N-pyridin-3-yl or n-pyrazin-2-yl carboxamides as agents increasing level of hdlp cholesterol

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

 

The scope of the invention

The present invention relates to N-pyridin-3-yl or N-pyrazin-2-yl carboxamide compounds, which are agents that increase the level of HDL cholesterol, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances.

In particular, the invention relates to compounds of formula I

where A, R1-R7are as described below, and their isomeric forms and their pharmaceutically acceptable salts.

Compounds according to the invention are agents that increase the level of HDL cholesterol, and therefore can be used in therapeutic and/or prophylactic treatment of diseases and disorders such as dyslipidemia, atherosclerosis and cardiovascular diseases.

Atherosclerosis and the accompanying ischemic heart disease are the leading cause of death in the industrialized world. It is established that the risk of developing coronary heart disease is strictly correlated with the levels of certain lipids in the plasma. Lipids are transported in the blood by lipoproteins. The General structure of lipoproteins is a core of neutral lipids (triglyceride and cholesterol ester), and a shell of polar lipids (phospholipids and neeterificirovannah cholesterol). is there are 3 different classes of plasma lipoproteins with different lipids in the core: low-density lipoprotein (LDL), which is rich in cholesterol esters (CE); high-density lipoprotein (HDL), which is also rich in cholesterol esters (CE); and lipoprotein very low density (VLDL), which is rich in triglycerides (TG). Different lipoproteins can be separated based on their different speeds flotation, density or size.

High levels of LDL cholesterol (LDL-C) and triglycerides are in direct communication, whereas high levels of HDL cholesterol (HDL-C) are in reverse due to the risk of development of cardiovascular diseases.

There is not a completely satisfactory resulting in increased HDL therapies. Niacin can significantly increase HDL, but has serious limitations in terms of portability, which weaken the adherence to treatment. Fibrates and inhibitors of HMG-COA reductase (hydroxymethylglutaryl-coenzyme A-reductase from HMG CoA reductase) increase the level of HDL cholesterol is very moderately (-10-12%). As a result there is a significant unmet medical need for well-hyphenated agent, which can significantly increase the levels of HDL in plasma.

Thus, agents that increase HDL cholesterol, can be used as medicines for the treatment and/or prevention of atherosclerosis, peripheral vascular disease, dyslipidemia, is hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion damage, angioplasticheskih restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxemia.

In addition, agents that increase HDL cholesterol, can be used in combination with another compound, this compound is an inhibitor of HMG-COA reductase inhibitor secretion of microsomal protein transfer of triglycerides (MTP) / ApoB (Apolipoprotein b), an activator of PPAR (receptor-activated proliferation peroxisome), inhibitor of the reuptake of bile acids, an inhibitor of protein transfer of cholesterol esters (SETR from cholesteryl ester transfer protein, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, vibrator, Niacin, preparations containing Niacin or other agonists NMA, ion exchange resins, antioxidant, inhibitor of ACAT (acyl-COA-cholesterol-acyltransferase) or sequestrants bile acids.

Thus, the subject of the present invention is to provide compounds that are effective agents that increase HDL cholesterol. It has been found that the compounds of formula I for infusion is his invention is very useful for the treatment and/or prevention of diseases and disorders, which can be treated with agents that increase HDL cholesterol, i.e. the compounds of formula I are particularly useful for the treatment and/or prevention of dyslipidemia, atherosclerosis and cardiovascular diseases. Also the subject of the present invention is to provide compounds which, when therapeutically active concentrations that increases HDL concentrations, do not interact with the receptor SW. The reason is that the ligands of the receptor SW may impair therapeutic value of agents that increase the level of HDL cholesterol, as agonists and antagonists of the receptor SW can lead to side effects.

Detailed description of the invention

Unless otherwise stated, the following definitions are provided for illustration and definition of value and volume of different terms used here to describe the invention.

In this description, the term "lower" is used to denote a group consisting of one to seven, particularly from one to four carbon atoms.

The term "alkyl", alone or in combination with other groups, refers to a branched or unbranched monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, especially from one to sixteen carbon atoms, more specifically from one to ten, the volume of carbon.

The term "lower alkyl" or "C1-7-alkyl", alone or in combination, signifies an alkyl group with straight chain or branched chain of 1 to 7 carbon atoms, in particular alkyl group with straight or branched chain of 1 to 6 carbon atoms and more specifically an alkyl group with straight or branched chain of 1 to 4 carbon atoms. Examples of C1-7alkyl groups are straight and branched chain is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric of Penteli, isomeric sexily and isomeric Gately, in particular ethyl, propyl, isopropyl and tert-butyl.

The term "lower alkoxy" or "C1-7-alkoxy" refers to the group R'-O-, where R' represents lower alkyl and the term "lower alkyl" has the previously given significance. Examples of lower alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, in particular methoxy.

The term "lower alkoxyalkyl" or "C1-7-alkoxy-C1-7-alkyl" refers to lower alkyl group, as defined above, which is mono - or polyamidine lower alkoxy group, as defined above. Examples of the lower alkoxyalkyl groups are, for example, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-O-CH2-CH3and groups, particularly preveden the e here as an example. More specifically, the lower alkoxyalkyl is methoxyethyl.

The term "lower hydroxyalkyl" or "hydroxy-C1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl group substituted by hydroxy group. Of particular interest With3-7-hydroxyalkyl group. Examples of lower hydroxyalkyl groups are 2-hydroxybutyl, 3-hydroxy-2,2-dimethylpropyl and groups, especially given here as an example.

The term "lower hydroxyimino-alkyl" or "hydroxyimino-C1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl group is replaced by hydroxyimino group (=N-OH). Of particular interest is 1-hydroxykynurenine group-C(=N-OH)-CH3.

The term "lower alkoxyimino-alkyl" or "C1-7-alkoxyimino-C1-7-alkyl" refers to lower alkyl group as defined above where at least one of the hydrogen atoms of the lower alkyl groups substituted lower alkoxyimino group (=N-OR, R=lower alkyl). Examples of lower alkoxyimino-alkyl groups are 1-methoxyaminomethyl or 1-etoksietil. More specifically lower alkoxyimino-alkyl is 1-methoxyaminomethyl (-C(=N-och3)-CH3).

The term "recloak is l" or "C 3-7-cycloalkyl" denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, sikorksy or cycloheptyl, especially cyclopropyl.

The term "lower cycloalkenyl" or "C3-7-cycloalkyl-C1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted cycloalkyl group. Among lower cycloalkenyl groups of special interest cyclopropylmethyl.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, of particular interest are fluorine, chlorine and bromine. More specifically, halogen refers to fluorine and chlorine.

The term "lower halogenated" or "halogen-C1-7-alkyl" refers to lower alkyl groups which are mono - or polyamidine halogen, preferably fluorine or chlorine, most preferably fluorine. Examples of the lower halogenating groups are, for example, -CF3, -CHF2, -CH2Cl, -CH2CF3, -CH(CF3)2, -CF2-CF3, -CH2-CH2-CF3, -CH(CH3)-CF3and groups, especially given here as an example. Special interest groups are trifluoromethyl (-CF3), 2,2,2-triptorelin (-CH2CF3) and 1,1,1-Cryptor-propan-2-yl (-CH(CH3)-CF3).

The term "lower halogenoalkane" or "halogen-C1-7-alkoxy" refers to lower alkoxy groups which are mono - or polyamidine halogen, preferably fluorine or chlorine, most preferably fluorine. Examples of the lower halogenating groups are, for example, -OCF3, -OCHF2, -OCH2Cl, -OCH2CF3, -Och(CF3)2, -OCF2-CF3and-och(CH3)-CF3.

The term "cyano" refers to the group-CN.

The term "amino" refers to the group-NH2.

The term "azido" denotes the group-N=N+=N-.

The term "carbarnoyl" or "aminocarbonyl" refers to the group-CO-NH2.

The term "lower carbamoylethyl" or "carbarnoyl-C1-7-alkyl" refers to lower alkyl groups as defined above, where one of the hydrogen atoms of the lower alkyl groups substituted carbamoyl group. Examples of the lower carbamoylethyl groups are 3-carbamoylethyl, 4-carbamoylmethyl and 5-carbamoylmethyl, more specifically 4-carbamoylmethyl.

The term "lower alkylaryl" refers to the group-CO-R", where R" is a lower alkyl as defined previously. "Lower alkylcarboxylic" refers to the group-NH-CO-R", where R" is a lower alkyl as defined previously.

The term "lower alkylcarboxylic" or "C1-7-alkylcarboxylic-C1-7 -alkyl" refers to lower alkyl groups as defined above, where one of the hydrogen atoms of the lower alkyl groups substituted lower alkylcarboxylic group. An example of the lower alquilervillapeniscola group is ethylcarbodiimide.

The term "lower alkylaminocarbonyl" or "C1-7-alkylaminocarbonyl" refers to the group-CO-NH-R, where R is a lower alkyl group, as defined above. An example of the lower alkylaminocarbonyl group is methylaminoethanol.

The term "lower phenylalkyl or phenyl-C1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl group substituted phenyl group. In particular, the lowest phenylalkyl means benzyl.

The term "heterocyclyl" refers to saturated or partially unsaturated 3-, 4-, 5-, 6- or 7-membered ring which may include one, two or three heteroatoms selected from N, O and S. Examples heterocyclyl rings include piperidinyl, piperazinil, azetidine, azepine, pyrrolidinyl, pyrazolidine, imidazoline, imidazolidine, oxazolidine, isoxazolidine, morpholine, thiazolidine, isothiazolinones, oxiranyl, thiadiazolidine, oxetanyl, DIOXOLANYL, dihydrofurane, tetrahydrofuranyl, dihydropyran, tetrahydropyranyl and myomorpha the Nile. Of particular interest is tetrahydrofuranyl group.

The term "lower geterotsiklicheskikh" or "heterocyclyl-C1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted heterocyclyl group, as defined above.

The term "heteroaryl" refers to an aromatic 5 - or 6-membered ring which may contain one, two or three atoms selected from N, O and S. Examples of heteroaryl groups are, for example, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl, isothiazolin, thiadiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, oxadiazolyl, tetrazolyl, Pentapolis or pyrrolyl. The term "heteroaryl" also includes bicyclic groups containing two 5 - or 6-membered ring in which one or both rings are aromatic and may contain one, two or three atoms selected from nitrogen, oxygen or sulfur, such as chinoline, ethenolysis, cinnoline, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, honokalani, benzothiazolyl, benzotriazolyl, indolyl, indazoles and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl. Heteroaryl group may be mono - or tizamidine lower alkyl, hydroxy, cyano or halogen. Of special interest by heteroarylboronic are furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolin, [1,2,3]thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

The term "lower heteroaromatic" or "heteroaryl-C1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted heteroaryl group, as defined above.

"Isomeric forms" are all forms of compounds characterized by the presence of the same molecular formula, but differ in the nature or sequence of connection of their atoms or the arrangement of their atoms in space. Preferably isomeric forms differ in the arrangement of their atoms in space and can also be called "stereoisomers". Stereoisomers that are not mirror images of each other, are called "diastereoisomers" and stereoisomers that are analagies mirror images are called "enantiomers", or sometimes optical isomers. The carbon atom connected to four different substituents, is called a "chiral center".

The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids and the cat is who do not have their own properties, which is not desirable. Salts are obtained from inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, n-toluensulfonate acid, salicylic acid, N-acetylcysteine and the like. Thus, the preferred pharmaceutically acceptable salts include the acetate, bromide, chloride, formate, fumarate, maleate, mesilate, nitrate, oxalate, phosphate, sulfate, tartrate and tosylate compounds of formula I. in Addition, pharmaceutically acceptable salts can be obtained by adding inorganic bases or organic bases free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium and the like. Salts derived from organic bases include, but are not limited to, salts of primary, W the secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, diethylamine, lysine, arginine, N-ethylpiperidine, piperidine, piperazine and the like. The compound of formula I may also be in the form zwitterions or in the form of hydrates. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are hydrochloride.

The present invention relates to compounds of the formula

where

A is selected from CH or N;

R1selected from the group consisting of lower alkyl,

cycloalkyl,

lower cycloalkenyl,

lower hydroxyalkyl,

lower alkoxyalkyl,

lower halogenoalkane,

lower carbamoylethyl,

lower alkylcarboxylic,

lower phenylalkyl,

lower geterotsiklicheskikh where heterocyclyl group not substituted or substituted by oxo,

lower heteroallyl, where the heteroaryl group is not substituted or mono - or di-substituted lower alkyl, and

phenyl which is not substituted or mono - or di-substituted with halogen;

R2and R6independently from each other represent hydrogen or halogen;

R3and R5independently from each other using the Ana group, consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenoalkane, lower halogenoalkane and cyano;

R4selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenoalkane, lower halogenoalkane, amino, azido and cyano;

R7selected from the group consisting of lower alkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

lower hydroxyimino-alkyl, lower alkoxyimino-alkyl,

lower cycloalkyl, specified cycloalkyl not substituted or substituted by hydroxy,

lower heterocyclyl,

phenyl, the said phenyl is not substituted or is substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen-free,

heteroaryl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen;

and their pharmaceutically acceptable salts.

The compounds of formula I of the present invention are those where R1selected from the group consisting of lower alkyl, cycloalkyl, lower cycloalkenyl, lower hydroxyalkyl, lower alkoxyalkyl, lower halogenoalkane, lower carbamoylethyl, lower al is ylcarbonylglycine, lower phenylalkyl, lower geterotsiklicheskikh where heterocyclyl group not substituted or substituted by oxo, or lower heteroallyl, where the heteroaryl group is not substituted or mono - or di-substituted lower alkyl.

In particular, the invention relates to compounds of formula I, where R1selected from cycloalkyl, lower cycloalkenyl, lower alkoxyalkyl and lower halogenoalkane. More specifically, R1selected from cyclobutyl, cyclopropylmethyl, 2-methoxyethyl and lower halogenoalkane. Even more specifically, R1is cyclopropylmethyl or lower halogenated. Most specifically, R1represents a 2,2,2-triptorelin or 1,1,1-Cryptor-propan-2-yl, the greatest interest is R1which is 2,2,2-triptorelin.

The compounds of formula I according to the invention are those where R2and R6independently from each other represent hydrogen or halogen. The compounds of formula I, where R2and R6represent hydrogen, are particularly interesting.

In addition, the invention relates to compounds of formula I, where R3and R5independently from each other selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenoalkane, lower halogenoalkane and cyano. In particular, the invention relates to compounds of formula I,where R 3and R5selected from hydrogen, halogen and lower alkyl, more specifically hydrogen, fluorine, chlorine and methyl.

In addition, the invention relates to compounds of formula I, where R4selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenoalkane, lower halogenoalkane, amino, azido and cyano. More specifically, R4represents lower alkyl or halogen. Most specifically, R4represents halogen, especially chlorine.

The compounds of formula I according to the invention, moreover, are those where R7selected from the group consisting of lower alkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

lower hydroxyimino-alkyl, lower alkoxyimino-alkyl,

lower cycloalkyl, specified cycloalkyl not substituted or substituted by hydroxy,

lower heterocyclyl,

phenyl, the said phenyl is not substituted or is substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen, and

heteroaryl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen.

One group of compounds of the formula I according to the invention are the E. where R7represents lower alkyl, in particular methyl, propyl or butyl.

Another group of compounds of formula I of the present invention are those where R7represents phenyl, the said phenyl is not substituted or is substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen, or heteroaryl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen.

Of particular interest are compounds of the formula I according to the invention, where R7is heteroaryl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen. In particular, the invention relates to compounds of formula I, where R7is heteroaryl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, cyano, lower alkylaminocarbonyl and halogen. More specifically the invention relates to compounds of formula I, where R7is heteroaryl selected the C group, consisting of furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazoline, [1,2,3]thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen. Even more specifically, R7is heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyridazinyl and pyrimidinyl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen. Especially R7represents pyridyl, said pyridyl is not substituted or is substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen.

