) and the mixture was stirred �ri a temperature in the range from -78°C to 0°C for one hour. The reaction solution was poured into a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→7:3) to give 3-cyclopropyl-2-methoxy-6-[(E)-1-[4-(methylsulfanyl)phenyl]-2-(tetrahydrofuran-3-yl)ethenyl]pyridine (122 mg, 14%) as a colorless oil.

(2) Specified in the title compound was obtained as colorless powder (25 mg) by carrying out essentially the same reaction as in example 1-1(2), except that used 3-dihydro-2-methoxy-6-[(E)-1-[4-(methylsulfanyl)phenyl]-2-(tetrahydrofuran-3-yl)ethenyl]pyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 0,54-to 0.67 (m, 2H) 0,86-of 1.03 (m, 2H), 1,77-of 1.93 (m, 1H), 1,96-of 2.20 (m, 2H), 2,53 (s, 3H), 2,77-2,98 (m, 1H), 3,52-3,63 (m, 1H), 3,66-3,99 (m, 3H), of 5.81 (d, J=7,3 Hz, 1H), 6.32 per (d, J=9.9 Hz, 1H), Is 6.81 (d, J=7,3 Hz, 1H), 7,02-7,13 (m, 2H), 7.23 percent-to 7.33 (m, 2H), 10,23-10,40 (user.s, 1H).

MS(+): 354 [M+H]+.

Example 1-48

6-{(E)-1-[4-(Cyclopropanesulfonyl)phenyl]-2-(tetrahydrofuran-3-yl)ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 153]

Specified in the title compound was obtained as colorless powder (37 mg) conducting essentially �aka the same reaction as in example 1-47, except that used [4-(cyclopropanesulfonyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-68.

1H NMR (300 MHz, CDCl3) δ M. D. 0,66-0,83 (m, 2H), 1,06-to 1.21 (m, 2H), 1,82-to 2.13 (m, 2H), 2,14-of 2.30 (m, 1H), 2,78-3,02 (m, 1H) and 3.59 (t, J=8,2 Hz, 1H), 3,69-4,07 (m, 3H), 5,94 (d, J=7.5 Hz, 1H), 6,66 (d, J=9.8 Hz, 1H), 7,04-7,15 (m, 2H), 7,35-of 7.48 (m, 2H), 7,61-7,74 (m, 1H), 11,43-11,68 (user.s, 1H).

MS(+): 408 [M+H]+.

Example 1-49

3-Cyclopropyl-6-{(1E)-1-[4-(methylsulfanyl)phenyl]-3-(tetrahydrofuran-3-yl)prop-1-EN-1-yl}pyridin-2(1H)-he

[Formula 154]

Specified in the title compound was obtained as colorless powder (36 mg) by carrying out essentially the same reaction as in example 1-47, except that used 1-phenyl-5-{[2-(tetrahydrofuran-3-yl)ethyl]sulfonyl}-1H-tetrazole obtained in reference example 3-8.

1H NMR (300 MHz, CDCl3) δ M. D. vary between 0.52 to 0.67 (m, 2H), 0,82-of 1.04 (m, 2H), 1,37-1,58 (m, 1H), 1,97-to 2.14 (m, 2H), 2,15-of 2.24 (m, 2H), 2.26 and-2,39 (m, 1H), 2,52 (s, 3H), 3,25-3,39 (m, 1H), 3,63-of 3.91 (m, 3H), 5,86 (d, J=7,1 Hz, 1H), for 6.24 (t, J=7,3 Hz, 1H), 6,83 (d, J=7,3 Hz, 1H), 7,02-7,12 (m, 2H), 7.23 percent-7,32 (m, 2H), 9,24-9,45 (user.s, 1H).

MS(+): 368 [M+H]+.

Example 1-50

6-[(1E)-1-(3-Chloro-4-methoxyphenyl)-3-(tetrahydrofuran-2-yl)prop-1-EN-1-yl]-3-cyclopropylidene-2(1H)-he

[Formula 155]

Specified in the title compound was obtained as colorless powder (6.7 mg) conducting �about basically the same reaction as in examples 1-47(1) and 1-16(2)-(4) sequentially, except that used 1-phenyl-5-{[2-(tetrahydrofuran-2-yl)ethyl]sulfonyl}-1H-tetrazole obtained in reference example 3-7 instead of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole and used (4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-55.

1H NMR (300 MHz, CDCl3) δ M. D. from 0.54 to 0.69 (m, 2H), 0,86-1,02 (m, 2H), 1,35-of 1.52 (m, 1H), 1,79-of 2.16 (m, 4H), 2,24-2,41 (m, 2H), 3,66-with 3.79 (m, 1H), 3,80-4,00 (m, 5H), 5,87 (d, J=7,2 Hz, 1H), 6,30 (t, J=7.5 Hz, 1H), about 6,82 (d, J=7,3 Hz, 1H), 6,91-of 6.99 (m, 1H), 7,02-7,10 (m, 1H), 7,22 (d, J=2,2 Hz, 1H), 9,01-9,27 (user.s, 1H).

MS(+): 386 [M+H]+.

Example 1-51

3-Dihydro-6-[(E)-1-(4-methoxyphenyl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridin-2(1H)-he

[Formula 156]

Specified in the title compound was obtained as colorless powder (51 mg) by carrying out essentially the same reaction as in example 1-16(1) to(4), except that used triphenyl(tetrahydro-2H-Piran-4-ylmethyl)phosphonite (described in J. Med. Chem., 51(14), 2008, 4340-4345) instead (cyclopentylmethyl)triphenylphosphite and used (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-54.

1H NMR (300 MHz, CDCl3) δ M. D. 0,53-to 0.67 (m, 2H), of 0.88 to 0.99 (m, 2H), 1,40-1,71 (m, 4H), 2,03-2,17 (m, 1H), 2,25-2,43 (m, 1H), 3,17-3,7 (m, 2H), 3,86 (s, 3H), a 3.87-3,94 (m, 2H), of 5.85 (d, J=7,3 Hz, 1H), 6,10 (d, J=9.8 Hz, 1H), 6.75 in-6,86 (m, 1H), 6,89-of 6.99 (m, 2H), 7,03-7,13 (m, 2H), 9,53-9,71 (user.s, 1H).

MS(+): 352 [M+H]+.

Example 1-52

3-Dihydro-6-[(E)-1-(4-ethoxyphenyl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridin-2(1H)-he

[Formula 157]

Specified in the title compound was obtained as a colorless powder (23 mg, (four stages)) by carrying out essentially the same reaction as in example 1-51, except that used ethyliodide instead of methyliodide.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.54 and 0.64 (m, 2H), of 0.88 to 0.99 (m, 2H), 1,46 (t, J=7,0 Hz, 3H), of 1.50 to 1.68 (m, 4H), 2,02-to 2.18 (m, 1H), 2.26 and-of 2.45 (m, 1H), 3,18-3,36 (m, 2H), 3,83-3,98 (m, 2H), 4,08 (sq, J=7,0 Hz, 2H), 5,88 (d, J=7,2 Hz, 1H), 6,04 (d, J=9,6 Hz, 1H), about 6,82 (d, J=7.9 Hz, 1H), 6,89-of 6.96 (m, 2H), 7,02-to 7.09 (m, 2H), 9,24-9,39 (user.s, 1H).

MS(+): 366 [M+H]+.

Example 1-53

6-[(E)-1-(3-Chloro-4-methoxyphenyl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]-3-cyclopropylidene-2(1H)-he

[Formula 158]

(1) 6-[(E)-1-(4-{[tert-Butyl(dimethyl)silyl]oxy}-3-chlorophenyl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]-3-cyclopropyl-2-methoxypyridine was obtained as a colorless powder (400 mg, 41%) by carrying out essentially the same reaction as in example 1-1(1), except she used triphenyl(tetrahydro-2H-Piran-4-ylmethyl)phosphonite instead (cyclopentylmethyl)triphenylphosphite and used (4-{[tert-butyl(dimethyl)silyl]ACS�}-3-chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon, obtained in reference example 1-55.

(2) 4-[(E)-1-(5-Cyclopropyl-6-methoxypyridine-2-yl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]phenol was obtained as a yellow amorphous substance (300 mg, 97%) by carrying out essentially the same reaction as in example 1-16(2), except that used 6-[(E)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]-3-cyclopropyl-2-methoxypyridine.

(3) the Crude product containing 3-dihydro-2-methoxy-6-[(E)-1-(4-methoxyphenyl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridine (134 mg), were obtained by carrying out essentially the same reaction as in example 1-16(3), except that used 4-[(E)-1-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]phenol.

(4) Specified in the title compound was obtained as a colorless powder (56 mg, 43%) by carrying out essentially the same reaction as in example 1-16(4), except that used 3-dihydro-2-methoxy-6-[(E)-1-(4-methoxyphenyl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 0,51-of 0.71 (m, 2H), of 0.95 (dt, J=10,6, a 4.3 Hz, 2H), 1,40-1,80 (m, 4H), of 2.00-2.20 (m, 1H), 2,23-of 2.45 (m, 1H), 3,14-of 3.42 (m, 2H), a 3.87-3,95 (m, 2H), 3,96 (s, 3H), 5.78% was established (d, J=7,2 Hz, 1H), 6,14 (d, J=9,8 Hz, 1H), 6,73-6,86 (m, 1H), at 6.92-was 7.08 (m, 2H), 7,17 (d, J=2,0 Hz, 1H), 9.66 as per-9,95 (user.s, 1H).

MS(+): 386 [M+H]+.

Example 1-54

6-[(E)-1-(3-Chloro-4-methoxyphenyl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]-3-(trifluoromethyl)pyridin-2(1H)he

[Formula 159]

Specified in the title compound was obtained as white solid (6.7 mg, 21% (two steps)) by carrying out essentially the same reaction as in examples 1-53(1) and 1-1(2) sequentially, except that used the (3-chloro-4-methoxyphenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-73.

1H NMR (300 MHz, CDCl3) δ M. D. 1,41-to 1.82 (m, 4H), 2,23-of 2.42 (m, 1H), 3,20-3,36 (m, 2H), 3,88-4,10 (m, 2H), 3,97 (s, 3H), of 5.83 (d, J=7,7 Hz, 1H), 6,61 (d, J=9.8 Hz, 1H), 6,98 (d, J=8,3 Hz, 1H), 7,06 (DD, J=8,6, and 2.1 Hz, 1H), 7,18 (d, J=2.1 Hz, 1H), 7,65 (d, J=7,4 Hz, 1H).

MS(+): 414 [M+H]+.

Example 1-55

6-[(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-(tetrahydro-2H-Piran-4-yl)ethenyl]-3-methylpyridine-2(1H)-he

[Formula 160]

(1) 6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-(tetrahydro-2H-Piran-4-yl)ethenyl}-2-methoxy-3-methylpyridine was obtained as a colorless amorphous substance (400 mg, 35%) by carrying out essentially the same reaction as in example 1-53(1), except that used [3-chloro-4-(methylsulfanyl)phenyl]methoxy-5-methylpyridine-2-ylmethanol obtained in reference example 1-40.

(2) Specified in the title compound was obtained as colorless powder (82 mg, 39%) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-(t�trihydro-2H-Piran-4-yl)ethenyl}-2-methoxy-3-methylpyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 1,40-1,80 (m, 4H), 2,14 (s, 3H), 2,21-2,40 (m, 1H), 2,54 (s, 3H), 3,21-to 3.38 (m, 2H), 3,81 is 4.03 (m, 2H), of 5.72 (d, J=7,0 Hz, 1H), 6,29 (d, J=9.8 Hz, 1H), 7,02-7,10 (m, 1H), 7,11-7.23 percent (m, 3H), 10,53-10.71 in (user.s, 1H).

MS(+): 376 [M+H]+.

Example 1-56

6-{(E)-1-[3-Chloro-4-(methyl-sulfonyl)phenyl]-2-(tetrahydro-2H-Piran-4-yl)ethenyl}-3-methylpyridine-2(1H)-he

[Formula 161]

Specified in the title compound was obtained as colorless powder (86 mg) by carrying out essentially the same reaction as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-(tetrahydro-2H-Piran-4-yl)ethenyl}-2-methoxy-3-methylpyridine obtained in example 1-55(1).

1H NMR (300 MHz, CDCl3) δ M. D. 1,42-1,89 (m, 4H), 2,07-of 2.33 (m, 4H), 3,21-to 3.41 (m, 5H), 3,86 is 4.03 (m, 2H), to 5.58 (d, J=7,0 Hz, 1H), 6,55 (d, J=9.9 Hz, 1H), 7,09-7,20 (m, 1H), to 7.33 (DD, J=8,1, 1.6 Hz, 1H), 7,41 (s, 1H), 8,22 (d, J=8,1 Hz, 1H), 11,63-11,91 (user.s, 1H).

MS(+): 430 [M+Na]+.

Example 1-57

6-[(E)-1-{3-Chloro-4-[3-(diethylamino)propoxy]phenyl}-2-(tetrahydro-2H-Piran-4-yl)ethenyl]-3-cyclopropylidene-2(1H)-he

[Formula 162]

(1) potassium Carbonate (214 mg) and (3 bromopropane)(tert-butyl)dimethylsilane (240 μl) was added to a solution of 2-chloro-4-[(E)-1-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]phenol obtained in example 1-53(2) (200 mg) in N,N-dimethylformamide (4 ml) and the mixture was stirred at 65�C for 1.5 hours and at room temperature over night. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:1) to give 6-{(E)-1-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-3-chlorophenyl]-2-(tetrahydro-2H-Piran-4-yl)ethenyl}-3-cyclopropyl-2-methoxypyridine in the form of a colorless oil (245 mg, 80%).

(2) Specified in the title compound was obtained as colorless powder (60 mg) by carrying out essentially the same reaction as in example 1-26(2) to(5), except that used 6-{(E)-1-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-3-chlorophenyl]-2-(tetrahydro-2H-Piran-4-yl)ethenyl}-3-cyclopropyl-2-methoxypyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 0,55-0,66 (m, 2H), 0,91-1,00 (m, 2H), 1,02-1,10 (m, 6H), 1,42-1,70 (m, 4H), 1,92-2,17 (m, 3H), 2,23-of 2.42 (m, 1H), of 2.57 (q, J=7,2 Hz, 4H), 2,64-to 2.74 (m, 2H), 3,18-3,37 (m, 2H), 3,85-3,99 (m, 2H), 4,07-4,20 (m, 2H), of 5.81 (d, J=7,3 Hz, 1H), of 6.06 (d, J=9.8 Hz, 1H), was 6.77-6,86 (m, 1H), at 6.92-7,05 (m, 2H), 7,15 (d, J=the 1.7 Hz, 1H), 9,26-9,49 (user.s, 1H).

MS(+): 485 [M+H]+.

Example 1-58

3-Cyclopropyl-6-{(E)-1-(4-ethylphenyl)-2-[(1S)-3-oxocyclopentyl]ethenyl}pyridin-2(1H)-he

[Formula 163]

(1) 1 M Solution hexamethyldisilazide lithium in tetrahydrofuran (4.0 ml) was added to races�thief 5-({[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]methyl}sulfonyl)-1-phenyl-1H-tetrazole, obtained in reference example 3-1 (2,01 g) in tetrahydrofuran (20 ml) in a stream of gaseous nitrogen at -78°C and the mixture was stirred at -78°C for one hour. Added a solution of (5-cyclopropyl-6-methoxypyridine-2-yl)(4-ethylphenyl)methanone obtained in reference example 1-53 (700 mg) in tetrahydrofuran (10 ml) and the mixture was stirred at a temperature in the range from -78°C to 0°C for one hour. The reaction solution was poured into a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:chloroform=1:1) to give 3-cyclopropyl-6-[(E)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]-1-(4-ethylphenyl)ethenyl]-2-methoxypyridine in the form of a colorless amorphous substance (270 mg, 24%).

(2) Specified in the title compound was obtained as a colorless powder (56 mg, 33%) by carrying out essentially the same reaction as in example 1-1(2), except that used 3-cyclopropyl-6-[(E)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]-1-(4-ethylphenyl)ethenyl]-2-methoxypyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 0,52-0,66 (m, 2H), 0,83-1,03 (m, 2H), of 1.29 (t, J=7,6 Hz, 3H), 1,75-1,95 (m, 1H), 200-2,25 (m, 4H), 2,27-of 2.44 (m, 2H), 2,70 (sq, J=7.5 Hz, 2H), 2,80-2,99 (m, 1H), of 5.81 (d, J=7,3 Hz, 1H), 6,39 (d, J=9,5 Hz, 1H), is 6.81 (d, J=8,1 Hz, 1H,) to 7.09 (d, J=8,1 Hz, 2H), 7,18-7,32 (m, 2H), is 10.51-10,68 (user.s, 1H).

MS(+): 348 [M+H]+.

Example 1-59

6-{(E)-1-(3-Chloro-4-ethoxyphenyl)-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-ethylpyridine-2(1H)-he

[Formula 164]

(1) 6-{(E)-1-(4-{[tert-Butyl(dimethyl)silyl]oxy}-3-chlorophenyl)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-3-ethyl-2-methoxypyridine was obtained as a colorless powder (250 mg, 37%) by carrying out essentially the same reaction as in example 1-58(1), except that was used (4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-ethyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-50.

(2) Specified in the title compound was obtained as a pale yellow amorphous substance (71 mg, 49% (three stages)) by carrying out essentially the same reaction as in example 1-16(2) to(4), except that used 6-{(E)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-3-ethyl-2-methoxypyridine and used ethyliodide instead of methyliodide.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.16 (t, J=7.5 Hz, 3H), of 1.51 (t, J=6,9 Hz, 3H), 1,80-of 1.98 (m, 1H), 2,02-of 2.27 (m, 3H), 2,30-2,45 (m, 2H), 2,52 (sq, J=7,7 Hz, 2H), 2,78-3,02 (m, 1H), 4,16 (sq, J=7,0 Hz, 2H), 5.78% was established (d, J=7,2 Hz, 1H), Of 6.49 (d, J=9,6 Hz, 1H), at 6.92-6,98 (m, 1H), 7,01-7,06 (m, 1H), 7,14 (d, J=7,2 Hz, 1H), 7,21 (d, J=2,0 Hz, 1H), 10,99-11,22 (user.s, 1H).

p> MS(+): 386 [M+H]+.

Example 1-60

6-{(E)-1-[4-(Cyclopropanesulfonyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 165]

(1) 6-{(E)-1-[4-(Cyclopropanesulfonyl)phenyl]-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-2-methoxy-3-methylpyridine was obtained as a colorless amorphous substance(48 mg, 10%) by carrying out essentially the same reaction as in example 1-58(1) except that used [4-(cyclopropanesulfonyl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon obtained in reference example 1-37.

(2) Specified in the title compound was obtained as colorless powder (18 mg) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-{(E)-1-[4-(cyclopropanesulfonyl)phenyl]-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-2-methoxy-3-methylpyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 0,71-0,81 (m, 2H), 1,07-1,17 (m, 2H), 1,81-of 1.96 (m, 1H), 2,12-of 2.27 (m, 4H), 2,12 (s, 3H), 2,30-2,45 (m, 2H), 2,82-3,00 (m, 1H), of 5.83 (d, J=7,0 Hz, 1H), 6,38 (d, J=9,6 Hz, 1H), 7,10 (d, J=8,5 Hz, 2H)That made 7.16 interest (DD, J=7,1, of 1.2 Hz, 1H), of 7.36-the 7.43 (user.s, 2H).

MS(+): 366 [M+H]+.

Example 1-61

6-{(E)-1-[4-(Cyclopropanesulfonyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 166]

Specified in the title compound was obtained as a colorless powder (28 mg, 31% (two steps)) was conducted�eat essentially the same reaction, as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(E)-1-[4-(cyclopropanesulfonyl)phenyl]-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-2-methoxy-3-methylpyridine obtained in example 1-60(1).

1H NMR (300 MHz, CDCl3) δ M. D. 1,04-1,20 (m, 2H), 1,32-1,49 (m, 2H), of 1.85-2,03 (m, 1H), 2,04-2,22 (m, 5H), 2,23-of 2.46 (m, 3H), 2,49-2,63 (m, 1H), 2,68-of 2.93 (m, 1H), 5,63 (l, J=7,0 Hz, 1H), 6,63 (d, J=9,6 Hz, 1H), 7,10-of 7.19 (m, 1H), 7,35-7,51 (m, 2H), 7,98 (d, J=8.4 Hz, 2H), 11,36-11,72 (user.s, 1H).

MS(+): 398 [M+H]+.

Example 1-62

6-{(E)-1-[4-(Cyclopropanesulfonyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-ethylpyridine-2(1H)-he

[Formula 167]

Specified in the title compound was obtained as colorless powder (62 mg) by carrying out essentially the same reaction as in examples 1-58(1), 1-2 and 1-1(2) sequentially except that used [4-(cyclopropanesulfonyl)phenyl](5-ethyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-49.

1H NMR (300 MHz, CDCl3) δ M. D. 1,01-1,24 (m, 5H), 1,35-is 1.51 (m, 2H), 1,82-2,03 (m, 1H), 2,04-of 2.23 (m, 2H), 2,25-of 2.44 (m, 3H), 2,46-2,63 (m, 3H), of 2.66-2,87 (m, 1H), 5,63 (l, J=7,1 Hz, 1H), 6,73 (d, J=9.8 Hz, 1H), 7,14 (d, J=7,3 Hz, 1H), of 7.42 (d, J=8.4 Hz, 2H), 7,98 (d, J=8.4 Hz, 2H), 11,77-12,05 (user.s, 1H).

MS(+): 412 [M+H]+.

Example 1-63

6-{(E)-1-[4-(Cyclopropanesulfonyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 168]

Specified in zag�lowke compound was obtained as white solid (53 mg, 5% (three stages)) by carrying out essentially the same reaction as in examples 1-58 and 1-2, in sequence, except that used [4-(cyclopropanesulfonyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-68.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.08-1,17 (m, 2H), 1,40-of 1.48 (m, 2H), 1,97-of 2.16 (m, 3H), 2.26 and-of 2.43 (m, 3H), 2,50-2,61 (m, 1H), 2,68-2,83 (m, 1H), of 5.72 (d, J=7.5 Hz, 1H), 7,05 (d, J=9.9 Hz, 1H), 7,41 (d, J=8,2 Hz, 2H), 7,67 (d, J=7.5 Hz, 1H), 8,00 (d, J=8,5 Hz, 2H).

MS(+): 452 [M+H]+.

Example 1-64

6-{(E)-1-[4-(Methylsulfanyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-(propane-2-yl)pyridin-2(1H)-he

[Formula 169]

Specified in the title compound was obtained as colorless powder (54 mg, 6% (two steps)) by carrying out essentially the same reaction as in examples 1-58(1) and 1-1(2) sequentially except that used [6-methoxy-5-(propan-2-yl)pyridin-2-yl][4-(methylsulfanyl)phenyl]methanon obtained in reference example 1-76.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.16 (d, J=6,8 Hz, 6H), 1,76-of 1.96 (m, 1H), 2,01-of 2.24 (m, 3H), 2,27 is 2.43 (m, 2H), 2,53 (s, 3H), 2,76-of 2.97 (m, 1H), 3,05-3,24 (m, 1H), of 5.83 (d, J=7,1 Hz, 1H), gold 6.43 (d, J=9,5 Hz, 1H), 7,05-of 7.19 (m, 3H), 7,22-7,38 (m, 2H), 10,47-10.71 in (user.s, 1H).

MS(+): 368 [M+H]+.

Example 1-65

3-Cyclopropyl-6-{(E)-1-[4-(methylsulfanyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}pyridin-2(1H)-he

[Formula 170]

Specified in the header with�unity was obtained as a colorless powder (83 mg, 14% (two steps)) by carrying out essentially the same reaction as in examples 1-58(1) and 1-1(2) sequentially except that was used (5-cyclopropyl-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanon obtained in reference example 1-51.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.55 and 0.64 (m, 2H), 0,86-0,97 (m, 2H), 1,81-of 1.95 (m, 1H), 2,00-2,25 (m, 4H), 2,27-2,42 (m, 2H), 2,53 (s, 3H), 2,77-of 2.97 (m, 1H), 5.78% was established (d, J=7,3 Hz, 1H), 6,41 (d, J=9,6 Hz, 1H), is 6.81 (DD, J=7,3, 0.6 Hz, 1H), 7,07-7,14 (m, 2H), 7,25-7,32 (m, 2H), 10,62-10,90 (user.s, 1H).

MS(+): 366 [M+H]+.

Example 1-66

3-Cyclopropyl-6-{(E)-1-{4-[3-(diethylamino)propoxy]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}pyridin-2(1H)-he

[Formula 171]

Specified in the title compound was obtained as a brown amorphous substance (18 mg, 8% (five stages)) by carrying out essentially the same reaction as in examples 1-58(1) and 1-26(2) to(5) sequentially, except that used [4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl](5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-56.

1H NMR (300 MHz, CDCl3) δ M. D. 0,52-0,65 (m, 2H), 0,85-to 0.96 (m, 2H), of 1.06 (t, J=7,1 Hz, 6H), 1,75-2,42 (m, 9H), 2,51-of 2.72 (m, 6H), 2,80-2,98 (m, 1H), of 4.05 (t, J=6.3 Hz, 2H), 5.78% was established (d, J=7,2 Hz, 1H), 6,44 (d, J=9,6 Hz, 1H), 6,80 (d, J=7,2 Hz, 1H), 6,93 (d, J=8.4 Hz, 2H), to 7.09 (d, J=to 8.7 Hz, 2H).

MS(+): 449 [M+H]+.

Example 1-67

6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-methylpyridine-2(1H)-on�

[Formula 172]

(1) 6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-2-methoxy-3-methylpyridine was obtained as a colorless amorphous substance (230 mg, 15%) by carrying out essentially the same reaction as in example 1-58(1) except, what used [3-chloro-4-(methylsulfanyl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon obtained in reference example 1-40.

(2) Specified in the title compound was obtained as colorless powder (50 mg, 55%) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-2-methoxy-3-methylpyridine.

1H NMR (600 MHz, CDCl3) δ M. D. 1,79-1,99 (m, 1H), 2,11 (s, 3H), 2,08-of 2.28 (m, 3H), 2,32-2,42 (m, 2H), 2,51 (s, 3H), 2,76-2,99 (m, 1H), 5,69 (d, J=6,9 Hz, 1H), 6,55 (d, J=9,6 Hz, 1H), was 7.08 (d, J=7,8 Hz, 1H), 7,14 (d, J=7,3 Hz, 1H), of 7.19 (s, 2H), 11,51-11,67 (user.s, 1H).

MS(+): 374 [M+H]+.

Example 1-68

6-{(E)-1-[3-Chloro-4-(methyl-sulfonyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 173]

Specified in the title compound was obtained as colorless powder (35 mg, 42% (two steps)) by carrying out essentially the same reaction as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(E)-1-[3-chloro-4-(methyls�lpanel)phenyl]-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-2-methoxy-3-methylpyridine, obtained in example 1-67(1).

1H NMR (600 MHz, CDCl3) δ M. D. 1,90-2,02 (m, 1H), 2,10 (s, 3H), 2,12-of 2.20 (m, 2H), 2,23-2,32 (m, 1H), 2,33-of 2.45 (m, 2H), 2,69-2,83 (m, 1H), 3,34 (s, 3H), to 5.58 (d, J=6,9 Hz, 1H), 6,70 (d, J=9,6 Hz, 1H), 7,15-of 7.19 (m, 1H), to 7.33 (DD, J=8,0, 1.6 Hz, 1H), of 7.42 (d, J=1.4 Hz, 1H), 8,21 (d, J=8,3 Hz, 1H).

MS(+): 406 [M+H]+.

Example 1-69

6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-ethylpyridine-2(1H)-he

[Formula 174]

Specified in the title compound was obtained as colorless powder (49 mg, 26% (two steps)) by carrying out essentially the same reaction as in examples 1-58(1) and 1-1(2) sequentially except that used [3-chloro-4-(methylsulfanyl)phenyl](5-ethyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-46.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.16 (t, J=7.5 Hz, 3H), 1,82-of 1.99 (m, 1H), 2,05-2,45 (m, 5H), 2,46-2,59 (m, 5H), 2,72-2,98 (m, 1H), 5,73 (d, J=7,1 Hz, 1H), to 6.58 (d, J=9,6 Hz, 1H), 7,03-made 7.16 interest (m, 2H), 7,17-7,24 (m, 2H), to 11.35-11,60 (user.s, 1H).

MS(+): 388 [M+H]+.

Example 1-70

6-{(E)-1-[3-Chloro-4-(methyl-sulfonyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-ethylpyridine-2(1H)-he

[Formula 175]

Specified in the title compound was obtained as colorless powder (17 mg, 43%) by carrying out essentially the same reaction as in example 1-2, except that used 6-{(E)- 1-[3-chloro-4-(methylsulfanyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-FL�pyridin-2(1H)-he, obtained in example 1-69.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.16 (t, J=7.5 Hz, 3H), 1,84-2,03 (m, 1H), 2,06-of 2.24 (m, 2H), 2.26 and-of 2.45 (m, 3H), 2,52 (sq, J=7,4 Hz, 2H), 2,65-2,89 (m, 1H), 3,35 (s, 3H), 5,61 (d, J=7,1 Hz, 1H), 6,78 (d, J=9.8 Hz, 1H), 7,15 (d, J=7,1 Hz, 1H), 7,30-7,39 (m, 1H), 7,44 (s, 1H), 8,23 (d, J=8,1 Hz, 1H), 12,01-12,39 (user.s, 1H).

MS(+): 420 [M+H]+.

Example 1 to 71

6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 176]

(1) 6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-3-cyclopropyl-2-methoxypyridine was obtained as a pale yellow powder (610 mg, 40%) by carrying out essentially the same reaction as in example 1-58(1) except, what used [3-chloro-4-(methylsulfanyl)phenyl](5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-52.

(2) Specified in the title compound was obtained as colorless powder (131 mg, 68%) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-3-cyclopropyl-2-methoxypyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 0,51-to 0.67 (m, 2H), 0,84-of 1.05 (m, 2H), 1,81-2,00 (m, 1H), 2,02-of 2.24 (m, 3H), 2,25-of 2.46 (m, 3H), 2,52 (s, 3H), 2,74-of 2.97 (m, 1H), of 5.68 (d, J=7,3 Hz, 1H), 6,61 (d, J=9,6 Hz, 1H), is 6.81 (s, 1H), 7,04-made 7.16 interest (m, 1H), 7,15-7,22 (m, 2H), 11,63-11,95 (user.s, 1H).

MS(+): 400 [M+H] +.

Example 1-72

6-{(E)-1-[3-Chloro-4-(methyl-sulfonyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 177]

Specified in the title compound was obtained as colorless powder (74 mg, 33% (two steps)) by carrying out essentially the same reaction as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-3-cyclopropyl-2-methoxypyridine obtained in example 1 to 71(1).

1H NMR (300 MHz, CDCl3) δ M. D. 0,54-to 0.67 (m, 2H), 0,86-of 1.01 (m, 2H), 1.85 to of 2.23 (m, 4H), of 2.25-2,51 (m, 3H), 2,64-of 2.91 (m, 1H), 3,35 (s, 3H), to 5.57 (d, J=7,1 Hz, 1H), 6,70-6,91 (m, 2H), 7,31-7,38 (m, 1H), 7,43 (d, J=1.6 Hz, 1H), 8,22 (d, J=8,1 Hz, 1H), 12,13-12,38 (m, 1H).

MS(+): 432 [M+H]+.

Example 1-73

6-{(E)-1-{3-Chloro-4-[(3-hydroxypropyl)sulfanyl]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 178]

(1) 6-{(E)-1-{4-[(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-2-methoxy-3-methylpyridine was obtained as a colorless amorphous substance (510 mg, 37%) by carrying out essentially the same reaction, as in example 1-58(1) except that used {4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}(6-methoxy-5-methylpyridine-2-yl)methanon, received� in reference example 1-41.

(2) Specified in the title compound was obtained as a pale yellow powder (10 mg, 19%) by carrying out essentially the same reaction as in example 1-5(2), except that used 6-{(E)-1-{4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-2-methoxy-3-methylpyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 1,81 and 2.26 (m, 10H), 2,29-of 2.45 (m, 2H), 2,77-to 2.94 (m, 1H), 3,13 (t, J=7,2 Hz, 2H), 3,85 (t, J=6,0 Hz, 2H), 5,77 (d, J=7,2 Hz, 1H), gold 6.43 (d, J=9,6 Hz, 1H), 7,06 (DD, J=8,1, a 1.9 Hz, 1H), 7,14-7,20 (m, 1H), 7,21 (d, J=the 1.7 Hz, 1H), to 7.33 (d, J=8,1 Hz, 1H).

MS(+): 418 [M+H]+.

Example 1-74

6-{(E)-1-{3-Chloro-4-[(3-hydroxypropyl)sulfonyl]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 179]

Specified in the title compound was obtained as colorless powder (6.5 mg, 10% (two steps)) by carrying out essentially the same reaction as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(E)-1-{4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-2-methoxy-3-methylpyridine obtained in example 1-73(1).

1H NMR (300 MHz, CDCl3) δ M. D. 1,85-2,48 (m, 11H), 2,68-2,86 (m, 1H), 3,57-to 3.67 (m, 2H), 3,81 (t, J=5,9 Hz, 2H), 5,61 (d, J=7,0 Hz, 1H), 6,72 (d, J=9.8 Hz, 1H), 7,15-of 7.23 percent (m, 1H), 7,31-value of 7, 37 (m, 1H), 7,43 (d, J=1.4 Hz, 1H), To 8.19 (d, J=8,1 Hz, 1H).

MS(+): 450 [M+H]+.

Example 1-75

6-{(E)--{3-Chloro-4-[(3-hydroxypropyl)sulfanyl]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-ethylpyridine-2(1H)-he

[Formula 180]

(1) 6-{(E)-1-{4-[(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-3-ethyl-2-methoxypyridine was obtained as a colorless amorphous substance (570 mg, 39%) by carrying out essentially the same reaction, as in example 1-58(1) except that used {4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}(5-ethyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-48.

(2) Specified in the title compound was obtained as a pale yellow powder (24 mg, 42%) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-{(E)-1-{4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-3-ethyl-2-methoxypyridine.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.16 (t, J=7.5 Hz, 3H), of 1.80 and 2.26 (m, 6H), 2,28-of 2.44 (m, 2H), 2,46-2,59 (m, 2H), 2,76-2,95 (m, 1H), 3,13 (t, J=7,2 Hz, 2H), 3,85 (t, J=6,0 Hz, 2H), 5,79 (d, J=7,2 Hz, 1H), 6,47 (d, J=9.8 Hz, 1H), 7,06 (DD, J=8,1, a 1.9 Hz, 1H), 7,11-of 7.19 (m, 1H), 7,21 (d, J=the 1.7 Hz, 1H), to 7.33 (d, J=8,1 Hz, 1H).

MS(+): 432 [M+H]+.

Example 1-76

6-{(E)-1-{3-Chloro-4-[(3-hydroxypropyl)sulfonyl]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-ethylpyridine-2(1H)-he

[Formula 181]

Specified in the title compound was obtained as a pale yellow powder (16 mg, 17% (two �Tadei)) by carrying out essentially the same reaction, as in examples 1-2 and 1-1(2) sequentially, except that used 6-{(E)-1-{4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-3-ethyl-2-methoxypyridine, obtained in example 1-75(1).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.17 (t, J=7.5 Hz, 3H), 1,84-2,59 (m, 10H), 2,68-2,86 (m, 1H), 3,58-to 3.67 (m, 2H), 3,82 (t, J=5,9 Hz, 2H), 5,65 (d, J=7,2 Hz, 1H), 6,71 (d, J=9.8 Hz, 1H), 7,14-7,20 (m, 1H), 7,34 (DD, J=8,1, 1.6 Hz, 1H), 7,43 (d, J=the 1.7 Hz, 1H), 8,20 (d, J=8,1 Hz, 1H).

MS(+): 464 [M+H]+.

Example 1-77

6-{(E)-1-(3-Chloro-4-{[3-(diethylamino)propyl]sulfanyl}phenyl)-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-ethylpyridine-2(1H)-he

[Formula 182]

(1) 3-({2-Chloro-4-[(E)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfanyl)propan-1-ol was obtained as a colorless amorphous substance (222 mg, 88%) by carrying out essentially the same reaction as in example 1-16(2), except that used 6-{(E)-1-{4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}-3-ethyl-2-methoxypyridine obtained in example 1-75(1).

(2) Specified in the title compound was obtained as a colorless amorphous substance (36 mg) by carrying out essentially the same reaction as in example 1-26(3) to(5), except that used 3-({2-chloro-4-[(E)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-di�casero[4,4]non-7-yl]-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfanyl)propan-1-ol.

1H NMR (300 MHz, CDCl3) δ M. D. from 1.00 to 1.23 (m, 9H), 1,81-2,02 (m, 4H), 2,06-of 2.28 (m, 3H), 2,31-of 2.44 (m, 2H), 2,46-to 2.74 (m, 7H), 2,79-of 2.97 (m, 1H), 3,00-3,13 (m, 2H), of 5.75 (d, J=7,2 Hz, 1H), of 6.52 (d, J=9,5 Hz, 1H), 7,06 (DD, J=8,0, The 1.8 Hz, 1H), 7,14 (d, J=7,2 Hz, 1H), 7,21 (d, J=1.9 Hz, 1H), 7,32 (d, J=8,2 Hz, 1H), the 11.04 is 11.28 (user.s, 1H).

MS(+): 487 [M+H]+.

Example 1-78

6-{(E)-1-(3-Chloro-4-{[3-(diethylamino)propyl]sulfonyl}phenyl)-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-ethylpyridine-2(1H)-he

[Formula 183]

Specified in the title compound was obtained as a colorless amorphous substance (21 mg) by carrying out essentially the same reaction as in example 1-27(1)-(2), except that used 3-({2-chloro-4-[(E)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]-1-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]phenyl}sulfanyl)propan-1-ol obtained in example 1-77(1).

1H NMR (300 MHz, CDCl3) δ M. D. 0,93-of 1.05 (m, 6H), of 1.16 (t, J=7.5 Hz, 3H), 1,86-2,05 (m, 4H), 2,07-of 2.25 (m, 3H), 2.26 and-2,63 (m, 9H), 2,67-2,88 (m, 1H), 3.46 in-3,70 (m, 2H), to 5.58 (d, J=7,2 Hz, 1H), of 6.79 (d, J=9.8 Hz, 1H), 7,15 (d, J=7,2 Hz, 1H), 7,34 (DD, J=8,0, 1.6 Hz, 1H), of 7.42 (d, J=1.6 Hz, 1H), to 8.19 (d, J=7.9 Hz, 1H).

MS(+): 519 [M+H]+.

Example 1-79

6-{(E)-1-{3-Chloro-4-[3-(diethylamino)propoxy]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 184]

(1) 2-Chloro-4-{(E)-1-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}phenol (429 mg, 31% (two steps)) was obtained by carrying out in fact the same reaction, as in examples 1-58(1) and 1-16(2), successively, using (4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanone obtained in reference example 1-55.

(2) Specified in the title compound was obtained as a brown amorphous substance (167 mg, 48% (stage four)) by carrying out essentially the same reaction as in examples 1-16(3) and 1-26(3) to(5) sequentially, except that used 2-chloro-4-{(E)-1-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4,4]non-7-yl]ethenyl}phenol and used 3-bromo-1-propanol instead of methyliodide.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.56 to 0.63 (m, 2H), 0,86-0,97 (m, 2H), of 1.05 (t, J=7,2 Hz, 6H), 1,88-of 2.44 (m, 9H), 2,56 (sq, J=7.2 Hz, 4H), 2,68 (t, J=7.5 Hz, 2H), 2,77-2,96 (m, 1H), 4,12 (t, J=6,1 Hz, 2H), 5,74 (d, J=7,2 Hz, 1H), Gold 6.43 (d, J=9,5 Hz, 1H), 6,80 (d, J=7.5 Hz, 1H), at 6.92 (d, J=8,5 Hz, 1H), 7,01 (DD, J=8,5, 2,0 Hz, 1H), 7,18 (d, J=the 1.7 Hz, 1H), 10,78-of 11.02 (user.s, 1H).

MS(+): 483 [M+H]+.

Example 1-80

6-{(E)-1-{3-Chloro-4-[4-(diethylamino)butoxy]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 185]

Specified in the title compound was obtained as a pale yellow amorphous substance (23 mg, 25% (four stages)) by carrying out essentially the same reaction as in example 1-79(2), except that used 2-chloro-4-{(E)-1-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro�[4,4]non-7-yl]ethenyl}phenol, obtained in example 1-79(1), and used 4-bromo-1-butanol instead of 3-bromo-1-propanol.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.52 to 0.68 (m, 2H), 0.88 to 1.00 each (m, 2H), of 1.05 (t, J=7,0 Hz, 6H), 1,63-1,78 (m, 2H), 1,78-of 1.98 (m, 3H), 1,98-of 2.24 (m, 4H), 2,24-of 2.44 (m, 2H), 2,44-2,71 (m, 6H), 2,78-of 2.97 (m, 1H), of 4.09 (t, J=6,1 Hz, 2H), 5,80 (d, J=7,4 Hz, 1H), between 6.30 (d, J=9.4 Hz, 1H), is 6.81 (d, J=7,4 Hz, 1H), 6,94 (d, J=8,6 Hz, 1H), 7,01 (DD, J=8,2, 2,0 Hz, 1H), 7,18 (d, J=2,0 Hz, 1H), for 9.88-10,39 (user.s, 1H).

MS(+): 497 [M+H]+.

Example 1 to 81

6-{(E)-1-[3-Chloro-4-(3-hydroxypropoxy)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 186]

Specified in the title compound was obtained as white solid (67 mg, 11% (four stages)) by carrying out essentially the same reaction as in examples 1-58(1) and 1-16(2)-(4) sequentially, except that used 4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-69, and used 3-bromo-1-propanol instead of methyliodide.

1H NMR (300 MHz, CDCl3) δ M. D. 1,78-of 2.50 (m, 8H), 2,74-2,98 (m, 1H), 3,94 (t, J=5.7 Hz, 2H), to 4.26 (t, J=5.7 Hz, 2H), 5,84 (d, J=7,8 Hz, 1H), 6,86 (d, J=9.4 Hz, 1H), 6,97-was 7.08 (m, 2H), 7,20 (d, J=1.6 Hz, 1H), 7,66 (d, J=7,4 Hz, 1H), 12,11-12,29 (user.s, 1H).

MS(+): 456 [M+H]+.

Example 1-82

6-{(E)-1-{3-Chloro-4-[(3-hydroxypropyl)sulfanyl]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 187]

Specified in the title compound was obtained as white solid (5.2 mg, 4% (two steps)) by carrying out essentially the same reaction as in example 1-58, except that used {4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-70.

1H NMR (300 MHz, CDCl3) δ M. D. 1,74-of 2.20 (m, 5H), 2,20-2,48 (m, 3H), 2,73-to 2.94 (m, 1H), 3,14 (t, J=7,0 Hz, 2H), 3,85 (t, J=6,1 Hz, 2H), 5,84 (d, J=7,8 Hz, 1H), 6,90 (d, J=9.8 Hz, 1H), 7,06 (DD, J=8,2, 1.6 Hz, 1H), 7,20 (d, J=1.6 Hz, 1H), 7,35 (d, J=8,2 Hz, 1H), 7,67 (d, J=7,8 Hz, 1H), 12,21-12,42 (user.s, 1H).

MS(+): 472 [M+H]+.

Example 1-83

6-{(E)-1-{3-Chloro-4-[3-(diethylamino)propoxy]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 188]

Specified in the title compound was obtained as a pale brown amorphous substance (137 mg, 7% (six steps)) by carrying out essentially the same reaction as in example 1-79, except that used 4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-69.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.06 (t, J=7,2 Hz, 6H), 1,90-of 2.44 (m, 8H), 2,50-2,63 (m, 4H), 2,63 is 2.76 (m, 2H), 2,76-of 2.93 (m, 1H), 4,14 (t, J=6,1 Hz, 2H), 5,84 (d, J=7.5 Hz, 1H), of 6.87 (d, J=9,5 Hz, 1H), 6,98 (d, J=8,5 Hz, 1H), 7,02 (DD, J=8,5, of 1.7 Hz, 1H), 7,18 (d, J=the 1.7 Hz, 1H), 7,66 (d, J=7.5 Hz, 1H).

MS(+): 511 [M+H]+ .

