5-hydroxypyrimidine-4-carboxamide derivative

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of the structural formula (1), which possesses the activity increasing erythropoietin production. In formula

R1 represents a group of the structural formula

,

in which R4 and R5, each independently, represent a hydrogen atom, halogen atom or C1-C6alkyl group, R6 represents a hydrogen atom, halogen atom or C1-C6alkyl group, R7 represents a hydroxyC1-C6alkyl group, hydroxyhalogenC1-C6alkyl group, C1-C6alkoxyC1-C6alkyl group, which can have 1 substituent, independently selected from a group of substituents α, (C1-C6alkoxy)carbonyl group, C1-C6alkoxyC1-C6alkoxyC1-C6alkyl group, hydroxyC1-C6alkoxygroup, C1-C6alkylcarbamoyl group, (C1-C6alkyl)(C1-C6alkyl) carbamoyl group, (C1-C6alkyl)(C1-C6alkyl) carbamoylC1-C6alkyl group or C2-C7alkanoyloxyC1-C6alkyl group, α represents a hydroxygroup, Q1 ring represents a piperidinyl group, rings Q2 and Q3 represent a phenyl or pyridyl group, X represents a simple bond or methylene, R2 represents a C1-C3alkyl group and R3 represents a hydrogen atom.

EFFECT: invention relates to a pharmaceutical composition, containing the said compounds, to the application of a compound for obtaining a medication for the enhancement of erythropoietin production and to a method of treatment or prevention of a disease, caused by reduced erythropoietin production, such as anaemia.

33 cl, 1 tbl, 55 ex

 

DERIVED 5-HYDROXYPYRIMIDINE-4-CARBOXAMIDE

DESCRIPTION

The technical field to which the invention relates

The present invention relates to compounds of low molecular weight having the activity of enhancing the production of erythropoietin.

Art

Erythropoietin (hereinafter abbreviated referred to as EPO) is a glycoprotein hormone that is essential for hematopoiesis erythrocytes. It is usually secreted from the kidneys and stimulates the production of red blood cells effects on red cells, stem cells, present to the bone marrow. In diseases that have an inherent decrease in EPO production (such as chronic renal failure), because the production of red blood cells is reduced and symptoms of anemia, the proposed treatment is in the form of substitution therapy with use of gene-recombinant human EPO. However, this gene-recombinant human EPO is characterized as having disadvantages, namely that it is a biological drug and is associated with high costs for health care, is a little convenient due to the fact that is introduced by injection, and has antigenicity.

On the other hand, it is known that compounds such as pyridine derivatives, proizvodno�e cinnoline, derivatives of quinoline, isoquinoline derivatives of (see patent documents 1-6 and 8), derivatives of 6-hydroxy-2,4-dioxotetrahydrofuran (see patent document 7) or derivatives of 4-hydroxypyrimidine-5-carboxamide (see patent document 9), are low molecular weight inducers of EPO. Furthermore, the known derivatives of 5-hydroxypyrimidine-4-carboxamide (international publication no WO 2009/131127 or international publication no WO 2009/131129).

Documents of prior art

Patent documents

[Patent document 1] international publication no WO 2003/049686

[Patent document 2] international publication no WO 2003/053997.

[Patent document 3] international publication no WO 2004/108681.

[Patent document 4] international publication no WO 2006/133391.

[Patent document 5] international publication no WO 2007/038571.

[Patent document 6] international publication no WO 2007/136990.

[Patent document 7] international publication no WO 2007/150011.

[Patent document 8] international publication no WO 2008/002576.

[Patent document 9] international publication no WO 2009/117269.

Description of the invention

Object of the invention

The authors of the present invention have conducted studies with the aim of providing new compounds with low molecular weight that have excellent, polysilsesquioxane EPO activity and are applicable for the treatment of diseases, caused by reduced production of EPO, and for the purpose of providing medicines containing such compounds.

Ways to achieve the goal

When resolving the above problems, the authors present invention found that novel compounds having the structure 5-hydroxypyrimidine-4-carboxamide, possess excellent that increase the production of EPO activity and that they are effective for the treatment of diseases caused by the low production of EPO, which thus led to the completion of the present invention.

According to the present invention proposed new derivatives of 5-hydroxypyrimidine-4-carboxamide, represented by the following General formula (1), their pharmacologically acceptable esters or their pharmacologically acceptable salts (hereinafter collectively called compounds of the present invention).

Namely, the present invention relates to the following items:

(1) the compound represented by the following General formula (1):

in which

R1represents a group represented by the following General formula (1A)

in which

R4and R5each independently represents a hydrogen atom, a halogen atom or a C1-C6alkyl group,

R6PR�dstanley a hydrogen atom, a halogen atom, C1-C6alkyl group, carbamoyl group, (C1-C6alkyl)carbamoyl group or (C1-C6alkyl)(C1-C6alkyl)carbamoyl group

R7is hydraxis1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, hydroxylases1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkoxyl1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, (C1-C6alkoxy)carbonyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkoxyl1-C6alkoxyl1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, hydroxys1-C6alkoxygroup, which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkylcarboxylic group which may have 1 or 2 substituent independently selected from the group of substituents α, (C1-C6alkyl)(C1-C6alkyl)carbamoyl group which may have 1 �Lee 2 Deputy, independently selected from the group of substituents α, S1-C6alkoxycarbonyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkylcarboxylic1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, (C1-C6alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S2-C7alkanolamines, which may have 1 or 2 substituent independently selected from the group of substituents α, S2-C7alkanolamines1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, or C2-C7alkanoyloxy1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α,

the group of substituents α is a group consisting of a carbonyl group, a hydroxy-group, amino group, carboxypropyl, carbamoyl group, C1-C6alkoxygroup, halogen1-C6alkoxygroup, S2-C7alkanolamines, hydroxyisopropyl and C1-C6alkoxyimino,

the ring Q1performance�possessing a monocyclic heterocyclic group (where the heterocyclic group comprises a 5-7-membered aromatic heterocycle and the non-aromatic heterocycle and contains 1 or 2 atoms, selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom),

the ring Q2represents a monocyclic hydrocarbon cyclic group (where the cyclic hydrocarbon group includes a 5-7-membered aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring, or monocyclic heterocyclic group (where the heterocyclic group comprises a 5-7-membered aromatic heterocycle and the non-aromatic heterocycle and contains 1 or 2 atoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom),

the ring Q3represents a monocyclic hydrocarbon cyclic group (where the cyclic hydrocarbon group includes a 5-7-membered aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring, or monocyclic heterocyclic group (where the heterocyclic group comprises a 5-7-membered aromatic heterocycle and the non-aromatic heterocycle and contains 1 or 2 atoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom), and

X represents a simple bond, methylene or ethylene,

R2represents C1-C3alkyl group or methylsulfonyl group and

R3represents a hydrogen atom or a methyl group, f�macological acceptable ether complex or its pharmacologically acceptable salt,

(2) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to the above item (1), where R2represents a methyl group or methylsulfonyl group

(3) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to the above item (1), where R2represents a methyl group,

(4) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(3), where R3represents a hydrogen atom,

(5) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(4), where R4represents a hydrogen atom,

(6) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(5), where R5represents a hydrogen atom, a halogen atom or a methyl group,

(7) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(5), where R5represents a hydrogen atom,

(8) the compound, its pharmacologist�Cesky acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(7), where R6represents a hydrogen atom, a halogen atom or a methyl group,

(9) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(7), where R6represents a hydrogen atom,

(10) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(9), where R7is hydraxis1-C6alkyl group, hydroxylases1-C6alkyl group, C1-C6alkoxyl1-C6alkyl group, hydroxys1-C6alkoxyl1-C6alkyl group, (C1-C6alkoxy)carbonyl group, C1-C6alkoxyl1-C6alkoxyl1-C6alkyl group, hydroxys1-C6alkoxygroup, S1-C6alkylcarboxylic group, (C1-C6alkyl)(C1-C6alkyl)carbamoyl group, hydroxys1-C6alkylcarboxylic group, C1-C6alkoxycarbonyl group, C1-C6alkylcarboxylic1-C6alkyl group, (C1-C6alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group or hydroxys1-C6alkitab�oils 1-C6alkyl group,

(11) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(9), where R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1,1-debtor-2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxyethoxymethyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group, methylcarbamoylmethyl group, dimethylcarbamoyl group, gidroksietilirovanny group or hydroxyethylaminomethyl group

(12) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(9), where R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxybutyl� group 2-hydroxy-1,1-dimethylethylene group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, ethoxycarbonyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethylcarbamoyl group

(13) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(12), where the ring Q1represents a monocyclic heterocyclic group (where the heterocyclic group includes a 6-membered aromatic heterocycle and the non-aromatic heterocycle and contains 1 or 2 nitrogen atom),

(14) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(12), where the ring Q1is piperidino group

(15) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(14), where the ring Q2represents a monocyclic hydrocarbon cyclic group (where the cyclic hydrocarbon group includes a 6-membered aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring or a monocyclic hetero�Klionsky group (where the heterocyclic group includes a 6-membered aromatic heterocycle and the non-aromatic heterocycle and contains 1 or 2 nitrogen atom),

(16) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(14), where the ring Q2represents a phenyl group or pyridyloxy group

(17) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(16), where the ring Q3represents a monocyclic hydrocarbon cyclic group (where the cyclic hydrocarbon group includes a 6-membered aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring or a monocyclic heterocyclic group (where the heterocyclic group includes a 6-membered aromatic heterocycle and the non-aromatic heterocycle and contains 1 or 2 nitrogen atom),

(18) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(16), where the ring Q3represents a phenyl group or pyridyloxy group

(19) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(18), where X is a single bond or methylene,

(20) the compound, its pharmacologists�Eski acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(4), where

R1represents a group represented by the following General formula (1B)

where

R5represents a hydrogen atom, a halogen atom or a C1-C6alkyl group,

R6represents a hydrogen atom, a halogen atom, C1-C6alkyl group, carbamoyl group, C1-C6alkylcarboxylic group or (C1-C6alkyl)(C1-C6alkyl)carbamoyl group

R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1,1-debtor-2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxyethoxymethyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group, methylcarbamoylmethyl group, dimethylcarbamoyl group, gidroksietilirovanny group or hydroxyethylaminomethyl group

V, W and Y each independently represent a carbon atom (and�Audi 1 hydrogen atom) or a nitrogen atom and

X represents a single bond or methylene,

(21) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(4), where

R1is a group represented by any of the following formulas from the General formula (1B-1) to General formula (1B-8)

where

R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1,1-debtor-2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxyethoxymethyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group, methylcarbamoylmethyl group, dimethylcarbamoyl group, gidroksietilirovanny group or hydroxyethylaminomethyl group

(22) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) (), where

R1is a group represented by any of following General formula (1B-1), General formula (1B-2), General formula (1B-3), General formula (1B-4), General formula (1B-5) or General formula (1B-6)

where

R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1,1-debtor-2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxyethoxymethyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group, methylcarbamoylmethyl group, dimethylcarbamoyl group, gidroksietilirovanny group or hydroxyethylaminomethyl group

(23) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above items (20) to(22), where R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethylene group, 2-hydroxypropyl group 3-hydroxypropyl group 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, ethoxycarbonyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethylcarbamoyl group

(24) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above items (20)-(22) where in the case when R7is a group having a hydroxy-group, (hydroxys1-C6alkyl group, hydroxylases1-C6alkyl group, hydroxys1-C6alkoxygroup, hydroxys1-C6alkylcarboxylic group or hydroxys1-C6alkylcarboxylic1-C6alkyl group), a hydroxy-group forms an ester bond with the C1-C6alkanoyloxy group

(25) the compound or its pharmacologically acceptable salt according to the above item (1), selected from the following compounds:

({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[4'-(acetoxymethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-({1-[4'-(1-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(2-hydroxypropyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(2-hydroxy-1,1-dimethylethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[4'-(dimethylcarbamoyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-6-methyl-2-({1-[4'-(methylcarbamoyl)biphenyl-4-yl]piperidine-4-yl}methyl)pyrimidine-4-yl]carbonyl}amino)acetic acid

[({2-[(1-{4'-[2-(dimethylamino)-2-oxoethyl]biphenyl-4-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{4-[4-(gidroximetil)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{4-[3-(gidroximetil)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

{[(5-hydroxy-2-{[1-(4-{5-[1-(methoxyethoxy)ethyl]pyridin-2-yl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

[({2-[(1-{4-[5-(1-the ACO�hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{4-[5-(gidroximetil)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({2-[(1-{4-[5-(ethoxycarbonyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({2-[(1-{4-[2-(ethoxycarbonyl)benzyl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

{[(5-hydroxy-2-{[1-(4-{[6-(2-hydroxyethoxy)pyridin-3-yl]methyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

[({5-hydroxy-2-[(1-{5-[4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{5-[4-(2-hydroxypropyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{5-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

({[2-({1-[2-chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(gidroximetil)-2-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3'-chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)UK�usnei acid,

({[5-hydroxy-2-({1-[4'-(gidroximetil)-2'-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(gidroximetil)-2,3'-dimethyldiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(2-hydroxybutyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[({5-hydroxy-2-[(1-{4-[4-(2-hydroxypropyl)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{4-[4-(2-hydroxy-1,1-dimethylethyl)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

({[2-({1-[4'-(1,1-debtor-2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[4'-(1,1-debtor-2-hydroxypropyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[4'-(1,1-debtor-2-hydroxy-2-methylpropyl") biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

{[(5-[(2,2-dimethylpropanoyl)oxy]-2-{[1-(4'-{[(2,2-dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

{[(2-{[1-(4'-{[(2,2-dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-5-hydrox�-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

({[5-hydroxy-2-({1-[4'-(methoxymethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[2'-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3'-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[2-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(gidroximetil)-3'-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3',5'-debtor-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3',5'-dichloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3',5'-dimethyl-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[({5-hydroxy-2-[(1-{4'-[2-hydroxy-3-methoxypropyl]biphenyl-4-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic sour�s,

({[5-hydroxy-2-({1-[4'-(3-hydroxypropyl methyl]biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(gidroximetil)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[({2-[(1-{5-[3-fluoro-4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({2-[(1-{5-[3-chloro-4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, or

[({5-hydroxy-2-[(1-{5-[4-(gidroximetil)-3-methylphenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

(26) a pharmaceutical composition containing as active ingredient a compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to any one of the above clauses from (1) to (25),

(27) the pharmaceutical composition according to the above item (26) for the prevention and/or treatment of anaemia,

(28) the pharmaceutical composition according to the above item (27), where the anemia is nephrogenic anemia, anemia of prematurity, anemia associated with chronic disease, anemia associated with cancer chemotherapy, cancerous anemia, anemia associated with inflammation, or a�EMEA, concomitant congestive heart failure,

(29) the pharmaceutical composition according to the above item (27), where the anemia is anemia related to chronic kidney disease,

(30) the pharmaceutical composition according to the above item (26) for the production of erythropoietin,

(31) the administration of the compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to any one of the above paragraphs (1) to(25) for receiving medicines,

(32) the use according to the above item (31), where the medicament is a medicament for prevention and/or treatment of anaemia,

(33) the use according to the above item (32), where the anemia is nephrogenic anemia, anemia of prematurity, anemia associated with chronic disease, anemia associated with cancer chemotherapy, cancerous anemia, anemia associated with inflammation, or anemia associated with congestive heart failure,

(34) anemia according to the above item (32), where the anemia is anemia related to chronic kidney disease,

(35) the method for producing erythropoietin containing the introduction of a pharmacologically effective amount of a compound, pharmacologically acceptable ester or er� pharmacologically acceptable salt according to any one of the above paragraphs (1) to(25) to a mammal or a bird,

(36) a method for the treatment or prevention of disease, containing the introduction of a pharmacologically effective amount of a compound, pharmacologically acceptable ester or pharmacologically acceptable salt according to any one of the above paragraphs (1) to(25) to a mammal,

(37) the method according to the above item (36), where the disease is anemia,

(38) the method according to the above item (36), where the disease is nephrogenic anemia, anemia of prematurity, anemia associated to chronic diseases, anemia, concomitant cancer chemotherapy, cancerous anemia, anemia associated with inflammation, or anemia, concomitant congestive heart failure,

(39) the method according to the above item (36), where the disease is anemia related to chronic kidney disease,

(40) the method according to any one of the above paragraphs (36) through(39), where the mammal is man,

(41) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to any one of the above paragraphs (1) to(25) for use in the method of treatment or prophylaxis of a disease,

(42) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to the above item (41), where disease�education anemia

(43) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to the above item (41), where the disease is nephrogenic anemia, anemia of prematurity, anemia associated to chronic diseases, anemia, concomitant cancer chemotherapy, cancerous anemia, anemia associated with inflammation, or anemia, concomitant congestive heart failure, or

(44) the compound, its pharmaceutically acceptable ether complex or its pharmacologically acceptable salt according to the above item (41), where the disease is anemia related to chronic kidney disease.

In one aspect, the present invention offers

(45) the compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to the above item (1), where

R6represents a hydrogen atom, a halogen atom or a C1-C6alkyl group, and

R7is hydraxis1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, hydroxylases1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, (C1-C6alkoxy)carbonyl group, to�ora may have 1 or 2 Deputy, independently selected from the group of substituents α, S1-C6alkoxyl1-C6alkoxyl1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, hydroxys1-C6alkoxygroup, which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkylcarboxylic group which may have 1 or 2 substituent independently selected from the group of substituents α, (C1-C6alkyl)(C1-C6alkyl)carbamoyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkoxycarbonyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkylcarboxylic1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, (C1-C6alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S2-C7alkanolamines, which may have 1 or 2 substituent independently selected from the group of substituents α, or C2-C7alkanolamines1-C6alkyl group�, which may have 1 or 2 substituent independently selected from the group of substituents α.

The compound of the present invention, represented by the above General formula (1) has the skeleton of a 5-hydroxypyrimidine-4-carboxamide. The substituent in position 2 of the pyrimidine ring has 3 cyclic group and the cyclic group have a certain Deputy. The compound of the present invention, its pharmacologically acceptable ester or pharmacologically acceptable salt has excellent activity that increases the production of EPO.

Below is the explanation of the substituents in the compound of the present invention.

“Halogen atom” in the symbols R4, R5and R6refers to fluorine atom, chlorine atom, bromine atom or iodine atom, preferably the fluorine atom.

“C1-C3the alkyl group in R2refers to an alkyl group with unbranched or branched chain having 1-3 carbon atoms. Examples include methyl group, ethyl group, propyl group and isopropylene group.

“C1-C6alkyl group” in the symbols R4, R5and R6refers to an alkyl group with unbranched or branched chain having 1-6 carbon atoms. Examples include a methyl group, an ethyl group�, propyl group, isopropylene group, butyl group, sec-butyl group, tert-butyl group, pentelow group, isopentyl group, 2-methylbutyl group, neopentylene group, 1-ethylpropyl group, hexoloy group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group and the like. C1-C6the alkyl group preferably represents C1-C4alkyl group, more preferably C1-C3alkyl group.

“Hydraxis1-C6the alkyl group in R7refers to a group in which one or more hydrogen atoms (preferably 1 or 2 of the hydrogen atom) of the above “C1-C6alkyl group substituted by a hydroxy-group. Examples include hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxy-1,1-dimethylethylene group, 2-hydroxybutyl group, 2-hydroxypentanal group and the like group. Hydraxis1-C6alkyl �group preferably represents hydraxis 1-C4alkyl group, preferably hydraxis1-C3alkyl group.

“Hydroxylases1-C6the alkyl group in R7refers to a group in which 1 or 2 hydrogen atom at the carbon atom of the above “hydraxis1-C6alkyl group” substituted with the above “halogen atom”. Examples include 1-fluoro-2-hydroxyethylene group, 1,1-debtor-2-hydroxyethylene group, 1-fluoro-2-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 1,1-debtor-3-hydroxypropyl group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group and the like group. Hydroxylases1-C6the alkyl group preferably represents hydroxylases1-C4alkyl group, more preferably hydroxylases1-C3alkyl group.

“C1-C6Alkoxyl1-C6the alkyl group in R7refers to a group in which 1 hydrogen atom of the above “C1-C6alkyl group” substituted by the following “C1-C6alkoxygroup”. Examples include methoxymethyl group, methoxyamino group, methoxypropyl group, methoxybutyl group, ethoxymethylene group, ethoxyethylene group, ethoxypropanol group, ethoxymethylene group, methoxyphenyl�first group and the like. C1-C6Alkoxyl1-C6the alkyl group preferably represents C1-C4alkoxyl1-C4alkyl group, more preferably C1-C2alkoxyl1-C2alkyl group.

“C1-C6Alkoxygroup” in the definition of the group α of substituents refers to a group in which the above “C1-C6alkyl group linked to the oxygen atom. Examples include a methoxy group, an ethoxy group, n-propoxylate, n-butoxypropyl, second-butoxypropan, tert-butoxypropan, n-phenoxypropan and the like. C1-C6Alkoxygroup preferably represents C1-C4alkoxygroup, more preferably C1-C2alkoxygroup.

“Halogens1-C6alkoxygroup” in the definition of the group α of substituents refers to a group in which 1 or 2 hydrogen atoms of the above “C1-C6alkoxygroup” substituted with the above “halogen atom”. Examples include formatexample, climatograph, 1-peritonsillar, 1-chlorethoxyfos, 2-peritonsillar, 1,2-deferredcomp and the like. Halogens1-C6alkoxygroup preferably represents Halogens1-C4alkoxygroup, more preferably Halogens1-C3alcox�group.

“C1-C6Alkoxyimino” in the definition of the group α of substituents refers to a group in which the above “C1-C6alkoxygroup” is associated with aminogroups. Examples include methoxyimino, amoxiillin, propoxyimino, isopropoxide, butoxysilane, isobutoxide, Deut-butoxysilane, tert-butoxysilane, pentoxifylline, isopentene, 2-methylbutadiene and the like. C1-C6Alkoxyimino preferably represents C1-C4alkoxyimino, more preferably C1-C3alkoxyimino.

“(C1-C6Alkoxy)carbonyl group” in the definition of R7refers to a group in which the above “C1-C6alkoxygroup” is connected to the carbonyl group. Examples include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, n-butoxycarbonyl group and the like. (C1-C6Alkoxy)carbonyl group preferably represents (C1-C4alkoxy)carbonyl group, more preferably (C1-C3alkoxy)carbonyl group.

“C1-C6Alkoxyl1-C6alkoxyl1-C6alkyl group” in the definition of R7refers to a group in which 1 hydrogen atom in C1-C 6alkoxy specified above “C1-C6alkoxyl1-C6alkyl group” substituted with the above “C1-C6alkoxygroup”. Examples include methoxyethoxymethyl group, ethoxymethyleneamino group, methoxyethoxyethoxy group (for example, 1-methoxyethoxymethyl group), 2-ethoxymethyleneamino group, 3-methoxyethoxymethyl group and the like. C1-C6Alkoxyl1-C6alkoxyl1-C6the alkyl group preferably represents C1-C4alkoxyl1-C4alkoxyl1-C4alkyl group, more preferably C1-C2alkoxyl1-C2alkoxyl1-C2alkyl group.

“Hydraxis1-C6alkoxygroup” in the definition of R7refers to a group in which 1 hydrogen atom of the above “C1-C6alkoxygroup” substituted hydroxy-group. Examples include hydroxyethoxy, hydroxyethoxy (for example, 2-hydroxyethoxy), 2-hydroxypropoxy and the like. Hydraxis1-C6alkoxygroup preferably represents hydraxis1-C4alkoxygroup, more preferably, hydroxys1-C2alkoxygroup.

“C1-C6Alkilirovanny group” in the definitions of R6 and R7refers to a group in which 1 hydrogen atom carbamoyl group substituted with the above “C1-C6alkyl group”. Examples include methylcarbamoyl group, ethylcarbitol group, propylnorapomorphine group and the like. C1-C6Alkilirovanny group preferably represents C1-C4alkylcarboxylic group, more preferably C1-C3alkylcarboxylic group.

“(C1-C6Alkyl)(C1-C6alkyl)carnemolla group” in the definitions of R6and R7refers to a group in which 2 hydrogen atoms carbamoyl group substituted with the above “C1-C6alkyl group”. Examples include dimethylcarbamoyl group, methylethylcarbinol group, methylpropionyl group, diethylcarbamoyl group and the like. (C1-C6Alkyl)(C1-C6alkyl)carnemolla group preferably represents (C1-C4alkyl)(C1-C4alkyl)carbamoyl group, more preferably (C1-C2alkyl)(C1-C2alkyl)carbamoyl group.

“C1-C6Alkoxycarbonyl group” in the definition of R7refers to a group in which 1 hydrogen atom carbamoyl group substituted specified in�above “C 1-C6alkoxygroup”. Examples include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group and the like. C1-C6Alkoxycarbonyl group preferably represents C1-C4alkoxycarbonyl group, more preferably C1-C3alkoxycarbonyl group.

“C1-C6Alkylcarboxylic1-C6alkyl group” in the definition of R7refers to a group in which 1 hydrogen atom of the above “C1-C6alkyl group” substituted with the above “C1-C6alkylcarboxylic group”. Examples include methylcarbamoylmethyl group, ethylcarbodiimide group, propylnorapomorphine group, methylcarbamoylmethyl group, ethylcarboxylate group and the like. C1-C6Alkylcarboxylic1-C6the alkyl group preferably represents C1-C4alkylcarboxylic1-C4alkyl group, more preferably C1-C2alkylcarboxylic1-C2alkyl group.

“(C1-C6Alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group” in the definition of R7refers to a group in which 1 hydrogen atom of the above “C1-C6alkyl �the group” substituted with the above “(C 1-C6alkyl)(C1-C6alkyl)carbamoyl group”. Examples include dimethylcarbamoyl group, ethylmethylamino group and the like. (C1-C6Alkyl)(C1-C6alkyl)carbamoyl1-C6the alkyl group preferably represents (C1-C4alkyl)(C1-C6alkyl)carbamoyl1-C4alkyl group, more preferably (C1-C2alkyl)(C1-C2alkyl)carbamoyl1-C2alkyl group.

“C2-C7Alkanolamine” in the definitions of R7and the group α of substituents include, for example, a group in which alcoolica group with unbranched or branched chain having 2-7 carbon atoms (e.g., acetyl group, propylaniline group, Butyrina group, isobutylene group, pantaneira group, pivellina group, valerina group, isovaleryl group, hexanoyl group, heptanoyl group and the like) linked to the amino group. Examples include acetylamino, propionamido, bucillamine, isobutylamino, pentanediamine and the like. C2-C7Alkanolamine preferably represents C2-C5alkanolamine, more preferably C2-C 4alkanolamines.

“C2-C7Alkanolamines1-C6alkyl group” in the definition of R7refers to a group in which 1 hydrogen atom of the above “C1-C6alkyl group” substituted with the above “C2-C7alkanolamines”. Examples include acetylaminophenol group, propionylthiocholine group, butyrylthiocholine group, isobutylamino group, pentanedinitrile group and the like. C2-C7Alkanolamines1-C6the alkyl group preferably represents C2-C5alkanolamines1-C4alkyl group, more preferably C2-C3alkanolamines1-C2alkyl group.

“C2-C7Alkanoyloxy1-C6alkyl group” in the definition of R7refers to a group in which the hydrogen atom is the oxygen atom of the above “hydraxis1-C6alkyl group” substituted with the above “C2-C7alkanoyloxy group”. Examples include acetilcisteina group, propionylthiocholine group, butyrylcholine group, isobutyryloxy group, pentanedinitrile group and the like. C2-C7Alkanoyloxy1-C6alkyl group predpochtitel�but represents C 2-C5alkanoyloxy1-C4alkyl group, more preferably C2-C3alkanoyloxy1-C2alkyl group.

“Monocyclic hydrocarbon group” in the definitions of ring Q2and ring Q3refers to saturated, partially unsaturated or unsaturated 5-7-membered monocyclic hydrocarbon group. Examples include monocyclic aromatic hydrocarbon groups such as phenyl group; and monocyclic non-aromatic hydrocarbon groups, such as cyclopentene group, pirazinokarbazolovogo cyclohexyl group, cycloheptyl group, cyclopentenyl group, cyclohexenyl group and cycloheptenyl group. In the present invention is preferred 6-membered aromatic hydrocarbon group or non-aromatic hydrocarbon group, and more preferred is a 6-membered aromatic hydrocarbon group.

“Monocyclic heterocyclic group” in the definitions of ring Q1, ring Q2and ring Q3refers to saturated, partially unsaturated or unsaturated 5-7-membered monocyclic heterocyclic group containing 1 or 2 atoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom. Examples include a monocyclic neuropathies�their heterocyclic group, such as tetrahydrofuranyl group, tetrahydropyranyl group, DIOXOLANYL group, dioksidina group, dixaphedrine group, pyrrolidinyl group, piperideine group, aseanindia group, dihydropyridine group, dihydropyridine group, tetrahydropyridine group, piperazinyl group, morpholinyl group, dihydrooxazolo group and dihydrothiazine group; monocyclic aromatic heterocyclic groups such as pyrrolidine group, Peregrina group, tamilna group, furilla group, pyrimidinyl group, Pernilla group, pyridazinyl group, personilnya group, pyrazolidine group, imidazolidinyl group, thiazolidine group, isothiazolinone group, oxazolidine group and isoxazolidine group and the like. As the “monocyclic heterocyclic group” in the present invention is preferred 6-membered aromatic heterocyclic group or non-aromatic heterocyclic group containing 1 or 2 nitrogen atom, and more preferred is a 6-membered aromatic heterocyclic group or non-aromatic heterocyclic group containing 1 atom of nitrogen. As the monocyclic heterocyclic group in the ring Q1even more preferred is 6-members�tion of non-aromatic heterocyclic group, containing 1 nitrogen atom.

Values of R1in the compound of the present invention are specified below.

In the compound of the present invention, R1refers to a group represented by the following General formula (1A)

In the above General formula (1A), each of R4and R5independently refers to a hydrogen atom, halogen atom or C1-C6alkyl group, and R6refers to a hydrogen atom, halogen atom, C1-C6alkyl group, carbamoyl group, C1-C6alkylcarboxylic group or (C1-C6alkyl)(C1-C6alkyl)carbamoyl the group.

In the present invention, R4preferably represents a hydrogen atom.

In the present invention, R5preferably represents a hydrogen atom, a halogen atom or a methyl group and more preferably a hydrogen atom.

In the present invention, R6preferably represents a hydrogen atom, a halogen atom or a methyl group, more preferably a hydrogen atom, a chlorine atom or a methyl group and more preferably a hydrogen atom.

In the present invention, R7is hydraxis1-C6alkyl group which may have 1 or 2 substituent independently selected from the group α W�of mustiala, hydroxylases1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkoxyl1-C6alkyl group which may have 1 or 2 substituent independently selected from the group α of substituents, (C1-C6alkoxy)carbonyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkoxyl1-C6alkoxyl1-C6alkyl group which may have 1 or 2 substituent independently selected from the group α of substituents, hydroxys1-C6alkoxygroup, which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkylcarboxylic group which may have 1 or 2 substituent independently selected from the group α of substituents, (C1-C6alkyl)(C1-C6alkyl)carbamoyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkoxycarbonyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S1-C6alkylcarboxylic1-C6alkyl group which may have 1 or 2 substituent independently selected from the group α of substituents (C 1-C6alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, S2-C7alkanolamines, which may have 1 or 2 substituent independently selected from the group of substituents α, S2-C7alkanolamines1-C6alkyl group which may have 1 or 2 substituent independently selected from the group of substituents α, or C2-C7alkanoyloxy1-C6alkyl group which may have 1 or 2 substituent independently selected from the group α of substituents, and the group α of substituents refers to a group consisting of a carbonyl group, a hydroxy-group, amino group, carboxypropyl, carbamoyl group, C1-C6alkoxygroup, halogen1-C6alkoxygroup, S2-C7alkanolamines, hydroxyisopropyl and C1-C6alkoxyimino.

The group α of substituents in the present invention preferably is a group consisting of a hydroxy-group, C1-C6alkoxygroup, halogen1-C6alkoxygroup and C2-C7alkanolamine, more preferably the group consisting of hydroxyl groups and C1-C2alkoxygroup.

In the present invention, R7preferably �predstavljaet hydraxis 1-C6alkyl group, dihydroxy1-C6alkyl group, (C1-C6alkoxy)hydraxis1-C6alkyl group, (Halogens1-C6alkoxy)hydraxis1-C6alkyl group, (C2-C7alkanolamine)hydraxis1-C6alkyl group, hydroxylases1-C6alkyl group, dihydroxyethane1-C6alkyl group, (C1-C6alkoxy)hydroxylases1-C6alkyl group, (Halogens1-C6alkoxy)hydroxylases1-C6alkyl group, (C2-C7alkanolamine)hydroxylases1-C6alkyl group, C1-C6alkoxyl1-C6alkyl group, hydroxys1-C6alkoxyl1-C6alkyl group, dihydroxy1-C6alkoxyl1-C6alkyl group, (Halogens1-C6alkoxy)1-C6alkoxyl1-C6alkyl group, (C2-C7alkanolamine)1-C6alkoxyl1-C6alkyl group, (C1-C6alkoxy)carbonyl group, (hydroxys1-C6alkoxy)carbonyl group, (C1-C6alkoxyl1-C6alkoxy)carbonyl group, (Halogens1-C6alkoxyl1-C6alkoxy)carbonyl�a second group, (C2-C7alkanolamines1-C6alkoxy)carbonyl group, C1-C6alkoxyl1-C6alkoxyl1-C6alkyl group, hydroxys1-C6alkoxyl1-C6alkoxyl1-C6alkyl group, C1-C6alkoxyl1-C6alkoxyl1-C6alkoxyl1-C6alkyl group, Halogens1-C6alkoxyl1-C6alkoxyl1-C6alkoxyl1-C6alkyl group, C2-C7alkanolamines1-C6alkoxyl1-C6alkoxyl1-C6alkyl group, hydroxys1-C6alkoxygroup, digitoxin1-C6alkoxygroup, (C1-C6alkoxy)hydraxis1-C6alkoxygroup, (Halogens1-C6alkoxy)hydraxis1-C6alkoxygroup, (C2-C7alkanoyl)aminogenesis1-C6alkoxygroup, S1-C6alkylcarboxylic group, hydroxys1-C6alkylcarboxylic group, C1-C6alkoxyl1-C6alkylcarboxylic group, Halogens1-C6alkoxyl1-C6alkylcarboxylic group, (C2-C7alkanolamine)1-C6alkylcarboxylic group, (C1-C6alkyl)(C1-C6alkyl)the carbs�ilen group, (hydroxys1-C6alkyl)(C1-C6alkyl)carbamoyl group, (C1-C6alkoxyl1-C6alkyl)(C1-C6alkyl)carbamoyl group (Halogens1-C6alkoxyl1-C6alkyl)(C1-C6alkyl)carbamoyl group, (C2-C7alkanolamines1-C6alkyl)(C1-C6alkyl)carbamoyl group, digitoxin1-C6alkylcarboxylic group, (C1-C6alkoxy)hydraxis1-C6alkylcarboxylic group (Halogens1-C6alkoxy)hydraxis1-C6alkylcarboxylic group, (C2-C7alkanolamine)hydraxis1-C6alkylcarboxylic group, C1-C6alkoxycarbonyl group, hydroxys1-C6alkoxycarbonyl group, (C1-C6alkoxyl1-C6alkoxy)carbamoyl group (Halogens1-C6alkoxyl1-C6alkoxy)carbamoyl group, (C2-C7alkanolamines1-C6alkoxy)carbamoyl group, C1-C6alkylcarboxylic1-C6alkyl group, hydroxys1-C6alkylcarboxylic1-C6alkyl group, (C1-C6alkoxyl1-C6alkyl)carbamoyl1-C6alkyl group, (Halogens1-C6/sub> alkoxyl1-C6alkyl)carbamoyl1-C6alkyl group, (C2-C7alkanolamines1-C6alkyl)carbamoyl1-C6alkyl group, (C1-C6alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group, (hydroxys1-C6alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group, (C1-C6alkoxyl1-C6alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group, (Halogens1-C6alkoxyl1-C6alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group, (C2-C7alkanolamines1-C6alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group, (C1-C6alkoxy)hydraxis1-C6alkylcarboxylic1-C6alkyl group, (Halogens1-C6alkoxy)hydraxis1-C6alkylcarboxylic1-C6alkyl group or (C2-C7alkanolamine)hydraxis1-C6alkylcarboxylic1-C6alkyl group, more preferably hydraxis1-C6alkyl group, hydroxylases1-C6alkyl group, C1-C6alkoxyl1-C6alkyl group, hydroxys1-C6alkoxyl1 -C6alkyl group, (C1-C6alkoxy)carbonyl group, C1-C6alkoxyl1-C6alkoxyl1-C6alkyl group, hydroxys1-C6alkoxygroup, S1-C6alkylcarboxylic group, (C1-C6alkyl)(C1-C6alkyl)carbamoyl group, hydroxys1-C6alkylcarboxylic group, C1-C6alkoxycarbonyl group, C1-C6alkylcarboxylic1-C6alkyl group, (C1-C6alkyl)(C1-C6alkyl)carbamoyl1-C6alkyl group or hydroxys1-C6alkylcarboxylic1-C6alkyl group, more preferably a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1,1-debtor-2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxyethoxymethyl group, 1-methoxyethoxymethyl group 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group, methylcarbamoylmethyl�ing group, dimethylcarbamoyl group, gidroksietilirovanny group or hydroxyethylaminomethyl group, and particularly preferably a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, ethoxycarbonyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethylcarbamoyl group.