In particular, the invention relates to compounds of formula I, where R7selected from the group consisting of furan-2-yl, 5-methyl-furan-2-yl, furan-3-yl, 5-methyl-oxazol-4-yl, 2,4-dimethyl-oxazol-5-yl, isoxazol-5-yl, 3-methyl-isoxazol-4-yl, 3,5-dimethyl-isoxazol-4-yl, 5-methyl-isoxazol-3-yl, 1H-pyrazole-3-yl, 1-methyl-1H-pyrazole-3-the La, 1,3-dimethyl-1H-pyrazole-4-yl, 2-methyl-2H-pyrazole-3-yl, 5-methyl-2H-pyrazole-3-yl, 2,5-dimethyl-2H-pyrazole-3-yl, thiazol-2-yl, 5-methyl-thiazol-2-yl, isothiazol-5-yl, 4-methyl-[1,2,3]thiadiazole-5-yl, pyridin-2-yl, 3-methylpyridin-2-yl, pyridine-3-yl, 2,4-debtor-pyridin-3-yl, 2-methyl-pyridin-3-yl, 5-methyl-pyridin-3-yl, 6-methyl-pyridin-3-yl, 5-cyano-pyridin-3-yl, 5-bromo-pyridine-3-yl, 5-iodine-pyridine-3-yl, 5-methoxy-pyridine-3-yl, pyridine-4-yl, 2-methyl-pyridin-4-yl, 3-methyl-pyridine-4-yl, 2-hydroxy-pyridine-4-yl, 5-hydroxy-pyridine-2-yl, pyrazin-2-yl, pyridazin-3-yl, pyrimidine-4-yl, pyrimidine-5-yl and 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-Il. More specifically, R7selected from pyridin-3-yl, 3-methyl-isoxazol-4-yl, pyridazin-3-yl, 1,3-dimethyl-1H-pyrazole-4-yl and 5-methyl-oxazol-4-yl. Most specifically, R7represents pyridin-3-yl.

In particular, the invention relates to compounds of formula I, where a represents CH. The compounds are derivatives of pyridine of the formula

where

R1selected from the group consisting of lower alkyl,

cycloalkyl,

lower cycloalkenyl,

lower hydroxyalkyl,

lower alkoxyalkyl,

lower halogenoalkane,

lower carbamoylethyl,

lower alkylcarboxylic,

lower phenylalkyl,

lower geterotsiklicheskikh, g is e heterocyclyl group not substituted or substituted by oxo,

lower heteroallyl, where the heteroaryl group is not substituted or mono - or di-substituted lower alkyl, and

phenyl which is not substituted or mono - or di-substituted with halogen;

R2and R6independently from each other represent hydrogen or halogen;

R3and R5independently from each other selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenoalkane, lower halogenoalkane and cyano;

R4selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenoalkane, lower halogenoalkane, amino, azido and cyano;

R7selected from the group consisting of lower alkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

lower hydroxyimino-alkyl, lower alkoxyimino-alkyl,

lower cycloalkyl, specified cycloalkyl not substituted or substituted by hydroxy,

lower heterocyclyl,

phenyl, the said phenyl is not substituted or is substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen-free,

heteroaryl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and g is lagena;

and their pharmaceutically acceptable salts.

Particularly the present invention relates to compounds of the formula

where

R1selected from the group consisting of lower alkyl,

cycloalkyl,

lower cycloalkenyl,

lower hydroxyalkyl,

lower alkoxyalkyl,

lower halogenoalkane,

lower carbamoylethyl,

lower alkylcarboxylic,

lower phenylalkyl,

lower geterotsiklicheskikh where heterocyclyl group not substituted or substituted by oxo,

lower heteroallyl, where the heteroaryl group is not substituted or mono - or di-substituted lower alkyl, and

phenyl which is not substituted or mono - or di-substituted with halogen;

R2and R6independently from each other represent hydrogen or halogen;

R3and R5independently from each other selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenoalkane, lower halogenoalkane and cyano;

R4selected from the group consisting of hydrogen, lower alkoxy, halogen, lower halogenoalkane, lower halogenoalkane, amino, azido and cyano;

R7selected from the group consisting of lower alkyl,

lower hydroxyalkyl,

lower cycloalkyl, specified cycloalkyl not substituted or substituted by hydroxy,

<> lower heterocyclyl,

phenyl, the said phenyl is not substituted or is substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy and halogen,

heteroaryl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, cyano and halogen;

and their pharmaceutically acceptable salts.

The invention relates to compounds of formula I, where a is an n Compounds are derivatives of pyrazine formula

where

R1selected from the group consisting of lower alkyl,

cycloalkyl,

lower cycloalkenyl,

lower hydroxyalkyl,

lower alkoxyalkyl,

lower halogenoalkane,

lower carbamoylethyl,

lower alkylcarboxylic,

lower phenylalkyl,

lower geterotsiklicheskikh where heterocyclyl group not substituted or

substituted by oxo,

lower heteroallyl, where the heteroaryl group is not substituted or mono - or di-substituted lower alkyl, and

phenyl which is not substituted or mono - or di-substituted with halogen;

R2and R6independently from each other represent hydrogen or halogen;

R3and R5independently from each other selected from the group consisting of hydrogen, is schego of alkyl, lower alkoxy, halogen, lower halogenoalkane, lower halogenoalkane and cyano;

R4selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenoalkane, lower halogenoalkane, amino, azido and cyano;

R7selected from the group consisting of lower alkyl,

lower hydroxyalkyl, lower alkoxyalkyl,

lower hydroxyimino-alkyl, lower alkoxyimino-alkyl,

lower cycloalkyl, specified cycloalkyl not substituted or substituted by hydroxy,

lower heterocyclyl,

phenyl, the said phenyl is not substituted or is substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen-free,

heteroaryl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, cyano, lower alkylaminocarbonyl and halogen;

and their pharmaceutically acceptable salts.

Specific compounds of formula I of the present invention are as follows:

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pentanol acid,

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-benzamide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-the toxi)-pyridine-3-yl]-isonicotinamide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-acetamide", she

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-butyramide,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridine-2-carboxylic acid,

N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-benzamide,

N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-acetamide", she

N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-nicotinamide,

N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-isonicotinamide,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrazin-2-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 2,5-dimethyl-2H-pyrazole-3-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3-methyl-isoxazol-4-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1-methyl-1H-pyrazole-3-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-isoxazol-3-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridazin-3-carboxylic acid,

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-3-methyl-isonicotinamide,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrimidine-5-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 2-methyl-2H-pyrazole-3-carboxylic acid,

[5-(4-the ENT-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide of 2,4-dimethyl-oxazol-5-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide isothiazol-5-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-2H-pyrazole-3-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide of 1H-pyrazole-3-carboxylic acid,

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-methyl-isonicotinamide,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-thiazole-2-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid,

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-6-methyl-nicotinamide,

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-methyl-nicotinamide,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide isoxazol-5-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3,5-dimethyl-isoxazol-4-carboxylic acid,

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-hydroxy-isonicotinamide,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1,3-dimethyl-1H-pyrazole-4-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrimidine-4-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide a thiazole-2-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3-methyl-pyridine-2-carb is a new acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-oxazol-4-carboxylic acid,

N-(5-(3,4-dimetilfenil)-6-(2,2,2-triptoreline)pyridine-3-yl)-nicotinamide,

N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-nicotinamide, and pharmaceutically acceptable salts.

Additional compounds of formula I of the present invention are as follows:

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-hydroxy-pyridine-2-carboxylic acid,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-nicotine amide,

(S)-N-(5-(4-chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)pyridine-3-yl)pyridazin-3-carboxamide,

(S)-N-(5-(4-chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)pyridine-3-yl)nicotinamide,

N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,

N-(5-(3-chloro-4-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,

N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,

N-(5-(4-ethylphenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,

(S)-N-(6-(4-chlorophenyl)-5-(1,1,1-tryptophan-2-yloxy)pyrazin-2-yl)nicotinamide,

N-(6-(4-chlorophenyl)-5-(2,2,2-triptoreline)pyrazin-2-yl)nicotinamide,

N-(6-(4-chlorophenyl)-5-cyclobutenedione-2-yl)nicotinamide,

N-(6-(4-chlorophenyl)-5-cyclobutenedione-2-yl)pyrimidine-5-carboxamide,

N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-Carbo who said,

N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,

N-(5-(3-chloro-4-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,

N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,

N-(5-(4-ethylphenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,

N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-hydroxyisoleucine,

N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide,

N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-2,4-differntiated,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-hydroxybenzamide,

N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-canonicalname,

N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide,

N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide,

N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide,

N-(5-(4-ethylphenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)furan-2-carboxamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)furan-3-carboxamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methylfuran-2-carboxamide,

N-(5-(4-chloro-3-were)-6-(2-methox is ethoxy)pyridine-3-yl)benzamid,

(R)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)tetrahydrofuran-2-carboxamide,

(S)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)tetrahydrofuran-3-carboxamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamid,

N-(5-(4-amino-3-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-idnicating,

N-(5-phenyl-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,

N-(5-(4-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,

N-(5-(3-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methoxynicotinic,

N-(5-(4-chlorophenyl)-6-cyclobutadiene-3-yl)pyrazin-2-carboxamid,

N-(5-(4-chlorophenyl)-6-cyclobutadiene-3-yl)nicotinamide,

N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamid,

N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamid,

[5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-yl]-amide 6-methyl-oxazol-4-carboxylic acid,

N-[5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-yl]-5-methyl-nicotinamide,

N5-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-N2-methylpyridine-2,5-dicarboxamide,

5-bromo-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-triffterer the XI)pyridine-3-yl)-2-methoxypropane,

N3-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-N5-methylpyridin-3,5-dicarboxamide,

(+)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-methoxypropane,

(E)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-(methoxyimino)propanamide,

and their pharmaceutically acceptable salts.

More specifically, the compounds of formula I of the present invention are as follows:

N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide,

N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-nicotinamide,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3-methyl-isoxazol-4-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridazin-3-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1,3-dimethyl-1H-pyrazole-4-carboxylic acid,

[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-oxazol-4-carboxylic acid,

N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-nicotinamide,

N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,

(3)-N-(6-(4-chlorophenyl)-5-(1,1,1-tryptophan-2-yloxy)pyrazin-2-yl)nicotinamide,

N-(6-(4-chlorophenyl)-5-cyclobutenedione-2-yl)pyrimidine-5-carboxamide,

N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-guide oxybenzone,

N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-canonicalname,

N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methylfuran-2-carboxamide,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamid,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methoxynicotinic,

N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-methoxypropane,

and their pharmaceutically acceptable salts.

Even more specifically, the invention relates to a compound of formula I, which is N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide and its pharmaceutically acceptable salts.

Also more specifically the invention relates to a compound of formula I, which is N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-nicotinamide and its pharmaceutically acceptable salts.

Also more specifically the invention relates to a compound of formula I, which is N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methoxynicotinic and its pharmaceutically acceptable salts.

The compounds of formula I can be obtained by the process according to which a link connection of the formula

where a and R1- R6Vlada such as defined above, with an acid of the formula

where R7is the same as defined above, with a binder in basic terms

and optionally translate the resulting compound of formula I, its pharmaceutically acceptable salt.

Binders for the reaction of compounds of formula II with an acid of the formula III are, for example, N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexaflurophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (NOVT), O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU) or O-benzotriazole-N,N,N',N'-tetramethyl-urani-hexaphosphate (HBTU). More specifically, the binder is a HBTU. Suitable bases include triethylamine, diisopropylethylamine and especially N-methylmorpholin.

The synthesis of compounds of General structure I-A can be performed according to the scheme 1.

Following the procedure according to scheme 1, compound AA (3-bromo-2-chloro-5-nitro-pyridine, CAS RN 5470-17-7) can be used as the starting material. AA is available.

Compound AB can be obtained from the AA during the reaction with a suitably substituted primary or secondary alcohol R1-OH in the presence of a base, e.g. the R sodium hydride, in the presence or absence of an inert solvent, such as dimethylformamide, at temperatures from room temperature to the boiling point of the solvent, preferably at room temperature.

Compound AC can be obtained from AB during recovery, using numerous options known in the art for the recovery of aromatic nitro-group. A convenient way to restore is to use tin chloride in a suitable solvent mixture, preferably in ethanol with added hydrochloric acid, at temperatures from room temperature to elevated temperatures, preferably at 25°C.

Scheme 1

Compound II can be obtained from the AU during binding suitably substituted aryl metal particles of the formula AD, especially arylboronic acid or ether of arylboronic acid, in the presence of a suitable catalyst, particularly a palladium catalyst and more particularly mixtures of palladium (II) acetate / triphenylphosphine or complexes of palladium (II) chloride - dppf (1,1'-bis(diphenyl-phosphino)ferrocene), and bases, such as triethylamine, sodium carbonate or potassium phosphate, in an inert solvent, such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxyethane.

The compounds of formula AD containing functional group, unfavorable for palladium-catalyzed Suzuki reactions, can be with the purpose of carrying out this reaction are protected with suitable protecting group (P). Suitable amino protective groups are, for example, benzyloxy-carbonyl (Z), tert-butyloxycarbonyl (VOS), while suitable acid protective groups are, for example, benzyl (EAP), benzoyloxymethyl (CMV), methoxyethoxymethyl (MEM) or allyl groups, and silyl groups such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl esters (for more information, see in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rdedition). The removal of the protective group can be performed by suitable methods known in the art.

Compound I-A can be obtained from II and the appropriate acid of the formula III in the course of suitable reactions for the formation of amide linkages. These reactions are known in the art. For example, binding reagents, such N,N'-carbonyl-diimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexaflurophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (NOVT), O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU) or O-benzotriazol-N',N,N',N'-tetramethyl-Urania-hexaphosphate (HBTU) which you can use to accomplish this transformation. A convenient method consists in using, for example, HBTU and bases, for example N-methylmorpholine, in an inert solvent, such as, for example, dimethylformamide, at room temperature.

Following the alternative procedure according to scheme 2, compound AC can be used as the starting material.

Connection BD can be obtained from the AU and the corresponding acid of formula III in the course of suitable reactions for the formation of amide linkages. These reactions are known in the art. For example, binding reagents, such N,N'-carbonyl-diimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexaflurophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (NOVT), O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU) or O-benzotriazole-N,N,N,N'-tetramethyl-Urania-hexaphosphate (HBTU) can be used to implement such a transformation. A convenient method consists in using, for example, HBTU and bases, for example N-methylmorpholine, in an inert solvent, such as, for example, dimethylformamide, at room temperature.

Compound I can be obtained from BD during binding suitably substituted aryl metal particles of the formula AD, especially arylboronic acid or ether of arylboronic KIS is the notes, in the presence of a suitable catalyst, particularly a palladium catalyst and more particularly mixtures of palladium (II) acetate / triphenylphosphine or complexes of palladium (II) chloride - dppf (1,1'-bis(diphenyl-phosphino)ferrocene), and bases, such as triethylamine, sodium carbonate or potassium phosphate, in an inert solvent, such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxyethane.

Scheme 2

The compounds of formula AD, containing functional groups which are unfavorable for palladium-catalyzed Suzuki reactions, can be with the purpose of carrying out this reaction are protected with suitable protecting group (P). Suitable amino protective groups are, for example, benzyloxy-carbonyl (Z), tert-butyloxycarbonyl (VOS), while suitable acid protective groups are, for example, benzyl (Bn), benzoyloxymethyl (CMV), methoxyethoxymethyl (MEM) or allyl groups, and silyl groups such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl esters (for more information, see in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rdedition). The removal of the protective group can be performed by suitable methods known in the art.