Example 1-84

6-{(E)-1-(3-Chloro-4-{[3-(diethylamino)propyl]sulfanyl}phenyl)-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 189]

Specified in the title compound was obtained as a colorless amorphous substance (20 mg, 4% (five stages)) by carrying out essentially the same reaction as in examples 1-58(1) and 1-26(2) to(5) sequentially, except that used {4-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfanyl]-3-chlorophenyl}[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon, obtained in reference example 1-70.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.11 (t, J=7,2 Hz, 6H), 1,88-2,47 (m, 8H), 2,59-2,78 (m, 6H), 2,78-2,90 (m, 1H), 3,06 (t, J=7,2 Hz, 2H), of 5.81 (d, J=7.5 Hz, 1H), 6,95 (d, J=9,5 Hz, 1H), 7,06 (DD, J=8,2 and 1.7 Hz, 1H), of 7.19 (d, J=the 1.7 Hz, 1H), 7,34 (d, J=7,8 Hz, 1H), 7,66 (d, J=7,8 Hz, 1H).

MS(+): 527 [M+H]+.

Example 1-85

6-{(E)-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-[(1S)-3-hydroxycyclopent]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 190]

Of sodium borohydride (11 mg) was added to a suspension of 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-cyclopropylamino-2(1H)-she obtained in example 1 to 71 (50 mg) in a mixture of ethanol-tetrahydrofuran (2.5 ml, 4:1) while cooling with ice and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into 0.5 M hydrochloric acid with subsequent�slip by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→9:1) obtaining specified in the title compound (35 mg, 60%) as a colorless amorphous substance.

Diastereomer mixture (colorless amorphous substance)

MS(+): 402 [M+H]+.

Example 1-86

6-{(E)-1-{3-Chloro-4-[3-(diethylamino)propoxy]phenyl}-2-[(1S)-3-hydroxycyclopent]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 191]

Of sodium borohydride (4.4 mg) was added to a solution of 6-{(E)-1-{3-chloro-4-[3-(diethylamino)propoxy]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-she obtained in example 1-83 (30 mg) in methanol (0.15 ml) at room temperature and the mixture was stirred at room temperature for 30 minutes. Was added to the reaction solution, water and saturated salt solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was washed with diethyl ether obtaining specified in the title compound (10 mg, 34%) as pale-yellow solids.

Diastereomer mixture (pale same�toe solid)

MS(+): 513 [M+H]+.

Example 1-87

6-{(E)-1-{3-Chloro-4-[3-(diethylamino)propoxy]phenyl}-2-[(1S)-3-hydroxycyclopent]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 192]

Specified in the title compound (4.4 mg, 15%) was obtained as pale-yellow solids by carrying out essentially the same reaction as in example 1-86, except that used 6-{(E)-1-{3-chloro-4-[3-(diethylamino)propoxy]phenyl}-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-cyclopropylamino-2(1H)-he obtained in example 1-79.

Diastereomer mixture (pale yellow solid)

MS(+): 485 [M+H]+.

Example 1 to 88

6-[(E)-1-(3-Chloro-4-methoxyphenyl)-2-(CIS-4-hydroxycyclohexyl)ethenyl]-3-cyclopropylidene-2(1H)-he

[Formula 193]

(1) 6-[(E)-1-(4-{[tert-Butyl(dimethyl)silyl]oxy}-3-chlorophenyl)-2-(CIS-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)ethenyl]-3-cyclopropyl-2-methoxypyridine was obtained as a pale yellow amorphous substance (620 mg, 61%) by carrying out essentially the same reaction as in example 1-47(1), except that used 5-{[(CIS-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methyl]sulfonyl}-1-phenyl-1H-tetrazole obtained in reference example 3-4, instead of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole and used (4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)(5-Cyclops�sawdust-6-methoxypyridine-2-yl)methanon, obtained in reference example 1-55.

(2) Specified in the title compound was obtained as colorless powder (77 mg, 35% (three stages)) by carrying out essentially the same reaction as in example 1-16(2) to(4), except that used 6-[(E)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)-2-(CIS-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)ethenyl]-3-cyclopropyl-2-methoxypyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 0,49-to 0.67 (m, 2H), with 0.83 to 1.06 (m, 2H), 1,28-of 1.88 (m, 8H), 1,99-of 2.27 (m, 2H), 3,83-4,13 (m, 4H), 5,80 (d, J=7,3 Hz, 1H), 6,19 (d, J=10.0 Hz, 1H), is 6.81 (d, J=7,3 Hz, 1H), 6,93-6,98 (m, 1H), 7,01-to 7.09 (m, 1H), 7,18 (d, J=2,0 Hz, 1H), at 9.38-9,60 (user.s, 1H).

MS(+): 400 [M+H]+.

Example 1-89

6-[(E)-1-(3-Chloro-4-methoxyphenyl)-2-(TRANS-4-hydroxycyclohexyl)ethenyl]-3-cyclopropylidene-2(1H)-he

[Formula 194]

Specified in the title compound was obtained as colorless powder (91 mg, 4.7 per cent (four stages)) by carrying out essentially the same reaction as in example 1 to 88(1)(2), except that used 5-{[(TRANS-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methyl]sulfonyl}-1-phenyl-1H-tetrazole obtained in reference example 3-5.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.49 to 0.69 (m, 2H), 0,82-0,98 (m, 2H), 1,07-1,46 (m, 4H), 1,54-to 1.82 (m, 2H), 1,88-to 2.29 (m, 4H), 3,39-and 3.72 (m, 1H), 3,96 (s, 3H), of 5.75 (d, J=7,3 Hz, 1H), 6,09 (d, J=10.0 Hz, 1H), is 6.81 (s, 1H), 6,90-was 7.08 (m, 2H), 7,17 (d, J=2,0 Hz, 1H), for 9.47-10,10 (user.s, 1H).

MS(+): 400 [M+H]+.

Example 1-90

6-[(E)-1-[4(Cyclopropylmethyl)phenyl]-2-(TRANS-4-hydroxycyclohexyl)ethenyl]-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 195]

Specified in the title compound was obtained as colorless powder (50 mg) by carrying out essentially the same reaction as in example 1-89, except that used [4-(cyclopropanesulfonyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-68.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.65-0,83 (m, 2H), 1,05-1,50 (m, 6H), 1.62 V-1,76 (m, 2H), 1,96 (d, J=11.3 Hz, 3H), 2,15-of 2.28 (m, 1H), 3,49-3,70 (m, 1H), of 5.83-5,95 (m, 1H), 6,45-6,59 (m, 1H), 7,07 (d, J=8,5 Hz, 2H), of 7.42 (d, J=8,2 Hz, 2H), 7,65 (d, J=7.5 Hz, 1H).

MS(+): 436 [M+H]+.

Example 1-91

6-[(E)-1-[4-(Cyclopropanesulfonyl)phenyl]-2-(TRANS-4-hydroxycyclohexyl)ethenyl]-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 196]

Specified in the title compound was obtained as a pale yellow powder (44 mg, 55%) by carrying out essentially the same reaction as in example 1-2, except that used 6-[(E)-1-[4-(cyclopropanesulfonyl)phenyl]-2-(TRANS-4-hydroxycyclohexyl)ethenyl]-3-(trifluoromethyl)pyridin-2(1H)-he obtained in example 1-90.

1H NMR (300 MHz, DMSO-d6) δ M. D. 0,88-to 1.37 (m, 8H), 1,53-of 1.66 (m, 2H), 1,73-1,94 (m, 3H), 2,89-3,01 (m, 1H), 4,46 (d, J=4.5 Hz, 1H), 5,54-5,69 (m, 1H), 6,45-6,59 (m, 1H), of 7.48 (d, J=8.4 Hz, 2H), 7,78 (d, J=8,2 Hz, 1H), 7,96 (d, J=8.4 Hz, 2H), 12,23-12,38 (user.s, 1H).

MS(+): 468 [M+H]+.

Example 1-92

3-Cyclopropyl-6-{(1E)-4-hydroxy-1-[4-(methylsulfanyl)phenyl]but-1-ene-1-yl}PIR�DIN-2(1H)-he

[Formula 197]

(1) 6-{(1E)-4-{[tert-Butyl(dimethyl)silyl]oxy}-1-[4-(methylsulfanyl)phenyl]but-1-ene-1-yl}-3-cyclopropyl-2-methoxypyridine was obtained as a colorless oil (360 mg, 19%) by carrying out essentially the same reaction as in example 1-47(1), except that used 5-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)sulfonyl]-1-phenyl-1H-tetrazol.

(2) (3E)-4-(5-cyclopropyl-6-methoxypyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-ol was obtained as a colorless oil (260 mg, 96%) by carrying out essentially the same reaction as in example 1-16(2), except that used 6-{(1E)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[4-(methylsulfanyl)phenyl]but-1-ene-1-yl}-3-cyclopropyl-2-methoxypyridine.

(3) Specified in the title compound was obtained as a colorless oil (45 mg, 40%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (3E)-4-(5-cyclopropyl-6-methoxypyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-ol.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.49 and 0.59 (m, 2H), 0,86-1,00 (m, 2H), 2,03-of 2.16 (m, 1H), 2,36-2,48 (m, 2H), 2,51 (s, 3H), 3,69-of 3.78 (m, 2H), of 3.91 is 3.40 (user.s, 1H), 5,79 (d, J=7,3 Hz, 1H), is 6.51 (t, J=7,4 Hz, 1H), to 6.88 (DD, J=7,3, 0.8 Hz, 1H), 7,10-to 7.18 (m, 2H), 7.23 percent-7,31 (m, 2H).

MS(+): 328 [M+H]+.

Example 1-93

3-Cyclopropyl-6-{(1E)-4-hydroxy-1-[4-(methyl-sulfonyl)phenyl]but-1-ene-1-yl}pyridin-2(1H)-he

[Formula 198]

Specified in the title compound was obtained as a colorless oil (17 mg, 44%) by carrying out essentially the same reaction as in example 1-2, except that used 3-cyclopropyl-6-{(1E)-4-hydroxy-1-[4-(methylsulfanyl)phenyl]but-1-ene-1-yl}pyridin-2(1H)-he obtained in example 1-92(3).

1H NMR (300 MHz, CDCl3) δ M. D. from 0.42 to 0.63 (m, 2H), 0.88 to was 1.06 (m, 2H), 1,95-of 2.23 (m, 1H), 2,31-of 2.50 (m, 2H), 3,11 (s, 3H), 3,64-to 3.96 (m, 2H), 4,18-4,40 (user.s, 1H), of 5.68 (d, J=7,3 Hz, 1H), 6,63 (t, J=7.5 Hz, 1H), at 6.92 (d, J=7,3 Hz, 1H), 7,47 (d, J=8.4 Hz, 2H), 7,98 (d, J=8,5 Hz, 2H), 12,26-of 12.55 (user.s, 1H).

MS(+): 360 [M+H]+.

Example 1-94

N-{(3E)-4-(5-Cyclopropyl-6-oxo-1,6-dihydropyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-yl}acetamide

[Formula 199]

(1) Phthalimide (154 mg) and triphenylphosphine (275 mg) was added to a solution of (3E)-4-(5-cyclopropyl-6-methoxypyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-ol obtained in example 1-92(2) (275 mg) in tetrahydrofuran (10 ml) and the mixture was cooled with ice in a stream of nitrogen gas. Added to it 40% solution of diethylazodicarboxylate in toluene (0,477 ml) and the mixture was stirred at room temperature for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure Rast�oritel. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→1:1) to give 2-{(3E)-4-(5-cyclopropyl-6-methoxypyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-yl}-1H-isoindole-1,3(2H)-dione as a colorless amorphous substance (320 mg, 84%).

(2) hydrazine Monohydrate (1 ml) was added to a solution of 2-{(3E)-4-(5-cyclopropyl-6-methoxypyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-yl}-1H-isoindole-1,3(2H)-dione (320 mg) in ethanol (4 ml) and the mixture was stirred at 95°C for one hour. The reaction solution was poured into 3 M sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure solvent obtaining (3E)-4-(5-cyclopropyl-6-methoxypyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-amine as a colorless amorphous substance (225 mg, 97%).

(3) Acetic anhydride (85 mg) was added to a solution of (3E)-4-(5-cyclopropyl-6-methoxypyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-amine (95 mg) in pyridine (1 ml) under cooling with ice and the mixture was stirred at room temperature for one hour. The reaction solution was poured into 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous� magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→0:1), to obtain N-{(3E)-4-(5-cyclopropyl-6-methoxypyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-yl}acetamide as a colorless amorphous substance (87 mg, 81%).

(4) 48% bromoethanol acid (2 ml) was added to a solution of N-{(3E)-4-(5-cyclopropyl-6-methoxypyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-yl}acetamide (87 mg) in 1,4-dioxane (2 ml) and the mixture was stirred at 80°C for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was recrystallized from a mixed solvent of chloroform-ethyl acetate-hexane. Filtration gave specified in the title compound as a colorless solid (54 mg, 64%).

1H NMR (300 MHz, DMSO-d6) δ M. D. of 0.47-0.65 m, 2H), 0,76-of 0.91 (m, 2H), of 1.76 (s, 3H), 1,89-of 2.05 (m, 1H), 2,12 (kV, J=7,1 Hz, 2H), 2,51 (s, 3H), 3,04-3,18 (m, 2H), 5,38-of 5.55 (m, 1H), from 6.22 gold 6.43 (m, 1H), at 6.84 (d, J=7,2 Hz, 1H), 7,04-7,15 (m, 2H), 7,22-of 7.36 (m, 2H), to 7.77-7,96 (m, 1H), to 11.11-11,33 (user.s, 1H).

MS(+): 369 [M+H]+.

Example 1 to 95

N-{(3E)-4-(5-Cyclopropyl-6-oxo-1,6-dihydropyridine-2-yl)-4-[4-(methyl-sulfonyl)phenyl]but-3-EN-1-yl}acetamide

[Formula 200]

Specified in the title compound was obtained as a colorless oil (29 mg, 64%) by carrying out essentially the same reaction as in example 1-2, except that used N-{(3E)-4-(5-cyclopropyl-6-oxo-1,6-dihydropyridine-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-EN-1-yl}acetamide obtained in example 1-94(4).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.52 to 0.69 (m, 2H), 0,82-1,02 (m, 2H), 1,92-2,10 (m, 4H), 2,27-2.49 USD (m, 2H), 3,13 (s, 3H), 3,30-of 3.53 (m, 2H), 5,65 (d, J=7.5 Hz, 1H), 6,60 (t, J=7.5 Hz, 1H), 6,89 (d, J=7.9 Hz, 1H), of 7.19-7,28 (m, 1H), 7,35-of 7.48 (m, 2H), to 7.89-8,08 (m, 2H), 12,05-12,23 (user.s, 1H).

MS(+): 401 [M+H]+.

Example 1-96

3-Cyclopropyl-6-{(1E)-5-hydroxy-1-[4-(methylsulfanyl)phenyl]pent-1-EN-1-yl}pyridin-2(1H)-he

[Formula 201]

Specified in the title compound was obtained as colorless powder (117 mg, 14% (two steps)) by carrying out essentially the same reaction as in examples 1-47(1) and 1-1(2) sequentially except that used 5-[(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)sulfonyl]-1-phenyl-1H-tetrazol.

1H NMR (300 MHz, CDCl3) δ M. D. 0,49-to 0.67 (m, 2H), 0,86-1,08 (m, 2H), 1,62-to 1.77 (m, 2H), 2.00 in to 2.14 (m, 1H), of 2.21 (sq, J=7.5 Hz, 2H), 3,62 (t, J=6,2 Hz, 2H), of 5.85 (d, J=7,1 Hz, 1H), of 6.31 (t, J=7.5 Hz, 1H), 6,83 (d, J=8,1 Hz, 1H), To 7.09 (d, J=8,5 Hz, 2H), 7,27 (d, J=8,5 Hz, 2H).

MS(+): 342 [M+H]+.

Example 1-97

3-Cyclopropyl-6-{(1E)-5-hydroxy-1-[4-(methyl-sulfonyl)phenyl]pent-1-EN-1-yl}pyridin-2(1H)-he

[Formula 202]

Specified in the title compound was obtained as a colorless oil (84 mg, 75%) by carrying out essentially the same reaction as in example 1-2, except that used 3-cyclopropyl-6-{(1E)-5-hydroxy-1-[4-(methylsulfanyl)phenyl]pent-1-EN-1-yl}pyridin-2(1H)-he obtained in example 1-96.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.47-0,74 (m, 2H), 0,84-of 1.04 (m, 2H), 1,49-of 1.88 (m, 1H), 1,98-to 2.13 (m, 2H), 2,14-to 2.29 (m, 2H), 3,13 (s, 3H), 3,54-3,71 (m, 2H), 5,65 (d, J=7,3 Hz, 1H), a 6.53 (t, J=7.5 Hz, 1H), of 6.85 (s, 1H), of 7.42 (d, J=8,5 Hz, 2H), 7,99 (d, J=8,5 Hz, 2H).

MS(+): 374 [M+H]+.

Example 1-98

6-{(1E)-1-[4-(Cyclopropanesulfonyl)phenyl]-5-hydroxymet-1-EN-1-yl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 203]

Specified in the title compound was obtained as colorless powder (65 mg) by carrying out essentially the same reaction as in example 1-96, except that used [4-(cyclopropanesulfonyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-68.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.68 to 0.82 (m, 2H), 1,06-of 1.18 (m, 2H), 1,69-to 1.86 (m, 2H), 2,13-is 2.37 (m, 3H), 3,58-3,71 (m, 2H), 5,93 (d, J=7,8 Hz, 1H), of 6.79 (t, J=7,6 Hz, 1H), 7,03-7,14 (m, 2H), value of 7, 37-of 7.46 (m, 2H), 7,67 (d, J=8.4 Hz, 1H), 11,34-11,66 (user.s, 1H).

MS(+): 396 [M+H]+.

Example 1-99

6-{(1E)-1-[4-(Cyclopropanesulfonyl)phenyl]-5-hydroxymet-1-EN-1-yl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 204]

Specified in the title�VKE compound was obtained as a colorless oil (63 mg, 92%) by carrying out essentially the same reaction as in example 1-2, except that used 6-{(1E)-1-[4-(cyclopropanesulfonyl)phenyl]-5-hydroxymet-1-EN-1-yl}-3-(trifluoromethyl)pyridin-2(1H)-he obtained in example 1-98.

1H NMR (300 MHz, CDCl3) δ M. D. 0,98-1,17 (m, 2H), 1,34-of 1.48 (m, 2H), 1,69-of 1.92 (m, 2H), 2,14-of 2.32 (m, 2H), 2,44-2,62 (m, 1H), 3,47-with 3.79 (m, 2H), 5,77 (d, J=7,6 Hz, 1H), 6,98 (t, J=7.5 Hz, 1H,) 7,34-7,49 (m, 2H), 7,68 (d, J=7.9 Hz, 1H), 7,92-with 8.05 (m, 2H), 12,21-of 12.59 (user.s, 1H).

MS(+): 450 [M+Na]+.

Example 1-100

6-{(E)-1-[4-(Cyclopropanesulfonyl)phenyl]-2-[1-(gidroximetil)cyclopropyl]ethenyl}-3-methylpyridine-2(1H)-he

[Formula 205]

Specified in the title compound was obtained as a pale yellow solid (3.2 mg, 1% (three stages)) by carrying out essentially the same reaction as in examples 1-47(1), 1-2 and 1-1(2) sequentially except that used [4-(cyclopropanesulfonyl)phenyl](6-methoxy-5-methylpyridine-2-yl)methanon obtained in reference example 1-37, and used 5-({[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}sulfonyl)-1-phenyl-1H-tetrazole obtained in reference example 3 to 13, instead of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole.

1H NMR (500 MHz, CDCl3) δ M. D. of 0.47-0,52 (m, 2H), 0,58-0,65 (m, 2H), 1,00-1,15 (m, 2H), 1,30 -1,45 (m, 2H), 2,14 (s, 3H), 2,50-of 2.57 (m, 1H), 3,41 (s, 2H), 5,82 (d, J=7,1 Hz, 1H), 6,60 (s, 1H), 7,21 (d, J=7,0 Hz, 1H), EUR 7.57 (d, J=8,3 Hz, 2H), 7,92 (d, J=8,3 Hz, 2H).

MS(+): 386 [M+H]+.

Example 1-101

6-{(1E,3S)-1-[4-(Cyclopropanesulfonyl)phenyl]-4-hydroxy-3-methylbut-1-EN-1-yl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 206]

Specified in the title compound was obtained as white solid (22 mg, 4% (three stages)) by carrying out essentially the same reaction as in examples 1-47(1), 1-2 and 1-1(2) sequentially except that used [4-(cyclopropanesulfonyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-68, and used 5-{[(2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl"] sulfonyl}-1-phenyl-1H-tetrazole obtained in reference example 3-14, instead of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole.

1H NMR (300 MHz, CDCl3) δ M. D. 1,02-of 1.18 (m, 5H), 1,38-of 1.47 (m, 2H), 2,42-2,60 (m, 2H), 3,52-3,65 (m, 2H), 5,82 (d, J=7,4 Hz, 1H), 6,62 (d, J=10.1 Hz, 1H), 7,44 (d, J=8,6 Hz, 2H), of 7.70 (d, J=7,7 Hz, 1H), 7,97 (d, J=8,0 Hz, 2H).

MS(+): 428 [M+H]+.

Example 1-102

6-{(1E,3R)-1-[4-(Cyclopropanesulfonyl)phenyl]-4-hydroxy-3-methylbut-1-EN-1-yl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 207]

Specified in the title compound was obtained as white solid (24 mg, 13% (three stages)) by carrying out essentially the same reaction as in examples 1-47(1), 1-2 and 1-1(2) sequentially except that used [4-(cyclopropanesulfonyl�)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon, obtained in reference example 1-68, and used 5-{[(2S)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl"] sulfonyl}-1-phenyl-1H-tetrazole obtained in reference example 3-15, instead of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole.

1H NMR (300 MHz, CDCl3) δ M. D. 1,00-1,20 (m, 5H), 1,38-of 1.47 (m, 2H), 2,20-2,39 (user.s, 1H), 2,42-2,62 (m, 2H), 3,52-3,68 (m, 2H), 5,82 (d, J=7,4 Hz, 1H), 6,61 (d, J=10.7 Hz, 1H), 7,44 (d, J=8,3 Hz, 2H), of 7.70 (d, J=7,4 Hz, 1H), 7,97 (d, J=8,0 Hz, 2H), 11,95-12,20 (user.s, 1H).

MS(+): 428 [M+H]+.

Example 1-103

3-Chloro-6-{(E)-2-cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]ethenyl}pyridin-2(1H)-he

[Formula 208]

Specified in the title compound was obtained by carrying out essentially the same reaction as in example 1-1, except that used the (5-chloro-6-methoxypyridine-2-yl)[4-(cyclopropanesulfonyl)phenyl]methanon obtained in referential example 1-2.

1H NMR (300 MHz, CDCl3) δ M. D. 0,57-0,65 (m, 2H), 1,07-1,17 (m, 2H), 1,35-1,55 (m, 4H), 1,58-of 1.75 (m, 4H), 2,24-2,36 (m, 2H), 5,48-of 5.60 (m, 1H), 6,45 (d, J=9.8 Hz, 1H), 7,11 (d, J=8,1 Hz, 2H), 7,40 (d, J=8,1 Hz, 2H), 7,58 (d, J=7,8 Hz, 1H), 11,93-12,18 (user.s, 1H).

MS(+): 372 [M+H]+.

Example 1-104

3-Chloro-6-{(E)-2-cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]ethenyl}pyridin-2(1H)-he

[Formula 209]

Specified in the title compound was obtained by carrying out essentially the same reaction as in example 1-2, except �we used 3-chloro-6-{(E)-2-cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]ethenyl}pyridin-2(1H)-he, obtained in example 1-103.

1H NMR (300 MHz, CDCl3) δ M. D. from 1.07 to 1.17 (m, 2H), 1,38-of 1.47 (m, 2H), 1,49-1,59 (m, 4H), 1,71-of 1.84 (m, 4H), 2,31-of 2.44 (m, 1H), 2,49-2,61 (m, 1H), 5,77 (d, J=7,6 Hz, 1H), of 6.49 (d, J=10.1 Hz, 1H), 7,39 (d, J=8,6 Hz, 2H), 7,47 (d, J=7,8 Hz, 1H), 7,96 (d, J=8,6 Hz, 2H), 10,42-10,75 (user.s, 1H).

MS(+): 404 [M+H]+.

Example 1-105

N-{4-[(E)-1-(5-Chloro-6-oxo-1,6-dihydropyridine-2-yl)-2-cyclopentylacetyl]phenyl}acetamide

[Formula 210]

(1) 48% bromoethanol acid (2 ml) was added to a solution of tert-butyl {4-[(5-chloro-6-methoxypyridine-2-yl)carbonyl]phenyl}carbamate obtained in reference example 1-89, in 1,4-dioxane (5 ml) and the mixture was stirred at an ambient temperature of 65°C for one hour. Was added to the reaction solution, saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→9:1) to give 6-[(E)-1-(4-Dapsone base)-2-cyclopentylacetyl]-3-chloropyridin-2(1H)-it is in the form of a yellow oil (326 mg, quantitative).

(2) Acetic anhydride (5 ml) was added to 6-[(E)-1-(4-Dapsone base)-2-cyclopentylacetyl]-3-chloropyridin-2(1H)-ONU (173 mg) and the mixture was stirred at room temperature for 15 minutes. Was added to the reaction�nnomo a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration evaporated under reduced pressure solvent and the residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→0:1). The resulting oil was converted into a powder using ethyl acetate, and the process of filtering gave specified in the title compound as a light yellow powder (75 mg, 38%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,34-of 1.54 (m, 4H), 1,63-of 1.83 (m, 4H), 2,22 (s, 3H), 2,40-by 2.55 (m, 1H), 5,94 (d, J=7,6 Hz, 1H), of 6.20 (d, J=10.0 Hz, 1H), 7,13 (d, J=8.4 Hz, 2H), 7,22 (s, 1H), 7,47 (d, J=7,8 Hz, 1H), 7,56 (d, J=to 8.7 Hz, 2H).

MS(+): 357 [M+H]+.

Example 1-106

1-{4-[(E)-1-(5-Chloro-6-oxo-1,6-dihydropyridine-2-yl)-2-cyclopentylacetyl]phenyl}urea

[Formula 211]

A solution of potassium cyanate (41 mg) in water (2 ml) was added to a solution of 6-[(E)-1-(4-Dapsone base)-2-cyclopentylacetyl]-3-chloropyridin-2(1H)-she obtained in example 1-105(1) (153 mg) in a mixture of acetic acid (2 ml)-water (1 ml) and the mixture was stirred at room temperature for 30 minutes. Was added to the reaction solution successively saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over sodium sulfate. After filtration evaporated under reduced pressure the solvent ostatok was purified by chromatography on a column of silica gel (chloroform:methanol=9:1→8:2). The resulting oil was converted into a powder using ethyl acetate, and the process of filtering gave specified in the title compound as a light yellow powder (37 mg, 21%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,32-of 1.55 (m, 4H), 1,59-to 1.77 (m, 4H), 2,35-of 2.46 (m, 1H), 5,47-5,59 (m, 1H), 5,88 (s, 2H), 6,39 (d, J=10.0 Hz, 1H), 7,00 (d, J=8,6 Hz, 2H), 7,43 (d, J=to 8.7 Hz, 2H), 7,56 (d, J=7,6 Hz, 1H), 8,64 (s, 1H).

MS(+): 358 [M+H]+.

Example 1-107

6-{(E)-1-[4-(methyl-sulfonyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}-3-(propane-2-yl)pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (18 mg) by carrying out essentially the same reaction as in examples 1-58(1), 1-1(2) 1-2, sequentially, except that used [6-methoxy-5-(propan-2-yl)pyridin-2-yl][4-(methylsulfanyl)phenyl]methanon obtained in reference example 1-76.

1H NMR (300 MHz, CDCl3) δ M. D. 0,99-1,32 (m, 6H), 1,75-of 2.50 (m, 6H), 2,61-2,88 (m, 1H), 2,98-3,30 (m, 4H), 5,50-5,80 (m, 1H), 6,66-6,83 (m, 1H), 7,06-7,21 (m, 1H), 7,38-to 7.55 (m, 2H), to 7.89-8,16 (m, 2H), 11,66-12,13 (user.s, 1H).

MS(+): 400 [M+H]+.

Example 1-108

3-Cyclopropyl-6-{(E)-1-[4-(methyl-sulfonyl)phenyl]-2-[(1S)-3-oxocyclopentyl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (55 mg) by carrying out essentially the same reaction as in examples 1-58(1), 1-1(2) 1-2, sequentially, except that was used (5-cyclopropyl-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]m�Thanon, obtained in reference example 1-51.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.53 to 0.68 (m, 2H), of 0.82 and 1.05 (m, 2H), 1,84-2,48 (m, 7H), 2,63-2,89 (m, 1H), is 3.08 3.21-in (m, 3H), 5,46-5,64 (m, 1H), 6,65-at 6.92 (m, 2H), 7,38-7,52 (m, 2H), 7,95-8,09 (m, 2H), 11,84-12,19 (user.s, 1H).

MS(+): 398 [M+H]+.

Example 1-109

3-Chloro-6-[(E)-1-[4-(propane-2-yl)phenyl]-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridin-2(1H)-he

(1) 4-Isopropylaniline acid (103 mg), Tris(dibenzylideneacetone)dipalladium (38 mg), three(2-furyl)phosphine (58 mg), cesium carbonate (273 mg) and water (0.5 ml) was added to a solution of 6-[(Z)-1-bromo-2-(tetrahydro-2H-Piran-4-yl)ethenyl]-3-chloro-2-methoxypyridine (140 mg) in 1,4-dioxane (3 ml) and the mixture was stirred at 90°C for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:1) to give 3-chloro-2-methoxy-6-[(E)-1-[4-(propane-2-yl)phenyl]-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridine containing impurities, in the form of a yellow oil (170 mg).

(2) Specified in the title compound was obtained as a colorless powder (61 mg) by carrying out essentially the same reaction as in example 1-1(2), except that used 3-chloro-2-methoxy-6-[(E)-1-[4-(propane-2-yl)FeNi�]-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridine.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.31 (d, J=7,0 Hz, 6H), 1,48-of 1.75 (m, 4H), of 2.21-2,48 (m, 1H), 2,87-of 3.04 (m, 1H), 3,21-3,39 (m, 2H), 3,82 is 4.03 (m, 2H), 5,93 (d, J=7,6 Hz, 1H), 6,27 (d, J=9.8 Hz, 1H), 7,04-7,10 (m, 2H), 7.24 to 7,34 (m, 2H), 7,47 (d, J=7,6 Hz, 1H), 10,26-10,48 (user.s, 1H).

MS(+): 358 [M+H]+.

Example 1-110

3-Chloro-6-[(E)-1-[4-(cyclopropanesulfonyl)phenyl]-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (151 mg) by carrying out essentially the same reaction as in examples 1-109(1), 1-1(2) 1-2, sequentially, except that used [4-(cyclopropylamino)phenyl]Bronevoy acid instead of 4-isopropylaniline acid.

1H NMR (300 MHz, CDCl3) δ M. D. 0,90-1,25 (m, 2H), 1,30-1,49 (m, 2H), 1,48-1,62 (m, 2H), 1,65-of 1.93 (m, 2H), 2,05-2,36 (m, 1H), 2,45-2,70 (m, 1H), 3,09-3,51 (m, 2H), 3,76-4,17 (m, 2H), 5,67 (d, J=7,8 Hz, 1H), 6,62 (d, J=9.9 Hz, 1H), Of 7.36-the 7.43 (m, 2H), 7,47 (d, J=7,6 Hz, 1H), 7,93-8,03 (m, 2H), 12,08-12,18 (user.s, 1H).

MS(+): 420 [M+H]+.

Example 1-111

3-Chloro-6-[(E)-1-[4-(morpholine-4-yl)phenyl]-2-(tetrahydro-2H-Piran-4-yl)ethenyl]pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (29 mg, 23% (two steps)) by carrying out essentially the same reaction as in examples 1-109(1) and 1-1(2) sequentially, except that used 4-morpholinomethyl)Bronevoy acid instead of 4-isopropylaniline acid.

1H NMR (300 MHz, CDCl3) δ M. D. 1,45-1,80 (m, 4H), 2,27-of 2.54 (m, 1H), 3,14-of 3.42 (�, 6H), 3,73 is 4.03 (m, 6H), of 5.99 (d, J=7,6 Hz, 1H), 6,19 (d, J=9.8 Hz, 1H), 6,86-7,00 (m, 2H), 7,01-7,10 (m, 2H), 7,47 (d, J=7,6 Hz, 1H), 9,87-10,15 (user.s, 1H).

MS(+): 401 [M+H]+.

Example 1-112

6-[(E)-1-(4-Acetylphenyl)-2-(tetrahydro-2H-Piran-4-yl)ethenyl]-3-chloropyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (82 mg, 73% (two steps)) by carrying out essentially the same reaction as in examples 1-109(1) and 1-1(2) sequentially, except that used 4-acetylphenyl)Bronevoy acid instead of 4-isopropylaniline acid.

1H NMR (300 MHz, CDCl3) δ M. D. 1,45-of 1.64 (m, 2H), 1,69-of 1.88 (m, 2H), 2,17-of 2.35 (m, 1H), of 2.66 (s, 3H), 3,21-3,35 (m, 2H), 3,88-was 4.02 (m, 2H), for 5.66 (d, J=7,6 Hz, 1H), 6,61 (d, J=9.8 Hz, 1H), 7,28-7,34 (m, 2H), 7,44 (d, J=7,6 Hz, 1H), 7,98-8,07 (m, 2H), 12,11-to 12.28 (user.s, 1H).

MS(+): 358 [M+H]+.

Example 1-113

3-Chloro-6-[(1E)-3-[4-(methyl-sulfonyl)phenyl]-1-(tetrahydro-2H-Piran-4-yl)prop-1-EN-2-yl]pyridin-2(1H)-he

(1) 1-(methyl bromide)-4-(methyl-sulfonyl)benzene (110 mg), trimethylsilane (12,5 µl) and 1,2-dibromoethane (8,6 ml) was added to a solution of zinc powder (78 mg) in tetrahydrofuran (4 ml) in the presence of gaseous argon and the mixture was stirred at 80°C for two hours. The reaction solution was adjusted again to room temperature. Added a solution of Tris(dibenzylideneacetone)diplegia (45 mg), three(2-furyl)phosphine (69 mg) and 6-[(Z)-1-bromo-2-(tetrahydro-2H-Piran-4-yl)ethenyl]-3-chloro-2-methoxypyridine (380 mg) in tetrahydro�uranium (2 ml) and the mixture was stirred at 90°C for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→0:1) to give 3-chloro-2-methoxy-6-[(1E)-3-[4-(methyl-sulfonyl)phenyl]-1-(tetrahydro-2H-Piran-4-yl)prop-1-EN-2-yl]pyridine as a yellow oil (110 mg).

(2) Specified in the title compound was obtained as colorless powder (64 mg) by carrying out essentially the same reaction as in example 1-1(2), except that used 3-chloro-2-methoxy-6-[(1E)-3-[4-(methyl-sulfonyl)phenyl]-1-(tetrahydro-2H-Piran-4-yl)prop-1-EN-2-yl]pyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 1,53-1,90 (m, 4H), 2,50-2,78 (m, 1H), of 3.04 (s, 3H), 3,33-3,55 (m, 2H), of 3.91-4,08 (m, 4H), of 6.06 (d, J=7,6 Hz, 1H), 6,39 (d, J=9,3 Hz, 1H), 7,38 (d, J=8,2 Hz, 2H), of 7.48 (d, J=7,7 Hz, 1H), 7,78-a 7.92 (m, 2H), 12,15-12,35 (user.s, 1H)

MS(+): 408 [M+H]+.

Patterns of examples 1-107 - 1-113 shown below.

Table 12

Example 2-1

6-{2-Cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethyl}-3-methylpyridine-2(1H)-he

[Formula 212]

(1) a Solution Of 2.46 M n-utility in hexane (1,11 ml) was added to a solution of 2-methoxy-3-methyl-6-[4-(methylsulfanyl)benzyl]pyridine obtained in reference example 2-1 (400 mg) in tetrahydrofuran (5 ml) in the presence of gaseous argon at -78°C and the mixture was stirred at -35°C for 30 minutes. The reaction solution was cooled again to -78°C and added a solution of cyclopentylmethyl 4-methylbenzenesulfonate (549 mg) in tetrahydrofuran (3 ml), after which the mixture was stirred at a temperature in the range from -78°C to 0°C for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by preparative TLC (hexane:ethyl acetate=19:1) to give 6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethyl}-2-methoxy-3-methylpyridine as a colorless amorphous substance (220 mg, 42%).

(2) 48% bromoethanol acid (2 ml) was added to a solution of 6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethyl}-2-methoxy-3-methylpyridine (220 mg) in acetonitrile (2 ml) and the mixture was stirred at 110°C for two hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated R�the target salt, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=0:1) obtaining specified in the title compound as a colorless amorphous substance (200 mg, 94%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,02-of 1.29 (m, 2H), 1,37-of 1.84 (m, 7H), 1,94-2,05 (m, 2H), 2,10 (s, 3H), 2,46 (s, 3H), of 3.69-3,83 (m, 1H), 6,03 (d, J=6,8 Hz, 1H), 7,15-7,24 (m, 5H), 10,18-10,35 (m, 1H).

MS(+): 328 [M+H]+.

Example 2-2

6-{2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethyl}-3-methylpyridine-2(1H)-he

[Formula 213]

Potassium carbonate (324 mg) and Oxon(R) (1.45 g) were successively added to a solution of 6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethyl}-3-methylpyridine-2(1H)-she (154 mg) in a mixture of acetone-water (10 ml) under cooling with ice and the mixture was stirred at 0°C for 30 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=0:1) obtaining specified in the title compound as a colorless amorphous substance (20 mg, 12%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,02-of 1.29 (m, 2H), 1,38-to 1.87 (m, 7H), 1,952,16 (m, 5H), 3,03 (s, 3H), 3,88-was 4.02 (m, 1H), 6,10 (d, J=7,0 Hz, 1H), 7,18-7,30 (m, 1H), 7,49-to 7.60 (m, 2H), 7,80-7,90 (m, 2H), 11,38-at 11.57 (user.s, 1H).

MS(+): 360 [M+H]+.

Example 2-3

6-{2-Cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]ethyl}-3-methylpyridine-2(1H)-he

[Formula 214]

10% palladium-activated carbon (50 mg) was added to a mixed solution of 6-{(E)-2-cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]ethenyl}-3-methylpyridine-2(1H)-she synthesized in example 1-11 (50 mg) in tetrahydrofuran and methanol (2 ml, 1:1) and the mixture was stirred in a stream of hydrogen gas at room temperature for three hours. The reaction solution was filtered through celite and then the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=1:1→0:1) obtaining specified in the title compound as a colorless amorphous substance (33 mg, 60%).

1H NMR (300 MHz, CDCl3) δ M. D. 0,96-of 1.26 (m, 3H), 1,29-of 1.39 (m, 2H), 1,42-of 1.83 (m, 8H), 1,98-2,10 (m, 2H), 2,13 (s, 3H), 2,33-2,51 (m, 1H), 3,83-of 4.04 (m, 1H), 6,10 (d, J=7,0 Hz, 1H), 7,20-7,29 (m, 1H), 7,45-to 7.55 (m, 2H), 7,76-7,86 (m, 2H), 11,31-11,48 (user.s, 1H).

MS(+): 386 [M+H]+.

The compounds of examples 2-4 - 2-25 synthesized by carrying out essentially the same reaction as in example 1-2, 2-1 or 2-3.

Example 2-4

6-{1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylmethyl}-3-methylpyridine-2(1H)-he

Specified in the header connection�Uchali in the form of a colorless amorphous material (320 mg, 80%).

1H NMR (300 MHz, CDCl3) δ M. D. to 1.02 and 1.28 (m, 2H), 1,38-to 1.82 (m, 7H), 1,94-2,04 (m, 2H), 2,12 (d, J=0.9 Hz, 3H), of 2.45 (s, 3H), and 3.72-3,81 (m, 1H), 6,03 (d, J=7,0 Hz, 1H), 7,06-7,11 (m, 1H), 7,15-7,24 (m, 2H), 7,29 (d, J=1.9 Hz, 1H).

MS(+): 362 [M+H]+.

Example 2-5

6-{1-[3-Chloro-4-(methyl-sulfonyl)phenyl]-2-cyclopentylmethyl}-3-methylpyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (150 mg, 40%).

1H NMR (300 MHz, CDCl3) δ M. D. to 1.02 to 1.31 (m, 2H), 1,38-of 1.85 (m, 7H), 1,96-2,12 (m, 2H), 2,15 (d, J=0.9 Hz, 3H), 3,23 (s, 3H), of 3.91-was 4.02 (m, 1H), 6,11 (d, J=7,0 Hz, 1H), 7,22-7,31 (m, 1H), 7,49 (DD, J=8,2 and 1.7 Hz, 1H), 7,63 (d, J=the 1.7 Hz, 1H), 8,04 (d, J=8,2 Hz, 1H), 12,52-12,80 (user.s, 1H).

MS(+): 394 [M+H]+.

Example 2-6

6-{2-Cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethyl}-3-ethylpyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (200 mg, 25% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,97-1,24 (m, 5H), 1,35-of 1.84 (m, 7H), 1,91-2,07 (m, 2H), 2,40-of 2.66 (m, 5H), 3,61-3,83 (m, 1H), of 6.06 (d, J=7,0 Hz, 1H), 7,11-7,24 (m, 5H), 10,04-of 10.34 (user.s, 1H).

MS(+): 342 [M+H]+.

Example 2-7

6-{2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethyl}-3-ethylpyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (180 mg, 82%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,04-1,30 (m, 5H), 1,35-of 1.84 (m, 7H), 1,98-2,19 (m, 2H), 2,48-of 2.64 (m, 2H), 3,02 (s, 3H), 3,92-4,08 (m, 1H), 6,13 (d, J=7,0 Hz, 1H), 7,24 (d, J=7,2 Hz, 1H), 7,61 (d, J=8,6 Hz, 2H), 7,84 (d, J=8.4 Hz, 2H), 12,53-12,71 (user.s, 1H).

MS(+): 74 [M+H] +.

Example 2-8

6-{2-Cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethyl}-3-propylpyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (80 mg, 20% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.95 (t, J=7.38 per Hz, 3H), 1,04-1,30 (m, 2H), 1,36-of 1.85 (m, 9H), 1,94-2,07 (m, 2H), 2,39-2,51 (m, 5H), 3,69-3,83 (m, 1H), 6,04 (d, J=6,8 Hz, 1H), 7,11-7.23 percent (m, 5H), 10,23-10,40 (user.s, 1H).

MS(+): 356 [M+H]+.

Example 2-9

6-{2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethyl}-3-propylpyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (60 mg, 68%).

1H NMR (300 MHz, CDCl3) δ M. D. 0,92-1,02 (m, 3H), 1,05-1,30 (m, 2H), 1,36-of 1.85 (m, 9H), 2,02-2,17 (m, 2H), 2,44-of 2.57 (m, 2H), 3,02 (s, 3H), 3,94-4,06 (m, 1H), 6,11 (d, J=7,0 Hz, 1H), 7,22 (d, J=7,0 Hz, 1H), 7,53-7,65 (m, 2H), 7,79-7,90 (m, 2H), 12,45-12,75 (user.s, 1H).

MS(+): 388 [M+H]+.

Example 2-10

6-{2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (102 mg, 35%).

1H NMR (300 MHz, CDCl3) δ M. D. 0,64-0,74 (m, 2H), 0.87 to 0.99 (m, 2H), 1,03-1,31 (m, 2H), 1,34-of 1.84 (m, 7H), 1,97-2,17 (m, 3H), 3,02 (s, 3H), 3,98 (t, J=7,7 Hz, 1H), 6,10 (d, J=7,2 Hz, 1H), 6,95 (d, J=7,2 Hz, 1H), 7,51-of 7.62 (m, 2H), 7,79-to 7.89 (m, 2H), 11,92 to 12.24 (user.s, 1H).

MS(+): 386 [M+H]+.

Example 2-11

6-(2-Cyclopentyl-1-{4-[(3-hydroxypropyl)sulfonyl]phenyl}ethyl)-3-ethylpyridine-2(1H)-he

Specified in the title compound was obtained as a devil�Veten amorphous substance (26 mg, 52%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,02-of 1.27 (m, 4H), 1,38-of 1.85 (m, 8H), 1,90-of 2.23 (m, 4H), 2,44-of 2.64 (m, 2H), is 3.08-or 3.28 (m, 2H), 3,61-of 3.78 (m, 2H), a 3.87-4,06 (m, 1H), 6,15 (d, J=7,0 Hz, 1H), 7,24 (d, J=7,0 Hz, 1H), 7,44-7,61 (m, 2H), 7,76-7,86 (m, 2H), 11,54-11,91 (user.s, 1H).