In the present invention, X preferably represents a single bond or methylene and more preferably a single bond.

In the present invention, R1represents preferably a group represented by the following General formula (1B).

Chemical formula 7

In the above formula (1B), each of V, W and Y independently refers to the carbon atom (having 1 hydrogen atom) or a nitrogen atom, X refers to a single bond or methylene, R5refers to a hydrogen atom, halogen atom or C1-C6alkyl group, R6refers to a hydrogen atom, halogen atom, C1-C6alkyl group, carbamoyl group, C1-C6Ala�carbamoyl group or (C 1-C6alkyl)(C1-C6alkyl)carbamoyl group, and R7refers to the hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethylene group, 1,1-debtor-2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxyethoxymethyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group, methylcarbamoylmethyl group, dimethylcarbamoyl group, hydrooximethylcarbamile group or hydroxyethylaminomethyl group. The above R7preferably represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, ethoxycarbonyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethyl�carbamoylmethyl group.

In the compounds of the present invention, more preferably R1is a group represented from the following General formulas (1B-1) to General formula (1B-8).

Even more preferably, R1represents a group represented by the following General formula (1B-1), General formula (1B-2), General formula (1B-3), General formula (1B-5) or the General formula (1B-6).

In the above formulas from the General formula (1B-1) to General formula (1B-8) R7refers to the hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethylene group, 1,1-debtor-2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxyethoxymethyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group, methylcarbamoylmethyl group, dimethylcarbamoyl group, hydrooximethylcarbamile group or hydroxyethylaminomethyl group. Specified �ove R 7preferably represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, ethoxycarbonyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethylcarbamoyl group.

In the compounds of the present invention, R2refers to C1-C3alkyl group or methylsulfonylamino group, preferably a methyl group or methylsulfonyl group and more preferably a methyl group.

In the compounds of the present invention, R3refers to a hydrogen atom or methyl group, preferably hydrogen atom.

The term “pharmacologically acceptable ester” in the present invention refers to the case where the compound of the present invention has a hydroxyl group and/or carboxytherapy, the ester compound obtained by the formation of ester bonds between these groups and the pharmacologically acceptable group.

Examples of the group which forms the ester linkage with the hydroxy-group of compounds of the present invention, including�up in “C 2-C7albanileria group having 2-7 carbon atoms, such as acetyl group, propylaniline group, Butyrina group, isobutylene group, pantaneira group, pivellina group, valerina group and isovaleryl group; “aryl-C2-C7albanileria groups, such as phenylacetylene group; or arylcarbamoyl groups, such as benzoline group, and the preferred group is the acetyl group. In this context, “aryl-C2-C7alcoolica group” refers to a group in which 1 hydrogen atom of the above “C2-C7alkanoyloxy group” substituted group, an aromatic hydrocarbon ring such as a phenyl group.

In the compounds of the present invention in the case where R7refers to the substituent having a hydroxy-group (hydroxys1-C6alkyl group, hydroxylases1-C6alkyl group, hydroxys1-C6alkoxygroup, hydroxys1-C6alkylcarboxylic group or hydroxy C1-C6alkylcarboxylic1-C6alkyl group), wherein the said hydroxy-group can form an ester bond with the above “C2-C7alkanoyloxy group (preferably acetyl group).

Examples of the group which forms slojnoe�RNA communication with carboxypropyl compounds of the present invention, include the above “C1-C6alkyl group”, preferably a methyl group or ethyl group.

Pharmacologically acceptable ester compounds of the present invention may be itself the pharmacological activity or it can be used as a prodrug. In the case where the aforementioned pharmacologically acceptable ester is used as a prodrug, ester itself does not have pharmacological activity, but the compound formed by hydrolysis of ester bonds in vivo, may have pharmacological activity.

The compound of the present invention preferably is a compound selected from the following compounds or pharmacologically acceptable salt:

({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[4'-(acetoxymethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(1-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(2-hydroxypropyl)biphenyl-4-yl]piperid�n-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(2-hydroxy-1,1-dimethylethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[4'-(dimethylcarbamoyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-6-methyl-2-({1-[4'-(methylcarbamoyl)biphenyl-4-yl]piperidine-4-yl}methyl)pyrimidine-4-yl]carbonyl}amino)acetic acid

[({2-[(1-{4'-[2-(dimethylamino)-2-oxoethyl]biphenyl-4-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{4-[4-(gidroximetil)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{4-[3-(gidroximetil)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

{[(5-hydroxy-2-{[1-(4-{5-[1-(methoxyethoxy)ethyl]pyridin-2-yl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

[({2-[(1-{4-[5-(1-acetoxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{4-[5-(gidroximetil)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({-[(1-{4-[5-(ethoxycarbonyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({2-[(1-{4-[2-(ethoxycarbonyl)benzyl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

{[(5-hydroxy-2-{[1-(4-{[6-(2-hydroxyethoxy)pyridin-3-yl]methyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

[({5-hydroxy-2-[(1-{5-[4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{5-[4-(2-hydroxypropyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{5-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

({[2-({1-[2-chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(gidroximetil)-2-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3'-chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(gidroximetil)-2'-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(gidroximetil)-2,3'-dimethyldiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}aminouksusnoy acid,

({[5-hydroxy-2-({1-[4'-(2-hydroxybutyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[({5-hydroxy-2-[(1-{4-[4-(2-hydroxypropyl)benzyl]phenyl}piperidine-4-yl}methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({5-hydroxy-2-[(1-{4-[4-(2-hydroxy-1,1-dimethylethyl)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

({[2-({1-[4'-(1,1-debtor-2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[4'-(1,1-debtor-2-hydroxypropyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[4'-(1,1-debtor-2-hydroxy-2-methylpropyl") biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

{[(5-[(2,2-dimethylpropanoyl)oxy]-2-{[1-(4'-{[(2,2-dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

{[(2-{[1-(4'-{[(2,2-dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

({[5-hydroxy-2-({1-[4'-(methoxymethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[2'-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyr�idin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3'-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[2-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(gidroximetil)-3'-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3',5'-debtor-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3',5'-dichloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[2-({1-[3',5'-dimethyl-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[({5-hydroxy-2-[(1-{4'-[2-hydroxy-3-methoxypropyl]biphenyl-4-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

({[5-hydroxy-2-({1-[4'-(3-hydroxypropyl methyl]biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-hydroxy-2-({1-[4'-(gidroximetil)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)uksosn�th acid,

[({2-[(1-{5-[3-fluoro-4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,

[({2-[(1-{5-[3-chloro-4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, or

[({5-hydroxy-2-[(1-{5-[4-(gidroximetil)-3-methylphenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid.

In the compounds of the present invention depending on the types of substituents may be present geometric isomers or tautomers. In addition, in the case where the compounds of the present invention have an asymmetric carbon atom, can be present as optical isomers. These separated isomers (e.g. enantiomers or diastereomers) and mixtures thereof (e.g., racemate or diastereomeric mix) included in the present invention. In addition, labeled compounds, namely, compounds in which one or more atoms of the compounds of the present invention is substituted with an appropriate radioactive isotope or non-radioactive isotope in any ratio are also included in the present invention.

In the case where the compound of the present invention has a basic group such as an amino group can, if desired, to obtain pharmacologically acceptable acid-additive salt. PR�measures such acid additive salts include salts of hydrohalic acids, such as hydrohloride, hydrochloride, hydrobromide or hydroiodide; salts of inorganic acids such as nitrates, perchlorates, sulfates or phosphates; lower alkanesulfonyl, such as methanesulfonate, triftormetilfullerenov or econsultancy; arylsulfonate, such as benzolsulfonat or p-toluensulfonate; salts of organic acids such as acetate, malate, fumarate, succinates, citrates, tartrates, oxalates or maleate, and salts of amino acids such as infinity, glutamate or aspartate, and the preferred salts are hydrohalic acids and salts of organic acids.

In the case where the compound of the present invention have an acidic group such as carboxylate, you can usually get a pharmacologically acceptable basic additive salt. Examples of such basic additive salts include alkali metal salts such as sodium salt, potassium salt or lithium salt; salts of alkaline earth metals such as calcium salts or magnesium salts; inorganic salts such as ammonium salts, and salts of organic amines such as salts of dibenzylamine, morpholine salt, salts of alkyl ether phenylglycine, salts of Ethylenediamine, salts of N-methylglucamine salt of diethylamine salts of triethylamine, salt cyclohexylamine, salt dicyclohexylamine, salts of N,N'-dibenziletilendiaminom, diethanolamine salt, with�whether N-benzyl-N-(2-phenylethane)amine, salt, piperazine salt of Tetramethylammonium salt or Tris(gidroximetil)aminomethane.

Compounds of the present invention can also be present in free form or solvate. Although there were no specific restrictions solvate, provided that it is pharmaceutically acceptable, preferred specific examples include hydrates and ethanolate or the like. In addition, in the case where the compound represented by the General formula (1), there is a nitrogen atom, it may be in the form of N-oxide, and these solvates and form the N-oxide is also included in the scope of the present invention.

Although the compounds of the present invention may be present in the form of various isomers, including geometric isomers such as CIS-form or TRANS-form, tautomers, or optical isomers such as d-form or l-form, depending on the types of substituents and combinations thereof, compounds of the present invention includes all isomers and mixtures of isomers in any relationship, if the relationship is not specifically limited.

Furthermore, compounds of the present invention may contain non-natural ratio of isotopes in one or more of the atoms that constitute such compounds. Examples of isotopes include deuterium (2N;D), tritium (3N;T), iodine-125 (125I), carbon-14 (14�) or the like. Furthermore, compounds of the present invention can be Radiometrie radioisotopes such as, for example, tritium (3H), iodine-125 (125I), carbon-14 (14C) or the like. Radiometrie compound is useful as a therapeutic or prophylactic agent, reagent for research (e.g., reagent for analysis) and diagnostic agent (e.g., agent for diagnostic imaging in vivo). Compounds of the present invention containing all the relations of radioactive or non-radioactive isotopes that are included in the scope of the present invention.

Compounds of the present invention can also be obtained by applying various known synthetic methods, depending on its basic skeleton or types of substituents. Thus, depending on the types of functional groups can be protected with this functional group with a suitable protective group at the stages from the parent compound to the intermediate product or to replace it by a group that could easily transform this functional group. Examples of such functional groups include an amino group, a hydroxy-group, carboxypropyl and the like, and examples of the protective group include the protective groups described, for example, Protective Groups in Organic Synthesis, 3rded., Greene, T. W. and Wuts, P. G. M., JohnWiley & Sons, Inc., New York, 1999, and these protective groups can appropriately be selected and used depending on reaction conditions. Accordingly such methods, a desired compound can be obtained by introduction of a protective group and the reaction followed by removal of the protective group, if necessary, or transformation into the desired group. The resulting compound of the present invention can be identified and their composition or purity can be analyzed with standard analytical methods such as elemental analysis, NMR, mass spectroscopy or IR analysis.

The original substances or reagents used to obtain the compounds of the present invention, can be purchased from commercial suppliers or can be synthesized according to the methods described in the literature.

In the present invention examples of anemia include nephrogenic anemia, anemia of prematurity, anemia incidental to chronic diseases, anemia incidental to cancer chemotherapy, cancerous anemia, anemia associated with inflammation, and anemia incidental to congestive heart failure. Examples of anemia related to chronic diseases include anemia associated with chronic renal diseases, and examples of anaemia associated with chronic kidney disease include the chronic� renal failure. In addition, a patient who is administered a compound of the present invention may be a patient who receives or does not receive dialysis.

[The invention]

Compounds of the present invention, their pharmacologically acceptable esters or their pharmaceutically acceptable salts exhibit excellent increase the production of EPO activity in the system for analysis, which is used in Hep3B cells, and have excellent security. Namely, the production of EPO can be increased by the introduction of a pharmaceutical composition containing the compound of the present invention, its pharmacologically acceptable ester or pharmacologically acceptable salt to a mammal (such as man, cow, horse or pig) or poultry (such as chicken). Thus, a pharmaceutical composition containing a compound of the present invention, its pharmacologically acceptable ester or pharmacologically acceptable salt can be used for prophylaxis and/or treatment of diseases caused by decreased EPO, or diseases or pathological States in which the content of EPO decreases, such as ischemic cerebrovascular disease, or for autotransfusion patients who will be subjected to a surgical operation. Examples of diseases caused lower�concentrations of EPO, include anemia and especially nephrogenic anaemia (stage dialysis, stage canning), anemia of prematurity, anemia incidental to chronic diseases, anemia incidental to cancer chemotherapy, cancerous anemia, anemia associated with inflammation, and anemia incidental to congestive heart failure.

Method of carrying out the invention

The following are examples of representative methods for obtaining compounds of the present invention. In addition, methods of preparation of the present invention is not limited to the following examples.

Compounds having the General formula (1) of the present invention, can be obtained according to the methods described below.

(Stage 1)

Stage 1 is the stage of obtaining compounds having the General formula (1) compounds having the General formula (2), which is then described.

In the above formulas, R1- R3have the same values as described previously, R8refers to a substituted or unsubstituted aryl group or heteroaryl group, R1Aand R1bbelong to the group, which may be the above R1or its predecessor, the R2Arefers to a group, which may be the above R2or her predecessor, and groups from the Pro1to Pro4from�Asada to the protective groups of the respective functional groups, selected from known protective groups (for example, described in Protective Groups in Organic Synthesis, 3rded., Greene, T. W., Wuts, P. G. M., John Wiley & Sons, Inc., New York, 1999, etc.). Although there were no specific restrictions for groups of Pro1to Pro4provided that they are stable during the reaction and does not inhibit the reaction, preferably Pro1represents a benzyl group, Pro2represents a tert-butyl group, Pro3represents a methyl group, ethyl group, tert-butyl group or benzyl group and Pro4represents a tert-butoxycarbonyl group. Although there were no specific limits for the X1in stage 1-1C, stage 1-1d or stage 1-1E, provided that she is a surrogate, which forms a leaving group together with the oxygen to which it is attached, it preferably represents triftormetilfullerenov group.

Below is a detailed description of each stage.

(Stage 1-1)

Stage 1-1 stage is the stage of obtaining compounds having the General formula (3), from compounds having the General formula (2) which will then be described. Examples of major reactions include:

stage 1-1A: reaction of removing the protective group Pro2;

stage 1-1b: a condensation reaction with an amino acid or salt of an amino acid having the General formula H NCH(R3)CO2Pro3;

stage 1-1C: the reaction of introducing a leaving group (-OH1) to hydroxyl group in position 6 and

stage 1-1d: the reaction of the leaving group (-OH1in the substituent R2a. In addition, if required, add

stage 1-1E: the reaction of R1ain R1b. Stage 1-1A to 1-1E can be performed in any order.

(Stage 1-1A)

This stage is the stage of removal of the protective group Pro2. Appropriately you can choose the known method described, for example, in Protective Groups in Organic Synthesis, 3rded., Greene, T. W., Wuts, P. G. M., John Wiley & Sons, Inc., New York, 1999, etc., appropriate Pro2and this step is carried out in accordance with it. In the context of the tert-butyl group is chosen as the preferred Pro2and describe the way in which Pro2turn in the hydrogen atom with the use of a base in an inert solvent (stage 1-1A1), and the way in which Pro2turn in a hydrogen atom with an acid in an inert solvent (stage 1-1A2), but this stage is not limited to this.

(Stage 1-1A1)

This stage is the stage of turning Pro2in the hydrogen atom using a suitable base in an inert solvent.

Although there were no specific restrictions for used solvent, provided that it is not inhib�anticipated the reaction and dissolves the original compound to some extent, preferred examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; alcohols such as methanol, ethanol or tert-butanol; esters such as ethyl acetate or propyl acetate; NITRILES such as acetonitrile; amides such as formamide or N,N-dimethylformamide; sulfoxides such as dimethylsulfoxide; a mixture of various organic solvents in an arbitrary ratio, and mixtures thereof with water at an arbitrary ratio.

Although there were no specific restrictions for used grounds, provided that it is used as a base in conventional reactions, examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine or pyridine; carbonates of alkali metals such as sodium carbonate or potassium carbonate; carbonates of alkaline earth metals such as calcium carbonate; bicarbonates of alkali metals such as potassium bicarbonate, bicarbonates of alkaline earth metals such as calcium hydrogen carbonate, hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide; hydroxides of alkaline earth met�low, such as calcium hydroxide and phosphates of alkali metals, such as trikaliotis.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -10 to 150°C and preferably from 10 to 90°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 1 minute to 24 hours and preferably from 10 minutes to 6 hours.

After completion of the reaction, the desired compound can be obtained in the form of solid substances by distillation of the organic solvent and adding the acid. On the other hand, in the case where it is impossible to obtain a solid substance by adding acid, the desired compound can be obtained by extraction of the organic matter with an organic solvent such as ethyl acetate, drying of the organic layer is usually applied by the procedure and then concentrating it under reduced pressure.

The resulting compound can be further purified, if necessary, by conventional means, such as recrystallization, re-precipitation, column chromatography on silica gel or similar.

(Stage 1-1A2)

This stage is the stage of turning Pro2in the hydrogen atom with the use of a suitable acid in an inert solvent.

Although there were no specific�s limitations of the employed solvent, provided that it does not inhibit the reaction and dissolves the original compound to some degree, preferable examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; alcohols such as methanol or ethanol; NITRILES such as acetonitrile; amides such as formamide or N,N-dimethylformamide; sulfoxides, such as dimethyl sulfoxide; a mixture of many organic solvents in an arbitrary ratio, and mixtures thereof with water at an arbitrary ratio.

Although there were no specific restrictions for used acid, provided that it is used as an acid in the conventional reactions, examples include inorganic acids such as hydrochloric acid or sulfuric acid; Lewis acid such as boron TRIFLUORIDE, boron trichloride, tribromide boron or attributively; and organic acids such as trifluoroacetic acid.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -100 to 150°C and preferably from -78 to 100°C.

Changing with�under the parent compounds, reagents and the like, the reaction time is usually from 5 minutes to 24 hours and preferably from 10 minutes to 6 hours.

After completion of the reaction, the desired compound can be obtained in the form of solid substances by distillation of the organic solvent and adding a base. On the other hand, in the case where it is impossible to obtain a solid substance by adding a base, the desired compound can be obtained by extraction of the organic matter with an organic solvent such as ethyl acetate, drying of the organic layer is usually applied by the procedure and then concentrating it under reduced pressure.

The resulting compound can be further purified, if necessary, using conventional means, such as recrystallization, re-precipitation, column chromatography on silica gel or similar.

(Stage 1-1b)

This stage is the stage of condensation of the carboxylic acid, obtained in stage 1-1A, and amino acids or amino acid salt having the General formula H2NCH(R3)CO2Pro3and condensation is carried out with the use of a condensation agent in an inert solvent and in the presence or in the absence of the base.

Although there were no specific restrictions for used solvent, provided that it does not inhibit the reaction and dissolves the original compound�s to a certain extent, preferred examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; alcohols such as methanol, ethanol or tert-butanol; NITRILES, such as acetonitrile; amides such as formamide or N,N-dimethylformamide; sulfoxides such as dimethylsulfoxide; a mixture of various organic solvents in an arbitrary ratio, and a mixture thereof with water at an arbitrary ratio.

Although there were no specific restrictions for used grounds, provided that it is used as a base in conventional reactions, preferable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine or pyridine; carbonates of alkali metals such as sodium carbonate or potassium carbonate; carbonates of alkaline earth metals such as calcium carbonate; bicarbonates of alkali metals such as potassium bicarbonate; carbonates of alkaline earth metals such as calcium hydrogen carbonate; hydroxides of alkali metals such as sodium hydroxide; hydroxides of alkaline earth metal�s, such as calcium hydroxide and phosphates of alkali metals, such as trikaliotis.

Although there were no specific restrictions applied by the condensation agent, provided that it is used as a condensation agent, which forms an amide bond (e.g., Shoichi Kusumoto et al., Experimental Science Course IV, Chemical Society of Japan, Maruzen Publishing, 1990; by Nobuo Izumiya et al., Peptide Synthesis Basics and Experimentation, Maruzen Publishing, 1985), preferred examples include hexaflurophosphate O-benzotriazole-N,N,N',N'-tetramethyluronium (HBTU), tetrafluoroborate 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurea (TBTU), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), para-toluensulfonate 4-(2-{[(cyclohexylamino)methylene]amino}ethyl-4-methylmorpholin-4 settings (SMS), dicyclohexylcarbodiimide (DCC), 1,1'-carbonylbis-(1H-imidazole) (CDI), hexaflurophosphate (1H-benzotriazole-1-yloxy)(triprolidine-1-yl)phosphonium (PyBOP), hexaflurophosphate bromine(triprolidine-1-yl)phosphonium (PyBrOP), chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (DMT-MM), 2-chloro-4,6-dimethoxy-1,3,5-triazine (DMT) and the like. You can also add an additive such as 1-hydroxy-benzotriazole (NOVT) or N,N-dimethylaminopyridine.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -10°C to 150°C and preferably from 0°C to 100°C.

Changing in accordance with the outcome�bubbled compounds reagents and the like, the reaction time is usually from 5 minutes to 48 hours and preferably from 10 minutes to 24 hours.

After completion of the reaction the desired compound of this reaction can be obtained, for example, by concentration of the reaction mixture, adding an organic solvent such as ethyl acetate, and washing with water followed by separation of the organic layer containing the desired compound, drying with anhydrous sodium sulfate, and the like, and Stripping of solvent.

The resulting compound can be further purified, if necessary, using conventional means, such as recrystallization, re-precipitation, column chromatography on silica gel or similar.

(Stage 1-1C)

This stage is the stage of transformation of the hydroxyl group in position 6 in the leaving group (-OH1and the transformation is carried out by reaction of the hydroxyl group with the acid chloride of the acid or acid anhydride in an inert solvent and in the presence or in the absence of the base.

Although there were no specific restrictions for used solvent, provided that it does not inhibit the reaction and dissolves the original compound to some degree, preferable examples of the solvent include aromatic hydrocarbons such as benzene, toluene or the COP�lol; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; NITRILES, such as acetonitrile; amides such as formamide or N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixture of many organic solvents in an arbitrary ratio.

Although there were no specific restrictions for used acid chloride or acid anhydride, provided that it is the acid chloride of the acid or acid anhydride, which has a X1so the group-OH1becomes known to the leaving group, preferred examples include anhydrides substituted or unsubstituted alkylsulfonic acids or anhydrides arylsulfonic acid such as the anhydride triftormetilfullerenov acid, a substituted or unsubstituted alkylsulfonate or arylsulfonate, such as methanesulfonate or p-toluensulfonate, and the anhydrides of substituted or unsubstituted alkylphosphonic acids or anhydrides arylphosphine acids.

Although there were no specific restrictions for used grounds, provided that it is used as a base in conventional reactions, the preferred PR�measures include an organic base, such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine or pyridine; carbonates of alkali metals such as sodium carbonate or potassium carbonate; carbonates of alkaline earth metals such as calcium carbonate; bicarbonates of alkali metals such as potassium bicarbonate; carbonates of alkaline earth metals such as calcium hydrogen carbonate; hydroxides of alkali metals such as sodium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide and phosphates of alkali metals, such as trikaliotis.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -100°C to 150°C and preferably from -80°C to 40°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 5 minutes to 24 hours and preferably from 10 minutes to 6 hours.

After completion of the reaction the desired compound of this reaction can be obtained, for example, by concentration of the reaction mixture, adding an organic solvent such as ethyl acetate, and washing with water followed by separation of the organic layer containing the desired compound, drying with anhydrous sodium sulfate, and the like, and Stripping of solvent.

The resulting connection can complete�till then cleaned, if necessary, using conventional means, such as recrystallization, re-precipitation, column chromatography on silica gel or similar.

(Stage 1-1d)

This stage is the stage of conversion of the leaving group (-OH1in the substituent R2a. In the case where R2arepresents an alkyl group or alkenyl group, this step is carried out by reaction of the leaving group with a compound alcivar or connection alcanivorax in an inert solvent, in the presence or in the absence of base, in the presence or in the absence of additives and in the presence of a metal catalyst (1-1d1). In addition, in the case where R2ais methylsulfanyl group, this step is carried out by reaction of the leaving group with matatila salt or metal mecantile in an inert solvent and in the presence or in the absence of the base (1-1d2).

(Stage 1-1d1)

This stage is the stage of conversion of the leaving group (-OH1) in the alkyl group or the alkenyl group and it is carried out by reaction of the leaving group with a compound alcivar or connection alcanivorax in an inert solvent, in the presence or in the absence of base, in the presence or in the absence of additives and in the presence of a metal catalyst. This reaction suitably chosen �W conditions known methods, described, for example, Zou, G., Reddy, Y. K., Falck, J. R., Tetrahedron Lett., 2001, 42, 7213; Molander, G. A., Yun, C.-S., Tetrahedron, 2002, 58, 1465; Tsuji, J., Palladium Peagents and Catalysts, John Wiley & Sons, Inc., England, 2004; Metal-Catalyzed Cross-Coupling Reactions, de Meijere, A., Diederich, F., Wiley-VCH, Weinheim, 2004, and the like, and this step is carried out in accordance with them. Although the reaction conditions of this stage are preferably the following, they are not limited by them.

Although there were no specific restrictions for used solvent, provided that it does not inhibit the reaction and dissolves the original compound to some degree, preferable examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; alcohols such as methanol, ethanol or tert-butanol; NITRILES, such as acetonitrile; amides, such as formamide or N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixture of many organic solvents in an arbitrary ratio and mix them with water in an arbitrary ratio.

Although there were no specific restrictions for used grounds, provided that it is used as a base in conventional reactions, preferred�Stateline examples include organic bases, such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine or pyridine; carbonates of alkali metals such as sodium carbonate or potassium carbonate; carbonates of alkaline earth metals such as calcium carbonate; bicarbonates of alkali metals such as potassium bicarbonate; carbonates of alkaline earth metals such as calcium hydrogen carbonate, hydroxides of alkali metals such as sodium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide, phosphates of alkali metals, such as trikaliotis, and alkoxides of metals such as tert-butoxide, sodium or tert-butoxide potassium.

Although there were no specific limits for additives used, provided that it is used in the known methods, preferred examples include metal oxides such as silver oxide or aluminum oxide; phosphines, such as triphenylphosphine, three-tert-butylphosphine, tricyclohexylphosphine, tri-(o-tolyl)phosphine, diphenylphosphinite, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS) or 2,2'-bis(diphenylphosphino)-1,1'-binaphtyl (BINAP); phosphine oxides, such as oxide triphenylphosphine; metal salts such as lithium chloride, potassium fluoride or cesium fluoride, and ammonium salts, such as bromide of tetrabutylammonium. They can� also be used in combination in an arbitrary ratio.

Although there were no specific restrictions for used metal catalyst, provided that it is used in the known methods, preferred examples include palladium catalysts such as tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, palladium diacetate, a complex of palladium dichloride-diphenylphosphinite, a complex of palladium dichloride-benzonitrile, a complex of palladium dichloride-acetonitrile, bis(dibenzylideneacetone)palladium, Tris(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridin-[1,3-bis(2,6-diisopropylphenyl)imidazole-2-Illidan]palladium or palladium on charcoal.

Although there were no specific restrictions for used connection alcivar or connection alcanivorax, provided that it is used as a reagent known reaction, examples include metalpart, broadcast motivarte, salt metal trifter(methyl)paranoid, Ethelbert, broadcast ethelberta or metal salt ethyltryptamine, in the case where R2arepresents an alkyl group, and pinivora, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolan, broadcast vinylboronate, metal salt vinyltrifluoroborate, Allibert, broadcast alleviate or a metal salt of allyl(Cryptor)paranoid in the case where R2ais altenloh.

There were no specific limits for essential parts of the ether of alkylborane, metal metal salt of trifter(alkyl)paranoid, essential parts of the ether of alkenylboronic and metal metal salt of trifter(alkenyl)paranoid, provided that they are known compounds or are synthesized according to known methods.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -10°C to 200°C and preferably from 0°C to 150°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 5 minutes to 48 hours and preferably from 10 minutes to 12 hours.

After completion of the reaction the desired compound of this reaction can be obtained, for example, by concentration of the reaction mixture, adding an organic solvent such as ethyl acetate, and washing with water followed by separation of the organic layer containing the desired compound, drying with anhydrous sodium sulfate, and the like, and Stripping of solvent.

The resulting compound can be further purified, if necessary, using conventional means, such as recrystallization, re-precipitation, column chromatography on silica gel or similar.

In addition, in the case where R2ais with�fight alkenyl group, this alkenyl group can be converted to the corresponding alkyl group by carrying out the hydrogenation reaction under the reaction conditions analogous to the reaction conditions in stage 1-a, which are described later.

(Stage 1-1d2)

This stage is the stage of conversion of the leaving group (-OH1in methylsulfanyl group and it is carried out by reaction of mecantile or metal salt of mecantile in an inert solvent and in the presence or in the absence of the base.

Although there were no specific restrictions for used solvent, provided that it does not inhibit the reaction and dissolves the original compound to some degree, preferable examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; NITRILES, such as acetonitrile; amides such as formamide or N,N-dimethylformamide; alcohols, such as methanol or ethanol; sulfoxides such as dimethyl sulfoxide; a mixture of many organic solvents in any ratio, and their mixture with water in an arbitrary ratio.

Although there were no specific restrictions for used �of atella in a metal salt of matatila, preferred examples include alkali metals such as sodium, and alkaline earth metals such as magnesium.

Although there were no specific restrictions for used grounds, provided that it is used as a base in conventional reactions, preferable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine or pyridine; carbonates of alkali metals such as sodium carbonate or potassium carbonate; carbonates of alkaline earth metals such as calcium carbonate; bicarbonates of alkali metals such as potassium bicarbonate; carbonates of alkaline earth metals such as calcium hydrogen carbonate; hydroxides of alkali metals such as sodium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide; phosphates of alkali metals, such as trikaliotis, and alkoxides of metals such as tert-butoxide, sodium or tert-butoxide potassium.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -10°C to 150°C and preferably from 0°C to 100°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 5 minutes to 48 hours and preferably from 10 minutes to 12 hours.

After completion of the reaction the desired compound of this reaction can be obtained, for example, by concentration of the reaction mixture, adding an organic solvent such as ethyl acetate, and washing with water followed by separation of the organic layer containing the desired compound, drying with anhydrous sodium sulfate, and the like, and Stripping of solvent.

The resulting compound can be further purified, if necessary, using conventional means, such as recrystallization, re-precipitation, column chromatography on silica gel or similar.

(Stage 1-1st)

This stage is the stage of transformation of R1ain R1band the method of synthesis varies according to the types of heterocycles ring Q1. Below is a description of the case when R1ait has a ring of Q1the ring Q1represents heterocycle containing a nitrogen atom, and heterocycl has a protective group Pro4this nitrogen atom.

Examples of important reactions (stages 1-1E) include the following reactions:

stage 1-e: the reaction of removing the protective group Pro4and

stage 1-e: the reaction of introduction of the substituent R8.

The above reaction stage 1-e and stage 1-e show the case when R1ais a piperidine-4-ilen group having a protective group Po 4in position 1, and the following explanation stage 1-e show a case where Pro4represents a tert-butoxycarbonyl group, but stage 1-e is not limited to them.

(Stage 1-e)

This stage is the stage of obtaining compounds having the General formula (5) or (8). Depending on Pro4used as a protective group, appropriately choosing a method is known, for example as described in Protective Groups in Organic Synthesis, 3rded., Greene, T. W., Wuts, P. G. M., John Wiley & Sons, Inc., New York, 1999, or similar method, and this step is carried out in accordance with it. In the case where the Pro4represents a tert-butoxycarbonyl group, this step is carried out by adding a suitable reagent to the compound having the General formula (4) or (7), in an inert solvent.

Although there were no specific restrictions for used solvent, provided that it does not inhibit the reaction and dissolves the original compound to some degree, preferable examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; esters such as ethyl acetate or propyl acetate; NITRILES such as AC�control; amides, such as formamide or N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide, and a mixture of various organic solvents in an arbitrary ratio.

Although there were no specific restrictions for used reagent, provided that it is used as a reagent that removes the protective tert-butoxycarbonyl group in the conventional reactions, preferable examples include inorganic acids such as hydrochloric acid or sulfuric acid; organic acids such as acetic acid or trifluoroacetic acid; Lewis acid such as trimethylsilylmethyl or boron TRIFLUORIDE, the anhydrides of acids such as acetyl chloride; hydroxides of alkali metals such as sodium hydroxide.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -10°C to 100°C and preferably from 10°C to 50°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 5 minutes to 24 hours and preferably from 10 minutes to 6 hours.

After completion of the reaction, the solid substance can be obtained by distillation of the solvent and addition of n-hexane or similar solvent to the resulting residue. This substance is produced by filtration and then dried,�the will with the salt of the compound, having the General formula (5) or (8). On the other hand, in the case where it is impossible to obtain a solid substance by adding n-hexane, the desired compound can be obtained by extraction of the organic matter with an organic solvent such as ethyl acetate, followed by concentration of the organic layer after drying, it is usually applied procedure or his concentration when he is at low pressure.

(Stage 1-e)

This stage can be carried out in accordance with (i) stage 1-a-1; (ii) a combination of stages 1-e-2 and 1-a-3 or (iii) a combination of stages 1-e-2, 1-a-4 and 1-e-5.

[Stage 1-a-1]

This stage is the stage of obtaining compounds having the General formula (6) or (9), and it is carried out by reaction of substituted or unsubstituted helgaleena or heteroarylboronic, or areipseparated or heteroarylboronic containing ring Q2the ring Q3with a compound having the General formula (5) or (8), in an inert solvent, in the presence or in the absence of base, in the presence or in the absence of additives and in the presence of a metal catalyst. This condition is the reaction of appropriately selected from known methods described, for example, Tsuji, J., Palladium Peagents and Catalysts, John Wiley & Sons, Inc., England, 2004; Jiang, L., Buchwald, S. L. Palladium-Catalyzed Aromatic Carbon-Nitrogen Bond Formation; Metal-Catalyzed Cross-Coupling Reactions, de Meijere, A, Diederich, F., Wiley-VCH, Weinheim, 2004, Chapter 13, etc., and this step is carried out in accordance with them. Although the reaction conditions of this stage are preferably such as described below, they are not limited by them.