Following the procedure according to scheme 3, the compound CA (3-bromo-5-chloro-2-fluoro-pyridine, CAN 88448-87-5) can be used as the starting material. SA is available.

Connection ST can be obtained from SA during binding suitably substituted aryl metal particles of the formula AD, especially arylboronic acid or ether of arylboronic acid, in the presence of a suitable catalyst, particularly a palladium catalyst and more particularly mixtures of palladium (II) acetate / triphenylphosphine or complexes of palladium (II) chloride - dppf (1,1'-bis(diphenyl-phosphino)ferrocene), and bases, such as triethylamine, sodium carbonate or potassium phosphate, in an inert solvent, such as dimethylformamide, toluene, tetrahydrofuran, acetonitrile and dimethoxyethane.

The compounds of formula AD, containing functional groups which are unfavorable for palladium-catalyzed Suzuki reactions, can be with the purpose of carrying out this reaction are protected with suitable protecting group (P). Suitable amino protective groups are, for example, benzyloxy-carbonyl (Z), tert-butyloxycarbonyl (VOS), while suitable acid protective groups are, for example, benzyl (Bn), benzoyloxymethyl (CMV), methoxyethoxymethyl (MEM) or allyl groups, and silyl groups such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl esters (for more information, see in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rdedition). Remove protective grapevine to perform appropriate ways, known in this technical field.

The connection of the SS can be obtained from the ST. during the reaction with a suitably substituted primary or secondary alcohol R1-OH in the presence of a base such as sodium hydride, in the presence or absence of an inert solvent, such as dimethylformamide, at temperatures from room temperature to the boiling point of the solvent, preferably at room temperature.

Compounds of General formula CD can be obtained from compounds of General formula SS during catalyzed by the transition metal, namely catalyzed by palladium, preferably catalyzed by palladium (II) chloride - dppf reaction with carbon monoxide in a suitable solvent such as a primary alcohol, particularly methanol, under pressure of carbon monoxide from 1 to 200 bar, in particular from 1 to 70 bar and temperatures from 0 to 150°C., especially from 1 to 100°C.

Saponification of the resulting ester CD by methods well known to the skilled technician in the art, leads to the acids of General formula CE.

Compounds of General formula CF can be obtained from compounds of General formula CE by rearrangement of kurzius, preferably when processed with diphenylphosphoryl azide and a base, particularly triethylamine in boiling tert-butanol. Remove the protective group of the carbamates of General Faure the uly CF methods, well known in the art, which will give amines of General formula II. Alternative amines of General formula II can be obtained from the acids of General formula CE during the synthesis of the corresponding primary amide with subsequent rearrangement of Hoffmann.

Scheme 3

Compound I can be obtained from II and the appropriate acid of the formula III in the course of suitable reactions for the formation of amide linkages. These reactions are known in the art. For example, binding reagents, such N,N'-carbonyl-diimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexaflurophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (NOVT), O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU) or O-benzotriazole-N,N,N',N'-tetramethyl-Urania-hexaphosphate (H BTU) can be used to implement such a transformation. A convenient method consists in using, for example, HBTU and bases, for example N-methylmorpholine, in an inert solvent, such as, for example, dimethylformamide, at room temperature.

Following the procedure according to scheme 4, compounds of General formula DA (the synthesis of which is described, for example. in WO 2008040651 and WO 2008040649) can be used as starting substances, to obtain compounds the Oia General formula I-C.

In particular, compounds of General formula DB can be obtained from compounds of General formula DA during the reaction with a suitably substituted primary or secondary alcohol R1-OH in the presence of a base such as cesium carbonate, in the presence or absence of an inert solvent, such as dimethyl sulfoxide, at temperatures from room temperature to the boiling point of the solvent, particularly at room temperature.

Saponification of the resulting ester of the General formula DB of ways, well known to the skilled technician in the art, leads to the acids of General formula DC.

Compounds of General formula DD can be obtained from compounds of General formula DC through rearrangement of kurzius, preferably when processed with diphenylphosphoryl azide and a base, particularly triethylamine in boiling tert-butanol. Remove the protective group of the carbamates of General formula DD by methods well known in the art, which will give amines of General formula IV. Alternative amines of General formula IV can be obtained from the acids of General formula DC during the synthesis of the corresponding primary amide with subsequent rearrangement of Hoffmann.

Compounds of General formula I can be obtained from the IV and the corresponding acids of formula III in the course of suitable reactions for the formation of amide linkages. These reactions is known in the art. For example, binding reagents, such N,N-carbonyl-diimidazole (CDI), N,N-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexaflurophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (NOVT), O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU) or O-benzotriazole-N,N,N',N'-tetramethyl-Urania-hexaphosphate (HBTU) can be used to implement such a transformation. A convenient method consists in using, for example, HBTU and bases, for example N-methylmorpholine, in an inert solvent, such as, for example, dimethylformamide, at room temperature.

Scheme 4

Compounds of General formula I-a or I-b can be, if necessary, known in the art methods subjected to further processing to other compounds of the same General formula. This may, for example, to enable the removal of the protective group by methods known in the art (see in T. W. Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rdedition); or simple transformations of functional groups, for example the conversion of ketogroup in hydroxyimino or methoxyimino group.

As described above, the compounds of formula I of the present invention or apharmaceutical acceptable salts can be used as medicines for the treatment and/or prevention of diseases, which can be treated with agents that increase HDL cholesterol. Examples of such diseases are atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplasticheskih restenosis, hypertension, vascular complications of diabetes, obesity or endotoxicosis. Of particular interest is the use as a drug for the treatment and/or prevention of dyslipidemia, atherosclerosis and cardiovascular diseases.

Therefore, the invention also relates to pharmaceutical compositions comprising a compound of formula I, as defined above, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and/or excipient. The pharmaceutical compositions used in the treatment and/or prevention of diseases that can be treated with agents that increase HDL cholesterol.

Thus, the invention relates to pharmaceutical compositions, as defined above, for use in the treatment and/or prevention of atherosclerosis, diseases of periphery the definition of vessels, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplasticheskih restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia.

In another embodiment the invention relates to a method of treatment and/or prevention of diseases that can be treated with agents that increase HDL cholesterol, according to which administered a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt to a patient in need. Examples of such diseases are atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplasticheskih restenosis, hypertension, and vascular complications of diabetes, obesity or endotoxicosis. Preferred is a method of treatment and/or prevention of dyslipidemia, atherosclerosis and cardiovascular Zab is problems.

The invention relates to compounds of the formula I or their pharmaceutically acceptable salts for use as pharmaceuticals. Namely, the invention relates to compounds of the formula I or their pharmaceutically acceptable salts for use as agents that increase HDL cholesterol. Thus, the invention relates to compounds of the formula I or their pharmaceutically acceptable salts for use in the treatment and/or prevention of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplasticheskih restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia, in particular, for use in the treatment and/or prophylaxis of dyslipidemia, atherosclerosis and cardiovascular diseases.

In addition, the invention relates to the use of compounds of formula I, as defined above, or their pharmaceutically acceptable salts to obtain drugs for the treatment and/or prevention of diseases that can be treated with agents that increase HDL cholesterol. Example, and such diseases are atherosclerosis, the peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplasticheskih restenosis, hypertension, vascular complications of diabetes, obesity or endotoxicosis. Of particular interest is the use of compounds of formula I, as defined above, or their pharmaceutically acceptable salts to obtain drugs for the treatment and/or prevention of dyslipidemia, atherosclerosis and cardiovascular diseases.

In addition, agents that increase the level of HDL cholesterol, the formula I are used in combination or connection with another connection, the connection specified is selected from the group consisting of an inhibitor of HMG-COA reductase inhibitor secretion of microsomal protein transfer of triglycerides (MTP)/Ares, PPAR activator, inhibitor of protein transfer of cholesterol esters (SETR), an inhibitor of reuptake of bile acids, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, fibrate, Niacin, a preparation containing Niacin or other agonists NMA, ion-exchange resin, an antioxidant, an inhibitor of ACAT or sequestrants bile acids.

Consequently the nutrient, the invention also relates to pharmaceutical compositions comprising a compound of formula I, as defined above, or its pharmaceutically acceptable salt in combination or Association with another compound selected from the group consisting of an inhibitor of HMG-COA reductase inhibitor secretion of microsomal protein transfer of triglycerides (MTP)/Ares, PPAR activator, inhibitor of protein transfer of cholesterol esters (SETR), an inhibitor of reuptake of bile acids, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, fibrate, Niacin, a preparation containing Niacin or other agonists NMA, ion-exchange resin, an antioxidant, the ACAT inhibitor or sequestrants bile acids, and pharmaceutically acceptable carrier and/or excipient.

In addition, the invention relates to compounds of formula I, as defined above, or their pharmaceutically acceptable salts in combination or Association with a compound selected from the group consisting of an inhibitor of HMG-COA reductase inhibitor secretion of microsomal protein transfer of triglycerides (MTP)/Ares, PPAR activator, inhibitor of protein transfer of cholesterol esters (SETR), an inhibitor of reuptake of bile acids, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, fibrate, Niacin, a preparation containing Niacin or other the agonists NMA, ion-exchange resin, an antioxidant, an inhibitor of ACAT or sequestrants bile acids for use in the treatment and/or prophylaxis of diseases, such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular diseases such as angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplasticheskih restenosis, hypertension, vascular complications of diabetes, obesity or endotoxicosis.

The invention relates to a method of treatment and/or prevention of diseases that can be treated with agents that increase HDL cholesterol, according to which administered a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt in combination or Association with a therapeutically effective amount of a compound selected from the group consisting of an inhibitor of HMG-COA reductase inhibitor secretion of microsomal protein transfer of triglycerides (MTP)/Ares, PPAR activator, inhibitor of protein transfer of cholesterol esters (SETR), an inhibitor of reuptake of bile acids, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, fibrate, Niacin, a drug that is terasawa Niacin, or other agonists NMA, ion-exchange resin, an antioxidant, an inhibitor of ACAT or sequestrants bile acids.

The pharmaceutical composition

The compounds of formula I and/or their pharmaceutically acceptable salts can be used in the form of pharmaceutical compositions for enteral, parenteral or local administration. They can be administered, e.g. orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, orally, for example in the form for oral, rectal, for example in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions for intramuscular, intravenous or subcutaneous injection, or topically, for example in the form of ointments, creams or oils. Of particular interest is oral administration.

Manufacture of pharmaceutical preparations can be done in a way that is familiar to any qualified specialist in this field of technology, bringing the described compounds of formula I and/or their pharmaceutically acceptable salts, possibly in combination with other therapeutically valuable compounds in herbal medicinal form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carriers and, if required, conventional farmace the political auxiliaries.

Suitable carriers are not only inorganic carriers, but also organic media. Thus, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used as carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active substance in the case of soft gelatin capsules carriers are usually not needed). Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carriers for drugs topical application are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

Conventional stabilizers, preservatives, wetting and the emulsion is yousie agents, improve the consistency of the agents for improving taste agents, salts for regulating the osmotic pressure, buffer substances, soljubilizatory, dyes, masking agents and antioxidants are considered as pharmaceutical excipients.

Therapeutically effective amount or dosage of the compounds of formula I can vary within wide limits depending on the controlled disease, age and individual condition of the patient and the route of administration, and will, of course, be selected according to the individual requirements in each particular case. For adult patients seen daily dose of from about 1 to 100 mg, especially from approximately 1 to 50 mg. depending on the severity of the disease and the accuracy of the pharmacokinetic profile of the compound may be one or more of the daily dosage units, for example 1-3 metered units.

Pharmaceutical compositions typically contain approximately 1-100 mg, preferably 5-50 mg of the compounds of formula I.

The following examples C1-C3 illustrate the normal composition of the present invention and only submit it.

Example C1

Coated film-coated tablets containing the following ingredients can be manufactured in the usual way:

IngredientsPills
Engine:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Lactose water60,0 mg70.0 mg
Povidone K3012.5 mg15,0 mg
Sodium starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(Kernel weight)120,0 mg350,0 mg
Film wrapper:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mgTalc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient is sifted and mixed with microcrystalline cellulose and the mixture granularit with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed, which gives the engine 120 or 350 mg, respectively. Kernel varnished aqueous solution / suspension of the above-mentioned film shell.

Example C2

Capsules containing the following ingredients can be manufactured in the usual way:

IngredientsOn capsule
The compound of formula (1)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

Components are screened, mixed and filled capsule is a size 2.

Example C3

Injectable solutions may have the following composition:

The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidin sufficient quantity for pH 5.0
Water for injection solutionsto 1.0 ml

The active ingredient dissolved in a mixture of polyethylene glycol 400 and water for injection (part). Bring the pH to 5.0 with acetic acid. The volume was adjusted to 1.0 ml by adding the remaining amount of water. The solution is filtered, filled them ampoules using a valid surplus, and sterilized.

Pharmacological tests

The following tests were performed to determine the activity of compounds of the formula I and their valuable pharmacological properties.

Detection of increased expression of protein AWSA in cells

The ability of compounds according to the invention to increase the protein level AUSA re-define the cultures of macrophages TNR-1 in 96-well microplate. The cells are sown when the initial density of 100,000 cells/well in 100 μl medium and differentiate with sticky macrophages with the addition of PMA (100 nm) for 68 hours in 10% em is ionalnoi bovine serum, 3 µl/l beta-mercaptoethanol, RPMI-1640 medium. The cells are then incubated with RPMI-1640 medium containing 1% ETS, 25 μg/ml acetylated LDL for 24 hours at 37°C. After incubation with acetylated LDL cells are washed twice with 50 µl FBSR and incubated with 100 μl of RPMI-1640 medium containing interest connection, solubilization in DMSO, for an additional 24 hours. The final concentration of DMSO in the presence of the support cells at 0.5%. Analysis of the binding of Area-I when using High Content Image Analysis is initiated when replacing with fresh medium, RPMI without phenol red, 0.2% BSA containing AlexaFluor®647 labeled Area-I for 2 h/37°C/5% CO2. The cells are then fixed with 4% formaldehyde in FBSR (15 min, K. T.). Then the kernel paint solution hahsta (3 μm FBSR) and the cytoplasm stained Cell Mask Blue (2 mg/ml FBSR), 15 min, K. T. At the end of stained cells fixed with the second portion of the formaldehyde. Fixed and stained cells are washed and stored in FBSR at 4°C, and they can be read directly up to one month after receipt. The fact that binding of Area-I really reflected the level AVSA in the cell, it was shown by loss of signal when the expression AWSA was artificially reduced by transfection with small interfering RNA.

Alexa Fluor 647-labeled Apolipoprotein A-I (20 nm) was prepared as follows: Ryoko is pinentry Apolipoprotein A-I (Area-(I) the person was replaced in the buffer 0.02 M NaHCO 3at pH of 8.2 desalted on NAP column (GE Healthcare) and brought to a concentration of 40 μm (1,13 mg/ml) in regulation with the same buffer. Area-I becomes fluorescently labeled by incubation with Alexa Fluor operations ether carboxylic acid (Alexa Fluor 647, Invitrogen A-20006) at a molar ratio of 2:1 (Alexa to ApoA-I) for 1 hour with shaking at K. so the Remaining unbound label was removed by replacing the buffer to 0.02 M NaHCO3at pH of 8.2.

Check images and data was performed on a confocal apparatus for reading tablet OPERA, using a 20x water-immersion lens and UP or 405 laser system to identify cell nuclei and 635 laser system for the identification of fluorescent ApoA-I. Eight areas of review were recorded on the hole. Image recording and analysis was performed using software Acapella. Background fluorescence, detektiruya in the control wells without ApoA-I read.

