Tetrahydro-naphthyridine derivatives and method of their obtaining

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

 

The technical field to which the invention relates.

The present invention relates to a new derived tetrahydronaphthalene possessing inhibitory activity against protein transfer cholesterolemia ether (SETR).

The level of technology

Through a series of epidemiological studies, it was found that hypercholesterinemia, in particular high serum cholesterol to low density lipoprotein (LDL), is a risk factor arteriosclerotic diseases. Indeed, medicines, can reduce LDL-cholesterol, such as inhibitors of 3-hydroxy-3-methylglutaryl-COA (HMG-CoA)reductase inhibitor, used to prevent coronary artery disease (ischemic heart disease) and showed in many large-scale clinical trials that they can to some extent be useful. However, their preventive effect on coronary heart disease is to some extent limited and is still not satisfactory.

Recently, through a series of epidemiological studies and large-scale clinical trials found that low serum levels of high density lipoprotein (HDL) is a strong risk factor arteriosclerotic diseases. It is known that HDL has a different anteater accelerationtime effects, and focus on the potentiality of drugs that increase the level of HDL-cholesterol as a means to prevent or treat arteriosclerotic diseases. However, there is no medication that can be used satisfactorily for this purpose. Fibrates and inhibitors of HMG-CoA-reductase have only low activity increases HDL-cholesterol; derivatives of nicotinic acid can significantly increase HDL, but have serious portability issues. There is therefore a need for well-hyphenated agent, which can significantly increase the levels of HDL-cholesterol, preventing or reversing the progression of atherosclerosis.

It is known that many proteins involved in the mechanism of regulation of the catabolism of various lipoproteins. Among them draws attention to the role of protein transfer cholesterolemia ether (SETR). SETR is a protein responsible for the transfer cholesterolemia ester (CE) and triglyceride between lipoproteins and mediates the transfer of CE from HDL to LDL or lipoprotein very low density (VLDL). In line with this activity SETR very much affects the lipid composition of lipoprotein particles. For example, it is known that the introduction of the neutralizing monoclonal antibodies to SER rabbit or hamster increases the levels of HDL cholesterol and reduces LDL-cholesterol is in. In addition, a person with reduced or eliminated activity SETR due to mutations of the gene are detected elevated levels of HDL-cholesterol and decreased levels of LDL-cholesterol. On the other hand, it is known that transgenic mice and rats, designed for expression SETR reveal decreased levels of HDL-cholesterol and elevated levels of LDL-cholesterol. Thus, it is believed that SETR greatly contributes to the regulation of serum lipids and thereby causes a change in the profile of serum lipids, such as reducing the level of HDL-cholesterol and increased LDL-cholesterol. Thus, it is assumed that a high value activity SETR will induce arteriosclerosis.

Indeed, the activity SETR varies depending on the type of animal. It is known that arteriosclerotic damage easily formed by the introduction of cholesterol in animals with high activity SETR, such as rabbits, whereas such damage is unlikely to occur in animals with low activity SETR, such as rats. In addition, it is confirmed that continuous suppression activity SETR the introduction of antisense oligodeoxynucleotide led to such effects as increasing the level of HDL-cholesterol and decrease arteriosclerosis of injuries received in the stern of cholesterol is in the rabbits.

The above finding indicates that the activity SETR is in negative correlation with HDL-cholesterol and that inhibition activity SETR should reduce the degree of risk accepted in relation arteriosclerotic diseases. Thus, it is expected that compounds capable of inhibiting the activity SETR, can block the transfer of cholesterol from HDL to LDL, thus increasing HDL-cholesterol, which tends to prevent arteriosclerosis, and reducing LDL-cholesterol, which tends to exacerbate atherosclerosis. In this way, these compounds can serve as a useful preventive or therapeutic agent for arteriosclerotic diseases, hyperlipemia or dyslipidemia and for the first time to provide effective medical treatment.

Examples of compounds with SER-inhibitory activity include derivatives of tetrahydronaphthalene. Cm. WO00/17164, WO00/17165, WO00/17166.

However, these compounds have drawbacks. Namely, they are poorly soluble in water and cannot be absorbed sufficiently in vivo, a sufficient level in the blood for the manifestation of medical action can hardly be achieved even with the introduction of plain form for oral administration. Cm. WO03/63868.

Thus, there is a critical need for new compounds, which is shown above disadvantages are eliminated.