MS(+): 418 [M+H]+.

Example 2-12

6-{2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]ethyl}-3-(propane-2-yl)pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (36 mg, 97%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,02-of 1.29 (m, 7H), 1,39-of 1.88 (m, 8H), 2,02-of 2.20 (m, 2H), 3,02 (s, 3H), 3,06-3,23 (m, 1H), 3,89-4,06 (m, 1H), 6,15 (d, J=7,2 Hz, 1H), 7.23 percent (d, J=6,5 Hz, 1H), 7,53-7,69 (m, 2H), 7,81-7,96 (m, 2H), 12,18-12,41 (user.s, 1H).

MS(+): 388 [M+H]+.

Example 2-13

6-[1-(3-Chloro-4-{[3-(diethylamino)propyl]sulfonyl}phenyl)-2-cyclopentylmethyl]-3-methylpyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (315 mg).

1H NMR (300 MHz, CDCl3) δ M. D. 1,05-1,90 (m, 15H), from 2.07 to 2.32 (m, 5H) 2,34-2,56 (m, 2H), 3,02-of 3.42 (m, 6H), 3.45 points-to 3.64 (m, 2H), 4,34 (t, J=7.5 Hz, 1H), about 6,82 (d, J=6,8 Hz, 1H), EUR 7.57-7,80 (m, 3H), 8,06 (d, J=7.9 Hz, 1H), 10,87-11,13 (user.s, 1H).

MS(+): 493 [M+H]+.

Example 2-14

6-(1-{3-Chloro-4-[(3-hydroxypropyl)sulfonyl]phenyl}-2-cyclopentylmethyl)-3-methylpyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (36 mg, 51% (three stages)).

1H NMR (300 MHz, CDCl3) δ M. D. 1,02-of 1.29 (m, 2H), 1,37-of 1.83 (m, 6H), 1,88-of 2.21 (m, 8H), 3,43-3,55 (m, 2H), 3,71 (t, J=5,9 Hz, 2H), 3,96 (t, J=8,0 Hz, 1H), 6,13 (�, J=7,0 Hz, 1H), 7,25-7,31 (m, 1H), of 7.48 (DD, J=8,2 and 1.7 Hz, 1H), 7.62 mm (d, J=the 1.7 Hz, 1H), 8,00 (d, J=8,1 Hz, 1H).

MS(+): 438 [M+H]+.

Example 2-15

6-{3-Cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]propyl}-3-methylpyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (88 mg, 88%).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.91-of 1.12 (m, 4H), 1,14-of 1.39 (m, 4H), 1.41 to of 1.64 (m, 4H), 1.65 V-1,83 (m, 3H), 1,88-of 2.20 (m, 5H), 2,36-2,49 (m, 1H), 3,86 (t, J=7,7 Hz, 1H), 6,12 (d, J=7,0 Hz, 1H), 7,21-7,32 (m, 1H), of 7.46-7,58 (m, 2H), The 7.75-7,84 (m, 2H), 11,74-11,98 (user.s, 1H).

MS(+): 400 [M+H]+.

Example 2-16

6-{2-Cyclohexyl-1-[4-(methylsulfanyl)phenyl]ethyl}-3-methylpyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (750 mg, 55% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,85-1,02 (m, 2H), 1,04-1,20 (m, 4H), 1,48-1,94 (m, 7H), 2,10 (s, 3H), 2,46 (s, 3H), 3,81-3,93 (m, 1H), 6,01 (d, J=6,8 Hz, 1H), 7,11-7,24 (m, 5H), 10,30-10,48 (user.s, 1H).

MS(+): 342 [M+H]+.

Example 2-17

6-{2-Cyclohexyl-1-[4-(methyl-sulfonyl)phenyl]ethyl}-3-methylpyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (105 mg, 87%).

1H NMR (300 MHz, CDCl3) δ M. D. 0,82-1,23 (m, 6H), 1,52-of 2.06 (m, 7H), to 2.13 (s, 3H), 3,02 (s, 3H), 4,00-4,18 (m, 1H), 6,08 (d, J=7,0 Hz, 1H), 7,18-7,31 (m, 1H), 7,49-7,63 (m, 2H), 7,78-7,90 (m, 2H), 12,13-12,38 (user.s, 1H).

MS(+): 374 [M+H]+.

Example 2-18

3-Methyl-6-{1-[4-(methylsulfanyl)phenyl]-2-(tetrahydro-2H-Piran-4-yl)ethyl}pyridin-2(1H)-he

The decree�TES in the title compound was obtained as a colorless amorphous substance (220 mg, 65% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 1,18-1,46 (m, 3H), of 1.48-1,72 (m, 2H), 1,82 is 2.01 (m, 2H), 2,10 (s, 3H), 2,46 (s, 3H), 3,16-3,35 (m, 2H), 3,78-was 4.02 (m, 3H), 6,01 (d, J=6,8 Hz, 1H), 7,11-7,24 (m, 5H), 10,91-11,14 (user.s, 1H).

MS(+): 344 [M+H]+.

Example 2-19

3-Methyl-6-{1-[4-(methyl-sulfonyl)phenyl]-2-(tetrahydro-2H-Piran-4-yl)ethyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (410 mg, 78%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,25-1,45 (m, 3H), 1,51-of 1.75 (m, 2H), 1,91-2,11 (m, 2H), 2,13 (d, J=0.9 Hz, 3H), 3,03 (s, 3H), 3,19-to 3.34 (m, 2H), 3,84-3,98 (m, 2H), 4,06-4,20 (m, 1H), 6,09 (d, J=7,0 Hz, 1H), 7.23 percent-7,31 (m, 1H), 7,52-of 7.64 (m, 2H), 7,81-to 7.89 (m, 2H), 12,88-13,08 (user.s, 1H).

MS(+): 376 [M+H]+.

Example 2-20

3-Methyl-6-{1-[4-(methylsulfanyl)phenyl]-2-(4-oxocyclohexyl)ethyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (22 mg, 12% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 1,33-to 1.69 (m, 3H), 1,94-2,42 (m, 11H), 2,47 (s, 3H), 3,81-was 4.02 (m, 1H), 5,93-6,09 (m, 1H), 7,15-7,29 (m, 5H), 10,91-at 11.23 (user.s, 1H).

MS(+): 356 [M+H]+.

Example 2-21

3-Methyl-6-{1-[4-(methyl-sulfonyl)phenyl]-2-(4-oxocyclohexyl)ethyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (56 mg, 20%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,39-1,59 (m, 3H), of 1.97-2,43 (m, 11H), of 3.04 (s, 3H), 4,03-4,18 (m, 1H), 6,09 (d, J=7,2 Hz, 1H), 7.23 percent-7,31 (m, 1H), 7,54-7,67 (m, 2H), 7,81-of 7.93 (m, 2H), 12,49-12,72 (user.s, 1H).

MS(+): 388 [M+H]+.

Example -22

3-Methyl-6-{1-[4-(methylsulfanyl)phenyl]-2-[(1R)-3-oxocyclopentyl]ethyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (170 mg, 13% (two steps)).

Diastereomer mixture (colorless amorphous substance)

MS(+): 342 [M+H]+.

Example 2-23

3-Methyl-6-{1-[4-(methyl-sulfonyl)phenyl]-2-[(1R)-3-oxocyclopentyl]ethyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (86 mg, 54%).

Diastereomer mixture (colorless amorphous substance)

MS(+): 374 [M+H]+.

Patterns of examples 2-4 - 2-23 shown below.

Table 13-1

Table 13-2

Example 2-24

3-Chloro-6-(2-cyclopentyl-1-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}ethyl)pyridin-2(1H)-he

[Formula 215]

Specified in the title compound (183 mg, 90%) was obtained as a colorless amorphous substance.

1H NMR (300 MHz, CDCl3) δ M. D. from 1.07 to 1.28 (m, 2H), 1,42-of 1.80 (m, 7H), 2,04 (t, J=7,6 Hz, 2H), At 2.26 (s, 3H), 2,45-2,52 (m, 4H), 2,99-3,09 (m, 4H), 3,93 (t, J=7.9 Hz, 1H), 6,11 (d, J=7,2 Hz, 1H), of 7.46 (d, J=8.4 Hz, 2H), 7,55 (d, J=7.5 Hz, 1H), 7,68 (d, J=8,6 Hz, 2H).

MS(+): 464 [M+H]+.

Example 2-25

3-Chloro-6-{2-cyclopentyl-1-[4-(cyclopropanesulfonyl)phenyl]ethyl}pyridin-2(1H)-he

[Formula 216]

Specified in the title compound (70 mg, 49%) was obtained as colorless powder.

1H NMR (300 MHz, CDCl3) δ M. D. 0,83 with 0.93 (m, 2H), 0,98-of 1.85 (m, 11H), 2,00-2,12 (m, 2H), 2,37-2,52 (m, 1H), 3,97 (t, J=7,7 Hz, 1H), 6.18 of (d, J=7.5 Hz, 1H), 7,51 (d, J=8,2 Hz, 2H), EUR 7.57 (d, J=7.5 Hz, 1H), 7,82 (d, J=8,2 Hz, 2H), 11,67-12,04 (user.s, 1H).

MS(+): 406 [M+H]+.

Example 3-1

TRANS-6-{-1-[3-Chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylmethyl}-3-methylpyridine-2(1H)-he

[Formula 217]

1.0 M solution of diethylzinc in n-hexane (0.6 ml) was added to a solution of 6-{(E)-1-[3-chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylacetyl}-3-methylpyridine-2(1H)-she obtained in example 1-18 (36,0 mg) in dichloromethane (2.5 ml) in a nitrogen atmosphere under cooling with ice and then slowly added dropwise a solution of diiodomethane (322 mg) in dichloromethane (1.5 ml). After stirring at room temperature for 12 hours, the reaction mixture was added a saturated solution of ammonium chloride. After extraction with ethyl acetate the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and s�those was filtered and evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (NH silica gel, chloroform:hexane=3:2→1:0) with obtaining specified in the title compound as colorless solid (8.2 mg, 22%).

1H NMR (300 MHz, CDCl3) δ M. D. 0,80-1,10 (m, 2H), 1,20-1,80 (m, 10H), of 2.09 (s, 3H), 2,47 (s, 3H), of 5.99 (d, J=6,9 Hz, 1H), to 7.09 (d, J=8.4 Hz, 1H), made 7.16 interest (d, J=7,2 Hz, 1H), 7,21 (DD, J=8,4, a 1.8 Hz, 1H), 7,32 (d, J=1.5 Hz, 1H), 9,05-9,35 (user.s, 1H).

MS(+): 374 [M+H]+.

Example 3-2

TRANS-6-{1-[3-Chloro-4-(methyl-sulfonyl)phenyl]-2-cyclopentylmethyl}-3-methylpyridine-2(1H)-he

[Formula 218]

Water (0.2 ml) and Oxon(R) (99 mg) was added to a solution of TRANS-6-{1-[3-chloro-4-(methylsulfanyl)phenyl]-2-cyclopentylmethyl}-3-methylpyridine-2(1H)-she obtained in example 3-1 (20.0 mg) in methanol-tetrahydrofuran (1:1) (1.5 ml) under cooling with ice and the mixture was stirred at room temperature for one day. Another added Oxon(R) (99 mg and 66 mg every four hours), confirming the progress of the reaction with LC-MS, and the mixture was stirred for 31 hours in total. Was added to the reaction mixture water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then filtered. Evaporated under reduced pressure the solvent. The residue was purified by preparative TLC (NH silica gel, chloroform) with poluchenierazreshenija in the title compound as colorless solid (7.7 mg, 41%).

1H NMR (300 MHz, CDCl3) δ M. D. 0.80 to about 0.98 (m, 2H), 1,20-1,50 (m, 7H), 1,50-1,78 (m, 3H), to 2.13 (s, 3H), 3,25 (s, 3H), 6,13 (d, J=7,2 Hz, 1H), 7,21 (DD, J=6,9, 0.9 Hz, 1H), 7,53 (DD, J=8,1, of 1.8 Hz, 1H), 7,68 (d, J=1,8 Hz, 1H), 8,04 (d, J=8,1 Hz, 1H), 11,15-of 11.45 (user.s, 1H).

MS(+): 406 [M+H]+.

Example 3-3

TRANS-6-{2-Cyclopentyl-1-[4-(methylsulfanyl)phenyl]cyclopropyl}-3-methylpyridine-2(1H)-he

[Formula 219]

Specified in the title compound was obtained as a colorless amorphous substance (71 mg, 20%) by carrying out essentially the same reaction as in example 3-1, except that used 6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-methylpyridine-2(1H)-he obtained in example 1-7.

1H NMR (300 MHz, CDCl3) δ M. D. 0,84-to 1.77 (m, 12H), 2,07 (d, J=0.9 Hz, 3H), 2.49 USD (s, 3H), 5,96 (d, J=6,9 Hz, 1H), 7,15 (DD, J=6,9, 0.9 Hz, 1H), 7,21 (s, 4H), 8,40-and 8.50 (user.s, 1H).

MS(+): 340 [M+H]+.

Example 3-4

TRANS-6-{2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]cyclopropyl}-3-methylpyridine-2(1H)-he

[Formula 220]

Specified in the title compound was obtained as a colorless amorphous substance (28 mg, 42%) by carrying out essentially the same reaction as in example 3-2, except that used TRANS-6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]cyclopropyl}-3-methylpyridine-2(1H)-he obtained in example 3-3.

1H NMR (300 MHz, CDCl3) δ M. D. 0,75-1,00 (m, 1H), 1,20-of 1.75 (m, 11H), 2,10 (�, 3H), 3,05 (s, 3H), 6,11 (d, J=7,0 Hz, 1H), 7,20 (DD, J=8,2, of 1.2 Hz, 1H), 7.62 mm (d, J=8,2 Hz, 2H), a 7.85 (d, J=8,2 Hz, 2H), 10,40-11,00 (user.s, 1H).

MS(+): 372 [M+H]+.

Example 3-5

CIS-6-{2-Cyclopentyl-1-[4-(methylsulfanyl)phenyl]cyclopropyl}-3-methylpyridine-2(1H)-he

[Formula 221]

(1) Solution hexamethyldisilazide lithium in tetrahydrofuran (1 M, 5.5 ml) was added to a solution of (cyclopentylmethyl)triphenylphosphite (1,73 g, 3,66 mmol) in tetrahydrofuran (5 ml) in a nitrogen atmosphere under cooling with ice and the mixture was stirred under cooling with ice for one hour. Was added to the reaction solution, a solution of (6-methoxy-5-methylpyridine-2-yl)[4-(methylsulfanyl)phenyl]methanone obtained in reference example 1-36 (1.0 g) in tetrahydrofuran (2.5 ml) under cooling with ice and the mixture was stirred at room temperature for 16 hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. Evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:hexane=1:9→1:2) to give (Z)-6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-2-methoxy-3-methylpyridine (493 mg, 40%) as a more polar product.

(2) a 1.0 M solution of diethylzinc in n-hexane (5,96 ml) was added to a solution of (Z)-6-{2-cyclopentyl-[4-(methylsulfanyl)phenyl]ethenyl}-2-methoxy-3-methylpyridine (405 mg) in dichloromethane (20 ml) in a nitrogen atmosphere under cooling with ice and then slowly added dropwise a solution of diiodomethane (3.2 g) in dichloromethane (8 ml). After stirring at room temperature for 4 hours, the reaction mixture was added a saturated solution of ammonium chloride. After extraction with ethyl acetate the organic phase was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (chloroform:hexane=1:5), to obtain CIS-6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]cyclopropyl}-2-methoxy-3-methylpyridine (127 mg, 30%).

(3) 48% bromoethanol acid (1.0 ml) was added to a solution of CIS-6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]cyclopropyl}-2-methoxy-3-methylpyridine (100 mg) in acetonitrile (1.0 ml) and the mixture was stirred at 95°C for one hour. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (NH silica gel, chloroform:hexane=1:1) obtaining specified in the title compound as a colorless amorphous substance (91 mg, 94%).

1H NMR (300 MHz, DMSO-d6) δ M. D. 0,94-of 1.04 (m, 1H), 1,10-1,90 (m, 11H), of 1.92 (s, 3H), 2,42 (s,3H), 6,11 (d, J=5.3 Hz, 1H), made 7.16 interest-7,20 (user.s, 4H), from 7.24 (d, J=7,0 Hz, 1H), 11,20-11,40 (user.s, 1H).

MS(+): 340 [M+H]+.

Example 3-6

CIS-6-{2-Cyclopentyl-1-[4-(methyl-sulfonyl)phenyl]cyclopropyl}-3-methylpyridine-2(1H)-he

[Formula 222]

Specified in the title compound was obtained as a colorless amorphous substance (71 mg, 72%) by carrying out essentially the same reaction as in example 3-2, except that used CIS-6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]cyclopropyl}-3-methylpyridine-2(1H)-he obtained in example 3-5.

1H NMR (300 MHz, CDCl3) δ M. D. 1,15-1,90 (m, 12H), of 2.09 (s, 3H), 3,01 (s, 3H), 6.18 of (d, J=7,0 Hz, 1H), from 7.24 (DD, J=7,0, a 1.2 Hz, 1H), 7,45 (d, J=8,2 Hz, 2H), 7,80 (d, J=8,2 Hz, 2H), 10,20-10,85 (user.s, 1H).

MS(+): 372 [M+H]+.

Example 4-1

3-Cyclopropyl-6-{(E)-1-[4-(methylsulfanyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 223]

(1) 1 M solution hexamethyldisilazide lithium in tetrahydrofuran (6,68 ml) was added to a solution of (5R)-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-2-one obtained in reference example 3-2 (1,07 g) in tetrahydrofuran (10 ml) at -78°C in a stream of gaseous nitrogen and the mixture was stirred at -78°C for 30 minutes. Added a solution of (5-cyclopropyl-6-methoxypyridine-2-yl)[4-(methylsulfanyl)phenyl]methanone obtained in reference example 1-51 (500 mg) in tetrahydrofuran (10 ml) and �rity stirred at -78°C for one hour. The reaction solution was poured into a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:ethyl acetate=1:2) to give (5R)-5-{(E)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(methylsulfanyl)phenyl]ethenyl}pyrrolidin-2-one as a colorless oil (50,6 mg, 8%).

(2) Specified in the title compound was obtained as colorless powder (21 mg, 45%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-{(E)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(methylsulfanyl)phenyl]ethenyl}pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.46 to 0.75 (m, 2H), 0,85-1,11 (m, 2H), 2,00-to 2.18 (m, 2H), 2,21-2,43 (m, 3H), 2,53 (s, 3H), 4,12-4,31 (m, 1H), 5.78% was established (d, J=7,3 Hz, 1H), 6,25-system 6.34 (user.s, 1H), gold 6.43 (s, 1H), 6,83 (d, J=7.9 Hz, 1H), was 7.08 (d, J=8,5 Hz, 2H), 7.23 percent-7,34 (m, 2H), 11,47-11,66 (user.s, 1H).

MS(+): 367 [M+H]+.

Example 4-2

3-Chloro-6-{(E)-1-(3-chloro-4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 224]

(1) (5R)-5-[(E)-2-(3-Chloro-4-ethoxyphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it was obtained as a colorless oil (180 mg, 17% by carrying out essentially the same reaction, as in example 4-1(1), except that used the (3-chloro-4-ethoxyphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon obtained in reference example 1-24, and used (5R)-5-[(1,3-benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-2-he obtained in reference example 3-12, instead of (5R)-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-2-one. Was also obtained (5R)-5-[2-(3-chloro-4-ethoxyphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (E:Z=1:1 mixture) as a colorless oil (182 mg).

(2) Specified in the title compound was obtained as colorless powder (118 mg, 73%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-[(E)-2-(3-chloro-4-ethoxyphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.51 (t, J=7,0 Hz, 3H), 2,19-of 2.57 (m, 4H), of 4.09-4,30 (m, 3H), 5.78% was established (d, J=7,8 Hz, 1H), 6,50 (d, J=9,2 Hz, 1H), 6,94-7,01 (m, 1H), 7,05-7,14 (m, 2H), 7,22 (d, J=2,2 Hz, 1H), of 7.48 (d, J=7,8 Hz, 1H), 12.84 per-13,14 (user.s, 1H).

MS(+): 393 [M+H]+.

Example 4-3

3-Chloro-6-{1-(3-chloro-4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he

[Formula 225]

(1) (5R)-5-[2-(3-Chloro-4-ethoxyphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethyl]pyrrolidin-2-it was obtained as a colorless amorphous substance (73 mg, 91%) by carrying out essentially the same reaction as in example 2-3, except that used a mixture of (5R)-5-[2-(3-Chloe�-4-ethoxyphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (E:Z=1:1), obtained in example 4-2(1).

(2) Specified in the title compound was obtained as a colorless amorphous substance (43 mg, 61%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-[2-(3-chloro-4-ethoxyphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethyl]pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.46 (t, J=7,0 Hz, 3H), 1,71-of 1.92 (m, 2H), 2,09-2.49 USD (m, 4H), 3.46 in-of 3.69 (m, 1H), 3,89-4,15 (m, 3H), 6,00-6,05 (m, 1H), of 6.85-6,91 (m, 1H), 7,13-7,25 (m, 1H), 7,29-7,35 (m, 1H), 7,50-7,51 (m, 1H).

MS(+): 395 [M+H]+.

The compounds of examples 4-4 - 4-38 synthesized by carrying out essentially the same reaction as in example 4-1 or 4-2.

Example 4-4

3-Cyclopropyl-6-{(E)-1-(4-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (78 mg, 21% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. at 0.50 to 0.67 (m, 2H), 0,92-of 1.03 (m, 2H), 1,98-2,19 (m, 2H), 2,19-2,47 (m, 3H), is 2.40 (s, 3H), 4,08-4,22 (m, 1H), 5,79 (d, J=7,4 Hz, 1H), of 6.26 (s, 1H), 6,40 (d, J=9.1 Hz, 1H), 6,83 (d, J=7,2 Hz, 1H), 7,05 (d, J=8,0 Hz, 2H), 7,22 (d, J=7,7 Hz, 2H), 11,28-11,48 (user.s, 1H).

MS(+): 335 [M+H]+.

Example 4-5

3-Cyclopropyl-6-{(E)-1-(4-ethylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (30 mg, 12% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,50-0,70 (m, 2H), 0,80-1,05 (m, 2H), of 1.29 (t, J=7,8 Hz, 3H), 1,95-2,19 (m, 2H), 2,19-of 2.43 (m, 3H), 2,70 (�., J=7,8 Hz, 2H), 4,08-of 4.25 (m, 1H), 5,84 (d, J=7,3 Hz, 1H), 5,95 (s, 1H), of 6.31 (d, J=9,2 Hz, 1H), of 6.85 (d, J=7,3 Hz, 1H), 7,06 (d, J=8,3 Hz, 2H), 7,25 (d, J=8,3 Hz, 2H), 10,50-of 10.73 (user.s, 1H).

MS(+): 349 [M+H]+.

Example 4-6

3-Cyclopropyl-6-{(E)-1-(4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (44 mg, 16% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,55-0,70 (m, 2H), of 0.91 was 1.06 (m, 2H), 1,45 (t, J=7,0 Hz, 3H), 1,97-of 2.20 (m, 2H), 2,22-of 2.46 (m, 3H), 4,07 (sq, J=7,0 Hz, 2H), is 4.21 (DD, J=16,0, 7,0 Hz, 1H), 5,86 (d, J=7,4 Hz, 1H), 6,08 (s, 1H), 6,29 (d, J=9.1 Hz, 1H), at 6.84 (d, J=7,4 Hz, 1H), at 6.92 (d, J=9.1 Hz, 2H), 7,06 (d, J=9.1 Hz, 2H), of 10.73-10,92 (user.s, 1H).

MS(+): 365 [M+H]+.

Example 4-7

3-Cyclopropyl-6-{(E)-1-(3-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (46 mg, 18% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.54 to 0.63 (m, 2H), 0,90-1,05 (m, 2H), 1,43 (t, J=6,9 Hz, 3H), 1,92-2,17 (m, 2H), 2,20-2,48 (m, 3H), 3,95-to 4.28 (m, 3H), 5,67-5,79 (m, 1H), 5,94 (d, J=7,2 Hz, 1H), of 6.25 (d, J=9,3 Hz, 1H), 6,60-6,68 (m, 1H), 6,71 (d, J=7.5 Hz, 1H), of 6.85 (d, J=7,2 Hz, 1H), 6,94 (DD, J=8,1, 2,1 Hz, 1H).

MS(+): 365 [M+H]+.

Example 4-8

3-Cyclopropyl-6-{(E)-1-[3-(3-hydroxypropoxy)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (17 mg, 9% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.58 and 0.64 (m, 2H), 0,94-1,00 (m, 2H), ,00-2,16 (m, 5H), 2,21-2,41 (m, 3H), 3,86 (t, J=5.7 Hz, 2H), 4,08-4,22 (m, 3H), 5,87 (d, J=7,4 Hz, 1H), 6,12-6.18 of (user.s, 1H), 6,33 (d, J=8,9 Hz, 1H), 6,65 to 6.75 (m, 2H), 6,83 (d, J=7,4 Hz, 1H), 6,86-to 6.95 (m, 1H), 7,32 (t, J=8,0 Hz, 1H), 10,63-of 11.02 (user.s, 1H).

MS(+): 395 [M+H]+.

Example 4-9

3-Cyclopropyl-6-{(E)-1-[3-(4-hydroxyethoxy)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (16 mg, 6% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,45-0,70 (m, 2H), 0,85-1,05 (m, 2H), 1,62-of 2.45 (m, 10H), 3,71 (t, J=6.3 Hz, 2H), 3,92-4,08 (m, 2H), 4,10-to 4.23 (m, 1H), of 5.75 (d, J=7,4 Hz, 1H), 6,50 (d, J=8,9 Hz, 1H), 6,69 (s, 1H), 6,73 (d, J=7,4 Hz, 1H), 6,80 (d, J=7,4 Hz, 2H), 6,91 (d, J=7,7 Hz, 1H), 7,30 (t, J=7.9 Hz, 1H).

MS(+): 409 [M+H]+.

Example 4-10

6-{(E)-1-(3-Chloro-4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as a colorless solid (17 mg, 12% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.50 to 0.68 (m, 2H), 0,90-1,05 (m, 2H), 1,51 (t, J=6,9 Hz, 3H), 2,00-2,20 (m, 2H), 2,20-2,45 (m, 3H), 4,10-to 4.23 (m, 3H), of 5.75 (d, J=7,2 Hz, 1H), 6,44 (d, J=to 8.7 Hz, 1H), 6,54 (s, 1H), at 6.84 (d, J=7.5 Hz, 1H), 6,94 (d, J=8.4 Hz, 1H), 7,01 (DD, J=8,1, 2,1 Hz, 1H), made 7.16 interest (d, J=2.1 Hz, 1H), 11,70-11,90 (user.s, 1H).

MS(+): 399 [M+H]+.

Example 4-11

6-{(E)-1-[3-Chloro-4-(4-hydroxyethoxy)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as white solid (22 mg, 9% (two steps)).

1H �Mr (300 MHz, CDCl3) δ M. D. of 0.50 to 0.75 (m, 2H), 0,92-of 1.07 (m, 2H), 1,75-1,90 (m, 2H), 1,90-2,20 (m, 4H), 2,20-2,48 (m, 3H), of 3.77 (t, J=6,1 Hz, 2H), 4,04-to 4.23 (m, 3H), 5,77 (d, J=7,4 Hz, 1H), 6,36-6,50 (m, 2H), of 6.85 (d, J=7,4 Hz, 1H), 6,90-7,07 (m, 2H), 7,17 (s, 1H), 11,50-11,80 (user.s, 1H).

MS(+): 443 [M+H]+.

Example 4-12

3-Cyclopropyl-6-{(E)-1-[4-(cyclopropanesulfonyl)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (54 mg, 3% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.57 to 0.68 (m, 2H), 0,70-0,78 (m, 2H), 0,92-of 1.04 (m, 2H), 1,10-1,21 (m, 2H), 1,92-of 2.20 (m, 3H), and 2.26 (s, 3H), 2,28-of 2.50 (m, 3H), 4,20-4,27 (m, 1H), 5,93 (d, J=7,3 Hz, 1H), 5,98 (s, 1H), of 6.26 (d, J=9,2 Hz, 1H), about 6,82-at 6.92 (m, 2H), 6,97 (DD, J=7,9, the 2.0 Hz, 1H), EUR 7.57 (d, J=8,3 Hz, 1H), 10,27-10,64 (user.s, 1H).

MS(+): 407 [M+H]+.

Example 4-13

3-Chloro-6-{(E)-1-[3-chloro-4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (156 mg, 32% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.70 to 0.82 (m, 2H), 1,10-of 1.29 (m, 2H), 2,06-of 2.20 (m, 1H), 2,20-2,60 (m, 4H), 4,12-4,30 (m, 1H), of 5.81 (d, J=7.9 Hz, 1H), a 6.53 (d, J=9,2 Hz, 1H), 6,94 (s, 1H), 7,12 (DD, J=8,3, of 1.7 Hz, 1H), 7,17 (d, J=the 1.7 Hz, 1H), 7,50 (d, J=7.9 Hz, 1H), 7,63 (d, J=8,3 Hz, 1H), 12,93-13,01 (user.s, 1H).

MS(+): 421 [M+H]+.

Example 4-14

3-Chloro-6-{(E)-1-(4-ethylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (64 mg, 15% (two steps)).

p> 1H NMR (300 MHz, CDCl3) δ M. D. of 1.29 (t, J=7.5 Hz, 3H), 1.65 V and 1.95 (user.s, 1H), 2,18-of 2.58 (m, 4H), 2,70 (sq, J=7.5 Hz, 2H), 4,13-4,35 (m, 1H), 5.78% was established (d, J=7.5 Hz, 1H), 6,50 (d, J=9,0 Hz, 1H), 7,12 (d, J=7,8 Hz, 2H), 7,26 (d, J=7,8 Hz, 2H), of 7.46 (d, J=7.5 Hz, 1H).

MS(+): 343 [M+H]+.

Example 4-15

3-Chloro-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(propane-2-yl)phenyl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (21 mg, 5% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.29 (s, 3H), of 1.31 (s, 3H), 2,07-of 2.50 (m, 4H), 2,90-3,02 (m, 1H), 4,17-to 4.28 (m, 1H), 5,93 (d, J=7.5 Hz, 1H), 6,04-6,15 (m, 1H), 6,38 (d, J=9,0 Hz, 1H), to 7.09 (d, J=7,8 Hz, 2H), 7,29 (d, J=8,1 Hz, 2H), 7,50 (d, J=7.5 Hz, 1H), 11,50-11,84 (user.s, 1H).

Example 4-16

3-Chloro-6-[(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-(4-propylphenyl)ethenyl]pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (21 mg, 7% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,99 (t, J=7,4 Hz, 3H), 1,69 (sq t, J=to 7.5, 7.5 Hz, 2H), 2,12-2,51 (m, 4H), of 2.64 (t, J=7,6 Hz, 2H), 4,15-4,27 (m, 1H), of 5.89 (d, J=7,4 Hz, 1H), 6,23 (s, 1H), 6,41 (d, J=9,0 Hz, 1H), was 7.08 (d, J=7,8 Hz, 2H), 7,21-7,27 (m, 2H), 7,50 (d, J=7,8 Hz, 1H), a 12.03-12,12 (user.s, 1H).

MS(+): 357 [M+H]+.

Example 4-17

6-{(E)-1-(4-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he

Specified in the title compound was obtained as white solid (51 mg, 15% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. is 0.96 (t, J=7,4 Hz, 3H), of 1.40 (sq t, J=to 7.5, 7.5 Hz, 2H), 1,57-1,70 (m, 2H), 2,16-2,52 (m, 4H), of 2.66 (t, J=7,8 �C, 2H), 4,16-to 4.26 (m, 1H), 5,82 (d, J=7,4 Hz, 1H), of 6.46 (d, J=9.4 Hz, 1H), 6,63 (s, 1H), to 7.09 (d, J=8,2 Hz, 2H), 7,24 (d, J=8,2 Hz, 2H), of 7.48 (d, J=7,8 Hz, 1H), 12,60-12,67 (user.s, 1H).

MS(+): 371 [M+H]+.

Example 4-18

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he

Specified in the title compound was obtained as white solid (52 mg, 14% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 1,38 (s, 9H), 2,10-of 2.25 (m, 1H), 2,30-by 2.55 (m, 3H), 4,15-of 4.35 (m, 1H), 5,97 (d, J=7,7 Hz, 1H), 6,01-6,15 (user.s, 1H), 6,37 (d, J=9,2 Hz, 1H), 7,10 (DD, J=6,6, 1.5 Hz, 2H), of 7.46 (d, J=6,6 Hz, 2H), 7,52 (d, J=7,4 Hz, 1H), 11,30-11,70 (user.s, 1H).

MS(+): 371 [M+H]+.

Example 4-19

3-Chloro-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(trifluoromethyl)phenyl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (125 mg, 37% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 2,20-2,42 (m, 4H), 4,08-4,17 (m, 1H), for 5.66 (d, J=7,8 Hz, 1H), 6,65 (d, J=9.4 Hz, 1H), 7,41 (d, J=8,2 Hz, 2H), 7,47 (d, J=7,8 Hz, 1H), 7,68-the 7.75 (m, 3H), 13,19-13,30 (user.s, 1H).

MS(+): 383 [M+H]+.

Example 4-20

3-Chloro-6-{(E)-1-[3-chloro-4-(3-methylbutoxy)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (27 mg, 21% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,99 (s, 3H), 1,01 (s, 3H), 1,78 (TD, J=6,6 Hz, 6,6 Hz, 2H), 1,84-of 1.97 (m, 1H), 2,12-by 2.55 (m, 4H), 4,08 (t, J=6.3 Hz, 2H), 4,17-4,22 (m, 1H), of 5.85 (d, J=7,8 Hz, 1H), gold 6.43 (d, J=9,6 Hz, 1H), 6,40-of 6.52 (m, 1H), 6,97 (d, J=to 8.7 Hz, 1H), 7,05(DD, J=8,6, 2,0 Hz, 1H), of 7.19 (d, J=2.1 Hz, 1H), 7,51 (d, J=7.5 Hz, 1H), 12,30-by 12.74 (user.s, 1H).

MS(+): 435 [M+H]+.

Example 4-21

3-Chloro-6-{(E)-1-{3-chloro-4-[(4-methylpentyl)oxy]phenyl}-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (21 mg, 7% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.95 (d, J=6,5 Hz, 6H), 1,31-1,71 (m, 3H), 1,80-of 1.98 (m, 2H), 2,10-2,53 (m, 4H), 4,06 (t, J=6,5 Hz, 2H), 4,22 (DD, J=16,0, and 7.8 Hz, 1H), 5,87 (d, J=7,4 Hz, 1H), 6,28 (s, 1H), 6,41 (d, J=9,0 Hz, 1H), Of 6.96 (d, J=8,2 Hz, 1H), 7,03 (DD, J=8,2, 2,0 Hz, 1H), of 7.19 (d, J=2,0 Hz, 1H), 7,51 (d, J=7,8 Hz, 1H), 12,15-12,30 (user.s, 1H).

MS(+): 449 [M+H]+.

Example 4-22

3-Chloro-6-{(E)-1-[3-chloro-4-(2-methylpropoxy)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (5 mg, 5% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.09 (d, J=7,0 Hz, 6H), 2,09-2,52 (m, 5H), 3,83 (d, J=6.1 Hz, 2H), 4,22 (DD, J=16,0, 7,0 Hz, 1H), of 5.81 (d, J=7,8 Hz, 1H), 6,47 (d, J=9,0 Hz, 1H), was 6.77 (s, 1H), 6,95 (d, J=8,6 Hz, 1H), 7,06 (DD, J=8,6, 2,0 Hz, 1H), 7,20 (d, J=2,0 Hz, 1H), 7,50 (d, J=7,8 Hz, 1H), 12,70-of 12.92 (user.s, 1H).

MS(+): 421 [M+H]+.

Example 4-23

3-Chloro-6-{(E)-1-(3,4-dimethylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (56 mg, 12% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 2,14-of 2.27 (m, 2H), to 2.29 (s, 3H), 2,31 (s, 3H), 2,33-2,52 (m, 2H), 4,15-of 4.25 (m, 1H), 5,86 (d, J=7,8 Hz, 1H), 6,44 d, J=9,0 Hz, 1H), 6,47 (s, 1H), 6,87-to 6.95 (m, 2H), of 7.19 (d, J=7,4 Hz, 1H), of 7.48 (d, J=7,8 Hz, 1H), 12,35-12,45 (user.s, 1H).

MS(+): 343 [M+H]+.

Example 4-24

3-Chloro-6-{(E)-1-(3-chloro-4-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (40 mg, 10% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 2,16-2,40 (m, 3H), 2,43 (s, 3H), 2,45-of 2.54 (m, 1H), 4,11-4,22 (m, 1H), 5.78% was established (d, J=7,8 Hz, 1H), 6,54 (d, J=9.4 Hz, 1H), 6,80 (s, 1H), 7,01 (d, J=7,8 Hz, 1H), of 7.19 (s, 1H), 7,30 (d, J=7,8 Hz, 1H), Of 7.48 (d, J=7,4 Hz, 1H), 12,88-12,98 (user.s, 1H).

MS(+): 363 [M+H]+.

Example 4-25

3-Chloro-6-{(E)-1-[4-methyl-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (41 mg, 18% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 2,20-2,50 (m, 4H), of 2.57 (s, 3H), 4,05-of 4.35 (user.s, 1H), 5,73 (d, J=6,6 Hz, 1H), 6,40-of 6.85 (m, 2H), 7,35-7,45 (m, 3H), of 7.46 and 7.60 (m, 1H), 12,50-13,40 (user.s, 1H).

MS(+): 397 [M+H]+.

Example 4-26

3-Chloro-6-{(E)-1-[4-(4-hydroxybutyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (15 mg, 4% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 1,40-1,90 (m, 5H), 2,10-of 2.58 (m, 4H), 2,69 (t, J=7,4 Hz, 2H), 3,69 (t, J=6,1 Hz, 2H), 4,10-to 4.28 (m, 1H), 5.78% was established (d, J=7,7 Hz, 1H), 6,48 (d, J=8,9 Hz, 1H), 6,80-to 6.95 (user.s, 1H), 7,10 (d, J=8,0 Hz, 2H), 7,24 (d, J=7,1 Hz, 2H), of 7.46 (d, J=7,7 Hz, 1H), 12,60-13,00 (user.s, 1H).

MS(+): 387 [M+H]+.

�example 4-27

3-Chloro-6-{(E)-1-[3-chloro-4-(ethylsulfanyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (315 mg (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.43 (t, J=7,4 Hz, 3H), 2,17-of 2.57 (m, 4H), 3,02 (sq, J=7,4 Hz, 2H), 4,10-of 4.33 (m, 1H), 5,79 (d, J=7,8 Hz, 1H), a 6.53 (d, J=9,2 Hz, 1H), at 6.92-7,04 (user.s, 1H), 7,10 (DD, J=8,1, 2,0 Hz, 1H), 7,21 (d, J=1.9 Hz, 1H), 7,29 (d, J=8,1 Hz, 1H), 7,50 (d, J=7,6 Hz, 1H), of 12.92-13,10 (user.s, 1H).

MS(+): 431 [M+Na]+.

Example 4-28

3-Chloro-6-{(E)-1-{4-[2-(2-methylpropoxy)ethyl]phenyl}-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (24 mg, 9% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,89 (d, J=6,5 Hz, 6H), 1,79-of 1.93 (m, 1H), 2,11-of 2.54 (m, 4H), of 2.93 (t, J=6,8 Hz, 2H), up 3.22 (d, J=6,5 Hz, 2H), to 3.67 (t, J=7,0 Hz, 2H), 4,20 (DD, J=16,0, and 7.8 Hz, 1H), 5,79 (d, J=7,8 Hz, 1H), 6,48 (d, J=9,0 Hz, 1H), 6,55-6,72 (user.s, 1H), 7,11 (d, J=8,2 Hz, 2H), 7,30 (d, J=8,2 Hz, 2H), 7,47 (d, J=7,8 Hz, 1H), of 12.55-12,78 (user.s, 1H).

MS(+): 415 [M+H]+.

Example 4-29

3-Chloro-6-{(E)-1-[4-(2-methylpropyl") phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (56 mg, 20% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. were 0.94 (s, 3H), of 0.96 (s, 3H), 1,84-of 1.98 (m, 1H), 2,12-2,47 (m, 4H), 2,52 (d, J=7,2 Hz, 2H), 4,16-to 4.26 (m, 1H), 5,86 (d, J=8,1 Hz, 1H), 6.32 per (s, 1H), gold 6.43 (d, J=9,0 Hz, 1H), was 7.08 (d, J=8,1 Hz, 2H), 7,21 (d, J=8.4 Hz, 2H), 7,49 (d, J=7.5 Hz, 1H), 12,17-of 12.37 (�wide.with that 1H).

MS(+): 371 [M+H]+.

Example 4-30

3-Chloro-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(triptoreline)phenyl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (57 mg, 19% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 2,22-2,60 (m, 4H), 4,10-is 4.21 (m, 1H), 5,71 (d, J=7.5 Hz, 1H), 6,56 (d, J=9,6 Hz, 1H), 7,25-7,40 (m, 4H), 7,47 (d, J=7.5 Hz, 1H), 12,95-13,20 (user.s, 1H).

MS(+): 399 [M+H]+.

Example 4-31

3-Chloro-6-{(E)-1-(2,4-dimethylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (6.9 mg, 2% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 2,00-by 2.55 (m, 10H), 3,92-4,10 (m, 1H), 5,64-5.78% was established (m, 0,5 H), 5,80-of 5.92 (m, 1.5 H), 6,45-of 6.65 (m, 1H), 6,95-7,00 (m, 1H), 7,02-7,15 (m, 2H), 7,47 (d, J=7,7 Hz, 1H).

MS(+): 343 [M+H]+.

Example 4-32

3-Chloro-6-{(E)-1-[3-chloro-4-(propane-2-yloxy)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (71 mg, 22% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D., of 1.42 (s, 3H), of 1.44 (s, 3H), of 2.05-2,60 (m, 4H), 4,10-4,30 (m, 1H), 4,55-of 4.75 (m, 1H), 5,87 (d, J=7,7 Hz, 1H), 6,25-6,36 (user.s, 1H), 6,41 (d, J=8,6 Hz, 1H), 6,95-7,05 (m, 2H), 7,18 (s, 1H), 7,51 (d, J=7,7 Hz, 1H), 12,20-12,45 (user.s, 1H).

MS(+): 407 [M+H]+.

Example 4-33

3-Chloro-6-{(E)-1-[4-(cyclopentylmethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as �escitalo amorphous substance (71 mg (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 1,59-1,89 (m, 6H), 2,04-2,59 (m, 6H), 3,51-with 3.79 (m, 1H), 4,14-4,31 (m, 1H), of 5.83 (d, J=7,6 Hz, 1H), of 6.46 (d, J=9,0 Hz, 1H), 6,60-6,75 (user.s, 1H), to 7.09 (d, J=8.4 Hz, 2H), of 7.36 (d, J=8.4 Hz, 2H), 7,49 (d, J=7,8 Hz, 1H), 12,53-12,78 (user.s, 1H).

MS(+): 415 [M+H]+.

Example 4-34

3-Chloro-6-{(E)-1-[4-(cyclopropanesulfonyl)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (94 mg, 16% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,70-0,78 (m, 2H), 1,12-to 1.21 (m, 2H), 2,08-2,52 (m, 5H), and 2.26 (s, 3H), 4,20-4,32 (m, 1H), 5,90 (d, J=7,6 Hz, 1H), between 6.30-6,50 (m, 2H), at 6.92 (s, 1H), 7,00 (d, J=7.9 Hz, 1H), 7,51 (d, J=7,6 Hz, 1H), 7,58 (d, J=8,3 Hz, 1H), 12,10-12,36 (user.s, 1H).

MS(+): 401 [M+H]+.

Example 4-35

3-Chloro-6-{(E)-1-[4-(methylsulfanyl)-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as white solid (108 mg, 15% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 2,21-2,53 (m, 4H), 2,58 (s, 3H), 4,17 (DD, J=16,0, 7,4 Hz, 1H), 5,70-5.78% was established (m, 1H), is 6.51-6,63 (m, 1H), 6,95 (s, 1H), 7,30-7,52 (m, 4H), 13,01-13,28 (user.s, 1H).