Using the program XLfit3 (ID Business Solutions Ltd. UK), model 205 for Dose Response One Site is used to calculate the values of the EU50. Compounds of the present invention increase the level of protein AWSA more than 45% at a concentration of 3 μm. Preferred compounds show the values of the EU50in the range from 0.1 μm to 10 μm in the analysis of protein detection ASA. Even more preferred compounds according to the present izobreteny the matter EU 50in the range from 0.1 μm to 3 μm.

Table 1:
Efficiency increase protein ASA
Example% increase AWSA at 3 micronsEU50[µm]
1>45% at 3 microns
22.69
32.28
4>45% at 3 microns
5>45% at 3 microns
6>45% at 3 microns
7>45% at 3 microns
82.77
9>45% at 3 microns
10 6.51
11>45% at 3 microns
12>45% at 3 microns
13>45% at 3 microns
14>45% at 3 microns
15>45% at 3 microns
166.05
172.31
18>45% at 3 microns
191.39
206.4
211.37
22>45% at 3 microns
230.72
24 2.31
252.65
26>45% at 3 microns
27>45% at 3 microns
28>45% at 3 microns
29>45% at 3 microns
303.86
31>45% at 3 microns
321
33>45% at 3 microns
342.4
35>45% at 3 microns
360.51
37>45% at 3 microns
382.91
392.23
403.31
41>45% at 3 microns
428.54
435.95
441.26
451.03
46>45% at 3 microns
471.36
48>45% at 3 microns

Example% increase AWSA at 3 micronsEC50[µm]
490.3
501.5
51>45% at 3 microns
52>45% at 3 microns
53>45% at 3 microns
54>45% at 3 microns
55>45% at 3 microns
56>45% at 3 microns
57>45% at 3 microns
582.2
593.9
60>45% at 3 microns
61>45% at 3 microns
622.39
0.68
641.08
650.27
66>45% at 3 microns
67>45% at 3 microns
68>45% at 3 microns
69>45% at 3 microns
70>45% at 3 microns
71>45% at 3 microns
720.78
73>45% at 3 microns
74>45% at 3 microns
75>45% at 3 microns
76gt; 45% at 3 microns
770.72
78>45% at 3 microns
79>45% at 3 microns
80>45% at 3 microns
812.56
82>45% at 3 microns
83>45% at 3 microns
84>45% at 3 microns
85>45% at 3 microns
86>45% at 3 microns
87>45% at 3 microns
88>45% at 3 microns
89 3.31

Analysis of the excretion of cholesterol

The ability of compounds according to the invention to stimulate the excretion of cholesterol is determined in repeated cell cultures TNR-1 in 96-well microplate. The cells are sown when the initial density of 150,000 cells/well and differentiated to macrophages with the addition of PMA (100 ng/ml) for 72 hours in 10% fetal bovine serum, 3 µl/l beta-mercaptoethanol, RPMI-1640 medium. Cells are washed once with RPMI-1640 and load with RPMI-1640 medium containing 2% ETS, 50 μg/ml acetylated LDL and 10 µci/ml of [3H]cholesterol for 48 hours at 37°C. After loading, the cells are washed once with RPMI-1640 and incubated with interest compound from solutions of DMSO for an additional 24 hours in RPMI-1640 medium containing 1 mg/ml bovine serum albumin (BSA), which do not contain fatty acids. After incubation, cells are washed once, and excretion of cholesterol cause by adding 10 μg/ml Apolipoprotein AI in RPMI-1640 containing 1 mg/ml BSA, and in the presence of compounds for an additional 6 hours. After incubation, the radioactivity determined in the supernatant fluids, and cholesterol excretion expressed as percent stimulation relative to repeated cultures treated only with DMSO. Sigmoidal curves were built using the software XLfit3 (ID Business Solutons Ltd. UK), and determine the values of the EU50.

Compounds of the present invention show the values EC50in the range from 0.1 μm to 3.0 μm in the analysis of the excretion of cholesterol. Preferably the compounds of the present invention have values EU50in the range from 0.1 μm to 1.5 μm.

Affinity receptors SW and SW

The affinity of the compounds according to the invention for cannabinoid receptors was determined using membrane preparations from cells of embryonic human kidney (SOME from human embryonic kidney), in which the receptor SW person temporarily transferout using the system of the virus Semliki forest combined with [3H]-CP-55,940 as radioligand. After incubation of freshly prepared drug cell membranes with [3H]-ligand, with or without the addition compounds according to the invention, the separation of bound and free ligand was carried out during filtration through glass fiber filters. The radioactivity on the filter was measured by scintillation method.

The affinity of the compounds according to the invention for cannabinoid receptors SV was determined using membrane preparations from cells of embryonic human kidney (SOME), in which the receptor SW person temporarily transferout using the system of the virus Semliki forest combined with [3H]-CP-55,940 as radioligand. After incubation of freshly prepared drug tile is cnyh membranes with [ 3H]-ligand, with or without the addition compounds according to the invention, the separation of bound and free ligand was carried out during filtration through glass fiber filters. The radioactivity on the filter was measured by scintillation method.

The ability of compounds to displace radioligand [3H]-CP-55,940 was measured at a concentration of 10 μm and the values as [% inhibition at 10 μm] for both analyses receptors SW and SW. The lower the % of inhibition, the lower the likelihood of adverse effects based on the inhibition of receptor SW or SW.

Compounds of the present invention show values below 50% inhibition in both assays receptor SW and SW at a concentration of 10 μm. Preferably the compounds of the present invention show values below 35% inhibition in both assays receptor SW and SW and even more preferably below 20% in both tests.

td align="center"> 16
Table 2:
Affinity receptors SW and SV
ExampleThe affinity to the receptor CV [% inhibition at 10 μm]The affinity to the receptor CV [% inhibition at 10 μm]
145/td> 9.2
2334.9
3298.0
4361.9
519-5.4
64711
7131.2
85215
9249.6
103628
1125-1.2
12224
13163
143810
15272
34-1
1716-3
18373
1925-10
20349
21291
22458
2312-8
2425-1
2525-1
263711
274710

ExampleThe affinity to the receptor CV [% inhibition at 10 μm]The affinity to the receptor CV [% inhibition at 10 μm]
2836-6
294119
3027-4
31447
32210.9
3322-2
343110
3518-3
36182
37278
381215
391916
4019-5
41318
42 236
43316
441514
451113
4640-1
47345
4840-2
4939-3
5039-1
51486
52346
53210
542110
55354
56350
570-18
583-13
592218
6038-2
611712
62-44
635-1
6492
65195
66305
67339
68264
693518
704915
7141 4
7225-7
731322
7417-7

ExampleThe affinity to the receptor CV [% inhibition at 10 μm]The affinity to the receptor CV [% inhibition at 10 μm]
75315
7615
773316
782526
792913
801614
81215
822937
8327/td> -5
84233
85385
86485
8719-15
884116
89355

An additional demonstration of the biological activities of the compounds of the present invention can be performed using the following tests in vivo, which are well known in the art.

Impact on the levels of lipids in the plasma at the skinny rats receiving food

The effect of compounds of the formula I on the levels of lipids in plasma was determined on the skinny rats Sprague-Dole receiving food compounds administered orally with artificial food. After one week of acclimatization, the blood samples were collected from animals 4 hours not to receive this food, for the determination of lipids in the plasma. Then, animals were assigned to experimental groups based on levels of HDL-cholesterol. The compounds of formula I was administered the artificially once a day for five days. Control animals received only the filler. Blood was collected on the fifth day, rats, 4 hours not receiving before meals, 2 hours after the final injection for analysis of lipids in plasma. Total cholesterol, HDL cholesterol and triglycerides were determined by measuring total cholesterol, HDL cholesterol and triglycerides using colorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). The number of HDL-C were also determined using exclusion chromatography on a column of superpose-6 using the SMART system (Pharmacia). The distribution of lipoproteins is calculated based on the Gaussian distribution for each peak, using the approximation of a nonlinear least squares method to calculate the area under the curve. Also determined the concentration of compounds in plasma.

Impact on the levels of lipids in the plasma of obese rats receiving food with high fat content

The ability of compounds to modify the lipid levels in the plasma were also determined on fat male rats Sprague-Dole 28-29 days after injection of the compounds. Male rats Sprague-Dole at the age of 10 weeks were given food with high fat diet for 3 weeks. Obese rats were divided into groups in accordance with the uniform BW (body weight) and FI (varindex) for a week before treatment. Processing was carried out in the form of dietary supplements. On the 9th day the blood was collected in the morning with little or no anesthesia (retroorbital way) after a meal, i.e. 4 hours after eating excluded. Plasma was separated from blood by low-speed centrifugation, and selected organs were collected (for example liver, fat). Total cholesterol, HDL cholesterol and triglycerides were determined by measuring total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides using colorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). The number of HDL-C were also determined using exclusion chromatography on a column of superpose-6 using the SMART system (Pharmacia). The distribution of lipoproteins is calculated based on the Gaussian distribution for each peak, using the approximation of a nonlinear least squares method to calculate the area under the curve. Also determined the concentration of compounds in plasma.

Impact on the levels of lipids in the plasma hamsters

The ability of compounds to alter the levels of lipids in plasma was determined in hamsters after 5 days of daily administration of compounds. The studies used male hamsters at the age of 6-8 weeks. After one week of acclimatization, the blood samples were collected from animals 4 hours not to receive this food, for the determination of lipids in the plasma. Then, animals were assigned to experimental groups based on levels of HDL-cholesterol. Compounds were introduced artificially once a day for five days. Control animals received the only filler. Blood was collected on the fifth day of the hamsters, 4 hours not receiving before meals, 2 hours after the final injection for analysis of lipids in plasma. Total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides were determined using colorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). Quantitatively the levels of HDL cholesterol, LDL cholesterol and VLDL cholesterol was also determined using exclusion chromatography on a column of superpose-6 using the SMART system (Pharmacia). The distribution of lipoproteins is calculated based on the Gaussian distribution for each peak, using the approximation of a nonlinear least squares method to calculate the area under the curve. Also determined the concentration of compounds in plasma.

Impact on the levels of lipids in the plasma hamsters receiving food with cholesterol/fat

The ability of compounds to alter the levels of lipids in plasma was determined in hamsters after 5 days of daily administration of compounds. The studies used male hamsters at the age of 6-8 weeks. After one week of acclimatization, the blood samples were collected from animals 4 hours not to receive this food, for the determination of lipids in the plasma. Then, animals were assigned to experimental groups based on levels of HDL-cholesterol. Compounds were introduced artificially once a day for p is days. Control animals received only the filler. Blood was collected on the fifth day of the hamster, 4 hours not receiving before meals, 2 hours after the final injection for analysis of lipids in plasma. Total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides were determined using colorimetric enzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). The HDL cholesterol was also determined after selective deposition of HDL from plasma by standard methods.

Examples

MS = mass spectrometry; EI = electron ionization; ESI = elektrorazpredelenie; NMR data are presented in ppm (5) relative to the internal standard tetramethylsilane and reference signal capture deuterium from the sample solvent (d6-DMSO unless otherwise stated); the binding constants (J) are in Hertz, so pl. = melting point; so bales. = boiling temperature; HPLC=LC = liquid chromatography, Rt = retention time, TLC = thin layer chromatography, K. T. = room temperature, DIPEA = diisopropylethylamine, DFFA = diphenylphosphinite, TBTU = O-(benzotriazol-1-yl)-N,N',N'-tetramethyl-urani-tetrafluoroborate; TEMPO = radical 2,2,6,6-Tetra-methylpiperidin-1-oxyl, DMF = dimethylformamide, DMSO = dimethylsulfoxide, THF = tetrahydrofuran, CAN=registration number CAS.

The intermediate compounds

Example

Obtain 3-bromo-5-nitro-2-(2,2,2-Cryptor-ethoxy)-pyridine

Sodium hydride (3.2 g, 80,02 mmol) was carefully added in small portions to 2,2,2-triptoreline (registration number CAS 75-89-8) (60 ml) at 0°C under nitrogen atmosphere and stirred at 25°C for 30 minutes. Then added 3-bromo-2-chloro-5-nitropyridine (registration number CAS 5470-17-7) (2 g, 8,42 mmol) in triptoreline, and the reaction mixture was heated under reflux for 16 hours. The solvent is evaporated in vacuo, and the residue was transferred into water and was extracted with ethyl acetate (3×120 ml). The combined organic layers were washed with water and brine, dried over Na2SO4and concentrated, giving the crude residue (3 g). The crude residue was purified by column chromatography (3% ethyl acetate/hexane) gave the desired product (2.4 g, 95%) as a yellow liquid. MS (LC/MS): does not respond, NMR is consistent with structure:1H-NMR (400 MHz, CDCl3):δ 4.90 (m, 2H), 8.68 (d, 1H), 8.98 (d, 1H).

The example In

Obtain 3-bromo-2-cyclopropylmethoxy-5-nitro-pyridine

To a solution of sodium hydride (2,21 g, 55,34 mmol) in anhydrous DMF (20 ml) was added cyclopropylmethanol (registration number CAS 2516-33-8) (12,45 ml, 153,2 mmol) under nitrogen atmosphere at 0°C and the reaction mixture was stirred at 25°C for 30 minutes. Then 3-bromo-2-chloro-5-nitro ridin (registration number CAS 5470-17-7) (7,3 g, 30,74 mmol) was added dropwise at 0°C and was stirred for two hours at 25°C. Water (60 ml) was added to the reaction mixture and was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water and brine, dried over Na2SO4and evaporated under reduced pressure, which gave the crude residue (12 g). The crude residue was purified by column chromatography (2% ethyl acetate/hexane) gave the desired product (of 2.06 g, 32%) as a pale yellow solid, and 1.7 g of unreacted 3-bromo-2-chloro-5-nitropyridine allocated. MS (LC/MS): does not respond, NMR is consistent with structure:1H-NMR (400 MHz, CDCl2):δ 0.41 (m, 2H), 0.65 (m, 2H), 1.32 (m, 1H), 4.34 (d, 2H), 8.60 (d, 1H), 8.96 (d, 1H).

The example

Getting 5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine

To a solution of 3-bromo-5-nitro-2-(2,2,2-Cryptor-ethoxy)-pyridine (2.4 g, of 7.97 mmol) in ethanol (100 ml) was added HCl (0.3 ml) and tin chloride (10.5 g, 55,81 mmol) at 25°C and the reaction mixture was stirred for 4 hours at 25°C. After complete consumption of the original substances (control by TLC), the ethanol evaporated under reduced pressure, diluted with ethyl acetate, neutralized with an aqueous solution of Na2CO3and filtered through a pad of celite. The organic layer was separated, and the aqueous layer was more AXT who was agarawala with ethyl acetate (2×120 ml). The combined organic layers were washed with saline, dried over Na2SO4and evaporated in vacuo, giving the desired compound (2.1 g, 97%) as a brown liquid. It was used as such in the next stage without additional purification. MS (LC/MS): does not respond, NMR is consistent with structure:1H-NMR (400 MHz, CDCl3): δ 4.70 (m, 2H), 7.30 (d, 1H), 7.54 (d, 1H).

Example D

Getting 5-bromo-6-cyclopropylmethoxy-pyridine-3-ylamine

To a solution of 3-bromo-2-cyclopropylmethoxy-5-nitro-pyridine (600 mg, are 2.19 mmol) in methanol (30 ml) was added water (15 ml), zinc dust (1 g, shed 15.37 mmol) and ammonium chloride (1.28 g, 24,09 mmol) at 25°C., and the reaction mixture was stirred for 45 minutes at 25°C. After complete consumption of the starting substances (control by TLC) the reaction mixture was filtered through a pad of celite, and the filtrate evaporated under reduced pressure, that would give the crude residue. The residue was dissolved in dichloromethane and washed with water and brine. The organic portion was dried over Na2SO4and evaporated, giving the compound (507 mg, 95%). This compound was used in the next stage without additional purification. MS (LC/MS): 244,0 (M+H).