Although there were no specific restrictions for used solvent, provided that it does not inhibit the reaction and dissolves the original compound to some degree, preferable examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; alcohols such as methanol, ethanol or tert-butanol; NITRILES, such as acetonitrile; amides, such as formamide or N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixture of many organic solvents in an arbitrary ratio and mix them with water in an arbitrary ratio.

Although there were no specific restrictions for used grounds, provided that it is used as a base in conventional reactions, preferable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine or pyridine; carbonates �Christmas metals, such as sodium carbonate or potassium carbonate; carbonates of alkaline earth metals such as calcium carbonate; bicarbonates of alkali metals such as potassium bicarbonate; carbonates of alkaline earth metals such as calcium hydrogen carbonate; hydroxides of alkali metals such as sodium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide; acetates of alkali metals such as sodium acetate or potassium acetate; phosphates of alkali metals, such as trikaliotis; alkoxides of metals such as tert-butoxide, sodium or tert-butoxide potassium; ORGANOMETALLIC amides, such as diisopropylamide lithium or hexamethyldisilazide sodium, ORGANOMETALLIC compounds such as tert-butyllithium, and metal hydrides such as potassium hydride.

Although there were no specific limits for additives used, provided that it is used in the known methods, preferred examples include metal oxides such as silver oxide or aluminum oxide; phosphines, such as triphenylphosphine, three-tert-butylphosphine, tricyclohexylphosphine, tri-(o-tolyl)phosphine, diphenylphosphinite, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS) or 2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl (BINAP); phosphine oxides, such as ACS�d triphenylphosphine; metal salts such as lithium chloride, potassium fluoride or cesium fluoride, and ammonium salts, such as bromide of tetrabutylammonium. They can be used in combination in an arbitrary ratio.

Although there were no specific restrictions for used metal catalyst, provided that it is used in the known methods, preferred examples include palladium catalysts such as tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, palladium diacetate, a complex of palladium dichloride-diphenylphosphinite, a complex of palladium dichloride-benzonitrile, a complex of palladium dichloride-acetonitrile, bis(dibenzylideneacetone)palladium, Tris(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridin-[1,3-bis(2,6-diisopropylphenyl)imidazole-2-Illidan]palladium or palladium on charcoal.

Pseudohalogen relates to a compound having a group of pseudohalogen, and a group of pseudohalogen belongs to the group, which is known to be subjected to oxidative accession to the transition metal catalyst with a low valence, in the same way as the atoms of halogen in the reaction combinations, with the use of a transition metal catalyst. Although there were no specific restrictions for a group of pseudohalogen, provided that it is a group, the cat�Paradise participates in the above oxidation reaction of accession, examples include sulfonyloxy, such as triftormetilfullerenov, methysulfonylmethane or t-toluensulfonate; alloctype, such as acetyloxy; diazonium groups and phosphonylmethoxypropyl.

There were no specific restrictions for used substituted or unsubstituted helgaleena or heteroarylboronic, or areipseparated or heteroarylboronic, provided that he is a known compound or synthesized according to known methods.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -10°C to 200°C and preferably from 0°C to 150°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 5 minutes to 48 hours and preferably from 10 minutes to 12 hours.

After completion of the reaction the desired compound of this reaction can be obtained, for example, by concentration of the reaction mixture, adding an organic solvent such as ethyl acetate, and washing with water followed by separation of the organic layer containing the desired compound, drying with anhydrous sodium sulfate, and the like, and Stripping of solvent.

The resulting compound can be further purified, if neo�required, with the use of conventional means, such as recrystallization, re-precipitation, column chromatography on silica gel or similar.

(Stage 1-a-2)

This phase is a stage of reaction of substituted or unsubstituted helgaleena or heteroarylboronic, or areipseparated or heteroarylboronic containing ring Q2and not containing a ring Q3with a compound having the General formula (5) or (8), in an inert solvent, in the presence or in the absence of base, in the presence or in the absence of additives and in the presence of a metal catalyst.

This stage as per stage 1-a-1.

(Stage 1-a-3)

This phase is a stage of reaction of the compounds having a leaving group such as a halogen atom or a group-OH1the ring Q2step 1-e-2, with a substituted or unsubstituted arylboronic acid or heteroarylboronic acid in an inert solvent, in the presence or in the absence of base, in the presence or in the absence of additives and in the presence of a metal catalyst, to produce a compound having the General formula (6) or (9). The condition of this reaction is appropriately selected from known methods, described for example in publications Miyaura, N., Yamada, K., Suzuki, A., Tetrahedron Lett., 1979, 36, 3437; Miyaura, ., Suzuki, A., Chem. Rev., 1995, 95, 2457, etc., and this step is carried out in accordance with them. Although the reaction conditions of this stage are preferably such as described below, they are not limited by them.

Although there were no specific restrictions for used solvent, provided that it does not inhibit the reaction and dissolves the original compound to some extent, and preferred examples include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; alcohols such as methanol, ethanol or tert-butanol; NITRILES, such as acetonitrile; amides, such as formamide or N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixture of many organic solvents in an arbitrary ratio and mix them with water in an arbitrary ratio.

Although there were no specific restrictions for used grounds, provided that it is used as a base in conventional reactions, preferable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine or pyridine; alkali metal carbonates�in, such as sodium carbonate or potassium carbonate; carbonates of alkaline earth metals such as calcium carbonate; bicarbonates of alkali metals such as potassium bicarbonate; carbonates of alkaline earth metals such as calcium hydrogen carbonate, hydroxides of alkali metals such as sodium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide; acetates of alkali metals such as sodium acetate or potassium acetate; phosphates of alkali metals, such as trikaliotis; alkoxides of metals such as tert-butoxide, sodium or tert-butoxide potassium; ORGANOMETALLIC amides, such as diisopropylamide lithium or hexamethyldisilazide sodium, ORGANOMETALLIC compounds such as tert-butyllithium, and metal hydrides such as potassium hydride.

Although there were no specific limits for additives used, provided that it is used in the known methods, preferred examples include metal oxides such as silver oxide or aluminum oxide; phosphines, such as triphenylphosphine, three-tert-butylphosphine, tricyclohexylphosphine, tri-(o-tolyl)phosphine, diphenylphosphinite, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS) or 2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl (BINAP); phosphine oxides, such as ACS�d triphenylphosphine; metal salts such as lithium chloride, potassium fluoride or cesium fluoride, and ammonium salts, such as bromide of tetrabutylammonium. They can be used in combination in an arbitrary ratio.

Although there were no specific restrictions for used metal catalyst, provided that it is used in the known methods, preferred examples include palladium catalysts such as tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, palladium diacetate, a complex of palladium dichloride-diphenylphosphinite, a complex of palladium dichloride-benzonitrile, a complex of palladium dichloride-acetonitrile, bis(dibenzylideneacetone)palladium, Tris(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridin-[1,3-bis(2,6-diisopropylphenyl)imidazole-2-Illidan]palladium or palladium on charcoal.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -10°C to 200°C and preferably from 0°C to 150°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 5 minutes to 48 hours and preferably from 10 minutes to 12 hours.

After completion of the reaction the desired compound of this reaction can be obtained, for example, by concentration of the reaction�Oh mixture, the addition of organic solvent, such as ethyl acetate, and washing with water followed by separation of the organic layer containing the desired compound, drying with anhydrous sodium sulfate, and the like, and Stripping of solvent.

The resulting compound can be further purified, if necessary, using conventional means, such as recrystallization, re-precipitation, column chromatography on silica gel or similar.

(Stage 1-a-4)

This phase is a stage of reaction of the compounds having a leaving group such as a halogen atom or a group-OH1the ring Q2step 1-e-2, with a boron reagent in an inert solvent in the presence or in the absence of base, in the presence or in the absence of additives and in the presence of a metal catalyst, to thereby transforming it into the corresponding boron compound. The condition of this reaction is appropriately selected from known methods, described for example in publications Ishiyama, T., Murata, M., Miyaura, N. J. Org. Chem., 1995, 60, 7508; Ishiyama, T., Takagi, J., Ishida, K., Miyaura, N., Anastasi, N. R., Hartwig, J. F., J. Am. Chem. Soc., 2002, 124, 390; Ishiyama, T., Takagi, J., Hartwig, J. F., Miyaura, N., Angew. Chem. Int. Ed., 2002, 41, 3056, and similar publications, and this step is carried out in accordance with them. Although the reaction conditions of this stage are preferably such as described nor�e, they are not limited by them.

Although there were no specific restrictions for used solvent, provided that it does not inhibit the reaction and dissolves the original compound to some extent, and preferred examples include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; alcohols such as methanol, ethanol or tert-butanol; NITRILES, such as acetonitrile; amides, such as formamide or N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixture of many organic solvents in an arbitrary ratio and mix them with water in an arbitrary ratio.

Although there were no specific restrictions for used boron reagent, provided that it is used in the known methods, preferred examples include 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di-1,3,2-dioxaborolan.

Although there were no specific restrictions for used grounds, provided that it is used as a base in conventional reactions, preferable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-�ethylmorpholine, lutidine or pyridine; carbonates of alkali metals such as sodium carbonate or potassium carbonate; carbonates of alkaline earth metals such as calcium carbonate; bicarbonates of alkali metals such as potassium bicarbonate; carbonates of alkaline earth metals such as calcium hydrogen carbonate; hydroxides of alkali metals such as sodium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide; acetates of alkali metals such as sodium acetate or potassium acetate; phosphates of alkali metals, such as trikaliotis; alkoxides of metals such as tert-butoxide, sodium or tert-butoxide potassium; ORGANOMETALLIC amides, such as diisopropylamide lithium or hexamethyldisilazide sodium; ORGANOMETALLIC compounds such as tert-butyllithium, and metal hydrides such as potassium hydride.

Although there were no specific limits for additives used, provided that it is used in the known methods, preferred examples include metal oxides such as silver oxide or aluminum oxide; phosphines, such as triphenylphosphine, three-tert-butylphosphine, tricyclohexylphosphine, tri-(o-tolyl)phosphine, diphenylphosphinite, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS) or 2,2'-bis(diphenylphosphino�about)-1,1'-dinaphthyl (BINAP); the phosphine oxides, such as oxide triphenylphosphine; metal salts such as lithium chloride, potassium fluoride or cesium fluoride, and ammonium salts, such as bromide of tetrabutylammonium. They can be used in combination in an arbitrary ratio.

Although there were no specific restrictions for used metal catalyst, provided that it is used in the known methods, preferred examples include palladium catalysts such as tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, palladium diacetate, a complex of palladium dichloride-diphenylphosphinite, a complex of palladium dichloride-benzonitrile, a complex of palladium dichloride-acetonitrile, bis(dibenzylideneacetone)palladium, Tris(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridin-[1,3-bis(2,6-diisopropylphenyl)imidazole-2-Illidan]palladium or palladium on charcoal.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -10°C to 200°C and preferably from 0°C to 150°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 5 minutes to 48 hours and preferably from 10 minutes to 12 hours.

After completion of the reaction the desired compound of this reaction can�about to receive, for example, by concentration of the reaction mixture, adding an organic solvent such as ethyl acetate, and washing with water followed by separation of the organic layer containing the desired compound, drying with anhydrous sodium sulfate, and the like, and Stripping of solvent.

The resulting compound can be further purified, if necessary, using conventional means, such as recrystallization, re-precipitation, column chromatography on silica gel or similar.

(Stage 1-a-5)

This phase is a stage of reaction of boron compounds obtained in stage 1-a-4, with substituted or unsubstituted helgaleena or heteroarylboronic, or areipseparated or heteroarylboronic containing ring Q3in an inert solvent, in the presence or in the absence of base, in the presence or in the absence of additives and in the presence of a metal catalyst, thereby obtaining compounds having the General formula (6) or (9).

This stage can be carried out in accordance with the stage 1-a-3.

(Stage 1-2)

Stage 1-2 is the stage of obtaining compounds having the General formula (1) compounds having the formula (3).

Examples of important reactions include:

stage 1-2A: the reaction of removing the protective group Pro1;

<> stage 1-2b: the reaction of removing the protective group Pro3.

In addition, if required, add:

stage 1-2C: the reaction of R1bin R1and

stage 1-2d: the reaction of R2ain R2. Stage 1-2A to 1-2d may be performed in any order.

(Stage 1-2A)

This stage is the stage of removal of the protective group Pro1. Depending on the applicable Pro1can appropriately choose the known method described, for example, Protective Groups in Organic Syntesis, 3rded., Greene, T. W., Wuts, P. G. M., John Wiley & Sons, Inc., New York, 1999, and similar publications, and this reaction is conducted according to them. In this context, the benzyl group is selected as the preferred Pro1and describes the way in which Pro1turn in the hydrogen atom with the use of the catalyst in the hydrogen atmosphere, in an inert solvent, in the presence or in the absence of additives (stage 1-a), the way in which Pro1turn in the hydrogen atom with a catalyst in the presence of organic compounds that can serve as a source of hydrogen in the atmosphere of nitrogen or argon, in an inert solvent and in the presence or in the absence of additives (stage 1-2A2), or the way in which Pro1turn in the hydrogen atom with the use of a suitable acid in an inert solvent (stage 1-2A3), but atodorov is not limited thereto.

(Stage 1-a)

This stage is the stage of turning Pro1in the hydrogen atom with the use of the catalyst in the hydrogen atmosphere, in an inert solvent and in the presence or in the absence of the additive.

Although there were no specific restrictions for used solvent, provided that it does not inhibit the reaction and dissolves the original compound to some extent, and preferred examples include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; alcohols such as methanol or ethanol; NITRILES such as acetonitrile; amides, such as formamide or N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixture of many organic solvents in an arbitrary ratio and mix them with water in an arbitrary ratio.

Although there were no specific limits for additives used, provided that it is used in the known methods, examples include hydrochloric acid.

Although there were no specific restrictions for used metal catalyst, provided that it is used in the known methods involving�plant examples include palladium on charcoal, Tris(triphenylphosphine)radicore hydroxide or palladium.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -100°C to 150°C and preferably from 0°C to 100°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 1 minute to 24 hours and preferably from 5 minutes to 10 hours.

After completion of the reaction the desired compound of this reaction can be obtained, for example, by filtration to separate insoluble substances and concentration of the filtrate under reduced pressure. The resulting compound can be further purified, if necessary, using a conventional method such as recrystallization, re-precipitation, column chromatography on silica gel or similar method.

In the case where R2arepresents the alkenyl group, the alkenyl group can be converted to the corresponding alkyl group in this stage.

(Stage 1-2A2)

This stage is the stage of turning Pro1in the hydrogen atom with a catalyst in the presence of organic compounds that can serve as a source of hydrogen in the atmosphere of nitrogen or argon, in an inert solvent and in the presence or in the absence of the additive.

Although not ima�tsya specific limits for the employed solvent, provided that it does not inhibit the reaction and dissolves the original compound to some extent, and preferred examples include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; alcohols such as methanol or ethanol; NITRILES such as acetonitrile; amides such as formamide or N,N-dimethylformamide; sulfoxides, such as dimethyl sulfoxide; a mixture of many organic solvents in an arbitrary ratio and mix them with water in an arbitrary ratio.

Although there were no specific restrictions for used organic compounds, provided that it is used in the known methods, examples include formic acid.

Although there were no specific limits for additives used, provided that it is used in the known methods, examples include hydrochloric acid.

Although there were no specific restrictions for used metal catalyst, provided that it is used in the known methods, preferred examples include palladium on charcoal, Tris(triveneto�fin)radicore, the palladium hydroxide, or the like.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -100°C to 150°C and preferably from -78°C to 100°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 5 minutes to 24 hours and preferably from 10 minutes to 6 hours.

After completion of the reaction the desired compound of this reaction can be obtained, for example, by concentration of the reaction mixture, adding an organic solvent such as ethyl acetate, and washing with water followed by separation of the organic layer containing the desired compound, drying with anhydrous sodium sulfate, and the like, and Stripping of solvent.

The resulting compound can be further purified, if necessary, using a conventional method such as recrystallization, re-precipitation, column chromatography on silica gel or similar method.

(Stage 1-2A3)

This stage is the stage of turning Pro1in the hydrogen atom with the use of a suitable acid in an inert solvent. This stage as per stage 1-1A2.

(Stage 1-2b)

This stage is the stage of removal of the protective group Pro3. This stage as per stage 1. In the case where the Pro3represents a benzyl group, this stage can also be based on the stage 1-a.

(Stage 1-2C)

This stage is the stage of transformation of R1bin R1. This stage as per stage 1-e. In the case where R1bhas a protective group, this stage also contains the same stage of removal of protection. Depending on the protective group, choose an appropriate known method described, for example, Protective Groups in Organic Synthesis, 3rded., Greene, T. W., Wuts, P. G. M., John Wiley & Sons, Inc., New York, 1999, etc., and this step is carried out in accordance with them. In this context, the preferred protective groups are used methoxymethyl group or tert-butyl(dimethyl)silyl group, and describe the way in which protective methoxymethyl group is removed with acid in an inert solvent (stage 1-2C1), the way in which the protective tert-butyl(dimethyl)silyl group is removed with acid in an inert solvent (stage 1-2C2) or the way in which the protective tert-butyl(dimethyl)silyl group is removed with the use of fluorine compounds in an inert solvent (stage 1-2C3), but this method is not limited thereto.

(Stage 1-2S1)

This stage is the stage of removal of the protective methoxymethyl group and can holds� according to stage 1-1A2.

(Stage 1-2C2)

This stage is the stage of removal of the protective tert-butyl(dimethyl)silyl groups and can be performed under stage 1-1A2.

(Stage 1-2C3)

This stage is the stage of removal of the protective tert-butyl(dimethyl)silyl group, and it is carried out with the use of fluorine compounds in an inert solvent.

Although there were no specific restrictions for used solvent, provided that it does not inhibit the reaction and dissolves the original compound to some extent, and preferred examples include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloro methane or chloroform; esters, such as ethyl acetate or propyl acetate; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; alcohols such as methanol, ethanol or tert-butanol; NITRILES, such as acetonitrile; amides, such as formamide or N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixture of many organic solvents in an arbitrary ratio and mix them with water in an arbitrary ratio.

Although there were no specific restrictions for used fluorine compounds, provided that it is used in the removal of silyl protective groups, preferred examples include � the fluoride tetrabutylammonium, divertioculitis Tris(dimethylamino)sulfone or the like.

Changing in accordance with the parent compounds, reagents and the like, the reaction temperature is usually from -100°C to 150°C and preferably from -20°C to 100°C.

Changing in accordance with the parent compounds, reagents and the like, the reaction time is usually from 5 minutes to 24 hours and preferably from 10 minutes to 6 hours.

After completion of the reaction the desired compound of this reaction can be obtained, for example, by concentration of the reaction mixture, adding an organic solvent such as ethyl acetate, and washing with water followed by separation of the organic layer containing the desired compound, drying with anhydrous sodium sulfate, and the like, and Stripping of solvent.

The resulting compound can be further purified, if necessary, using a conventional method such as recrystallization, re-precipitation, column chromatography on silica gel or similar method.

(Stage 1-2d)

This stage is the stage of transformation of R2ain R2and in the case where R2arepresents the alkenyl group, the alkenyl group can be converted to the corresponding alkyl group according to stage 1-a.

(Stage 2)

Stage 2 is stage get�of compounds (2), used in stage 1.

In the above formulas, R1ahas the same meaning as previously, and Pro5it refers to the protective group, each functional group, selected from a known protective groups (for example, groups from the publication Protective Groups in Organic Synthesis, 3rded., Greene, T. W., Wuts, P. G. M., John Wiley & Sons, Inc., New York, 1999, etc.). Although there were no specific restrictions for Pro5provided that it is stable during the reaction and does not inhibit the reaction, preferred is a methyl group.

Compound having the General formula (2), can be synthesized using a known method (for example, (i) the way in which the substituted ethanimine (10) and the diester of a 2-alkyloxy-3-oceanfree acid (11), synthesized according to a known method, condensed in the presence of base: Dreher, S. D., Ikemoto, N., Gresham, V., Liu, J., Dormer, P. G., Balsells, J., Mathre, D., Novak, T., Armstrong III, J. D., Tetrahedron Lett., 2004, 45, 6023, or (ii) the way in which condensed N-replacement ethanimine (12) and a diester acetylenedicarboxylic acid (13): Culbertson, T. P., J. Heterocycl. Chem., 1979, 16, 1423), or with the use of a method according to a known method.

The reaction products obtained according to each of the above stages, is isolated and purified in the form of desolato, their salts or various types of solvates, such as hydrates. Their salts can floor�cation according to the conventional method. The isolation or purification is carried out with the use of conventional methods such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various types of chromatography or the like.

Each type of isomer is possible to allocate according to conventional methods with the use of differences in physical-chemical properties of the isomers. For example, optical isomers can be divided in the usual methods of separation of optical isomers (for example, by fractional crystallization, chromatography, etc.). In addition, optical isomers can also be obtained from the appropriate optically active compounds.

The preparation containing the compound of the present invention as an active ingredient, get with the use of additives such as carrier and excipient used for conventional drug. Introduction compounds of the present invention can be performed by oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc. or parenteral administration by injection (e.g., intravenous injection, intramuscular injection, etc.), suppository, percutaneous agents, nasal agents, forms for inhalation, or the like forms. The dose and frequency of administration of the compounds of the present invention is appropriately determined on an individual basis, adopt�I into account factors such as the symptoms and the age or sex of the person who administered the compound. Dose is usually about 0.001 to 100 mg/kg per injection for an adult human in case of oral administration, and in the case of intravenous administration, the dose usually is 0.0001-10 mg/kg per administration for an adult. Frequency of administration is usually 1-6 times per day or once per day to once per 7 days. The introduction of a patient who receives dialysis is preferably carried out once before or after each dialysis (preferably before dialysis) that a patient receives.

Solid preparations for oral administration according to the present invention may be tablets, powders, pellets or similar forms. Such drugs receive the conventional way by mixing one or more active substances with inert excipient, a lubricant, a disintegrating agent or an auxiliary agent for dissolution. Excipients may be, for example, lactose, mannitol or glucose. The lubricant may be, for example, magnesium stearate. A disintegrating agent may be, for example, the sodium salt of carboxymethylcel. Tablets or pills can be made with a sugar coating or, if necessary, with a coating soluble in the stomach, or enteric coated.

Liquid preparations for peroral�the introduction of CSOs can be pharmaceutically acceptable emulsions, liquids, suspensions, syrups, elixirs or the like forms. Such drugs can include commonly used inert solvents such as purified water or ethanol) and can optionally include soljubilizatory, wetting agents, suspendresume agents, sweeteners, corrigent, flavoring agents or preservatives.

Injections for parenteral administration may be sterile aqueous or non-aqueous liquid preparations, suspensions or emulsions. Aqueous solvents for injectable preparations may be, for example, distilled water or physiological saline solution. Non-aqueous solvents for injection can be, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (name of the Pharmacopoeia of Japan). These preparations may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or agents to facilitate the dissolution. These preparations can be sterilized, for example, by passing through a retaining bacteria filter, include bactericide or irradiation. In addition, as these medications can also apply a composition obtained by dissolving or suspendirovanie sterile tendonopathy in sterile water or solvent for injection before use.

Examples

Although the following examples and test examples for explaining the present invention in more detail, the scope of the present invention is not limited thereto.

(Example 1)

({[5-Hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 12]

(1) tert-Butyl-4-(cyanomethylene)piperidine-1-carboxylate

[Chemical formula 13]

Dieticiansupervised (16 ml, 100 mmol) was dissolved in tetrahydrofuran (360 ml) and the solution in a nitrogen atmosphere at -78°C was added a solution of hexamethyldisilazide lithium in tetrahydrofuran (1 M, 100 ml, 100 mmol) and a solution of tert-butyl-4-oxopiperidine-1-carboxylate (18 g, 91 mmol) in tetrahydrofuran (36 ml) followed by stirring the mixture at the same temperature for 40 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate and the extract was washed with a saturated aqueous solution of ammonium chloride. After distilling off the solvent under reduced pressure, the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,41 (hexane/ethyl acetate=3/1) tonkel�the'ynoy chromatography concentrated under reduced pressure, while receiving specified in the title compound (22 g) as a white solid (quantitative yield).

1H-NMR (500 MHz, CDCl3) δ:5,19 (1H, s), 3,56-of 3.46 (4H, m), 2,56 (2H, t, J=5 Hz), 2,33 (2H, t, J=5 Hz), of 1.48 (9H, s).

(2) tert-Butyl-4-(cyanomethyl)piperidine-1-carboxylate

[Chemical formula 14]

tert-Butyl-4-(cyanomethylene)piperidine-1-carboxylate (20 g, 91 mmol) was dissolved in ethyl acetate (400 ml) was added 10% palladium on activated carbon, followed by stirring the mixture at room temperature for 3.5 hours under a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value or=0.38 (hexane/ethyl acetate=3/1), thin layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (23 g) as a white solid (quantitative yield).

1H-NMR (500 MHz, CDCl3) δ:4,24-4,07 (2H, m), 2,78-of 2.64 (2H, m), 2,32 (2H, d, J=6 Hz), 1,89-of 1.75 (3H, m), of 1.46 (9H, s), 1,32-to 1.21 (2H, m).

(3) Acetate tert-butyl-4-(2-amino-2-iminoethyl)piperidine-1-carboxylate

[Chemical formula 15]

tert-Butyl-4-(cyanomethyl)piperidine-1-carboxylate (91 mmol) was dissolved in ethanol (200 ml) was added an aqueous solution of hydroxylamine (50%, 17 ml, 170 mmol) followed by heating the mixture to boiling with reflux for 3.5 hours. The reaction solution was cooled and then concentrated under reduced pressure, while receiving tert-butyl-4-[2-amino-2-(hydroxyimino)ethyl]piperidine-1-carboxylate as a colorless amorphous solid substance.

This substance was dissolved in 1,4-dioxane (100 ml) at room temperature was added acetic anhydride (17 ml, 180 mmol) and triethylamine (15 ml, 180 mmol) followed by stirring the mixture at the same temperature for 2 hours. After diluting the reaction solution with ethyl acetate it was washed successively with water, dilute hydrochloric acid and water and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure the resulting solid was washed with hexane, while receiving tert-butyl-4-[2-(acetoacetamide)-2-aminoethyl]piperidine-1-carboxylate as a white solid.

It was dissolved in ethanol (200 ml) was added dichloro methane (40 ml) and 10% palladium on charcoal (3.6 g), followed by stirring in hydrogen atmosphere at room temperature for 5 hours. The reaction�nny solution was filtered through celite and then the filtrate was concentrated under reduced pressure, while receiving specified in the title compound (24 g, 79 mmol) as a white solid (yield 85%).

1H-NMR (500 MHz, DMSO-d6) δ: 3,99-3,86 (2H, m), 2,81-of 2.58 (2H, m), of 2.23 (2H, d, J=8 Hz), of 1.85 (1H, m), of 1.64 (3H, s), 1,64-of 1.56 (2H, m), of 1.40 (9H, s), 0,99-of 1.08 (2H, m).

(4) tert-Butyl-5-(benzyloxy)-2-{[1-(tert-butoxycarbonyl)piperidine-4-yl]methyl}-6-hydroxypyrimidine-4-carboxylate

[Chemical formula 16]

Diisopropylamine (30 ml, 210 mmol) was dissolved in tetrahydrofuran (100 ml) and dropwise at 3°C was added a solution of n-utility in hexane (2, 77 M, 77 ml, 210 mmol) followed by stirring at -78°C for 30 minutes to give the solution of diisopropylamide lithium (LDA) in tetrahydrofuran.

tert-Butylmethacrylate (34 g, 210 mmol) and methyl(benzyloxy)acetate (35 g, 190 mmol) was dissolved in tetrahydrofuran (250 ml) and, dropwise, in a nitrogen atmosphere was added a solution of LDA in tetrahydrofuran obtained at -78°C, followed by stirring at the same temperature for 3 hours. The temperature of the reaction solution was gradually raised to -40°C and was then added hydrochloric acid (2 M, 210 ml) followed by extraction of the mixture with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate and the solvent was distilled under reduced pressure, getting PR� 4-tert-butyl-1-methyl-2-(benzyloxy)-3-accountant (62 g) as a yellow oil.

A portion of this oil (36 g, 120 mmol) acetate and tert-butyl-4-(2-amino-2-iminoethyl)piperidine-1-carboxylate (24 g, 79 mmol) was dissolved in methanol (240 ml) at 3°C was added a solution of sodium methoxide in methanol (28%, 48 ml, 240 mmol) followed by stirring the mixture at room temperature for 14.5 hours. To the reaction solution was added hydrochloric acid (1 M, 130 ml) and then precipitated solid was collected by filtration, while receiving specified in the title compound (26 g, 52 mmol) as a white solid (yield 66%).

1H-NMR (500 MHz, CDCl3) δ: 7,47-7,44 (2H, m), 7,40-7,31 (3H, m), 5,23 (2H, s), 4,21-of 3.91 (2H, m), 2,74-of 2.58 (2H, m), 2,62 (2H, d, J=7 Hz), of 2.06 (1H, m), 1,69-to 1.60 (2H, m), of 1.53 (9H, s) of 1.43 (9H, s), 1,28-of 1.16 (2H, m).

(5) tert-Butyl-5-(benzyloxy)-2-{[1-(tert-butoxycarbonyl)piperidine-4-yl]methyl}-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine-4-carboxylate

[Chemical formula 17]

tert-Butyl-5-(benzyloxy)-2-{[1-(tert-butoxycarbonyl)piperidine-4-yl]methyl}-6-hydroxypyrimidine-4-carboxylate (5.0 g, 10 mmol) was dissolved in dichloromethane (100 ml) and at -78°C was added triftormetilfullerenov anhydride (2.1 ml, 12 mmol) and triethylamine (2.1 ml, 15 mmol) followed by stirring at the same temperature for 30 minutes. After concentrating the reaction solution under reduced pressure the resulting residue was purified chromate�the graphy on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0.63 and (hexane/ethyl acetate=2/1), thin layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (6.0 g, 9.5 mmol) as a yellow oil (yield 95%).

1H-NMR (500 MHz, CDCl3) δ: 7,44-of 7.36 (5H, m), 5,14 (2H, s), 4,21-3,95 (2H, m), is 2.88 (2H, d, J=7 Hz), 2,80-2,62 (2H, m), 2,07 (1H, m), 1,67-to 1.60 (2H, m), of 1.57 (9H, s), of 1.46 (9H, s), 1,27-of 1.17 (2H, m).

(6) tert-Butyl-5-(benzyloxy)-2-{[1-(tert-butoxycarbonyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate

[chemical formula 18]

tert-Butyl-5-(benzyloxy)-2-{[1-(tert-butoxycarbonyl)piperidine-4-yl]methyl}-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine-4-carboxylate (6.0 g, 9.5 mmol) was dissolved in tetrahydrofuran (90 ml) at room temperature was added methylboronic acid (1.8 g, 30 mmol), silver oxide (6.7 g, 29 mmol), potassium carbonate (4.0 g, 29 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]paradigalla-dichloro methane (0.78 g, 0.96 mmol) followed by heating to boiling with reflux for 3 hours in a nitrogen atmosphere. The reaction solution was cooled to room temperature and then the insoluble substance was separated by filtration. After concentrating the filtrate under reduced pressure the resulting residue was purified by chromatography nakaloke silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,34 (hexane/ethyl acetate=2/1), thin layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (4.4 g, 8,8 mmol) as a yellow oil (yield 93%).

1H-NMR (500 MHz, CDCl3) δ: 7,44-7,34 (5H, m), 5,00 (2H, s), 4,17-3,98 (2H, m), 2,85 (2H, d, J=7 Hz), 2,77-of 2.64 (2H, m), of 2.44 (3H, s), is 2.09 (1H, m), 1,66-1,59 (2H, m), 1,59 (9H, s), of 1.45 (9H, s), 1,30-1,19 (2H, m).

(7) Hydrochloride tert-butyl-5-(benzyloxy)-6-methyl-2-(piperidine-4-ylmethyl)pyrimidine-4-carboxylate

[chemical formula 19]

tert-Butyl-5-(benzyloxy)-2-{[1-(tert-butoxycarbonyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate (4.4 g, 8,8 mmol) was dissolved in ethyl acetate (44 ml) was added a solution of hydrogen chloride in ethyl acetate (4 M, 68 ml, 270 mmol) followed by stirring the mixture at room temperature for 3 hours. To the reaction solution was added hexane (100 ml) and ethyl acetate (100 ml), thereby precipitating solid. The formed solid substance was collected by filtration and dried under reduced pressure, while receiving specified in the title compound (3.7 g, 8.5 mmol) as a white solid (yield 95%).

1H-NMR (500 MHz, DMSO-d6) δ: 7,47-7,34 (5H, m), 4,99 (2H, s), 3,26-3,1 8 (2H, m), 2,90-2,78 (2H, m), 2,78 (2H, d, J=7 Hz), 2, 46 (3H, s), 2,12 (1H, m), 1,78-1,70 (2H, m) of 1.51 (9H, s, 1,51-of 1.39 (2H, m).

(8) [(4'-Bromophenyl-4-yl)methoxy](tert-butyl)dimethylsilane

[chemical formula 20]

(4'-Bromodiphenyl-4-yl)methanol (0.70 g, 2.7 mmol) and imidazole (0.54 g, 8,0 mmol) was dissolved in tetrahydrofuran (20 ml) and under an atmosphere of nitrogen was added tert-butyldimethylchlorosilane (1.2 g, 8.0 mmol) followed by stirring at room temperature for 1 hour. To the reaction solution was added water, and the solution was extracted with ethyl acetate and then washed sequentially with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After concentrating the organic layer under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,90 (hexane/ethyl acetate=9/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0.92 g, 2.4 mmol) as a white solid (yield 91%).

1H-NMR (500 MHz, CDCl3) δ: 7,55 (2H, d, J=8 Hz), 7,52 (2H, d, J=8 Hz), was 7.45 (2H, d, J=8 Hz), 7,40 (2H, d, J=8 Hz), 4,78 (2H, C), 0, 96 (9H, s), of 0.12 (6H, s).

(9) tert-Butyl-5-(benzyloxy)-2-({1-[4'-({[tert-butyl(dimethyl)silyl]oxy}methyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate

[Chemical formula 21]

p>

Hydrochloride tert-butyl-5-(benzyloxy)-6-methyl-2-(piperidine-4-ylmethyl)pyrimidine-4-carboxylate (1.0 g, 2.3 mmol), [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane (0.92 g, 2.4 mmol), tert-butoxide sodium (0,67 g, 7.0 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (X-PHOS) (0.11 g, 0,23 mmol) and Tris(dibenzylideneacetone)dipalladium (0.11 g, 0.12 mmol) was suspended in toluene (50 ml) followed by heating the mixture to boiling with reflux for 3 hours in a nitrogen atmosphere. The reaction solution was cooled to room temperature and was filtered through celite and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0.50 (a hexane/ethyl acetate=2/1), thin layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0.98 g, 1.4 mmol) as a yellow oil (yield 61%).

1H-NMR (500 MHz, CDCl3) δ: 7,52 (2H, d, J=8 Hz), 7,49 (2H, d, J=8 Hz), 7,45-7,32 (7H, m), of 6.99 (2H, d, J=8 Hz), 5,01 (2H, s), 4,76 (2H, s), 3,73 (2H, d, J=12 Hz) or 2.91 (2H, d, J=7 Hz), of 2.75 (2H, t, J=12 Hz), Of 2.46 (3H, s), 2,17-of 2.06 (1H, m), of 1.80 (2H, d, J=12 Hz), 1,59 (9H, s), a 1.54 (2H, kV, J=12 Hz), of 0.95 (9H, s), of 0.11 (6H, s).