MS(+): 429 [M+H]+.

Example 4-36

3-Chloro-6-{(E)-1-[3-(cyclopropylmethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as pale brown powder (3.2 mg).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.65-0.75 (m, 2H), 1,05-of 1.16 (m, 2H), 2,14-of 2.54 (m, 5H), 4,15-4,27 (m, 1H), 5,82 (d, J=7,8 Hz, 1H), 6,54 d, J=9,2 Hz, 1H), 6,69 (s, 1H), 6,95 (dt, J=7,4, 1,4 Hz, 1H), 7,15 (t, J=1.6 Hz, 1H), 7,31-7,53 (m, 4H).

MS(+): 409 [M+Na]+.

Example 4-37

3-Chloro-6-{(E)-1-[4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as pale brown powder (55 mg).

1H NMR (300 MHz, CDCl3) δ M. D. 0,60-0,83 (m, 2H), 1,01-1,21 (m, 2H), 2,01-of 2.58 (m, 5H), 4,10-of 4.38 (m, 1H), of 5.85 (d, J=7,6 Hz, 1H), of 6.46 (d, J=9,0 Hz, 1H), 6,60-6,73 (user.s, 1H), 7,11 (d, J=8.4 Hz, 2H), 7,43 (d, J=8.4 Hz, 2H), 7,49 (d, J=7,6 Hz, 1H), 12,47-12,79 (m, 1H).

MS(+): 409 [M+Na]+.

Example 4-38

3-Chloro-6-{(E)-1-[3-chloro-4-(4-hydroxyethoxy)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless solid (64 mg, 18% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 1,76-of 1.88 (m, 2H), 1,94-2,04 (m, 2H), 2,10-2,56 (m, 4H), of 3.78 (t, J=6,2 Hz, 2H), 4,14 (t, J=6,0 Hz, 2H), 4,16-to 4.28 (m, 1H), 5,84 (d, J=7.5 Hz, 1H), 6,44 (d, J=9,0 Hz, 1H), 6,39-of 6.52 (user.s, 1H), 6,97 (d, J=8.4 Hz, 1H), 7,05 (DD, J=8,6, 2,0 Hz, 1H), 7,20 (d, J=2.1 Hz, 1H), 7,51 (d, J=7.5 Hz, 1H), 12,34-12,64 (user.s, 1H).

MS(+): 437 [M+H]+.

Patterns of examples 4-4 - 4-38 shown below.

Table 14-1

Table 14-2

Table 14-3

Table 14-4

Example 4-39

6-{(E)-2-[(3R)-1-Acetylpyrrolidine-3-yl]-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 226]

Specified in the title compound was obtained as a pale yellow amorphous substance (52 mg) by carrying out essentially the same reaction as in example 4-1, except that used 1-[(3S)-3-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-1-yl]Etalon obtained in reference example 3-10.

MS(+): 417 [M+Na]+.

Example 4-40

6-[(E)-2-[(3R)-1-Acetylpyrrolidine-3-yl]-1-(4-ethylphenyl)ethenyl]-3-chloropyridin-2(1H)-he

[Formula 227]

Specified in the title compound was obtained as a colorless solid (24 mg, 9% (two steps)) by carrying out essentially the same reaction as in example 4-39, IP�the shutdown, I used (5-chloro-6-methoxypyridine-2-yl)(4-ethylphenyl)methanon obtained in reference example 1-9, and used 1-{(3S)-3-[(1,3-benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-1-yl}Etalon obtained in reference example 3-17, instead of 1-[(3S)-3-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-1-yl]ethanone.

1H NMR (300 MHz, CDCl3) δ M. D. 1,18-1,34 (m, 3H), 1,94-2,34 (m, 6H), 2,58-3,03 (m, 3H), 3,21-of 3.43 (m, 1H), 3,55 (d, J=to 8.7 Hz, 1H), 3,60-of 3.80 (m, 1H), 5,73 (DD, J=7,8, and 2.7 Hz, 1H), 6,69 (DD, J=14,6, and 9.5 Hz, 1H), 7,06-7,14 (m, 2H), 7,21-7,31 (m, 2H), 7,45 (DD, J=of 7.7 and 1.7 Hz, 1H), 12,41-13,19 (user.s, 1H).

MS(+): 371 [M+H]+.

Example 4-41

6-[(E)-2-[(3R)-1-Acetylpyrrolidine-3-yl]-1-(3-chloro-4-ethoxyphenyl)ethenyl]-3-chloropyridin-2(1H)-he

[Formula 228]

Specified in the title compound was obtained as white solid (24 mg, 6% (two steps)) by carrying out essentially the same reaction as in example 4-40, except that used the (3-chloro-4-ethoxyphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon obtained in reference example 1-24.

1H NMR (300 MHz, CDCl3) δ M. D. 1,35-1,60 (m, 3H) 2,03 (s, 3H), 2,08-of 2.20 (m, 1H), 2,75-3,05 (m, 1H), 3,25-3,47 (m, 2H), 3,50-3,80 (m, 3H), 4,10-4,20 (m, 2H), 5,75-to 5.85 (m, 1H), gold 6.43-6,63 (m, 1H), about 6,82-7,05 (m, 2H), of 7.19 (DD, J=3,6, Of 2.1 Hz, 1H), 7,47 (d, J=7,1 Hz, 1H).

MS(+): 421 [M+H]+.

Example 4-42

6-{(E)-2-(1-Acetylpiperidine-4-yl)-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 229]

Specified in the title compound was obtained as colorless powder (52 mg, 3,5% (two steps)) by carrying out essentially the same reaction as in example 4-1, except that used 1-(4-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}piperidine-1-yl)Etalon obtained in reference example 3-9.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.55 and 0.64 (m, 2H), from 0.87 to 0.97 (m, 2H), 1,35-of 1.54 (m, 1H), 1,66-of 1.74 (m, 2H), of 2.06 (s, 3H), 2,07 to 2.14 (m, 2H), 2,23-of 2.38 (m, 1H), 2,38-2,51 (m, 1H), 2,54 (s, 3H), 2,87-3,00 (m, 1H), 3,76 (d, J=12,4 Hz, 1H), 4,56 (d, J=13,8 Hz, 1H), 5,72-5,80 (m, 1H), 6,15-to 6.25 (m, 1H), of 6.79 (d, J=7.5 Hz, 1H), was 7.08 (d, J=8.4 Hz, 2H), 7,28 (d, J=8,5 Hz, 2H), 10,11-10,45 (user.s, 1H).

MS(+): 409 [M+H]+.

Example 4 to 43

6-{(E)-2-(1-Acetylpiperidine-4-yl)-1-[4-(methyl-sulfonyl)phenyl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 230]

Specified in the title compound was obtained as colorless powder (20 mg, 31%) by carrying out essentially the same reaction as in example 1-2, except that used 6-{(E)-2-(1-acetylpiperidine-4-yl)-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-cyclopropylamino-2(1H)-he obtained in example 4-42.

1H NMR (300 MHz, DMSO-d6) δ M. D. of 0.53 to 0.61 (m, 2H), of 0.77-0.87 (m, 2H), 1,18-1,46 (m, 2H), 1,48-of 1.64 (m, 2H), 1,90-1,95 (m, 1H), of 1.97 (s, 3H), of 2.06-of 2.20 (m, 1H), 2,85-3,01 (m, 1H), or 3.28 (s, 3H), 3,29-3,30 (m, 1H), 3,73 (d, J=13.5 Hz, 1H), 4,20 (d, J=13.2 Hz, 1H), 5,27-of 5.45 (m, 1H), 6,44 (d, J=10.1 Hz, 1H), 6,83 (d, J=7.5 Hz, 1H), of 7.46 (d, J=8.4 Hz, 2H), 7,97 (d, J=8.4 Hz, 2H), 11,31-11,55 (user.s, 1H).

MS(+): 463 [M+Na]+.

�reamer 4-44

6-{(E)-2-(1-Acetylisatin-3-yl)-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 231]

Specified in the title compound was obtained as colorless powder (7,3 mg) by carrying out essentially the same reaction as in example 4-1, except that used 1-(3-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}azetidin-1-yl)Etalon obtained in reference example 3-11.

1H NMR (300 MHz, CDCl3) δ M. D. from 0.55 to 0.69 (m, 2H), of 0.91-of 1.03 (m, 2H), equal to 1.82 (s, 3H), a 2.01-2,19 (m, 1H), 2,53 (s, 3H), 3,27-of 3.43 (m, 1H), a 3.87-3,99 (m, 1H), 4,01-to 4.26 (m, 3H), 5.78% was established-of 5.89 (m, 1H), 6,63-6,78 (m, 1H), about 6,82 (d, J=7,3 Hz, 1H), 6,99 (d, J=8.4 Hz, 2H), 7,27 (d, J=8.4 Hz, 2H).

MS(+): 381 [M+H]+.

Example 4-45

3-Cyclopropyl-6-{(E)-2-[(2R)-1-methyl-5-oxopyrrolidin-2-yl]-1-[4-(methylsulfanyl)phenyl]ethenyl}pyridin-2(1H)-he

[Formula 232]

Specified in the title compound was obtained as colorless powder (9.5 mg) by carrying out essentially the same reaction as in example 4-1, except that used the (5R)-1-methyl-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-2-he obtained in reference example 3-3.

1H NMR (300 MHz, CDCl3) δ M. D. 0,52-0,66 (m, 2H), 0.88 to was 1.06 (m, 2H), of 1.85-2.49 USD (m, 5H), 2,53 (s, 3H), of 2.75 (s, 3H), 3,93-of 4.09 (m, 1H), 5,79 (d, J=7,3 Hz, 1H), 6,45 (d, J=9,6 Hz, 1H), of 6.79 (d, J=6,8 Hz, 1H), to 7.09 (d, J=8.4 Hz, 2H), 7,25-the 7.43 (m, 2H), 10,98 made 11.32 (user.s, 1H).

MS(+): 381 [M+H]+.

Example 4-46

3-Chloro-6-{(E)-1-[4-(qi�lapropranolol)phenyl]-2-[(3R)-1-propellerdriven-3-yl]ethenyl}pyridin-2(1H)-he

[Formula 233]

(1) tert-Butyl (3R)-3-{2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(cyclopropanesulfonyl)phenyl]ethenyl}pyrrolidin-1-carboxylate (EZ mixture) was obtained as crude product (630 mg) by carrying out essentially the same reaction as in example 4-2(1), except that used the (5-chloro-6-methoxypyridine-2-yl)[4-(cyclopropanesulfonyl)phenyl]methanon obtained in referential example 1-2 (406 mg), and used tert-butyl (3S)-3-[(1,3-benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-1-carboxylate obtained in reference example 3-16.

(2) Trifluoroacetic acid (1.5 ml) was added to a solution of tert-butyl (3R)-3-{2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(cyclopropanesulfonyl)phenyl]ethenyl}pyrrolidin-1-carboxylate (EZ mixture) (296 mg) in dichloromethane (3 ml) under cooling with ice, followed by stirring for three hours. The reaction solution was concentrated under reduced pressure to obtain 3-chloro-6-{1-[4-(cyclopropanesulfonyl)phenyl]-2-[(3R)-pyrrolidin-3-yl]ethenyl}-2-methoxypyridine (EZ mixture) in the form of a crude product (235 mg).

(3) Propionitrile (58 μl) was added to a solution of 3-chloro-6-{1-[4-(cyclopropanesulfonyl)phenyl]-2-[(3R)-pyrrolidin-3-yl]ethenyl}-2-methoxypyridine (EZ mixture) (235 mg) and triethylamine (83 μl) in tetrahydrofuran (6 ml) under cooling with ice and the mixture was stirred at room temperature for four� hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:5) to give 1-[(3R)-3-{2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(cyclopropanesulfonyl)phenyl]ethenyl}pyrrolidin-1-yl]propane-1-one (EZ mixture) in the form of a crude product (363 mg).

(4) 1-[(3R)-3-{(E)-2-(5-Chloro-6-methoxypyridine-2-yl)-2-[4-(cyclopropanesulfonyl)phenyl]ethenyl}pyrrolidin-1-yl]propane-1-it was obtained as a colorless solid (215 mg, 66%) by carrying out essentially the same reaction as in example 1-2, except that used 1-[(3R)-3-{2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(cyclopropanesulfonyl)phenyl]ethenyl}pyrrolidin-1-yl]propane-1-he (EZ mixture) (303 mg). Was obtained 1-[(3R)-3-{2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(cyclopropanesulfonyl)phenyl]ethenyl}pyrrolidin-1-yl]propane-1-he (EZ mixture) as a colorless amorphous substance (49 mg, 15%).

(5) Specified in the title compound was obtained as a colorless solid (47 mg, 84%) by carrying out essentially the same reaction as in example 1-1(2), except that used 1-[(3R)-3-{(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(cyclopropanesulfonyl)�enyl]ethenyl}pyrrolidin-1-yl]propane-1-he.

1H NMR (300 MHz, CDCl3) δ M. D. 1,06-of 1.16 (m, 5H), 1,38-of 1.47 (m, 2H), 1,60-of 2.38 (m, 2H), 2,25 (sq, J=7,8 Hz, 2H), 2,50-2,60 (m, 1H), 2,60-of 2.91 (m, 1H), 3,20-3,88 (m, 4H), 5,59-5,65 (m, 1H), 6,83 (t, J=10.5 Hz, 1H), of 7.42 (DD, J=8,3, 2,3 Hz, 2H), of 7.48 (d, J=7,8 Hz, 1H), 7,95-8,03 (m, 2H), of 12.8 and 13.3 (user.s, 1H).

MS(+): 461 [M+H]+.

MS(-): 459 [M-H]-.

Example 4-47

6-[(E)-2-[(2R)-1-Acetylpyrrolidine-2-yl]-1-(4-ethylphenyl)ethenyl]-3-chloropyridin-2(1H)-he

[Formula 234]

(1) 3-Chloro-6-{1-(4-ethylphenyl)-2-[(2R)-pyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he (E:Z=1:3 mixture) was obtained as a yellow solid (230 mg, 73% (two steps)) by carrying out essentially the same reaction as in example 4-1, except that used the (5-chloro-6-methoxypyridine-2-yl)(4-ethylphenyl)methanon obtained in reference example 1-9, and used tert-butyl (2R)-2-[(1,3-benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-1-carboxylate obtained in reference example 3-18, instead of (5R)-5-{[(1-phenyl-1H-tetrazol 5-yl)sulfonyl]methyl}pyrrolidin-2-one.

(2) Triethylamine (15,3 ml) was added to a solution of 3-chloro-6-{1-(4-ethylphenyl)-2-[(2R)-pyrrolidin-2-yl]ethenyl}pyridin-2(1H)-it (E:Z=1:3 mixture) (32.9 mg) in methylene chloride (1 ml) at room temperature was added acetyl chloride (7,8 μl) under cooling with ice, whereupon the mixture was stirred under cooling with ice for 30 minutes. Was added triethylamine (15,3 µl) and acetyl chloride (7,8 μl) under cooling with ice and the mixture was stirred at �hladanie ice for another 30 minutes. Was added to the reaction solution with water followed by extraction with methylene chloride. The organic layer was filtered through diatomaceous earth and then the solvent was concentrated under reduced pressure. To the obtained residue was added acetonitrile (329 μl) and 48% bromoethanol acid (329 μl) and the mixture was stirred at 50°C for one hour. Separately was added triethylamine (121 μl) and acetyl chloride (61,6 μl) to a solution of 3-chloro-6-{1-(4-ethylphenyl)-2-[(2R)-pyrrolidin-2-yl]ethenyl}pyridin-2(1H)-it (E:Z=1:3 mixture) (190 mg) in methylene chloride (2 ml) under cooling with ice and the mixture was stirred under cooling with ice for 30 minutes. Was added to the reaction solution with water followed by extraction with methylene chloride. The organic layer was filtered through diatomaceous earth and then the solvent was concentrated under reduced pressure. To the obtained residue was added acetonitrile (1.9 ml) and 48% bromoethanol acid (1.9 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction solutions were respectively neutralized with a saturated aqueous sodium bicarbonate at room temperature, were pooled and extracted with ethyl acetate. The organic layer was filtered through diatomaceous earth and then the solvent was concentrated under reduced pressure. The obtained residue was purified column chromatography on NH-Seeley�agile (hexane:ethyl acetate=1:1→ethyl acetate:methanol=4:1) to give yellow oil. The resulting oil was converted into a powder using acetonitrile, and the process of filtering gave specified in the title compound as a colorless solid (49 mg, 23%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,20-1,40 (m, 3H), 1,76-of 2.32 (m, 7H), 2,60 is 2.80 (m, 2H), 3,38-3,74 (m, 2H), 4,16-4,29 (m, 0,45 H), 4,39-4,52 (m, H 0,55), 5,88 (d, J=7,8 Hz, 0,55 H), of 6.02 (d, J=7,8 Hz 0,45 H), 6,21-6.35 mm (m, H 0,55), 6,35-of 6.49 (m, 0,45 H), 7,07 (d, J=7,8 Hz, 0,9 H), 7,22-7,30 (m, 3,1 H), of 7.42 (d, J=7.5 Hz, 0,55 H), 7,49 (d, J=7.5 Hz, 0,45 H), to 10.38-10,55 (user.s, 1H).

MS(+): 371 [M+H]+.

Example 4-48

3-Chloro-6-{(E)-1-(4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 235]

(1) 1 M solution hexamethyldisilazide lithium in tetrahydrofuran (35 ml) was added to a solution of (5R)-5-[(1,3-benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-2-one obtained in reference example 3-12 (5,01 g) in tetrahydrofuran (150 ml) at -78°C in a stream of gaseous nitrogen and the mixture was stirred at -78°C for 40 minutes. Added a solution of (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(5-chloro-6-methoxypyridine-2-yl)methanone obtained in reference example 1-28 (3.2 g) in tetrahydrofuran (20 ml) and the mixture was stirred at -78°C for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced�th pressure of the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:ethyl acetate=7:3→3:7) to give (5R)-5-[(E)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one as a colorless oil (688 mg, 17%).

(2) Specified in the title compound was obtained as colorless powder (62 mg, 43% (three stages)) by carrying out essentially the same reaction as in examples 1-16(2)-(3) and 1-1(2) sequentially, except that used the (5R)-5-[(E)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he used ethyliodide instead of methyliodide.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.45 (t, J=7,0 Hz, 3H), 2,11-of 2.54 (m, 4H), 4,00-4,13 (m, 2H), 4,17-of 4.33 (m, 1H), of 5.83 (d, J=7,8 Hz, 1H), to 6.42 (d, J=9,0 Hz, 1H), 6,64-6,81 (user.s, 1H), 6,87-of 6.99 (m, 2H), 7,05-7,15 (m, 2H), of 7.48 (d, J=7,6 Hz, 1H), 12,56-12,78 (user.s, 1H).

MS(+): 359 [M+H]+.

Example 4-49

3-Chloro-6-{(E)-1-(4-ethoxy-3-fluorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 236]

Specified in the title compound was obtained as colorless powder (22 mg) by carrying out essentially the same reaction as in example 4-48(1)(2), except that used 4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorophenyl)(5-chloro-6-methoxypyridine-2-yl)methanon obtained in reference example 1-26.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.50 (t, J=7,0 Hz, 3H), 2,11-2,53 (�, 4H), 4,18-4,30 (m, 3H), 5,86 (d, J=7,6 Hz, 1H), 6,29-6,37 (user.s, 1H), to 6.42 (d, J=9,0 Hz, 1H), 6,86-7,07 (m, 3H), 7,51 (d, J=7,6 Hz, 1H).

MS(+): 377 [M+H]+.

Example 4-50

3-Chloro-6-{(E)-1-(4-ethoxy-3-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 237]

(1) (5R)-5-[(E)-2-(4-{[tert-Butyl(dimethyl)silyl]oxy}-3-methylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it was obtained as a colorless amorphous substance (1.41 g, 24%) by carrying out essentially the same reaction as in example 4-48(1), except I used (4-{[tert-butyl(dimethyl)silyl]oxy}-3-methylphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon obtained in reference example 1-25.

(2) (5R)-5-[(E)-2-(5-Chloro-6-methoxypyridine-2-yl)-2-(4-hydroxy-3-methylphenyl)ethenyl]pyrrolidin-2-it was obtained as a colorless amorphous substance (610 mg, 94%) by carrying out essentially the same reaction as in example 1-16(2), except that used the (5R)-5-[(E)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it.

(3) (5R)-5-[(E)-2-(5-Chloro-6-methoxypyridine-2-yl)-2-(4-ethoxy-3-methylphenyl)ethenyl]pyrrolidin-2-it was obtained as a pale blue amorphous substance (356 mg, 95%) by carrying out essentially the same reaction as in example 1-16(3), except that used the (5R)-5-[(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-(4-hydroxy-3-methylphenyl)ethenyl]pyrrolidin�-2-he used ethyliodide instead of methyliodide.

(4) Specified in the title compound was obtained as colorless powder (140 mg, 40%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-[(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-(4-ethoxy-3-methylphenyl)ethenyl]pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.46 (t, J=7,0 Hz, 3H), of 2.23 (s, 3H), 2.26 and-by 2.55 (m, 4H), 4,08 (sq, J=7,0 Hz, 2H), 4,19-4,30 (m, 1H), 5,87 (d, J=7,6 Hz, 1H), 6,39 (d, J=9,0 Hz, 1H), 6,61 (s, 1H), at 6.84 (d, J=8,1 Hz, 1H), 6,91-7,00 (m, 2H), of 7.48 (d, J=7,8 Hz, 1H), 12,38-12,57 (user.s, 1H).

MS(+): 373 [M+H]+.

Example 4-51

3-Chloro-6-{(E)-1-[4-ethoxy-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 238]

Specified in the title compound was obtained as colorless powder (45 mg) by carrying out essentially the same reaction as in example 4-48(1)(2), except that used a [4-{[tert-butyl(dimethyl)silyl]oxy}-3-(trifluoromethyl)phenyl](5-chloro-6-methoxypyridine-2-yl)methanon obtained in reference example 1-27.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.49 (t, J=7,0 Hz, 3H), 2,19-of 2.54 (m, 4H), 4,12-to 4.23 (m, 3H), 5,77 (d, J=7,8 Hz, 1H), 6,50 (d, J=9,2 Hz, 1H), 6,73 (s, 1H), 7,06 (d, J=to 8.7 Hz, 1H), 7,30-of 7.36 (m, 1H), 7,39 (d, J=2,2 Hz, 1H), 7,51 (d, J=7,6 Hz, 1H), 12,83-of 12.92 (user.s, 1H).

MS(+): 427 [M+H]+.

Example 4-52

3-Chloro-6-{(E)-1-[4-(3-hydroxypropoxy)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 239]

(1) potassium Carbonate (470 mg) and (3 bromopropane)-tert-butyldimethylsilyl (600 μl) were successively added to a solution of (5R)-5-[(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-(4-hydroxy-3-methylphenyl)ethenyl]pyrrolidin-2-one obtained in example 4-50(2) (610 mg) in N,N-dimethylformamide (10 ml) and the mixture was stirred at room temperature for 15 hours and at 65°C for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=6:4→2:8) to give (5R)-5-[(E)-2-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-3-methylphenyl]-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one as a colorless amorphous substance (879 mg, 97%).

(2) Specified in the title compound was obtained as colorless powder (34 mg, 23%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-[(E)-2-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-3-methylphenyl]-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. 2,04-2,19 (m, 2H), 2,24 (s, 3H), 2,28-of 2.54 (m, 4H), 3,82-3,99 (m, 2H), 4,07-4,34 (m, 3H), 5,90 (d, J=7,6 Hz, 1H), 6,23-of 6.46 (m, 2H), 6,72-was 7.08 (m, 3H), 7,50 (d, J=7,6 Hz, 1H), 11,89-12,2 (W, 1H).

MS(+): 403 [M+H]+.

Example 4-53

3-Cyclopropyl-6-{(E)-1-[4-(methyl-sulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 240]

Specified in the title compound was obtained as colorless powder (27 mg, 42%) by carrying out essentially the same reaction as in example 1-2, except that used 3-cyclopropyl-6-{(E)-1-[4-(methylsulfanyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he obtained in example 4-1.

1H NMR (300 MHz, CDCl3) δ M. D. 0,49-0,72 (m, 2H), 0,88-1,10 (m, 2H), 1,97-2,19 (m, 2H), 2,22-2,48 (m, 3H), 3,14 (s, 3H), 3,95-is 4.21 (m, 1H), 5,67 (d, J=7,1 Hz, 1H), 6,38-is 6.51 (user.s, 1H), 6,56 (d, J=9,6 Hz, 1H), of 6.85 (d, J=7,1 Hz, 1H), of 7.36-7,49 (m, 2H), 7,93-8,13 (m, 2H).

MS(+): 399 [M+H]+.

Example 4-54

3-Cyclopropyl-6-{(E)-1-[4-(cyclopropanesulfonyl)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 241]

Specified in the title compound was obtained as a colorless solid (11 mg, 26%) by carrying out essentially the same reaction as in example 1-2, except that used 3-cyclopropyl-6-{(E)-1-[4-(cyclopropanesulfonyl)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he obtained in example 4-12.

1H NMR (300 MHz, CDCl3) δ M. D. 0,50-0,70 (m, 2H), 0,92-of 1.05 (m, 2H), 1,05-1,18 (m, 2H), 1,35-1,45 (m, 2H), 2,00-2,20 (m, 2H), 2,20-of 2.50 (m, 3H), 2,60-2,70 (m, 1H), 2,78 (s, 3H), 4,03-4,18 (m, 1H), 5,66 d, J=6,9 Hz, 1H), to 6.57 (d, J=9,0 Hz, 1H), 6,83 (d, J=7.5 Hz, 1H), 6,95 (s, 1H), 7,15-of 7.25 (m, 2H), 7,99 (d, J=to 8.7 Hz, 1H), 11,80-12,30 (user.s, 1H).

MS(+): 439 [M+H]+.

Example 4-55

3-Chloro-6-{(E)-1-[4-(cyclopropanesulfonyl)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 242]

Specified in the title compound was obtained as white solid (27 mg, 42%) by carrying out essentially the same reaction as in example 1-2, except that used 3-chloro-6-{(E)-1-[4-(cyclopropanesulfonyl)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he obtained in example 4-34.

1H NMR (300 MHz, CDCl3) δ M. D. 1,05-1,18 (m, 2H), 1,34-of 1.45 (m, 2H), 2,20-2,45 (m, 3H), 2,45-2,60 (m, 1H), 2,60-2,73 (m, 1H), 2,80 (s, 3H), 4,08-4,19 (m, 1H), 5,69 (d, J=7.9 Hz, 1H), only 6.64 (d, J=9,2 Hz, 1H), 7,26-7,29 (m, 2H), Of 7.48 (d, J=7,6 Hz, 1H), of 7.88 (s, 1H), 8,01 (d, J=8,3 Hz, 1H), 13,12-13,28 (user.s, 1H).

MS(+): 433 [M+H]+.

Example 4-56

3-Chloro-6-{(E)-1-[4-(methyl-sulfonyl)-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 243]

Specified in the title compound was obtained as white solid (20 mg, 29%) by carrying out essentially the same reaction as in example 1-2, except that used 3-chloro-6-{(E)-1-[4-(methylsulfanyl)-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he obtained in example 4-35.

1H NMR (300 MHz, CDCl 3) δ M. D. of 1.98-2.49 USD (m, 4H), 3,24 (s, 3H), 3,88-of 4.04 (m, 1H), 5,49-of 5.60 (m, 1H), of 6.49-6,61 (m, 1H), 6,99-7,10 (m, 1H), 7,41-of 7.46 (m, 1H), 7,65-7,78 (m, 2H), 8,28-of 8.39 (m, 1H), 12,02-to 12.28 (user.s, 1H).

MS(+): 461 [M+H]+.

Example 4-57

3-Chloro-6-{(E)-1-[4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 244]

Specified in the title compound was obtained as pale brown powder (31 mg) by carrying out essentially the same reaction as in example 1-2, except that used 3-chloro-6-{(E)-1-[4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he obtained in example 4-37.

1H NMR (300 MHz, CDCl3) δ M. D. 0,99-1,25 (m, 2H), 1,36-of 1.48 (m, 2H), 2,16-of 2.43 (m, 3H), 2,46-2,63 (m, 2H), 3,98-4,27 (m, 1H), 5,67 (d, J=7,8 Hz, 1H), 6,66 (d, J=9,5 Hz, 1H), 7,39-7,54 (m, 3H), members, 7.59-7,75 (user.s, 1H), 8,00 (d, J=8,5 Hz, 2H), 13,00-13,33 (user.s, 1H).

MS(+): 441 [M+Na]+.

Example 4-58

3-Chloro-6-{(E)-1-[3-chloro-4-(ethylsulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 245]

Specified in the title compound was obtained as colorless powder (54 mg) by carrying out essentially the same reaction as in example 1-2, except that used 3-chloro-6-{(E)-1-[3-chloro-4-(ethylsulfanyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he obtained in example 4-27.

1H NMR (300 MHz, CDCl3) δ M. D. 1,30-1,46 (m, 3H), 2,22-2,61 (m, 4H), 338-3,58 (m, 2H), 4,01-4,20 (m, 1H), 5,67 (d, J=7,8 Hz, 1H), 6,68 (d, J=9,5 Hz, 1H), of 7.42 (DD, J=8,1, of 1.7 Hz, 1H), 7,47-7,56 (m, 2H), EUR 7.57-7,66 (user.s, 1H), 8,23 (d, J=8,1 Hz, 1H), 13,08-13,37 (user.s, 1H).

MS(+): 463 [M+Na]+.

Example 4-59

3-Chloro-6-{(E)-1-[3-chloro-4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 246]

Specified in the title compound was obtained as white solid (33 mg, 32%) by carrying out essentially the same reaction as in example 1-2, except that used 3-chloro-6-{(E)-1-[3-chloro-4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he obtained in example 4-13.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.10-1.20 (m, 2H), 1,37-of 1.50 (m, 2H), 2,21-2,48 (m, 3H), 2,48-of 2.64 (m, 1H), 3,00-3,19 (m, 1H), 4,06-is 4.21 (m, 1H), 5,70 (d, J=7.9 Hz, 1H), to 6.67 (d, J=8,9 Hz, 1H), value of 7, 37 (DD, J=7,9, 1.3 Hz, 1H), of 7.48 (d, J=1.3 Hz, 1H), 7,52 (d, J=7,6 Hz, 1H), 8,12 (d, J=7.9 Hz, 1H), 12,97-13,33 (user.s, 1H).

MS(+): 453 [M+H]+.

Example 4-60

3-Chloro-6-{(E)-1-[4-(cyclopentylmethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 247]

Specified in the title compound was obtained as a colorless powder (13 mg) by carrying out essentially the same reaction as in example 1-2, except that used 3-chloro-6-{(E)-1-[4-(cyclopropanesulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he obtained in example 4-33.

1H NMR (30 MHz, CDCl3) δ M. D. 1,58-of 1.74 (m, 2H), 1,75-2,02 (m, 4H), 2,06-of 2.23 (m, 2H), 2,24-of 2.44 (m, 3H), 2,44-2,62 (m, 1H), 3,44-3,73 (m, 1H), 3,97-4,20 (m, 1H), 5,64 (d, J=7,6 Hz, 1H), 6,66 (d, J=9,3 Hz, 1H), of 7.42 and 7.55 (m, 3H), Members, 7.59-7,70 (user.s, 1H), 8,00 (d, J=8,2 Hz, 2H), 13,06-13,34 (user.s, 1H).

MS(+): 447 [M+H]+.

Example 4-61

3-Chloro-6-{(E)-1-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 248]

(1) tert-Butyl 4-[(4-{(E)-1-(5-chloro-6-methoxypyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}phenyl)sulfonyl]piperazine-1-carboxylate was obtained as a colorless amorphous substance (620 mg, 28%) by carrying out essentially the same reaction as in example 4-48(1), except that used tert-butyl 4-({4-[(5-chloro-6-methoxypyridine-2-yl)carbonyl]phenyl}sulfonyl)piperazine-1-carboxylate obtained in reference example 1-23.

(2) the Crude product containing (5R)-5-{(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(piperazine-1-ylsulphonyl)phenyl]ethenyl}pyrrolidin-2-he obtained by carrying out essentially the same reaction as in example 1-46(2), except that used tert-butyl 4-[(4-{(E)-1-(5-chloro-6-methoxypyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}phenyl)sulfonyl]piperazine-1-carboxylate.

(3) (5R)-5-[(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}ethenyl]pyrrolidin-2-it was obtained as a colorless amorphous substance (234 mg, 98%) holding p� basically the same reaction as in example 1-46(3), except that used the (5R)-5-{(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(piperazine-1-ylsulphonyl)phenyl]ethenyl}pyrrolidin-2-it.

(4) Specified in the title compound (69 mg, 30%) was obtained by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-[(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}ethenyl]pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. 2,17-2,43 (m, 7H), 2,46-of 2.64 (m, 4H), 3,01-of 3.21 (m, 4H), 3,90-4,22 (m, 1H), 5,63 (l, J=7,6 Hz, 1H), 6,63 (d, J=9,5 Hz, 1H), 7,34-of 7.64 (m, 4H), 7,82-of 7.88 (m, 2H).

MS(+): 477 [M+H]+.

Example 4-62

6-{(E)-1-{3-Chloro-4-[4-(diethylamino)butoxy]phenyl}-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 249]

Specified in the title compound was obtained as a colorless solid (20 mg, 6% (three stages)) by carrying out essentially the same reaction as in examples 4-2(1) and 1-26(4) to(5) sequentially, except that used 4-{2-chloro-4-[(5-cyclopropyl-6-methoxypyridine-2-yl)carbonyl]phenoxy}butyl 4-methylbenzenesulfonate obtained in reference example 1-65.

1H NMR (300 MHz, CDCl3) δ M. D. 0,56-to 0.67 (m, 2H), of 0.96 and 1.10 (m, 8H), 1.65 V-1,76 (m, 2H), 1,84-1,94 (m, 2H), 2,00-of 2.16 (m, 2H), 2,24-2,42 (m, 3H), 2,50-2,62 (m, 6H), 4,10 (t, J=6.3 Hz, 2H), 4,14-4,24 (m, 1H), 5,84 (d, J=7,2 Hz, 1H), 6,02 (s, 1H), 6,29 (d, J=9,0 Hz, 1H), of 6.85 (d, J=7,2 Hz, 1H), at 6.92-7,02 (m, 2H), made 7.16 interest (d, J=1,8 Hz, 1H), of 10.5-11,00 (user.with that 1H).

MS(+): 498 [M+H]+.

Example 4-63

3-Chloro-6-{(E)-1-{3-chloro-4-[4-(diethylamino)butoxy]phenyl}-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 250]

Specified in the title compound was obtained as white solid (48 mg, 21% (three stages)) by carrying out essentially the same reaction as in examples 4-2(1) and 1-26(4) to(5) sequentially, except that used 4-{2-chloro-4-[(5-chloro-6-methoxypyridine-2-yl)carbonyl]phenoxy}butyl 4-methylbenzenesulfonate obtained in reference example 1-35.

1H NMR (300 MHz, CDCl3) δ M. D. was 1.04 (t, J=7,2 Hz, 6H), 1,61-to 1.77 (m, 2H), 1,77-of 1.97 (m, 2H), 2,18-2,61 (m, 10H), 4,10 (t, J=6.3 Hz, 2H), 4,17-to 4.28 (m, 1H), of 5.81 (d, J=7,8 Hz, 1H), 6,47 (d, J=9,0 Hz, 1H), 6.75 in (s, 1H), 6,97 (d, J=8,6 Hz, 1H), 7,06 (DD, J=8,6, 2,0 Hz, 1H), 7,20 (d, J=2,0 Hz, 1H), 7,49 (d, J=7,8 Hz, 1H).

MS(+): 492 [M+H]+.

Example 4-64

3-Chloro-6-{(E)-1-{3-chloro-4-[4-(pyrrolidin-1-yl)butoxy]phenyl}-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 251]

Specified in the title compound was obtained as a colorless solid (3 mg, in 0.9% (three stages)) by carrying out essentially the same reaction as in example 4-63, except that used pyrrolidine instead of diethylamine.

1H NMR (300 MHz, CDCl3) δ M. D. 1,71-2,68 (m, 18H), 4,11 (t, J=6.3 Hz, 2H), 4,22 (DDD, J=7,8 Hz 7,8 Hz and 7.8 Hz, 1H), 5,84 (d, J=7,8 Hz, 1H), 6,45 (d, J=9,0 Hz, 1H), of 6.49-6,58 (user.s, 1H), of 6.96 (d, J=8.4 Hz, 1H), 7,05 (DD, J=8,3, 2,3 Hz, 1H), of 7.19 (d, J=1,8 Hz, 1H), 7,50 (d, J=7.5 Hz, 1H).

Example 4-65

3-Cyclopropyl-6-{(E)-1-{4-[3-(diethylamino)propoxy]phenyl}-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 252]

(1) (5R)-5-[(E)-2-[4-(3-{[tert-Butyl(dimethyl)silyl]oxy}propoxy)phenyl]-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (77 mg, 16%) was obtained by carrying out essentially the same reaction as in example 4-2(1), except use [4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl](5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-56.

(2) Triethylamine (0.031 inch ml), di-tert-BUTYLCARBAMATE (39 mg) and 4-dimethylaminopyridine (18 mg) were successively added to a solution of (5R)-5-[(E)-2-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (77 mg) in tetrahydrofuran (3 ml) at room temperature. The mixture was stirred at room temperature for 20 hours, adding neskoko time di-tert-BUTYLCARBAMATE. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and filtered. Then evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=100:0��4:1) obtaining tert-butyl (2R)-2-[(E)-2-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]-5-oxopyrrolidin-1-carboxylate (89 mg, 97%).

(3) Specified in the title compound was obtained as white solid (19 mg, 31% (four stages)) by carrying out essentially the same reaction as in example 1-26(2) to(5), except that used tert-butyl (2R)-2-[(E)-2-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)phenyl]-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]-5-oxopyrrolidin-1-carboxylate.

1H NMR (300 MHz, CDCl3) δ M. D. 0,48-0,58 (m, 2H), 0,89-of 1.05 (m, 2H), of 1.06 (t, J=7,1 Hz, 6H), 1.85 to of 2.45 (m, 7H), 2,50-2,70 (m, 6H), of 4.04 (t, J=6,4 Hz, 2H), 4,12-of 4.25 (m, 1H), 5,77 (d, J=7,4 Hz, 1H), 6,39 (d, J=8,9 Hz, 1H), 6,45-6,60 (user.s, 1H), about 6,82 (d, J=7,4 Hz, 1H), 6,91 (d, J=8,6 Hz, 2H), 7,06 (d, J=8,6 Hz, 2H).

MS(+): 450 [M+H]+.

Example 4-66

3-Chloro-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(pyrrolidin-1-ylmethyl)phenyl]ethenyl}pyridin-2(1H)-he

[Formula 253]

(1) (5R)-5-[2-(5-Chloro-6-methoxypyridine-2-yl)-2-{4-[(3-methylbutoxy)methyl]phenyl}ethenyl]pyrrolidin-2-he (E:Z=1:2 mixture) (448 mg, 95%) was obtained by carrying out essentially the same reaction as in example 4-2(1), except that used the (5-chloro-6-methoxypyridine-2-yl){4-[(3-methylbutoxy)methyl]phenyl}methanon obtained in reference example 1-10.

(2) 48% bromoethanol acid (4 ml) was added to a solution of (5R)-5-[2-(5-chloro-6-methoxypyridine-2-yl)-2-{4-[(3-methylbutoxy)methyl]phenyl}ethenyl]pyrrolidin-2-one (E:Z=1:2 mixture) (396 mg) in acetonitrile (4 ml) at room temperature and the mixture was stirred at 70°C in tech�of three hours. Sequentially added to the reaction solution at room temperature, saturated aqueous sodium bicarbonate and water, followed by extraction with chloroform. The organic layers were dried over anhydrous sodium sulfate and filtered. Then evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol=50:1→5:1) to give 6-{1-[4-(methyl bromide)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-it (E:Z=1:2 mixture) (321 mg, 85%).

(3) Pyrrolidin (0,062 ml) was added to a solution of 6-{1-[4-(methyl bromide)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-it (E:Z=1:2 mixture) (30 mg) in acetonitrile (1.2 ml) at room temperature and the mixture was stirred at room temperature for five hours.

Separately added pyrrolidine (0,424 ml) to a solution of 6-{1-[4-(methyl bromide)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-it (E:Z=1:2 mixture) (206 mg) in acetonitrile (8,24 ml) at room temperature and the mixture was stirred at room temperature for one hour. Was added to the reaction solution successively water and a saturated solution of ammonium chloride at room temperature and the mixture was combined with subsequent extraction with chloroform. The organic layers were dried over anhydrous sodium sulfate and filtered. Then evaporated under reduced� pressure the solvent. The obtained residue was purified by preparative TLC (chloroform:methanol=5:1) obtaining specified in the title compound as a white solid (70 mg, 30%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,70-1,90 (m, 4H), 2,15-to 2.65 (m, 8H), 3,65 (d, J=1,8 Hz, 2H), 4,10-of 4.26 (m, 1H), 5,76 (d, J=7,7 Hz, 1H), 6,50 (d, J=9,5 Hz, 1H), 7,06 (s, 1H), 7,14 (d, J=7,7 Hz, 2H), 7,39 (d, J=7,7 Hz, 2H), 7,45 (d, J=7,7 Hz, 1H).

MS(+): 398 [M+H]+.

Example 4-67

3-Cyclopropyl-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(propane-2-yl)phenyl]ethenyl}pyridin-2(1H)-he

[Formula 254]

(1) (5R)-5-{2-(5-the Cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}pyrrolidin-2-he (E:Z=7:2) was obtained as a colorless amorphous substance (67 mg, 14%) by carrying out essentially the same reaction as in example 4-2(1), except I used (5-cyclopropyl-6-methoxypyridine-2-yl)[4-(propane-2-yl)phenyl]methanon obtained in reference example 1-79. Was also obtained (5R)-5-{(Z)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}pyrrolidin-2-it is in the form of a colorless amorphous substance (236 mg, 49%).

(2) Specified in the title compound was obtained as a colorless solid (34 mg) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-{2-(5-the cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}pyrrolidin-2-he (E:Z=7:2).

1H NMR (300 MHz, CDCl3 ) δ M. D. 0,55-0,70 (m, 2H), were 0.94 was 1.06 (m, 2H), 1,30 (C, 3H), 1,32 (s, 3H), 1,99-2,19 (m, 2H), 2,24-2,49 (m, 3H), 2,90-3,03 (m, 1H), 4,15-to 4.28 (m, 1H), 5,84-5,98 (user.s, 1H), 5,94 (d, J=7,4 Hz, 1H), 6,27 (d, J=8,9 Hz, 1H), of 6.87 (d, J=7,4 Hz, 1H), 7,07 (d, J=8,3 Hz, 2H), 7,21-7,34 (m, 2H), 10,17-10,47 (user.s, 1H).

MS(+): 363 [M+H]+.

Example 4-68

6-{(E)-1-(4-tert-Butylphenyl)-2-[(3R)-1-propanolamide-3-yl]ethenyl}-3-chloropyridin-2(1H)-he

[Formula 255]

Specified in the title compound was obtained as white solid (48 mg, 38% (two steps)) by carrying out essentially the same reaction as in example 4-1, except that used 4-tert-butylphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon obtained in reference example 1-7, and used 1-{(3S)-3-[(1,3-benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-1-yl}propane-1-he obtained in reference example 3-19, instead of (5R)-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-2-one.

1H NMR (300 MHz, CDCl3) δ M. D. 1,13 (TD, J=7,4, 2,0 Hz, 3H), of 1.36 (d, J=2,0 Hz, 9H), 1,87-of 2.32 (m, 4H), 2,76-3,02 (m, 1H), 3,25-with 3.79 (m, 4H), 5,88 (DD, J=13,1, and 7.8 Hz, 1H), 6,48 (DD, J=31,7 at 9.6 Hz, 1H), 7,10 (DD, J=8,2, 2.5 Hz, 2H), 7,41-7,49 (m, 3H)

MS(+): 413 [M+H]+.

Examples 4-69 and 4-70

6-{1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-chloropyridin-2(1H)-he

[Formula 256]

(1) (5R)-5-[2-(4-tert-Butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (E:Z≥9:1) (110 mg, 28%) was obtained by carrying out essentially like this W� reaction as in example 4-2(1), except that used 4-tert-butylphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon obtained in reference example 1-7. Was also obtained (5R)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (E:Z=2:8) (172 mg, 44%).