Example F

Getting 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine

It is aStore 5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (2.1 g, 7,74 mmol) in DME, ethanol, water (3:1:1) (50 ml) in a sealed tube was added 4-Chlorfenvinphos acid (registration number CAS 1679-18-1) (1.8 g, are 11.62 mmol) and potassium phosphate (4.9 g, 23,22 mmol), and then the reaction mixture was purged of Izotov within 15 minutes. Then was added Pd(dppf)2Cl2(651 mg, of 0.93 mmol) to the reaction mixture and was heated at 100°C for 4 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (3×20 ml). The organic layer was washed with water, brine, dried over Na2SO4and evaporated in vacuo gave the crude substance (1.9 grams). The crude substance was purified by column chromatography (20-25% ethyl acetate/hexane) gave the desired product (1.3 g, 56%) as a brown liquid. MS (LC/MS): 303,0 (M+H).

Example F

Getting 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-ylamine

Specified in the title compound was synthesized in analogy to Example E, using 5-bromo-6-cyclopropylmethoxy-birdin-3-ylamine and 4-Chlorfenvinphos acid (44%). MS (LC/MS): 275,2 (M+H).

Example G

Obtaining N-[5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide

To a solution of nicotinic acid (454 mg, of 3.69 mmol) in DMF (33 ml), was added TBTU (1.18 g, of 3.69 mmol), N,N-diisopropylethylamine (and 3.16 ml, 18.4 mmol) and 5-bro is-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (1 g, of 3.69 mmol). The brown mixture was stirred in an argon atmosphere for 3 hours at room temperature. After evaporation of DMF brown oil was separated between ethyl acetate (50 ml) and 1 M NaOH (30 ml). The aqueous layers was extracted again with ethyl acetate (1×50 ml). The organic portion was washed with water (2×25 ml) and brine (25 ml), then dried over MgSO4and concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 40 g, 10% to 100% ethyl acetate in heptane) gave the desired product as a white solid (580 mg; 42%); MS (EI): 376,1; 378,0 (M+H).

Example 1

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pentanol acid

To a solution of 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (50 mg, 0,165 mmol) and valerianic acid (36 mg, 0,247 mmol) in DMF (5 ml) was added N-methyl-morpholine (51 mg, 0.5 mmol) and HBTU (94 mg, 0,247 mmol) and the reaction mixture was stirred for 16 hours at 25°C. the Reaction mixture was poured into water and was extracted with ethylcatechol (3×20 ml). United an ethyl acetate portion was dried over Na2SO4and evaporated, which gave the crude compound (60 mg). The crude substance was purified using prep. HPLC and the desired product (30 mg, 47%) was obtained as a sticky white solid. MS (LC/MS): 387,2 (M+H).

Example 2

Obtaining N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-benzamide

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and benzoic acid as starting substances, MS (LC/MS): 407,2 (M+H).

Example 3

Obtaining N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and nicotinic acid as starting substances, MS (LC/MS): 408,0 (M+H).

Example 4

Obtaining N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-isonicotinamide

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and isonicotinoyl acid as starting substances, MS (LC/MS): 408,0 (M+H).

Example 5

Obtaining N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-ndimethylacetamide

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and acetic acid as starting substances, MS (LC/MS): 345,0 (M+H).

Note the p 6

Obtaining N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-butyramide

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and n-butane acid as starting substances, MS (LC/MS): 373,2 (M+H).

Example 7

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridine-2-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and pyridine-2-carboxylic acid as starting substances, MS (LC/MS): 408,0 (M+H).

Example 8

Obtaining N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-benzamide

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-ylamine and benzoic acid as starting substances, MS (LC/MS): TO 379.2 (M+H).

Example 9

Obtaining N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-ndimethylacetamide

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-ylamine and acetic acid as starting substances, MS (THE X/MS): 317,2 (M+H).

Example 10

Obtaining N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-nicotinamide

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-ylamine and nicotinic acid as starting substances, MS (LC/MS): 380,2 (M+H).

Example 11

Obtaining N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-isonicotinamide

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-ylamine and isonicotinoyl acid as starting substances, MS (LC/MS): 380,2 (M+H).

Example 12

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrazin-2-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 2-pyrazinecarboxamide acid as starting substances, MS (LC/MS): 409,6 (M+H).

Example 13

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 2,5-dimethyl-2H-pyrazole-3-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-the feast of the Dean-3-ylamine and 1,3-dimethyl-1H-pyrazole-5-carboxylic acid as starting compounds, MS (LC/MS): 425,6 (M+H).

Example 14

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3-methyl-isoxazol-4-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 3-methyl-4-isoxazolidinone acid as starting substances, MS (LC/MS): 412,2 (M+H).

Example 15

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1-methyl-1H-pyrazole-3-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 1-methyl-1H-pyrazole-3-carboxylic acid as starting substances, MS (LC/MS): 411,0 (M+H).

Example 16

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-3-isoxazolecarboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 5-methyl-3-isoxazolidinone acid as starting substances, MS (LC/MS): 412,2 (M+H).

Example 17

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3-pyridineboronic acid

Specified the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 3-pyridazinone acid as starting substances, MS (LC/MS): 409,0 (M+H).

Example 18

Getting amide N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-3-methyl-4-pyridineboronic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 3-methyl-4-pyridylcarbonyl acid as starting substances, MS (LC/MS): 422,0 (M+H).

Example 19

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-pyrimidinecarbonitrile acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 5-pyrimidinecarbonitrile acid as starting substances, MS (LC/MS): 409,0 (M+H).

Example 20

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1-methyl-1H-pyrazole-5-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 1-methyl-1H-pyrazole-5-carboxylic acid as starting substances, MS (LC/MS): 409,2 (M-N).

Example 21

Recip is of [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide of 2,4-dimethyl-5-oxazolidinone acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 2,4-dimethyl-5-oxazolidinone acid as starting substances, MS (LC/MS): TO 426.2 (M+H).

Example 22

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-isothiazolinones acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 5-isothiazolinones acid as starting substances, MS (LC/MS): 414,0 (M+H).

Example 23

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 5-methyl-1H-pyrazole-3-carboxylic acid as starting substances, MS (LC/MS): 409,2 (M-N).

Example 24

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide of 1H-pyrazole-3-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 1H-pyrazole-3-carboxylic acid as starting compounds MS (LC/MS): 395,2 (M-N).

Example 25

Getting amide N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-methyl-4-pyridineboronic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 2-methyl-4-pyridylcarbonyl acid as starting substances, MS (LC/MS): 422,0 (M+H).

Example 26

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 6-methyl-2-thiazol-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 5-methyl-2-diazocarbonyl acid as starting substances, MS (LC/MS):428,2 (M+H).

Example 27

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 4-methyl-1,2,3-thiadiazole-5-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 4-methyl-1,2,3-thiadiazole-5-carboxylic acid as starting substances, MS (LC/MS): 429,2 (M+H).

Example 28

Getting amide N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-6-methyl-3-pyridineboronic acid

Specified in the header connect the imposition synthesized by analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 6-methyl-3-pyridylcarbonyl acid as starting substances, MS (LC/MS): 420,4 (M-N).

Example 29

Getting amide N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-methyl-3-pyridineboronic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 2-methyl-3-pyridylcarbonyl acid as starting substances, MS (LC/MS): 421,8 (M+H).

Example 30

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-isoxazolecarboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 5-isoxazolidinone acid as starting substances, MS (LC/MS): 398,0 (M+H).

Example 31

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3,5-dimethyl-4-isoxazolecarboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 3,5-dimethyl-4-isoxazolidinone acid as starting substances, MS (LC/MS): TO 426.2 (M+H).

Example 32

Getting amide N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-1,2-dihydro-2-oxo-4-pyridineboronic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 1,2-dihydro-2-oxo-4-pyridylcarbonyl acid as starting substances, MS (LC/MS): 424,0 (M+H).

Example 33

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1,3-dimethyl-1H-pyrazole-4-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 1,3-dimethyl-1H-pyrazole-4-carboxylic acid as starting substances, MS (LC/MS): 425,0 (M+H).

Example 34

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 4-pyrimidinecarboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 4-pyrimidinecarbonitrile acid as starting substances, MS (LC/MS): 409,0 (M+H).

Example 35

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 2-diazocarbonyl acid

Specified in the title compound was synthesized in analogy to Example 1 using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 2-diazocarbonyl acid as starting substances, MS (LC/MS): 414,0 (M+H).

Example 36

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3-methyl-2-pyridineboronic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 3-methyl-2-pyridylcarbonyl acid as starting substances, MS (LC/MS): 422,0 (M+H).

Example 37

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-4-oxazolidinone acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 5-methyl-4-oxazolidinone acid as starting substances, MS (LC/MS): 412,2 (M+H).

Example 38

Obtaining N-(5-(3,4-dimetilfenil)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide

A 25 ml sealed tube N-(5-bromo-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide (200 mg, 532 mmol) was combined with toluene (11 ml). In an atmosphere of argon was added 3,4-dimethylbenzophenone acid (160 mg, 1.06 mmol), aqueous sodium carbonate (2 M, of 0.53 ml) and Pd(dppf)2Cl2(12 mg, to 0.016 mmol). After two hours at 90°With dark red suspension was cooled to room temperature, diluted with ethyl acetate (10 ml) and washed with water (0 ml) and brine (10 ml). The aqueous layer was re-extracted with ethyl acetate (15 ml). The organic layers were dried over MgSO4and concentrated in vacuum. Crystallization from ethyl acetate/heptane (5 ml, 1/2) gave a white solid (96 mg), the filtrate is evaporated to dryness and was purified by column chromatography (silica gel, 20 g, 10% to 100% ethyl acetate in heptane) gave the second part of the desired product as a white solid (139 mg). The total yield was 65%; MS (EI): 402,3 (M+H).

Example 39

Obtaining N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide

A 25 ml sealed tube N-(5-bromo-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide (520 mg, 1.38 mmol) was combined with toluene (20 ml). In an atmosphere of argon was added 4-chloro-3-methylphenylimino acid (471 mg, 2.77 mmol), aqueous sodium carbonate (2 M, 1,38 ml) and Pd(dppf)2Cl2(30 mg, 0,041 mmol). After two hours at 90°C dark red suspension was cooled to room temperature, diluted with ethyl acetate (10 ml) and washed with water (10 ml) and brine (10 ml). The aqueous layer was re-extracted with ethyl acetate (15 ml). Organic layers were dried over MgSO4and concentrated in vacuum. The crude compound (760 mg) was purified using flash chromatography (silica gel, 20 g, 20% to 100% ethyl acetate in heptane) gave specified in the header Conn is out in the form of a light brown solid (575 mg, 98%); MS (EI): TO 422.8 (M+H).

Example 40

Obtain [5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-hydroxy-pyridine-2-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 5-hydroxy-2-pyridylcarbonyl acid (CAN 15069-92-8) as starting materials; LC-MS (size UV peak / ESI) 96,3%, 422,0523 (M-N)-.

Example 41

Obtaining N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-nicotine amide

Specified in the title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine and 5-methyl-3-pyridylcarbonyl acid (CAN 3222-49-9) as starting materials; MS (EI) 422,1 (M+N)+.

Example 42

Obtain (S)-N-(5-(4-chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)pyridine-3-yl)pyridazin-3-carboxamide

a) 5-Chloro-3-(4-chloro-phenyl)-2-fluoro-pyridine

A mixture of 3-bromo-6-chloro-2-fluoro-pyridine (CAN 884494-87-5; 2.0 g, 9.50 mmol), 4-Chlorfenvinphos acid (CAN 1679-18-1; 1.5 g, 9.50 mmol); tetrakis(triphenylphosphine)-palladium (0.55 g, 0.48 mmol) and potassium carbonate (2.6 g, 19 mmol) in water (50 ml) and THF (50 ml) was heated under reflux for 18 hours. The reaction mixture is about what was lagali, was diluted with ethyl acetate, the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried with MgSO4and the solvent was removed in vacuum. The residue was purified by column chromatography (on silica gel with a gradient of heptane to heptane:ethyl acetate = 9:1), which gave specified in the header of the product (2.2 g, 95%) as a white solid; MS (ESI): 241,0 (M)+.

b) 5-Chloro-3-(4-chloro-phenyl)-2-((5)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridine

To the mixture 1,133 g (S)-1,1,1-Cryptor-2-propanol in 10 ml of anhydrous DMF was added 397 mg of sodium hydride (60%) and the mixture was stirred at room temperature for 30 minutes. The resulting solution was added dropwise with K. so the solution 2,185 g of 5-chloro-3-(4-chloro-phenyl)-2-fluoro-pyridine in 20 ml of anhydrous DMF. Then the reaction mixture was stirred at room temperature for 2 hours. The resulting light yellow mixture was divided between water and ethyl acetate, the phases were separated. The organic phase was dried over MgSO4and was purified by chromatography on silica gel with a gradient of heptane to heptane:ethyl acetate=9:1, which gave 2,330 g (76,80%) specified in the title compounds as a colorless liquid; MS (ESI) 336,1 (M+N)+.

C) (S)-Methyl 5-(4-chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)nicotinate

It races the thief 2,42 g of 5-chloro-3-(4-chloro-phenyl)-2-((5)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridine in 50 ml of methanol was added 1,09 g of triethylamine and 0,484 g of PdCl 2.dppf.CH2Cl2. The mixture was heated to 150°C in an atmosphere of 70 bar of carbon monoxide for 20 hours. The reaction mixture was cooled to room temperature. Solids were removed by filtration, the mother liquor is evaporated and purified via chromatography on silica gel using a gradient of heptane to heptane:ethyl acetate 85:15, which gave 0,862 g (33%) indicated in the title compounds as a light yellow oil; MS (ESI) 359 (M+).

d) (5)-5-(4-Chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)nicotinic acid

To a solution of 0,860 g (S)-methyl 5-(4-chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)nicotinate in 9 ml of tetrahydrofuran was added 3 ml of 1 M solution of lithium hydroxide in water and the mixture was stirred at room temperature overnight. The solvent is evaporated and the residue was acidified by adding 1 M hydrochloric acid to pH 2. Added ethyl acetate and the phases were separated. The organic phase was dried over MgSO4and the solvent was removed, which gave 830 mg (100%) specified the title compound as a pale yellow solid; MS (ESI) 344,1 (M-N)-.

(e) tert-Butyl ether [5-(4-chloro-phenyl)-6-((8)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridine-3-yl]-carbamino acid

(S)-5-(4-Chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)nicotinic acid (0,300 g, 868 mmol) suspended in tert-bout the OLE (3.0 ml). DFFA (358 mg, 282 μl) and triethylamine (of 87.8 mg, 120 μl, 868 mmol) was added and the reaction mixture was stirred at 100°C during the night. The mixture was cooled to room temperature, extracted with ethyl acetate and sodium carbonate solution, the organic phase was dried with MgSO4and concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 20 g, 5% to 25% ethyl acetate in heptane) gave 0.36 g (99%) indicated in the title compound as a white solid; MS (EI) 417,3 (M+N)+.

f) 5-(4-Chloro-phenyl)-6-((8)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridine-3-ylamine

Triperoxonane acid (2,74 g of 1.85 ml of 24.0 mmol) was added to (S)-tert-butyl 5-(4-chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)pyridine-3-ylcarbamate (0,350 g, 840 mmol). The resulting yellow solution was stirred at K. T. for 1 hour. The solvent is evaporated. The residue was separated between ethyl acetate and 1 m solution of Na2CO3, the organic phase was dried with MgSO4and concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 20 g, 5% to 50% EtOAc in heptane) gave 0,22 g (82%) indicated in the title compound as light brown oil; MS (EI) is 317.1 (M+N)+.

g) (S)-N-(5-(4-Chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)pyridine-3-yl)pyridazin-3-carboxamide

Pyridazin-3-carboxylic acid (CAN 2164-61-6; to 43.1 mg, 347 μmol) suspended in DMF (1.0 ml). Added TBTU (112 mg, 347 μmol), ethyldiethanolamine (102 mg, 131 μl, 789 μmol) and 5-(4-chloro-phenyl)-6-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridine-3-ylamine (0,100 g, 316 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate and 1 M citric acid solution; the organic phase was dried with MgSO4and concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 10 g, 10% to 50% ethyl acetate in heptane) gave 0.11 g (83%) indicated in the title compound as a white solid; MS (EI) 423,1 (M+N)+.