(10) tert-Butyl-5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}IU�yl)-6-methylpyrimidin-4-carboxylate

[Chemical formula 22]

tert-Butyl-5-(benzyloxy)-2-({1-[4'-({[tert-butyl(dimethyl)silyl]oxy}methyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate (0.98 g, 1.4 mmol) was dissolved in 1,4-dioxane (10 ml) was added a solution of hydrogen chloride in dioxane (4 M, 1.0 ml, 4 mmol) followed by stirring at room temperature for 1.5 hours. To the reaction solution for neutralization was added a saturated solution of sodium bicarbonate, followed by extraction of the mixture with ethyl acetate and then the organic layer was concentrated under reduced pressure, while receiving specified in the header connection (0,81 g, 1,4 mmol) as a yellow oil (yield 99%).

1H-NMR (500 MHz, CDCl3) δ: 7,56 (2H, d, J=8 Hz), 7,50 (2H, d, J=8 Hz), 7,45-7,34 (7H, m), 7,00 (2H, d, J=8 Hz), 5,01 (2H, s), 4.72 in (2H, s), 3,73 (2H, d, J=12 Hz) or 2.91 (2H, d, J=7 Hz), to 2.76 (2H, t, J=12 Hz), Of 2.46 (3H, s), 2,17-of 2.06 (1H, m), of 1.80 (2H, d, J=12 Hz), 1,59 (9H, s), a 1.54 (2H, kV, J=12 Hz).

(11) Ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 23]

tert-Butyl-5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate (0,81 g, 1,4 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml) and added aqueous solution of hydroxy�and sodium (5 M, 10 ml, 50 mmol) followed by stirring at 50°C for 15 minutes. The reaction solution was cooled to room temperature and was added hydrochloric acid (5 M, 10 ml, 50 mmol), followed by extraction of the mixture with ethyl acetate. The organic layer was concentrated under reduced pressure, obtaining 5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylic acid as a yellow solid.

This substance was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml) was added the hydrochloride of the ethyl ester of glycine (0.30 g, 2.1 mmol), chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (0,51 g, 1.8 mmol) and N-methylmorpholin (of 0.39 ml, 3.5 mmol) followed by stirring the mixture at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: dichloro methane/ethyl acetate) and the fraction corresponding to the Rf value=0,60 (hexane/ethyl acetate=1/4) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0.32, 0.53 mmol) as a yellow solid (yield 38%).

1H-NMR (500 MHz, CDCl3) δ: to 8.36 (1H, t, J=6 Hz), 7,56 (2H, d, J=8 Hz), 7,52-7,47 (4H, m), 743-7,34 (5H, m), 7, 00 (2H, d, J=8 Hz), 5,12 (2H, s), 4,73 (2H, d, J=6 Hz), 4,30 is 4.19 (4H, m), of 3.75 (2H, d, J=12 Hz), 2,90 (2H, d, J=7 Hz), 2,78 (2H, t, J=12 Hz), 2,47 (3H, s), 2,17-2,07 (1H, m), To 1.79 (2H, d, J=12 Hz), 1,59-of 1.48 (2H, m), 1,32 (3H, t, J=7 Hz).

(12) Ethyl({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 24]

Ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0,43 g, 0.71 mmol) was dissolved in a mixed solvent of ethyl acetate (20 ml) and dichloromethane (20 ml) was added 10% palladium on charcoal (0,080 g), followed by stirring at room temperature for 2.5 hours under a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure, thereby precipitating solid. The formed solid substance was collected by filtration and dried under reduced pressure, while receiving specified in the header connection (0,34 g, 0.66 mmol) as a white solid (yield 93%).

MS m/z: 519 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 11,83 (1H, s), 9,52 (1H, t, J=6 Hz), 7,54 (2H, d, J=8 Hz), 7,50 (2H, d, J=8 Hz), 7,34 (2H, d, J=8 Hz), of 6.99 (2H, d, J=8 Hz), to 5.17 (1H, Shir.C), 4,50 (2H, s), is 4.15 (2H, kV, J=7 Hz), of 4.09 (2H, d, J=6 Hz), 3,74 (2H, d, J=12 Hz), 2,79 (2H, d, J=7 Hz), 2,70 (2H, t, J=12 Hz), of 2.45 (3H, s), 2,15-2,05 (1H, m), by 1.68 (2H, d, J=12 Hz), To 1.37 (2H, kV, J=12 Hz), to 1.21 (3H, t, J= Hz).

(13) ({[5-Hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

Ethyl({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.22 g, 0,42 mmol) was dissolved in a mixed solvent of methanol (5 ml) and tetrahydrofuran (5 ml) and added aqueous solution of sodium hydroxide (1 M, 5.0 ml) followed by stirring the mixture at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and the resulting residue was added hydrochloric acid (1 M, 5.0 ml), thereby precipitating solid. The formed solid substance was collected by filtration and dried under reduced pressure, while receiving specified in the title compound (0.17 g, 0.35 mmol) as pale yellowish white solid (yield 82%).

MS m/z: 491 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,87 (1H, Shir.C), 11,92 (1H, s), of 9.42 (1H, t, J=6 Hz), 7,54 (2H, d, J=8 Hz), 7,50 (2H, d, J=8 Hz), 7,34 (2H, d, J=8 Hz), 7,00 (2H, d, J=8 Hz), to 5.17 (1H, t, J=6 Hz), 4,51 (2H, d, J=6 Hz), 4,01 (2H, d, J=6 Hz), 3,74 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,70 (2H, t, J=12 Hz), of 2.45 (3H, s), 2,15-2,04 (1H, m), by 1.68 (2H, d, J=12 Hz), to 1.37 (2H, kV, J=12 Hz).

(Example 2)

({[2-({1-[4'-(Acetoxymethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 25]

p>

({[5-Hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid (0.13 g, 0.27 mmol) was dissolved in acetonitrile (8 ml) and added acetic anhydride (0,063 ml, 0.67 mmol), triethylamine (0,092 ml, 0.66 mmol) and 4-dimethylaminopyridine (0,081 g, 0.66 mmol) followed by stirring the mixture at room temperature for 3 hours. After concentrating the reaction solution under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: dichloro methane/methanol) and the fraction corresponding to the Rf value=0,20 (dichloro methane/methanol=9/1) thin-layer chromatography was concentrated under reduced pressure, thereby precipitating solid. The formed solid substance was collected by filtration and dried under reduced pressure, while receiving specified in the header connection (0,070 g, 0,13 mmol) as a pale yellowish white solid (yield 50%).

MS m/z: 533 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,86 (1H, Shir.C) 11,91 (1H, s), of 9.42 (1H, Shir.C) members, 7.59 (2H, d, J=8 Hz), 7,52 (2H, d, J=8 Hz), 7,39 (2H, d, J=8 Hz), 7,00 (2H, d, J=8 Hz), 5.08 mm (2H, s), 4,01 (2H, d, J=6 Hz), of 3.75 (2H, d, J=12 Hz), 2,78 (2H, d, J=6 Hz), 2,71 (2H, t, J=12 Hz), of 2.44 (3H, s), 2,16-2,03 (1H, m), 2,07 (3H, s), by 1.68 (2H, d, J=12 Hz), of 1.36 (2H, kV, J=12 Hz).

(Example 3)

({[5-Hydroxy-2-({1-[4'-(1-hydroxic�l)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 26]

(1) Ethyl-({[2-{[1-(4'-acetylbiphenyl-4-yl)piperidine-4-yl]methyl}-5-(benzyloxy)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 27]

According to the examples 1-(9) and 1-(11), but using 1-(4'-bromodiphenyl-4-yl)ethanone instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound (yield 35%) was obtained as yellow solids.

1H-NMR (400 MHz, CDCl3) δ: 8,35 (1H, t, J=5 Hz), 7,99 (2H, d, J=9 Hz), 7,65 (2H, d, J=9 Hz), 7,56 (2H, d, J=9 Hz), 7,51-7,47 (2H, m), of 7.42-7,34 (3H, m), 7,01 (2H, d, J=9 Hz), 5,13 (2H, s), 4,27 (2H, kV, J=7 Hz), 4,25 (2H, d, J=5 Hz), with 3.79 (2H, d, J=13 Hz), 2,90 (2H, d, J=7 Hz), of 2.81 (2H, t, J=13 Hz), 2,62 (3H, C), 2,47 (3H, s), 2,20-of 2.09 (1H, m), of 1.80 (2H, d, J=13 Hz), 1,59-of 1.47 (2H, m), 1,32 (3H, t, J=7 Hz).

(2) Ethyl({[5-hydroxy-2-({1-[4'-(1-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 28]

Ethyl-({[2-{[1-(4'-acetylbiphenyl-4-yl)piperidine-4-yl]methyl}-5-(benzyloxy)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0,67 g, 1.1 mmol) was dissolved in a mixed solvent of ethyl acetate (35 ml) and dichloromethane (35 ml) was added 10% platinum on activated carbon (0.65 g), followed by stirring at room temperature for 8 hours in hydrogen atmosphere. After filtering the reaction solution through celite �intrat concentrated under reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: dichloro methane/ethyl acetate) and the fraction corresponding to the Rf value=0,27 (dichloro methane/ethyl acetate=1/3) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0,44 g, 0,82 mmol) as a white solid (yield 77%).

MS m/z: 533 (M+H)+;

1H-NMR (400 MHz, CDCl3) δ: at 11.37 (1H, s), and 8.50 (1H, t, J=6 Hz), 7,54 (2H, d, J=8 Hz), 7,49 (2H, d, J=9 Hz), 7,41 (2H, d, J=9 Hz), of 6.99 (2H, d, J=8 Hz), 4,98-of 4.90 (1H, m), 4,29 (2H, kV, J=7 Hz), to 4.23 (2H, d, J=6 Hz), 3,74 (2H, d, J=12 Hz), 2,84 (2H, d, J=7 Hz), to 2.76 (2H, t, J=12 Hz), of 2.54 (3H, s), 2,13-of 2.01 (1H, m), 1,78 (2H, d, J=12 Hz), 1,59-of 1.45 (2H, m), 1,54 (3H, d, J=7 Hz), of 1.33 (3H, t, J=7 Hz).

(3) ({[5-Hydroxy-2-({1-[4'-(1-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to example 1-(13), but using ethyl({[5-hydroxy-2-({1-[4'-(1-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate instead of ethyl({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate specified in the title compound (yield 96%) was obtained as pale brown solids.

MS m/z: 505 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 9,31 (1H, t, J=6 Hz), 7,52 (2H, d, J=8 Hz), of 7.48 (2H, d, J=9 Hz), 7,35 (2H, d, J=8 Hz), 6,98 (2H, d, J=9 G�), 5,13 (1H, Shir.C), 4.72 in (1H, q, J=7 Hz), 3,92 (2H, d, J=6 Hz), and 3.72 (2H, d, J=13 Hz), 2,78 (2H, d, J=7 Hz), 2,69 (2H, t, J=13 Hz), 2,43 (3H, s), 2,14-2,03 (1H, m), by 1.68 (2H, d, J=13 Hz), of 1.33 (3H, d, J=6 Hz), 1,42-of 1.30 (2H, m).

(Example 4)

({[5-Hydroxy-2-({1-[4'-(2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 29]

(1) tert-Butyl-[2-(4-itfinal)ethoxy]dimethylsilane

[Chemical formula 30]

According to example 1-(8), but using 2-(4-itfinal)ethanol instead of (4'-bromodiphenyl-4-yl)methanol specified in the title compound was obtained (yield 97%) as a colorless oil.

1H-NMR(500 MHz, CDCl3) δ: members, 7.59 (2H, d, J=8 Hz), of 6.96 (2H, d, J=8 Hz), of 3.77 (2H, t, J=7 Hz), of 2.75 (2H, t, J=7 Hz), 0,86 (9H, s), of 0.03 (6H, s).

(2) [2-(4'-Bromodiphenyl-4-yl)ethoxy](tert-butyl)dimethylsilane

[Chemical formula 31]

tert-Butyl-[2-(4-itfinal)ethoxy]dimethylsilane (7.1 g, a 19.6 mmol), (4-bromophenyl)Bronevoy acid (4.8 g, 23,9 mmol), n-hydrate trikaliotis (10.4 g, of 49.0 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]paradigalla-dichloro methane (0.80 g, 0.98 mmol) was suspended in 1,2-dimethoxyethane (150 ml) followed by stirring the mixture at room temperature for 4 hours in a nitrogen atmosphere. After filtering the reaction solution through celite, the filtrate kontsentrirovaniya reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane) and the fraction corresponding to the Rf value=0,90 (hexane/ethyl acetate=19/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (2.0 g, 5.1 mmol) as a white solid (yield 26%).

1H-NMR (500 MHz, CDCl3) δ: EUR 7.57 (2H, d, J=8 Hz), 7,50 (2H, d, J=8 Hz), 7,47 (2H, d, J=8 Hz), 7,31 (2H, d, J=8 Hz), 3,86 (2H, t, J=7 Hz), 2,89 (2H, t, J=7 Hz), of 0.91 (9H, s), of 0.03 (6H, s).

(3) ({[5-Hydroxy-2-({1-[4'-(2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9) to 1-(13), but using [2-(4'-bromodiphenyl-4-yl)ethoxy](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 15%) as a pale yellowish white solid.

MS m/z: 505 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,88 (1H, Shir.C) 11,91 (1H, s), 9,41 (1H, t, J=6 Hz), of 7.48 (4H, d, J=8 Hz), 7,24 (2H, d, J=8 Hz), of 6.99 ( 2H, d, J=8 Hz), a 4.65 (1H, t, J=6 Hz), 4,01 (2H, d, J=6 Hz), 3,73 (2H, d, J=12 Hz), 3,61 (2H, kV, J=6 Hz), 2,78 (2H, d, J=7 Hz), 2,75-of 2.66 (4H, m), of 2.44 (3H, s), 2,15-2,04 (1H, m), by 1.68 (2H, d, J=12 Hz), to 1.37 (2H, kV, J=12 Hz).

(Example 5)

({[5-Hydroxy-2-({1-[4'-(2-hydroxypropyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Hee�the algebraic formula 32]

(1) 2-(4'-Bromodiphenyl-4-yl)-N-methoxy-N-methylacetamide

[Chemical formula 33]

(4'-Bromodiphenyl-4-yl)acetic acid (12 g, 37 mmol) was dissolved in a mixed solvent of tetrahydrofuran (200 ml) and methanol (200 ml) was added the hydrochloride of N,O-dimethylhydroxylamine (5.4 g, 56 mmol), chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (15 g, 60 mmol) and N-methylmorpholin (6,1 ml, 56 mmol) followed by stirring the mixture at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure to the resulting residue were added ethyl acetate and the organic layer was washed with water. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,45 (hexane/ethyl acetate=1/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (12 g, 37 mmol) as a white solid (yield 100%).

1H-NMR (500 MHz, CDCl3) δ: 7,55 (2H, d, J=8 Hz), 7,51 (2H, d, J=8 Hz), was 7.45 (2H, d, J=8 Hz), value of 7, 37 (2H, d, J=8 Hz), 3,82 (2H, s), to 3.67 (3H, s), up 3.22 (3H, s).

(2) (4'-Bromodiphenyl-4-yl)acetone

[Chemical formula 34]

the Solution metallice in simple diethyl ether (40 ml, 44 mmol) was diluted with tetrahydrofuran (120 ml) and at -78°C was added a solution of 2-(4'-bromodiphenyl-4-yl)-N-methoxy-N-methylacetamide (12 g, 37 mmol) in tetrahydrofuran (50 ml) followed by stirring at the same temperature for 30 minutes. To the reaction solution was added water, followed by extraction of the mixture with ethyl acetate and then the solvent was distilled at reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0.50 (a hexane/ethyl acetate=4/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (7.6 g, 26 mmol) as a white solid (yield 71%).

1H-NMR (500 MHz, CDCl3) δ: 7,56 (2H, d, J=8 Hz), 7,53 (2H, d, J=8 Hz), was 7.45 (2H, d, J=8 Hz), 7,27 (2H, d, J=8 Hz), 3,76 (2H, s), of 2.21 (3H, s).

(3) 1-(4'-Bromodiphenyl-4-yl)propan-2-ol

[Chemical formula 35]

(4'-Bromodiphenyl-4-yl)acetone (7.6 g, 26 mmol) was dissolved in ethanol (250 ml) and at 0°C was added sodium borohydride (1.2 g, 32 mmol) followed by stirring the mixture at the same temperature for 30 minutes. After concentrating the reaction solution under reduced pressure to the resulting residue were added ethyl acetate and the organic layer was washed with water. P�after distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,45 (hexane/ethyl acetate=4/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (7.6 g, 26 mmol) as a white solid (yield 99%).

1H-NMR (500 MHz, CDCl3) δ: 7,56 (2H, d, J=8 Hz), 7,51 (2H, d, Hz), was 7.45 (2H, d, J=8 Hz), 7,30 (2H, d, J=8 Hz), 4,07 (1H, 2,84 (1H, DD, J=13 Hz, 5 Hz), 2,73 (1H, DD, J=13 Hz, 3 Hz), 1,58-1,49 (1H, m), of 1.28 (3H, d, J=6 Hz).

(4) [2-(4'-Bromodiphenyl-4-yl)-1-methylethoxy](tert-butyl)dimethylsilane

[Chemical formula 36]

According to example 1-(8), but using 1-(4'-bromodiphenyl-4-yl)propan-2-ol instead of (4'-bromodiphenyl-4-yl)methanol specified in the title compound was obtained (96%) as a white solid.

1H-NMR (500 MHz, CDCl3) δ: 7,54 (2H, d, J=8 Hz), was 7.45 (2H, d, J=8 Hz), 7,44 (2H, d, J=8 Hz), 7,24 (2H, d, J=8 Hz), 4,04-3,93 (1H, m), 2,80-of 2.67 (2H, m), of 1.17 (3H, d, J=6 Hz), and 0.83 (9H, s) to -0.05 (3H, s) -0,17 (3H, C).

(5) ({[5-Hydroxy-2-({1-[4'-(2-hydroxypropyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9) to 1-(13), but using [2-(4'-bromodiphenyl-4-yl)-1-methylethoxy](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 35%) as a white solid.

MS mz: 519 (M+H) +;

1H-NMR (400 MHz, DMSO-d6) δ: 12,89 (1H, Shir.C), 11,92 (1H, s), 9,41 (1H, t, J=6 Hz), 7,49 (2H, d, J=9 Hz), of 7.48 (2H, d, J=9 Hz), 7,22 ( 2H, d, J=8 Hz), 6,98 (2H, d, J=8 Hz), 4,58 (1H, d, J=5 Hz), 4,01 (2H, d, J=6 Hz), 3,86-with 3.79 (1H, m), 3,73 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,74-to 2.65 (3H, m), of 2.57 (1H, DD, J=13 Hz, 6 Hz), of 2.44 (3H, s), 2,09-2,00 (1H, m), 1,69 (2H, d, J=12 Hz), of 1.36 (2H, DQC, J=12 Hz, 3 Hz), of 1.05 (3H, d, J=6 Hz).

(Example 6)

({[5-Hydroxy-2-({1-[4'-(2-hydroxy-1,1-dimethylethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 37]

(1) Ethyl-2-(4'-bromodiphenyl-4-yl)-2-methylpropionate

[Chemical formula 38]

Ethyl-(4'-bromodiphenyl-4-yl)acetate (7.6 g, 24 mmol) was dissolved in tetrahydrofuran (130 ml) and at 0°C was added sodium hydride (55%, 3.1 g, 71 mmol) followed by stirring at room temperature for 30 minutes. To the reaction solution was added methyliodide (4.4 ml, 71 mmol) followed by stirring at room temperature for additional 20 hours. To the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction of the mixture with ethyl acetate and then the solvent was distilled at reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction of matching�upon the value of Rf=0,50 (hexane/ethyl acetate=10/1) thin-layer chromatography, concentrated under reduced pressure, while receiving specified in the title compound (6.2 g, 18 mmol) as a yellow oil (yield 76%).

1H-NMR (500 MHz, CDCl3) δ: 7,55 (2H, d, J=8 Hz), 7,52 (2H, d, J=8 Hz), was 7.45 (2H, d, J=8 Hz), 7,40 (2H, d, J=8 Hz), 4,14 (2H, kV, J=7 Hz), to 1.61 (6H, s) to 1.21 (3H, t, J=7 Hz).

(2) 2-(4'-Bromodiphenyl-4-yl)-2-methylpropan-1-ol

[Chemical formula 39]

Ethyl-2-(4'-bromodiphenyl-4-yl)-2-methylpropionate (6.2 g, 18 mmol) was dissolved in tetrahydrofuran (150 ml) and at 0°C was added hydride (0,68 g, 18 mmol) followed by stirring the mixture at the same temperature for 1.5 hours. To the reaction solution was added water and the insoluble substance was separated by filtration through celite, followed by extraction with ethyl acetate. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,40 (hexane/ethyl acetate=1/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (5.0 g, 16 mmol) as a white solid (yield 92%).

1H-NMR (500 MHz, CDCl3) δ: members, 7.59-7,51 (4H, m), 7,49-the 7.43 (4H, m), 3,66 (2H, s), 1,38 (6H, s).

(3) 4-Bromo-4'-[2-(methoxyethoxy)-1,1-dimethylethyl]biphenyl

[Chemical resistance�Kaya formula 40]

2-(4'-Bromodiphenyl-4-yl)-2-methylpropan-1-ol (5.0 g, 16 mmol) was dissolved in toluene (40 ml) and added chloromethylation ether (2.5 ml, 33 mmol) and N,N-diisopropylethylamine (3.6 ml, 21 mmol) followed by stirring at room temperature for 17 hours. After diluting the reaction solution with ethyl acetate organic layer was washed with water. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,45 (hexane/ethyl acetate=10/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (5.8 g, 16 mmol) as a white solid (yield 100%).

1H-NMR (500 MHz, CDCl3) δ: 7,54 (2H, d, J=8 Hz), 7,51 (2H, d, J=8 Hz), 7,47 (2H, d, J=8 Hz), was 7.45 (2H, d, J=8 Hz), 4,58 (2H, C), 3, 60 (2H, s), 3,27 (3H, s), of 1.39 (6H, s).

(4) ({[5-Hydroxy-2-({1-[4'-(2-hydroxy-1,1-dimethylethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9) to 1-(13), but using 4-bromo-4'-[2-(methoxyethoxy)-1,1-dimethylethyl]instead of diphenyl [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 25%) as a white solid prophetic�TBA.

MS m/z: 533 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,86 (1H, Shir.C) 11,91 (1H, s), 9,41 (1H, t, J=5 Hz), 7,50 (2H, d, J=9 Hz), of 7.48 (2H, d, J=9 Hz), 7,39 (2H, d, J=8 Hz), of 6.99 (2H, d, J=8 Hz), 4,67 (1H, Shir.(C), of 4.00 (2H, d, J=5 Hz), 3,73 (2H, d, J=12 Hz), 3,42 (2H, s), 2,78 (2H, d, J=7 Hz), 2,70 (2H, t, J=12 Hz), of 2.45 (3H, s), 2,15-2,05 (1H, m), by 1.68 (2H, d, J=12 Hz), of 1.36 (2H, DQC, J=12 Hz, 3 Hz)That is 1.23 (6H, s)

(Example 7)

({[2-({1-[4'-(Dimethylcarbamoyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 41]

According to the examples 1-(9) and 1-(11) to 1-(13), but using 4'-bromo-N,N-dimethylbiphenyl-4-carboxamide instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 29%) as a pale yellowish white solid.

MS m/z: 532 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,88 (1H, Shir.C) 11,91 (1H, s), 9,40 (1H, t, J=6 Hz), 7,65 (2H, d, J=8 Hz), 7,56 (2H, d, J=8 Hz), the 7.43 ( 2H, d, J=8 Hz), 7,01 (2H, d, J=8 Hz), 4,01 (2H, d, J=6 Hz), 3,7 7 (2H, d, J=12 Hz), of 2.97 (6H, Shir.C), 2,78 (2H, d, J=7 Hz), 2,73 (2H, t, J=12 Hz), of 2.44 (3H, s), 2,16-2,05 (1H, m), 1,69 (2H, d, J=1 2 Hz), of 1.36 (2H, kV, J=12 Hz).

(Example 8)

({[5-Hydroxy-6-methyl-2-({1-[4'-(methylcarbamoyl)biphenyl-4-yl]piperidine-4-yl}methyl)pyrimidine-4-yl]carbonyl}amino)acetic acid

[Chemical formula 42]

According to the examples 1-(9) and 1-(11) to 1-(13), but using 4'-bromo-N-methylbiphenyl-4-carboxamidine [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane, specified in the title compound was obtained (yield 20%) as a yellow solid.

MS m/z: 518 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 9,28 (1H, Shir.C) to 8.42 (1H, d, J=4 Hz), 7,86 (2H, d, J=8 Hz), to 7.68 (2H, d, J=8 Hz), members, 7.59 (2H, d, J=8 Hz), 7,01 (2H, d, J=8 Hz), 3,86 (2H, Shir.(C), of 3.78 (2H, d, J=12 Hz), of 2.81-2,69 (7H, m), of 2.44 (3H, s), 2,15-2,05 (1H, m), 1,69 (2H, d, J=12 Hz), of 1.36 (2H, kV, J=12 Hz).

(Example 9)

[({2-[(1-{4'-[2-(Dimethylamino)-2-oxoethyl]biphenyl-4-yl}piperidine-4-yl)methyl]-5-methoxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 43]

(1) 2-(4'-Bromodiphenyl-4-yl)-N,N-dimethylacetamide

[Chemical formula 44]

(4'-Bromodiphenyl-4-yl)acetic acid (1.0 g, 3.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol (20 ml) was added dimethylamine hydrochloride (0.42 g, 5.2 mmol), chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (1.3 g, 4.7 mmol) and N-methylmorpholin (0,95 ml, about 8.6 mmol) followed by stirring the mixture at room temperature for 18 hours. After concentrating the reaction mixture under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: dichloro methane/ethyl acetate) and the fraction corresponding to the Rf value=0,55 (dichloro methane/ethyl acetate=1/1) thin-layer chromatography, concentreren�whether under reduced pressure, while receiving specified in the header connection (0,82 g, 2.6 mmol) as a white solid (yield 75%).

1H-NMR (500 MHz, CDCl3) δ: 7,55 (2H, d, J=8 Hz), 7,51 (2H, d, J=8 Hz), 7,44 (2H, d, J=8 Hz), to 7.33 (2H, d, J=8 Hz), of 3.75 (2H, s), of 3.04 (3H, s), to 2.99 (3H, s).

(2) [({2-[(1-{4'-[2-(Dimethylamino)-2-oxoethyl]biphenyl-4-yl}piperidine-4-yl)methyl]-5-methoxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to the examples 1-(9) and 1-(11) to 1-(13), but using 2-(4'-bromodiphenyl-4-yl)-N,N-dimethylacetamide instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 11%) as a pale yellowish white solid.

MS m/z: 546 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 11,92 (1H, Shir.C) 9,39 (1H, t, J=6 Hz), 7,52 (2H, d, J=8 Hz), 7,49 (2H, d, J=8 Hz), 7,24 (2H, d, J=8 Hz ), of 6.99 (2H, d, J=8 Hz), of 4.00 (2H, d, J=6 Hz), 3,74 (2H, d, J=12 Hz), of 3.69 (2H, s), 3,01 (3H, C), 2,84 (3H, s), 2,78 (2H, d, J=7 Hz), 2,70 (2H, t, J=12 Hz), of 2.44 (3H, s), 2,15-2,04 (1H, m), by 1.68 (2H, d, J=12 Hz), to 1.37 (2H, kV, J=12 Hz).

(Example 10)

[({5-Hydroxy-2-[(1-{4-[4-(gidroximetil)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 45]

(1) 1-Bromo-4-{4-[(methoxyethoxy)methyl]benzyl}benzene

[Chemical formula 46]

[4-(4-Bromobenzyl)phenyl]methanol (2.7 g, 9.6 mmol) was dissolved in tetrahydrofuran (50 ml) and at 0°C was added Ki�Reid sodium (55%, 0.50 g, 12 mmol) followed by stirring at the same temperature for 30 minutes in a nitrogen atmosphere. To the reaction solution at 0°C was dropwise added a solution of chloromethylation simple ether (1.0 g, 13 mmol) in tetrahydrofuran (10 ml) followed by stirring at room temperature for 4 hours. To the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction with its ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,55 (hexane/ethyl acetate=4/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (2.5 g, 7.8 mmol) as a colorless oil (yield 81%).

1H-NMR (500 MHz, CDCl3) δ: 7,39 (2H, d, J=8 Hz), 7,28 (2H, d, J=8 Hz), 7,15 (2H, d, J=8 Hz), to 7.04 (2H, d, J=8 Hz), 4,70 (2H, s), 4,56 (2H, s), 3,92 (2H, s) to 3.41 (3H, s).

(2) Ethyl{[(5-Hydroxy-2-{[1-{4-{4-[(methoxyethoxy)methyl]benzyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetate

[Chemical formula 47]

According to the examples 1-(9), 1-(11) and 1-(12), but using 1-bromo-4-{4-[(methoxyethoxy)IU�yl]benzyl}benzene instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane, specified in the title compound was obtained (yield 33%) as a yellow oil.

1H-NMR (500 MHz, CDCl3) δ: 11,36 (1H, s), 8,49 (1H, t, J=5 Hz), 7,28-7.23 percent (2H, m), made 7.16 interest (2H, d, J=8 Hz), to 7.04 (2H, d, J=7 Hz), 6,86 (2H, d, J=7 Hz), 4,69 (2H, s), 4,55 (2H, s), 4,28 (2H, kV, J=7 Hz), 4,22 (2H, d, J=5 Hz), 3,89 (2H, s), 3,61 (2H, d, J=12 Hz), 3,40 (3H, s), 2,82 (2H, d, J=7 Hz), of 2.66 (2H, t, J=12 Hz), 2,53 (3H, C), 2,05-of 1.98 (1H, m), of 1.75 (2H, d, J=12 Hz), 1,54-of 1.44 (2H, m), 1,32 (3H, t, J=7 Hz).

(3) Ethyl-[({2-[(1-{4-[4-(acetoxymethyl)benzyl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate

[Chemical formula 48]

Ethyl-{[(5-hydroxy-2-{[1-{4-{4-[(methoxyethoxy)methyl]benzyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetate (1.1 g, 1.9 mmol) was dissolved in ethyl acetate (14 ml) at room temperature was added a solution of hydrogen chloride in dioxane (4 M, 7 ml, 28 mmol) followed by stirring at the same temperature for 12 hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate and then the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,60 (hexane/ethyl acetate=1/1) thin�layer chromatography, concentrated under reduced pressure, while receiving specified in the title compound (0.74 g, 1.3 mmol) as a yellow oil (yield 69%).

1H-NMR (500 MHz, CDCl3) δ: to 11.35 (1H, s), 8.48 to (1H, t, J=5 Hz), 7,28-7.23 percent (2H, m), 7,17 (2H, d, J=7 Hz), to 7.04 (2H, d, J=7 Hz), 6,86 (2H, d, J=7 Hz), of 5.06 (2H, s), 4,28 (2H, kV, J=7 Hz), 4,22 (2H, d, J=5 Hz), 3,89 (2H, s), 3,61 (2H, d, J=12 Hz), 2,82 (2H, d, J=7 Hz), of 2.66 (2H, t, J=12 Hz), 2,53 (3H, s), of 2.08 (3H, s), 2,05-of 1.97 (1H, m), 1,77-1,70 (2H, m), 1,54-of 1.46 (2H, m), 1,32 (3H, t, J=7 Hz).

(4) [({5-Hydroxy-2-[(1-{4-[4-(gidroximetil)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to example 1-(13), but using ethyl-[({2-[(1-{4-[4-(acetoxymethyl)benzyl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate instead of ethyl({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate specified in the header connection receive (yield 61%) as a yellow solid.

MS m/z: 505 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 11,90 (1H, s), at 9.38 (1H, t, J=6 Hz), 7,20 (2H, d, J=7 Hz), 7,13 (2H, d, J=7 Hz), 7,02 (2H, d, J=8 Hz), about 6,82 (2H, d, J=8 Hz), 5,08 (1H, t, J=6 Hz), 4,42 (2H, d, J=6 Hz), of 4.00 (2H, d, J=6 Hz), with 3.79 (2H, s), 3,58 (2H, d, J=12 Hz), to 2.76 (2H, d, J=7 Hz), 2,58 (2H, t, J=12 Hz), 2,43 (3H, s) 2,03 (1H, Shir.(C), of 1.65 (2H, d, J=12 Hz), 1,38-of 1.29 (2H, m).

(Example 11)

[({5-Hydroxy-2-[(1-{4-[3-(gidroximetil)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid/p>

[Chemical formula 49]

(1) [3-(4-Bromobenzyl)phenyl]methanol

[Chemical formula 50]

4-Bromobenzylamine (6.1 g, 22 mmol) and [3-(gidroximetil)phenyl]Bronevoy acid (3.0 g, 20 mmol) was dissolved in a mixed solvent of toluene (40 ml), ethanol (30 ml) and water (20 ml) in a nitrogen atmosphere was added tetrakis(triphenylphosphine)palladium (1.1 g, 1.0 mmol) and sodium carbonate (4.2 g, 40 mmol) followed by heating the mixture to boiling with reflux for 6 hours. To the reaction solution was added water, followed by its extraction with ethyl acetate and then the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,75 (hexane/ethyl acetate=1/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (4.7 g, 17 mmol) as a yellow oil (yield 85%).

1H-NMR (500 MHz, CDCl3) δ: 7,40 (2H, d, J=8 Hz), 7,29 (1H, t, J=8 Hz), 7,22 (1H, d, J=8 Hz), 7,17 (1H, s), 7,10 (1H, d, J=8 Hz), 7,06 (2H, d, J=8 Hz), of 4.66 (2H, s), 3,93 (2H, s), of 1.65 (1H, Shir.C).

(2) 1-Bromo-4-{3-[(methoxyethoxy)methyl]benzyl}benzene

[Chemical formula 51]

img src="https://img.russianpatents.com/1205/12052132-s.jpg" height="8" width="36" />

According to the example 10-(1), but using [3-(4-bromobenzyl)phenyl]methanol instead of [4-(4-bromobenzyl)phenyl]methanol specified in the title compound (yield 65%) was obtained as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: 7,40 (2H, d, J=7 Hz), 7,28 (1H, t, J=7 Hz), 7,21 (1H, d, J=7 Hz), made 7.16 interest (1H, s), was 7.08 (1H, d, J=7 Hz), 7,06 (2H, d, J=7 Hz), 4,70 (2H, s), 4,56 (2H, s), 3,93 (2H, s), 3,40 (3H, s).

(3) [({5-Hydroxy-2-[(1-{4-[3-(gidroximetil)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to the examples 1-(9), 1-(11), 1-(12), 1-(10) and 1-(13), but using 1-bromo-4-{3-[(methoxyethoxy)methyl]benzyl}benzene instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 23%) as a yellow solid.

MS m/z: 505 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,89 (1H, Shir.C) 11,91 (1H, s), 9,41 (1H, t, J=6 Hz), 7,21 (1H, t, J=7 Hz), 7,14 (1H, s), 7,10 (1H, d, J=7 Hz), 7,06 (1H, d, J=7 Hz), 7,05-7,00 (2H, m), 6,87-of 6.79 (2H, m), 5,14 (1H, Shir.(C), of 4.44 (2H, s), of 4.00 (2H, d, J=6 Hz), 3,80 (2H, Shir.C) 3,58 (2H, d, J=12 Hz), to 2.76 (2H, d, J=7 Hz), 2,64-of 2.54 (2H, m), 2,43 (3H, s), 2,04 (1H, Shir.C), 1,70-to 1.61 (2H, m), 1,40-of 1.29 (2H, m).