(2) 5% palladium-activated carbon (30 mg) was added to a solution of (5R)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (E:Z=2:8) (150 mg) in methanol in a stream of hydrogen gas and the mixture was stirred at room temperature for seven hours. The reaction solution was filtered through celite and evaporated under reduced pressure the solvent. The obtained residue was purified column chromatography on NH-silica gel (chloroform) and then was purified by preparative TLC (chloroform), to obtain (5R)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethyl]pyrrolidin-2-one as pale brown amorphous substance (110 mg, 73%).

(3) 48% bromoethanol acid (1 ml) was added to a solution of (5R)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethyl]pyrrolidin-2-one (100 mg) in 1,4-dioxane (2 ml) and the mixture was stirred at room temperature for 30 minutes and at 65°C for 30 minutes. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then the flash steam�Wali under reduced pressure the solvent. The obtained residue was purified by preparative TLC (chloroform:methanol=10:1) to give 6-{1-(4-tert-butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-chloropyridin-2(1H)-she, which was separated by preparative HPLC (Inertsil ODS-3 (20 mm i.d. (EXT.d.) × 250 mm L, GL Sciences Inc.), 40°C, flow rate: 10 ml/min, acetonitrile:water=40:60). The fraction containing a single diastereoisomer, - eluted with a retention time of 43 minutes, concentrated to obtain specified in the title compound as a white solid (18 mg, 19%) (example 4-69).

1H NMR (300 MHz, CDCl3) δ M. D. 1,30 (C, 9H), 1,80-2,00 (m, 1H), 2,12-by 2.55 (m, 5H), 3,60-of 3.78 (m, 1H), 3,95-4,10 (m, 1H), 6,09 (d, J=8,0 Hz, 1H), 7,21 (d, J=8,3 Hz, 2H), 7,30-the 7.43 (m, 3H), 7,52 (d, J=7,4 Hz, 1H), 12,15-12,40 (user.s, 1H).

MS(+): 373 [M+H]+.

The fraction containing a single diastereoisomer, - eluted with the retention time of 48 minutes, concentrated to obtain specified in the title compound as a white solid (28 mg, 29%) (example 4-70).

1H NMR (300 MHz, CDCl3) δ M. D. 1,30 (C, 9H), 1,63-of 1.85 (m, 1H), 2,10-by 2.55 (m, 5H), 3,41-3,62 (m, 1H), 3,95 (DD, J=9,5, 6.3 Hz, 1H), 6,03 (d, J=7,4 Hz, 1H), 7,02-to 7.18 (user.s, 1H), 7.23 percent (d, J=8,0 Hz, 2H), of 7.36 (d, J=8,0 Hz, 2H), 7,49 (d, J=7,4 Hz, 1H), 11,30-11,65 (user.s, 1H).

MS(+): 373 [M+H]+.

Example 4-71

6-{(E)-1-(4-tert-Butyl-3-chlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he

[Formula 257]

Specified in the header connection received � as a colorless solid (10 mg) by carrying out essentially the same reaction, as in example 4-2, except that used a mixture of (4-tert-butyl-3-chlorophenyl)(5-chloro-6-methoxypyridine-2-yl)methanone and (5-chloro-6-methoxypyridine-2-yl)[3-chloro-4-(prop-1-EN-2-yl)phenyl]methanone (1:1) obtained in referential example 1-80.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.52 (s, 9H), of 2.09 and 2.26 (m, 1H), 2.26 and-of 2.54 (m, 3H), 4,21 (TD, J=7,6, 8,0 Hz, 1H), of 5.89 (d, J=8,0 Hz, 1H), 6,15-6,22 (m, 1H), to 6.42 (d, J=9,5 Hz, 1H), 7,01 (DD, J=8,2, 1.6 Hz, 1H), made 7.16 interest (d, J=1,8 Hz, 1H), 7,45-7,54 (m, 2H), 11,95-12,19 (user.s, 1H).

MS(+): 405 [M+H]+.

Example 4-72

6-{(E)-1-(4-tert-Butylphenyl)-2-[(3R)-1-(ethylsulfonyl)pyrrolidin-3-yl]ethenyl}-3-chloropyridin-2(1H)-he

[Formula 258]

Specified in the title compound was obtained as white solid (65 mg, 25% (two steps)) by carrying out essentially the same reaction as in example 4-1, except that used 4-tert-butylphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon obtained in reference example 1-7, and used 2-({[(3S)-1-(ethylsulfonyl)pyrrolidin-3-yl]methyl}sulfonyl)-1,3-benzothiazol, obtained in reference example 3-20, instead of (5R)-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-2-one.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.34 (t, J=7,6 Hz, 3H), of 1.37 (s, 9H), 2,05-2,17 (m, 2H), 2,87-3,06 (m, 3H), 3,26-3,39 (m, 2H), 3,53 is 3.57 (m, 2H), 5,86 (d, J=7,6 Hz, 1H), a 6.53 (d, J=9,6 Hz, 1H), was 7.08 (d, J=8,3 Hz, 2H), 7,44-7,47 (m, 3H), 11,70-11,73 (user.s, 1H).

MS(+): 449 [M+H]+.

Example 4-73

3-Chloro-6-{(E)-1-[4-(4-methoxybutyl�l)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 259]

Specified in the title compound was obtained as white solid (70 mg, 9% (two steps)) by carrying out essentially the same reaction as in example 4-2, except that used the (5-chloro-6-methoxypyridine-2-yl)[4-(4-methoxybutyl)phenyl]methanon obtained in referential example 1 to 81.

1H NMR (300 MHz, CDCl3) δ M. D. 1,40-1,98 (m, 4H), 2,11-to 2.85 (m, 6H), 3,34 (s, 3H), 3,41 (t, J=6,0 Hz, 2H), 4,08-of 4.33 (m, 1H), 5,76 (d, J=7,7 Hz, 1H), 6,50 (d, J=8,9 Hz, 1H), 6,93-value of 7, 37 (m, 5H), 7,45 (d, J=7,7 Hz, 1H), Of 12.75-13,20 (user.s, 1H).

MS(+): 401 [M+H]+.

Example 4-74

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(trifluoromethyl)pyridin-2(1H)-he

[Formula 260]

Specified in the title compound was obtained as white solid (122 mg, 19% (two steps)) by carrying out essentially the same reaction as in example 4-2, except that used 4-tert-butylphenyl)[6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanon obtained in reference example 1-82.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 2,10-of 2.58 (m, 4H), 4,14-4,30 (m, 1H), 5,90 (d, J=7,4 Hz, 1H), 6,60 (d, J=6.3 Hz, 1H), 6,70-6,98 (user.s, 1H), 7,12 (d, J=8,3 Hz, 2H), 7,45 (d, J=8,3 Hz, 2H), 7,66 (d, J=7,7 Hz, 1H).

MS(+): 405 [M+H]+.

Example 4-75

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2S)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he

[Formula 261]

(1) (5S)--[2-(4-tert-Butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (EZ mixture) (750 mg, 99%) were obtained by carrying out essentially the same reaction as in example 4-1(1), except that used 4-tert-butylphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon obtained in reference example 1-7, and used (5S)-5-[(1,3-benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-2-he obtained in reference example 3-21, instead of (5R)-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-2-one.

(2) Specified in the title compound was obtained as white solid (11 mg, 3%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5S)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (EZ mixture).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 2,02-2,22 (m, 1H), 2,25-2,53 (m, 3H), 4,15-4,32 (m, 1H), 5,93 (s, 1H), of 5.99 (d, J=7,4 Hz, 1H), 6,33 (d, J=8,9 Hz, 1H), was 7.08 (d, J=8,0 Hz, 2H), 7,45 (d, J=8,3 Hz, 2H), 7,51 (d, J=8,0 Hz, 1H), of 11.02-11,25 (user.s, 1H).

MS(+): 371 [M+H]+.

Examples 4-76 and 4-77

6-{1-(4-tert-Butylphenyl)-2-[(2S)-5-oxopyrrolidin-2-yl]ethyl}-3-chloropyridin-2(1H)-he

[Formula 262]

Specified in the title compound was obtained as white solid (46 mg, 13% (two steps)) by carrying out essentially the same reaction as in examples 4-69 and 4-70(2)(3), consecutively, except that used the (5S)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (EZ mixture) obtained Primera 4-75(1), separation of a mixture of preparative HPLC (Inertsil ODS-3 (20 mm i.d. × 250 mm L, GL Sciences Inc.), 40°C, flow rate: 10 ml/min, acetonitrile:water=40:60) and concentrating the fraction containing a single diastereoisomer, - eluted with a retention time of 44 minutes (example 4-76).

1H NMR (300 MHz, CDCl3) δ M. D. 1,30 (C, 9H), 1,80-2,05 (m, 1H), 2,10-by 2.55 (m, 5H), 3,59-of 3.75 (m, 1H), 3,95-4,11 (m, 1H), 6,07 (d, J=7,7 Hz, 1H), 7,22 (d, J=8,0 Hz, 2H), 7,34 (d, J=8,3 Hz, 2H), 7,52 (d, J=7,7 Hz, 1H), 7,55-7,73 (m, 1H), 12,50-12,90 (user.s, 1H).

MS(+): 373 [M+H]+.

The fraction containing a single diastereoisomer, - eluted with the retention time of 49 minutes, concentrated to obtain specified in the title compound as a white solid (55 mg, 15% (two steps)) (example 4-77).

1H NMR (300 MHz, CDCl3) δ M. D. 1,30 (C, 9H) 1,60-1,90 (m, 1H) 2,11-2,52 (m, 5H) 3,41-3,62 (m, 1H) 3,90-4,08 (m, 1H) 6,03 (d, J=7,7 Hz, 1H) 7,29 (d, J=8,6 Hz, 2H) 7,35 (d, J=8,3 Hz, 2H) 7,38 was 7.45 (user.s, 1H) 7,49 (d, J=7,4 Hz, 1H) 11,70-12,10 (user.s, 1H)

MS(+): 373 [M+H]+.

Example 4-78

6-{(E)-1-(4-Chlorophenyl)-2-[(3R)-1-(cyclopropanecarbonyl)pyrrolidin-3-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 263]

(1) tert-Butyl (3R)-3-[2-(4-chlorophenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-carboxylate (EZ mixture) (1.03 g, 63%) and tert-butyl (3R)-3-[(E)-2-(4-chlorophenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-carboxylate (358 mg, 22%) was obtained by carrying out essentially the�Oh reactions, as in example 4-46(1), except that used the (4-chlorophenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in referential example 1 to 95.

(2) {(3R)-3-[(E)-2-(4-Chlorophenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-yl}(cyclopropyl)methanon was obtained as a brown amorphous substance (79 mg, 83% (two steps)) by carrying out essentially the same reaction as in example 4-46(2)(3), consecutively, except that used tert-butyl (3R)-3-[(E)-2-(4-chlorophenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-carboxylate and used cyclopropanecarbonitrile as Alliluyeva reagent.

(3) Specified in the title compound was obtained as white solid (62 mg, 83%) by carrying out essentially the same reaction as in example 1-1(2) except that used {(3R)-3-[(E)-2-(4-chlorophenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-yl}(cyclopropyl)methanon.

L-column ODS-a 4.6×250 mm

0.01 M acetate buffer:MeCN = 40:60 vol./vol., 40°C, 1.0 ml/min, 254 nm

Rt = 7,843 min

MS(+): 409 [M+H]+.

MS(-): 407 [M-H]-.

Example 4-79

3-Chloro-6-{(E)-1-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 264]

Specified in the title compound was obtained as a colorless solid (10 mg, 4% (two hundred�AI)) by carrying out essentially the same reaction, as in example 4-2, except that used the (5-chloro-6-methoxypyridine-2-yl)(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanon obtained in reference example 1-83.

1H NMR (300 MHz, CDCl3) δ M. D. 1,98-2,12 (m, 1H), 2,29-of 2.50 (m, 3H), equal to 2.94 (s, 3H), 3,32-to 3.38 (m, 2H), 4,27-to 4.36 (m, 3H), 5,67-5,74 (user.s, 1H), 6,11-6,19 (m, 2H), is 6.51 (d, J=1.2 Hz, 1H), 6,54-6,60 (m, 1H), 6,60-6,68 (m, 1H), 7,50-to 7.55 (m, 1H), 9,81-10,14 (user.s, 1H).

MS(+): 386 [M+H]+.

Example 4-80

3-Cyclopropyl-6-{(1R)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(propane-2-yl)phenyl]ethyl}pyridin-2(1H)-he

[Formula 265]

(1) tert-Butyl (2R)-2-{(Z)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}-5-oxopyrrolidin-1-carboxylate was obtained as a colorless oil (235 mg, 93%) by carrying out essentially the same reaction as in example 4-65(2), except that used the (5R)-5-{(Z)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}pyrrolidin-2-he obtained in example 4-67(1).

(2) tert-Butyl (2R)-2-{2-(5-the cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethyl}-5-oxopyrrolidin-1-carboxylate was obtained as a colorless amorphous substance (211 mg, 89%) by carrying out essentially the same reaction as in example 4-69 and 4-70(2), except that used tert-butyl (2R)-2-{(Z)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}-5-oxopyrrolidin-1-carboxylate.

(3) Trifluoroacetic acid� (1 ml) was added to a solution of tert-butyl (2R)-2-{2-(5-the cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethyl}-5-oxopyrrolidin-1-carboxylate (211 mg) in methylene chloride (2 ml) under cooling with ice and the mixture was stirred under cooling ice for 75 minutes. Was added to the reaction solution, saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent to obtain (5R)-5-{2-(5-the cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethyl}pyrrolidin-2-she (176,5 mg, quantitative).

(4) Specified in the title compound was obtained as a colorless solid (12 mg, 15%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-{2-(5-the cyclopropyl-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethyl}pyrrolidin-2-he, the separation of the mixture preparative HPLC (Inertsil ODS-3 (20 mm i.d. × 250 mm L, GL Sciences Inc.), 40°C, flow rate: 10 ml/min, acetonitrile:water=40:60) and concentrating the fraction containing a single diastereoisomer, - eluted with a retention time of 39 minutes.

1H NMR (300 MHz, CDCl3) δ M. D. 0,51-0,70 (m, 2H), 0,81 was 1.06 (m, 2H), 1,21 (s, 3H), 1,24 (s, 3H), 1,62-of 1.81 (m, 1H), 1,91-2,48 (m, 6H), 2,79-2,96 (m, 1H), 3,42-3,58 (m, 1H), 3,93-of 4.05 (m, 1H), 5,97 (d, J=7,2 Hz, 1H), 6,91 (d, J=6,9 Hz, 1H), 7,18 (d, J=7,8 Hz, 2H), 7,21-7,34 (m, 2H), 7,43 (s, 1H), 11,75-12,08 (user.s, 1H).

MS(+): 365 [M+H]+.

Example 4-81

6-{(E)-1-[3-Chloro-4-(propan-2-yl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 266]

(1) (5R-5-[(E)-2-[3-Chloro-4-(propan-2-yl)phenyl]-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it was obtained as a colorless amorphous substance (37 mg, 19%) by carrying out essentially the same reaction as in example 4-2(1), except that used [3-chloro-4-(propan-2-yl)phenyl](5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-84. Was also obtained (5R)-5-[(Z)-2-[3-chloro-4-(propan-2-yl)phenyl]-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it is in the form of a colorless amorphous substance (65 mg, 32%).

(2) Specified in the title compound was obtained as a colorless solid (17 mg, 48%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-[(E)-2-[3-chloro-4-(propan-2-yl)phenyl]-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.51 to 0.68 (m, 2H), 0,92-1,08 (m, 2H), 1,28 (s, 3H), of 1.30 (s, 3H), 2,00-2,19 (m, 2H), 2,23-2,49 (m, 3H), 3,37-3,52 (m, 1H), 4,13-to 4.23 (m, 1H), 5,75-5,80 (m, 1H), 6,04-6,30 (user.s, 1H), between 6.30-6,48 (m, 1H), 6,86 (d, J=7.5 Hz, 1H), 6,98-7,07 (m, 1H), 7,14 (d, J=1.5 Hz, 1H), 7,34 (d, J=8,1 Hz, 1H), 10,65-11,79 (user.s, 1H).

MS(+): 397 [M+H]+.

Example 4-82

3-Chloro-6-{(Z)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(propane-2-yl)phenyl]ethenyl}pyridin-2(1H)-he

[Formula 267]

(1) (5R)-5-{(E)-2-(5-Chloro-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}pyrrolidin-2-he (38 mg) was obtained by carrying out essentially the same reaction as in example 4-2(1), except that used the (5-chloro-6-methoxypyridine-2-yl)[4-(propane-2-yl)phenyl]methanon, poluchennym reference example 1-11. Were also obtained (5R)-5-{(Z)-2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}pyrrolidin-2-he (223 mg) and EZ mixture (230 mg).

(2) Specified in the title compound was obtained as a colorless solid (37 mg, 20%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-{(Z)-2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. 1,23 (s, 3H), 1,25 (s, 3H), 1,85-2,00 (m, 1H), 2,24-of 2.50 (m, 3H), 2,84-2,98 (m, 1H), 4,32 (TD, J=8,1, 8,6 Hz, 1H), 6,08-6.18 of (m, 2H), 7,11-7,35 (m, 4H), members, 7.59-to 7.68 (m, 1H), 12,53-13,01 (user.s, 1H).

MS(+): 357 [M+H]+.

Example 4-83

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

[Formula 268]

(1) (5R)-5-[(E)-2-(4-tert-Butylphenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (216 mg, 55%) was obtained by carrying out essentially the same reaction as in example 4-2(1), except that used 4-tert-butylphenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon, obtained in reference example 1-85. Were also obtained (5R)-5-[(Z)-2-(4-tert-butylphenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (93 mg, 24%) and EZ mixture (46 mg, 12%).

(2) Specified in the title compound was obtained as white solid (74 mg, 36%) by carrying out essentially the same reaction as in example 1-1(2), W� except use of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. 0,50-0,65 (m, 2H), 0,90-of 1.04 (m, 2H), of 1.36 (s, 9H), 2.00 in to 2.18 (m, 2H), 2,22-of 2.46 (m, 3H), 4,16-4,27 (m, 1H), 5,86 (d, J=7,2 Hz, 1H), 6,15-6,25 (user.s, 1H), 6.35 mm (d, J=9.8 Hz, 1H), of 6.85 (d, J=7,2 Hz, 1H), was 7.08 (d, J=7,8 Hz, 2H), of 7.42 (d, J=8.4 Hz, 2H), 10,92-11,20 (user.s, 1H).

MS(+): 377 [M+H]+.

Example 4-84

3-Chloro-6-{(E)-1-[3-chloro-4-(propan-2-yl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 269]

(1) (5R)-5-{(E)-2-(5-Chloro-6-methoxypyridine-2-yl)-2-[3-chloro-4-(propan-2-yl)phenyl]ethenyl}pyrrolidin-2-it was obtained as a colorless amorphous substance (77 mg, 26%) by carrying out essentially the same reaction as in example 4-2(1), except I used (5-chloro-6-methoxypyridine-2-yl)[3-chloro-4-(propan-2-yl)phenyl]methanon obtained in reference example 1-86. Was also obtained (5R)-5-{2-(5-chloro-6-methoxypyridine-2-yl)-2-[3-chloro-4-(propan-2-yl)phenyl]ethenyl}pyrrolidin-2-he (EZ mixture) as a colorless amorphous substance (179 mg, 60%).

(2) Specified in the title compound was obtained as a colorless solid (53 mg, 71%) by carrying out essentially the same reaction as in example 1-1(2), except that used the (5R)-5-{(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-[3-chloro-4-(propan-2-yl)phenyl]ethenyl}pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.29 (s, 3H), 131 (C 3H), 2,12-of 2.54 (m, 4H), 3,25-3,50 (m, 1H), 4,22 (TD, J=7,8, 7,4 Hz, 1H), of 5.85 (d, J=7.5 Hz, 1H), 6,40 (s, 1H), 6,47 (d, J=9.8 Hz, 1H), 7,06 (DD, J=7,8, a 1.8 Hz, 1H), 7,17 (d, J=1.5 Hz, 1H), of 7.36 (d, J=7,8 Hz, 1H), 7,51 (d, J=7.5 Hz, 1H), 12,44-12,56 (user.s, 1H).

MS(+): 391 [M+H]+.

Example 4-85

3-Chloro-6-{2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(propane-2-yl)phenyl]ethyl}pyridin-2(1H)-he

[Formula 270]

Specified in the title compound was obtained as a colorless solid (58 mg, 17% (two steps)) by carrying out essentially the same reaction as in examples 4-69 and 4-70(2)(3), consecutively, except that used the (5R)-5-{2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}pyrrolidin-2-he (EZ mixture), obtained in example 4-82(1), the separation of the mixture preparative HPLC (Inertsil ODS-3 (20 mm EXT.d. × 250 mm L, GL Sciences Inc.), 40°C, flow rate: 10 ml/min, acetonitrile:water=40:60) and concentrating the fraction containing a single diastereoisomer, - eluted with a retention time of 35 minutes.

1H NMR (300 MHz, CDCl3) δ M. D. 1,22 (s, 3H), 1,24 (s, 3H), 1,61-of 1.85 (m, 1H), 2,13-by 2.55 (m, 5H), 2,80-of 2.97 (m, 1H), 3,45-3,59 (m, 1H), 3,90-of 4.04 (m, 1H), 6,02 (d, J=7,7 Hz, 1H), 7,15-7,28 (m, 4H), 7,28-7,40 (user.s, 1H), 7,49 (d, J=7,1 Hz, 1H), 11,67-11,99 (user.s, 1H).

MS(+): 359 [M+H]+.

Example 4-86

3-Chloro-6-{1-[3-chloro-4-(propan-2-yl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he

[Formula 271]

Specified in the header connection received in sidebusting solid (83 mg, 5% (two steps)) by carrying out essentially the same reaction as in examples 4-69 and 4-70(2)(3), consecutively, except that used the (5R)-5-{2-(5-chloro-6-methoxypyridine-2-yl)-2-[3-chloro-4-(propan-2-yl)phenyl]ethenyl}pyrrolidin-2-he (EZ mixture) obtained in example 4-84(1), separation of a mixture of preparative HPLC (CHIRALPAK IA (10 mm EXT.d. × 250 mm L, Daicel Chemical Industries, LTD.), 40°C, flow rate: 3 ml/min, ethanol:hexane=20:80) and concentrating the fraction containing a single diastereoisomer, - eluted with a retention time of 32 minutes.

1H NMR (300 MHz, CDCl3) δ M. D. 1,21 (s, 3H), 1,23 (s, 3H), 1,68-to 1.82 (m, 1H), 2,15-2,51 (m, 5H), or 3.28-of 3.42 (m, 1H), 3,47-3,59 (m, 1H), 3,92 is 4.03 (m, 1H), 6,02 (d, J=7,7 Hz, 1H), 7,22-7,29 (m, 2H), 7,32 (s, 1H), 7,50 (d, J=7,4 Hz, 1H), 7,47-EUR 7.57 (user.s, 1H), 12,14-12,40 (user.s, 1H).

MS(+): 393 [M+H]+.

Example 4-87

6-{1-(3-Chloro-4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he

[Formula 272]

(1) (5R)-5-[(E)-2-(3-Chloro-4-ethoxyphenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (1,32 g, 35%) was obtained by carrying out essentially the same reaction as in example 4-2(1), except that used the (3-chloro-4-ethoxyphenyl)(5-cyclopropyl-6-methoxypyridine-2-yl)methanon obtained in reference example 1-62. Were also obtained (5R)-5-[(Z)-2-(3-chloro-4-ethoxyphenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (0,97 g, 26%) and EZ mixture (1,28 mg, 34%).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.53-0,72 (m, 2H), of 0.91-1,02 (m, 2H), 1,46 (t, J=6,9 Hz, 3H), 1,60-of 1.85 (m, 1H), 2,07 -2,46 (m, 6H), 3,41-3,58 (m, 1H), a 3.87-3,98 (m, 1H), 4,08 (sq, J=6,9 Hz, 2H), 5,95 (d, J=6,9 Hz, 1H), about 6,82-of 6.96 (m, 2H), 7,03-7,11 (user.s, 1H), 7,20 (DD, J=8,2, 2,3 Hz, 1H), 7,34 (d, J=2,3 Hz, 1H), 11,67-11,88 (user.s, 1H).

MS(+): 401 [M+H]+.

Example 4-88

3-Chloro-6-{(E)-1-(4-cyclopropylmethyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 273]

(1) (5R)-5-[2-(5-Chloro-6-methoxypyridine-2-yl)-2-(4-cyclopropylmethyl)ethenyl]pyrrolidin-2-he (EZ mixture) was obtained as a colorless solid (322 mg, 72%) by carrying out essentially the same reaction as in example 4-2(1), except that used the (5-chloro-6-methoxypyridine-2-yl)(4-cyclopropylmethyl)methanon, obtained in reference example 1-87.

(2) Specified in the title compound was obtained as a colorless solid (48 mg, 50%) held�eat essentially the same reaction, as in example 1-1(2), except that used the (5R)-5-[2-(5-chloro-6-methoxypyridine-2-yl)-2-(4-cyclopropylmethyl)ethenyl]pyrrolidin-2-he (EZ mixture).

1H NMR (300 MHz, CDCl3) δ M. D. 0,72-0,78 (m, 2H), 1,00-1,08 (m, 2H), 1,89-of 1.99 (m, 1H), 2,10-of 2.50 (m, 4H), 4,21 (TD, J=7,4 Hz, 7.8 Hz, 1H), 5,88 (d, J=7,7 Hz, 1H), 6,16-6,20 (user.s, 1H), 6,39 (d, J=9,2 Hz, 1H), to 7.04 (d, J=8,0 Hz, 2H), 7,12 (d, J=8,3 Hz, 2H), of 7.48 (d, J=7,7 Hz, 1H), 11,90-12,07 (user.s, 1H).

MS(+): 355 [M+H]+.

Example 4-89

3-Chloro-6-(1-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl)pyridin-2(1H)-he

[Formula 274]

Specified in the title compound was obtained by carrying out essentially the same reaction as in example 2-3, except that used 3-chloro-6-{(E)-1-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he obtained in example 4-61.

1H NMR (300 MHz, CDCl3) δ M. D. 1,73-1,98 (m, 2H), 2,19-2,60 (m, 11H), 2,88-3,16 (m, 4H), 3,48-3,86 (m, 1H), 4,04-to 4.23 (m, 1H), 6,05-6,15 (m, 1H), 7,47-of 7.64 (m, 3H), 7,67-to 7.77 (m, 2H).

MS(+): 479 [M+H]+.

Example 4-90

3-Chloro-6-{(E)-1-[4-(cyclopropylamino)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

[Formula 275]

Specified in the title compound was obtained by carrying out essentially the same reaction as in example 4-2, except that used the (5-chloro-6-methoxypyridine-2-yl)[4-(cyclopropylamino)phenyl]methanon, �must register in referential example 1 to 88.

1H NMR (300 MHz, CDCl3) δ M. D. 0,76-0,88 (m, 4H), 2,07-of 2.23 (m, 1H), 2.26 and-of 2.50 (m, 3H), 3,71-3,84 (m, 1H), 4,18-4,30 (m, 1H), 5,95 (d, J=7,6 Hz, 1H), 6,10 (s, 1H), 6.35 mm (d, J=9,0 Hz, 1H), 7,04-7,15 (m, 4H), 7,52 (d, J=7,6 Hz, 1H).

MS(+): 371 [M+H]+.

Example 4-91

6-{(E)-1-(4-tert-Butylphenyl)-2-[(3R)-pyrrolidin-3-yl]ethenyl}-3-chloropyridin-2(1H)-he

(1) tert-Butyl (3R)-3-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-carboxylate (EZ mixture) was obtained as a white amorphous substance (964 mg, 86%) by carrying out essentially the same reaction as in example 4-2(1), except that used 4-tert-butylphenyl)(5-chloro-6-methoxypyridine-2-yl)methanon obtained in reference example 1-7, and used tert-butyl (3S)-3-[(1,3-benzothiazol-2-ylsulphonyl)methyl]pyrrolidin-1-carboxylate obtained in reference example 3-16.

(2) 6-{(E)-1-(4-tert-Butylphenyl)-2-[(3R)-pyrrolidin-3-yl]ethenyl}-3-chloro-2-methoxypyridine (131 mg, 62%) was obtained by implementing the same reaction as in example 4-46(2), using tert-butyl (3R)-3-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-carboxylate (EZ mixture).

(3) Specified in the title compound was obtained as white solid (50 mg, 41%) by carrying out essentially the same reaction as in example 1-1(2), except that used 6-{(E)-1-(4-tert-butylphenyl)-2-[(3R)-pyrrolidin-3-yl]ethenyl}-3-chloro-2-methoxypyridine.

1H NMR (300 MHz, CDCl3 ) δ M. D. of 1.36 (s, 9H), 1,68-of 1.73 (m, 1H), 1,92-of 1.99 (m, 1H), 2,67-2,82 (m, 2H), 2,88-of 2.92 (m, 1H), 3,01-3,11 (m, 2H), 5,95 (d, J=7,8 Hz, 1H), 6,40 (d, J=9.8 Hz, 1H), to 7.09 (d, J=8,6 Hz, 2H), of 7.42 (d, J=8,6 Hz, 2H), 7,47 (d, J=7,4 Hz, 1H).

MS(+): 357 [M+H]+.

MS(-): 355 [M-H]-.

Example 4-92

6-{(E)-1-(4-tert-Butylphenyl)-2-[(3R)-1-(cyclopropanecarbonyl)pyrrolidin-3-yl]ethenyl}-3-chloropyridin-2(1H)-he

(1) 6-{1-(4-tert-Butylphenyl)-2-[(3R)-pyrrolidin-3-yl]ethenyl}-3-chloro-2-methoxypyridine (EZ mixture) (3,01 g, 94%) was obtained by implementing the same reaction as in example 4-46(2), using tert-butyl (3R)-3-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-carboxylate (EZ mixture) obtained in example 4-91(1).

(2) {(3R)-3-[2-(4-tert-Butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-yl}(cyclopropyl)methanon (EZ mixture) (106 mg, 91%) was obtained by carrying out essentially the same reaction as in example 4-46(3), except that used 6-{1-(4-tert-butylphenyl)-2-[(3R)-pyrrolidin-3-yl]ethenyl}-3-chloro-2-methoxypyridine (EZ mixture) and used cyclopropanecarbonitrile as Alliluyeva reagent.

(3) Specified in the title compound was obtained as white solid (57 mg, 55%) by carrying out essentially the same reaction as in example 1-1(2) except that used {(3R)-3-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-yl}(cyclopropyl)methanon (EZ mixture).

L-column ODS-a 4.6×250 m�

0.01 M acetate buffer:MeCN = 40:60 vol./vol., 40°C, 1.0 ml/min, 254 nm

Rt = 10,331 min

MS(+): 425 [M+H]+.

MS(-): 423 [M-H]-.

Example 4-93

6-{(E)-1-(4-tert-Butylphenyl)-2-[(3R)-1-(tetrahydro-2H-Piran-4-ylcarbonyl)pyrrolidin-3-yl]ethenyl}-3-chloropyridin-2(1H)-he

Specified in the title compound was obtained as white solid (55 mg, 42% (two steps)) by carrying out essentially the same reaction as in example 4-92(2)(3), consecutively, except that used tetrahydro-2H-Piran-4-carbonylchloride as Alliluyeva reagent.

L-column ODS-a 4.6×250 mm

0.01 M acetate buffer:MeCN = 40:60 vol./vol., 40°C, 1.0 ml/min, 254 nm

Rt = 12,228 min

MS(+): 469 [M+H]+.

MS(-): 467 [M-H]-.

Example 4-94

6-{(E)-1-(4-tert-Butylphenyl)-2-[(3R)-1-(3,4-diferensial)pyrrolidin-3-yl]ethenyl}-3-chloropyridin-2(1H)-he

(1) Specified in the title compound was obtained as a colorless oil (34 mg, 15% (two steps)) by carrying out essentially the same reaction as in example 4-92(2)(3), consecutively, except that used 4-(chloromethyl)-1,2-differental as alkylating reagent.

(2) 4 M hydrogen chloride-1,4-dioxane solution (1 ml) was added to the specified in the title compound (34 mg). After ultrasonic irradiation for one minute, the evaporated solvent with obtaining monohydrochloride specified in the header connection in the form of b�logo solid (31 mg, 95%).

L-column ODS-a 4.6×250 mm

0.01 M acetate buffer:MeCN = 40:60 vol./vol., 40°C, 1.0 ml/min, 254 nm

Rt = 6,553 min

MS(+): 483 [M+H]+.

MS(-): 481 [M-H]-.

Example 4-95

6-{(E)-1-(4-tert-Butylphenyl)-2-[(3R)-1-(2-methylpropyl") pyrrolidin-3-yl]ethenyl}-3-chloropyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (68 mg, 41% (two steps)) by carrying out essentially the same reaction as in example 4-92(2)(3), consecutively, except that used 1-chloro-2-methylpropan as alkylating reagent.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.89 (DD, J=6,5, 2.5 Hz, 6H), of 1.35 (s, 9H), 1,65-1,80 (m, 2H), 1,94-of 2.08 (m, 1H), 2,13-of 2.24 (m, 2H), 2,27-of 2.33 (m, 1H), 2,42-of 2.50 (m, 1H), 2,61-2,78 (m, 2H), 2,80-of 2.93 (m, 1H), 5,97 (d, J=7,4 Hz, 1H), To 6.42 (d, J=10,2 Hz, 1H), 7,06 (d, J=8,2 Hz, 2H), 7,40 (d, J=8,2 Hz, 2H), 7,47 (d, J=7,8 Hz, 1H), 10,04-10,28 (user.s, 1H).

MS(+): 413 [M+H]+.

MS(-): 411 [M-H]-.

Examples 4-96 and 4-97

6-{1-(4-tert-Butylphenyl)-2-[(3S)-1-(cyclopropanecarbonyl)pyrrolidin-3-yl]ethyl}-3-chloropyridin-2(1H)- he

One diastereoisomer (A) specified in the title compound was obtained as white solid (60 mg, 23% (two steps)) by carrying out essentially the same reaction as in examples 4-69 and 4-70(2)(3), consecutively, except that used {(3R)-3-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-1-yl}(cyclopropyl)methanon (EZ mixture) obtained in example 4-92(2), the separation� mixture preparative HPLC (CHIRALPAK IB (20 mm EXT.d. × 250 mm L, Daicel Chemical Industries, LTD.), 40°C, flow rate: 10 ml/min, ethanol:hexane=20:80) and concentrating the fraction-eluted with a retention time of 15 minutes. Fraction-eluted with a retention time of 21 minutes, concentrated to give the other diastereoisomer (B) specified in the title compound as a white solid (73 mg, 28% (two steps)).

The diastereoisomer (A);

CHIRALPAK IB 4,62×50 mm 5 μm (DAICEL)

Hexane: EtOH = 90:10 vol./vol., 40°C, 1.0 ml/min, 254 nm

Rt = 19,675 min

MS(+): 427 [M+H]+.

MS(-): 425 [M-H]-.

The diastereoisomer (B);

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL)

Hexane:EtOH = 90:10 vol./vol., 40°C, 1.0 ml/min, 254 nm

Rt = 27,095 min

MS(+): 427 [M+H]+.

MS(-): 425 [M-H]-.

Patterns examples 4-91 - 4-97 shown below.

Table 15

Example 4-98

6-{(E)-1-(4-Chlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

(1) 1,4-Dioxane (4 ml) and water (0.4 ml) was added to a mixture of (5R)-5-[(Z)-2-bromo-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one obtained in reference example 4-24 (170 mg), 4-Chlorfenvinphos acid (160 mg), Tris(dibenzylideneacetone)diplegia (45 mg), three(2-furyl)phosphine (69 mg) and cesium carbonate (492 mg) and semipermissive at 90°C for 2.5 hours. Was added to the reaction solution, water and ethyl acetate and was filtered through celite, the insoluble material, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:50→0:100) to give (5R)-5-[(E)-2-(4-chlorophenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one as the crude product (250 mg).

(2) 1,4-Dioxane (4 ml) and 48% bromoethanol acid (2 ml) was added to (5R)-5-[(E)-2-(4-chlorophenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-ONU (250 mg) and the mixture was stirred at 65°C for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol=100:0→90:10) with obtaining specified in the title compound as colorless powder (65 mg, 68% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,48-0,70 (m, 2H), 0,92-1,12 (m, 2H), 1,95-to 2.18 (m, 2H), 2,16-by 2.55 (m, 3H), 3,94-to 4.28 (m, 1H), 5,67-to 5.85 (m, 1H), 6,16-6,28 (m, 1H), 6,45 (d, J=9,0 Hz, 1H), 6,83 (d, J=7,3 Hz, 1H), 7,07-7,17 (m, 2H), 7,35-7,51 (m, 2H), 11,36-11,69 (user.s, 1H).

MS(+): 355 [M+H]+./p>

The compounds of examples 4-99 - 4-142 synthesized by carrying out essentially the same reaction as in example 4-98, except that was used instead of 4-Chlorfenvinphos acid corresponding boranova acid or esters Baranovich acids ([4-(trifluoromethyl)phenyl]Bronevoy acid, (4-fluorophenyl)Bronevoy acid, (3,4-dichlorophenyl)Bronevoy acid, (2-fluoro-4-methylphenyl)Bronevoy acid, [3-chloro-4-(trifluoromethyl)phenyl]Bronevoy acid, (3-chloro-4-fluorophenyl)Bronevoy acid, [4-chloro-3-(trifluoromethyl)phenyl]Bronevoy acid, (3-chloro-4-methylphenyl)Bronevoy acid, (4-chloro-3-methylphenyl)Bronevoy acid, [6-(trifluoromethyl)pyridin-3-yl]Bronevoy acid, (2-chloro-4-methylphenyl)Bronevoy acid, [4-chloro-2-(trifluoromethyl)phenyl]Bronevoy acid, (4-chloro-3-fluorophenyl)Bronevoy acid, (3,4-differenl)Bronevoy acid, (4-fluoro-3-methylphenyl)Bronevoy acid, (3-fluoro-4-methylphenyl)Bronevoy acid, (3,4-dimethylphenyl)Bronevoy acid, [3-fluoro-4-(trifluoromethyl)phenyl]Bronevoy acid, [4-fluoro-3-(trifluoromethyl)phenyl]Bronevoy acid, [2,4-bis(trifluoromethyl)phenyl]Bronevoy acid, [3,5-bis(trifluoromethyl)phenyl]Bronevoy acid, (6-chloropyridin-3-yl)Bronevoy acid, (6-herperidin-3-yl)Bronevoy acid, (4-fluoro-2-hydroxyphenyl)Bronevoy acid, 2,3-dihydro-1-benzofuran-5-Voronovo acid, (4-chloro-3-methoxyphenyl)Bronevoy acid, (4-chloro-ethylphenyl)Bronevoy acid, [4-(triptoreline)phenyl]Bronevoy acid, [4-(deformedarse)phenyl]Bronevoy acid, [3-chloro-4-(triptoreline)phenyl]Bronevoy acid (reference example 5-2), [4-chloro-3-(triptoreline)phenyl]Bronevoy acid (reference example 5-3), [4-chloro-3-(deformedarse)phenyl]Bronevoy acid (reference example 5-4), 2-[4-(deformity)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (reference example 5-6), 2-[3-chloro-4-(deformity)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (reference example 5-5), 2-[4-(deformity)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (reference example 5-7), [4-methoxy-3-(trifluoromethyl)phenyl]Bronevoy acid, 2-[4-(deformity)-3-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (reference example 5-8), 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonyl}pyrrolidine, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzolsulfonat, [4-(morpholine-4-ylsulphonyl)phenyl]Bronevoy acid, the diamide N,N-dimethyl-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfuric acid (reference example 5-44), N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzosulfimide (reference example 5-10), 4,4,5,5-tetramethyl-2-{4-[(trifluoromethyl)sulfanyl]phenyl}-1,3,2-dioxaborolan and [6-(methyl-sulfonyl)pyridin-3-yl]Bronevoy acid), respectively.

Example 4-99

3-Cyclopropyl-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(trifluoromethyl)phenylethynyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (100 mg, 56% (two steps)).

1H NMR (300 MHz, DMSO-d6) δ M. D. of 0.49-0.65 m, 2H), 0,73-0,95 (m, 2H), 1,69-of 2.33 (m, 5H), 3,72-3,86 (m, 1H), 5,27-5,59 (m, 1H), gold 6.43-6,59 (m, 1H), 6,78-6,91 (m, 1H), of 7.36-7,56 (m, 2H), 7,72-7,86 (m, 3H), made 11.32-11,62 (user.s, 1H).

MS(+): 389 [M+H]+.

Example 4-100

3-Cyclopropyl-6-{(E)-1-(4-fluorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (42 mg, 41% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,49-0,73 (m, 2H), 0,93-1,06 (m, 2H), 2,00-to 2.18 (m, 2H), 2,19-2,48 (m, 3H), 4,06-is 4.21 (m, 1H), 5,71 (d, J=7,2 Hz, 1H), 6,33-6,50 (m, 2H), 6,83 (d, J=7,3 Hz, 1H), 7,04-7,22 (m, 4H), 11,53-11,85 (user.s, 1H).

MS(+): 339 [M+H]+.

Example 4-101

3-Cyclopropyl-6-{(E)-1-(3,4-dichlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (20 mg, 17% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. the 0.45 to 0.77 (m, 2H), 0,89-of 1.13 (m, 2H), 1,98-to 2.18 (m, 2H), measuring 2.20-2.49 USD (m, 3H), 4,00-to 4.23 (m, 1H), 5,67 (d, J=7,3 Hz, 1H), to 6.57 (d, J=9,2 Hz, 1H), 6,62-6,74 (m, 1H), 6,83 (DD, J=7,4, 0.7 Hz, 1H), to 7.04 (DD, J=8,2, 2,0 Hz, 1H), 7,28 (d, J=2,0 Hz, 1H), 7,51 (d, J=8,2 Hz, 1H), 12,05-12,29 (user.s, 1H).

MS(+): 389 [M+H]+

Example 4-102

3-Cyclopropyl-6-{(E)-1-(2-fluoro-4-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (60 mg, 57% (two steps)).

1H NMR (300 �Hz, CDCl3) δ M. D. from 0.54 to 0.69 (m, 2H), 0,92-of 1.03 (m, 2H), 1,98-2,17 (m, 2H), 2,21-of 2.38 (m, 3H), 2,41 (s, 3H), 4,00-4,18 (m, 1H), 5.78% was established (d, J=7,2 Hz, 1H), 5,82-of 5.91 (m, 1H), 6,56 (d, J=9,2 Hz, 1H), about 6,82 (d, J=7.5 Hz, 1H), 6,90-was 7.08 (m, 3H), 11,13-at 11.37 (user.s, 1H).

MS(+): 353 [M+H]+

Example 4-103

6-{(E)-1-[3-Chloro-4-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (67 mg, 45% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,52-0,66 (m, 2H), 0,93-of 1.04 (m, 2H), 2,03 to 2.14 (m, 2H), 2,23-of 2.45 (m, 3H), 4,04-4,13 (m, 1H), to 5.62 (d, J=7,3 Hz, 1H), 6,61 (d, J=9,2 Hz, 1H), 6,68 (s, 1H), 6,83 (d, J=7,3 Hz, 1H), 7,18-7,24 (m, 1H), 7,35 (s, 1H), of 7.75 (d, J=7,8 Hz, 1H), 12,11-12,24 (user.s, 1H).

MS(+): 423 [M+H]+.

Example 4-104

6-{(E)-1-(3-Chloro-4-fluorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as a colorless powder (56 mg, 42% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,55-0,65 (m, 2H), 0,95-of 1.03 (m, 2H), 2,03 to 2.14 (m, 2H), 2,23-of 2.43 (m, 3H), of 4.09-4,15 (m, 1H), 5,71 (d, J=7,3 Hz, 1H), 6,20-6,22 (m, 1H), gold 6.43 (d, J=9,2 Hz, 1H), at 6.84 (d, J=7,3 Hz, 1H), 7,03-was 7.08 (m, 1H), 7,18-7,24 (m, 2H), 11,36-11,49 (user.s, 1H).

MS(+): 373 [M+H]+.