Description of the invention

The present invention provides new derivatives of tetrahydronaphthalene with excellent SER-inhibitory activity, which addressed the shortcomings of existing SER-inhibiting compounds.

Thus, the present invention provides a compound of formula (I):

where R1means a hydrogen atom, optionally substituted alkoxycarbonyl group, optionally substituted karbamoilnuyu group, optionally substituted alkyl group, optionally substituted alkanoyloxy group, saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (this heterocyclic group optionally substituted), or a saturated or unsaturated monocyclic or bicyclic heterocyclic carbonyl group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (this heterocyclic group is optionally substituted).

R2means a hydrogen atom or optionally substituted alkyl group;

R3means a hydrogen atom or optionally substituted alkyl group;

R4means optionally substituted alkylenes group is y;

R5means saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen, where the specified heterocyclic group optionally substituted,

R6, R7and R8denote independently a hydrogen atom, a halogen atom, a hydroxy-group, a nitrogroup, cyano, optionally substituted alkyl group, optionally substituted by alkoxygroup, optionally substituted by alkylsulfonates, optionally substituted mono - or dialkylamino group or optionally substituted by an amino group; or

R6and R7or R7and R8may be combined at the ends with the formation of alkalinous group, where Allenova group optionally contains 1-3 heteroatoms independently selected from nitrogen atoms, sulfur and oxygen, and may have a Deputy (deputies); and

R10means an aromatic ring optionally containing 1-3 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (specified aromatic ring optionally substituted), or its pharmaceutically acceptable salt.

The compound (I) of the present invention includes a mixture of stereoisomers, corresponding stereoisomers in purified or substantially purified form. For example, the compounds of formula (I) can have one or more asymmetric carbon atoms and, therefore, can exist as individual enantiomers or diastereomers or mixtures thereof. These compounds include the corresponding isomers and their mixture. In addition, when compound (I) has a double bond can exist geometric isomers (CIS - and TRANS-forms), and when the compound (I) has a group containing an unsaturated bond such as carbonyl, can exist in tautomeric forms, and these compounds include the corresponding isomers and their mixture.

Further, pharmaceutically acceptable salts of compound (I) of the present invention include intramolecular salt, hydrate, MES or other

As used in the present description, the term "aromatic ring optionally containing 1-3 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen"means preferred 5-7-membered monocyclic aromatic ring, optionally substituted with 1-3 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen, specifically including the group of phenyl, furyl, thienyl, pyrrolyl, okiratli, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, azepine, oxepin and tiepins etc.

The term "saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1-4 heteroatoms, independently researched the Simo selected from oxygen atoms, sulfur and nitrogen” means the preferred saturated or unsaturated 5-8-membered heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen, specifically including the following groups. Examples of 5-membered heterocyclic groups include 2H-pyrrolyl, 3H-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, pyrrolidinyl, 1,3-DIOXOLANYL, oxazolyl, oxazolyl, oxazolidinyl, thiazolyl, imidazolyl, imidazolyl, imidazolidinyl, pyrazolyl, 2-pyrazoline, pyridazinyl, isoxazolyl, isothiazolin, tetrazolyl, 1,2-dithioles, 1,3-dithioles, 3H-1,2-oxathiolan, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 1,2,3,4-oxadiazolyl, 1,2,3,5-oxadiazolyl, 3H-1,2,3-doxazosin, 1,2,4-doxazosin, 1,3,2-doxazosin, 1,3,4-doxazosin, 5H-1,2,5-oxadiazolyl and 1,3-oxathiolan etc.

Examples of 6-membered heterocyclic groups include 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,2-dioxines, 1,3-dioxines, 1,4-dioxane, morpholine, 1,4-ditional, thiomorpholine, pyridazine, pyrimidine, pyrazinyl, piperazinil, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-tritional, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6N-1,3-oxazinyl, 6N-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazine, 1,4-oxazinyl, o-isoxazine, p-isoxazolyl, 1,2,5-oxathiazin the sludge, 1,2,6-oxathiazine, 1,4,2-oxadiazine and 1,3,5,2-oxadiazine etc.

Examples 7-membered heterocyclic groups include azepines, oxepin and tiepins etc.

Examples 8-membered heterocyclic groups include azocines, oxazinyl and tiiiny etc.