(Example 12)

[({5-Hydroxy-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 52]

(1) 2-(4-Bromophenyl)-5-[1-(methoxyethoxy)ethyl]pyridine

[Chemical formula 53]

6-(4-Bromophenyl)nicotinamidase (3.2 g, 12 mmol) was dissolved in tetrahydrofuran (50 ml) and, dropwise, at -78°C in an atmosphere of nitrogen was added a solution of metallice in simple diethyl ether (1.0 M, 15 ml, 15 mmol) followed by stirring at the same temperature for 1 hour. To the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction of the mixture with ethyl acetate and then the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,30 (hexane/ethyl acetate=2/1), thin layer chromatography was concentrated under reduced pressure, obtaining 1-[6-(4-bromophenyl)pyridin-3-yl]ethanol (2.0 g, 7.2 mmol) as a white solid (yield 59%).

According to the example 10-(1), but using 1-[6-(4-bromophenyl)pyridin-3-yl]ethanol (2.0 g, 7.2 mmol) instead of [4-(4-bromobenzyl)phenyl]methanol specified in the title compound was obtained (1.8 g, 5.6 mmol) as pale-yellow solids (yield 78%).

1H-NMR (500 MHz, CDCl3) δ: 8,64 (1H, C) a 7.87 (2H, d, J=9 Hz), 7,76 (1H, d, J=8 Hz), of 7.70 (1H, d, J=8 Hz), 7,60 (2H, d, J=9 Hz), 4,84 (1H, square, J=6 Hz), a 4.64 (1H, d, J=7 Hz), 4,58 (1H, d, J=7 Hz), to 3.38 (3H, C), A 1.54 (3H, d, J=6 Hz)

(2) Benzyl-({[5-(benzyloxy)-2-{[1-(4-{5-[1-(methoxyethoxy)ethyl]pyridin-2-yl}Fe�yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 54]

According to example 1-(9), but using 2-(4-bromophenyl)-5-[1-(methoxyethoxy)ethyl]pyridine instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane, tert-butyl-5-(benzyloxy)-2-{[1-(4-{5-[1-(methoxyethoxy)ethyl]pyridin-2-yl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate was obtained as yellow oil (yield 45%).

According to example 1-(11), but with the use of a p-toluensulfonate benzyl ester of glycine hydrochloride instead of ethyl ester of glycine and tert-butyl-5-(benzyloxy)-2-{[1-(4-{5-[1-(methoxyethoxy)ethyl]pyridin-2-yl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate instead of tert-butyl-5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate, specified in the title compound was obtained (quantitative yield) as a yellow oil.

1H-NMR (500 MHz, CDCl3) δ: 8,58 (1H, s), of 8.39 (1H, t, J=5 Hz), 7,91 (2H, d, J=9 Hz), 7,69-of 7.64 (2H, m), of 7.48 (2H, d, J=7 Hz), 7,40-7,22 (8H, m), 7,00 (2H, d, J=9 Hz), 5,24 (2H, s), 5,11 (2H, s), to 4.81 (1H, kV, J=7 Hz), 4,62 (1H, d, J=7 Hz), 4,58 (1H, d, J=7 Hz), 4,30 (2H, d, J=5 Hz), 3,80 (2H, d, J=12 Hz), to 3.38 (3H, s), is 2.88 (2H, d, J=7 Hz), 2,80 (2H, t, J=12 Hz), 2,47 (3H, s), 2,18-of 2.08 (1H, m), 1,78 (2H, d, J=12 Hz), 1,55-of 1.48 (2H, m), of 1.52 (3H, d, J=7 Hz).

(3) Benzyl-[({5-(benzyloxy)-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate

[Chemical formula 55]

Benzyl-({[5-(benzyloxy)-2-{[1-(4-{5-[1-(methoxyethoxy)ethyl]pyridin-2-yl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.80 g, 1.1 mmol) was dissolved in ethyl acetate (6 ml) was added a solution of hydrogen chloride in dioxane (4 M, 1.5 ml, 6.0 mmol) followed by stirring at room temperature for 1.5 hours. After adding to the reaction solution of hexane precipitated solid substance was collected by filtration using hexane. Thereto was added saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate and then the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,30 (hexane/ethyl acetate=1/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0.32, 0.49 mmol) as a yellow solid (yield 44%).

MS m/z 686 (M+H)+.

(4) [({5-Hydroxy-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

Benzyl-[({5-benzyloxy-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.10 g, 0.16 mmol) dissolve�Yali in ethyl acetate (30 ml) was added 10% palladium on charcoal (0.25 g) followed by stirring at room temperature for 9 hours under a hydrogen atmosphere. After filtering the reaction solution through celite, the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: ethyl acetate/methanol) and the fraction corresponding to the Rf value=0,10 (ethyl acetate/methanol=4/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0.045 g, 0,089 mmol) as a yellow solid (yield 56%).

MS m/z: 506 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: of 9.42 (1H, t, J=5 Hz), 9,06 (1H, s), 8,23 (1H, d, J=8 Hz), and 8.04 (2H, d, J=8 Hz), 7,98 (1H, d, J=8 Hz), to 7.04 (2H, d, J=8 Hz), 4,35 (1H, q, J=7 Hz), of 4.00 (2H, d, J=5 Hz), 3,88 (2H, d, J=13 Hz), 2,83-of 2.77 (4H, m), of 2.44 (3H, s), 2,20-2,17 (1H, m), by 1.68 (2H, d, J=13 Hz), to 1.38 (3H, d, J=7 Hz), of 1.36 and 1.33 (2H, m).

(Example 13)

{[(5-Hydroxy-2-{[1-(4-{5-[1-(methoxyethoxy)ethyl]pyridin-2-yl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

[Chemical formula 56]

According to example 12-(4), but with the use of benzyl-({[5-(benzyloxy)-2-{[1-(4-{5-[1-(methoxyethoxy)ethyl]pyridin-2-yl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate obtained in example 12-(2) instead of benzyl-[({5-(benzyloxy)-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate specified in segaloviciene was obtained as a pale brown solid (yield 39%).

MS m/z: 550 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: of 9.23 (1H, Shir.C) 8,52 (1H, d, J=2 Hz), of 7.93 (2H, d, J=8 Hz), 7,82 (1H, d, J=8 Hz), 7,74 (1H, DD, J=8 Hz, 2 Hz), 7,00 (2H, d, J=8 Hz), 4,76 (1H, q, J=7 Hz), USD 4.61 (1H, d, J=7 Hz), 4,50 (1H, d, J=7 Hz), 3,84-to 3.76 (4H, m), of 3.25 (3H, s), 2,78-of 2.72 (4H, m), 2,43 (3H, s), 2,13-2,05 (1H, m), 1,69 (2H, d, J=12 Hz), of 1.44 (3H, d, J=7 Hz), 1,40-of 1.30 (2H, m).

(Example 14)

[({2-[(1-{4-[5-(1-Acetoxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 57]

(1) Benzyl-[({2-[(1-{4-[5-(1-acetoxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-(benzyloxy)-6-methylpyrimidin-4-yl}carbonyl)amino]acetate

[Chemical formula 58]

Benzyl-[({5-(benzyloxy)-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.24 g, 0.35 mmol) obtained in example 12-(3), was dissolved in dichloromethane (30 ml) and added acetic anhydride (0,050 ml, 0.52 mmol) and triethylamine (1.8 ml) followed by stirring at room temperature for 12 hours. To the reaction solution was added acetic anhydride (1.8 ml) and pyridine (0.90 ml) followed by stirring for additional 12 hours and then was added a saturated aqueous solution of sodium bicarbonate, followed by extraction of the mixture with ethyl acetate. After concentrating organicheskoj� layer under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,40 (hexane/ethyl acetate=1/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0.12 g, 0.17 mmol) as a yellow oil (yield 48%).

1H-NMR (500 MHz, CDCl3) δ: 8,62 (1H, with), to 8.38 (1H, t, J=5 Hz), 7,90 (2H, d, J=9 Hz), to 7.68-7,63 (2H, m), of 7.48 (2H, d, J=7 Hz), 7,40-7,21 (8H, m), 7,00 (2H, d, J=9 Hz), of 5.92 (1H, square, J=6 Hz), 5,24 (2H, s), 5,11 (2H, C), 4,30 (2H, d, J=5 Hz), 3,80 (2H, d, J=13 Hz), is 2.88 (2H, d, J=7 Hz), of 2.81 (2H, t, J=13 Hz), 2,47 (3H, s), 2,16-2,05 (1H, m), is 2.09 (3H, C), 1,78 (2H, d, J=13 Hz), 1,58 (3H, d, J=6 Hz), 1,57-of 1.48 (2H, m).

(2) [({2-[(1-{4-[5-(1-Acetoxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to example 12-(4), but using benzyl-[({2-[(1-{4-[5-(1-acetoxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-(benzyloxy)-6-methylpyrimidin-4-yl}carbonyl)amino]acetate instead of benzyl-[({5-(benzyloxy)-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate specified in the title compound was obtained (yield 98%) as pale-yellow solids.

MS m/z: 548 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 9,40 (1H, t, J=6 Hz), to 8.57 (1H, d, J=2 Hz), of 7.93 (2H, d, J=9 Hz), 7,82 (1H, d, J=8 Hz), 7,78 (1H, DD, J=8 Hz, 2 Hz), 7,00 (2H, d, J=9 Hz), of 5.83 (1H, square, J=6 Hz), 3,98 (2H, d, J=6 Hz), 3,81 (2H, d, J=12 Hz), 2,79-to 2.73 (4H, m), of 2.44 (3H, s), 2,16-of 2.08 (1H, m), is 2.05(3H, (C), by 1.68 (2H, d, J=12 Hz), of 1.52 (3H, d, J=6 Hz), 1,40-of 1.30 (2H, m).

(Example 15)

[({5-Hydroxy-2-[(1-{4-[5-(gidroximetil)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 59]

(1) 2-(4-Bromophenyl)-5-[(methoxyethoxy)methyl]pyridin

[Chemical formula 60]

According to example 11-(1) but using (6-bromopyridin-3-yl)methanol instead of 4-bromobenzylamine and 4-brompheniramine acid instead of [3-(gidroximetil)phenyl]Bronevoy acid, [6-(4-bromophenyl)pyridin-3-yl]methanol was obtained as white solid (yield 51%).

According to the example 10-(1), but using [6-(4-bromophenyl)pyridin-3-yl]methanol instead of [4-(4-bromobenzyl)phenyl]methanol specified in the title compound was obtained (quantitative yield) as a white solid.

1H-NMR (500 MHz, CDCl3) δ: 8.66 roubles (1H, s), of 7.88 (2H, d, J=8 Hz), to 7.77 (1H, d, J=8 Hz), of 7.70 (1H, d, J=8 Hz), 7,60 (2H, d, J=8 Hz), 4,74 (2H, C), a 4.65 (2H, s), 3.43 points (3H, s).

(2) Ethyl{[(5-hydroxy-2-{[1-(4-{5-[(methoxyethoxy)methyl]pyridin-2-yl}phenyl)pyridin-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetate

[Chemical formula 61]

According to the examples 1-(9), 1-(11) and 1-(12), but using 2-(4-bromophenyl)-5-[(methoxyethoxy)methyl]pyridine instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 22%) as a white solid.

MS m/z: 564 (M++ N);

1H-NMR (500 MHz, CDCl3) δ: at 11.37 (1H, s), at 8.60 (1H, s), and 8.50 (1H, t, J=5 Hz), 7,90 (2H, d, J=8 Hz), of 7.70 (1H, d, J=8 Hz), 7,65 (1H, d, J=8 Hz), 7,00 (2H, d, J=8 Hz), 4,73 (2H, s), 4,62 (2H, s), 4,28 (2H, kV, J=7 Hz), 4,22 (2H, d, J=5 Hz), with 3.79 (2H, d, J=12 Hz), 3,42 (3H, s), 2,84-of 2.77 (4H, m), of 2.54 (3H, s), 2,13-2,07 (1H, m), 1,78 (2H, d, J=12 Hz), 1,54-of 1.46 (2H, m), of 1.33 (3H, t, J=7 Hz).

(3) [({5-Hydroxy-2-[(1-{4-[5-(gidroximetil)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to the examples 12 to(3) and 1-(13), but using ethyl{[(5-hydroxy-2-{[1-(4-{5-(methoxyethoxy)methyl]pyridin-2-yl}phenyl)piperidine-4-yl]methyl)-6-methylpyrimidin-4-yl)carbonyl]amino}acetate instead of benzyl-({[5-(benzyloxy)-2-{[1-(4-{5-[1-(methoxyethoxy)ethyl]pyridin-2-yl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate specified in the title compound was obtained (yield 87%) as a yellow solid.

MS m/z: 492 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 9,39 (1H, t, J=5 Hz), and 8.50 (1H, s), 7,92 (2H, d, J=8 Hz), 7,80 (1H, d, J=8 Hz), 7,71 (1H, d, J=8 Hz), 7,00 (2H, d, J=8 Hz), 5,28 (1H, t, J=5 Hz), 4,52 (2H, d, J=5 Hz), 3,98 (2H, d, J=5 Hz), 3,80 (2H, d, J=13 Hz), 2,79-of 2.72 (4H, m), of 2.44 (3H, s), 2,17-2,07 (1H, m), by 1.68 (2H, d, J=13 Hz), 1,40-of 1.30 (2H, m).

(Example 16)

[({2-[(1-{4-[5-(Ethoxycarbonyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 62]

(1) Ethyl 6-(4-bromophenyl)nicotine�

[Chemical formula 63]

According to example 11-(1) but using ethyl-6-bromonicotinate instead of 4-bromobenzylamine and 4-brompheniramine acid instead of [3-(gidroximetil)phenyl]Bronevoy acid specified in the title compound was obtained (yield 98%) as a white solid.

1H-NMR (500 MHz, CDCl3) δ: 9,28 (1H, C) to 8.36 (1H, d, J=8 Hz), 7,96 (2H, d, J=8 Hz), 7,80 (1H, d, J=8 Hz), of 7.64 (2H, d, J=8 Hz), of 4.44 (2H, kV, J=7 Hz), of 1.43 (3H, t, J=7 Hz).

(2) tert-Butyl-5-(benzyloxy)-2-[(1-{4-[5-(ethoxycarbonyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-carboxylate

[Chemical formula 64]

According to example 1-(9), but using ethyl-6-(4-bromophenyl)nicotinate instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 23%) as a yellow oil.

1H-NMR (500 MHz, CDCl3) δ: 9,21 (1H, C), compared to 8.26 (1H, d, J=8 Hz), 7,99 (2H, d, J=8 Hz), 7,72 (1H, d, J=8 Hz), 7,43-7,38 (5H, m), 7,00 (2H, d, J=8 Hz), 5,01 (2H, s), 4,42 (2H, square, J=7 Hz), 3,83 (2H, d, J=12 Hz), 2,91-of 2.81 (4H, m), 2,46 (3H, C), 2,20-2,12 (1H, m), of 1.80 (2H, d, J=12 Hz), 1,59 (9H, s), 1,57-of 1.48 (2H, m) of 1.42 (3H, t, J=7 Hz).

(3) Ethyl-6-{4-[4-({4-[(2-tert-butoxy-2-oxoethyl)carbamoyl]-5-hydroxy-6-methylpyrimidin-2-yl}methyl)piperidine-1-yl]phenyl}nicotinate

[Chemical formula 65]

tert-Butyl-5-(benzyloxy)-2-[(1-{4-[5-(ethoxycarbonyl)pyridin-2-yl]phenyl}p�of peridin-4-yl)methyl]-6-methylpyrimidin-4-carboxylate (0.25 g, 0,40 mmol) was dissolved in dichloromethane (5 ml) and added trifluoroacetic acid (10 ml) followed by stirring the mixture at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and was added saturated aqueous sodium bicarbonate solution, followed by extraction of the mixture with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled under reduced pressure, while receiving 2-[(1-{4-[5-(ethoxycarbonyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-carboxylic acid.

This acid was dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol (20 ml) was added hydrochloride tert-butyl ester of glycine (0.13 g, 0,80 mmol), chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-ml-4-methylmorpholine (0.22 g, 0,80 mmol) and N-methylmorpholin (0,40 ml, 4.0 mmol) followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and added ethyl acetate and then the organic layer was washed with water. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,70 (hexane/ethyl acetate=1/1) thin-layer Chr�matography, concentrated under reduced pressure, while receiving specified in the header connection (0,043 g, 0,073 mmol) as a yellow solid (yield 18%).

1H-NMR (500 MHz, CDCl3) δ: of 11.45 (1H, s) 9,21 (1H, s), is 8.46 (1H, t, J=5 Hz), 8,29-8,23 (1H, m), 7,99 (2H, d, J=7 Hz), 7,74-to 7.68 (1H, m), of 6.99 (2H, d, J=7 Hz), 4,42 (2H, square, J=7 Hz), of 4.12 (2H, d, J=5 Hz), 3,84 (2H, d, J=13 Hz), 2,89-to 2.79 (4H, m), of 2.54 (3H, s), 2,15-of 2.08 (1H, m), 1,86-of 1.45 (4H, m), of 1.52 (9H, s), of 1.42 (3H, t, J=7 Hz).

(4) [({2-[(1-{4-[5-(Ethoxycarbonyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

Ethyl-6-{4-[4-({4-[(2-tert-butoxy-2-oxoethyl)carbamoyl]-5-hydroxy-6-methylpyrimidin-2-yl}methyl)piperidine-1-yl]phenyl}nicotinate (0,043 g, 0,073 mmol) was dissolved in dichloromethane (5 ml) at room temperature was added trifluoroacetic acid (5 ml) followed by stirring for 12 hours. To the reaction solution was added hydrochloric acid (1 M), followed by its extraction with ethyl acetate and then the organic layer was concentrated under reduced pressure. After purification of the resulting residue by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: ethyl acetate/methanol), the fraction corresponding to the Rf value=0,10 (ethyl acetate/methanol=4/1) thin-layer chromatography was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, followed�m adding diisopropyl simple ether and then precipitated solid was collected by filtration with the use of simple diisopropyl ether, while receiving specified in the header connection (0,020 g, 0,037 mmol) as pale-yellow solids (yield 51%).

MS m/z: 534 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 9,36 (1H, Shir.C), 9,06 (1H, d, J=2 Hz), 8,23 (1H, DD, J=8 Hz, 2 Hz), and 8.04 (2H, d, J=9 Hz), 7,99 (1H, d, J=8 Hz), to 7.04 (2H, d, J=9 Hz), 4,35 (2H, kV, J=7 Hz), 3,93 (2H, Shir. C), 3,88 (2H, d, J=12 Hz), 2,83-of 2.77 (4H, m), of 2.45 (3H, s), 2,19-2,11 (1H, m), 1,70 (2H, d, J=12 Hz), 1,39-of 1.30 (2H, m), of 1.35 (3H, t, J=7 Hz).

(Example 17)

[({2-[(1-{4-[2-(Ethoxycarbonyl)benzyl]phenyl}piperidine-4-yl)-methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)-amino] - acetic acid

[Chemical formula 66]

(1) Ethyl-2-(4-bromobenzyl)benzoate

[Chemical formula 67]

According to example 11-(1), but using [2-(ethoxycarbonyl)phenyl]Bronevoy acid instead of [3-(gidroximetil)phenyl]Bronevoy acid specified in the title compound was obtained (yield 78%) as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: 7,92 (1H, d, J=8 Hz), 7,44 (1H, t, J=8 Hz), value of 7, 37 (2H, d, J=8 Hz), 7,31 (1H, t, J=8 Hz), 7,20 (1H, d, J=8 Hz), 7,02 (2H, d, J=8 Hz), 4,33 (2H, s), 4,28 (2H, kV, J=7 Hz), is 1.31 (3H, t, J=7 Hz).

(2) Hydrochloride tert-butyl-({[5-(benzyloxy)-6-methyl-2-(piperidine-4-ylmethyl)pyrimidine-4-yl]carbonyl}amino)acetate

[Chemical formula 68]

According to the examples 1-(11) and 1-(7), but using tert-butyl-5-(benzyloxy)-2-{[1-(tert-butoxycarbonyl)PI�uridin-4-yl]methyl}-6-methylpyrimidin-4-carboxylate, obtained in example 1-(6) instead of tert-butyl-5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate hydrochloride and tert-butyl ester of glycine hydrochloride instead of ethyl ester of glycine, specified in the title compound was obtained (yield 72) as a white solid.

1H-NMR (500 MHz, CD3OD) δ: of 7.46-7,45 (2H, m), of 7.36-of 7.35 (3H, m), 5,11 (2H, s), of 4.05 (2H, s), 3,38 (2H, d, J=13 Hz), 2,99 (2H, t, J=13 Hz), 2,90 (2H, d, J=7 Hz), of 2.45 (3H, s), 2,36-of 2.27 (1H, m), of 1.92 (2H, d, J=13 Hz), 1,56-of 1.49 (2H, m), 1,49 (9H, s).

(3) Ethyl-2-{4-[4-({5-(benzyloxy)-4-[(2-tert-butoxy-2-oxoethyl)carbamoyl]-6-methylpyrimidin-2-yl}methyl)piperidine-1-yl]benzyl}benzoate

[Chemical formula 69]

According to example 1-(9), but with the use of hydrochloride tert-butyl-({[5-(benzyloxy)-6-methyl-2-(piperidine-4-ylmethyl)pyrimidine-4-yl]carbonyl}amino)acetate hydrochloride instead of tert-butyl-5-(benzyloxy)-6-methyl-2-(piperidine-4-ylmethyl)pyrimidine-4-carboxylate and ethyl-2-(4-bromobenzyl)benzoate instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 72%) as a white solid.

MS m/z: 693 (M+H)+.

(4) [({2-[(1-{4-[2-(Ethoxycarbonyl)benzyl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to example 16(4), but using ethyl-2-{4-[4-({5-(benzy�oxy)-4-[(2-tert-butoxy-2-oxoethyl)carbamoyl]-6-methylpyrimidin-2-yl}methyl)piperidine-1-yl]benzyl}benzoate instead of ethyl-6-{4-[4-({4-[(2-tert-butoxy-2-oxoethyl)carbamoyl]-5-hydroxy-6-methylpyrimidin-2-yl}methyl)piperidine-1-yl]phenyl}nicotinate, specified in the title compound was obtained (yield 12%) as a yellow solid.

MS m/z: 547 (M+H)+;

1H-NMR (500 MHz, CD3OD) δ: 7,82 (1H, d, J=8 Hz), of 7.46 (1H, t, J=8 Hz), 7,30 (1H, t, J=8 Hz), 7,27 (1H, d, J=8 Hz), 7,07 (4H, br.C), 4,30 (2H, s), 4,24 (2H, kV, J=7 Hz), of 4.05 (2H, s), 3,58 (2H, d, J=12 Hz), 2,90 (2H, t, J=12 Hz), 2,84 (2H, d, J=7 Hz), 2.49 USD (3H, s), 2,21-2,12 (1H, m), equal to 1.82 (2H, d, J=12 Hz), 1,62-of 1.53 (2H, m), of 1.27 (3H, t, J=7 Hz).

(Example 18)

{[(5-Hydroxy-2-{[1-(4-{[6-(2-hydroxyethoxy)pyridin-3-yl]methyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

[Chemical formula 70]

(1) N,6-Dimethoxy-N-methyl nicotine amide

[Chemical formula 71]

According to the example 5-(1), but with the use of 6-methoxynicotinic acid instead of (4'-bromodiphenyl-4-yl)acetic acid specified in the title compound was obtained (yield 92%) as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: 8,65 (1H, s), 8,00 (1H, d, J=9 Hz), 6,76 (1H, d, J=9 Hz), 3,99 (3H, C), 3,58 (3H, s), to 3.38 (3H, s).

(2) (4-Bromophenyl)(6-methoxypyridine-3-yl)methanon

[Chemical formula 72]

1,4-Dibromobenzyl (6.5 g, 27 mmol) was dissolved in tetrahydrofuran (120 ml) and at -78°C was added a solution of n-utility in hexane (2.6 M, 10 ml, 27 mmol) followed by stirring at the same temperature for 30 minutes. To the reaction solution was added a solution of N-dimethoxy-N-methyl nicotine amid (2.7 g, 14 mmol) in tetrahydrofuran (20 ml) followed by stirring at -78°C for an additional 30 minutes. To the reaction solution was added water, followed by extraction of the solution with ethyl acetate and then the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0.50 (a hexane/ethyl acetate=10/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (2.8 g, 9.4 mmol) as a white solid (yield 69%).

1H-NMR (500 MHz, CDCl3) δ: 8,59 (1H, s), 8,07 (1H, d, J=8 Hz), 7,66 (4H, s), of 6.85 (1H, d, J=8 Hz), 4,03 (3H, s).

(3) 2-{[5-(4-Bromobenzyl)pyridin-2-yl]oxy}ethanol

[Chemical formula 73]

(4-Bromophenyl))6-methoxypyridine-3-yl)methanon (0.88 g, 3.0 mmol), hydrazine monohydrate (1.5 ml, 30 mmol) and potassium hydroxide (0,60 g, 12 mmol) was dissolved in ethylene glycol (10 ml) followed by stirring the solution at 140°C for 20 minutes. After cooling the reaction solution to room temperature, water was added, followed by extraction with diethyl simple ether. After concentrating the organic layer under reduced pressure the resulting residue was purified by chromatographie� on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,30 (hexane/ethyl acetate=1/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the header connection (0,38 g, 1,2 mmol) as a colorless oil (yield 41%).

1H-NMR (500 MHz, CDCl3) δ: 7,95 (1H, s), 7,41 (2H, d, J=8 Hz), of 7.36 (1H, d, J=9 Hz), 7,03 (2H, d, J=8 Hz), 6,72 (1H, d, J=9 Hz), 4,48-4,35 (2H, m), 3,97-3,90 (2H, m), 3,85 (2H, s), 3,84-of 3.75 (1H, m).

(4) 5-(4-Bromobenzyl)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyridin

[Chemical formula 74]

According to example 1-(8), but using 2-{[5-(4-bromobenzyl)pyridin-2-yl]oxy}ethanol instead of (4'-bromodiphenyl-4-yl)methanol specified in the header connection receive (yield 77%) as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: 7,96 (1H, s), 7,40 (2H, d, J=8 Hz), 7,31 (1H, d, J=8 Hz), 7,02 (2H, d, J=8 Hz), 6,68 (1H, d, J=8 Hz), 4,37-4,32 (2H, m), 3,98 was 3.92 (2H, m), 3,83 (2H, s), to 0.89 (9H, s), of 0.07 (6H, s).

(5) Ethyl({[5-(benzyloxy)-2-{[1-(4-{[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyridin-3-yl]methyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 75]

According to the examples 1-(9) and 1-(11), but using 5-(4-bromobenzyl)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyridine instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in Zago�Ofce compound was obtained as a crude product.

MS m/z 768 (M+H)+.

(6) Ethyl({[5-(benzyloxy)-2-{[1-(4-{[6-(2-hydroxyethoxy)pyridin-3-yl]methyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 76]

The crude product ethyl-({[5-(benzyloxy)-2-{[1-(4-{[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyridin-3-yl]methyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate was dissolved in tetrahydrofuran (20 ml) and at 0°C was added a solution of fluoride of tetrabutylammonium in tetrahydrofuran (1.0 M, 1.4 ml, The 4.8 mmol) followed by stirring the mixture at the same temperature for 1 hour. To the reaction solution was added water, followed by extraction with ethyl acetate and then the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0.50 (ethyl acetate) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0.31 g, 0.47 mmol) as a yellow oil (yield 66%).

1H-NMR (500 MHz, CDCl3) δ: 8,35 (1H, t, J=5 Hz), 7,95 (1H, s), of 7.48 (1H, d, J=6 Hz), 7,43-7,32 (5H, m), 7,03 (2H, d, J=9 Hz), of 6.87 (2 H, d, J=9 Hz), 6,71 (1H, d, J=6 Hz), 5,12 (2H, s), 4,46-4,40 (2H, m), 4,27 (2H, kV, J=7 Hz), 4,25 (2H, d, J=5 Hz), 4,04-to 3.96 (1H, m), 3,97-3,90 (2H, m), 3,81 (2H, C), 363 (2H, d, J=12 Hz), 2,89 (2H, d, J=7 Hz), 2,69 (2H, t, J=12 Hz), 2,46 (3H, s), 2,11-2,04 (1H, m), of 1.76 (2H, d, J=12 Hz), of 1.53 (2H, DQC, J=12 Hz, 3 Hz), 1,32 (3H, t, J=7 Hz).

(7) {[(5-Hydroxy-2-{[1-(4-{[6-(2-hydroxyethoxy)pyridin-3-yl]methyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

According to the examples 1 to 12 and 1-(13), but using ethyl({[5-(benzyloxy)-2-{[1-(4-{[6-(2-hydroxyethoxy)pyridin-3-yl]methyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate instead of ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl-6-methylpyrimidin-4-yl]carbonyl}amino)acetate specified in the title compound was obtained (yield 50%) as a white solid.

MS m/z: 536 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,87 (1H, Shir.C) 11,90 (1H, s), 9,39 (1H, t, J=5 Hz), 8,00 (1H, s), of 7.48 (1H, d, J=8 Hz), 7,03 (2H, d, J=8 Hz), 6,83 (2H, d, J=8 Hz), 6,71 (1H, d, J=8 Hz), 4,80 (1H, Shir.C), 4,25-of 4.16 (2H, m), 4,00 (2H, d, J=5 Hz), 3,74 (2H, s), 3,72-3,63 (2H, m), 3,58 (2H, d, J=12 Hz), to 2.76 (2H, d, J=7 Hz), at 2.59 (2H, t, J=12 Hz), 2,43 (3H, s), 2,09-2,00 (1H, m), 1,64 (2H, d, J=12 Hz), of 1.33 (2H, DQC, J=12 Hz, 3 Hz).

(Example 19)

[({5-Hydroxy-2-[(1-{5-[4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 77]

(1) tert-Butyl-5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate

[Chemical formula 78]

Hydrochloride tert-butyl-5-(benzyloxy)-6-methyl-2-(piperidine-4-ylmethyl)pyrimidine-4-carboxylate (6.5 g, 15 mmol), 2,5-dibromopyridine (5.3 g, 7.5 mmol) and potassium carbonate (6.2 g, 45 mmol) was suspended in N,N-dimethylformamide (150 ml) followed by stirring the suspension at 100°C for 22 hours. The reaction solution was concentrated under reduced pressure followed by the addition of ethyl acetate and then the organic layer was washed with water. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,40 (hexane/ethyl acetate=4/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (2.3 g, 4.1 mmol) as a colorless oil (yield 27%).

1H-NMR (500 MHz, CDCl3) δ: 8,16 (1H, s), 7,49 (1H, d, J=9 Hz), 7,45-of 7.33 (5H, m), 6,55 (1H, d, J=9 Hz), 5,01 (2H, s), is 4.21 (2H, d, J=12 Hz), 2,87 (2H, t, J=7 Hz), 2,83 (2H, t, J=12 Hz), of 2.45 (3H, s), 2,24-to 2.14 (1H, m), of 1.75 (2H, d, J=12 Hz), 1,59 (9H, s), to 1.37 (2H, DQC, J=12 Hz, 3 Hz).

(2) tert-Butyl-5-(benzyloxy)-2-[(1-{5-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-carboxylate

[Chemical formula 79]

tert-Butyl-5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidine-4-yl]m�Teal}-6-methylpyrimidin-4-carboxylate (1.1 g, 2.0 mmol) was dissolved in 1,4-dioxane (20 ml) was added bis(pinacolato)diboron (0,60 g, 2,4 mmol), the complex [1,1'-bis(diphenylphosphino)ferrocene]paradigalla-dichloro methane (0.16 g, 0.20 mmol) and potassium acetate (0.59 g, 6.0 mmol) followed by heating the mixture to boiling with reflux for 21 hours. The reaction solution was cooled to room temperature and then the insoluble substance was separated by filtration through celite and the filtrate was concentrated under reduced pressure, while receiving tert-butyl-5-(benzyloxy)-6-methyl-2-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl}piperidine-4-yl)methyl]pyrimidine-4-carboxylate.

This product was dissolved in a mixed solvent of toluene (16 ml), ethanol (10 ml) and water (10 ml) was added tert-butyl-[(4-iodobenzyl)oxy]dimethylsilane (0.84 g, 2.4 mmol), tetrakis(triphenylphosphine)palladium (0.46 g, 0,40 mmol) and sodium carbonate (1.1 g, 10 mmol) followed by heating to boiling with reflux for 1 hour. After cooling the reaction solution to room temperature, water was added, followed by extraction of the mixture with ethyl acetate. After concentrating the organic layer under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to ve�icine Rf=0,40 (hexane/ethyl acetate=4/1) thin-layer chromatography, concentrated under reduced pressure, while receiving specified in the header connection (0,82 g, 1,2 mmol) as a pale yellow oil (yield 59%).

1H-NMR (500 MHz, CDCl3) δ: 8,43 (1H, s), 7,69 (1H, d, J=9 Hz), 7,49 (2H, d, J=8 Hz), 7,43-of 7.35 (5H, m), 7,41 (2H, d, J=8 Hz), 6,73 (1H, d, J=9 Hz), 5,01 (2H, s), of 4.77 (2H, s), 4,32 (2H, d, J=12 Hz), 2,87 (2H, t, J=7 Hz), 2,83 (2H, t, J=12 Hz), 2,46 (3H, s), 2.26 and-of 2.16 (1H, m), 1,78 (2H, d, J=12 Hz), to 1.60 (9H, s), 1,43 (2H, DQC, J=12 Hz, 3 Hz), of 0.96 (9H, s), of 0.12 (6H, s).

(3) [({5-Hydroxy-2-[(1-{5-[4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to the examples 1-(10) to 1-(13), but using tert-butyl-5-(benzyloxy)-2-[(1-{5-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-carboxylate instead of tert-butyl-5-(benzyloxy)-2-({1-[4'-({[tert-butyl(dimethyl)silyl]oxy}methyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate, specified in the title compound was obtained (yield 50) as a white solid.

MS m/z: 492 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 8,99 (1H, Shir.C) to 8.42 (1H, s), 7,80 (1H, d, J=9 Hz), 7,56 (2H, d, J=8 Hz), 7,35 (2H, d, J=8 Hz), 6,90 (1H, d, J=9 Hz), 5,20 (1H, Shir.C), 4,51 (2H, s), 4,32 (2H, d, J=13 Hz), 3,51 (2H, Shir.C) of 2.83 (2H, t, J=13 Hz), is 2.74 (2H, d, J=7 Hz), 2,42 (3H, s), 2,20-of 2.08 (1H, m), by 1.68 (2H, d, J=13 Hz), 1.26 in (2H, DQC, J=13 Hz, 3 Hz).

(Example 20)

[({5-Hydroxy-2-[(1-{5-[4-(2-hydroxypropyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-metile�imidan-4-yl}carbonyl)amino]acetic acid

[Chemical formula 80]

(1) 1-Bromo-4-[2-(methoxyethoxy)propyl]benzene

[Chemical formula 81]

According to example 6-(3), but using 1-(4-bromophenyl)propan-2-ol instead of 2-(4'-bromodiphenyl-4-yl)-2-methylpropan-1-ol, specified in the title compound was obtained (yield 89%) as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: 7,40 (2H, d, J=8 Hz), to 7.09 (2H, d, J=8 Hz), a 4.64 (1H, d, J=7 Hz), 4,50 (1H, d, J=7 Hz), 3,96-3,83 (1H, m), 3,18 (3H, C), 2,84-2,73 (1H, m), 2,72-2,61 (1H, m), of 1.17 (3H, d, J=6 Hz).

(2) [({5-Hydroxy-2-[(1-{5-[4-(2-hydroxypropyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to examples 19-(2) and 1-(10) to 1-(13), but using 1-bromo-4-[2-(methoxyethoxy)propyl]benzene instead of tert-butyl-[(4-iodobenzyl)oxy]dimethylsilane specified in the header connection receive (yield 11%) as a white solid.