Example 4-105

6-{(E)-1-[4-Chloro-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (60 mg, 40% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,54-to 0.67 (m, 2H), were 0.94 was 1.06 (m, 2H), 2,08-of 2.16 (m, 2H), 2,23-2.44 m, 3H), 4,06-4,11 (m, 1H), 5,63 (l, J=7,3 Hz, 1H), 6,40 (user.s, 1H), 6,55 (d, J=9,2 Hz, 1H), at 6.84 (d, J=7,3 Hz, 1H), 7,31-7,35 (m, 1H), of 7.48-7,51 (m, 1H), members, 7.59 (d, J=8,3 Hz, 1H), 11,84-12,04 (user.s, 1H).

MS(+): 423 [M+H]+.

Example 4-106

6-{(E)-1-(3-Chloro-4-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (54 mg, 48% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.56 and 0.64 (m, 2H), 0,95-1,02 (m, 2H), 2,01-2,17 (m, 2H), 2,24-2,41 (m, 3H), 2,43 (s, 3H), 4,10-is 4.21 (m, 1H), 5,79 (d, J=7,2 Hz, 1H), 6,08 (user.s, 1H), 6,40 (d, J=9,0 Hz, 1H), at 6.84 (d, J=7,3 Hz, 1H), 6,93-of 6.99 (m, 1H), 7,12-7,17 (m, 1H), 7,26-to 7.33 (m, 1H).

MS(+): 369 [M+H]+.

Example 4-107

6-{(E)-1-(4-Chloro-3-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (38 mg, 36% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.56 and 0.64 (m, 2H), 0,95-1,02 (m, 2H), 2,03-2,17 (m, 2H), 2,21-2,39 (m, 3H), is 2.40 (s, 3H), of 4.09-4,19 (m, 1H), 5,74 (d, J=7,3 Hz, 1H), 6,36 (user.s, 1H) 6,45 (d, J=9,2 Hz, 1H), 6,83 (d, J=7,3 Hz, 1H), 6,90-6,98 (m, 1H), 7,02-7,05 (m, 1H) of 7.36-of 7.42 (m, 1H).

MS(+): 369 [M+H]+.

Example 4-108

3-Cyclopropyl-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[6-(trifluoromethyl)pyridin-3-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (22 mg, 18% (two steps)).

MS (+): 390 [M+H]+.

Example 4-109

6-{(E)-1-(2-Chloro-4-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

�specified in the title compound was obtained as colorless powder (40 mg, 36% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,54-0,70 (m, 2H), of 0.91-of 1.03 (m, 2H), 1,94-of 2.44 (m, 8H), 3,87-4,06 (m, 1H), 5,60-of 5.72 (m, 1H), 5,79-5,96 (m, 1H), to 6.57-6,72 (m, 1H), 6.75 in-6,84 (m, 1H), 7,00-7,10 (m, 1H), 7,11-of 7.19 (m, 1H), 7,29-7,34 (m, 1H), 11.21 per-11,47 (user.s, 1H).

MS(+): 369 [M+H]+.

Example 4-110

6-{(E)-1-[4-Chloro-2-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (35 mg, 28% (two steps)).

MS(+): 423 [M+H]+.

Example 4-111

6-{(E)-1-(4-Chloro-3-fluorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (46 mg, 35% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. of 0.53 and 0.64 (m, 2H), 0,93-1,02 (m, 2H), 2,07-2,17 (m, 2H), 2,21-2,44 (m, 3H), of 4.09-4,16 (m, 1H), 5,65 (d, J=7,3 Hz, 1H), 6,60 (d, J=9,2 Hz, 1H), about 6,82 (d, J=7,8 Hz, 1H), 6,93-6,97 (m, 1H), 6,99-to 7.04 (m, 2H), 7,45 (t, J=7,8 Hz, 1H), 12,26-of 12.59 (user.s, 1H).

MS(+): 373 [M+H]+.

Example 4-112

3-Cyclopropyl-6-{(E)-1-(3,4-differenl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (47 mg, 37% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,55-0,66 (m, 2H), were 0.94-of 1.04 (m, 2H), 2,06-of 2.15 (m, 2H), 2,24-of 2.44 (m, 3H), 4,11-4,16 (m, 1H), 5,70 (d, J=7,3 Hz, 1H), 6,40-to 6.42 (m, 1H), 6,48 (d, J=9,2 Hz, 1H), at 6.84 (d, J=7,3 Hz, 1H), 6,91-to 6.95 (m, 1H), 6,99-7,05 (m, 1H), 7,20-7,26 (m, 1H), 11,68-11,76 (user.s, 1H).

MS(+): 357 [M+H]+.

Example 4-113

3-Cyclopropyl-6-{(E)-1-(for-3-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (43 mg, 34% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,55-0,66 (m, 2H), 0,93-1,03 (m, 2H), 2,01-of 2.16 (m, 2H), 2,22-of 2.44 (m, 3H), of 2.30 (d, J=1.4 Hz, 3H), 4,10-4,20 (m, 1H), 5,79 (d, J=7,3 Hz, 1H), 6,13 (user.s, 1H), 6,36 (d, J=9,2 Hz, 1H), 6,83 (s, 1H), at 6.92-7,00 (m, 2H), 7,02-7,10 (m, 1H), 10,95-to 11.11 (user.s, 1H).

MS(+): 353 [M+H]+.

Example 4-114

3-Cyclopropyl-6-{(E)-1-(3-fluoro-4-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (15 mg, 12% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,56-0,65 (m, 2H), of 0.96 for 1.01 (m, 2H), 2,01-of 2.15 (m, 2H), 2,24-2,42 (m, 3H), 2,33 (s, 3H), 4,14-4,19 (m, 1H), of 5.81 (d, J=7,3 Hz, 1H), 6,05 (user.s, 1H), 6,37 (d, J=9,2 Hz, 1H), 6,83 (s, 3H), 7,22-7,26 (m, 1H), 10,96-11,12 (user.s, 1H).

MS(+): 353 [M+H]+.

Example 4-115

3-Cyclopropyl-6-{(E)-1-(3,4-dimethylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (93 mg, 75% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,57-0,65 (m, 2H), 0,94-1,00 (m, 2H), 2,00-to 2.13 (m, 2H), 2,23-2,42 (m, 3H), 2,28 (s, 3H), 2,31 (s, 3H), 4,16-is 4.21 (m, 1H), 5,87 (user.s, 1H), of 5.92 (d, J=7,3 Hz, 1H), of 6.26 (d, J=9,2 Hz, 1H), at 6.84 (d, J=6,9 Hz, 1H), 6,86-6,91 (m, 2H), 7,18 (d, J=7,8 Hz, 1H), 10,29-10,42 (user.s, 1H).

MS(+): 349 [M+H]+.

Example 4-116

3-Cyclopropyl-6-{(E)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound palusalu the form of a colorless powder (102 mg, 71% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,54-0,66 (m, 2H), 0,95-1,04 (m, 2H), 2,07-to 2.18 (m, 2H), 2,24-of 2.46 (m, 3H), 4,06-to 4.14 (m, 1H), 5,63 (l, J=7,3 Hz, 1H), 6,61 (d, J=9,2 Hz, 1H), 6,81 (user.s, 1H), at 6.84 (d, J=7,3 Hz, 1H), 7,06-7,14 (m, 2H), 7,68 (t, J=7,6 Hz, 1H), 12.16 to 12,36 (m, 1H).

MS(+): 407 [M+H]+.

Example 4-117

3-Cyclopropyl-6-{(E)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (116 mg, 80% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. of 0.53-0,66 (m, 2H), 0,95-1,05 (m, 2H), 2,07-of 2.16 (m, 2H), 2,23-of 2.45 (m, 3H), 4,05-4,11 (m, 1H), to 5.62 (d, J=7,3 Hz, 1H), 6,50-6,59 (m, 2H), 6,81-6,90 (m, 1H), 7,29 (t, J=9,6 Hz, 1H), value of 7, 37-7,44 (m, 2H), 11,96-12,13 (m, 1H).

MS(+): 407 [M+H]+.

Example 4-118

6-{(E)-1-[2,4-Bis(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (25 mg, 15% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. of 0.57 to 0.69 (m, 2H), 0,93-of 1.04 (m, 2H), 2,00-to 2.18 (m, 3H), 2,19-2,31 (m, 1H), 2,32-of 2.46 (m, 1H), 3,76-3,82 (m, 1H), of 5.40 (DD, J=7,3, 1,4 Hz, 1H), 6,78 (DD, J=7,3, 3.7 Hz, 1H), of 6.79-6,86 (m, 1H), 7,39-7,52 (m, 1H), to 7.89-7,94 (m, 1H), with 8.05 (d, J=12,8 Hz, 1H).

MS(+): 457 [M+H]+.

Example 4-119

6-{(E)-1-[3,5-Bis(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (90 mg, 55% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,50-0,56 (m, 1H), and 0.61-066 (m, 1H), 0,96-1,05 (m, 2H), 2,10-to 2.18 (m, 2H), 2,23-of 2.30 (m, 1H), 2,31-of 2.43 (m, 2H), 3,98-of 4.04 (m, 1H), of 5.55 (d, J=7,3 Hz, 1H), 6,74 (d, J=9,2 Hz, 1H), of 6.85 (d, J=7,3 Hz, 1H), of 7.64 (s, 2H), 7,95 (s, 1H).

MS(+): 457 [M+H]+.

Example 4-120

6-{(E)-1-(6-Chloropyridin-3-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (49 mg, 39% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,55-0,59 (m, 1H), 0,61-0,66 (m, 1H), 0,97-of 1.07 (m, 2H), 2,08-of 2.16 (m, 2H), 2.26 and-of 2.44 (m, 3H), of 4.09-to 4.14 (m, 1H), 5,64 (d, J=7,3 Hz, 1H), of 6.49-a 6.53 (m, 1H), 6,62 (d, J=9,2 Hz, 1H), of 6.85 (d, J=7,3 Hz, 1H), 7,41 (d, J=8,3 Hz, 1H), 7,51 (DD, J=8,3, 2,3 Hz, 1H), 8,24 (d, J=1,8 Hz, 1H).

MS(+): 356 [M+H]+.

Example 4-121

3-Cyclopropyl-6-{(E)-1-(6-herperidin-3-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (2 mg, 2% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,56-to 0.67 (m, 2H), 0,97-of 1.07 (m, 2H), 2,06-of 2.15 (m, 2H), 2,27-of 2.45 (m, 3H), 4,10-4,15 (m, 1H), of 5.68 (d, J=7,3 Hz, 1H), 6,11 (user.s, 1H), 6,50 (d, J=9,2 Hz, 1H), of 6.85 (d, J=7,3 Hz, 1H), 7,03 (DD, J=8,5, 2.5 Hz, 1H), 7,63 (TD, J=7,9, 2.5 Hz, 1H), 8,06-8,09 (m, 1H), 11,43-11,55 (user.s, 1H).

MS(+): 340 [M+H]+.

Example 4-122

3-Cyclopropyl-6-{(E)-1-(4-fluoro-2-hydroxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (30 mg, 24% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,52-0,61 (m, 2H), 1,24-1,32 (m, 2H), 2,03-2,10 (m, 2H), 2,22 (DD, J=12,8, and 5.0 Hz, 1H), 2,30-of 2.38 (m, 2H), 4,08-to 4.14 (m, 1H), 5,76-5,84 (m, 1H), 6,62 (TD, J=8,2, and 2.3 Hz, 2H), was 6.77 (DD, J=10,1, 2,3 Hz, 1H), of 6.79-6,83 (m, 1H), 6,89-6,94 (m, 1H), of 6.96-7,02 (m, 1H).

MS(+): 355 [M+H]+.

Example 4-123

3-Cyclopropyl-6-{(E)-1-(2,3-dihydro-1-benzofuran-5-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (40 mg, 31% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,51-to 0.67 (m, 2H), 0,89-of 1.04 (m, 2H), 1,98-2,19 (m, 2H), 2,21-by 2.55 (m, 3H), 3,14-3,29 (m, 2H), 4,12-4,30 (m, 1H), 4,55-of 4.75 (m, 2H), 5,82-of 5.91 (m, 1H), 6,23-6,36 (m, 2H), 6,76-6,94 (m, 3H), 6,95-7,00 (m, 1H), 11,03-at 11.23 (user.s, 1H).

MS(+): 363 [M+H]+.

Example 4-124

6-{(E)-1-(4-Chloro-3-methoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (45 mg, 33% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,55-to 0.67 (m, 2H), were 0.94-of 1.03 (m, 2H), 2,04-of 2.15 (m, 2H), 2,22-of 2.45 (m, 3H), 3,89 (s, 3H), 4,14-4,19 (m, 1H), 5,77 (d, J=7,3 Hz, 1H), 6,36 (user.s, 1H), 6,44 (d, J=9,2 Hz, 1H), 6,71 to 6.75 (m, 2H), 6,83 (d, J=7,3 Hz, 1H), of 7.42 (d, J=to 8.7 Hz, 1H), 11,41-11,59 (user.s, 1H).

MS(+): 385 [M+H]+.

Example 4-125

6-{(E)-1-(4-Chloro-3-ethylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (49 mg, 36% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,55-0,66 (m, 2H), were 0.94-of 1.03 (m, 2H), 1,24 (t, J=7,6 Hz, 3H), 2,03-of 2.15 (m, 2H), 2,22-of 2.43 (m, 3H), 2,78 (sq, J=7.5 Hz, 2H), 4,11-4,17 (m, 1H), 5,77 (d, J=7,3 Hz, 1H), 6,94 (DD, J=8,0, and 2.1 Hz, 1H), 7,03(d, J=1,8 Hz, 1H), 7,39 (d, J=8,3 Hz, 1H), 11.21 per-11,33 (user.s, 1H).

MS(+): 383 [M+H]+.

Example 4-126

3-Cyclopropyl-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(triptoreline)phenyl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (52 mg, 49% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,55-0,65 (m, 2H), were 0.94-of 1.04 (m, 2H), 2,05-of 2.16 (m, 2H), 2,24-of 2.44 (m, 3H), 4,10-4,16 (m, 1H), 5,70 (d, J=7,3 Hz, 1H), 6,36 (user.s, 1H), of 6.49 (d, J=9,2 Hz, 1H), 6,81-6,86 (m, 1H), 7,20-of 7.24 (m, 2H), 7,25-7,30 (m, 2H), 11,59-11,73 (user.s, 1H).

MS(+): 405 [M+H]+.

Example 4-127

3-Cyclopropyl-6-{(E)-1-[4-(deformedarse)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (41 mg, 30% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,55-0,66 (m, 2H), 0,95-of 1.03 (m, 2H), 2,04-of 2.15 (m, 2H), 2,24-2,43 (m, 3H), 4,11-4,18 (m, 1H), 5,73 (d, J=7,3 Hz, 1H), of 6.26 (user.s, 1H), 6,44 (d, J=9,2 Hz, 1H), to 6.57 (t, J=73,0 Hz, 1H), at 6.84 (d, J=7,3 Hz, 1H), 7,18 (s, 4H), 11,40-11,51 (user.s, 1H).

MS(+): 387 [M+H]+.

Example 4-128

6-{(E)-1-[3-Chloro-4-(triptoreline)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (59 mg, 45% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,54-0,66 (m, 2H), 0,95-1,05 (m, 2H), 2,07-of 2.16 (m, 2H), 2.26 and-of 2.44 (m, 3H), 4,10-4,16 (m, 1H), of 5.68 (d, J=7,3 Hz, 1H), 6,50 (user.s, 1H), a 6.53 (d, J=9,2 Hz, 1H), of 6.85 (d, J=6,9 Hz, 1H), 7,11-7,15 (m, 1H), 7,30-7,32 (m, 1H), value of 7, 37-7,41 (m, 1H), 11,83 is 12.01 (user.s, 1H).

MS(+): 439 [M+H]+.

Example 4-129

6-{(E)-1-[4-Chloro-3-(triptoreline)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (72 mg, 61% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,53-to 0.67 (m, 2H), 0,95-1,05 (m, 2H), 2,07-of 2.15 (m, 2H), 2,23-of 2.44 (m, 3H), 4,08-4,16 (m, 1H), for 5.66 (d, J=7,3 Hz, 1H), is 6.51 (user.s, 1H), to 6.57 (d, J=9,2 Hz, 1H), at 6.84 (d, J=7,3 Hz, 1H), 7,10 (DD, J=8,0, and 2.1 Hz, 1H), 7,17 (s, 1H), 7,54 (d, J=8,3 Hz, 1H), 12,12-12,27 (user.s, 1H).

MS(+): 439 [M+H]+.

Example 4-130

6-{(E)-1-[4-Chloro-3-(deformedarse)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (12 mg, 41% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,56-0,66 (m, 2H), 0,95-1,04 (m, 2H), 2,04-of 2.15 (m, 2H), 2,25-of 2.44 (m, 3H), 4,11-4,16 (m, 1H), of 5.72 (d, J=7,3 Hz, 1H), 6,27 (user.s, 1H), 6,45 (d, J=9,2 Hz, 1H), 6,62 (t, J=72,9 Hz, 1H), at 6.84 (d, J=7,3 Hz, 1H), 7,00-7,03 (m, 1H), 7,10 (user.s, 1H), 7,51 (d, J=8,3 Hz, 1H), 11,40-11,56 (user.s, 1H).

MS(+): 421 [M+H]+.

Example 4-131

3-Cyclopropyl-6-{(E)-1-[4-(deformity)-3-fluorophenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (20 mg, 32% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.48 to 0.69 (m, 2H), 0,93-of 1.05 (m, 2H), 2,06-of 2.20 (m, 2H), 2,22-2,48 (m, 3H), 4,03-is 4.21 (m, 1H), 5,60-5,69 (m, 1H), 6,55-only 6.64 (m, 1H), 6,69-7,14 (m, 5H), 7.62 mm-7,73 (m, 1H), 12,11-12,36 (user.s, 1H).

MS(+): 389 [M+H]+.

PR�measures 4-132

6-{(E)-1-[3-Chloro-4-(deformity)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

Specified in the title compound was obtained as colorless powder (50 mg, 46% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,50-0,79 (m, 2H), 0,88-1,08 (m, 2H), 2,02-of 2.20 (m, 2H), 2,22-2,48 (m, 3H), was 4.02-4,19 (m, 1H), 5,55-5,70 (m, 1H), to 6.57-6,68 (m, 1H), 6.75 in-to 7.18 (m, 3H), 7,20-7,30 (m, 2H), 7,66-7,79 (m, 1H), 12.16 to 12,44 (user.s, 1H).

MS(+): 405 [M+H]+.

Example 4-133

3-Cyclopropyl-6-{(E)-1-[4-(deformity)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (50 mg, 36% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,50-0,70 (m, 2H), 0,88-1,10 (m, 2H), 2,01-2,41 (m, 5H), 2,43-2,49 (m, 3H), 4,05-4,22 (m, 1H), 5,64-at 5.76 (m, 1H), gold 6.43-to 6.57 (m, 2H), 6,60-7,01 (m, 2H), 7,03-7,15 (m, 2H), 7,49-7,62 (m, 1H), 11,75-12,02 (user.s, 1H).

MS(+): 385 [M+H]+.

Example 4-134

3-Cyclopropyl-6-{(E)-1-[4-methoxy-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (70 mg, 47% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. from 0.42 to 0.75 (m, 2H), 0,93-of 1.09 (m, 2H), 2,03-2,19 (m, 2H), 2.21 are of 2.42 (m, 3H), 3,96 (s, 3H), 4,06-4,20 (m, 1H), to 5.62-5,74 (m, 1H), 6,45-6,54 (m, 1H), 6,55-only 6.64 (m, 1H), of 6.79-to 6.88 (m, 1H), 7,01-7,12 (m, 1H), 7,27-7,41 (m, 2H), 11,90-12,10 (user.s, 1H).

MS(+): 419 [M+H]+.

Example 4-135

3-Cyclopropyl-6-{(E)-1-[4-(deformity)-3-methoxyphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-on�

Specified in the title compound was obtained as colorless powder (12 mg, and 8.4% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 0,44-0,73 (m, 2H), of 0.87-1,17 (m, 2H), 1.93 and-by 2.55 (m, 5H), 3,78-3,93 (m, 3H), 4,04-of 4.38 (m, 1H), of 5.72 (d, J=7,2 Hz, 1H), 6,39-7,21 (m, 6H), EUR 7.57-7,74 (m, 1H).

MS(+): 401 [M+H]+.

Example 4-136

3-Cyclopropyl-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(pyrrolidin-1-ylsulphonyl)phenyl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (69 mg, 43% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 0,54-to 0.67 (m, 2H), were 0.94-of 1.04 (m, 2H), 1,81-1,89 (m, 4H), 2,04-of 2.15 (m, 2H), 2.26 and-of 2.45 (m, 3H), 3,29-3,37 (m, 4H), 4,04-4,11 (m, 1H), 5,66-5,73 (m, 1H), 6,41-of 6.49 (m, 1H), at 6.84 (d, J=7,3 Hz, 1H), 7,34 (d, J=8,3 Hz, 2H), 7,90 (d, J=8,3 Hz, 2H).

MS(+): 454 [M+H]+.

Example 4-137

4-{(E)-1-(5-Cyclopropyl-6-oxo-1,6-dihydropyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}benzolsulfonat

Specified in the title compound was obtained as light brown powder (35 mg, 37% (two steps)).

1H NMR (600 MHz, DMSO-d6) δ M. D. of 0.53-of 0.62 (m, 2H), 0,80-0,89 (m, 2H), 1,79-1,90 (m, 1H), 1,95-2,02 (m, 1H), 2,03 to 2.14 (m, 2H), of 2.15 and 2.26 (m, 1H), 3,76-of 3.85 (m, 1H), levels lower than the 5.37 (user.s, 1H), of 6.49 (d, J=to 8.7 Hz, 1H), of 6.85 (user.s, 1H), 7,39-of 7.46 (m, 4H), 7,79 (s, 1H), 7,86 (d, J=8,3 Hz, 2H), made 11.32-11,58 (user.s, 1H).

MS(+): 400 [M+H]+.

Example 4-138

3-Cyclopropyl-6-{(E)-1-[4-(morpholine-4-ylsulphonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder�ka (12 mg, 11% (two steps)).

1H NMR (600 MHz, DMSO-d6) δ M. D. 0,55-0,66 (m, 2H), 0,80-0,89 (m, 2H), 1,83-of 1.93 (m, 1H), 1,95-2,04 (m, 1H), 2,05-of 2.15 (m, 2H), 2,16-of 2.27 (m, 1H), 2,88-2,96 (m, 4H), 3,60-3,70 (m, 4H), 3,80-3,89 (m, 1H), 5,43 (user.s, 1H), 6,44-to 6.57 (m, 1H), 6,86 (user.s, 1H), 7,50 (d, J=8,3 Hz, 2H), to 7.77 (d, J=8,3 Hz, 2H), 7,80 (s, 1H), 11,49 (user.s, 1H).

MS(+): 470 [M+H]+.

Example 4-139

The diamide N'-(4-{(E)-1-(5-cyclopropyl-6-oxo-1,6-dihydropyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}phenyl)-N,N-dimethylcarbinol acid

Specified in the title compound was obtained as gray powder (24 mg, 18% (two steps)).

1H NMR (300 MHz, DMSO-d6) δ M. D. 0,52-0,64 (m, 2H), 0,75-0,90 (m, 2H), 1,73-of 2.30 (m, 5H), 2,73 (s, 6H), 3.75 to USD 3.96 (m, 1H), 5,53 (s, 1H), 6,21-of 6.45 (m, 1H), 6,73-at 6.92 (m, 1H), 7,03-7,29 (m, 4H), 7,74 (s, 1H), to 9.93-10,14 (m, 1H), 11,26-11,49 (m, 1H).

MS(+): 443 [M+H]+.

Example 4-140

4-{(E)-1-(5-Cyclopropyl-6-oxo-1,6-dihydropyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide

Specified in the title compound was obtained as colorless powder (40 mg, 24% (two steps)).

1H NMR (600 MHz, DMSO-d6) δ M. D. of 0.55 to 0.61 (m, 2H), 0,81-0.87 (m, 2H), 1,79-of 2.25 (m, 5H), 3,03-of 3.09 (m, 2H), 3,29 (s, 3H), 3,49-to 3.56 (m, 2H), of 3.77-a 3.87 (m, 1H), 4,80 (t, J=5,5 Hz, 1H), 5,34-5,44 (m, 1H), gold 6.43-a 6.53 (m, 1H), 6,78-to 6.88 (m, 1H), 7,41-7,49 (m, 2H), 7,74-7,83 (m, 2H).

MS(-): 456 [M-H]-.

Example 4-141

3-Dihydro-6-[(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-{4-[(trifluoromethyl)sulfanyl]phenyl}ethenyl]pyridin-2(1H)-he

Specified in the title compound was obtained as BAA�colored powder (62 mg, 79% (two steps)).

1H NMR (600 MHz, METHANOL-d4) δ M. D. 0,60-0,65 (m, 2H), 0,91-0,95 (m, 2H), 1,97-of 2.06 (m, 2H), 2,22-of 2.44 (m, 3H), 4,10-4,17 (m, 1H), 5,79 (d, J=7,3 Hz, 1H), system 6.34 (d, J=9,2 Hz, 1H), 7,00 (d, J=7,3 Hz, 1H), 7,35-7,40 (m, 2H), 7,78 (d, J=7,8 Hz, 2H).

MS(+): 421 [M+H]+.

Example 4-142

3-Cyclopropyl-6-{(E)-1-[6-(methyl-sulfonyl)pyridin-3-yl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (42 mg, 53% (two steps)).

1H NMR (600 MHz, METHANOL-d4) δ M. D. 0,60-0,66 (m, 2H), 0,91-0,96 (m, 2H), 1,99-of 2.09 (m, 2H), 2,25-2,35 (m, 2H), 2,37-of 2.45 (m, 1H), or 3.28 (s, 3H), 4,05-4,15 (m, 1H), 5,75-5,84 (m, 1H), is 6.51 (d, J=9,6 Hz, 1H), 7,00 (d, J=7,3 Hz, 1H), 7,99 (DD, J=7,8, a 1.8 Hz, 1H), 8,17 (d, J=8,3 Hz, 1H), 8,63 (d, J=2,3 Hz, 1H).

MS(+): 400 [M+H]+.

Example 4-143

6-{(E)-1-[3-Chloro-4-(tetrahydro-2H-Piran-4-yloxy)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

(1) (5R)-5-[(E)-2-(3-Chloro-4-hydroxyphenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it was obtained as a brown oil (160 mg, 69%) by carrying out essentially the same reaction as in example 4-98(1), except that used 3-chloro-4-hydroxyphenylarsonic acid instead of 4-Chlorfenvinphos acid.

(2) Tetrahydro-4-pyranol (127 mg), 2.2 M solution of diisopropylcarbodiimide in toluene (0,655 ml) and triphenylphosphine (326 mg) was added to a solution of (5R)-5-[(E)-2-(3-chloro-4-hydroxyphenyl)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (160 �g) in tetrahydrofuran (3 ml) and the mixture was stirred at room temperature for four hours. The reaction solution was concentrated and the residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→0:1), to obtain (5R)-5-[(E)-2-[3-chloro-4-(tetrahydro-2H-Piran-4-yloxy)phenyl]-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one as a colorless amorphous substance (120 mg, 61%).

(3) Specified in the title compound was obtained as colorless powder (40 mg, 34%) by implementing the same reaction as in example 4-98(2), except that used the (5R)-5-[(E)-2-[3-chloro-4-(tetrahydro-2H-Piran-4-yloxy)phenyl]-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. 0,44-0,72 (m, 2H), of 0.91-1,10 (m, 2H), 1,78-of 1.97 (m, 2H), 1,99-2,19 (m, 4H), 2,23-of 2.50 (m, 3H), 3,54-and 3.72 (m, 2H), 3,94-of 4.09 (m, 2H), 4,10-4,29 (m, 1H), 4,50-4,70 (m, 1H), 5,79 (d, J=7,3 Hz, 1H), 6,31-of 6.49 (m, 2H), 6,80-6,90 (m, 1H), at 6.92-7,06 (m, 2H), 7,14-7,21 (m, 1H), 11.37 per-11,65 (user.s, 1H).

MS(+): 455 [M+H]+.

Example 4-144

3-Dihydro-6-[(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-(pyridin-4-yl)ethenyl]pyridin-2(1H)-he

(1) 4-Pyridylcarbinol (218 mg), Tris(dibenzylideneacetone)dipalladium (27 mg) and three(2-furyl)phosphine (42 mg) was added to a solution of (5R)-5-[(Z)-2-bromo-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one obtained in reference example 4-24 (100 mg) in 1,4-dioxane (2 ml) and the mixture was stirred at 90°C for four hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. Organic�ski layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified column chromatography on NH-silica gel (hexane:ethyl acetate=1:1→0:1), to obtain (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-(pyridin-4-yl)ethenyl]pyrrolidin-2-one as a colorless amorphous substance (42 mg).

(2) Specified in the title compound was obtained as colorless powder (20 mg) by carrying out essentially the same reaction as in example 4-98(2), except that used the (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-(pyridin-4-yl)ethenyl]pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. of 0.51 to 0.69 (m, 2H), 0,88-of 1.05 (m, 2H), 1,95-2,17 (m, 2H), 2,23-2,63 (m, 3H), 3,93-is 4.21 (m, 1H), for 5.66 (d, J=7,3 Hz, 1H), of 6.49 (d, J=9,3 Hz, 1H), at 6.84 (d, J=7.5 Hz, 1H), 7,07-7.23 percent (m, 2H), 8,53-8,77 (m, 2H).

MS(+): 322 [M+H]+.

Example 4-145

6-{(E)-1-(3-Chloro-4-hydroxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-he

1 M solution of tribromide boron in hexane (0.8 ml) was added to a solution of 6-{(E)-1-(3-chloro-4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-she obtained in example 4-10 (110 mg) in chloroform (2 ml) and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over b�wodnym magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=100:0→90:10) with obtaining specified in the title compound as a colorless amorphous substance (17,5 mg).

1H NMR (300 MHz, DMSO-d6) δ M. D. 0,51-0,66 (m, 2H), 0.76 is is 0.92 (m, 2H), 1,73-of 2.30 (m, 5H), 3,83-4,00 (m, 1H), 5,53 (d, J=7,3 Hz, 1H), 6.35 mm (d, J=9,5 Hz, 1H), of 6.85 (d, J=7,3 Hz, 1H), at 6.92-7,06 (m, 2H), 7,12-7,24 (m, 1H), 7,74-to 7.89 (m, 1H).

MS(+): 371 [M+H]+.

Example 4-146

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-1-methyl-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he

(1) 1,4-Dioxane (8 ml) and water (2 ml) was added to a mixture of (5R)-5-[(Z)-2-bromo-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one obtained in reference example 4-18 (531 mg), 4-tert-butylaniline acid (570 mg), Tris(dibenzylideneacetone)diplegia (147 mg), three(2-furyl)phosphine (224 mg) and cesium carbonate (1.04 g) and the mixture was stirred at 90°C for 2.5 hours. Was added to the reaction solution, water and ethyl acetate and was filtered through celite, the insoluble material, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=90:10→60:40) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)eteni�]pyrrolidin-2-one as pale-yellow amorphous substance (597 mg).

(2) 60% sodium hydride (27 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (185 mg) in tetrahydrofuran (5 ml) and the mixture was stirred at room temperature for 20 minutes. Added methyliodide (60 μl) and the mixture stirred at room temperature for 4.5 hours. Was added to the reaction solution, water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on NH-silica gel (hexane:ethyl acetate=80:20) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]-1-methylpyrrolidine-2-one as colorless powder (180 mg).

(3) 48% bromoethanol acid (3 ml) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]-1-methylpyrrolidine-2-one (152 mg) in 1,4-dioxane (6 ml) and the mixture was stirred at 65°C for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on NH-Seeley�agile (chloroform:methanol=100:0→98:2) to give a colorless powder (151 mg). The powder was recrystallized from a mixture of ethyl acetate-hexane to obtain specified in the title compound as colorless powder (99 mg).

1H NMR (600 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 2,01-of 2.09 (m, 1H), 2,15-of 2.23 (m, 1H), 2,29-2,36 (m, 1H), 2,49-of 2.57 (m, 1H), 2,79 (s, 3H), 4,03-4,08 (m, 1H), 5,94 (d, J=7,8 Hz, 1H), gold 6.43 (d, J=9,6 Hz, 1H), 7,11 (d, J=8,3 Hz, 2H), 7,44-7,51 (m, 3H), 11,24-11,34 (user.s, 1H).

MS(+): 385 [M+H]+.

Example 4-147

3-Chloro-6-{(E)-2-[(2R)-1-methyl-5-oxopyrrolidin-2-yl]-1-[4-(propane-2-yl)phenyl]ethenyl}pyridin-2(1H)-he

(1) 6-bromo-3-chloro-2-methoxypyridine (361 mg), cesium fluoride (246 mg), copper iodide (170 mg) and tetrakis(triphenylphosphine)palladium(0) (92 mg) was added to a solution of (5R)-1-(2,4-dimethoxybenzyl)-5-[(E)-2-[4-(propane-2-yl)phenyl]-2-(tributylstannyl)ethenyl]pyrrolidin-2-it, obtained in reference example 4-27 (543 mg) in N,N-dimethylformamide (6 ml) and the mixture was stirred at 65°C for 1.5 hours. Was added to the reaction solution, water and ethyl acetate. After filtration through celite the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→0:1), to obtain (5R)-5-{(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a yellow oil (268 mg).

(2) the Decree�Noah in the title compound was obtained as colorless powder (65 mg, 65% (two steps)) by carrying out essentially the same reaction as in reference example 4-16 and example 4-146(2)(3), except that used the (5R)-5-{(E)-2-(5-chloro-6-methoxypyridine-2-yl)-2-[4-(propane-2-yl)phenyl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-it.

1H NMR (300 MHz, CDCl3) δ M. D. of 1.31 (d, J=7,0 Hz, 6H), 1,98-2,41 (m, 3H), 2,46-2,63 (m, 1H), 2,80 (s, 3H), 2,88-3,13 (m, 1H), 3,92-4,19 (m, 1H), 5,88 (d, J=7,8 Hz, 1H), 6,50 (d, J=9.8 Hz, 1H), 7,10 (d, J=8,2 Hz, 2H), 7,32 (d, J=8,2 Hz, 2H), of 7.48 (d, J=7,8 Hz, 1H), 11,77-11,94 (user.s, 1H).

MS(+): 371 [M+H]+.

The compounds of examples 4-148 - 4-157 synthesized by carrying out essentially the same reaction as in example 4-146(1) and (3), except that was used instead of 4-tert-butylaniline acid corresponding boranova acid or esters Baranovich acid ((4-tert-butyl-2-methoxyphenyl)Bronevoy acid, naphthalene-2-Voronovo acid, naphthalene-1-Voronovo acid, biphenyl-4-Voronovo acid, (4-phenoxyphenyl)Bronevoy acid, (3-carbamoylphenoxy)Bronevoy acid, [4-(benzyloxy)phenyl]Bronevoy acid, {4-[(methyl-sulfonyl)amino]phenyl}Bronevoy acid, 1-propane-2-yl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (reference example 5-45) and 2-[4-(deformity)-3-(methyl-sulfonyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (reference example 5-9)), respectively.

Example 4-148

6-{(E)-1-(4-tert-Butyl-2-methoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]atani�}-3-chloropyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (100 mg, 57% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 2,02-of 2.58 (m, 4H), of 3.78 (s, 3H), 3,97-4,24 (m, 1H), 5,73-5,88 (m, 1H), 5,96 (d, J=7,6 Hz, 1H), of 6.46 (d, J=9,2 Hz, 1H), 6,87-7,11 (m, 3H), 7,49 (d, J=7,6 Hz, 1H), 10,98-11,27 (user.s, 1H).

MS(+): 401 [M+H]+.

Example 4-149

3-Chloro-6-{(E)-1-(naphthalene-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (45 mg, 82% (two steps)).

1H NMR (600 MHz, METHANOL-d4) δ M. D. 2,03-of 2.09 (m, 1H), 2,25-of 2.32 (m, 2H), 2,35-of 2.42 (m, 1H), 4,22-4,27 (m, 1H), 5,90 (d, J=7,3 Hz, 1H), gold 6.43 (d, J=9,2 Hz, 1H), 7,31 (DD, J=8,5, 1.6 Hz, 1H), 7,54-7,56 (m, 2H), 7,61 (d, J=7,8 Hz, 1H), 7,78-7,79 (m, 1H), 7,90-of 7.93 (m, 2H), 7,95 (d, J=to 8.7 Hz, 1H).

MS(+): 365 [M+H]+.

Example 4-150

3-Chloro-6-{(E)-1-(naphthalene-1-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (68 mg, 52% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 1,98-2,06 (m, 1H), of 2.21-of 2.28 (m, 2H), 2,43-of 2.50 (m, 1H), 3,90-4,01 (m, 1H), 5,76 (DD, J=7,6, with 5.3 Hz, 1H), of 6.96 (m, J=to 8.7 Hz, 1H), 7,35-7,44 (m, 2H), 7,50-7,63 (m, 3H), 7,73 (DD, J=12,8, 8,3 Hz, 1H), Compared to 7.97 (DD, J=12,6, of 8.0 Hz, 2H).

MS(+): 365 [M+H]+.

Example 4-151

6-{(E)-1-(Biphenyl-4-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (80 mg, 57% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 2,22-2,31 (m, 1H), 2,31-2,40 m, 2H), 2,44-2,52 (m, 1H), 4,26-4,31 (m, 1H), of 5.89 (d, J=7,8 Hz, 1H), a 6.53 (d, J=to 8.7 Hz, 1H), to 6.57 (s, 1H), 7,28 (d, J=8,3 Hz, 2H), value of 7, 37-of 7.42 (m, 1H), of 7.46-7,53 (m, 3H), 7,61-of 7.64 (m, 2H), 7,66-to 7.68 (m, 2H).

MS(+): 391 [M+H]+.

Example 4-152

3-Chloro-6-[(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-(4-phenoxyphenyl)ethenyl]pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (81 mg, 55% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 2,14-of 2.20 (m, 1H), 2,29-2,39 (m, 2H), 2,41-2,48 (m, 1H), 4,22-4,27 (m, 1H), 5,91 (d, J=7,8 Hz, 1H), 6,29 (s, 1H), 6,41 (d, J=9,2 Hz, 1H), 7,03 (d, J=to 8.7 Hz, 2H), 7,08-7,14 (m, 4H), of 7.19 (t, J=7,3 Hz, 1H), 7,40 (DD, J=8,5, 7,6 Hz, 2H), 7,52 (d, J=7,8 Hz, 1H).

MS(+): 407 [M+H]+.

Example 4-153

3-{(E)-1-(5-Chloro-6-oxo-1,6-dihydropyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}benzamide

Specified in the title compound was obtained as colorless powder (40 mg, 37% (two steps)).

1H NMR (300 MHz, DMSO-d6) δ M. D. 1,73-2,32 (m, 4H), of 3.77-3,94 (m, 1H), 5,44-5,70 (m, 1H), of 6.46-to 6.57 (m, 1H), 7,26-8,06 (m, 8H), 11,93-12,22 (user.s, 1H).

MS(-): 356 [M-H]-.

Example 4-154

6-{(E)-1-[4-(Benzyloxy)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he

Specified in the title compound was obtained as a yellow powder (45 mg, 35% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. 2,11-to 2.18 (m, 1H), 2,29-of 2.38 (m, 2H), 2,40-2,47 (m, 1H), 4,21-to 4.26 (m, 1H), 5,11 (s, 2H), of 5.92 (d, J=7,8 Hz, 1H), 6,11 (s, 1H), system 6.34 (d, J=to 8.7 Hz, 1H), 7,01-7,05 (m, 2H), 7,07-7,11 (m, 2H), 7,35-7,47 (m, 5H), 7,50 (d, J=7,8 Hz, 1H).

MS(+): 421 [M+H]+.

Example 4-155

N-(4-{(E)-1-(5-Chloro-6-oxo-,6-dihydropyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}phenyl)methanesulfonamide

Specified in the title compound was obtained as gray powder (79 mg, 92% (two steps)).

1H NMR (300 MHz, METHANOL-d4) δ M. D. 1,92-of 2.08 (m, 1H), 2,23-of 2.45 (m, 3H), 3,03 (s, 3H), 4,14-4,31 (m, 1H), 5,93 (d, J=7,6 Hz, 1H), of 6.31 (d, J=9,3 Hz, 1H), made 7.16 interest-7,25 (m, 2H), 7,31-value of 7, 37 (m, 2H), 7,63 (d, J=7,8 Hz, 1H).

MS(+): 408 [M+H]+.

Example 4-156

1-(4-{(E)-1-(5-Chloro-6-oxo-1,6-dihydropyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}phenyl)-3-propan-2-rocephine

Specified in the title compound was obtained as colorless powder (58 mg, 33% (two steps)).

1H NMR (300 MHz, DMSO-d6) δ M. D. 1,10 (d, J=6,5 Hz, 6H), 1,75-of 1.96 (m, 1H), 2,01-of 2.24 (m, 3H), to 3.67-3,84 (m, 1H), 3,92 is 4.03 (m, 1H), 5,48-5,70 (m, 1H), 6,00-6,08 (m, 1H), of 6.26-gold 6.43 (m, 1H), 7,07 (d, J=8.4 Hz, 2H), of 7.42 (d, J=8.4 Hz, 2H), 7.62 mm (d, J=7,6 Hz, 1H), to 7.77 (s, 1H), to 8.42 (s, 1H), 11,89-12,16 (user.s, 1H).

MS(+): 415 [M+H]+.

Example 4-157

3-Chloro-6-{(E)-1-[4-(deformity)-3-(methyl-sulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (46 mg, 42% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. 2,20-of 2.58 (m, 4H), 3,21 (s, 3H), was 4.02-4,12 (m, 1H), of 5.68 (d, J=7,6 Hz, 1H), 6,72 (d, J=9,3 Hz, 1H), 7,02-7,11 (user.s, 1H), 7,43-a 7.87 (m, 3H), 7,93-8,06 (m, 2H), 12,98-13,26 (user.s, 1H).

MS(+): 443 [M+H]+.

The compounds of examples 4-158 - 4-160 synthesized by carrying out essentially the same reaction as in example 4-146(1), except that used appropriate boranova acid or esters Baranovich to�slot ([4-(methylsulfinyl)phenyl]Bronevoy acid, [4-(methylcarbamoyl)phenyl]Bronevoy acid and (4-carbamoylphenoxy)Bronevoy acid) instead of 4-tert-butylaniline acid, respectively, and used 6-{(Z)-1-bromo-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he (referential example 4-19) instead of (5R)-5-[(Z)-2-bromo-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (reference example 4-18).

Example 4-158

3-Chloro-6-{(E)-1-[4-(methylsulfinyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (7.7 mg, 6.5 percent).

1H NMR (300 MHz, CDCl3) δ M. D. 2,20-2,41 (m, 3H), 2,42-2,62 (m, 1H), 2,82 (s, 3H), 4,07-to 4.23 (m, 1H), 5,64-of 5.75 (m, 1H), 6,62 (d, J=10.3 Hz, 1H), 7,34 (d, J=12.3 Hz, 1H), 7,43 (d, J=8.4 Hz, 2H), of 7.48 (d, J=7,6 Hz, 1H), of 7.75 (m, J=6,8 Hz, 2H), 12,88-13,22 (user.s, 1H).

MS(+): 377 [M+H]+.

Example 4-159

4-{(E)-1-(5-Chloro-6-oxo-1,6-dihydropyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-N-methylbenzamide

Specified in the title compound was obtained as colorless powder (11 mg, 10%).

1H NMR (600 MHz, METHANOL-d4) δ M. D. 1,96-2,05 (m, 1H), of 2.21-2,32 (m, 2H), 2,33-of 2.42 (m, 1H), 2,92 (s, 3H), 4,08-4,19 (m, 1H), 5,84 (d, J=7,3 Hz, 1H), 6,37 (d, J=9,6 Hz, 1H), to 7.33 (d, J=8,3 Hz, 2H), 7,60 (d, J=7,8 Hz, 1H), of 7.88 (s, 2H).

MS(+): 372 [M+H]+.

Example 4-160

4-{(E)-1-(5-Chloro-6-oxo-1,6-dihydropyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}benzamide

Specified in the title compound was obtained as colorless powder (2 mg, 4.4 per cent).

1H NMR (600 MHz, META�OL-d4) δ M. D. 1,91-2,02 (m, 1H), 2,13-to 2.40 (m, 3H), 4,04-4,13 (m, 1H), of 5.75 (d, J=7,8 Hz, 1H), 6,54 (d, J=9,6 Hz, 1H), 7,27-of 7.36 (m, 3H), 7,90 (d, J=8,3 Hz, 2H).

MS(+): 358 [M+H]+.