Example 43

Obtain (S)-N-(5-(4-chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)pyridine-3-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridine-3-ylamine (example 42f) and 3-pyridine-carboxylic acid (CAN 59-67-6) as starting materials; MS (EI) 422,0 (M+N)+.

Example 44

Obtaining N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-Cryptor-ethoxy)-the feast of the DIN-3-yl]-nicotinamide (example G) and b-(4-chloro-3-forfinal)-Bronevoy acid (CAN 137504-86-0) as starting compounds; LC-MS (size UV peak / ESI) 96,4%, 424,0482 (M-H)-.

Example 45

Obtaining N-(5-(3-chloro-4-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide (example G) and b-(3-chloro-4-forfinal)-Bronevoy acid (CAN 144432-85-9) as starting materials; LC-MS (size UV peak / ESI) 98,0%, 424,0483 (M-N)-.

Example 46

Obtaining N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide (example G) and b-(4-chloro-2-forfinal)-Bronevoy acid (CAN 160591-91-3) as starting materials; LC-MS (size UV peak / ESI) 97,2%, 424,0483 (M-N)-.

Example 47

Obtaining N-(5-(4-ethylphenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide (example G) and b-(4-ethylphenyl)-Bronevoy acid (CAN 63139-21-9) as starting materials; LC-MS (size UV peak / ESI) 100%, 402,1409 (M+N)+.

Example 48

Receipt is (S)-N-(6-(4-chlorophenyl)-5-(1,1,1-tryptophan-2-yloxy)pyrazin-2-yl)nicotinamide

a) Methyl ester of 6-(4-chloro-phenyl)-5-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyrazin-2-carboxylic acid

Methyl ester of 5-bromo-6-(4-chlorophenyl)-2-pyrazinecarboxamide acid (CAN 960247-79-4, 2,420 g, 7,39 mmol) was dissolved in anhydrous DMSO (25 ml). Added cesium carbonate (to 4.41 g, 8,13 mmol) and (8)-1,1,1-tryptophan-2-ol (927 mg, 8,13 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was divided between water and ethyl acetate; the organic phase was dried with MgSO4and concentrated in vacuum. The crude residue was purified using flash chromatography (silica gel, 100 g, from 10% to 50% ethyl acetate in heptane) gave 2,53 g (95%) indicated in the title compound as a yellow oil; MS (EI) 361,1 (M+N)+.

b) 6-(4-Chloro-phenyl)-5-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyrazin-2-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 42d, using methyl ester of 6-(4-chloro-phenyl)-5-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyrazin-2-carboxylic acid as starting materials; MS (ESI) 345,0 (M-N)-.

C) tert-Butyl ether [6-(4-chloro-phenyl)-5-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyrazin-2-yl]-carbamino acid

Specified in the title compound was synthesized in analogy to Example a, using 6-(4-chloro-dryer is l)-5-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyrazin-2-carboxylic acid as the starting material; MS (EI) 418,2 (M+N)+.

d) 6-(4-Chloro-phenyl)-5-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyrazin-2-ylamine

Specified in the title compound was synthesized in analogy to Example 42f, using tert-butyl ether [6-(4-chloro-phenyl)-5-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyrazin-2-yl]-carbamino acid as the starting material; MS (EI) 318,0 (M+N)+.

(e) (S)-N-(6-(4-Chlorophenyl)-5-(1,1,1-tryptophan-2-yloxy)pyrazin-2-yl)nicotinamide

6-(4-Chloro-phenyl)-5-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyrazin-2-ylamine (0,100 g, 315 mmol) was dissolved in anhydrous pyridine (1.0 ml), was added nicotinanilide hydrochloride (61,6 mg, 346 μmol) and the suspension was stirred at 140°C for 10 minutes under microwave irradiation. The solvent is evaporated and the crude substance was purified using flash chromatography (silica gel, 10 g, from 0% to 50% of CH2Cl2/Meon/NH39/1/0,1), which gave 0,121 g (91%) indicated in the title compound as a white solid; LC-MS (square UV peak / ESI) 100%, 423,0821 (M+N)+.

Example 49

Obtaining N-(6-(4-chlorophenyl)-5-(2,2,2-triptoreline)pyrazin-2-yl)nicotinamide

a) Methyl ester of 6-(4-chloro-phenyl)-5-(2,2,2-Cryptor-ethoxy)-pyrazin-2-carboxylic acid

Specified in the title compound was synthesized in which nologie Example 48A, using the methyl ester of 5-bromo-6-(4-chlorophenyl)-2-pyrazinecarboxamide acid (CAN 960247-79-4) and 2,2,2-triptorelin as starting materials; MS (EI) 347,1 (M+N)+.

b) 6-(4-Chloro-phenyl)-5-(2,2,2-Cryptor-ethoxy)-pyrazin-2-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 42d, using methyl ester of 6-(4-chloro-phenyl)-5-(2,2,2-Cryptor-ethoxy)-pyrazin-2-carboxylic acid as starting materials; MS (ESI) 331,1 (M-N)-.

C) tert-Butyl about you and ether [6-(4-chloro-phenyl)-5-(2,2,2-Cryptor-ethoxy)-pyrazin-2-yl]-carbamino acid

Specified in the title compound was synthesized in analogy to Example a, using 6-(4-chloro-phenyl)-5-(2,2,2-Cryptor-ethoxy)-pyrazin-2-carboxylic acid as starting materials; MS (EI) 404,3 (M+N)+.

d) 6-(4-Chloro-phenyl)-5-(2,2,2-Cryptor-ethoxy)-pyrazin-2-ylamine

Specified in the title compound was synthesized in analogy to Example 42f, using tert-butyl ether [6-(4-chloro-phenyl)-5-(2,2,2-Cryptor-ethoxy)-pyrazin-2-yl]-carbamino acid as the starting material; MS (EI) 304,0 (M+N)+.

e) N-(6-(4-Chlorophenyl)-5-(2,2,2-triptoreline)pyrazin-2-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example the m 48th, using 6-(4-chloro-phenyl)-5-(2,2,2-Cryptor-ethoxy)-pyrazin-2-ylamine (Example 49d) and nicotinanilide hydrochloride as starting materials; LC-MS (square UV peak / ESI) 95,7%, 407,0532 (M-N)-.

Example 50

Obtaining N-(6-(4-chlorophenyl)-5-cyclobutenedione-2-yl)nicotinamide

a) 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyrazin-2-carboxylic acid

Cyclopropylmethanol (1.54 g, 1.73 ml of 21.3 mmol) was diluted in anhydrous DMF (15 ml); parts) was added sodium hydride (512 mg, of 21.3 mmol) and the reaction mixture was stirred at room temperature for 15 minutes. The resulting solution was slowly added at <5°C to a solution of 5-bromo-6-(4-chlorophenyl)pyrazin-2-carboxylic acid (CAN 960247-80-7; 3,040 g, 9.7 mmol) in anhydrous DMF (15 ml). The reaction mixture was stirred at room temperature for 30 minutes, was added water and the mixture was acidified using 1 M HCl solution to pH 2. The mixture was extracted with ethyl acetate; the organic phases were combined, dried with MgSO4and concentrated in vacuum. The crude substance still contained starting material, and it was dissolved again in 15 ml of DMF; the solution was added cyclopropylmethanol (1,05 g of 1.18 ml, 14.5 mmol) and sodium hydride (582 mg, 14.5 mmol) in 15 ml DMF and the mixture was stirred at room temperature for 3 hours. Added water and the reaction is mesh was acidified using 1 M HCl solution to pH 2; the product was besieging that gave 2.55 g (86%) indicated in the title compound as a pale yellow solid; MS (ESI) 303,2 (M-N)-.

b) tert-Butyl ether [6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrazin-2-yl]-carbamino acid

Specified in the title compound was synthesized in analogy to Example a, using 6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrazin-2-carboxylic acid (Example 50A) as starting materials; MS (EI) 376.3 on (M+N)+.

C) 6-(4-Chloro-phenyl)-5-CYCLOBUTANE-pyrazin-2-ylamine

TFA (14.8 g, 10 ml, 130 mmol) was added to tert-butyl ether [6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrazin-2-yl]-carbamino acid (Example 50b, 1,365 g, 3.63 mmol). The resulting yellow solution was stirred at room temperature for 1 hour. The solvent is evaporated and the residue was separated between ethyl acetate and 1 m solution of Na2CO3; the organic phases were combined, dried with MgSO4and concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 100 g, from 10% to 50% ethyl acetate in heptane; then ethyl acetate/methanol 9/1, which gave of 0.133 g (13%) specified in the connection header (rearrangement) as a yellow oil; MS (EI) 276,1 (M+N)+.

d) N-(6-(4-Chlorophenyl)-5-cyclobutenedione-2-yl)nick is tinamed

Specified in the title compound was synthesized in analogy to Example 48th, using 6-(4-chloro-phenyl)-5-CYCLOBUTANE-pyrazin-2-ylamine (Example 50C) and nicotinanilide hydrochloride as starting materials; LC-MS (size UV peak / ESI) 97,4%, 381,1096 (M+H).

Example 51

Obtaining N-(6-(4-chlorophenyl)-5-cyclobutenedione-2-yl)pyrimidine-5-carboxamide

Specified in the title compound was synthesized in analogy to Example 42g, using 6-(4-chloro-phenyl)-5-CYCLOBUTANE-pyrazin-2-ylamine (Example 50) and 5-pyrimidinecarbonitrile acid (CAN 4595-61-3) as starting materials; LC-MS (size UV peak / ESI) 96,3%, 482,1073 (M+N)+.

Example 52

Obtaining N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide

a) [5-Bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrimidine-5-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 42g, using 5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example D) and 5-pyrimidinecarbonitrile acid (CAN 4595-61-3) as starting materials; MS (ESI) 375,2 (M-N)-.

b) N-(5-(4-Chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide

Specified in the header is connected to the e was synthesized in analogy to Example 39, using [5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrimidine-5-carboxylic acid (Example 52a) and(4-chloro-3-were)-Bronevoy acid (CAN 161950-10-3) as starting materials; LC-MS (size UV peak / ESI) 100%, 421,0698 (M-N)-.

Example 53

Obtaining N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide

Specified in the title compound was synthesized in analogy to Example 39, using [5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrimidine-5-carboxylic acid (Example 52) and(4-chloro-3-forfinal)-Bronevoy acid (CAN 137504-86-0) as starting materials; LC-MS (size UV peak / ESI) is 97.7%, 425,0448 (M-N)-.

Example 54

Obtaining N-(5-(3-chloro-4-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide

Specified in the title compound was synthesized in analogy to Example 39, using [5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrimidine-5-carboxylic acid (Example 52a) and(3-chloro-4-forfinal)-Bronevoy acid (CAN 144432-85-9) as starting materials; LC-MS (size UV peak / ESI) 93,5%, 425,0449 (M-N)-.

Example 55

Obtaining N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide

Specified in the title compound was synthesized according to the analogues of the Example 39, using [5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrimidine-5-carboxylic acid (Example 52a) and(4-chloro-2-forfinal)-Bronevoy acid (CAN 160591-91-3) as starting materials; LC-MS (size UV peak / ESI) 92,2%, 425,0446 (M-N)-.

Example 56

Obtaining N-(5-(4-ethylphenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide

Specified in the title compound was synthesized in analogy to Example 39, using [5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrimidine-5-carboxylic acid (Example 52a) and(4-ethylphenyl)-Bronevoy acid (CAN 63139-21-9) as starting materials; LC-MS (size UV peak / ESI) 100%, 403,1384 (M+N)+.

Example 57

Obtaining N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-hydroxyisoquinoline

a) 5-(4-Chloro-3-methyl-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine

Specified in the title compound was synthesized in analogy to Example 39, using 5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example D) and b-(4-chloro-3-were)-Bronevoy acid (CAN 161950-10-3) as starting materials; MS (EI) 317,0 (M+H)+.

b) N-(5-(4-Chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-hydroxyisoleucine

Specified in the title compound was synthesized by and is alogie Example 42g, using 5-(4-chloro-3-methyl-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example 57a) and 1,2-dihydro-2-oxo-4-pyridylcarbonyl acid (CAN 22282-72-0) as starting materials; LC-MS (size UV peak / ESI) 100%, 436,0689 (M-N)-.

Example 58

Obtaining N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

a) [5-Bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1,3-dimethyl-1H-pyrazole-4-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 42g, using 5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example D) and 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (CAN 78703-53-4) as starting materials; LC-MS (size UV peak / ESI) 100%, 393,0063 (M-N)-.

b) N-(5-(4-Chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

Specified in the title compound was synthesized in analogy to Example 39, using [5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (Example 58A) and(4-chloro-3-were)-Bronevoy acid (CAN 161950-10-3) as starting materials; LC-MS (size UV peak / ESI) for 96.1%, 439,1154 (M+N)+.

Example 59

Obtaining N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-the l)-2,4-differntiated

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-3-methyl-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example 57a) and 2,4-debtor-3-pyridylcarbonyl acid (CAN 849937-90-2) as starting materials; MS (EI) 458,2 (M+N)+.

Example 60

Obtaining N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-hydroxy-benzamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 2-hydroxy-benzoic acid (CAN 69-72-7) as starting materials; LC-MS (size UV peak / ESI) is 97.7%, 421,5080 (M-N)-.

Example 61

Obtaining N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-canonicalname

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-3-methyl-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example 57a) and 5-cyano-3-pyridylcarbonyl acid (CAN 887579-62-6) as starting materials; LC-MS (size UV peak / ESI) 98,7%, 445,0693 (M-N)-.

Example 62

Obtaining N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide

a) [5-Bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridazin-3-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 42g, using 5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example D) and 3-pyridazinone acid (CAN 2164-61-6) as starting materials; MS (ESI) 375,2 (M-N)-.

b) N-(5-(4-Chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide

Specified in the title compound was synthesized in analogy to Example 39, using [5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridazin-3-carboxylic acid (Example 62 (a) and-(4-chloro-3-were)-Bronevoy acid (CAN 161950-10-3) as starting materials; LC-MS (size UV peak / ESI) was 94.2%, 423,0828 (M+N)+.

Example 63

Obtaining N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide

Specified in the title compound was synthesized in analogy to Example 39, using [5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridazin-3-carboxylic acid (Example a) and b-(4-chloro-3-forfinal)-Bronevoy acid (CAN 137504-86-0) as starting materials; LC-MS (size UV peak / ESI) 100%, 425,0438 (M-N)-.

Example 64

Obtaining N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide

Specified in the title compound was synthesized by analogy with Primera, using [5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridazin-3-carboxylic acid (Example a) and b-(4-chloro-2-forfinal)-Bronevoy acid (CAN 160591-91-3) as starting materials; LC-MS (size UV peak / ESI) 98,7%, 427,0587 (M+N)+.