MS m/z: 520 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 9,32 (1H, t, J=5 Hz), 8,40 (1H, s), 7,79 (1H, d, J=9 Hz), 7,50 (2H, d, J=8 Hz), 7.23 percent (2H, d, J=8 Hz), 6,89 (1H, d, J=9 Hz), 4,60 (1H, Shir.C), 4,32 (2H, d, J=12 Hz), 3,90 (2H, d, J=5 Hz), 3,86-of 3.80 (1H, m), 2,83 (2H, t, J=7 Hz), to 2.76 (2H, d, J=7 Hz), 2,71-2,63 (2H, m), of 2.44 (3H, s), 2,09-2,00 (1H, m), of 1.66 (2H, d, J=12 Hz), 1,25 (2H, DQC, J=12 Hz, 3 Hz), was 1.04 (3H, d, J=6 Hz).

(Example 21)

[({5-Hydroxy-2-[(1-{5-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]uksosn�I acid

[Chemical formula 82]

According to the examples 20-(1) and 20(2), but using 2-(4-bromophenyl)-2-methylpropan-1-ol instead of 1-(4-bromophenyl)propan-2-ol, specified in the header connection receive (yield 11%) as a white solid.

MS m/z: 534 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: of 9.42 (1H, t, J=5 Hz), 8,40 (1H, d, J=3 Hz), 7,79 (1H, DD, J=9 Hz, 3 Hz), 7,51 (2H, d, J=8 Hz), 7,40 (2H, d, J=8 Hz), 6,89 (1H, d, J=9 Hz), 4,67 (1H, Shir.C), 4,32 (2H, d, J=13 Hz), of 4.00 (2H, d, J=5 Hz), 3,42 (2H, s), 2,83 (2H, d, J=7 Hz), to 2.76 (2H, t, J=12 Hz), of 2.44 (3H, s), 2,25-2,10 (1H, m), by 1.68 (2H, d, J=12 Hz), of 1.36 (2H, DQC, J=12 Hz, 3 Hz)That is 1.23 (6H, s).

(Example 22)

({[2-({1-[2-Chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 83]

(1) (4'-Bromo-2'-chlorodiphenyl-4-yl)methanol

[Chemical formula 84]

According to the example 4-(2), but using [4-(gidroximetil)phenyl]Bronevoy acid instead of 4-brompheniramine acid and 4-bromo-2-chloro-1-odensala instead of tert-butyl-[2-(4-itfinal)ethoxy]dimethylsilane specified in the title compound was obtained (yield 12%) as a yellow solid.

1H-NMR (500 MHz, CDCl3) δ: 7,65 (1H, d, J=2 Hz), of 7.48-7,40 (5H, m), 7,21 (1H, d, J=8 Hz), of 4.77 (2H, d, J=6 Hz), 1,71 (1H, t, J=6 Hz).

(2) [(4'-Bromo-2'-chlorodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane

[Chemical�die formula 85]

According to example 1-(8), but using (4'-bromo-2'-chlorodiphenyl-4-yl)methanol instead of (4'-bromodiphenyl-4-ml)methanol specified in the title compound was obtained (yield 90%) as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: of 7.64 (1H, d, J=2 Hz), 7,45 (1H, DD, J=8 Hz, 2 Hz), 7,41-of 7.36 (4H, m), 7,21 (1H, d, J=8 Hz), 4,80 (2H, s), is 0.96 (9H, s), of 0.13 (6H, s).

(3) Ethyl({[5-(benzyloxy)-2-({1-[2-chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 86]

According to the examples 1-(9) to 1-(11), but using [(4'-bromo-2'-chlorodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 62%) as a yellow amorphous solid substance.

1H-NMR (500 MHz, CDCl3) δ: 8,37 (1H, t, J=5 Hz), 7,53-up 7.17 (10H, m), 7,00 (1H, s), to 6.88 (1H, d, J=8 Hz), 5,13 (2H, s), 4.75 in (2H, d, J=6 Hz), 4,28 (2H, kV, J=7 Hz), to 4.26 (2H, d, J=5 Hz), 3,73 (2H, d, J=12 Hz), 2,90 (2H, d, J=7 Hz), 2,80 (2H, t, J=12 Hz), 2,47 (3H, s), 2,19-of 2.08 (1H, m), to 1.79 (2H, d, J=12 Hz), 1,62-of 1.45 (2H, m), 1,32 (3H, t, J=7 Hz).

(4) Ethyl-[({2-[(1-(2-chloro-4'-[(2,2,2-triptoreline)methyl]biphenyl-4-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate

[Chemical formula 87]

Ethyl({[5-(benzyloxy)-2-({1-[2-chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}IU�yl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.96 g, 1.5 mmol) was dissolved in dichloromethane (20 ml) and under an atmosphere of nitrogen was added trifluoroacetic acid (20 ml) followed by stirring at room temperature for 7 hours. To the reaction solution for neutralization was added aqueous sodium hydrogencarbonate solution, followed by extraction with a mixture of dichloromethane and then the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: dichloro methane/ethyl acetate) and the fraction corresponding to the Rf value=0,80 (dichloro methane/ethyl acetate = 4/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0.74 g, 1.3 mmol) as a yellow oil (yield 90%).

1H-NMR (500 MHz, CDCl3) δ: is 11.39 (1H, s), and 8.50 (1H, t, J=5 Hz), of 7.48 (2H, d, J=8 Hz), the 7.43 (2H, d, J=8 Hz), 7,20 (1H, d, J=9 Hz), of 6.99 (1H, s), 6,87 (1H, d, J=9 Hz), of 5.40 (2H, s), 4,29 (2H, kV, J=7 Hz), to 4.23 (2H, d, J=5 Hz), 3,73 (2H, d, J=12 Hz), 2,84 (2H, d, J=7 Hz), 2,79 (2H, t, J=12 Hz), by 2.55 (3H, s), 2,14-2,04 (1H, m), 1,78 (2H, d, J=12 Hz), 1,49 (2H, kV, J=12 Hz), of 1.33 (3H, t, J=7 Hz).

(5) ({[2-({1-[2-Chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to example 1-(13), but using ethyl-[({2-[(1-{2-chloro-4'-[(2,2,2-triptoreline)methyl]biphenyl-4-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}car�o'neill)amino]acetate instead of ethyl({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate, specified in the title compound was obtained (yield 55%) as a white solid.

MS m/z: 525 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 9,34 (1H, t, J=5 Hz), value of 7, 37-7,32 (4H, m), 7,20 (1H, d, J=9 Hz), 7,01 (1H, s), 6,97 (1H, d, J=9 Hz), with 5.22 (1H, Shir.C), a 4.53 (2H, s), 3,92 (2H, d, J=5 Hz), 3,76 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), is 2.74 (2H, t, J=12 Hz), of 2.44 (3H, s), 2,15-2,05 (1H, m), by 1.68 (2H, d, J=12 Hz), of 1.34 (2H, kV, J=12 Hz).

(Example 23)

({[5-Hydroxy-2-({1-[4'-(gidroximetil)-2-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 88]

(1) (4'-Bromo-2'-methylbiphenyl-4-yl)methanol

[Chemical formula 89]

According to the example 4-(2), but using [4-(gidroximetil)phenyl]Bronevoy acid instead of (4-(bromophenyl)Bronevoy acid and 4-bromo-1-iodo-2-methylbenzene instead of tert-butyl-[2-(4-itfinal)ethoxy]dimethylsilane specified in the title compound was obtained (yield of 7.1%) as a yellow oil.

1H-NMR (500 MHz, CDCl3) δ: 7,45-7,41 (3H, m), value of 7, 37 (1H, d, J=8 Hz), 7,29 (2H, d, J=8 Hz), to 7.09 (1H, d, J=8 Hz), of 4.77 (2H, d, J=6 Hz), 2,24 (3H, s), of 1.70 (1H, t, J=6 Hz).

(2) [(4'-Bromo-2'-methylbiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane

[Chemical formula 90]

According to example 1-(8), but using (4'-bromo-2'-methylbiphenyl-4-yl)methanol instead of (4'-bromodiphenyl-4-yl)methanol specified in the title compound �was lucali (yield 89%) as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: of 7.42 (1H, s), 7,39-7,34 (3H, m), 7,25 (2H, d, J=8 Hz), to 7.09 (1H, d, J=8 Hz), 4,79 (2H, s), 2,24 (3H, s), 0.9 to 7 (9H, s), of 0.13 (6H, s).

(3) ({[5-Hydroxy-2-({1-[4'-(gidroximetil)-2-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9) to 1-(13), but using [(4'-bromo-2'-methylbiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 27%) as a pale yellowish white solid.

MS m/z: 505 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 9,15 (1H, Shir.C) to 7.33 (2H, d, J=8 Hz), 7,24 (2H, d, J=8 Hz), 7,02 (1H, d, J=8 Hz), at 6.84 (1H, s), 6,80 (1H, d, J=8 Hz), 4,52 (2H, s), 3.75 to of 3.66 (4H, m), 2,77 (2H, d, J=7 Hz), of 2.66 (2H, t, J=12 Hz), 2,43 (3H, s), of 2.20 (3H, s), 2,10-of 1.99 (1H, m), 1,69 (2H, d, J=12 Hz), of 1.36 (2H, kV, J=12 Hz).

(Example 24)

({[2-({1-[3'-Chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 91]

(1) tert-Butyl-[(2-chloro-4-iodobenzyl)oxy]dimethylsilane

[Chemical formula 92]

2-Chloro-4-iodobenzoyl acid (5.0 g, 18 mmol) was dissolved in tetrahydrofuran (7 ml) and at 0°C was added a solution of a complex of borane-tetrahydrofuran in tetrahydrofuran (1 M, 21 ml, 23 mmol) followed by stirring the mixture at room�Oh temperature for 3 days. To the reaction solution was added water and saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and then the solvent was distilled under reduced pressure, to give (2-chloro-4-itfinal)methanol (4.8 g, 18 mmol) as a white solid (quantitative yield).

According to example 1-(8), but using (2-chloro-4-itfinal)methanol instead of (4'-bromodiphenyl-4-yl)methanol specified in the title compound was obtained (yield 95%) as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: 7,65 (1H, s), 7,61 (1H, d, J=9 Hz), 7,29 (1H, d, J=9 Hz), 4.72 in (2H, s), of 0.95 (9H, s), of 0.12 (6H, s).

(2) [(4'-Bromo-3-chlorodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane

[Chemical formula 93]

According to example 11-(1), but using tert-butyl-[(2-chloro-4-iodobenzyl)oxy]dimethylsilane instead of 4-bromobenzylamine and (4-bromophenyl)Bronevoy acid instead of [3-(gidroximetil)phenyl]Bronevoy acid specified in the title compound was obtained (yield 96%) as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: 7,63 (1H, d, J=8 Hz), EUR 7.57 (2H, d, J=8 Hz), 7,52-7,41 (4H, m), 4,82 (2H, s), and 0.98 (9H, s), and 0.15 (6H, s).

(3) ({[2-({1-[3'-Chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbon�l}amino)acetic acid

According to the examples 1-(9) to 1-(13), but using [(4'-bromo-3-chlorodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 31%) as a pale yellowish white solid.

MS m/z: 525 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,90 (1H, Shir.C), 11,92 (1H, s), of 9.42 (1H, t, J=Hz), 7,61-7,51 (5H, m), 7,02-of 6.96 (2H, m), 5,38 (1H, Shir.C) is 4.57 (2H, d, J=5 Hz), of 4.00 (2H, d, J=6 Hz), of 3.75 (2H, d, J=12 Hz), 2,80-of 2.66 (4H, m), of 2.44 (3H, s), 2,16-2,04 (1H, m), 1,67 (2H, d, J=12 Hz), of 1.35 (2H, kV, J=12 Hz).

(Example 25)

({[5-Hydroxy-2-({1-[4'-(gidroximetil)-2'-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 94]

(1) Methyl 4'-bromo-2-methylbiphenyl-4-carboxylate

[Chemical formula 95]

According to example 19-(2), but using methyl 4-bromo-3-methylbenzoate instead of tert-butyl-5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate and 1-bromo-4-iodobenzoyl instead of tert-butyl-[4-iodobenzyl)oxy]dimethylsilane specified in the header connection receive (yield 23%) as a white solid.

1H-NMR (500 MHz, CDCl3) δ: 7,96 (1H, s), 7,90 (1H, d, J=9 Hz), EUR 7.57 (2H, d, J=9 Hz), 7,27 (1H, d, J=9 Hz), 7,20 (2H, d, J=9 Hz), 3,94 (3H, s), is 2.30 (3H, s).

(2) [(4'-Bromo-2-methylbiphenyl-4-yl)methoxy](tre�-butyl)dimethylsilane

[Chemical formula 96]

According to example 6-(2), but with the use of methyl-4'-bromo-2-methylbiphenyl-4-carboxylate instead of ethyl 2-(4'-bromodiphenyl-4-yl)-2-methylpropionate, (4'-bromo-2-methylbiphenyl-4-yl)methanol was obtained (yield 97%) as a colorless oil.

According to example 1-(8), but using (4'-bromo-2-methylbiphenyl-4-yl)methanol instead of (4'-bromodiphenyl-4-yl)methanol specified in the title compound was obtained (71% yield) as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: 7,53 (2H, d, J=8 Hz), 7,24-7,14 (5H, m) to 4.75 (2H, s), of 2.25 (3H, s), is 0.96 (9H, s), of 0.13 (6H, s).

(3) ({[5-Hydroxy-2-({1-[4'-(gidroximetil)-2'-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9) to 1-(13), but using [(4'-bromo-2-methylbiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 17%) as a pale yellowish white solid.

MS m/z: 505 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 11,94 (1H, Shir.C), 9,41 (1H, Shir.C), 7,20-was 7.08 (5H, m), of 6.99-6,94 (2H, m), 4,47 (2H, s), 3,99 (2H, d, J=6 Hz), 3,71 (2H, d, J=12 Hz), 2,79 (2H, d, J=7 Hz), 2,68 (2H, t, J=12 Hz), of 2.45 (3H, s), of 2.23 (3H, s), 2,13-2,02 (1H, m), To 1.69 (2H, d, J=12 Hz), to 1.37 (2H, kV, J=12 Hz).

(Example 26)

({[5-Hydroxy-2-({1-[4'-(gidroximetil)-2,3 dimethyldiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-and�]carbonyl}amino)acetic acid

[Chemical formula 97]

(1) [(4'-Bromo-2',3-dimethyldiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane

[Chemical formula 98]

According to example 19-(2), but using [(4-bromo-2-methylbenzyl)oxy](tert-butyl)dimethylsilane instead of tert-butyl-5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate and 4-bromo-1-iodo-2-methylbenzene instead of tert-butyl-[(4-iodobenzyl)oxy]dimethylsilane, specified in the title compound was obtained (yield 34%) as a yellow oil.

1H-NMR (500 MHz, CDCl3) δ: of 7.46 (1H, d, J=8 Hz), 7,41 (1H, s), 7,35 (1H, d, J=8 Hz), 7,11 (1H, d, J=8 Hz), was 7.08 (1H, d, J=8 Hz), to 7.04 (1H, with), to 4.75 (2H, s), is 2.30 (3H, s), 2,24 (3H, s), of 0.97 (9H, s), of 0.13 (6H, s).

(2) ({[5-Hydroxy-2-({1-[4'-(gidroximetil)-2,3'-dimethyldiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9) to 1-(13), but using [(4'-bromo-2',3-dimethyldiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 45%) as a pale yellowish white solid.

MS m/z: 519 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 9,36 (1H, t, J=5 Hz), 7,35 (1H, d, J=8 Hz), was 7.08 (1H, d, J=8 Hz), 7,05 (1H, s), 7,01 (1H, d, J=8 Hz), 6,83 (1H, s), of 6.79 (1H, d, J=8 Hz), 4,51 (2H, s), 3,96 (2H, d, J=5 Hz), 3,70 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), of 2.66 (2H, t,J=12 Hz), Of 2.44 (3H, s), of 2.27 (3H, s), 2,19 (3H, s), 2,13-2,02 (1H, m), by 1.68 (2H, d, J=12 Hz), to 1.37 (2H, kV, J=12 Hz).

(Example 27)

({[5-Hydroxy-2-({1-[4'-(2-hydroxybutyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 99]

According to the examples from 5-(2) 5(5), but with the use of a mixed solution utility in benzene and cyclohexane (benzene/cyclohexane=9/1) solution instead of metallice in simple diethyl ether, specified in the header connection receive (yield of 3.6%) as pale-yellow solids.

MS m/z: 533 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,89 (1H, Shir.C) 11,91 (1H, s), 9,29 (1H, t, J=5 Hz), of 7.48 (2H, d, J=9 Hz), 7,47 (2H, d, J=9 Hz), 7,22 (2H, d, J=8 Hz), 6,98 (2H, d, J=8 Hz), 4,48 (1H, d, J=5 Hz), of 4.00 (2H, d, J=5 Hz), 3,86-of 3.80 (1H, m), 3,73 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,74-of 2.67 (2H, m), 2,63 (2H, d, J=6 Hz), of 2.44 ( 3H, s), 2,15-2,03 (1H, m), by 1.68 (2H, d, J=12 Hz), of 1.36 (2H, DQC, J=12 Hz, 3 Hz), of 1.35 to 1.22 (2H, m), Of 0.88 (3H, t, J=7 Hz).

(Example 28)

[({5-Hydroxy-2-[(1-{4-[4-(2-hydroxypropyl)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 100]

According to example 19-(2), but using 1-bromo-4-[2-(methoxyethoxy)propyl]benzene instead of tert-butyl-5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate and 1-bromo-4-(methyl bromide)benzene instead of tert-butyl-[(4-IODE�Zyl)oxy]dimethylsilane, the crude product 1-bromo-4-{4-[2-(methoxyethoxy)propyl]benzyl}benzene was obtained as a yellow oil.

According to the examples 1-(9) to 1-(13), but with the use of a crude product of 1-bromo-4-{4-[2-(methoxyethoxy)propyl]benzyl}benzene instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 15%) as a white solid.

MS m/z: 533 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,87 (1H, Shir.C) 11,91 (1H, s), of 9.42 (1H, t, J=5 Hz), was 7.08 (4H, s), 7,03 (2H, d, J=7 Hz), 6,83 (2H, d, J=7 Hz), a 4.53 (1H, Shir.(C), of 4.00 (2H, d, J=5 Hz), 3,76 (2H, s), 3,79-and 3.72 (1H, m), 3,58 (2H, d, J=12 Hz), to 2.76 (2H, t, J=7 Hz), 2,66-of 2.45 (4H, m), of 2.44 (3H, s), 2,09-2,00 (1H, m), of 1.66 (2H, d, J=12 Hz), of 1.35 (2H, DQC, J=12 Hz, 3 Hz), and 1.00 (3H, d, J=6 Hz).

(Example 29)

[({5-Hydroxy-2-[(1-{4-[4-(2-hydroxy-1,1-dimethylethyl)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 101]

According to example 28, but using 1-bromo-4-[2-(methoxyethoxy)-1,1-dimethylethyl]benzene instead of 1-bromo-4-[2-(methoxyethoxy)propyl]benzene, specified in the title compound was obtained (yield 12%) as a white solid.

MS m/z: 547 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 11,92 (1H, s), 9,43 (1H, t, J=5 Hz), 7.23 percent (2H, d, J=5 Hz), 7,11 (2H, d, J=5 Hz), to 7.04 (2H, Shir.(C), at 6.84 (2H, Shir.C) a 4.65 (1H, Shir.(C), of 4.00 (2H, d, J=5 Hz), 3,76 (2H, s), 3,58 (2H, d, J=12 Hz), 3,42 (2H, s), 2,78 (2H, d, J=7 Hz), 2,70 (2H, t, J=12 Hz), of 2.44 (3H, s), 2,11-2,00 (H, m), of 1.66 (2H, d, J=12 Hz), of 1.36 (2H, DQC, J=12 Hz, 3 Hz), of 1.17 (6H, C)

(Example 30)

({[2-({1-[4'-(1,1-Debtor-2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 102]

(1) Ethyl-(4'-bromodiphenyl-4-yl)(debtor)acetate

[Chemical formula 103]

According to example 11-(1) but using ethyl-4-idgenerator instead of 4-bromobenzylamine and (4-bromophenyl)Bronevoy acid instead of [3-(gidroximetil)phenyl]Bronevoy acid ethyl-(4'-bromodiphenyl-4-yl)acetate was obtained (71% yield) as a white solid.

Ethyl-(4'-bromodiphenyl-4-yl)acetate (3.1 g, 9.8 mmol) was dissolved in tetrahydrofuran (50 ml) followed by the addition of a solution hexamethyldisilazide lithium in tetrahydrofuran (1 M, 12 ml, 12 mmol) at -78°C in an atmosphere of nitrogen and stirring for 20 minutes and then added at the same temperature N-formentioned (3.7 g, 12 mmol) followed by stirring for 20 minutes. To the reaction solution at -78°C was added a solution of hexamethyldisilazide lithium in tetrahydrofuran (1 M, 12 ml, 12 mmol) followed by stirring for 20 minutes, and then at the same temperature was added N-formentioned (3.7 g, 12 mmol) followed by stirring for another 1 hour. To the reaction solution to�aslali a saturated aqueous solution of ammonium chloride followed by extraction of the solution with ethyl acetate and then the extract was concentrated under reduced pressure. The resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,70 (hexane/ethyl acetate=4/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (2.8 g, 7.8 mmol) as a pale yellow oil (yield 79%).

1H-NMR (500 MHz, CDCl3) l: to 7.68 (2H, d, J=8 Hz), 7,63 (2H, d, J=8 Hz), 7,61 (2H, d, J=8 Hz), of 7.46 (2H, d, J=8 Hz), 4,33 (2H, kV, J=7 Hz), of 1.33 (3H, t, J=7 Hz).

(2) 2-(4'-Bromodiphenyl-4-yl)-2,2-deflorator

[Chemical formula 104]

Ethyl-(4'-bromodiphenyl-4-yl)(debtor)acetate (2.8 g, 7.8 mmol) was dissolved in methanol (20 ml) and at 0°C was added sodium borohydride (0.59 g, 16 mmol) followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and to the residue was added hydrochloric acid (1 M) and the mixture then was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0.50 (a hexane/ethyl acetate=1/1) thin-layer chromatography, conc�grown under reduced pressure, while receiving specified in the title compound (2.4 g, 7,7 mmol) as a white solid (yield 99%).

1H-NMR (500 MHz, CDCl3) δ: of 7.64-of 7.58 (6H, m), 7,49-7,44 (2H, m), was 4.02 (2H, dt, J=13 Hz, 6 Hz).

(3) [2-(4'-Bromodiphenyl-4-yl)-2,2-diflorasone](tert-butyl)dimethylsilane

[Chemical formula 105]

According to example 1-(8), but using 2-(4'-bromodiphenyl-4-yl)-2,2-deperately instead of (4'-bromodiphenyl-4-yl)methanol specified in the title compound was obtained (yield 97%) as a colorless oil.

1H-NMR (500 MHz, CDCl3) δ: 7,61 was 7.56 (6H, m), 7,47 (2H, d, J=7 Hz), 3,99 (2H, t, J=12 Hz), of 0.85 (9H, s), of 0.02 (6H, s).

(4) Ethyl({[5-(benzyloxy)-2-({1-[4'-(1,1-debtor-2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 106]

According to the examples 1-(9) to 1-(11), but using [2-(4'-bromodiphenyl-4-yl)-2,2-diflorasone](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 59%) as a white solid.

MS m/z: 659 (M+H)+;

1H-NMR (500 MHz, CDCl3) δ: 8,37 (1H, d, J=5 Hz), a 7.62 (2H, d, J=8 Hz), 7,55-of 7.48 (6H, m), 7,41-of 7.35 (3H, m), 7,01 (2H, d, J=8 Hz), 5,12 (2H, s), 4,27 (2H, kV, J=6 Hz), 4,24 (2H, d, J=5 Hz), of 4.00 (2H, t, J=13 Hz), 3,76 (2H, d, J=12 Hz), 2,90 (2H, d, J=7 Hz), 2,80 (2H, t, J=12 Hz), 2,47 (3H, s), 2,19-of 2.08 (1H, m), 1,78 (2H, d, J=12 Hz), 1,60-of 1.48 (2H, m, 1,32 (3H, t, J=6 Hz).

(5) ({[2-({1-[4'-(1,1-Debtor-2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1 to 12 and 1-(13), but using ethyl({[5-(benzyloxy)-2-({1-[4'-(1,1-debtor-2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate instead of ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate specified in the title compound was obtained (yield 84%) as pale-yellow solids.

MS m/z: 541 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 11,92 (1H, s), 9,43 (1H, t, J=6 Hz), of 7.70 (2H, d, J=8 Hz), 7,56 (2H, d, J=8 Hz), 7,54 (2H, d, J=8 Hz), 7,09-6,97 (2H, m), 5,67 (1H, Shir.C), was 4.02 (2H, d, J=6 Hz), a 3.87 (2H, t, J=14 Hz), 3,76 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,78-of 2.67 (2H, m), of 2.45 (3H, s), 2,18-of 2.06 (1H, m), 1,69 (2H, d, J=12 Hz), 1,43-of 1.31 (2H, m).

(Example 31)

({[2-({1-[4'-(1,1-Debtor-2-hydroxypropyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 107]

(1) 1-(4'-Bromodiphenyl-4-yl)-1,1-ditropan-2-ol

[Chemical formula 108]

Ethyl-(4'-bromodiphenyl-4-yl)(debtor)acetate (1.8 g, 5.1 mmol) obtained in example 30-(1), was dissolved in tetrahydrofuran (20 ml) in a nitrogen atmosphere at -78°C was added a solution of metallice in diethyl p�the OST ether (1.1 M, 14 ml, 15 mmol) followed by stirring the mixture at the same temperature for 30 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate and then the extract was concentrated under reduced pressure, obtaining 1-(4'-bromodiphenyl-4-yl)-1,1-defloration in the form of a pale yellow oil.

The oil was dissolved in tetrahydrofuran (30 ml) was added sodium borohydride (0.59 g, 16 mmol) followed by stirring the solution at room temperature for 30 minutes. To the reaction solution was added hydrochloric acid (1 M) followed by extraction of the mixture with ethyl acetate and then the extract was washed with a saturated aqueous solution of sodium chloride and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,30 (hexane/ethyl acetate=4/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0.89 g, 2.7 mmol) as a yellow oil (yield 53%).

1H-NMR (500 MHz, CDCl3) δ: 7,63-EUR 7.57 (6H, m), of 7.46 (2H, d, J=9 Hz), 4,25-4,16 (1H, m), of 1.27 (3H, d, J=7 Hz).

(2) ({[2-({1-[4'-(1,1-Debtor-2-hydroxyprop�yl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9) and 1-(11) to 1-(13), but using 1-(4'-bromodiphenyl-4-yl)-1,1-ditropan-2-ol instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 19%) as pale-yellow solids.

MS m/z: 555 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 11,93 (1H, s), 9,44 (1H, t, J=6 Hz), 7,71 (2H, d, J=8 Hz), 7,70-7,52 (4H, m), 7,51 (2H, d, J=8 Hz), 4,13-of 4.04 (1H, m), 4,01 (2H, d, J=6 Hz), 3,79-3,70 (2H, m), 2,84-of 2.72 (2H, m), 2,80 (2H, d, J=7 Hz), of 2.45 (3H, s), 2,21-2,10 (1H, m), 1,78-to 1.69 (2H, m), 1,52-of 1.33 (2H, m), 1,10 (3H, d, J=6 Hz).

(Example 32)

({[2-({1-[4'-(1,1-Debtor-2-hydroxy-2-methylpropyl") biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 109]

(1) 1-(4'-Bromodiphenyl-4-yl)-1,1-debtor-2-methylpropan-2-ol

[Chemical formula 110]

Ethyl-(4'-bromodiphenyl-4-yl)(debtor)acetate (0.10 g, 0.28 mmol) obtained in example 30-(1), was dissolved in tetrahydrofuran (20 ml) in a nitrogen atmosphere at room temperature was added a solution of methylmagnesium in simple diethyl ether (3.0 M, 1.0 ml, 3.0 mmol) followed by stirring the mixture at the same temperature for 5 hours. To the reaction solution was added hydrochloric acid (1 M) followed by extraction of the mixture with ethyl acetate and then the extract was dried over anhydrous sulfate n�try. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,35 (hexane/ethyl acetate=4/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the header connection (0,063 g, 0.18 mmol) as a yellow oil (yield 62%).

1H-NMR (500 MHz, CDCl3) δ: 7,63 was 7.56 (6H, m), of 7.46 (2H, d, J=8 Hz), of 1.35 (6H, s).

(2) ({[2-({1-[4'-(1,1-Debtor-2-hydroxy-2-methylpropyl") biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9) and 1-(11) to 1-(13), but using 1-(4'-bromodiphenyl-4-yl)-1,1-debtor-2-methylpropan-2-ol instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 11%) as pale-yellow solids.

MS m/z: 569 (M+H)+.

1H-NMR (500 MHz, DMSO-d6) δ: 11,92 (1H, s), 9,43 (1H, t, J=6 Hz), 7,67 (2H, d, J=8 Hz), members, 7.59 and 7.55 (2H, m), 7,49 (2H, d, J=8 Hz), 7,08-7,00 (2H, m), 4,00 (2H, d, J=6 Hz), 3,76 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,78-2,70 (2H, m), of 2.45 (3H, s), 2,16-of 2.06 (1H, m), 1,70 (2H, d, J=12 Hz), 1,44-1,32 (2H, m), 1,19 (6H, s).

(Example 33)

{[(5-[(2,2-Dimethylpropanoyl)oxy]-2-{[1-(4'-{[(2,2-dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

[X�chemical formula 111]

(1) Benzyl-({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 112]

({[5-Hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid (0.30 g, 0.61 mmol) obtained in example 1-(13), was dissolved in dichloromethane (10 ml) was added the bromide (0,21 g, 1,2 mmol) and triethylamine (of 0.26 ml, 1.8 mmol) followed by stirring at room temperature for 2 days. After concentrating the reaction solution under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: dichloro methane/methanol) and the fraction corresponding to the Rf value=0,55 (dichloro methane/methanol=10/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the header connection (0,14 g, 0,24 mmol) as pale-yellow solids (yield 39%).

1H-NMR (400 MHz, CDCl3) δ: of 11.34 (1H, s), and 8.50 (1H, t, J=6 Hz), 7,56 (2H, d, J=9 Hz), 7,50 (2H, d, J=9 Hz), 7,40 (2H, d, J=9 Hz), of 7.42-7,34 (5H, m), 7,00 (2H, d, J=9 Hz), a 5.25 (2H, s), 4.72 in (2H, s), 4,28 (2H, d, J=6 Hz), 3,73 (2H, d, J=12 Hz), 2,83 (2H, d, J=7 Hz), to 2.76 (2H, t, J=12 Hz), of 2.54 (3H, s), 2,12-of 1.99 (1H, m), a 1.77 (2H, d, J=12 Hz), 1,71-of 1.43 (2H, m).

(2) 4-{[2-(Benzyloxy)-2-oxoethyl]carbamoyl}-2-{[1-(4'-{[(2,2-dim�dipropenyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-5-revelat

[Chemical formula 113]

Benzyl-({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.025 g, 0,043 mmol) and pualeilani (0.016 g, 0.13 mmol) was dissolved in dichloromethane (3 ml) and added pyridine (0,010 ml, 0.12 mmol) and 4-dimethylaminopyridine (0.016 g, 0.13 mmol) followed by stirring the mixture at room temperature for 2 days. After concentrating the reaction solution under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: dichloro methane/methanol) and the fraction corresponding to the Rf value=0,35 (hexane/ethyl acetate=2/1), thin layer chromatography was concentrated under reduced pressure, while receiving specified in the header connection (0,017 g, 0,022 mmol) as pale-yellow solids (yield 52%).

1H-NMR (400 MHz, CDCl3) δ: 8,44 (1H, t, J=5 Hz), 7,55 (2H, d, J=9 Hz), 7,50 (2H, d, J=9 Hz), 7,40-7,32 (7H, m), 7,00 (2H, d, J=9 Hz), with 5.22 (2H, s), 5,13 (2H, s), 4,24 (2H, d, J=5 Hz), 3,74 (2H, d, J=12 Hz), Of 2.92 (2H, d, J=7 Hz), 2,77 (2H, t, J=12 Hz), 2,47 (3H, s), 2,18-2,04 (1H, m), of 1.80 (2H, d, J=12 Hz), 1,61-of 1.47 (2H, m), 1,43 (9H, s), of 1.24 (9H, s).

(3) {[(5-[(2,2-Dimethylpropanoyl)oxy]-2-{[1-(4'-{[2,2-dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

According to example 12-(4), but with primenenie-{[2-(benzyloxy)-2-oxoethyl]carbamoyl}-2-{[1-(4'-{[(2,2-dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-5-revelate instead of benzyl-[({5-(benzyloxy)-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate, specified in the title compound was obtained (yield 43%) as pale-yellow solids.

MS m/z: 659 (M+H)+.

1H-NMR (400 MHz, CDCl3) δ: of 8.71 (1H, Shir.C), 7,47 (2H, d, J=8 Hz), 7,38 (2H, d, J=8 Hz), 7,32 (2H, d, J=8 Hz), at 6.84 (2H, d, J=8 Hz), 5,10 (2H, s), 3,80 (2H, Shir.C) to 3.56 (2H, d, J=12 Hz), 2,79 (2H, d, J=7 Hz), of 2.57 (2H, t, J=12 Hz), 2,32 (3H, s), 2,05-of 1.91 (1H, m), 1,64 (2H, d, J=12 Hz), of 1.45 to 1.31 (2H, m), of 1.28 (9H, s), to 1.22 (9H, s).

(Example 34)

{[(2-{[1-(4'-{[(2,2-Dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

[Chemical formula 114]

(1) Benzyl-({[5-benzyloxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 115]

According to example 1-(11), but using benzyl ester of glycine hydrochloride instead of ethyl ester of glycine, specified in the header connection receive (yield 42) as a white solid.

1H-NMR (500 MHz, CDCl3) δ: 8,37 (1H, t, J=5 Hz), 7,56 (2H, d, J=8 Hz), 7,50 (2H, d, J=9 Hz), of 7.48 (2H, d, J=8 Hz), of 7.42-7,31 (10H, m), 7,00 (2H, d, J=9 Hz), 5,24 (2H, s), 5,11 (2H, s), 4.72 in (2H, d, J=5 Hz), 4,30 (2H, d, J=5 Hz), 3,74 (2H, d, J=12 Hz), 2,89 (2H, d, J=7 Hz), 2,78 (2H, t, J=12 Hz), 2,46 (3H, C), 2,16-of 2.06 (1H, m), 1,78 (2H, d, J=12 Hz), of 1.65 (1H, t, J=5 Hz), 1,60-of 1.48 (2H, m).

(2) [4'-(4-{[5-(Benzyloxy)-4-{[2-(benzyloxy)-2-oxoethyl]carbamoyl}-6-methylpyrimidin-2-yl]methyl}piperidine-1-yl)WPPT�Neil-4-yl]Metreveli

[Chemical formula 116]

According to example 33-(2), but with the use of benzyl-({[5-benzyloxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate instead of benzyl-({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate specified in the title compound was obtained (yield 79%) as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ: 8,37 (1H, t, J=5 Hz), 7,55 (2H, d, J=8 Hz), 7,50 (2H, d, J=9 Hz), of 7.48 (2H, d, J=8 Hz), of 7.42 is 7.33 (10H, m), 7,00 (2H, d, J=9 Hz), 5,24 (2H, s), 5,13 (2H, s), 5,11 (2H, s), 4,30 (2H, d, J=5 Hz), of 3.75 (2H, d, J=12 Hz), 2,89 (2H, d, J=7 Hz), 2,78 (2H, t, J=12 Hz), 2,47 (3H, s), 2,18-of 2.06 (1H, m), to 1.79 (2H, d, J=12 Hz), 1,60-of 1.47 (2H, m), of 1.24 (9H, s).