Example 4-161

4-{(E)-1-(5-Chloro-6-oxo-1,6-dihydropyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-N,N-dimethylbenzamide

(1) 4-{(E)-1-(5-Chloro-6-methoxypyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}benzoic acid was obtained as a brown oil (131 mg, 97%) by carrying out essentially the same reaction as in example 4-146(1), except that used 4-carboxybenzeneboronic acid instead of 4-tert-butylaniline acid.

(2) Dimethylaminohydrolase (43 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (121 mg), monohydrate of 1-hydroxybenzotriazole (97 mg) and triethylamine were added to a mixed solution of 4-{(E)-1-(5-chloro-6-methoxypyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}benzoic acid (131 mg) in chloroform and N,N-dimethylformamide (4 ml, 3:1) and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated and the resulting residue was purified by chromatography on silica gel (chloroform:methanol=100:0→80:20) to give 4-{(E)-1-(5-chloro-6-methoxypyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-N,N-dimethylbenzamide in the form of a brown oil (139 mg, 99%).

(3) Specified in the title compound was obtained as light brown powder (5 mg, 3%) by carrying out essentially the same reaction, to�to in example 4-146(3), except that used 4-{(E)-1-(5-chloro-6-methoxypyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-N,N-dimethylbenzamide.

1H NMR (600 MHz, METHANOL-d4) δ M. D. 1,96-2,05 (m, 1H), 2,22-of 2.44 (m, 3H), 3,03 (s, 3H), 3,10 (s, 3H), 4,14-is 4.21 (m, 1H), 5,88 (d, J=7,8 Hz, 1H), 6,37 (d, J=9,6 Hz, 1H), 7,32 (d, J=7,8 Hz, 2H), 7,50 (d, J=7,8 Hz, 2H), 7,61 (d, J=7,8 Hz, 1H).

MS(+): 386 [M+H]+.

Example 4-162

6-{(E)-1-(4-tert-Butyl-2-hydroxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (35 mg) by carrying out essentially the same reaction as in example 4-145, except that used 6-{(E)-1-(4-tert-butyl-2-methoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-he obtained in example 4-148, instead of 6-{(E)-1-(3-chloro-4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylamino-2(1H)-she.

1H NMR (300 MHz, DMSO-d6) δ M. D., of 1.27 (s, 9H), 1,73-of 1.92 (m, 1H), 1,95-of 2.33 (m, 3H), of 3.77-3,94 (m, 1H), 5.40 to-5,59 (m, 1H), 6.35 mm-is 6.51 (m, 1H), 6,80-of 6.96 (m, 2H), 6,99-7,07 (m, 1H), 7,60 (d, J=7,6 Hz, 1H), 7,65-7,72 (user.s, 1H).

MS(+): 387 [M+H]+.

Example 4-163

N-(3-{(E)-1-(5-Chloro-6-oxo-1,6-dihydropyridine-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}phenyl)acetamide

The crude product was obtained by carrying out essentially the same reaction as in example 4-146(1) and (3), except that used 3-acetamidophenyl)Bronevoy acid instead of 4-tert-butylaniline acid. Add�Yali thereto acetic anhydride (0.5 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=100:0→90:10) with obtaining specified in the title compound as colorless powder (6.0 mg).

1H NMR (300 MHz, CDCl3) δ M. D. to 2.14 (s, 3H), 2,29-of 2.75 (m, 4H), 4,02-4,19 (m, 1H), 5,72-5,87 (m, 1H), 6,63-6,74 (m, 1H), 6,87-to 6.95 (m, 1H), 7,04-7,14 (m, 1H), 7,35-7,50 (m, 2H), 8,17-8,27 (m, 1H), 8,31-of 8.39 (m, 1H), quick 8.94-a 9.05 (m, 1H), 13,19-13,33 (user.s, 1H).

MS(+): 372 [M+H]+.

Example 4-164

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-methoxypyridine-2(1H)-he

(1) 6-iodo-3-methoxy-2-[(4-methoxybenzyl)oxy]pyridine obtained in reference example 4-33 (657 mg), cesium fluoride (269 mg), copper iodide (185 mg) and tetrakis(triphenylphosphine)palladium(0) (102 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in reference example 4-26 (604 mg) in N,N-dimethylformamide (6 ml) and the mixture was stirred at 65°C for 1.5 hours. Was added to the reaction solution, water and ethyl acetate. After filtration through celite the organic layer was washed with saturated brine. The organic layer was dried over betwo�NYM magnesium sulfate and was filtered, then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=3:1→1:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-methoxy-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a yellow oil (449 mg).

(2) Water (0.2 ml) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (72 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-methoxy-6-[(4-methoxybenzyl)oxy]-pyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (202 mg) in chloroform (4 ml) and the mixture was stirred at 65°C for 21 hours. Added chloroform. After filtration evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol=1:0→95:5→9:1) obtaining 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-methoxypyridine-2(1H)-she (65 mg).

(3) Anisole (1 ml) was added to a solution of 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-methoxypyridine-2(1H)-she (65 mg) in trifluoroacetic acid (2 ml) and the mixture was stirred at 80°C for nine hours. Evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=1:0→9:1) obtaining specified in the header connection in the form of colorless then�shka (29 mg).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 2,02-2,19 (m, 1H), 2,24-2,49 (m, 3H), a 3.87 (s, 3H), 4,13-to 4.28 (m, 1H), 5,91 (d, J=7,8 Hz, 1H), 6,17 (d, J=9,0 Hz, 1H), 6,47-6,56 (m, 1H), only 6.64 (d, J=7.9 Hz, 1H), to 7.09 (d, J=8,5 Hz, 2H), of 7.42 (d, J=8,5 Hz, 2H).

MS(+): 367 [M+H]+.

Example 4-165

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(deformedarse)pyridin-2(1H)-he

(1) 3-(Deformedarse)-6-iodo-2-[(4-methoxybenzyl)oxy]pyridine obtained in reference example 4-34 (727 mg), cesium fluoride (270 mg), copper iodide (187 mg) and tetrakis(triphenylphosphine)palladium (103 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in reference example 4-26 (609 mg) in N,N-dimethylformamide (6 ml) and the mixture was stirred at 75°C for two hours. Was added to the reaction solution, water and ethyl acetate. After filtration through celite the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=95:5→1:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-(deformedarse)-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless resin (511 mg).

(2) Water (0.4 ml) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.72 g) was added to races�thief (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-(deformedarse)-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (511 mg) in chloroform (8 ml) and the mixture was stirred at 65°C for 16 hours. Was added to the reaction solution water. After filtration evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:0→1:1→chloroform:methanol=1:0→95:5→9:1) with obtaining specified in the header connection in the form of a colorless oil (96 mg).

1H NMR (300 MHz, CDCl3) δ M. D. 1,20-1,25 (m, 1H), of 1.36 (s, 9H), 2,04-2,22 (m, 1H), 2,24-2,53 (m, 3H), 4,15-to 4.28 (m, 1H), 5,87 (d, J=7,8 Hz, 1H), 6,37 (d, J=9,0 Hz, 1H), of 6.46-6,59 (m, 1H), 6,69-7,25 (m, 1H), 7,10 (d, J=8,2 Hz, 2H), 7,44 (d, J=8.4 Hz, 2H), 12,11-12,46 (user.s, 1H).

MS(+): 403 [M+H]+.

Example 4-166

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(propane-2-yloxy)pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (170 mg, 60% (two steps)) by carrying out essentially the same reaction as in example 4-164(1) and (3), except that used 6-iodo-2-[(4-methoxybenzyl)oxy]-3-(propane-2-yloxy)pyridine obtained in reference example 4-35, instead of 6-iodo-3-methoxy-2-[(4-methoxybenzyl)oxy]pyridine.

1H NMR (300 MHz, DMSO-d6) δ M. D. 1,21 (d, J=6.1 Hz, 6H), of 1.31 (s, 9H), 1,72-of 1.92 (m, 1H), 1,97-2,31 (m, 3H), of 3.77-to 3.96 (m, 1H), 4,34-the 4.67 (m, 1H), of 5.29 votes-5.53 (m, 1H), 6,17 is 6.35 (m, 1H), 6,66-6,83 (m, 1H), 7,07-7,22 (m, 2H), Of 7.36-7,56 (m, 2H), 7,69-7,84 (m, 1H), 11,38-11,59 (user.s, 1H).

MS(+): 395 [M+H]+.

Example 4-167

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-propoxyphene-2(1H)-he

Specified in the title�VKE compound was obtained as a colorless amorphous substance (170 mg, 73% (two steps)) by carrying out essentially the same reaction as in example 4-164(1) and (3), except that used 6-iodo-2-[(4-methoxybenzyl)oxy]-3-propoxyphen obtained in reference example 4-32, instead of 6-iodo-3-methoxy-2-[(4-methoxybenzyl)oxy]pyridine.

1H NMR (300 MHz, DMSO-d6) δ M. D. of 0.95 (t, J=7,4 Hz, 3H), of 1.31 (s, 9H), 1,62-of 1.75 (m, 2H), 1,77-of 1.93 (m, 1H), of 1.97 and 2.26 (m, 3H), and 3.72-3,93 (m, 3H), of 5.34-of 5.50 (m, 1H), 6,20-6.32 per (m, 1H), 6,63-was 6.77 (m, 1H), 7,07-7,21 (m, 2H), 7,39-7,50 (m, 2H), 7,68-7,83 (m, 1H), 11,40-11,54 (user.s, 1H).

MS(+): 395 [M+H]+.

Example 4-168

3-(Cyclopentyloxy)-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(trifluoromethyl)phenyl]ethenyl}pyridin-2(1H)-he

(1) Tetrakis(triphenylphosphine)palladium(0) (30 mg) was added to a solution of (5R)-1-(2,4-dimethoxybenzyl)-5-{(E)-2-(tributylstannyl)-2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-2-one obtained in reference example 4-29 (184 mg), 3-(cyclopentyloxy)-6-iodo-2-methoxypyridine obtained in reference example 4-37 (169 mg), of cesium fluoride (80 mg) and copper iodide (60 mg) in N,N-dimethylformamide (2 ml) in a nitrogen atmosphere and the mixture was stirred at 65°C for three hours. The reaction solution was allowed to cool, after which was added water and ethyl acetate, followed by filtration through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced d�solvent suppression. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=19:1→1:1) to give (5R)-5-{(E)-2-[5-(cyclopentyloxy)-6-methoxypyridine-2-yl]-2-[4-(trifluoromethyl)phenyl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a light yellow oil (184 mg).

(2) 48% bromoethanol acid (3 ml) was added to a solution of (5R)-5-{(E)-2-[5-(cyclopentyloxy)-6-methoxypyridine-2-yl]-2-[4-(trifluoromethyl)phenyl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (184 mg) in 1,4-dioxane (2 ml) and the mixture was stirred at 65°C for 30 minutes. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. A solution of the residue in trifluoroacetic acid (4 ml) and anisole (2 ml) was stirred at 80°C for six hours. Evaporated from the reaction solution under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=100:1→4:1) and turned into a powder using a mixture of ethyl acetate-diethyl ether-hexane, obtaining specified in the header connection in the form of a colorless amorphous material (59 mg, 47%).

1H NMR (300 MHz, CDCl3) δ M. D. 1,50-1,60 (m, 2H), 1,74-2,00 (m, 6H), 2,15-2,53 (m, 4H), 4,01-4,17 (m, 1H), 4,59-4,71 (m, 1H), 5,63 (l, J=7,8 Hz, 1H), system 6.34 (d, J=9,2 Hz, 1H), to 6.57 (d, J=8,1 Hz, H), 6,96-7,06 (user.s, 1H), value of 7, 37 (d, J=7.9 Hz, 2H), of 7.70 (d, J=8,1 Hz, 2H), 12,29-12,52 (user.s, 1H).

MS(+): 433 [M+H]+.

Example 4-169

6-{(E)-1-(4-Chlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(3-hydroxypropoxy)pyridin-2(1H)-he

Specified in the title compound was obtained as a light brown amorphous substance (56 mg, 69% (two steps)) by carrying out essentially the same reaction as in example 4-168(1)(2), except that used 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-6-iodo-2-methoxypyridine obtained in reference example 4-38, and (5R)-5-[(E)-2-(4-chlorophenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he obtained in reference example 4-28.

1H NMR (600 MHz, METHANOL-d4) δ M. D. 1,92-2,02 (m, 3H), 2,18-of 2.32 (m, 2H), 2,32-to 2.40 (m, 1H), and 3.72 (t, J=6,2 Hz, 2H), 4,03 (t, J=6,2 Hz, 2H), 4,07-4,13 (m, 1H), 5.78% was established (d, J=7,8 Hz, 1H), 6.18 of (d, J=9,6 Hz, 1H), 6,83 (d, J=7,8 Hz, 1H), 7,20 (d, J=8,3 Hz, 2H), 7,44 (d, J=to 8.7 Hz, 2H).

MS(+): 389 [M+H]+.

Example 4-170

3-(3-Hydroxypropoxy)-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(trifluoromethyl)phenyl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (47 mg, 58% (two steps)) by carrying out essentially the same reaction as in example 4-168(1)(2), except that used 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-6-iodo-2-methoxypyridine obtained in reference example 4-38, instead of 3-(cyclopentyloxy)-6-iodo-2-methoxypyridine.

1H NMR (600 MHz, METHANOL-d4) δ M. D. 1,94-2,03 (m, 3H), 2,19-of 2.32 (m, 2H), 2,33-2,41 (m, 1H), and 3.72 (t, J=6,2 Hz, 2H), 4,00-4,10 (m, 3H), 5,73 (d, J=7,8 Hz, 1H), of 6.25 (d, J=9,2 Hz, 1H), about 6,82 (d, J=7,8 Hz, 1H), The 7.43 (d, J=8,3 Hz, 2H), of 7.75 (d, J=7,8 Hz, 2H).

MS(+): 423 [M+H]+.

Example 4-171

3-(3-Hydroxy-2,2-DIMETHYLPROPANE)-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(trifluoromethyl)phenyl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (8 mg, 33% (two steps)) by carrying out essentially the same reaction as in example 4-168(1)(2), except that used 3-(3-{[tert-butyl(diphenyl)silyl]oxy}-2,2-DIMETHYLPROPANE)-6-iodo-2-methoxypyridine obtained in reference example 4-39, instead of 3-(cyclopentyloxy)-6-iodo-2-methoxypyridine.

1H NMR (300 MHz, CDCl3) δ M. D. 1,10 (d, J=5.3 Hz, 6H), 2,04-2,52 (m, 4H), 3,65-3,83 (m, 2H), 4,04-4,17 (m, 1H), 4,23-4,37 (m, 2H), for 5.66 (d, J=7,8 Hz, 1H), of 6.31 (d, J=9,5 Hz, 1H), only 6.64 (d, J=7,8 Hz, 1H), 7,28-to 7.33 (user.s, 1H), 7,38 (d, J=7,8 Hz, 2H), of 7.70 (d, J=7.9 Hz, 2H).

MS(+): 451 [M+H]+.

Example 4-172

3-Cyclopropyl-6-{(Z)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (45 mg, 10% (two steps)) by carrying out essentially the same reaction as in example 4-168(1)(2), except that used 6-bromo-3-cyclopropyl-2-methoxypyridine obtained in reference example 4-20, and (5R)-1-(2,4-dimethoxybenzyl)-5-{(E)-2-(tributylstannyl)-2-[5-(trifluoromethyl)pyridin-2-yl]ethenyl}pyrrolidin-2-it, obtained in reference example 4-30.

1H NMR (300 MHz, CDCl3) δ M. D. 0,49-0,70 (m, 2H), 0,86-of 1.07 (m, 2H), 1,97-2,22 (m, 2H), 2,31-2,60 (m, 3H), 4,16-4,34 (m, 1H), 5,77 (d, J=7,3 Hz, 1H), gold 6.43-6,55 (m, 1H), 6,60 (d, J=9,0 Hz, 1H), 6,80-6,94 (m, 1H), of 7.36-of 7.48 (m, 1H), To 7.89 and 8.04 (m, 1H), 8,88-to 9.04 (m, 1H), 12,19-12,44 (user.s, 1H).

MS(+): 390 [M+H]+.

Example 4-173

3-Amino-6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

(1) Tetrakis(triphenylphosphine)palladium(0) (50 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in reference example 4-26 (296 mg), 6-iodo-2-methoxypyridine-3-amine obtained in reference example 4-31(1) (220 mg), of cesium fluoride (135 mg) and copper iodide (93 mg) in N,N-dimethylformamide (1.5 ml) in a nitrogen atmosphere and the mixture was stirred at 65°C for three hours. The reaction solution was allowed to cool, after which was added water and ethyl acetate, followed by filtration through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:4) to give (5R)-5-[(E)-2-(5-amino-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a light brown and�Ortega substances (152 mg, 68%).

(2) a Solution of (5R)-5-[(E)-2-(5-amino-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (198 mg) in trifluoroacetic acid (4 ml) and anisole (2 ml) was stirred at 80°C for six hours. Was added to the reaction solution, saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:4) to give (5R)-5-[(E)-2-(5-amino-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one as a light brown solid (61 mg, 44%).

(3) 48% bromoethanol acid (0.5 ml) was added to a solution of (5R)-5-[(E)-2-(5-amino-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one (20 mg) in 1,4-dioxane (1 ml) and the mixture was stirred at 65°C for 30 minutes. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→4:1) and crystallizable from a mixture of chloroform-ethyl acetate with Paul�the increase specified in the header connection in the form of light brown powder (8 mg, 44%).

1H NMR (300 MHz, METHANOL-d4) δ M. D. of 1.26 (s, 9H), 1,80-of 1.96 (m, 1H), 2,08-of 2.33 (m, 3H), 3,99-of 4.09 (m, 1H), for 5.66 (d, J=7,8 Hz, 1H), 5,94 (d, J=9,3 Hz, 1H), of 6.46 (d, J=7,6 Hz, 1H), 7,05 (d, J=8,5 Hz, 2H), 7,39 (d, J=8,5 Hz, 2H).

MS(+): 352 [M+H]+.

Example 4-174

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(dimethylamino)pyridin-2(1H)-he

(1) 37% solution of formamide (40 ml) was added to a solution of (5R)-5-[(E)-2-(5-amino-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one obtained in example 4-173(2) (40 mg) in acetonitrile (2 ml) under cooling with ice, followed by stirring for 10 minutes. To this mixture was added triacetoxyborohydride sodium (120 mg) and the mixture was stirred at room temperature for 15 hours. Was added to the reaction solution, saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then evaporated under reduced pressure the solvent to obtain (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(dimethylamino)-6-methoxypyridine-2-yl]ethenyl}pyrrolidin-2-one as a yellow oil (41 mg).

(2) 48% bromoethanol acid (0.5 ml) was added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(dimethylamino)-6-methoxypyridine-2-yl]ethenyl}pyrrolidin-2-one (41 mg) in 1,4-dioxane (1 ml) and the mixture was stirred at 65°C for 30 minutes. Added to R�promotional solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→4:1) and crystallizable from a mixture of chloroform-ethyl acetate to obtain specified in the title compound as a light yellow powder (11 mg, 26% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 1,92-of 2.06 (m, 1H), 2,22-2,47 (m, 3H), 2,89 (s, 6H), 4,11-4,22 (m, 1H), 5,72-5,80 (user.s, 1H), 5,97 (d, J=7,6 Hz, 1H), to 6.05 (d, J=9,2 Hz, 1H), 6,54 (d, J=9.9 Hz, 1H), 7,07 (d, J=8.4 Hz, 2H), 7,43 (d, J=8.4 Hz, 2H).

MS(+): 380 [M+H]+.

Example 4-175

3-Acetyl-6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

(1) Tetrakis(triphenylphosphine)palladium(0) (170 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in reference example 4-26 (1.00 g), 1-(6-bromo-2-methoxypyridine-3-yl)ethanone obtained in reference example 4-40 (674 mg), of cesium fluoride (447 mg) and copper iodide (308 mg) in N,N-dimethylformamide (10 ml) in a nitrogen atmosphere and the mixture was stirred at 65°C for one hour. The reaction solution was allowed to cool, after which was added water and ethyl acetate, followed by filtration through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and the saturation�NYM salt solution and dried over anhydrous magnesium sulfate, then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1) to give (5R)-5-[(E)-2-(5-acetyl-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as pale-yellow amorphous substance (773 mg).

(2) 48% bromoethanol acid (3.0 ml) was added to a solution of (5R)-5-[(E)-2-(5-acetyl-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (300 mg) in 1,4-dioxane (3.0 ml) and the mixture was stirred at 65°C for 0.5 hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. To a solution of the residue (278 mg) in trifluoroacetic acid (1 ml) was added anisole (2 ml) and the mixture was stirred at 80°C for 4.5 hours. Evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=1:0→9:1) obtaining specified in the title compound as a yellow powder (103 mg).

1H NMR (300 MHz, METHANOL-d4) δ M. D. of 1.36 (s, 9H), 1,94-2,11 (m, 1H), 2,18-2,48 (m, 3H), 2,61 (s, 3H), 4,18-4,32 (m, 1H), 6,04-6,17 (m, 1H), of 6.46 (d, J=9,3 Hz, 1H), 7,18 (d, J=8,5 Hz, 2H), 7,53 (d, J=8,5 Hz, 2H), 8,03-8,17 (m, 1H).

MS(+): 379 [M+H]+.

Example 4-176

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-ethylpyridine-2(1H)-he

(1) sodium Borohydride (108 mg) was added to a solution of (5R)-5-[(E)-2-(5-acetyl-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in example 4-175(1) (773 mg) in methanol while cooling with ice, followed by stirring for 40 minutes. The reaction solution was poured into water and was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After filtration evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane: ethyl acetate=1:0→1:1) to give (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(1-hydroxyethyl)-6-methoxypyridine-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless amorphous substance (388 mg).

(2) sodium Hydride (22 mg, 60% in oil) was added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(1-hydroxyethyl)-6-methoxypyridine-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (100 mg) in tetrahydrofuran (2 ml) under cooling with ice and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was warmed up to room temperature and added carbon disulphide (66,7 μl) followed by stirring for 30 minutes. Added methyliodide (68.5 per μl) and the mixture was stirred for 3.5 hours. Added to Rea�formulated solution with water followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=2:1→1:1) to give O-[1-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-yl)ethyl] S-methylcarbanilate in the form of a colorless oil (109 mg).

(3) tributyltin Hydride (91 μl) and azobisisobutyronitrile (8.5 mg) was added to a solution of O-[1-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-yl)ethyl] S-methylcarbanilate (109 mg) in toluene (2 ml) and the mixture was stirred at 120°C for 30 minutes. Was added to the reaction solution with water followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=3:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (65 mg).

(4) 48% bromoethanol acid (0.6 ml) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-ethyl-6-methoxypyridine-2-yl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (59 mg) in 1,4-dioxane (0.6 ml) and the mixture was stirred at 65�C for 1.5 hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→3:1) to give 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-ethylpyridine-2(1H)-it is in the form of a colorless oil (49 mg).

(5) Anisole (0.25 ml) was added to a solution of 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-ethylpyridine-2(1H)-she (49 mg) in trifluoroacetic acid (0.5 ml) and the mixture was stirred at 65°C for seven hours. Was added trifluoroacetic acid (0.5 ml) and the mixture was stirred for five hours, then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=1:0→9:1). The resulting crystals (25 mg) was recrystallized from a mixture of ethyl acetate-hexane to obtain specified in the title compound as colorless powder (20 mg).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.18 (t, J=7.5 Hz, 3H), of 1.36 (s, 9H), 1,99-of 2.09 (m, 1H), 2,24-of 2.44 (m, 3H), 2,50-2,60 (m, 2H), 4,16-to 4.26 (m, 1H), 5,59-5,70 (m, 1H), 6,04 (d, J=6,8 Hz, 1H), 6,20 (l, J=9,0 Hz, 1H), 7,07 (d, J=8,5 Hz, 2H), 7,18 (d, J=7,1 Hz, 1H), 7,44 (d, J=8,5 Hz, 2H).

MS(+): 365 [M+H]+ .

Example 4-177

3-Bromo-6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a light yellow amorphous substance (13 mg, 21%) by carrying out essentially the same reaction as in example 4-98(2), except that used the (5R)-5-[(E)-2-(5-bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-he obtained in reference example 4-42.

1H NMR (600 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 2,10-2,19 (m, 1H), 2,31-2,42 (m, 2H), 2,44-2,53 (m, 1H), 4,18-of 4.33 (m, 1H), 5,94 (d, J=7,79 Hz, 1H), 6,21 (user.s, 1H), 6,37 (d, J=9,2 Hz, 1H), 7,03-7,12 (m, 2H), of 7.46 (d, J=8,3 Hz, 2H), 7,74 (d, J=7,8 Hz, 1H).

Example 4-178

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-vinylpyridin-2(1H)-he

(1) Phenylboronic acid (57 mg), Tris(dibenzylideneacetone)dipalladium(0) (19 mg), three(2-furyl)phosphine (32 mg) and cesium carbonate (151 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one obtained in reference example 4-42 (80 mg), in a mixture of 1,4-dioxane (1.5 ml)-water (0.5 ml) and the mixture was stirred at an ambient temperature of 65°C for three hours. The reaction solution was allowed to cool, was diluted with ethyl acetate and filtered. The filtrate was washed with saturated brine and dried over sodium sulfate. After filtration evaporated under reduced pressure the solvent. The residue was purified by chromatog�FIA on a column of silica gel (hexane:ethyl acetate=9:1→3:2) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxy-5-vinylpyridin-2-yl)ethenyl]pyrrolidin-2-one as an orange oil (81 mg).

(2) 48% bromoethanol acid (1 ml) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxy-5-vinylpyridin-2-yl)ethenyl]pyrrolidin-2-one (81 mg) in 1,4-dioxane (2 ml) and the mixture was stirred at 65°C for 30 minutes. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform: methanol=10:0→4:1) and was cured with a mixture of ethyl acetate-hexane to give the desired product as a light yellow amorphous substance (41 mg, 43% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 1,84-of 1.98 (m, 1H), 2,11-2,34 (m, 3H), of 4.09-to 4.23 (m, 1H), 5,99-6,04 (user.s, 1H), 6,08 (d, J=7,3 Hz, 1H), of 6.31 (d, J=9,3 Hz, 1H), 7,12 (d, J=8,5 Hz, 2H), 7,30-7,49 (m, 6H), of 7.64-7,71 (m, 2H).

MS(+): 413 [M+H]+.

The compounds of examples 4-179 - 4-184 synthesized by carrying out essentially the same reaction as in example 4-178(1)(2), except that was used instead of phenylboronic acid corresponding boranova acid or esters Baranovich acid (pyridin-4-Voronovo acid, pyridine-3-Voronovo acid, 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole, 1-(2-methylpropyl")-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 1-methyl-4-(4,4,5,5-tetras�methyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazol), respectively.

Example 4-179

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3,4'-bipyridine-2(1H)-he

Specified in the title compound was obtained as a light yellow amorphous substance (37 mg, 37% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 1,87-2,04 (m, 1H), 2,15-2,42 (m, 3H), of 4.09-of 4.25 (m, 1H), 6,13 (d, J=7.5 Hz, 1H), 6,37 (d, J=9,2 Hz, 1H), a 6.53-6,61 (user.s, 1H), 7,12 (d, J=8,2 Hz, 2H), of 7.46 (d, J=8,2 Hz, 2H), members, 7.59 (d, J=7,6 Hz, 1H), 7,66 (d, J=5.8 Hz, 2H), 8,62 (d, J=5.4 Hz, 2H).

MS(+): 414 [M+H]+.

Example 4-180

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3,3'-bipyridine-2(1H)-he

Specified in the title compound was obtained as a light yellow amorphous substance (39 mg, 55% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 1,87 is 2.01 (m, 1H), 2,19-of 2.38 (m, 3H), 4,14-4,27 (m, 1H), 6,14 (d, J=7.5 Hz, 1H), 6,17-6,22 (user.s, 1H), system 6.34 (d, J=9,2 Hz, 1H), 7,12 (d, J=8.4 Hz, 2H), 7,31-value of 7, 37 (m, 1H), of 7.46 (d, J=8.4 Hz, 2H), 7,53 (d, J=7,3 Hz, 1H), 8,08-to 8.14 (m, 1H), 8,53-8,59 (m, 1H), is 8.84-of 8.90 (m, 1H).

MS(+): 414 [M+H]+.

Example 4-181

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(2,4-dimethyl-1,3-thiazol-5-yl)pyridin-2(1H)-he

Specified in the title compound was obtained as a light orange amorphous substance (17 mg, 16% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 1,97-of 2.08 (m, 1H), 2.26 and-of 2.43 (m, 3H), of 2.45 (s, 3H), of 2.66 (s, 3H), 4,15-4,27 (m, 1H), 6,14 (d, J=7,6 Hz, 1H), 6,28-6.32 per (m, 2H), 7,13 (d, J=8.4 Hz, 2H), 7,44-7,52 (m, 3H).

MS(+): 448 [M+H]+.

Example 4-182

6-{(E)-1-(Tret-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-[1-(2-methylpropyl")-1H-pyrazol-4-yl]pyridin-2(1H)-he

Specified in the title compound was obtained as a light yellow amorphous substance (13 mg, 21% (two steps)).

1H NMR (600 MHz, CDCl3) δ M. D. of 0.93 (d, J=6,4 Hz, 6H), of 1.37 (s, 9H), 2,11-to 2.29 (m, 2H), 2,31-of 2.43 (m, 2H), 2,50-of 2.58 (m, 1H), 3,96 (d, J=7,3 Hz, 2H), 4,25-4,31 (m, 1H), 6,28-6,33 (m, 2H), 6,39-6,44 (m, 1H), 7,10 (d, J=8,3 Hz, 2H), 7,47 (d, J=to 8.7 Hz, 2H), 7,81 (d, J=7,8 Hz, 1H), to 7.89 (s, 1H), of 8.25 (s, 1H).

MS(+): 459 [M+H]+.

Example 4-183

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-he

Specified in the title compound was obtained as a light yellow amorphous substance (46 mg, 64% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 1.93 and-of 2.09 (m, 1H), 2,24-2,51 (m, 3H), 3,92 (s, 3H), 4,17-to 4.28 (m, 1H), 6,02 (s, 1H), 6,13-6,22 (m, 2H), 7,11 (d, J=8,2 Hz, 2H), of 7.46 (d, J=8.4 Hz, 2H), members, 7.59 (d, J=7,3 Hz, 1H), 7,84 (s, 1H), 8,30 (s, 1H).

MS(+): 417 [M+H]+.

Example 4-184

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(1,2-oxazol-4-yl)pyridin-2(1H)-he

Specified in the title compound was obtained as a light yellow amorphous substance (16 mg, 31% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 1,95-of 2.16 (m, 1H), 2,23-2,53 (m, 3H), 4,20-4,32 (m, 1H), 6,17 (d, J=7.5 Hz, 1H), 6.32 per (d, J=9,3 Hz, 1H), is 6.51-6,57 (user.s, 1H), 7,12 (d, J=8,5 Hz, 2H), 7,47 (d, J=8,5 Hz, 2H), 7,58 (d, J=7.5 Hz, 1H), 8,63 (s, 1H), 9,35 (s, 1H).

MS(+): 404 [M+H]+.

Example 4-185

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-phenoxypyridine-2(1H)-he

(1) cesium Carbonate (151 mg) dobavlyali a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-it, obtained in reference example 4-42 (100 mg) and phenol (43 mg) in N-methylpyrrolidine (2 ml) in a nitrogen atmosphere and the mixture was stirred at room temperature for five minutes. To this mixture was added copper iodide (22 mg) and 2,2,6,6-tetramethyl-3,5-heptanedione (10 mg) and the mixture was stirred at 120°C for six hours. Was added to the reaction solution, water and ethyl acetate, followed by filtration through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:4) to give a mixture of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxy-5-phenoxypyridine-2-yl)ethenyl]pyrrolidin-2-one and (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (61 mg).

(2) 48% bromoethanol acid (2 ml) was added to a solution mixture of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxy-5-phenoxypyridine-2-yl)ethenyl]pyrrolidin-2-one and (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (61 mg) in 1,4-dioxane (1 ml) and the mixture was stirred at 65°C for 30 minutes. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous�m magnesium sulfate, then evaporated under reduced pressure the solvent. The residue was purified by preparative HPLC (Waters Sunfire 19×150 mm, 5 µm, speed: 20 ml/min, eluent: A=acetonitrile, B=0.1% solution of trifluoroacetic acid, gradient: 10% to 90%) and was cured with a mixture of ethyl acetate-hexane to obtain specified in the title compound as a colorless amorphous substance (22 mg, 22% (two steps)). Was also obtained crude (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he (15 mg).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.35 (s, 9H), 2,00-2,11 (m, 1H), 2,19-2,42 (m, 3H), of 4.09-4,22 (m, 1H), 5,87 (d, J=7,8 Hz, 1H), 6,17-6,27 (m, 2H), of 6.79 (d, J=7,8 Hz, 1H), 7,04-7,15 (m, 5H), 7,30-value of 7, 37 (m, 2H), of 7.42 (d, J=8.4 Hz, 2H).

MS(+): 429 [M+H]+.

Example 4-186

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

48% bromoethanol acid (0.5 ml) was added to a solution of crude (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one obtained in example 4-185(2) (15 mg) in 1,4-dioxane (1 ml) and the mixture was stirred at 65°C for 30 minutes. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→4:1). Semi�hot oil turned into powder, using a mixture of ethyl acetate-hexane, obtaining specified in the header connection in the form of an orange powder (2 mg).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), of 2.01 to 2.14 (m, 1H), 2,30-2,49 (m, 3H), 4,15-4,30 (m, 1H), 5,98-6,03 (m, 1H), 6,21-6,25 (user.s, 1H), 6,28 (d, J=9,2 Hz, 1H), 6,50-6,56 (m, 1H), to 7.09 (d, J=8.4 Hz, 2H), 7,31-7,39 (m, 1H), 7,44 (d, J=8.4 Hz, 2H).

MS(+): 337 [M+H]+.

The compounds of examples 4-187 - 4-189 synthesized by carrying out essentially the same reaction as in example 4-185(1)(2), except that used the corresponding phenols (p-cresol, 4-chlorophenol and 4-(trifter)phenol instead of phenol, respectively.

Example 4-187

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(4-methylphenoxy)pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (17 mg, 17% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.35 (s, 9H), 2,03-2,12 (m, 1H), 2,23-2,47 (m, 6H), 4,11-4,24 (m, 1H), 5,91 (d, J=7,8 Hz, 1H), 6,06-6,13 (user.s, 1H), 6.18 of (l, J=9,0 Hz, 1H), 6,74 (d, J=7,8 Hz, 1H), 6,99 (d, J=8,2 Hz, 2H), was 7.08 (d, J=8.4 Hz, 2H), 7,14 (d, J=8,1 Hz, 2H), 7,43 (d, J=8.4 Hz, 2H).

MS(+): 443 [M+H]+.

Example 4-188

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(4-chlorophenoxy)pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (9 mg, 8% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.35 (s, 9H), 2.00 in of 2.16 (m, 1H), of 2.21-of 2.54 (m, 3H), 4,14-to 4.26 (m, 1H), 5,88 (d, J=7,8 Hz, 1H), 6,28 (d, J=9,2 Hz, 1H), 6,89 (d, J=7,8 �C, 1H), at 6.92-6.97 in (user.s, 1H), 7,01 (d, J=8,9 Hz, 2H), was 7.08 (d, J=8,2 Hz, 2H), 7,27-7,31 (m, 2H), of 7.42 (d, J=8,2 Hz, 2H).

MS(+): 463 [M+H]+.

Example 4-189

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-[4-(trifluoromethyl)phenoxy]pyridine-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (3 mg, 2% (two steps)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 2,02-of 2.15 (m, 1H), 2,22-of 2.58 (m, 3H), 4,16-4,29 (m, 1H), 6,03 (d, J=7.9 Hz, 1H), 6,27 (d, J=9,2 Hz, 1H), 6,80-6,89 (user.s, 1H), 7,04-7,15 (m, 5H), 7,45 (d, J=8,2 Hz, 2H), 7,58 (d, J=8,5 Hz, 2H).

MS(+): 497 [M+H]+.

Example 4-190

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(4-hydroxybutyl)pyridin-2(1H)-he

(1) Complex pinacolone ether TRANS-4-(tert-butyldimethylsiloxy)-1-butene-1-Voronovo acid (296 mg), Tris(dibenzylideneacetone)dipalladium(0) (48 mg), three(2-furyl)phosphine (73 mg) and cesium carbonate (354 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in reference example 4-42(1) (300 mg) in a mixture of 1,4-dioxane (3 ml)-water (1 ml) and the mixture was stirred at an ambient temperature of 65°C for three hours. The reaction solution was allowed to cool, was diluted with ethyl acetate and filtered through celite. The filtrate was washed with saturated brine and dried over sodium sulfate. After filtration evaporated under reduced pressure races�veritel. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→3:2) to give (5R)-5-[(E)-2-{5-[(1E)-4-{[tert-butyl(dimethyl)silyl]oxy}but-1-ene-1-yl]-6-methoxypyridine-2-yl}-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a yellow oil (399 mg, 100%).

(2) 10% palladium-activated carbon (50 mg) and zinc bromide(II) (25 mg) was added to a solution of (5R)-5-[(E)-2-{5-[(1E)-4-{[tert-butyl(dimethyl)silyl]oxy}but-1-ene-1-yl]-6-methoxypyridine-2-yl}-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (226 mg) in methanol (5 ml) and the mixture was stirred at room temperature for five hours under a hydrogen atmosphere. The reaction solution was diluted with ethyl acetate and filtered through celite. The filtrate was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=7:3→1:9) to give (5R)-5-[(E)-2-[5-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-6-methoxypyridine-2-yl]-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (140 mg, 62%).

(3) 48% bromoethanol acid (0.5 ml) was added to a solution of (5R)-5-[(E)-2-[5-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-6-methoxypyridine-2-yl]-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrole�n-2-one (24 mg) in 1,4-dioxane (1 ml) and the mixture was stirred at 65°C for 30 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. A solution of the obtained residue in trifluoroacetic acid (2 ml) and anisole (1 ml) was stirred at 70°C for five hours. Evaporated from the reaction solution under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=100:1→4:1) and preparative HPLC (Waters Sunfire 19×150 mm, 5 µm, speed: 20 ml/min, eluent: A=acetonitrile, B=0.1% solution of trifluoroacetic acid, gradient: 10% to 90%) with obtaining specified in the title compound as a colorless amorphous substance (4 mg, 26%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 1,53-of 1.75 (m, 4H), 1,99-to 2.13 (m, 1H), 2,23-of 2.43 (m, 3H), 2,51-of 2.67 (m, 2H), 3,62-3,73 (m, 2H), 4,15-of 4.26 (m, 1H), of 5.83 (d, J=7,1 Hz, 1H), 6,40 (d, J=9,2 Hz, 1H), of 6.49-6,57 (user.s, 1H), to 7.09 (d, J=8,5 Hz, 2H), 7,15-of 7.23 percent (m, 1H), 7,41 (s, 2H).

MS(+): 409 [M+H]+.

Example 4-191

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-[4-(dimethylamino)butyl]pyridine-2(1H)-he

(1) a Solution of Tetra-n-butylammonium in tetrahydrofuran (1 ml) was added to a solution of (5R)-5-[(E)-2-[5-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-6-methoxypyridine-2-yl]-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (140 mg) in tetras�hydrofuran (4 ml) and the mixture was stirred at room temperature for three hours. Evaporated from the reaction solution under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→0:10) to give (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(4-hydroxybutyl)-6-methoxypyridine-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (101 mg, 86%).

(2) Triethylamine (50 µl) and methanesulfonamide (25 ml) was added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(4-hydroxybutyl)-6-methoxypyridine-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (144 mg) in chloroform (2 ml) and the mixture was stirred at room temperature for three hours. Was added thereto, triethylamine (50 µl) and methanesulfonamide (25 μl) and the mixture stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Evaporated under reduced pressure solvent obtaining 4-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-yl)butylmalonate in the form of a crude product. Was added 2 M dimethylamine (solution in methanol) (3 ml) to 4-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-yl)butylmethyl�NAT and the mixture was stirred at room temperature for 17 hours. Evaporated from the reaction solution the solvent and water was then added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=100:0→4:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-[4-(dimethylamino) - butyl]-6-methoxypyridine-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil.

(3) 48% bromoethanol acid (1.5 ml) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-[4-(dimethylamino) - butyl]-6-methoxypyridine-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one in 1,4-dioxane (2 ml) and the mixture was stirred at 65°C for 30 minutes. The reaction solution was poured into a saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. A solution of the residue in trifluoroacetic acid (4 ml) and anisole (2 ml) was stirred at 80°C for five hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with a saturated solution�m salt, dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform: methanol=100:1→3:1) and was cured using a mixture of diethyl ether-hexane, obtaining specified in the title compound as a light yellow amorphous substance (13 mg, 12% (four stages)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 1,47-1,58 (m, 4H), 2,00-2,09 (m, 1H), of 2.21 (s, 6H), of 2.25 is 2.44 (m, 5H), 2,49-of 2.58 (m, 2H), 4,16-4,27 (m, 1H), 5,72-5,77 (user.s, 1H), 6,03 (d, J=7,1 Hz, 1H), 6,17 (d, J=9,2 Hz, 1H), 7,07 (d, J=8,5 Hz, 2H), 7,18 (d, J=7,1 Hz, 1H), 7,44 (d, J=8,5 Hz, 2H).

MS(+): 436 [M+H]+.

The compounds of examples 4-192 - 4-198 synthesized by carrying out essentially the same reaction as in example 4-190(1) to(3), except that used appropriate boranova acid or esters Baranovich acid ((1E)-prop-1-EN-1-Voronovo acid, (1E)-pent-1-ene-1-Voronovo acid, cyclopent-1-ene-1-Voronovo acid, [(E)-2-cyclohexylethyl]Bronevoy acid, [(E)-2-phenylethenyl]Bronevoy acid, [(1E)-3-phenylprop-1-EN-1-yl]Bronevoy acid and tert-butyl(dimethyl){[(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-EN-1-yl]oxy}silane) instead of complex pinacolato ether TRANS-4-(tert-butyldimethylsiloxy)-1-butene-1-Voronovo acid, respectively.

Example 4-192

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]Eten�l}-3-propylpyridine-2(1H)-he

Specified in the title compound was obtained as colorless powder (6,1 mg, 6% (three stages)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.95 (t, J=7,4 Hz, 3H), of 1.36 (s, 9H), 1,50-1,72 (m, 2H), 1,96-to 2.13 (m, 1H), 2,22-of 2.45 (m, 3H), of 2.50 (t, J=7.5 Hz, 2H), 4,14-4,29 (m, 1H), 5,88-6,03 (m, 2H), for 6.24 (d, J=9,2 Hz, 1H), to 7.09 (d, J=8,1 Hz, 2H), made 7.16 interest (d, J=7,0 Hz, 1H), 7,44 (d, J=7,8 Hz, 2H), 9,95-10,21 (user.s, 1H).

MS(+): 379 [M+H]+

Example 4-193

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-pentylpyridine-2(1H)-he

Specified in the title compound was obtained as colorless powder (4 mg, 4% (four stages)).

1H NMR (300 MHz, CDCl3) δ M. D. of 0.82 to 0.94 (m, 3H), 1,27-of 1.41 (m, 13H), 1,51-1,62 (m, 2H), 1,98-of 2.16 (m, 1H), 2,22-of 2.44 (m, 3H), 2,48-of 2.57 (m, 2H), 4,13-4,27 (m, 1H), 5,91 (d, J=7,1 Hz, 1H), 6,29 (d, J=9,2 Hz, 1H), 6,33-6,39 (user.s, 1H), 7,10 (d, J=8.4 Hz, 2H), 7,15 (d, J=7,1 Hz, 1H), 7,43 (d, J=8.4 Hz, 2H).

MS(+): 407 [M+H]+.

Example 4-194

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopentenopyridine-2(1H)-he

Specified in the title compound was obtained as colorless powder (15 mg, 14% (three stages)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 1.41 to of 1.54 (m, 2H), 1,64-to 1.79 (m, 4H), 1,94-2,12 (m, 3H), 2,22-2,51 (m, 3H), 3,12-3,29 (m, 1H), 4,13-4,27 (m, 1H), 5,90-6,01 (m, 1H), 6,06-6,15 (m, 1H), 6,19-6,28 (m, 1H), 7,01-7,12 (m, 2H)That made 7.16 interest-7,22 (m, 1H), of 7.36-7,47 (m, 2H), becomes 9.97-10,31 (user.s, 1H).

MS(+): 405 [M+H]+.