Example 65

Obtaining N-(5-(4-ethylphenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide

Specified in the title compound was synthesized in analogy to Example 39, using [5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridazin-3-carboxylic acid (Example 62 (a) and-(4-ethylphenyl)-Bronevoy acid (CAN 63139-21-9) as starting materials; LC-MS (size UV peak / ESI) 98,9%, 403,1386 (M+N)+.

Example 66

Obtaining N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)furan-2-carboxamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 2-frankenboob acid (CAN 88-14-2) as starting materials; LC-MS (size UV peak / ESI) 98,0%, 397,0566 (M+N)+.

Example 67

Obtaining N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)furan-3-carboxamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-Ilam is n (F) and 3-frankenboob acid (CAN 488-93-7) as starting compounds; LC-MS (size UV peak / ESI) of 98.2%, 395,0414 (M-N)-.

Example 68

Obtaining N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methylfuran-2-carboxamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 5-methyl-2-frankenboob acid (CAN 1917-15-3) as starting materials; LC-MS (size UV peak / ESI) 98,0%, 409,574 (M-N)-.

Example 69

Obtaining N-(5-(4-chloro-3-were)-6-(2-methoxyethoxy)pyridine-3-yl)benzamide

a) 3-Bromo-2-(2-methoxy-ethoxy)-5-nitro-pyridine

To a solution of 2-methoxyethanol (8,81 g, 9,13 ml, 116 mmol) in anhydrous THF (150 ml) was added sodium hydride (4,63 g, 116 mmol) in a nitrogen atmosphere at 5°C or below and the reaction mixture was stirred at 25°C for 1 hour. Then was added dropwise 3-bromo-2-chloro-5-nitropyridine (CAN 5470-17-7) (25 g, 105 mmol) at 25°C. and was stirred at 25°C for 1 hour. To the reaction mixture was added ice water (150 ml) and was extracted with ethyl acetate (500 ml). The combined organic layers were washed with water and brine, dried over Na2SO4and evaporated under reduced pressure, which gave the crude residue (25,7 g). The crude substance was purified by column chromatography with 15% ethyl acetate/hexane), that gave the desired product (21,6 g, 74%) as a pale yellow solid; GC/MS (PID/STOR): 100%, 276,0 (M)+.

b) 5-Bromo-6-(2-methoxy-ethoxy)-pyridine-3-ylamine

Specified in the title compound was synthesized in analogy to Example C, using 3-bromo-2-(2-methoxy-ethoxy)-5-nitro-pyridine (Example 69A) as starting materials; LC-MS (size UV peak / ESI) 100%, 247,0084 (M+N)+.

C) 5-(4-Chloro-3-methyl-phenyl)-6-(2-methoxy-ethoxy)-pyridine-3-ylamine

Specified in the title compound was synthesized in analogy to Example E, using 5-bromo-6-(2-methoxy-ethoxy)-pyridine-3-ylamine (Example 69b) and(4-chloro-3-were)-Bronevoy acid (CAN 161950-10-3) as starting compounds; GC/MS (PID/EI):100%, 292 (M)+.

d) N-(5-(4-Chloro-3-were)-6-(2-methoxyethoxy)pyridine-3-yl)benzamid

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-3-methyl-phenyl)-6-(2-methoxy-ethoxy)-pyridine-3-ylamine (Example C) and benzoic acid as starting materials; LC-MS (size UV peak / ESI) 100%, 397,1307 (M+N)+.

Example 70

Obtain (RS)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)tetrahydrofuran-2-carboxamide

Specified in the title compound was synthesized by analogies Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and tetrahydro-2-frankenboob acid (CAN 16874-33-2) as initial substances; the enantiomers were separated using chiral HPLC (ChiralPak AD, 30% ethanol/n-heptane), was isolated (-) enantiomer; LC-MS (size UV peak / ESI) 100%, 401,0868 (M+N)+;αD20(MeOH)=-16.8°.

Example 71

Receive (SR)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-tetrahydrofuran-3-carboxamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and tetrahydro-3-frankenboob acid (CAN 89364-31-8) as initial substances; the enantiomers were separated using chiral HPLC (ChiralPak AD, 30% ethanol/n-heptane), was isolated (+) enantiomer; LC-MS (size UV peak/ESI) 98,1%, 401,0869 (M+N)+;αD20(MeOH)=+10.1°.

Example 72

Obtaining N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-meth is l-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 3,4-dihydro-4-methyl-2H-pyrido[3,2-b] 1,4-oxazin-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 479,2 (M+N)+.

Example 73

Obtaining N-(5-(4-amino-3-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-idnicating

a) Benzyl ester {4-[5-amino-2-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-chloro-phenyl}-carbamino acid

Specified in the title compound was synthesized in analogy to Example E, using 5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example) and fenilmetilovy ester of N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-carbamino acid (CAN 1218791-42-4) as starting materials; MS (EI) 452,1 (M+N)+.

b) Benzyl ether {2-chloro-4-[5-[(5-iodine-pyridine-3-carbonyl)-amino]-2-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-phenyl}-carbamino acid

Specified in the title compound was synthesized in analogy to Example 42g, using benzyl ester {4-[5-amino-2-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-chloro-phenyl}-carbamino acid (Example 73a) and 5-iodine-3-pyridylcarbonyl acid (CAN 15366-65-1) as starting materials; LC-MS (size UV peak / ESI) 68,6%, 683,4 (M+N)+.

C) N-(5-(4-Amino-3-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-idnicating

Benzyl ether {2-chloro-4-[5-[(5-iodine-pyridine-3-carbonyl)-amino]-2-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-phenyl}-carbamino acid (87 mg, 127 μmol), cooling, combined with triperoxonane acid (3 ml), which gave a brown solution. The reaction mixture was heated to room temperature and was stirred for 72 hours. The crude reaction mixture was concentrated in vacuo, poured into 50 ml of ethyl acetate and was extracted with 1 M NaOH (1×25 ml). The aqueous layer was washed with ethyl acetate (1×50 ml). The organic layers were combined, dried with Na2SO4and concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 20 g, 0% to 40% EtOAc in heptane) gave specified in the title compound (59 mg, 84%); LC-MS (size UV peak / ESI) 98,1%, 548,9795 (M+N)+.

Example 74

Obtaining N-(5-phenyl-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide (Example G) and phenyl-Bronevoy acid (CAN 98-80-6) as starting materials; LC-MS (size UV peak / ESI) 100%, 374,1107 (M+N)+.

Example 75

Obtaining N-(5-(4-shall terphenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide (Example G) and b-(4-forfinal)-Bronevoy acid (CAN 1765-93-1) as starting materials; LC-MS (size UV peak / ESI) 100%, 392,1005 (M+H)+.

Example 76

Obtaining N-(5-(3-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide (Example G) and b-(3-chlorophenyl)-Bronevoy acid (CAN 63503-60-6) as starting materials; LC-MS (size UV peak / ESI) 100%, 408,0719 (M+N)+.

Example 77

Obtaining N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methoxynicotinic

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 5-methoxy-3-pyridineboronic acid (CAN 20826-03-3) as starting materials; LC-MS (size UV peak / ESI) of 97.8%, 438,0812 (M+N)+.

Example 78

Obtaining N-(5-(4-chlorophenyl)-6-cyclobutadiene-3-yl)pyrazin-2-carboxamide

a) 5-Bromo-6-CYCLOBUTANE-nicotinic acid

5-Bromo-6-chloronicotinic acid (CA 29241-62-1; 3 g, 12.7 mmol) was dissolved in DMSO (30 ml) was added cyclobutanol (1.19 g, of 1.29 ml, 16.5 mmol) and potassium hydroxide (powder) (2.14 g, 38,1 mmol) and the reaction mixture was stirred at room temperature for 5 hours. Adding more cyclobutanol (0.5 ml) and KOH (1 g) and the reaction mixture was stirred at room temperature for another 2 days. Was added water (30 ml) and the mixture was acidified (cooling), 5 ml of 37% HCl in water (pH 2). The suspension was filtered and washed with water. The filter cake was dried in vacuum to obtain specified in the title compound (3.1 g, 88,7%) as a white solid; MS (ESI) 270,2 (M-N)-.

b) 5-(4-Chloro-phenyl)-6-CYCLOBUTANE-nicotinic acid

5-Bromo-6-CYCLOBUTANE-nicotinic acid (Example 78A; 1,531 g, 5,63 mmol), 4-chloro-phenylboronic acid (968 mg, to 6.19 mmol), potassium carbonate (1.56 g, 11.3 mmol) and tetrakis(triphenylphosphine)palladium (325 mg, 281 μmol) suspended in THF (38 ml) and water (38 ml). The reaction mixture was stirred at reflux (100°C.) over the weekend. THF was removed and the residue was separated between water (pH 2) and ethyl acetate; the organic phases were combined, dried with MgSO4and concentrated in vacuum to obtain specified in the title compound (Quant.) in a solid white; MS (ESI) 302,2 (M-N)-.

C) tert-Butyl ether [5(4-chlorophenyl)-6-CYCLOBUTANE-pyridine-3-yl]-carbamino acid

Specified in the title compound was synthesized in analogy to Example a, using 5-(4-chloro-phenyl)-6-CYCLOBUTANE-nicotinic acid (Example 78b) as starting materials; LC-MS (size UV peak / ESI) of 92.9%, 375,1456 (M+N)+.

d) 5-(4-Chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-ylamine

tert-Butyl ester of [5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-yl]-carbamino acid (1,042 g, 2,78 mmol) was dissolved in 4 M HCl in dioxane (10.4 ml of 41.7 mmol). The reaction mixture was a light yellow solution and it was stirred at room temperature for 1 hour. The mixture was separated between ethyl acetate and 1 m solution of Na2CO3. The organic phases were combined, dried with MgSO4and concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 100 g, 5% to 75% ethyl acetate in heptane) gave 0,358 g (46.9 per cent) indicated in the title compound as a light red oil; LC-MS (size UV peak / ESI) was 94.3%, 275,0950 (M+N)+.

e) N-(5-(4-Chlorophenyl)-6-cyclobutadiene-3-yl)pyrazin-2-carboxamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-ylamine (Example 78d) and 2-pyrazinecarboxamide acid (CAN 98-97-5) as the source is of exist; MS (EI) 381,2 (M+H)+.

Example 79

Obtaining N-(5-(4-chlorophenyl)-6-cyclobutadiene-3-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example 48th, using 5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-ylamine (Example 78 (d) and nicotinanilide hydrochloride as starting materials; MS (EI) 380,2 (M+N)+.

Example 80

Obtaining N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamide

Specified in the title compound was synthesized in analogy to Example 42f, using 5-(4-chloro-3-methyl-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example 57a) and 3,4-dihydro-4-methyl-2H-pyrido[3,2-b] 1,4-oxazin-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 493,1 (M+N)+.

Example 81

Obtaining N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamide

a) 5-(4-Chloro-3-fluoro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine

Specified in the title compound was synthesized in analogy to Example E, using 5-bromo-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example C) and b-(4-chloro-3-forfinal)-Bronevoy acid (CAN 137504-86-0) as starting materials; MS (e is) 379,3 (M+SLA) +.

b) N-(5-(4-Chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamid

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-3-fluoro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example e) and 3,4-dihydro-4-methyl-2H-pyrido[3,2-b] 1,4-oxazin-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 497,2 (M+N)+.

Example 82

Obtain [5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-yl]-amide 5-methyl-oxazol-4-carboxylic acid

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-ylamine (Example 78d) and 5-methyl-4-oxazolidinone acid (CAN 103879-58-9) as starting materials; LC-MS (size UV peak / ESI) 100%, 384,1102 (M+N)+.

Example 83

Obtaining N-[5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-yl]-5-methyl-nicotinamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-ylamine (Example 78d) and 5-methyl-3-pyridylcarbonyl acid (CAN 40473-04-9) as starting materials; MS (EI) 394,1 (M+N)+.

Example 84

Getting N5-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)the feast of the DIN-3-yl)-N2-methylpyridine-2,5-dicarboxamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 6-[(methylamino)-carbonyl]-3-pyridylcarbonyl acid (CAN 170464-32-1) as starting materials; MS (EI) 465,2 (M+N)+.

Example 85

Getting 5-bromo-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 5-bromo-3-pyridylcarbonyl acid (CAN 20826-04-4) as starting materials; LC-MS (size UV peak / ESI) 92.7%, the 485,9662 (M-N)-.

Example 86

Obtaining N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-methoxy-propanamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 2-methoxy-propanoic acid (CAN 4324-37-2) as starting materials; MS (EI) 389,2 (M+N)+,

Example 87

Obtaining N3-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-N5-methylpyridin-3,5-dicarboxamide

a) Ethyl ester 5-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylcarbonyl]-nicotinic acid

<> Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 3-ethyl ester 3,5-pyridinedicarboxylic acid (CAN 84254-37-5) as starting materials; MS (EI) 480,1 (M+N)+.

b) 5-[5-(4-Chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylcarbonyl]-nicotinic acid

Ethyl ester of 5-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylcarbonyl]-nicotinic acid (510 mg, 1.06 mmol) was combined with THF (25 ml), methanol (5 ml) and water (5 ml), which gave a light yellow suspension. The reaction mixture was stirred for 4 hours and concentrated in vacuum. The reaction mixture was poured into 100 ml ethyl acetate and was extracted with 1 M HCl (1×25 ml) and brine (1×25 ml). The aqueous phase was extracted with ethyl acetate (1×50 ml). The organic layers were combined, dried with Na2SO4and concentrated in vacuum. The crude substance was purified using flash chromatography (silica gel, 40 g, 0% to 100% ethyl acetate in heptane) gave 0.17 g (48.7 per cent) indicated in the title compound as a white solid; MS (ESI) 450,0 (M-N)-.

(C) N3-(5-(4-Chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-N5-methylpyridin-3,5-dicarboxamide

5-[5-(4-Chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylcarbonyl]-nicotinic KIS the GTC (120 mg, 260 mmol) and methylamine hydrochloride (140 mg, 2.6 mmol) was dissolved in DMF (3 ml). Added TBTU (125 mg, 390 μmol) and DIPEA (672 mg, 908 μl, 5.2 mmol). The reaction mixture was stirred at room temperature for 20 hours. The crude reaction mixture was concentrated in vacuo and purified using flash chromatography (silica gel, 10 g, from 0% to 100% ethyl acetate in heptane) gave 34 mg (28%) indicated in the title compound as a white solid; LC-MS (size UV peak / ESI) for 99.5%, 465,0928 (M+N)+.

Example 88

Obtain (+)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-methoxypropylamine

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 2-methoxy-propanoic acid (CAN 4324-37-2) as initial substances; the enantiomers were separated using chiral HPLC (ChiralPak AD, 10% ethanol / n-heptane); allocated (+) enantiomer; LC-MS (size UV peak / ESI) 100%, 389,0874 (M+N)+;αD20(MeOH)=+37.5°.

Example 89

Obtaining (E)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-(methoxyimino)about what UNAMID

a) N-[5-(4-Chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-oxo-propionamide

Specified in the title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-ylamine (Example E) and 2-oxo-propanoic acid (127-17-3) as starting materials; MS (EI) 373,0 (M+N)+.

b) (E)-N-(5-(4-Chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-(methoxyimino)-propanamide

N-[5-(4-Chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-oxo-propionamide (0,063 g, 169 mmol) was dissolved in methanol (1,00 ml). Added O-methyl-hydroxylamine hydrochloride (70,6 mg, 845 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent is evaporated and the residue is divided between water and ethyl acetate; the organic phase was dried with MgSO4and concentrated in vacuo, which gave 67 mg (89%) indicated in the title compound as a white solid; LC-MS (size UV peak / ESI) 99,0%, 402,0825 (M+N)+.