(3) {[(2-{[1-(4'-{[(2,2-Dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

According to example 12-(4), but with the use of[4'-(4-{[5-(benzyloxy)-4-{[2-(benzyloxy)-2-oxoethyl]carbamoyl}-6-methylpyrimidin-2-yl]methyl}piperidine-1-yl)biphenyl-4-yl]methylphenidate instead of benzyl-[({5-(benzyloxy)-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate specified in the header connection receive (yield 28%) as a yellow solid.

MS m/z: 575 (M+H)+;

1H-NMR (400 MHz, CDCl3) δ: 11,53 (1H, Shir.C), 8,58 (1H, Shir.C), 7,51 (4H, d, J=8 Hz), of 7.36 (2H,d, J=8 Hz), made 7.16 interest (2H, d, J=8 Hz), 5,12 (2H, s), of 3.69 (2H, d, J=12 Hz), 3,52 (2H, Shir.C), 2,93-to 2.74 (4H, m), of 2.50 (3H, s), 2,13-of 1.98 (1H, m), 1,87-1,59 (4H, m), of 1.24 (9H, s).

(Example 35)

({[5-Hydroxy-2-({1-[4'-(methoxymethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 117]

(1) (4'-Bromodiphenyl-4-yl)methylotrophy ether

[Chemical formula 118]

(4'-Bromodiphenyl-4-yl)methanol (1.2 g, 4.6 mmol) was dissolved in tetrahydrofuran (20 ml) in a nitrogen atmosphere at 4°C was added methyliodide (0,97 g, 6,8 mmol) and then sodium hydride (63%, 0.26 g, 6,8 mmol) followed by stirring the mixture at room temperature for 30 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/dichloro methane) and the fraction corresponding to the Rf value=0.50 (a hexane/dichloro methane=1/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (1.2 g, 4.3 mmol) as a white solid (yield 95%).

1H-NMR (500 MHz, CDCl3) δ: 7,58-7,53 (4H, m), of 7.48-7,44 (2H, m), 7,43-7,40 (2H, m), 4,50 (2H, s), 3,42 (3H, �).

(2) ({[5-Hydroxy-2-({1-[4'-(methoxymethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9), 1-(11), 22-(4) and 1-(13), but using (4'-bromodiphenyl-4-yl)methylotrophy simple ester instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 26%) as a pale yellowish white solid.

MS m/z: 505 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,90 (1H, Shir.C), 11,92 (1H, s), 9,40 (1H, t, J=6 Hz), EUR 7.57 (2H, d, J=8 Hz), 7,51 (2H, d, J=8 Hz), 7,34 ( 2H, d, J=8 Hz), 7,00 (2H, d, J=8 Hz), to 4.41 (2H, s), of 4.00 (2H, d, J=6 Hz), of 3.75 (2H, d, J=12 Hz), 3,29 (3H, s), 2,78 (2H, d, J=7 Hz), 2,71 (2H, t, J=12 Hz), of 2.44 (3H, s), 2,15-2,05 (1H, m), by 1.68 (2H, d, J=12 Hz), to 1.37 (2H, DQC, J=12 Hz, 3 Hz).

(Example 36)

({[2-({1-[2'-Fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 119]

(1) tert-Butyl-5-(benzyloxy)-2-{[1-(4-bromophenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate

[Chemical formula 120]

According to example 1-(9), but with the use of 1,4-dibromobenzene instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 18%) as an orange oil.

1H-NMR (500 MHz, CDCl3) δ: of 7.46-of 7.35 (5H, m), 7,31 (2H, d, J=8 Hz), 6,80 (2H, d, J=8 Hz), 5,01 (H, C), 3,62 (2H, d, J=12 Hz), 2,89 (2H, d, J=7 Hz), 2,69 (2H, t, J=12 Hz), 2,46 (3H, C), 2,15-of 2.03 (1 H, m), a 1.77 (2H, d, J=12 Hz), 1,59 (9H, s) of 1.51 (2H, kV, J=12 Hz).

(2) tert-Butyl-5-(benzyloxy)-2-({1-[4'-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2'-forgivenes-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate

[Chemical formula 121]

According to example 19-(2), but using tert-butyl-5-(benzyloxy)-2-{[1-(4-bromophenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate instead of tert-butyl-5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate and [(4-bromo-3-terbisil)oxy](tert-butyl)dimethylsilane instead of tert-butyl-[(4-iodobenzyl)oxy]dimethylsilane specified in the header connection receive (yield 16%) as a pale yellow oil.

1H-NMR (500 MHz, CDCl3) δ: of 7.48-of 7.35 (8H, m), 7,14-was 7.08 (2H, m), of 6.99 (2H, d, J=8 Hz), 5,01 (2H, C) to 4.75 (2H, s), 3,74 (2H, d, J=12 Hz) or 2.91 (2H, d, J=7 Hz), to 2.76 (2H, t, J=12 Hz), 2,47 (3H, s), 2,17-of 2.06 (1H, m), To 1.79 (2H, d, J=12 Hz), 1,58 (9H, s), a 1.54 (2H, kV, J=12 Hz), of 0.96 (9H, s), of 0.12 (6H, s).

(3) ({[2-({1-[2'-Fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(10), 1-(11), 22-(4) and 1-(13), but using tert-butyl-5-(benzyloxy)-2-({1-[4'-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2'-forgivenes-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate instead of tert-butyl-5-(benzyloxy)-2-({1-[4'-({[tert-BU�yl(dimethyl)silyl]oxy}methyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate, specified in the title compound was obtained (yield 37%) as a white solid.

MS m/z: 509 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,91 (1H, Shir.C), 11,92 (1H, s), 9,43 (1H, t, J=5 Hz), of 7.42 (1H, t, J=9 Hz), 7,39 (2H, d, J=8 Hz), 7,20-7,15 (2H, m), 7,01 (2H, d, J=8 Hz), is 5.33 (1H, Shir.C) 4,52 (2H, s), of 4.00 (2H, d, J=5 Hz), of 3.75 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,71-2,63 (2H, m), of 2.45 (3H, s), 2,16-of 2.06 (1H, m), 1,69 (2H, d, J=12 Hz), of 1.36 (2H, DQC, J=12 Hz, 3 Hz).

(Example 37)

({[2-({1-[3'-Fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 122]

According to the examples 36-(2), 1-(10), 1-(11), 22-(4) and 1-(13), but using [(4-bromo-2-terbisil)oxy](tert-butyl)dimethylsilane instead of [(4-bromo-3-terbisil)oxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 12%) as pale red solids.

MS m/z: 509 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,91 (1H, Shir.C), 11,92 (1H, s), 9,43 (1H, t, J=5 Hz), 7,55 (2H, d, J=8 Hz), 7,50-7,41 (2H, m), 7,38 (1H, d, J=12 Hz), of 6.99 (2H, d, J=8 Hz), and 5.26 (1H, Shir.(C), of 4.54 (2H, d, J=4 Hz), of 4.00 (2H, d, J=5 Hz), 3,76 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,77-of 2.67 (2H, m), of 2.45 (3H, s), 2,18-of 2.06 (1H, m), 1,69 (2H, d, J=12 Hz), of 1.36 (2H, DQC, J=12 Hz, 3 Hz).

(Example 38)

({[2-({1-[2-Fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 123]

(1) [(4'-Bromo-2'-forgivenes-4-yl)methoxy](tert-butyl)dimethylsilane

[Chemical formula 124]

According to the example 4-(2), but using tert-butyl[(4-iodobenzyl)oxy]dimethylsilane instead of tert-butyl-[2-(4-itfinal)ethoxy]dimethylsilane and (4-bromo-2-fluorophenyl)Bronevoy acid instead of (4-bromophenyl)Bronevoy acid specified in the header connection receive (yield 57%) as a yellow oil.

1H-NMR (500 MHz, CDCl3) δ: of 7.48 (2H, d, J=7 Hz), 7,40 (2H, d, J=7 Hz), 7,38-7,27 (3H, m), 4,79 (2H, s), of 0.97 (9H, s), of 0.12 (6H, s).

(2) ({[2-({1-[2-Fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9) to 1-(11), 22-(4) and 1-(13), but using [(4'-bromo-2'-forgivenes-4-yl)methoxy](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 19%) as a white solid.

MS m/z: 509 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,91 (1H, Shir.C), 11,92 (1H, s), 9,43 (1H, t, J=5 Hz), the 7.43 (2H, d, J=8 Hz), 7,35 (2H, d, J=8 Hz), to 7.33 ( 1H, d, J=8 Hz), 6,86-was 6.77 (2H, m), to 5.21 (1H, Shir.C), 4,51 (2H, s), of 4.00 (2H, d, J=5 Hz), of 3.78 (2H, d, J=12 Hz), 2,77 (2H, d, J=7 Hz), 2,77-2,70 (2H, m), of 2.44 (3H, s), 2,17-of 2.06 (1H, m), of 1.66 (2H, d, J=12 Hz), of 1.34 (2H, DQC, J=12 Hz, 3 Hz).

(Example 39)

({[2-({1-[3-Fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbylamine)acetic acid

[Chemical formula 125]

(1) [(4'-Bromo-3'-forgivenes-4-yl)methoxy](tert-butyl)dimethylsilane

[Chemical formula 126]

According to the example 4-(2), but using tert-butyl[(4-iodobenzyl)oxy]dimethylsilane instead of tert-butyl-[2-(4-itfinal)ethoxy]dimethylsilane and (4-bromo-3-fluorophenyl)Bronevoy acid instead of (4-bromophenyl)Bronevoy acid specified in the title compound was obtained (yield 73%) as a white solid.

1H-NMR (500 MHz, CDCl3) δ: members, 7.59 (1H, t, J=6 Hz), 7,52 (2H, d, J=7 Hz), 7,40 (2H, d, J=7 Hz), 7,35 (1H, d, J=11 Hz), 7,25 (1H, d, J=6 Hz), 4,79 (2H, s), of 0.97 (9H, s), of 0.12 (6H, s).

(2) ({[2-({1-[3-Fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to the examples 1-(9) to 1-(11), 22-(4) and 1-(13), but using [(4'-bromo-3'-forgivenes-4-yl)methoxy](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield of 5.2%) as a white solid.

MS m/z: 509 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,91 (1H, Shir.C) 11,93 (1H, s), of 9.42 (1H, t, J=5 Hz), 7,60 (2H, d, J=8 Hz), 7,47-7,39 (2H, m), of 7.36 (2H, d, J=8 Hz), to 7.09 (1H, t, J=9 Hz), with 5.22 (1H, t, J=5 Hz), 4,51 (2H, d, J=5 Hz), of 4.00 (2H, d, J=5 Hz), 3,36 (2H, d, J=12 Hz), of 2.81 (2H, d, J=7 Hz), 2,73-2,63 (2H, m), of 2.45 (3H, s), 2,13-2,03 (1H, m), 1,71 (2H, d, J=12 Hz), of 1.44 (2H, DQC, J=12 Hz, 3 Hz).

(Example 4)

({[5-Hydroxy-2-({1-[4'-(gidroximetil)-3'-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 127]

According to the examples 36-(2), 1-(10), 1-(11), 22-(4) and 1-(13), but using [(4-bromo-2-methylbenzyl)oxy](tert-butyl)dimethylsilane instead of [(4-bromo-3-terbisil)oxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 15%) as a white solid.

MS m/z: 505 (M+H)+;

1H-NMR (400 MHz, DMSO-d6) δ: 12,88 (1H, Shir.C) 11,91 (1H, s), at 9.38 (1H, t, J=6 Hz), 7,49 (2H, d, J=9 Hz), value of 7, 37 (1H, d, J=9 Hz), of 7.36 (1H, s), 7,35 (1H, d, J=9 Hz), 6,98 (2H, d, J=9 Hz), 5,02 (1H, Shir.C), 4,49 (2H, d, J=3 Hz), of 4.00 (2H, d, J=6 Hz), 3,73 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,70 (2H, dt, J=12 Hz, 3 Hz), of 2.44 (3H, s) to 2.29 (3H, s), 2,17-of 2.01 (1H, m), 1,69 (2H, d, J=12 Hz), To 1.37 (2H, DQC, J=12 Hz, 3 Hz).

(Example 41)

({[2-({1-[3',5'-Debtor-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 128]

According to the examples 36-(2), 1-(10), 1-(11), 22-(4) and 1-(13), but using [(4-bromo-2,6-diferensial)oxy](tert-butyl)dimethylsilane instead of [(4-bromo-3-terbisil)oxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 9%) as a white solid.

MS m/z: 527 (M+H)+;

1H-NMR (400 MHz, DMSO-d6) δ: 12,86 (1H, Shir.C) 11,90 (1H, s), 9,39(1H, t, J=6 Hz), 7,60 (2H, d, J=9 Hz), to 7.33 (2H, d, J=9 Hz), of 6.99 (2H, d, J=9 Hz), 5,19 (1H, Shir.C), 4,49 (2H, s), 4,01 (2H, d, J=6 Hz), with 3.79 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), of 2.75 (2H, t, J=12 Hz), of 2.44 (3H, s), 2,19-2,04 (1H, m), by 1.68 (2H, d, J=12 Hz), of 1.35 (2H, DQC, J=12 Hz, 3 Hz).

(Example 42)

({[2-({1-[3',5'-Dichloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 129]

According to the examples 36-(2), 1-(10), 1-(11), 22-(4) and 1-(13), but using [(4-bromo-2,6-dichlorobenzyl)oxy](tert-butyl)dimethylsilane instead of [(4-bromo-3-terbisil)oxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 15%) as a white solid.

MS m/z: 559 (M+H)+;

1H-NMR (400 MHz, DMSO-d6) δ: 12,88 (1H, Shir.C) 11,91 (1H, s), 9,40 (1H, t, J=6 Hz), 7,67 (2H, s), 7,60 (2H, d, J=9 Hz), of 6.99 (2H, d, J=9 Hz), 5,18 (1H, t, J=4 Hz), 4,68 (2H, d, J=4 Hz), 4,01 (2H, d, J=6 Hz), with 3.79 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,73 (2H, t, J=12 Hz), of 2.44 (3H, s), 2,19-2,05 (1H, m), by 1.68 (2H, d, J=12 Hz), of 1.34 (2H, DQC, J=12 Hz, 3 Hz).

(Example 43)

({[2-({1-[3',5'-Dimethyl-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 130]

According to the examples 36-(2), 1-(10), 1-(11), 22-(4) and 1-(13), but using [(4-bromo-2,6-dimethylbenzyl)oxy](tert-butyl)dimethylsilane instead of [(4-bromo-3-terbisil)oxy](tert-butyl)dimethylsilane, provide during account creation�e in the title compound was obtained (yield 4%) as a white solid.

MS m/z: 519 (M+H)+;

1H-NMR (400 MHz, DMSO-d6) δ: 12,87 (1H, Shir.C) 11,90 (1H, s), 9,39 (1H, t, J=6 Hz), of 7.48 (2H, d, J=9 Hz), 7,21 (2H, s), 6,97 (2H, d, J=9 Hz), a 4.65 (1H, t, J=5 Hz), 4,49 (2H, d, J=5 Hz), 4,01 (2H, d, J=6 Hz), and 3.72 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,70 (2H, dt, J=12 Hz, 3 Hz), of 2.44 (3H, s), 2,39 (6H, s), 2,16-2,02 (1H, m), by 1.68 (2H, d, J=12 Hz), to 1.37 (2H, DQC, J=12 Hz, 3 Hz).

(Example 44)

({[5-Hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid-d2

[Chemical formula 131]

(1) Ethyl({[5-(benzyloxy)-2-{[1-(4'-formeleditor-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 132]

Oxaliplatin (0.31 g, 2.5 mmol) was dissolved in dichloromethane (5 ml) and, dropwise, at -78°C was added a solution of dimethyl sulfoxide (0.18 g, 2,3 mmol) in dichloromethane (4 ml) followed by stirring the mixture at the same temperature for 15 minutes. To the reaction solution was dropwise added a solution of ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (1.0 g, 1.6 mmol) obtained in example 1-(11), in dichloromethane (26 ml) followed by stirring at the same temperature for 25 minutes and then dropwise added triethylamine (1.1 ml, 8.2 mmol) and the temperature was raised to room temperature on the length of�starting 1.5 hours. To the reaction solution was added water, followed by extraction with a mixture of dichloromethane and then the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (biotage AB Ltd., the solvent for elution: dichloro methane/etoac), while receiving specified in the title compound (0.85 g, 1.4 mmol) as a yellow solid (yield 85%).

1H-NMR (400 MHz, CDCl3) δ: 10,01 (1H, s), of 8.34 (1H, t, J=5 Hz), 7,90 (2H, d, J=8 Hz), 7,72 (2H, d, J=8 Hz), EUR 7.57 (2H, d, J=9 Hz), 7,51-of 7.46 (2H, m), of 7.42 is 7.33 (3H, m), 7,01 (2H, d, J=9 Hz), 5,12 (2H, s), 4,27 (2H, kV, J=7 Hz), 4,24 (2H, d, J=5 Hz), with 3.79 (2H, d, J=12 Hz), 2,90 (2H, d, J=7 Hz), 2,83 (2H, dt, J=12 Hz, 3 Hz), 2,47 (3H, s), 2,23-2,07 (1H, m), of 1.80 (2H, d, J=12 Hz), of 1.53 (2H, DQC, J=12 Hz, 3 Hz), 1,32 (3H, t, J=7 Hz).

(2) Ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate-d1

[Chemical formula 133]

Ethyl({[5-(benzyloxy)-2-{[1-[4'-formeleditor-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.85 g, 1.4 mmol) was dissolved in a mixed solvent of deuterated methanol (7.5 ml) and dichloromethane (7.5 ml) and at 0°C was added deuterated sodium borohydride (0,059 g, 1,4 mmol) followed by stirring the mixture at the same rate�the temperature within 45 minutes. To the reaction solution was added deuterated water, the solvent was distilled under reduced pressure and then the resulting residue was purified by chromatography on a column of silica gel (biotage AB Ltd., the solvent for elution: dichloro methane/etoac), while receiving specified in the title compound (0.74 g, 1.2 mmol) as a white solid (yield 87%).

1H-NMR (400 MHz, CDCl3) δ: 8,35 (1H, t, J=5 Hz), 7,55 (2H, d, J=8 Hz), 7,52-of 7.46 (2H, m), 7,50 (2H, d, J=9 Hz), 7,40 (2H, d, J=8 Hz), 7,38-of 7.35 (3H, m), 7,00 (2H, d, J=9 Hz), 5,12 (2H, s), 4,69 (1H, C) to 4.26 (2H, kV, J=7 Hz), 4,24 (2H, d, J=5 Hz), 3,74 (2H, d, J=12 Hz), 2,90 (2H, d, J=7 Hz), 2,78 (2H, dt, J=12 Hz, 3 Hz), 2,46 (3H, C), 2,19-2,05 (1H, m), to 1.79 (2H, d, J=12 Hz), 1,71 (1H, Shir.C) a 1.54 (2H, DQC, J=12 Hz, 3 Hz), 1,32 (3H, t, J=7 Hz).

(3) Ethyl({[5-(benzyloxy)-2-{[1-[4'-formeleditor-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate-d1

[Chemical formula 134]

According to example 44-(1), but using ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate-d1 instead of ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]the piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate specified in the title compound and ethyl-({[5-(benzyloxy)-2-{[1-[4'-formeleditor-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate was obtained as a mixture 5:1 (yield 87%).

1H-�Mr (400 MHz, CDCl3) δ: 10,01 (0,2 H, C) of 8.34 (1H, t, J=5 Hz), 7,90 (2H, d, J=8 Hz), 7,72 (2H, d, J=8 Hz), EUR 7.57 (2H, d, J=9 Hz), 7,51-of 7.46 (2H, m), of 7.42-7,32 (3H, m), 7,01 (2H, d, J=9 Hz), 5,12 (2H, s), 4,27 (2H, kV, J=7 Hz), 4,24 (2H, d, J=5 Hz), 3,80 (2H, d, J=12 Hz), 2,90 (2H, d, J=7 Hz), 2,83 (2H, dt, J=12 Hz, 3 Hz), 2,47 (3H, s), 2,22-of 2.08 (1H, m), to 1.79 (2H, d, J=12 Hz), of 1.53 (2H, DQC, J=12 Hz, 3 Hz), 1,32 (3H, t, J=7 Hz).

(4) Ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate-d2

[Chemical formula 135]

Operation examples 44-(2) and 44(3) was repeated twice using ethyl({[5-(benzyloxy)-2-{[1-[4'-formeleditor-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate-d1 and then carried out the operation of example 44-(2), while receiving specified in the title compound (yield 51%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 8,35 (1H, t, J=5 Hz), 7,56 (2H, d, J=8 Hz), 7,52-of 7.46 (2H, m), 7,50 (2H, d, J=9 Hz), 7,40 (2H, d, J=8 Hz), of 7.42 is 7.33 (3H, m), 7,00 (2H, d, J=9 Hz), 5,12 (2H, s), 4,27 (2H, kV, J=7 Hz), 4,24 (2H, d, J=5 Hz), 3,74 (2H, d, J=12 Hz), 2,90 (2H, d, J=7 Hz), 2,78 (2H, dt, J=12 Hz, 2 Hz), 2,47 (3H, s), 2,20-2,05 (1H, m), to 1.79 (2H, d, J=12 Hz), 1,64-of 1.49 (3H, m), 1,32 (3H, t, J=7 Hz).

(5) ({[5-Hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid-d2

According to the examples 22 to(4) and 1-(13), but using ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}AMI�about)acetate-d2 instead of ethyl({[5-(benzyloxy)-2-({1-[2-chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate and deuterated trifluoroacetic acid, methanol, an aqueous solution of sodium hydroxide and hydrochloric acid specified in the title compound was obtained (yield 80%) as yellowish-white solid.

MS m/z: 493 (M+H)+;

1H-NMR (400 MHz, DMSO-d6) δ: 12,88 (1H, Shir.C) 11,91 (1H, s), at 9.38 (1H, t, J=5 Hz), 7,54 (2H, d, J=9 Hz), 7,50 (2H, d, J=9 Hz), 7,34 (2H, d, J=9 Hz), of 6.99 (2H, d, J=9 Hz), 5,10 (1H, s), of 4.00 (2H, d, J=5 Hz), 3,73 (2H, d, J=12 Hz), 2,78 (2H, d, J=7 Hz), 2,71 (2H, dt, J=12 Hz, 3 Hz), of 2.44 (3H, s), 2,19-2,02 (1H, m), 1,69 (2H, d, J=12 Hz), to 1.37 (2H, DQC, J=12 Hz, 3 Hz).

(Example 45)

[({5-Hydroxy-2-[(1-{4'-[(2S)-2-hydroxypropyl]biphenyl-4-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 136]

(1) (2S)-1-(4'-Bromodiphenyl-4-yl)propan-2-ol

[Chemical formula 137]

A solution of n-butylacrylamide in tetrahydrofuran (2 M, 0,40 ml, 0,80 mmol) was diluted with tetrahydrofuran (1 ml) in a nitrogen atmosphere at 0°C was added a solution of n-utility in hexane (2.8 M 0,57 ml, 1.6 mmol) followed by stirring at the same temperature for 10 minutes to give the solution of tri-n-butylaniline in tetrahydrofuran.

4,4'-Dibromodiphenyl (0,62 g, 2.0 mmol) was dissolved in tetrahydrofuran (5 ml) in a nitrogen atmosphere at 0°C was added a solution of tri-n-butylaniline in tetrahydrofuran, and the mixture was stirred at the same temperature for 1 hour posleduyushim the addition of (2S)-2-methyloxirane (0.15 ml, 2.2 mmol). The temperature of the reaction solution was raised to room temperature, followed by stirring for 30 minutes and then was added a saturated aqueous solution of ammonium chloride followed by extraction of the mixture with ethyl acetate. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,40 (hexane/ethyl acetate=2/1), thin layer chromatography was concentrated under reduced pressure, while receiving specified in the header connection (0,23 g, 0,79 mmol) as a white solid (yield 39%).

Spectrum of1H NMR was the same as in example 5-(3).

(2) [(1S)-2-(4'-Bromodiphenyl-4-yl)-1-methylethoxy](tert-butyl)dimethylsilane

[Chemical formula 138]

(2S)-1-(4'-Bromodiphenyl-4-yl)propan-2-ol (0,23 g, 0,79 mmol) and imidazole (0.11 g, 1.6 mmol) was dissolved in N,N-dimethylformamide (5 ml) and under an atmosphere of nitrogen was added tert-butyldimethylchlorosilane (0.24 g, 1.6 mmol) followed by stirring the mixture at room temperature for 1 hour. To the reaction solution was added diethyl ether and subsequent washing with water and hydrochloric acid (1 M). After distilling off the solvent under reduced pressure�and the resulting residue was purified by chromatography on a column of silica gel (Moritex Corporation, the solvent for elution: hexane/ethyl acetate) and the fraction corresponding to the Rf value=0,80 (hexane/ethyl acetate=10/1) thin-layer chromatography was concentrated under reduced pressure, while receiving specified in the title compound (0.25 g, of 0.62 mmol) as a white solid (yield 78%).

Spectrum of1H NMR was the same as in example 5-(4).

(3) [({5-Hydroxy-2-[(1-{4'-[(2S)-2-hydroxypropyl]biphenyl-4-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to the examples 1-(9) to 1-(13), but using [(1S)-2-(4'-bromodiphenyl-4-yl)-1-methylethoxy](tert-butyl)dimethylsilane instead of [(4'-bromodiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 37%) as a white solid.

[α]D20A +8.9° (C=1.00, the DMFA).

MS spectra and1H NMR were the same as in example 5-(5).

(Example 46)

[({5-Hydroxy-2-[(1-{4'-[(2R)-2-hydroxypropyl]biphenyl-4-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 139]

According to the examples from 45-(1) to 45-(3), but using (2R)-2-methyloxirane instead of (2S)-2-methyloxirane specified in the header connection receive (yield 18%) as a white solid.

[α]D20Are -8.9° (C=1.00, the DMFA).

MS spectra and1H NMR were the same as in example 5-(5).

(Example 47)

[({5-Hydroxy-2-[(1-{4'-[(2S)-2-hydroxybutyl]biphenyl-4-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 140]

According to the examples from 45-(1) to 45-(3), but using (2S)-2-heteroxylan instead of (2S)-2-methyloxirane specified in the title compound was obtained (yield of 8.2%) as a white solid.

[α]D19+14,3° (C=1.00, the DMFA).

MS spectra and1H NMR were the same as in example 27.

(Example 48)

[({5-Hydroxy-2-[(1-{4'-[(2R)-2-hydroxybutyl]biphenyl-4-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 141]

According to the examples from 45-(1) to 45-(3), but using (2R)-2-heteroxylan instead of (2S)-2-methyloxirane specified in the title compound was obtained (yield of 8.2%) as a white solid.

[α]D20As 14.3° (C=1.00, the DMFA).

MS spectra and1H NMR were the same as in example 27.

(Example 49)

[({5-Hydroxy-2-[(1-{4'-[(2R)-2-hydroxy-3-methoxypropyl]biphenyl-4-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 142]

According to the examples from 45-(1) to 45(3), but using (2R)-2-(methoxymethyl)oxirane instead of (2S)-2-methyloxirane specified in the header with�connection receive (yield of 6.6%) as a white solid.

[α]D20And +6.5° (C=1.00, the DMFA).

MS m/z: 549 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,87 (1H, Shir.C) 11,91 (1H, s), 9,40 (1H, t, J=5 Hz), of 7.48 (2H, d, J=9 Hz), 7,47 (2H, d, J=9 Hz), 7.23 percent (2H, d, J=8 Hz), of 6.99 (2H, d, J=8 Hz), 4.75 in (1H, Shir.(C), of 4.00 (2H, d, J=5 Hz), 3,83-3,73 (1H, m), 3,73 (2H, d, J=12 Hz), 3,26 (3H, s), 3,23 (2H, d, J=5 Hz), 2,78 (2H, d, J=7 Hz), 2,74-of 2.67 (2H, m), 2,63 (2H, d, J=6 Hz), of 2.44 (3H, s), 2,15-2,03 (1H, m), by 1.68 (2H, d, J=12 Hz), of 1.36 (2H, DQC, J=12 Hz, 3 Hz).

(Example 50)

[({5-Hydroxy-2-[(1-{4'-[(2S)-2-hydroxy-3-methoxypropyl]biphenyl-4-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 143]

According to the examples from 45-(1) to 45(3), but using (2S)-2-(methoxymethyl)oxirane instead of (2S)-2-methyloxirane specified in the title compound was obtained (yield of 9.4%) as a white solid.

[α]D21-6.7° C (C=1.00, the DMFA).

MS spectra and1H NMR were the same as in example 49.

(Example 51)

({[5-Hydroxy-2-({1-[4'-(3-hydroxypropyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 144]

According to examples 36-(2) and 1-(10) to 1-(13), but using [3-(4-bromophenyl)propoxy](tert-butyl)dimethylsilane instead of [(4-bromo-3-terbisil)oxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 9%) as pale-yellowish-white TV�Gogo substances.

MS m/z: 519 (M++ N);

1H-NMR (500 MHz, DMSO-d6) δ: 12,88 (1H, Shir.C) 11,91 (1H, s), 9,40 (1H, t, J=6 Hz), 7,49 (2H, d, J=8 Hz), of 7.48 (2H, d, J=8 Hz), 7,22 (2H, d, J=8 Hz), 6,98 (2H, d, J=8 Hz), 4,47 (1H, t, J=6 Hz), 4,01 (2H, d, J=6 Hz), 3,73 (2H, d, J=12 Hz), 3.43 points (2H, kV, J=6 Hz), 2,78 (2H, d, J=7 Hz), 2,70 (2H, t, J=12 Hz), 2,61 (2H, t, J=7 Hz), of 2.44 (3H, s), 2,14-2,04 (1H, m), 1,76-of 1.65 (4H, m), and 1.37 (2H, DQC, J=12 Hz, 3 Hz).

(Example 52)

({[5-Hydroxy-2-({1-[4'-(gidroximetil)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

[Chemical formula 145]

(1) 2-[5-Bromo-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]propan-2-ol

[Chemical formula 146]

2-[5-Bromo-2-(gidroximetil)phenyl]propan-2-ol (1.1 g, 4.4 mmol) and imidazole (0.78 g, 12 mmol) was dissolved in N,N-dimethylformamide (5 ml) was added tert-butyldimethylchlorosilane (0.86 g, 5.7 mmol) followed by stirring the mixture at room temperature over night. To the reaction solution was added water, followed by extraction with hexane and then the extract was successively washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (biotage AB Ltd., the solvent for elution: hexane/ethyl acetate), �aluca thus specified in the title compound (1.1 g, 3.1 mmol) as a colorless oil (yield 70%).

1H-NMR (400 MHz, CDCl3) δ: the 7.43 (1H, d, J=2 Hz), 7,31 (1H, DD, J=8,2 Hz), made 7.16 interest (1H, d, J=8 Hz), is 4.93 (2H, s), 4,34 (1H, s) to 1.61 (6H, s), of 0.91 (9H, s), of 0.11 (6H, s).

(2) [(4-Bromo-2-isopropylbenzyl)oxy](tert-butyl)dimethylsilane

[Chemical formula 147]

2-[5-Bromo-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-phenyl]propan-2-ol (0.79 g, 2.2 mmol) was dissolved in dichloromethane (7 ml) and to the solution was successively dropwise at 0°C was added triethylamine (and 0.61 ml, 4.4 mmol) and methanesulfonamide (0,34 ml, 4.4 mmol) followed by stirring the mixture at room temperature for 3 hours. To the reaction solution was added water, hexane and ethyl acetate, followed by extraction of the mixture with hexane. The extract was washed sequentially with hydrochloric acid (1 M), saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate.

After concentrating the organic layer under reduced pressure the resulting residue was dissolved in dichloromethane (12 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.3 ml, 22 mmol) followed by stirring the mixture at room temperature over night. The reaction solution was concentrated under reduced pressure and added water and hexane, followed by extraction �MESI hexane. The extract was sequentially washed with hydrochloric acid (1 M), saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure the resulting residue was purified by chromatography on a column of silica gel (biotage AB Ltd., the solvent for elution: hexane), while receiving specified in the title compound (0.56 g, 1.6 mmol) as a colorless oil (yield 74%).

1H-NMR (400 MHz, CDCl3) δ: 7,39 (1H, d, J=9 Hz), 7,38 (1H, d, J=9 Hz), 7,25 (1H, Shir.C), to 5.21 (1H, s), 4,84 (1H, C), a 4.65 (2H, s), a 2.01 (3H, s), of 0.92 (9H, s), of 0.08 (6H, s).

(3) tert-Butyl-5-(benzyloxy)-2-({1-[4'-(gidroximetil)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate

[Chemical formula 148]

According to examples 36-(2) and 18(6), but using [(4-bromo-2-isopropylbenzyl)oxy](tert-butyl)dimethylsilane instead of [(4-bromo-3-terbisil)oxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 72%) as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ: 7,52-to 7.33 (8H, m), 7,49 (2H, d, J=9 Hz), of 6.99 (2H, d, J=9 Hz), 5,28-5,23 (1H, m), 5,01 (2H, s), 4,97-is 4.93 (1H, m), 4,71 (2H, s), 3,73 (2H, d, J=12 Hz) or 2.91 (2H, d, J=7 Hz), of 2.75 (2H, dt, J=12 Hz, 3 Hz), 2,46 (3H, s), 2,17-of 2.06 (4H, m), of 1.80 (2H, d, J=12 Hz), of 1.74 (1H, Shir.C), 1,59 (9H, s), of 1.53 (2H, DQC, J=12 Hz, 3 Hz).

(4) Ethyl({[5-(benzyloxy)-2-({1-[4'-(�hydroxymethyl)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 149]

According to example 1-(11), but using tert-butyl-5-(benzyloxy)-2-({1-[4'-(gidroximetil)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate instead of tert-butyl-5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate, specified in the title compound was obtained (yield 83%) as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ: to 8.36 (1H, t, J=5 Hz), 7,53 was 7.45 (6H, m), 7,41-7,30 (4H, m), of 6.99 (2H, d, J=9 Hz), 5,28-5,23 (1H, m), 5,12 (2H, s), 4,97-4,94 (1H, m), 4.72 in (2H, d, J=4 Hz), 4,27 (2H, kV, J=7 Hz), 4,25 (2H, d, J=5 Hz), 3,74 (2H, d, J=12 Hz), 2,90 (2H, d, J=7 Hz), 2,78 (2H, dt, J=12 Hz, 3 Hz), 2,47 (3H, s), 2,17-of 2.07 (4H, m), to 1.79 (2H, d, J=12 Hz), of 1.74 (1H, Shir.C) a 1.54 (2H, DQC, J=12 Hz, 3 Hz), 1,32 (3H, t, J=7 Hz).

(5) Ethyl({[5-hydroxy-2-({1-[4'-(gidroximetil)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate

[Chemical formula 150]

Ethyl({[5-(benzyloxy)-2-({1-[4'-(gidroximetil)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0,094 g, 0.14 mmol) was dissolved in methanol (3 ml) was added a complex of palladium on activated carbon-Ethylenediamine (0,090 g), followed by stirring the mixture at room temperature for 2 hours in hydrogen atmosphere. The reaction solution was filtered through celite, the filtrate conc�grown under reduced pressure and then the resulting residue was purified by chromatography on a column of silica gel (biotage AB Ltd., the solvent for elution: dichloro methane/etoac), while receiving specified in the header connection (0,049 g, 0,088 mmol) as yellowish-white amorphous solid (yield 60%).