Example 4-195

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(2-cyclohexylethyl)pyridin-2(1H)-he

Specified in the header connection�ie was obtained as a colorless amorphous substance (19 mg, 16% (three stages)).

1H NMR (300 MHz, METHANOL-d4) δ M. D. 0,86-of 1.04 (m, 2H), 1,13-of 1.40 (m, 13H), 1,41-is 1.51 (m, 2H), 1,60-to 1.86 (m, 5H), 1,92-2,07 (m, 1H), 2,20-2,42 (m, 3H), 2,44-2,56 (m, 2H), 4,14-4,27 (m, 1H), 5,90 (d, J=7,1 Hz, 1H), For 6.24 (d, J=9,3 Hz, 1H), 7,17 (d, J=8,1 Hz, 2H), 7,28 (d, J=7,3 Hz, 1H), 7,51 (d, J=8,1 Hz, 2H).

MS(+): 447 [M+H]+.

Example 4-196

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(2-phenylethyl)pyridin-2(1H)-he

Specified in the title compound was obtained as a yellow powder (13 mg, 11% (three stages)).

1H NMR (300 MHz, METHANOL-d4) δ M. D. 1,32-to 1.38 (m, 9H), 1,91-of 2.09 (m, 1H), of 2.21-2,41 (m, 3H), 2,69-of 2.93 (m, 4H), 4,13-to 4.26 (m, 1H), of 5.85 (d, J=7,1 Hz, 1H), of 6.25 (d, J=9,5 Hz, 1H), 7,07-7,28 (m, 8H), 7,50 (d, J=8,5 Hz, 2H).

MS(+): 441 [M+H]+.

Example 4-197

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(3-phenylpropyl)pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (30 mg, 46% (three stages)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 1,86-of 1.97 (m, 2H), 2,04 (m, J=17.6 Hz, 1H), 2,27-of 2.46 (m, 3H), 2,54-2,62 (m, 2H), 2,63-2,71 (m, 2H), 4,15-of 4.26 (m, 1H), 5,76 and 5.86 (user.s, 1H), 6,01 (d, J=7,0 Hz, 1H), 6,19 (d, J=8,9 Hz, 1H), 7,07 (d, J=8.4 Hz, 2H), 7,13-of 7.25 (m, 6H), 7,44 (d, J=8,5 Hz, 2H).

MS(+): 455 [M+H]+.

Example 4-198

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(3-hydroxypropyl)pyridin-2(1H)-he

Specified in the title compound was obtained as colorless powder (14 mg, 26% (three stages)).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 1,95-2,15 (m, 3H), 2,28-of 2.45 (m, 3H), 2,63 t, J=7.5 Hz, 2H), 4,15-4,27 (m, 1H), of 4.38 (t, J=6,5 Hz, 2H), of 5.81-5,88 (user.s, 1H), 6,02 (d, J=7,1 Hz, 1H), 6,23 (d, J=9,0 Hz, 1H), was 7.08 (d, J=8.4 Hz, 2H), of 7.19 (d, J=7,1 Hz, 1H), 7,45 (d, J=8.4 Hz, 2H).

MS(+): 395 [M+H]+.

The compounds of examples 4-199 and 4-200 synthesized by carrying out essentially the same reaction as in example 4-190(1) to(3), except that used the (5R)-5-[(E)-2-(4-chlorophenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he (reference example 4-28) and (5R)-1-(2,4-dimethoxybenzyl)-5-{(E)-2-(tributylstannyl)-2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-2-he (reference example 4-29) instead of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one.

Example 4-199

6-{(E)-1-(4-Chlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(4-hydroxybutyl)pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (50 mg, 32% (three stages)).

1H NMR (300 MHz, METHANOL-d4) δ M. D. 1,48-1,70 (m, 4H), 1,92-of 2.09 (m, 1H), 2,18-2,41 (m, 3H), 2,45-2,56 (m, 2H), 3,52-of 3.60 (m, 2H), 4,08-4,22 (m, 1H), of 5.85 (d, J=7,1 Hz, 1H), of 6.31 (d, J=9,6 Hz, 1H), 7.23 percent (d, J=8,5 Hz, 2H), 7,31 (d, J=7,3 Hz, 1H), 7,47 (d, J=8,5 Hz, 2H).

MS(+): 387 [M+H]+.

Example 4-200

3-(4-Hydroxybutyl)-6-{(E)-2-[(2R)-5-oxopyrrolidin-2-yl]-1-[4-(trifluoromethyl)phenyl]ethenyl}pyridin-2(1H)-he

Specified in the title compound was obtained as a colorless amorphous substance (39 mg, 28% (three stages)).

1H NMR (300 MHz, METHANOL-d4) δ M. D. 2,23-2,40 (m, 4H), 2,66-2,84 (m, 1), 2,92-3,15 (m, 3H), 3,19-or 3.28 (m, 2H), 4,25-of 4.33 (m, 2H), 4,78-4,91 (m, 1H), a 6.53 (d, J=7,1 Hz, 1H), 7,12 (d, J=9,5 Hz, 1H), with 8.05 (d, J=7,1 Hz, 1H), 8,18 (d, J=8,1 Hz, 2H), and 8.50 (d, J=8,2 Hz, 2H).

MS(+): 421 [M+H]+.

Example 4-201

3-(6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridine-3-yl)propanamide

(1) Tetrakis(triphenylphosphine)palladium(0) (80 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in reference example 4-26 (471 mg), tert-butyl 3-(6-bromo-2-methoxypyridine-3-yl)propanoate obtained in reference example 4-41 (436 mg), of cesium fluoride (209 mg) and copper iodide (144 mg) in N,N-dimethylformamide (4.5 ml) in a nitrogen atmosphere and the mixture was stirred at 65°C for one hour. The reaction solution was allowed to cool, after which was added water and ethyl acetate, followed by filtration through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1) to give tert-butyl 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-yl)propanoate in the form of a brown oil (293 mg).

(2) Anisole (1 ml) was added to a solution of tert-booth�l 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-yl)propanoate (293 mg) in trifluoroacetic acid (2 ml) and the mixture was stirred at 65°C for two hours. Evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol=1:0→9:1) to give 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-yl)propane acid as a colorless amorphous substance (172 mg).

(3) 48% bromoethanol acid (1.7 ml) was added to a solution of 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-yl)propane acid (172 mg) in 1,4-dioxane (1.7 ml) and the mixture was stirred at 65°C for two hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→9:1) to give 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridine-3-yl)propane acid as a yellow oil (153 mg).

(4) 1,1'-Carbonyldiimidazole (24,8 mg) was added to a solution of 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridine-3-yl)propane acid (to 77.8 mg) in tetrahydrofuran (1.6 ml). Then doba�Lyali 28% aqueous ammonia (0.2 ml) followed by stirring for 15 hours. The reaction system was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol=10:0→9:1) to give 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridine-3-yl)propanamide in the form of a colorless amorphous substance (82,6 mg).

(5) Anisole (0.3 ml) was added to a solution of 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridine-3-yl)propanamide (82,6 mg) in trifluoroacetic acid (0.6 ml) and the mixture was stirred at 80°C for 19 hours. Evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=1:0→9:1) obtaining specified in the header connection in the form of a colorless oil (14 mg).

1H NMR (300 MHz, METHANOL-d4) δ M. D. 1,31-to 1.38 (m, 9H), 1,90-of 2.09 (m, 1H), 2,19-2,41 (m, 3H), 2,44-2,60 (m, 2H), 2,72-2,83 (m, 2H), 4,14-to 4.26 (m, 1H), 5,86-5,93 (m, 1H), 6,28 (d, J=9,3 Hz, 1H), 7,10-7,20 (m, 2H), 7,30-value of 7, 37 (m, 1H), 7,45-7,53 (m, 2H).

MS(+): 408 [M+H]+.

Example 4-202

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridine-3-carbonitrile

(1) copper Cyanide (27 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in reference example 4-42(1) (90 mg) in N,N-dimethylformamide (5 ml) and �rity was stirred at an outside temperature of 180°C for two hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:1) to give 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-carbonitrile (32 mg, 40%).

(2) Trifluoroacetic acid (1 ml) was added to a solution of 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-carbonitrile (32 mg) in anisole (1 ml) and the mixture was stirred at 85°C overnight. Evaporated under reduced pressure solvent and then the residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→1:5). The compound obtained was dissolved in 1,4-dioxane (1 ml) was added 48% bromoethanol acid (1 ml), after which the mixture was stirred at 65°C for one hour. Was added to the reaction solution, saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (�exan:ethyl acetate=1:5→chloroform:methanol=5:1) obtaining specified in the title compound (8 mg, 36%) as colorless solids.

1H NMR (600 MHz, CDCl3) δ M. D. of 1.37 (s, 9H), 2,22-of 2.43 (m, 3H), 2,54-2,62 (m, 1H), 4,24-4,30 (m, 1H), 6,06-6,11 (m, 1H), of 6.52-of 6.65 (m, 2H), to 7.09 (d, J=8,3 Hz, 2H), of 7.48 (d, J=8,3 Hz, 2H), 7,78 (d, J=7,3 Hz, 1H).

MS(+): 362 [M+H]+.

Examples 4-203 and 4-204

6-{1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(1-hydroxycyclohexyl)pyridin-2(1H)-he

(1) (5R)-5-[(E)-2-(5-Bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-he obtained in reference example 4-42(1) (100 mg) was dissolved in tetrahydrofuran (5 ml) was added n-butyllithium at -78°C. After stirring for 30 minutes, was added dropwise CYCLOBUTANE. The mixture was stirred for another 30 minutes and then the reaction solution was added a solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1→1:1) to give 5-{2-(4-tert-butylphenyl)-2-[5-(1-hydroxycyclohexyl)-6-methoxypyridine-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (EZ mixture) (35 mg).

(2) Trifluoroacetic acid (1 ml) was added to a solution of 5-{2-(4-tert-butylphenyl)-2-[5-(1-hydroxycyclohexyl)-6-methoxypyridine-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (EZ mixture) (35 mg) in anisole (1 ml) and the mixture re�shivali at 85°C overnight. Evaporated under reduced pressure solvent and then the residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→1:5). The compound obtained was dissolved in 1,4-dioxane (1 ml) was added 48% bromoethanol acid (1 ml), after which the mixture was stirred at 65°C for one hour. Was added to the reaction solution, aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by preparative HPLC (Waters Sunfire 19×150 mm, 5 µm, speed: 20 ml/min, eluent: A=acetonitrile, B=0.1% solution of trifluoroacetic acid, gradient: 10-90%) to give a single isomer (A) specified in the title compound (1 mg, 8%) and another isomer (B) specified in the title compound (1.0 mg, 8%) as colorless powders.

Isomer (A)

1H NMR (600 MHz, CDCl3) δ M. D. of 1.34 (s, 9H), 1,55-of 1.66 (m, 1H), 1,83-2,52 (m, 9H), 2,71 (t, J=9,6 Hz, 1H), 4,14-4,22 (m, 1H), 6,16 (d, J=6,4 Hz, 1H), 6,28 (d, J=to 8.7 Hz, 1H), gold 6.43 (user.s, 1H), 6,65 (d, J=9,2 Hz, 1H), 7,05-7,12 (m, 2H), 7,44-7,53 (m, 3H).

MS(+): 407 [M+H]+.

Isomer (B)

1H NMR (600 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 1,55-of 1.66 (m, 1H), of 1.84-2.49 USD (m, 9H), 2,97-of 3.04 (m, 1H), 4,20-4,30 (m, 1H), 6,28 (d, J=7,3 Hz, 1H), 6,41 (d, J=9,2 Hz, 1H), 6,60 (user.s, 1H), 6,73 (d, J=to 8.7 Hz, 1H), to 7.09 (d, J=8,3 Hz, 2H), 7,47 (s, 2H), EUR 7.57-7,66 (m, 1H).

MS(+): 407 [M+H]+.

<> Example 4-205

3-Benzyl-6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-he

(1) in 0.05 M bromide Benzedrine(II) (385 μl), Tris(dibenzylideneacetone)dipalladium(0) (8.0 mg) and three(2-furyl)phosphine (15 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one obtained in reference example 4-42(2) (30 mg), in tetrahydrofuran (2 ml) and the mixture was stirred under microwave irradiation at 110°C for one hour. Was added to the reaction solution, a solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→1:0) to give (5R)-5-[(E)-2-(5-benzyl-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one (23 mg).

(2) 48% bromoethanol acid (1 ml) was added to a solution of (5R)-5-[(E)-2-(5-benzyl-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one (23 mg) in 1,4-dioxane (2 ml) and the mixture was stirred at 65°C for one hour. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. The residue was purified by preparative HPLC (Waters Sunfire 19×50 mm 5 μm, speed: 20 ml/min, eluent: A=acetonitrile, B=0.1% solution of trifluoroacetic acid, gradient: 10% to 90%) with obtaining specified in the title compound (11 mg, 50%) as colorless solids.

1H NMR (600 MHz, CDCl3) δ M. D. of 1.35 (s, 9H), 1,96-of 2.06 (m, 1H), 2,24-of 2.35 (m, 2H), 2,35-2,47 (m, 1H), 3,81-3,95 (m, 2H), 4,15-4,27 (m, 1H), 5,73-5,88 (m, 1H), 5,90-of 6.04 (m, 1H), 6,19 (user.s, 1H), 7,05 (d, J=7,8 Hz, 2H), 7,18-7,25 (m, 3H), 7,27-7,31 (m, 2H), of 7.42 (d, J=8,3 Hz, 2H).

MS(+): 427 [M+H]+.

Example 4-206

6-{(E)-1-(4-tert-Butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-(methylsulfanyl)pyridin-2(1H)-he

(1) Thiamethoxam sodium (44 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridine-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in reference example 4-42(1) (150 mg) in N,N-dimethylformamide (1.5 ml) and the mixture was stirred at room temperature for 20 hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=9:1→0:10) to give (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[6-methoxy-5-(methylsulfanyl)pyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (53 mg, 34%).

(2) 48 bromoethanol acid (1.5 ml) was added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[6-methoxy-5-(methylsulfanyl)pyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (53 mg) in 1,4-dioxane (2 ml) and the mixture was stirred at 65°C for 30 minutes. Was added to the reaction solution with water followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure the solvent. A solution of the residue in trifluoroacetic acid (4 ml) and anisole (2 ml) was stirred at 80°C for six hours. Evaporated from the reaction solution under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (chloroform:methanol=100:1→3:1) and preparative HPLC (Waters Sunfire 19×150 mm, 5 µm, speed: 20 ml/min, eluent: A=acetonitrile, B=0.1% solution of trifluoroacetic acid, gradient: 10-90%) and turned into a powder using a mixture of ethyl acetate-hexane, obtaining specified in the title compound as colorless powder (10 mg, 27%).

1H NMR (300 MHz, CDCl3) δ M. D. of 1.36 (s, 9H), 2,10-2,22 (m, 1H), 2,25-2,47 (m, 6H), 4,15-of 4.26 (m, 1H), of 5.92-5,99 (m, 2H), 6,39 (d, J=9,0 Hz, 1H), 6,99 (d, J=7,6 Hz, 1H), to 7.09 (d, J=8.4 Hz, 2H), 7,44 (d, J=8.4 Hz, 2H).

MS(+): 383 [M+H]+.

Examples 4-207 and 4-208

3-Cyclopropyl-6-{(1R)-1-(3,4-dichlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he (example 4-207)

3-Cyclopropyl-6-{(1S)-1-(3,4-dichlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he (example 4-208)

(1) 1,4-Dioxane (4 ml) and water (0.5 ml) was added to a mixture of (5R)-5-[(Z)-2-bromo-2-(5-cyclopropyl-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-one (300 mg), 3,4-dichloraniline acid (340 mg), Tris(dibenzylideneacetone)diplegia (81 mg), three(2-furyl)phosphine (124 mg) and cesium carbonate (867 mg) and the mixture was stirred at 90°C for three hours. Was added to the reaction solution, water and ethyl acetate and was filtered through celite, the insoluble material, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:50→0:100) to give (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-(3,4-dichlorophenyl)ethenyl]pyrrolidin-2-one as a colorless amorphous substance (250 mg, 69%).

(2) zinc Bromide (20 mg) and 10% palladium-activated carbon (40 mg) was added to a solution of (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-(3,4-dichlorophenyl)ethenyl]pyrrolidin-2-one (100 mg) in methanol (3 ml) and the mixture stirred at room temperature for 18 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, then the filtrate was concentrated under reduced pressure to obtain the crude (5R)-5-[2-(5-the cyclopropyl-6-methoxypyridine-2-yl)-2-(3,4-dichlorophenyl)ethyl]pyrrolidin-2-it is in the form of amorphous material (120 mg).

(3) 48% bromoethanol acid (2 ml) was added to a solution of (5R)-5-[2-(5-the cyclopropyl-6-methoxypyridine-2-yl)-2-(3,4-dichlorophenyl)ethyl]PI�Raiden-2-one (120 mg) in 1,4-dioxane (4 ml) and the mixture was stirred at 65°C for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (chloroform:methanol=100:0→90:10) to give (R,S) mixture specified in the header connection in the form of a brown amorphous substance (78 mg). The resulting material formulation was isolated using chiral HPLC column (CHIRALPAK IB, hexane:ethanol=20:80 by vol./vol., 40°C, 10 ml/min, 210 nm) to give 3-cyclopropyl-6-{(1R)-1-(3,4-dichlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-it is in the form of a colorless amorphous substance (33 mg) and 3-cyclopropyl-6-{(1S)-1-(3,4-dichlorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-it is in the form of a colorless amorphous substance (21 mg).

Example 4-207:

1H NMR (300 MHz, CDCl3) δ M. D. of 0.52 to 0.68 (m, 2H), 0,93-1,07 (m, 2H), 1,70-of 1.85 (m, 1H), 2,07-2,40 (m, 6H), 3,49-3,65 (m, 1H), 3,97-4,12 (m, 1H), of 5.92-of 6.04 (m, 1H), 6,90-7,02 (m, 1H), 7,07-7,15 (m, 1H), 7,15-7,22 (m, 1H), 7,29-of 7.36 (m, 1H), 7,62-7,74 (m, 1H), 13,04-13,16 (user.s, 1H).

MS(+): 391 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 4,670 min.

Example 4-208:

1H NMR (300 MHz, CDCl3) δ M. D. of 0.53-0,66 (m, 2H), 0,93-to 1.14 (m, 2H), 1,72-to 1.87 (m, 1H), 2,08-2,48 (m, 6H), 3,49-3,66 (m, 1H), 4,03-4,18 (m, 1H), 5,94-of 6.06 (m, 1H), 6,89-7,02 (m, 1H), 7,12-7,22 (m, 1H), of 7.36-7,47 (m, 2H), 7,78-of 7.88 (m, 1H), 13,28-13,51 (user.s, 1H).

MS(+): 391 M+H] +.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 9,879 min.

Examples and 4-209 4-210

3-Cyclopropyl-6-{1-(2,3-dihydro-1-benzofuran-5-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he

(1) (5R)-5-[(E)-2-(5-Cyclopropyl-6-methoxypyridine-2-yl)-2-(2,3-dihydro-1-benzofuran-5-yl)ethenyl]pyrrolidin-2-it was obtained as a colorless amorphous substance (240 mg) by carrying out essentially the same reaction as in examples 4-207 and 4-208(1), except that used 2,3-dihydro-1-benzofuran-5-Voronovo acid.

(2) 10% palladium-activated carbon (50 mg) was added to a solution of (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridine-2-yl)-2-(2,3-dihydro-1-benzofuran-5-yl)ethenyl]pyrrolidin-2-one (240 mg) in methanol (3 ml) and the mixture was stirred at room temperature for four hours in the hydrogen atmosphere. The reaction solution was filtered through celite and then the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1→0:1), to obtain (5R)-5-[2-(5-the cyclopropyl-6-methoxypyridine-2-yl)-2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-2-one in the form of an amorphous substance (200 mg).

(3) (R,S) mixture specified in the title compound was obtained as a yellow amorphous substance (78 mg) by carrying out essentially the same reaction as in examples 4-207 and 4-208(3), except Thu� used (5R)-5-[2-(5-the cyclopropyl-6-methoxypyridine-2-yl)-2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-2-it. The resulting material formulation was isolated using chiral HPLC column (CHIRALPAK IB, hexane:ethanol=30:70 vol./vol., 40°C, 10 ml/min, 210 nm) to give a single diastereoisomer (A) specified in the title compound as a colorless amorphous substance (50 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (45 mg).

The diastereoisomer (A):

1H NMR (300 MHz, CDCl3) δ M. D. 0,49-0,70 (m, 2H), 0,84-of 1.03 (m, 2H), 1,71-of 1.83 (m, 1H), 1,97-2,47 (m, 6H), 3,07-3,24 (m, 2H), 3,44-3,62 (m, 1H), 3,86-was 4.02 (m, 1H), 4,47-of 4.66 (m, 2H), 5,86-6,03 (m, 1H), 6,66-6,78 (m, 1H), of 6.85-of 6.96 (m, 1H), 7,00-was 7.08 (m, 1H), 7,09-to 7.18 (m, 2H).

MS(+): 365 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 40:60 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 4,949 min.

The diastereoisomer (B):

1H NMR (300 MHz, CDCl3) δ M. D. of 0.47-0,71 (m, 2H), 0,88-1,11 (m, 2H), 1,68-of 1.85 (m, 1H), 2,07-of 2.42 (m, 6H), 3,11-3,30 (m, 2H), 3,49-3,70 (m, 1H), of 3.91 of 4.09 (m, 1H), 4,50-a 4.65 (m, 2H), 5,90-6,09 (m, 1H), 6,67-6,78 (m, 1H), 6,90-6,98 (m, 1H), 7,05 (DD, J=8,16, to 1.79 Hz, 1H), 7,09-to 7.18 (m, 1H), 7,35-7,51 (m, 1H), of 12.59-12.84 per (user.s, 1H).

MS(+): 365 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 40:60 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 7,756 min.

The compounds of examples 4-211 - 4-234 were obtained by carrying out essentially the same reaction as in examples 4-207 and 4-208 or in the examples and 4-209 4-210, using appropriate boranova acid ((3-chloro-4-fluorophenyl)Bronevoy acid, (4-chloro-3-methylphenyl)Bronevoy acid, (3-chloro-4-methylphenyl)Bronevoy acid, (4-chloro-3-fluoro�enyl)Bronevoy acid, [3-fluoro-4-(trifluoromethyl)phenyl]Bronevoy acid, [4-chloro-3-(trifluoromethyl)phenyl]Bronevoy acid, (4-fluoro-3-methylphenyl)Bronevoy acid, 2-[3-chloro-4-(deformity)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (reference example 5-5), (4-chloro-3-methoxyphenyl)Bronevoy acid, [4-(deformedarse)phenyl]Bronevoy acid, 2-[4-(deformity)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (reference example 5-7) and 2-[4-(deformity)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (reference example 5-6)), respectively.

Examples 4-211 4-212 and

6-{1-(3-Chloro-4-fluorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he

Separation using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=50:50) gave a single diastereoisomer (A) specified in the header connection in the form of a colorless amorphous material (65 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (37 mg).

The diastereoisomer (A):

1H NMR (600 MHz, CDCl3) δ M. D. 0,59-to 0.67 (m, 2H), 0,94-1,00 (m, 2H), 1,70-to 1.77 (m, 1H), 2,07-2,40 (m, 6H), 3,47-3,52 (m, 1H), 3,97 (DD, J=9,6, 6,0 Hz, 1H), 5,98 (d, J=7,3 Hz, 1H), 6,93 (d, J=7,3 Hz, 1H), 7,03 (user.s, 1H), 7,10 (t, J=8,5 Hz, 1H), 7,22-7,27 (m, 1H), 7,41 was 7.45 (m, 1H), 11,97-12,10 (user.s, 1H).

MS(+): 375 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 40:60 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 4,360 min.

The diastereoisomer (B):

1H NMR (600 MHz, CDCl3) δ M. D. 0,57-0,65 (m, 2H), 0,98-of 1.07 (m, 2H), 1,74-to 1.82 (m, 1H), 212-2,18 (m, 1H), 2,21-2,40 (m, 5H), 3,55-of 3.60 (m, 1H), 4,08 (DD, J=10,3, with 5.3 Hz, 1H), 5,98 (d, J=7,3 Hz, 1H), 6,97 (d, J=7,3 Hz, 1H), 7,10 (t, J=8,5 Hz, 1H), 7,18-7,22 (m, 1H), 7,38 (DD, J=6,7, and 2.1 Hz, 1H), 7,71 (user.s, 1H), 13,17-13,26 (user.s, 1H).

MS(+): 375 [M+H]+.

Examples 4-213 and 4-214

6-{1-(4-Chloro-3-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he

Separation using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=20:80) gave a single diastereoisomer (A) specified in the title compound as a colorless amorphous substance (33 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (21 mg).

The diastereoisomer (A):

1H NMR (300 MHz, CDCl3) δ M. D. 0,51-0,73 (m, 2H), 0,83-of 1.04 (m, 2H), 1,68-of 1.83 (m, 1H), 2,02-of 2.38 (m, 9H), 3,36-3,59 (m, 1H), 3,86-4,01 (m, 1H), 5,87-of 6.04 (m, 1H), of 6.85-of 6.96 (m, 1H), 7,06-to 7.18 (m, 1H), 7,20-7,34 (m, 3H), 11,89-12,11 (user.s, 1H).

MS(+): 371 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 4,503 min.

The diastereoisomer (B):

1H NMR (300 MHz, CDCl3) δ M. D. of 0.49 to 0.68 (m, 2H), 0,93-of 1.13 (m, 2H), 1,70-to 1.86 (m, 1H), 2,06-2,41 (m, 9H), 3,48-to 3.67 (m, 1H), 4,00-4,10 (m, 1H), 5,93-6,01 (m, 1H), 6,87-of 6.99 (m, 1H), 7,06-7,14 (m, 1H), 7,14-7,21 (m, 1H), 7,26-of 7.36 (m, 1H), 7,68-7,80 (m, 1H), 13,04-13,24 (user.s, 1H).

MS(+): 371 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 8,440 min.

Examples 4-215 and 4-216

6-{1-(3-Chloro-4-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he

Separation via CHIRALAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=20:80) gave a single diastereoisomer (A) specified in the title compound as a colorless amorphous substance (48 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (35 mg).

The diastereoisomer (A):

1H NMR (300 MHz, CDCl3) δ M. D. of 0.51 to 0.68 (m, 2H), 0,90-1,02 (m, 2H), 1,62-of 1.74 (m, 1H), 1,99-2,41 (m, 9H), 3,40 is 3.57 (m, 1H), 3,90-4,01 (m, 1H), 5,93-6,03 (m, 1H), 6,87-of 6.96 (m, 1H), 7,07-7,21 (m, 2H), 7,26-7,31 (m, 1H), to 7.33-value of 7, 37 (m, 1H), 11,98-12,20 (user.s, 1H).

MS(+): 371 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 4,520 min.

The diastereoisomer (B):

1H NMR (300 MHz, CDCl3) δ M. D. of 0.52 to 0.68 (m, 2H), 0,93-1,07 (m, 2H), 1,70-of 1.85 (m, 1H), 2,07-2,40 (m, 9H), 3,49-3,65 (m, 1H), 3,97-4,12 (m, 1H), of 5.92-of 6.04 (m, 1H), 6,90-7,02 (m, 1H), 7,07-7,15 (m, 1H), 7,15-7,22 (m, 1H), 7,29-of 7.36 (m, 1H), 7,62-7,74 (m, 1H), 13,04-13,16 (user.s, 1H).

MS(+): 371 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 9,608 min.

Examples 4-217 and 4-218

6-{1-(4-Chloro-3-fluorophenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he

Separation using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=50:50) gave a single diastereoisomer (A) specified in the title compound as a colorless amorphous substance (50 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (33 mg).

The diastereoisomer (A):

1H NMR (600 M�C, CDCl3) δ M. D. of 0.58-0.67 and (m, 2H), 0,93-0,99 (m, 2H), 1,70-1,78 (m, 1H), 2,06-2,12 (m, 1H), 2,14-2,40 (m, 5H), 3.46 in-3,54 (m, 1H), 3,96-was 4.02 (m, 1H), of 5.99 (d, J=7,3 Hz, 1H), 6,93 (d, J=7,3 Hz, 1H), 7,05 (user.s, 1H), between 7.09-7.13 (m, 1H), 7,21-7,25 (m, 1H), 7,32-value of 7, 37 (m, 1H), 12,11-12,26 (m, 1H).

MS(+): 375 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 4,820 min.

The diastereoisomer (B):

1H NMR (600 MHz, CDCl3) δ M. D. 0,56-0,65 (m, 2H), 0,97-of 1.07 (m, 2H), 1,74-to 1.82 (m, 1H), 2,13-2,19 (m, 1H), 2,20-2,40 (m, 5H), 3,55-3,61 (m, 1H), 4,06-4,12 (m, 1H), 5,98 (d, J=7,3 Hz, 1H), 6,97 (d, J=7,3 Hz, 1H), 7,04-was 7.08 (m, 1H), 7,13-7,17 (m, 1H), 7,35 (t, J=8,0 Hz, 1H), 7,68 (user.s, 1H), 13,15-13,27 (m, 1H).

MS(+): 375 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 9,481 min.

Examples and 4-219 4-220

3-Cyclopropyl-6-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he

Separation using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=50:50) gave a single diastereoisomer (A) specified in the title compound as a colorless amorphous substance (68 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (36 mg).

The diastereoisomer (A):

1H NMR (600 MHz, CDCl3) δ M. D. of 0.59 to 0.68 (m, 2H), 0,94-1,00 (m, 2H), 1,71-to 1.79 (m, 1H), 2,06-to 2.13 (m, 1H), 2,18-of 2.44 (m, 5H), 3,47-3,54 (m, 1H), 4,05-4,10 (m, 1H), 6,02 (d, J=7,3 Hz, 1H), 6,95 (d, J=6,9 Hz, 1H), to 7.09 (user.s, 1H), 7,27-7,34 (m, 2H), 7,52-7,58 (m, 1H), 12,32-12,45 (user.s, 1H).

MS(+): 409 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane ethane�l = 40:60 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 4,098 min.

The diastereoisomer (B):

1H NMR (600 MHz, CDCl3) δ M. D. 0,57-0,66 (m, 2H), and 0.98-1,08 (m, 2H), 1,76-of 1.83 (m, 1H), 2,15-of 2.42 (m, 6H), 3,56-3,62 (m, 1H), 4,15-4,20 (m, 1H), 6,01 (d, J=7,3 Hz, 1H), 6,98 (d, J=7,3 Hz, 1H), 7,22 (d, J=9,6 Hz, 2H), 7,56 (m, J=7,8 Hz, 1H), 7,79 (user.s, 1H), 13,30-be 13.42 (user.s, 1H).

MS(+): 409 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 40:60 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 7,120 min.

Examples and 4-221 4-222

6-{1-[4-Chloro-3-(trifluoromethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he

Separation using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=50:50) gave a single diastereoisomer (A) specified in the title compound as a colorless amorphous substance (87 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (42 mg).

The diastereoisomer (A):

1H NMR (600 MHz, CDCl3) δ M. D. of 0.58-0.67 and (m, 2H), from 0.92 to 0.99 (m, 2H), 1,71-to 1.79 (m, 1H), 2,06-2,12 (m, 1H), 2,17-of 2.45 (m, 5H), 3,47-of 3.53 (m, 1H), 4,07 (DD, J=9,2, 6,4 Hz, 1H), of 5.99 (d, J=7,3 Hz, 1H), 6,93 (d, J=6,9 Hz, 1H), 7,14 (user.s, 1H), 7,47 (d, J=8.4 Hz, 1H), 7,55 (DD, J=8,4, and 2.2 Hz, 1H), 7,71 (d, J=2,2 Hz, 1H), of 12.37-12,49 (user.s, 1H).

MS(+): 425 [M+H]+.

The diastereoisomer (B):

1H NMR (600 MHz, CDCl3) δ M. D. 0,57-0,65 (m, 2H), and 0.98-1,08 (m, 2H), 1,75-to 1.82 (m, 1H), 2,13-2,19 (m, 1H), of 2.21-2,41 (m, 5H), 3,56-3,62 (m, 1H), 4,15 (DD, J=10,6, 5,0 Hz, 1H), 5,98 (d, J=7,3 Hz, 1H), 6,98 (d, J=7,3 Hz, 1H), 7,44-7,49 (m, 2H), of 7.64 (d, J=1.4 Hz, 1H), to 7.77 (user.s, 1H), 13,18-13,31 (user.s, 1H).

MS(+): 425 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DICEL), hexane:ethanol = 40:60 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 7,961 min.

Examples 4-223 and 4-224

3-Cyclopropyl-6-{1-(4-fluoro-3-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he

Separation using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=50:50) gave a single diastereoisomer (A) specified in the title compound as a colorless amorphous substance (40 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (24 mg).

The diastereoisomer (A):

1H NMR (600 MHz, CDCl3) δ M. D. 0,57-0,65 (m, 2H), 0,92-0,98 (m, 2H), 1,69-of 1.76 (m, 1H), 2,06-2,39 (m, 6H), of 2.25 (d, J=1.4 Hz, 3H), 3.46 in-3,51 (m, 1H), 3,89 (DD, J=9,9, and 5.7 Hz, 1H), 5,97 (d, J=6,9 Hz, 1H), of 6.79 (user.s, 1H), 6,91 (d, J=7,3 Hz, 1H), 6,95-of 6.99 (m, 1H), 7,08-7,13 (m, 2H), 11,10-11,21 (user.s, 1H).

MS(+): 355 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 40:60 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = min. of 4.246

The diastereoisomer (B):

1H NMR (600 MHz, CDCl3) δ M. D. of 0.56 to 0.63 (m, 2H), 0,96-1,04 (m, 2H), 1,74-of 1.81 (m, 1H), 2,13-is 2.37 (m, 6H), and 2.26 (d, J=1.4 Hz, 3H), 3,54-of 3.60 (m, 1H), 4,01 (DD, J=9,4, 6.2 Hz, 1H), 5,98 (d, J=7,3 Hz, 1H), 6,93-of 6.99 (m, 2H), 7,07-7,12 (m, 2H), 7,39 (user.s, 1H), 12,52-12,64 (user.s, 1H).

MS(+): 355 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 40:60 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 6,970 min.

Examples 4-225 and 4-226

6-{1-[3-Chloro-4-(deformity)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he

Separation using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=30:70) gave about�in the diastereoisomer (A) specified in the title compound as a colorless amorphous substance (70 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (40 mg).

The diastereoisomer (A):

1H NMR (300 MHz, CDCl3) δ M. D. 0,56-0,70 (m, 2H), 0,93-1,02 (m, 2H), 1,71-to 1.79 (m, 1H), 2,03-of 2.46 (m, 6H), 3,43-3,56 (m, 1H), 4,01-to 4.14 (m, 1H), 5,98-6,07 (m, 1H), 6,66-7,13 (m, 2H), 7,30-7,38 (m, 1H), 7,39-of 7.46 (m, 1H), of 7.48-7,54 (m, 1H), 7,56-7,65 (m, 1H), 12,41-of 12.59 (user.s, 1H).

MS(+): 407 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 30:70 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 6,895 min.

The diastereoisomer (B):

1H NMR (300 MHz, CDCl3) δ M. D. 0,52-0,71 (m, 2H), of 0.90-1.14 in (m, 2H), 1,70-1,91 (m, 1H), 2,08-2,47 (m, 6H), 3,47-to 3.67 (m, 1H), 4,10-4,20 (m, 1H), 5,93-6,08 (m, 1H), 6,68-7,15 (m, 2H), 7,31-7,47 (m, 2H), 7,56-to 7.68 (m, 1H), 7,83-7,97 (m, 1H), 13,30-13,49 (user.s, 1H).

MS(+): 407 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 30:70 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 8,434 min.

Examples 4-227 and 4-228

6-{1-(4-Chloro-3-methoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-cyclopropylamino-2(1H)-he

Separation using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=50:50) gave a single diastereoisomer (A) specified in the header connection in the form of a colorless amorphous material (52 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (29 mg).

The diastereoisomer (A):

1H NMR (600 MHz, CDCl3) δ M. D. of 0.57 and 0.64 (m, 2H), 0,91-0,98 (m, 2H), 1,70-1,78 (m, 1H), 2,07-to 2.13 (m, 1H), 2,17-to 2.40 (m, 5H), 3,48-3,54 (m, 1H), 3,88 (s, 3H), of 3.95 (DD, J=9,9, and 5.7 Hz, 1H), of 5.99 (d, J=6,9 Hz, 1H), of 6.87 (DD, J=8,0, Of 2.1 Hz, 1H), 6,90 (d, J=6,9 Hz, 1H), 7,02 (d, J=1.9 Hz, 1H), 7,05 (user.s, 1H), 7,32 (d, J=8,3 Hz, 1H), 11,76-11,86 (user.s, 1H).

MS(+): 387 [M+H]+.

CHIRALPAKIB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 5,090 min.

The diastereoisomer (B):

1H NMR (600 MHz, CDCl3) δ M. D. of 0.57 to 0.63 (m, 2H), 0,96-1,04 (m, 2H), 1,74-of 1.80 (m, 1H), 2,16-of 2.38 (m, 6H), 3,58-to 3.64 (m, 1H), 3,89 (s, 3H), 4,06 (DD, J=9,2, 6,0 Hz, 1H), 6,00 (d, J=7,3 Hz, 1H), 6,86-6,90 (m, 2H), 6,95 (d, J=7,3 Hz, 1H), 7,32 (d, J=8,3 Hz, 1H), EUR 7.57 (user.s, 1H), 12,98-13,07 (user.s, 1H).

MS(+): 387 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = is at 8,486 min.

Examples 4-229 4-230 and

3-Dihydro-6-{1-[4-(deformedarse)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he

Separation using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=50:50) gave a single diastereoisomer (A) specified in the title compound as a colorless amorphous substance (59 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (35 mg).

The diastereoisomer (A):

1H NMR (600 MHz, CDCl3) δ M. D. 0,57-0,65 (m, 2H), 0,92-0,98 (m, 2H), 1,69-to 1.77 (m, 1H), 2,06-to 2.13 (m, 1H), 2,15-of 2.24 (m, 2H), 2.26 and-2,39 (m, 3H), 3.46 in-3,52 (m, 1H), 3,99 (DD, J=9,6, 6,0 Hz, 1H), 5,97 (d, J=7,3 Hz, 1H), of 6.49 (t, J=73,8 Hz, 1H), at 6.92 (d, J=7,3 Hz, 1H), 6,99 (user.s, 1H), to 7.09 (d, J=to 8.7 Hz, 2H), 7,35 (d, J=to 8.7 Hz, 2H), 11,65-11,77 (user.s, 1H).

MS(+): 389 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 4,742 min.

The diastereoisomer (B):

1H NMR (600 MHz, CDCl3) δ M. D. of 0.56 and 0.64 (m, 2H), 0,96-1,05 (m, 2H), 1,74-of 1.81 (m, 1H), 2,14-of 2.38 (m, 6H), 3,56-3,61 (m, 1H), 4,10 (DD, J=9,9, and 5.7 Hz, 1H), 5,98 (d, J=7,3 Hz, 1H), of 6.49 (t, =73,8 Hz, 1H), of 6.96 (d, J=7,3 Hz, 1H), to 7.09 (d, J=8,3 Hz, 2H), 7,32 (d, J=to 8.7 Hz, 2H), 7,63 (user.s, 1H), 12,98-throughout 13.09 (user.s, 1H).

MS(+): 389 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 7,778 min.

Examples 4-231 and 4-232

3-Dihydro-6-{1-[4-(deformity)-3-methylphenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he

Separation using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=30:70) gave a single diastereoisomer (A) specified in the header connection in the form of a colorless amorphous material (65 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (50 mg).

The diastereoisomer (A):

1H NMR (300 MHz, CDCl3) δ M. D. of 0.45 to 0.68 (m, 2H), 0,85-1,08 (m, 2H), 1,64-of 1.83 (m, 1H), 2,01-2,49 (m, 9H), 3,36-3,62 (m, 1H), 3,88-4,10 (m, 1H), 5,91-6,03 (m, 1H), 6,48-6,97 (m, 2H), 7,13-to 7.33 (m, 3H), of 7.42-7,52 (m, 1H).

MS(+): 387 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 4,923 min.

The diastereoisomer (B):

1H NMR (300 MHz, CDCl3) δ M. D. of 0.50 to 0.68 (m, 2H), 0,92-1,10 (m, 2H), 1,71-1,89 (m, 1H), 2,11-of 2.38 (m, 6H), 2,41 (s, 3H), 3,52-to 3.67 (m, 1H), 4,04-4,18 (m, 1H), of 5.92-of 6.06 (m, 1H), is 6.51-at 6.92 (m, 1H), 6,93-of 6.99 (m, 1H), 7,13-7,31 (m, 2H), 7,43-7,52 (m, 1H), 7,74-a 7.87 (m, 1H), 13,04-13,29 (user.s, 1H).

MS(+): 387 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 9,239 min.

Examples 4-233 and 4-234

3-Dihydro-6-{1-[4-(deformity)-3-fluorophenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he

Time�t using CHIRALPAK IB (40°C, flow rate: 10 ml/min, ethanol:hexane=30:70) gave a single diastereoisomer (A) specified in the title compound as a colorless amorphous substance (40 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (40 mg).

The diastereoisomer (A):

1H NMR (300 MHz, CDCl3) δ M. D. of 0.53 is 0.70 (m, 2H), 0,89-1,02 (m, 2H), 1,68-of 1.85 (m, 1H), 2,00-2,48 (m, 6H), 3,39-3,63 (m, 1H), 3,99-4,18 (m, 1H), 5,95-of 6.04 (m, 1H), 6,59-7,07 (m, 2H), of 7.19-7,39 (m, 3H), 7,47-of 7.62 (m, 1H), 12,38-12,66 (user.s, 1H).

MS(+): 391 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 4,843 min.

The diastereoisomer (B):

1H NMR (300 MHz, CDCl3) δ M. D. 0,51-0,74 (m, 2H), of 0.91-1.14 in (m, 2H), 1,72-1,89 (m, 1H), 2,09-2,51 (m, 6H), 3,52-3,68 (m, 1H), 4,08-of 4.25 (m, 1H), 5,95-6,10 (m, 1H), 6,64-7,06 (m, 2H), 7,12-7,25 (m, 2H), of 7.48-to 7.60 (m, 1H), 7,80-7,94 (m, 1H), 13,26-13,57 (user.s, 1H).

MS(+): 391 [M+H]+.

CHIRALPAK IB a 4.6×250 mm 5 μm (DAICEL), hexane:ethanol = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 9,704 min.

Examples and 4-235 4-236

3-Chloro-6-{1-(4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-he

(R,S) mixture specified in the title compound was obtained as a colorless amorphous substance (240 mg) by carrying out essentially the same reaction as in examples 1-16(2)(3) and 4-209 4-210 and(2)(3), consecutively, except that used the (5R)-5-[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-(5-chloro-6-methoxypyridine-2-yl)ethenyl]pyrrolidin-2-he obtained in example 4-48(1), and used�up ethyliodide instead of methyliodide. The mixture was separated using chiral HPLC (CHIRALCEL OD-H, 40°C, flow rate: 7 ml/min, ethanol:hexane=0:100) to give a single diastereoisomer (A) specified in the title compound as a colorless amorphous substance (38 mg) and the other diastereoisomer (B) specified in the title compound as a colorless amorphous substance (35 mg).

The diastereoisomer (A):

1H NMR (300 MHz, CDCl3) δ M. D. 1,20-a 1.54 (m, 3H), 1,59-1,90 (m, 1H), 2,00-of 2.72 (m, 5H), 3,35-to 3.64 (m, 1H), of 3.77-to 4.28 (m, 3H), 5,98 (d, J=7,6 Hz, 1H), 6,78-to 6.95 (m, 2H), made 7.16 interest-7,29 (m, 2H), 7,28-of 7.36 (m, 1H), 7,49 (d, J=7.5 Hz, 1H), 11,75-12,12 (user.s, 1H).

MS(+): 361 [M+H]+.

CHIRALCEL OD-H to 4.6×250 mm 5 μm (DAICEL), hexane:i-PrOH = 50:50 vol./vol., 40°C, 1.0 ml/min, 210 nm, Rt = 9,196 min.

The diastereoisomer (B):

1H NMR (300 MHz, CDCl3) δ M. D., of 1.41 (t, J=7,0 Hz, 3H), 1,82 is 2.01 (m, 1H), 2,09-of 2.58 (m, 5H), 3,53-3,73 (m, 1H), 3,95-4,07 (m,