1. The compounds of formula

where
A is selected from CH or N;
R1selected from the group consisting of
C3-6-cycloalkyl,
C3-6-cycloalkyl-C1-7-alkyl,
C1-7-alkoxy-C1-7-alkyl,
halogen-C1-7-alkyl;
R2and R6independently from each other represent hydrogen or halogen;
R3and R independently from each other selected from the group consisting of hydrogen, C1-7-alkyl and halogen;
R4selected from the group consisting of hydrogen, C1-7-alkyl, halogen and amino;
R7selected from the group consisting of C1-7-alkyl,
C1-7-alkoxy-C1-7-alkyl,
C1-7-alkoxyimino-C1-7-alkyl,
4-6-membered heterocyclyl containing one heteroatom O,
phenyl, the said phenyl is not substituted or is substituted by one hydroxy group, and
5-10-membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, the specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen;
and their pharmaceutically acceptable salts.

2. The compounds of formula I on p. 1, where R1represents a C3-6-cycloalkyl-C1-7-alkyl or halogen-C1-7-alkyl.

3. The compounds of formula I on p. 1, where R1represents a halogen-C1-7-alkyl.

4. The compounds of formula I on p. 1, where R2and R6represent hydrogen.

5. The compounds of formula I on p. 1, where R3and R5represent hydrogen or c1-7-alkyl.

6. The compounds of formula I on p. 1, where R4represents C1-7-alkyl or halogen.

7. The compounds of formula I on p. 1, where R4represents a halogen.

8. The compounds of formula I on p. 1, where R7represents Fe is Il, specified phenyl is not substituted or is substituted by one hydroxy, or 5-10-membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, the specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, hydroxy, cyano, c1-7-alkylaminocarbonyl and halogen.

9. The compounds of formula I on p. 1, where R7is a 5-10-membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, the specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, hydroxy, cyano, C1-7-alkylaminocarbonyl and halogen.

10. The compounds of formula I on p. 1, where heteroaryl selected from the group consisting of furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazoline, [1,2,3]thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, hydroxy, cyano, C1-7-alkylaminocarbonyl and halogen.

11. The compounds of formula I on p. 1, where a represents CH.

12. The compounds of formula I on p. 1 having the formula

where
R1selected from the group consisting of
C3-6-cycloalkyl,
C3-6-cycloalkyl-C1-7-alkyl,
C1-7-alkoxyl-7-alkyl,
halogen-C1-7-alkyl;
R2and R6independently from each other represent hydrogen or halogen;
R3and R5independently from each other selected from the group consisting of hydrogen, C1-7-alkyl and halogen;
R4selected from the group consisting of hydrogen, halogen and amino;
R7selected from the group consisting of C1-7-alkyl,
4-6-membered heterocyclyl containing one heteroatom O, phenyl specified phenyl is not substituted or is substituted by one hydroxy, and 5-10-membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, the specified heteroaryl not substituted or substituted by one or two groups selected from the group consisting of C1-7-alkyl, hydroxy, cyano and halogen;
and their pharmaceutically acceptable salts.

13. The compounds of formula I on p. 1, selected from the group consisting of
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pentanol acid,
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-benzamide,
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide,
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-isonicotinamide,
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-acetamide", she
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-butyramide,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridine-2-carboxylic acid,
N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-benzo the Ministry of foreign Affairs,
N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-acetamide", she
N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-nicotinamide,
N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-isonicotinamide,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrazin-2-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 2,5-dimethyl-2H-pyrazole-3-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3-methyl-isoxazol-4-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1-methyl-1H-pyrazole-3-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-isoxazol-3-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridazin-3-carboxylic acid,
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-3-methyl-isonicotinamide,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrimidine-5-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 2-methyl-2H-pyrazole-3-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide of 2,4-dimethyl-oxazol-5-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide isothiazol-5-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-2H-pyrazole-3-carboxylic acid,
[5-(4-chloro-F. the Nile)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide of 1H-pyrazole-3-carboxylic acid,
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-methyl-isonicotinamide,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-thiazole-2-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid,
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-6-methyl-nicotinamide,
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-methyl-nicotinamide,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide isoxazol-5-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3,5-dimethyl-isoxazol-4-carboxylic acid,
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-2-hydroxy-isonicotinamide,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1,3-dimethyl-1H-pyrazole-4-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyrimidine-4-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide a thiazole-2-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 3-methyl-pyridine-2-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-oxazol-4-carboxylic acid,
N-(5-(3,4-dimetilfenil)-6-(2,2,2-triptoreline)pyridine-3-yl)-nicotinamide,
N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-nicotinamide,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-e is hydroxy)-pyridine-3-yl]-amide 5-hydroxy-pyridine-2-carboxylic acid,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-nicotine amide,
(S)-N-(5-(4-chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)pyridine-3-yl)pyridazin-3-carboxamide,
(S)-N-(5-(4-chlorophenyl)-6-(1,1,1-tryptophan-2-yloxy)pyridine-3-yl)nicotinamide,
N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,
N-(5-(3-chloro-4-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,
N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,
N-(5-(4-ethylphenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,
(S)-N-(6-(4-chlorophenyl)-5-(1,1,1-tryptophan-2-yloxy)pyrazin-2-yl)nicotinamide,
N-(6-(4-chlorophenyl)-5-(2,2,2-triptoreline)pyrazin-2-yl)nicotinamide,
N-(6-(4-chlorophenyl)-5-cyclobutenedione-2-yl)nicotinamide,
N-(6-(4-chlorophenyl)-5-cyclobutenedione-2-yl)pyrimidine-5-carboxamide,
N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,
N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,
N-(5-(3-chloro-4-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,
N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,
N-(5-(4-ethylphenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,
N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-hydroxyisoquinoline,
N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-is)-1,3-dimethyl-1H-pyrazole-4-carboxamide,
N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-2,4-differntiated,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-hydroxybenzamide,
N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-canonicalname,
N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide,
N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide,
N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide,
N-(5-(4-ethylphenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)furan-2-carboxamide,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)furan-3-carboxamide,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methylfuran-2-carboxamide,
N-(5-(4-chloro-3-were)-6-(2-methoxyethoxy)pyridine-3-yl)benzamide,
(R)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)tetrahydrofuran-2-carboxamide,
(S)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)tetrahydrofuran-3-carboxamide,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamide,
N-(5-(4-amino-3-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-idnicating,
N-(5-phenyl-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,
N-(5-(4-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,
N-(5-(-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methoxynicotinic,
N-(5-(4-chlorophenyl)-6-cyclobutadiene-3-yl)pyrazin-2-carboxamide,
N-(5-(4-chlorophenyl)-6-cyclobutadiene-3-yl)nicotinamide,
N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamide,
N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamide,
[5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-yl]-amide 5-methyl-oxazol-4-carboxylic acid,
N-[5-(4-chloro-phenyl)-6-CYCLOBUTANE-pyridine-3-yl]-5-methyl-nicotinamide,
N5-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-N2-methylpyridine-2,5-dicarboxamide,
5-bromo-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-methoxypropylamine,
N3-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-N5-methylpyridin-3,5-dicarboxamide,
(+)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-methoxypropylamine,
(E)-N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-(methoxyimino)propanamide,
and their pharmaceutically acceptable salts.

14. The compounds of formula I on p. 1, selected from the group consisting of
N-[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-nicotinamide,
N-[5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridine-3-yl]-nicotinamide,
[5-(4-chloro-phenyl)-6-(2,2,2-three the tor-ethoxy)-pyridine-3-yl]-amide 3-methyl-isoxazol-4-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide pyridazin-3-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 1,3-dimethyl-1 H-pyrazole-4-carboxylic acid,
[5-(4-chloro-phenyl)-6-(2,2,2-Cryptor-ethoxy)-pyridine-3-yl]-amide 5-methyl-oxazol-4-carboxylic acid,
N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-nicotinamide,
N-(5-(4-chloro-3-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)nicotinamide,
(S)-N-(6-(4-chlorophenyl)-5-(1,1,1-tryptophan-2-yloxy)pyrazin-2-yl)nicotinamide,
N-(6-(4-chlorophenyl)-5-cyclobutenedione-2-yl)pyrimidine-5-carboxamide,
N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyrimidine-5-carboxamide,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-hydroxybenzamide,
N-(5-(4-chloro-3-were)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-canonicalname,
N-(5-(4-chloro-2-forfinal)-6-(2,2,2-triptoreline)pyridine-3-yl)pyridazin-3-carboxamide,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methylfuran-2-carboxamide,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-carboxamide,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-5-methoxynicotinic,
N-(5-(4-chlorophenyl)-6-(2,2,2-triptoreline)pyridine-3-yl)-2-methoxypropylamine, and their pharmaceutically acceptable salts.

15. Pharmaceutical compositions for improving holster is on HDL, comprising the compound of the formula I according to any one of paragraphs.1-14 and a pharmaceutically acceptable carrier and/or excipient.

16. The compounds of formula I according to any one of paragraphs.1-14 for use as a drug to increase HDL cholesterol.

17. The method of making the compounds of formula I as defined in any of paragraphs.1-14, according to which a link connection formulas

where a and R1- R6are as defined in paragraph 1, with an acid of the formula

where R7is as defined in paragraph 1, by using a binder with the basic conditions,
and optionally translate the resulting compound of formula I in a pharmaceutically acceptable salt.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene citrate salt. The invention also refers to pharmaceutical compositions containing the above citrate, and methods for using citrate in treating several conditions.

EFFECT: what is prepared is the new 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene salt and the pharmaceutical compositions on the basis thereof which can find application in medicine for treating a proliferative disorder.

17 cl, 30 dwg, 5 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of general formula [I]: or their pharmacologically acceptable salts, wherein R1 is C1-6 alkyl; R2 is C1-6 alkoxy; m and n mean 1; W means N; the ring A represents fragments of formula , or that can be substituted; X1 is a single bond, C1-6 alkylene group or -C(O)NR3-, wherein R3 is hydrogen, C1-6 alkyl or phenyl; and the ring B represents fragments of formula [5]-[11]: that can be substituted, and a pharmaceutical composition containing them.

EFFECT: new compounds possess activity inhibiting the amyloid beta production, and are effective as a therapeutic agent for treating an Aβ-caused disease, such as Alzheimer disease or Down syndrome.

10 cl, 48 tbl, 399 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula (I), where R1 represents alkoxygroup; U, V and W each represents CH or one of U, V and W represents N, and each other represents CH; A represents CH2 or O; G represents CH=CH-E, where E represents phenyl group, mono- or di-substituted with halogen, or G represents group of one of the formulas given below , , where Z represents CH or N, Q represents O or S and K represents O or S; or salt of such compound. In addition, invention also relates to pharmaceutical composition based on formula (I) compound for prevention or treatment of bacterial infection, as well as to application of claimed compounds for obtaining medication for prevention or treatment of bacterial infection.

EFFECT: novel compounds, which can be applied in treatment of bacterial infection, are obtained and described.

23 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of nucleoside derivatives - 1,2,5-oxadiazoles of general structural formula I where R1 and R2 are selected from phenylsulphonyl, substituted with one or more halogen atoms, nitro groups, carboxy groups, alkyl halides, CH3, OCH3, OCF3; X is selected from N or N→O; or R1 and R2 form a group, where R', R", R'" and R'''' are independently selected from hydrogen; halogens; nitro groups, hydroxy group, carboxy group, CH3; CH2Br; OCH3; phenylsulphonyl; phenylthio group; or the following groups: R' and R" can also be merged into one of the following common rings for inhibiting human immunodeficiency virus (HIV) replication. The invention also relates to a pharmaceutical composition based on compounds of formula I and a method of inhibiting HIV-1 subtypes A and B integrase, including forms which are resistant to raltegravir.

EFFECT: detecting novel activity in compounds of formula I, which can be used in medicine as HIV replication inhibitors.

3 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), possessing an activity with respect to cytokines, versions of based on them pharmaceutical compositions and their application. Formula (I) compounds can be applied for treatment or prevention asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gouty arthritis. In general formula (I) L is selected from the group, consisting of -C(O)-, -CH2-, Ar1 represents a mono-, di- or trisubstituted phenyl ring, where substituents are independently selected from the group, consisting of a halogen and -C1-4alkyl; Ar2 represents an optionally substituted thiadiazolyl ring, where the substituent represents -C1-4alkyl, -C3-5cycloalkyl, -methylcyclopropyl, phenyl or a 5- or 6-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring with 9 or 10 atoms, with the said heteroaromatic ring containing 1, 2 or 3 heteroatoms, selected from the group, consisting of S, O and N, where the said phenyl or heteroaromatic ring is optionally mono- or disubstituted with substituents, independently selected from the group, consisting of a halogen, -C1-6alkyl, optionally substituted with 1-4 fluorine atoms, -O-C1-6alkyl, -CF3 and oxo.

EFFECT: increased efficiency of the application of the compounds.

16 cl, 1 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,3,5-dithiazinanes of formula (1): wherein diphenylenediamine (diaminodiphenylmethane, diaminodiphenyl oxide) reacts with N-tert-butyl-1,3,5-dithiazinane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine: N-tert-butyl-1,3,5-dithiazinane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system (1:1, by volume) for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as antimicrobial and antifungual agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method for selective production of 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes of formula (1) where R = 4-C6H4-CH2-C6H4-4', 4-C6H4-O-C6H4-4', 4-H3COC6H3-C6H3OCH3-4', where diphenylenediamines (diaminodiphenylmethane, diaminodiphenyl oxide, dimethoxybenzidine) react with 1-oxa-3,6-dithiacycloheptane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine:1-oxa-3,6-dithiacycloheptane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system for 2.5-3.5 hours.

EFFECT: novel method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes, which can be used as antimicrobial, antifungal and anti-inflammatory agents, sorbents and extractants of precious metals and selective complexing agents.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 6-substituted isoquinoline and isoquinolinone derivatives of formula or to its stereoisomer and/or tautomer forms and/or a pharmaceutically acceptable salt, wherein R1 represents H, OH or NH2; R3 represents H; R4 represents H, a halogen atom, CN or (C1-C6)alkylene-(C6-C10)aryl; R5 represents H, a halogen atom, (C1-C6)alkyl; R7 represents H, a halogen atom, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 represents H; R9 and R6 are absent; R10 represents (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C6)hetrocycloalkyl, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C6)heterocycloalkyl; R11 represents H; R12 represents (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5)heteroaryl or (C6-C10)aryl; R13 and R14 independently represent H, (C1-C6)alkyl, (C1-C6)alkylene-R'; n is equal to 0; m is equal to 2 or 3; s is equal to 1 or 2; r is equal to 1; L represents O or NH; R' represents (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more OCH3; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more halogen atoms; wherein (C1-C8)heteroaryl group means (C1-C8)alkyl groups, wherein at least one carbon atom is substituted by O;. (C6)heterocycloalkyl group means a monocyclic carbon ring system containing 6 ring atoms wherein one carbon atom can be substituted by 1 oxygen atom or 1 sulphur atom which can be optionally oxidated; (C5)heteroaryl means a monoring system wherein one or more carbon atoms can be substituted by 1 nitrogen atom or 1 sulphur atom or a combination of various heteroatoms. Also, the invention refers to using the compound of formula (I) and to a therapeutic agent based on the compound of formula (I).

EFFECT: there are prepared new compounds effective for treating and/or preventing diseases associated with Rho-kinase and/or mediated by Rho-kinase by phosphorylation of myosin light chain phosphatase, and the compositions containing these compounds.

32 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of treating or relieving severity of disease in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease. Methods include introduction of effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or pharmaceutical composition, containing said compound, to patient.

EFFECT: treatment of relief of disease severity in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease.

16 cl, 15 tbl

FIELD: chemistry.

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

EFFECT: obtaining benzothiazine derivatives.

17 cl, 197 ex

FIELD: medicine, pharmaceutics.

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

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

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

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