1H-NMR (400 MHz, CDCl3) δ: at 11.37 (1H, Shir.C), 8,51 (1H, t, J=5 Hz), 7,50 (1H, s), 7,49 (2H, d, J=9 Hz), of 7.36 (2H, s), 7,00 (2H, d, J=9 Hz), 4,76 (2H, s), 4,28 (2H, kV, J=7 Hz), 4,22 (2H, d, J=5 Hz), 3,73 (2H, d, J=12 Hz), 3,38-of 3.25 (1H, m), 2,83 (2H, d, J=7 Hz), to 2.76 (2H, dt, J=12 Hz, 3 Hz), of 2.54 (3H, s), 2,14-of 1.99 (1H, m), 1,78 (2H, d, J=12 Hz), of 1.74 (1H, Shir.(C), of 1.52 (2H, DQC, J=12 Hz, 3 Hz), of 1.33 (3H, t, J=7 Hz), of 1.30 (6H, d, J=7 Hz).

(6) ({[5-Hydroxy-2-({1-[4'-(gidroximetil)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to example 1-(13), but using ethyl({[5-hydroxy-2-({1-[4'-(gidroximetil)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate instead of ethyl({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate specified in the title compound was obtained (yield 85%) as a white solid.

MS m/z: 533 (M+H)+;

1H-NMR (400 MHz, DMSO-d6) δ: 12,88 (1H, s), 11,92 (1H, s), 9,41 (1H, t, J=6 Hz), 7,51 (2H, Shir.C), 7,45 (1H, s), of 7.36 (2H, Shir.C), 7,02 (2H, Shir.C), 4,56 (2H, s), 4,01 (2H, d, J=6 Hz), and 3.72 (2H, d, J=12 Hz), or 3.28 is 3.15 (1H, m), 2,87-2,62 (2H, m), 2,80 (2H, d, J=7 Hz), of 2.45 (3H, s), 2,12 (1H, Shir.C), 1,80-to 1.61 (2H, m), 1,53-of 1.31 (2H, m), 1,23 (6H, d, J=7 Hz).

(Example 53)

[({2-[(1-{5-[3-Fluoro-4-(gidroximetil)�enyl]pyridin-2-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 151]

According to example 1-(11), but using tert-butyl-5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate (1.8 g, 3.2 mmol) obtained in example 19-(1) instead of tert-butyl-5-(benzyloxy)-2-({1-[4'-(gidroximetil)biphenyl-4-yl]the piperidine-4-yl}methyl)-6-methylpyrimidin-4-carboxylate, ethyl({[5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate was obtained (1.7 g, 2.9 mmol) as a pale yellow oil (yield 92%).

According to the examples 19-(2), 1-(10), 22-(4) and 1-(13), but using ethyl({[5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate instead of tert-butyl-5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-carboxylate and [(4-bromo-2-terbisil)oxy](tert-butyl)dimethylsilane instead of tert-butyl-[(4-iodobenzyl)oxy]dimethylsilane specified in the header connection receive (yield 21%) as a white solid.

MS m/z: 510 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,87 (1H, Shir.C), 11,92 (1H, s), at 9.38 (1H, t, J=5 Hz), is 8.46 (1H, d, J=3 Hz), the 7.85 (1H, DD, J=9 Hz, 3 Hz), 7,50-7,40 (3H, m), of 6.99 (1H, d, J=9 Hz), a 5.25 (1H, t, J=6 Hz), of 4.54 (2H, d, J=6 Hz), 4,33 (2H, d, J=13 Hz), 3,99 (2H, d, J=5 Hz), 2,85 (2H, t, J=13 Hz), to 2.76 (2H, d, J=7 Hz), of 2.44 (3H, s), of 2.25 to 2.14 (1H, m), of 1.66 (2H, d, J=13 Hz), 1,24 (2H, DQC, J=13 Hz, 3 Hz).

(Example 54)

[({2-[(1-{5-[3-Chloro-4-(GI�roximity)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 152]

According to example 53, but using [(4-bromo-2-chlorbenzyl)oxy](tert-butyl)dimethylsilane instead of [(4-bromo-2-terbisil)oxy](tert-butyl)dimethylsilane specified in the title compound was obtained (yield 22%) as a white solid.

MS m/z: 526 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,89 (1H, Shir.C), 11,92 (1H, s), 9,39 (1H, t, J=5 Hz), is 8.46 (1H, d, J=3 Hz), 7,86 (1H, DD, J=9 Hz, 3 Hz), 7,66 (1H, s), 7,63-7,54 (2H, m), 6,90 (1H, d, J=9 Hz), of 5.40 (1H, t, J=5 Hz), 4,57 (2H, d, J=5 Hz), 4,35 (2H, d, J=13 Hz), of 4.00 (2H, d, J=5 Hz), 2,85 (2H, t, J=13 Hz), 2,77 (2H, d, J=7 Hz), of 2.45 (3H, s), 2,25-of 2.16 (1H, m), 1,67 (2H, d, J=13 Hz), 1,25 (2H, DQC, J=13 Hz, 3 Hz).

(Example 55)

[({5-Hydroxy-2-[(1-{5-[4-(gidroximetil)-3-methylphenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[Chemical formula 153]

According to example 53, but using [(4-bromo-2-methylbenzyl)oxy](tert-butyl)dimethylsilane instead of [(4-bromo-2-terbisil)oxy](tert-butyl)dimethylsilane specified in the header connection receive (yield 18%) as a white solid.

MS m/z: 506 (M+H)+;

1H-NMR (500 MHz, DMSO-d6) δ: 12,89 (1H, Shir.C) 11,91 (1H, s), 9,39 (1H, t, J=5 Hz), to 8.41 (1H, d, J=2 Hz), 7,80 (1H, DD, J=9 Hz, 2 Hz), 7,41-of 7.35 (3H, m), to 6.88 (1H, d, J=9 Hz), to 5.05 (1H, t, J=5 Hz), 4,49 (2H, d, J=5 Hz), 4,32 (2H, d, J=13 Hz), of 4.00 (2H, d, J=5 Hz), 2,83 (2H, t, J=13 Hz), to 2.76 (2H, d, J=7 Hz), of 2.44 (3H, s) to 2.29 (3H, s), 2,24-to 2.14 (1H, m), of 1.66 (2H, �, J=13 Hz), 1,24 (2H, DQC, J=13 Hz, 3 Hz).

Examples of drugs

Example 1 preparation (for injection)

1,5% of the mass. the compounds of examples was stirred in 10% vol. the propylene glycol, then add water for injection to establish a predetermined volume and then sterilized, while receiving the drug for injection.

Example 2 preparation of (hard capsule)

100 mg of powdered compounds of examples 128,7 mg of lactose, 70 mg of cellulose and 1.3 mg of magnesium stearate were mixed, passed through a 60 mesh sieve and then, the resulting powders were placed in a 250 mg gelatin capsule No. 3, while receiving capsules.

Example 3 preparation (pill)

100 mg of powdered compounds of examples, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate were mixed and the mixture is preformed in a tabletting machine to give the tablet, and each had a mass of 200 mg. per tablet, if necessary, can be coated.

Example test

The pharmacological activity of the compounds of the present invention was confirmed by the following test.

The activity of tested compounds against induction in vitro erythropoietin (EPO) was evaluated using the cancer cell line Hep3B human liver (ATSS, Manassas, VA). Cells Nerve were cultured overnight at 37°C in the medium Needle, modified by way of Dulbecco (DMEM) in the presence of 10% savor�TCI fetal cow (FBS) (24-well plate, 1,0×105cells/well). After replacing the above medium with fresh DMEM (+10% FBS) containing the test compound dissolved in 0.5% dimethyl sulfoxide (DMSO) (obtained up to a concentration of 12.5 μm), or control in the form of a solvent (0.5% DMSO), the cells were cultured for 24 hours at 37°C. After separation of the supernatant of culture the concentration of EPO in the culture supernatant was quantitatively determined using ELISA kit human EPO (StemCell Technologies).

The concentration of EPO in the case of the compounds of each example of the test compounds were expressed as a multiple of the concentration of EPO in the control. The results are shown in table 1. The concentration of EPO in the case of the compounds of each example was significantly increased compared to the concentration of EPO control (solvent). That is, the compounds of the present invention exhibited superior that increase the production of EPO activity and are useful as medicines (in particular, medicines for the prevention or treatment of anaemia).

Industrial applicability

The compound of the present invention, its pharmacologically acceptable ester or pharmacologically acceptable salt has excellent that increase the production of EPO activity PE�Xia applicable for diseases or the like, caused by reduced production of EPO. In particular, the compound of the present invention, its pharmacologically acceptable ester or pharmacologically acceptable salt is useful as a drug for prevention and/or treatment of anaemia, preferably nephrogenic anemia, anemia of prematurity, anemia associated with chronic disease, anemia associated with cancer chemotherapy, cancerous anemia, anemia associated with inflammation, or anemia associated with congestive heart failure, more preferably of anemia associated with chronic kidney disease, and can also be used as a medicament for prevention and/or treatment of ischemic cerebrovascular disease.

1. The connection represented by the following General formula (1)

in which
R1represents a group represented by the following General formula (1A)

in which
R4and R5each independently represents a hydrogen atom, a halogen atom or a C1-C6alkyl group,
R6represents a hydrogen atom, a halogen atom or a C1-C6alkyl group,
R7is hydraxis1-C6alkyl group, hydroxychlor�na 1-C6alkyl group, C1-C6alkoxyl1-C6alkyl group which may have 1 substituent independently selected from the group of substituents α, (C1-C6alkoxy)carbonyl group, C1-C6alkoxyl1-C6alkoxyl1-C6alkyl group, hydroxys1-C6alkoxygroup, S1-C6alkylcarboxylic group, (C1-C6alkyl)(C1-C6alkyl) carbamoyl group, (C1-C6alkyl)(C1-C6alkyl) carbamoyl1-C6alkyl group or a C2-C7alkanoyloxy1-C6alkyl group,
the group of substituents α represents a hydroxy-group,
the ring Q1is piperidinyloxy group,
the ring Q2represents a phenyl group or pyridyloxy group,
the ring Q3represents a phenyl group or pyridyloxy group, and
X represents a simple bond or methylene,
R2represents C1-C3alkyl group, and
R3represents a hydrogen atom, pharmacologically acceptable ester or pharmacologically acceptable salt.

2. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where R2performance�et a methyl group.

3. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where R4represents a hydrogen atom.

4. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where R5represents a hydrogen atom, a halogen atom or a methyl group.

5. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where R5represents a hydrogen atom.

6. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where R6represents a hydrogen atom, a halogen atom or a methyl group.

7. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where R6represents a hydrogen atom.

8. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1,1-debtor-2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydrox�-2-methylpropyloxy group methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxyethoxymethyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethylcarbamoyl group.

9. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, ethoxycarbonyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethylcarbamoyl group.

10. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where
R1represents a group represented by the following General formula (1B)

where
R5represents a hydrogen atom, a halogen atom or a C1-C6alkyl group,
R6represents a hydrogen atom, a halogen atom or a C1 6alkyl group,
R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1,1-debtor-2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxyethoxymethyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethylcarbamoyl group,
V, W and Υ, each independently, represent an atom of carbon with 1 hydrogen atom, or a nitrogen atom, provided that W and Υ cannot both represent a nitrogen atom, and
X represents a single bond or methylene.

11. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where
R1is a group represented by any of the following formulas from the General formula (1B-1) to General formula (1B-8)

where
R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1,1-debtor-2-hydro�similou group 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl group, methoxyethoxymethyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethylcarbamoyl group.

12. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 1, where
R1is a group represented by any of following General formula (1B-1), General formula (1B-2), General formula (1B-3), General formula (1B-5) or the General formula (1B-6)

where
R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1,1-debtor-2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,1-debtor-2-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, 1,1-debtor-2-hydroxy-2-methylpropyloxy group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, methoxycarbonyl group, ethoxycarbonyl gr�foam, methoxyethoxymethyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethylcarbamoyl group.

13. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 10, where R7represents a hydroxymethyl group, 1-hydroxyethylene group, 2-hydroxyethylene group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxybutyl group, 2-hydroxy-1,1-dimethylethylene group, methoxymethyl group, 2-hydroxy-3-methoxypropyl group, ethoxycarbonyl group, 1-methoxyethoxymethyl group, 2-hydroxyethoxy, methylcarbamoyl group, dimethylcarbamoyl group or dimethylcarbamoyl group.

14. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt of claim 1, wherein in the case where R7is a group having a hydroxy-group, selected from hydraxis1-C6alkyl group, hydroxylases1-C6the alkyl group and hydroxys1-C6alkoxygroup, the hydroxy-group forms an ester bond with the C1-C6alkanoyloxy group.

15. The compound or its pharmacologically acceptable salt according to claim 1, selected from the following soy�of ineni:
({[5-hydroxy-2-({1-[4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[2-({1-[4'-(acetoxymethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-2-({1-[4'-(1-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-2-({1-[4'-(2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-2-({l-[4'-(2-hydroxypropyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-2-({1-[4'-(2-hydroxy-1,1-dimethylethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[2-({1-[4'-(dimethylcarbamoyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-6-methyl-2-({l-[4'-(methylcarbamoyl)biphenyl-4-yl]piperidine-4-yl}methyl)pyrimidine-4-yl]carbonyl}amino)acetic acid,
[({2-[(1-{4'-[2-(dimethylamino)-2-oxoethyl]biphenyl-4-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
[({5-hydroxy-2-[(1-{4-[4-(gidroximetil)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
[({5-hydroxy-2-[(1-{4-[3-(gidroximetil)benzyl]phenylpiperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
[({5-hydroxy-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
{[(5-hydroxy-2-{[1-(4-{5-[1-(methoxyethoxy)ethyl]pyridin-2-yl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid
[({2-[(1-{4-[5-(1-acetoxyethyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
[({5-hydroxy-2-[(1-{4-[5-(gidroximetil)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
[({2-[(1-{4-[5-(ethoxycarbonyl)pyridin-2-yl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
[({2-[(1-{4-[2-(ethoxycarbonyl)benzyl]phenyl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
{[(5-hydroxy-2-{[1-(4-{[6-(2-hydroxyethoxy)pyridin-3-yl]methyl}phenyl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid
[({5-hydroxy-2-[(1-{5-[4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
[({5-hydroxy-2-[(1-{5-[4-(2-hydroxypropyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
[({5-hydroxy-2-[(1-{5-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic to�slots,
({[2-({1-[2-chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-2-({1-[4'-(gidroximetil)-2-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[2-({1-[3'-chloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-2-({1-[4'-(gidroximetil)-2'-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-2-({1-[4'-(gidroximetil)-2,3'-dimethyldiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-2-({1-[4'-(2-hydroxybutyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
[({5-hydroxy-2-[(1-{4-[4-(2-hydroxypropyl)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
[({5-hydroxy-2-[(1-{4-[4-(2-hydroxy-1,1-dimethylethyl)benzyl]phenyl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
({[2-({1-[4'-(1,1-debtor-2-hydroxyethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[2-({l-[4'-(l,1-debtor-2-hydroxypropyl)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, ({[2-({1-[4'-(1,1-debtor-2-hydroxy-2-methylpropyl") biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
{[(5-[(2,2-dimethylpropanoyl)oxy]-2-{[1-(4'-{[(2,2-dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid
{[(2-{[1-(4'-{[(2,2-dimethylpropanoyl)oxy]methyl}biphenyl-4-yl)piperidine-4-yl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid
({[5-hydroxy-2-({1-[4'-(methoxymethyl)biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[2-({l-[2'-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[2-({1-[3'-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[2-({1-[2-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[2-({l-[3-fluoro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-2-({1-[4'-(gidroximetil)-3'-methylbiphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[2-({1-[3',5'-debtor-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyridin�n-4-yl]carbonyl}amino)acetic acid,
({[2-({1-[3',5'-dichloro-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[2-({1-[3',5'-dimethyl-4'-(gidroximetil)biphenyl-4-yl]piperidine-4-yl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
[({5-hydroxy-2-[(1-{4'-[2-hydroxy-3-methoxypropyl]biphenyl-4-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
({[5-hydroxy-2-({l-[4'-(3-hydroxypropyl]biphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
({[5-hydroxy-2-({l-[4'-(gidroximetil)-3'-isopropylphenyl-4-yl]piperidine-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid,
[({2-[(1-{5-[3-fluoro-4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid,
[({2-[(1-{5-[3-chloro-4-(gidroximetil)phenyl]pyridin-2-yl}piperidine-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, or
[({5-hydroxy-2-[(1-{5-[4-(gidroximetil)-3-methylphenyl]pyridin-2-yl}piperidine-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid.

16. Pharmaceutical composition for enhancing the production of erythropoietin, containing as active ingredient a pharmacologically effective amount of a compound, its pharmaceutically acceptable complex, ether or e�about pharmacologically acceptable salt according to any one of claims. 1-15.

17. Pharmaceutical composition according to claim 16 for the prevention and/or treatment of anemia.

18. Pharmaceutical composition according to claim 17, where the anemia is nephrogenic anemia, anemia of prematurity, anemia associated with chronic disease, anemia associated with cancer chemotherapy, cancerous anemia, anemia associated with inflammation, or anemia associated with congestive heart failure.

19. Pharmaceutical composition according to claim 17, where the anemia is anemia related to chronic kidney disease.

20. Use of a compound, pharmacologically acceptable ester or pharmacologically acceptable salt according to any one of claims. 1-15 for obtaining a medicinal product for enhancing the production of erythropoietin.

21. The use according to claim 20, wherein the medicament is a medicament for prevention and/or treatment of anemia.

22. The use according to claim 21, where the anemia is nephrogenic anemia, anemia of prematurity, anemia associated with chronic disease, anemia associated with cancer chemotherapy, cancerous anemia, anemia associated with inflammation, or anemia associated with congestive heart failure.

23. The use according to claim 21, where the anemia is anemia related to chronic kidney disease.

24. Method of producing an Erythro�oaten, comprising administering a pharmacologically effective amount of a compound, pharmacologically acceptable ester or pharmacologically acceptable salt according to any one of claims. 1-15 mammal or a bird.

25. A method for the treatment or prophylaxis of a disease caused by reduced production of erythropoietin, comprising administering a pharmacologically effective amount of a compound, pharmacologically acceptable ester or pharmacologically acceptable salt according to any one of claims. 1-15 mammal.

26. A method according to claim 25, where the disease is anemia.

27. A method according to claim 25, where the disease is nephrogenic anemia, anemia of prematurity, anemia associated to chronic diseases, anemia, concomitant cancer chemotherapy, cancerous anemia, anemia associated with inflammation, or anemia, concomitant congestive heart failure.

28. A method according to claim 25, where the disease is anemia related to chronic kidney disease.

29. A method according to claim 25, where the mammal is man.

30. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to any one of claims. 1-15 for use in the method of treatment or prophylaxis of a disease caused by reduced production of erythropoietin.

31. The connection, his pharmacologist�Cesky acceptable ester or its pharmacologically acceptable salt according to claim 30, where the disease is anemia.

32. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 30, where the disease is nephrogenic anemia, anemia of prematurity, anemia associated to chronic diseases, anemia, concomitant cancer chemotherapy, cancerous anemia, anemia associated with inflammation, or anemia, concomitant congestive heart failure.

33. Compound, its pharmacologically acceptable ester or pharmacologically acceptable salt according to claim 30, where the disease is anemia related to chronic kidney disease.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , wherein Y and Z are independently specified in a group of a) or b) so that one of Y or Z is specified in the group a), and another one - in the group b); the group a) represents i) substituted C6-10aryl; ii) C3-8cycloalkyl; iii) trifluoromethyl or iv) heteroaryl specified in a group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furasan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl and [1,2,3]thiadiazolyl; the group b) represents i) C6-10aryl; ii) heteroaryl specified in a group consisting of thiazolyl, pyridinyl, indolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridin-2-yl, furo[2,3-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl, quinolinyl, quinazolinyl, thienyl and benzimidazolyl; iii) benzofused heterocyclyl attached through a carbon atom, and when a heterocyclyl component contains a nitrogen atom, the carbon atom is optionally substituted by one substitute specified in a group consisting of C3-7cycloalkylcarbonyl; C3-7cycloalkylsulphonyl; phenyl; phenylcarbonyl; pyrrolylcarbonyl; phenylsulphonyl; phenyl(C1-4)alkyl; C1-6alkylcarbonyl; C1-6alkylsulphonyl; pyrimidinyl and pyridinyl; C3-7cycloalkylcarbonyl, phenyl, phenylcarbonyl, phenyl(C1-4)alkyl and phenylsulphonyl are optionally substituted by trifluoromethyl, or by one or two fluor-substitutes; iv) phenoxatiynyl; vi) fluoren-9-on-2-yl; vii) 9,9-dimethyl-9H-fluorenyl; viii) 1-chlornaphtho[2,1-b]thiophen-2-yl; ix) xanthen-9-on-3-yl; x) 9-methyl-9H-carbazol-3-yl; xi) 6,7,8,9-tetrahydro-5H-carbazol-3-yl; xiii) 3-methyl-2-phenyl-4-oxochromen-8-yl; or xiv) 1,3-dihydrobenzimidazol-2-on-5-yl optionally substituted by 1-phenyl, 1-(2,2,2-trifluoroethyl), 1-(3,3,3-trifluoropropyl) or 1-(4,4-difluorocyclohexyl); 1-phenyl is optionally substituted by one or more fluor-substitutes or trifluoromethyl; or xv) 4-(3-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl; R1 represents C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo or aryl(C1-3)alkyl; or when s is equal to 2 and R1 represents C1-3alkyl, the substitutes C1-3akyl is taken with a piperazine ring to form 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.2]octanyl ring system, and its pharmaceutical compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a method of obtaining a quinolone compound, which includes a stage of interaction of a dechloroquinolone compound, or its pharmaceutically acceptable salt, or ether with a chlorinating agent and acid, in which the molar ratio of the acid to the dechloroquinolone compound constitutes from 0.008 to 0.012 and in which less than 0.40% of a dimeric admixture is obtained in a percentage of the area counted per the obtained quinolone compound, and where the quinolone compound represents 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, or its pharmaceutically acceptable salt or ether, the dechloroquinolone compound represents 1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinolin-3-carboxylic acid, or its pharmaceutically acceptable salt, or ether and the dimeric admixture represents 1-amino-3-(azetidin-3-yloxy)propane-2-olbis(H,H'-quinolonecarboxylic acid) or its pharmaceutically acceptable salt or ether.

EFFECT: improved method of obtaining a quinolone derivative, useful as an anti-infective agent, is elaborated.

15 cl, 21 dwg, 2 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to pyrazine derivatives of formula I, as well as to their enanthiomers, diastereomers and pharmaceutically acceptable salts, wherein R1 is specified in a group consisting of ii) pyridinyl optionally having one substitute specified in a group consisting of C1-4alkoxy and cyano; and iii) pyrimidin-5-yl; or R1 optionally represents methoxymethyl, when Y represents ethinyl; Y represents ethinyl or a bond; R2 represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl substituted by methyl, phenyl has one to two substitutes independently specified in a group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, difluoromethyl, trifluoromethyl and hydroxy; or R2 represents phenyl having one C1-4alkylcarbonylamino or 1H-imidazol-1-yl substitute; X represents O or CH2; L is absent, and R3 represents 4-aminocyclohexyl, or L represents methylene, while R3 is specified in a group consisting of i) pyrrolidin-2-yl; ii) 1-aminoeth-1-yl; and iii) 1-aminocyclopent-1-yl; or R3 is combined into one cycle with L nitrogen atom to which L is attached to form piperazinyl. Besides, the invention refers to specific compounds, a pharmaceutical compound based on a compound of formula I, a method of treating pain and some neurodegenerative diseases.

EFFECT: there are produced new pyrazine derivative effective in treating pain and some neurodegenerative diseases.

21 cl, 3 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: present invention refers to compounds having formula III such as below, wherein: Q represents C(Y3) or N; R represents H, -R1, -R1-R2-R3, -R1-R3 or -R2-R3; R1 represents heteroaryl or heterocyclyl each of which is optionally substituted by one or more C1-6alkyls, hydroxyC1-6alkyls, oxogroups or halogenC1-6alkyls; R2 represents -C(=O), -O, -C(R2')2, -C(R2')2C(=O), -C(R2')2C(=O)NR2', C(R2')2 N(R2')C(=O), -C(=NH), -C(R2')2NR2' or -S(=O)2; each R2' independently represents H or C1-6alkyl; R3 represents H or R4; R4 represents C1-6alkyl, C1-6alkoxygroup, aminogroup, C1-6alkylaminogroup, di(C1-6alkyl)aminogroup, heterocyclyl, C1-10alkylheterocycloalkyl, heterocycloalkylC1-10alkyl each of which is optionally substituted by one or more C1-6alkyls, C1-6alkylaminogroups, di(C1-6alkyl)aminogroups, hydroxygroups, hydroxyC1-6alkyls, C1-6alkoxygroups, oxogroups or halogenC1-6alkyls; X represents CH; X' represents CH; and the rest symbols have values as specified in the patent claim. The compounds of formula III inhibit Bruton's tyrosine kinase (Btk). There are also described compositions containing the compounds of formula III, and at least one carrier, thinner or excipient, and a method for producing the compound of formula X in accordance with the following procedure.

EFFECT: compositions are effective for modulating Btk activity and treating diseases related to Btk hyperactivity, and can be used for treating inflammatory and autoimmune diseases related to disturbed B-cell proliferation, such as rheumatoid arthritis.

22 cl, 2 tbl, 260 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to bis-benzimidazole derivatives of formula I and their optional stereoisomers, pharmaceutically acceptable salts and solvates, wherein R and R' are independently specified in -CR1R2R3, phenyl substituted by 1 substitute specified in halogen; and tetrahydrofuranyl, wherein R1 is specified in C1-4alkyl optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl optionally substituted by 1, 2 or 3 substitutes optionally specified in halogen, C1-4alkoxy, trifluoromethoxy, or 2 substitutes on adjoining atoms of the ring form 1,3-dioxolane group; benzyl substituted by halogen or methoxy; pyridinyl; indolyl; pyridinylmethyl or indolylmethyl; R2 is specified in hydrogen, hydroxyl, di-C1-4alkylamino, (C3-6cycloalkyl) (C1-4alkyl)amino, C1-4alkylcarbonylamino, phenylamino, C1-4alkyloxycarbonylamino, (C1-4alkyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonylamino, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidin-1-yl, 3,3-difluoropiperidin-1-yl, morpholin-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and R3 represents hydrogen or C1-4alkyl or CR2R3 together form carbonyl; or CR1R3 form cyclopropyl group. The invention also refers to a pharmaceutical composition based on a compound of formula I.

EFFECT: there are prepared bis-benzimidazole derivatives possessing the inhibitory activity on hepatitis C virus.

9 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein pyridine rings A, B and C are independently unsubstituted or substituted by one or more substitutes independently specified in a group consisting of: C1-6-alkyl, halogen alkyl having 1-6 carbon atoms, Hal or OR13; L1 and L2 are independently specified in residues having formula or , wherein at least one of L1 or L2 has formula (b); R1 and R2 are independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; R3 is specified in hydrogen and C1-6-alkyl; R4, R5, R6 and R7 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R8, R9, R10 and R11 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R12 is specified in a group consisting of hydrogen and C1-6-alkyl; R13 is independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; p is equal to 1 or 2; q is equal to 0, 1 or 2, and Hal is specified in a group consisting of F, Cl, Br, and I, which can be used in treating a group of amyloid protein related disturbances and disorders.

EFFECT: preparing the compounds which can be used in treating a group of amyloid protein related disturbances and disorders.

17 cl, 1 dwg, 6 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a dye which contains a binding group in its molecular structure, wherein said binding group provides covalent bonding of said dye to a surface, and said binding group is represented by formula 1 , in which the binding site of said binding group inside said molecular structure of said dye is located at the terminal carbon atom marked with an asterisk in said formula. G is selected from -COOH, -SO3H, -PO3H2, -BO2H2 -SH, -OH, -NH2, A is selected from a group consisting of H, -CN, -NO2, -COOR, -COSR, -COR, -CSR, -NCS, -CF3, -CONR2, -OCF3, C6H5.mFm, in which m=1-5, R is H or any linear or branched alkyl chain of general formula -CnH2n+1 n=0-12, preferably 0-4, or any substituted or unsubstituted phenyl or biphenyl, where said dye is represented by formula (2) or formula (4), where said chromophore is a squarylium dye derivative or a croconium dye derivative, which is capable of absorbing light with a wavelength in the visible and/or infrared range, preferably in the range from 300 to 1200 nm or part thereof, wherein each derivative of said squarylium dye and said croconium dye has aromatic ring systems Ar1 and Ar2, that are bonded to the squarylium dye or croconium dye derivatives. The invention also relates to methods of producing chromophore which is part of a dye and is a dye itself, as well as devices using said dye and applications thereof as a sensitising agent and a sensor.

EFFECT: disclosed dyes are also capable of absorbing light in the long-wave spectral range.

32 cl, 23 ex, 20 dwg

Cytokine inhibitors // 2485113

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazole compounds of formula wherein the radical values A, X, R1, R2, R3 are presented in clause 1 of the patent claim.

EFFECT: there are disclosed pharmaceutical compositions of sail compounds for cytokine (eg TNFα or IL-1β) reduction.

16 cl, 107 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing heterocycle-substituted pyridine derivatives of general formula (I) by reacting a compound of general formula (III) with a compound of formula (II) in a solvent and in the presence of a catalyst based on palladium or a base, where R1, R2, X, Y, Q, A, Z, R, R3 and R4 are described in the claim.

EFFECT: method enables to obtain pyridine derivatives on an industrial scale.

7 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole and indazole compounds of formula in which n equals a whole number from 1 to 3, m equals 0 or 1, A denotes phenyl, X denotes C or N, R1 denotes hydrogen, alkyl, -(CH2)rNR7R8, where r equals a whole number from 1 to 5, and R7 and R8 independently denote hydrogen, alkyl or alkylcarbonyl, or can together form an optionally alkyl-substituted alkylene chain, where optionally one methylene is substituted with a N atom, R2 denotes hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, denotes -(CH2)pCO2R7, -(CH2)pOR7, -(CH2)pNR7R8, -NHR10, -N(H)S(O)2R7, -NHC(O)R10, -(CH2)pS(O)2R7 or (CH2)p-heterocycle-R10, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, R10 denotes hydrogen, oxo, alkylsulphonyl, alkylcarbonyl, alkyloxycarbonyl, alkoxy, alkyl or heterocycle, R3 denotes hydrogen, cyano, halogen, alkyl or phenyl, or denoes -(CH2)n-heterocycle or -(CH2)n-aryl, where n equals a whole number from 0 to 3, provided that R3 denotes phenyl when X denotes C and m=0, R4 denotes -YR11, where Y denotes a direct bond or -(CR7R8)pY′-, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, Y′ is selected from a group consisting of -O-, -S-, -NR12-, -NR12C(O)-, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)q- and -S(O)qNR12-, where R12 denotes hydrogen, alkyl, aryl or heteroaryl, q equals a whole number from 0 to 2, R11 is selected from a group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and -(CH2)tB-R13, where t equals a whole number from 0 to 3, B denotes heterocycle, heteroaryl or aryl, R13 denotes hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulphonyl, R5 denotes hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, R6 denotes (CR7R8)p-Z-D-W-R14, where Z denotes a direct bond, or is selected from a group consisting of -C(O)-, -C(O)O, -C(O)NR12- and -S(O)y-, y equals a whole number from 1 or 2, D denotes a direct bond, or denotes cycloalkyl, heteroaryl or heterocycle, W denotes a direct bond, or denotes -NR -, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)y-, -S(O)yNR12- or -NR12S(O)y, wherein R14 denotes hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, R5 and R6 together denote an alkylene chain, provided that R6 denotes cycloalkyl or heterocyclyl when X denotes N, where the heteroaryl is a 5-6-member aromatic ring containing 1-2 heteroatoms selected from N, O and S, the heterocycle is a 3-8-member ring containing 1-3 heteroatoms selected from N, O and S, where the alkyl, alkoxy, aryl, cycloalky, heterocycle and heteroaryl can be optionally substituted, and the substitutes, one or more, are selected from a group consisting of hydroxy, halogen, nitrile, amino, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo, and pharmaceutically acceptable salts or stereoisomers thereof. The invention also relates to a composition, as well as a method of preparing said composition.

EFFECT: obtaining novel biologically active compounds for preventing or treating necrosis and necrosis-associated diseases.

40 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to novel compound with inhibition effect on FAAH enzyme, corresponding to the general formula (I) where variables m, n, X, R1 and R2, R3, R4 and Y variables take values provided in the claim; to method of compound obtainment, and to compound application in therapy, and to pharmaceutical composition including compound of the formula (I).

EFFECT: improved method.

12 cl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new 2,7-substituted indoles of formula: its pharmaceutical salts, where n represents 0, 1 or 2; p represents 1 or 2; R1 represents phenyl, optionally substituted with one or two substitutes, chosen from a group, including halogen, C1-C12alkyl, halogenC1-C12alkyl; R2 represents a mono-valent saturated residue, consisting of one ring, containing six ring atoms, one or two of which are nitrogen atoms, and the others are carbon atoms, optionally substituted with one or two C1-C12alkyls; R3 represents H, C1-C12alkyl. The compounds have antagonist action to the "5-ГТ6" receptor.

EFFECT: possibility of using these compounds in pharmaceutical compositions in an effective quantity.

8 cl, 2 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of indole of the general formula (I): wherein R1 means -S(O)0-2-A wherein A means phenyl optionally substituted with one or some groups or some groups chosen from (lower)-alkyl, (lower)-alkoxy-group, halogen atom, (lower)-halogenalkyl, (lower)-alkylsulfonyl or (lower)-halogenalkylsulfonyl, naphthyl, pyridinyl or benzothiazolyl; R2 means hydrogen atom, (C1-C6)-alkyl; R3 means hydrogen atom, (C1-C6)-alkyl; R4 means hydrogen atom, or one radical among R5, R6 or R7 means group of the general formula (B) wherein W means group -CH- or nitrogen atom, and others mean independently hydrogen atom; R8 means hydrogen atom, (C1-C10)-alkyl; R9 and R10 mean independently hydrogen atom, or their pharmaceutically acceptable salts. Compounds of the formula (I) possess affinity to 5-HT6 receptors that allows their using in pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of sulfonamide of the general formula (I): wherein A means a substitute chosen from 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) optionally substituted with 1 or 2 halogen atoms, (C1-C4)-alkyl or phenyl radical, or 5- or 6-membered heteroaryl radical comprising 1 or 2 atoms of O, N or S; bicyclic heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from O, N or S and optionally substituted with 1 or 2 halogen atoms or (C1-C4)-alkyl; R1 means hydrogen atom (H), (C1-C4)-alkyl, benzyl; n means 0, 1, 2, 3 or 4; R2 means -NRR5 or the group of the formula: wherein a dotted line means optional chemical bond; R, R4 and R5 mean independently H or (C1-C4)-alkyl; or one of its physiologically acceptable salts. Compounds of the formula (1) possess antagonistic activity with respect to serotonin HT6-receptors that allows their using in pharmaceutical composition and for preparing a medicament.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

10 cl, 2 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to the field of pharmaceutics and deals with a pharmaceutical composition, which contains feline erythropoietin as an active ingredient, to which two or more polyethyleneglycol molecules with a non-branched chain are attached, with a water-soluble long-chain molecule having the molecular weight, constituting not less than 30 kDa and producing the haemopoietic effect. A haemopoietic medication and a medication for the treatment of anaemia are based on the said composition.

EFFECT: group of inventions provides the haemopoietic effect, which lasts for not less than seven days, when introduced to humans and/or animals.

8 cl, 4 dwg, 2 tbl, 2 ex

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