As used in the present description, the heterocyclic part of the “saturated or unsaturated monocyclic or bicyclic heterocyclic actigraphy containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen”, “saturated or unsaturated monocyclic or bicyclic heterocyclic carbonyl group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen” and “saturated or unsaturated monocyclic or bicyclic heterocyclic carbonylation containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen” means the above “saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1-4 heteroatoms independently selected from atoms of oxygen, sulfur and nitrogen”.

In such cases, when the binding position for such aromatic rings, heterocyclic group, etc. is not specified, it is assumed that this definition includes all possible positions svyazyvanie is. For example, the term “Peregrina group” means 2-, 3 - or 4-pyridyloxy group, and the term “thienyl group” means 2 - or 3-thienyl group. The same applies to other aromatic rings and heterocyclic groups.

When saturated or unsaturated monocyclic or bicyclic heterocyclic group, the heterocyclic oxygraph, heterocyclic carbonyl group, and the heterocyclic carbonylation, each containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen, has a Deputy (deputies), the specified substitution involves the oxidation of the heteroatom (heteroatoms in the heterocycle in the respective groups. Specifically, compounds having a heteroatom (the heteroatoms in the heterocycle of these groups, for example, N-oxide, S-oxide (SO) or S,S-dioxide (SO2), also included in the scope of the present invention.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl group" or "alkyl" means a straight or branched saturated hydrocarbon chain having 1-10 carbon atoms, and cyclic saturated hydrocarbon chain having 3 to 10 carbon atoms. As a straight or branched hydrocarbon chain are preferred chain having 2-10 carbon atoms, and more preferred are chain having 2-6 ATO is s carbon. Other preferred examples are alkyl group with a straight chain having 1-6 carbon atoms, in particular alkyl groups having 1-4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl and isohexyl, etc.

The term “alkoxygroup” or “alkoxy” means a straight or branched alkyloxy having 1-10 carbon atoms, and cyclic alkyloxy having 3-10 carbon atoms. As a straight or branched hydrocarbon chain are preferred chain having 2-10 carbon atoms, and more preferred are chain having 2-6 carbon atoms. Other preferred examples are alkoxygroup with a straight chain having 1-6 carbon atoms, in particular alkoxygroup having 1-4 carbon atoms. Examples of alkoxygroup include methoxy group, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentox, isopentane, neopentane, tert-pentox, hexose, isohexane, etc.

The term “Allenova group” or “alkylene” means a saturated hydrocarbon chain, in which the hydrogen atom is removed from each of the terminal carbons straight hydrocarbon chain. Preferred examples include the up alkylenes group, having 1-4 carbon atoms, specifically a group of methylene, ethylene, trimethylene and tetramethylene, etc. When used Allenova group contains 1-3 heteroatoms independently selected from nitrogen atoms, sulfur and oxygen, the term “alkylene” includes a group of formula: -O-(CH2)m-O-, -S-(CH2)m-S-, -NH-(CH2)m-NH - or-O-(CH2)m-NH- (where m is an integer of 1-4), or the like

The term "alcoolica group" or "alkanoyl" means a straight or branched alkylcarboxylic group having 1-10 carbon atoms, preferably alkylcarboxylic group having 1-6 carbon atoms, more preferably alkylcarboxylic group having 1-4 carbon atoms. Examples alkanoyloxy groups include acetyl, propionyl, butyryl, valeryl and pivaloyl, etc.

The term “Alchemilla group” or “alkenyl” means a straight or branched hydrocarbon chain having 2-10 carbon atoms and containing at least one double bond, preferably alkenylphenol group having 2-6 carbon atoms, more preferably alkenylphenol group having 2-4 carbon atoms. Examples alkenylphenol groups include vinyl, 1-propenyl, allyl, Isopropenyl, butenyl, butadienyl and pentenyl, etc.

As used in the claims and in the description, when the term “mono - or dia is Kil” refers to the dialkyl, these alkyl groups may be independent from each other. In addition, the compound of the following formula indicates that it takes the configuration of (2R*,4S*), where (2R*,4S*) refers to a mixture of (2R,4S) and (2S,4R).

Compounds of the present invention have SETR-inhibitory activity and are effective to increase HDL cholesterol and reduce LDL cholesterol. Thus, these compounds are useful in the prevention and/or treatment of diseases such as arteriosclerosis, hyperlipemia, etc.

The best way of carrying out the invention

Preferred compounds of the present invention are the compounds where R5means saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen, where the specified heterocyclic group optionally substituted by 1-5 substituents selected from the following groups:

the halogen atom, carbonyl group, a hydroxy-group, ceanography, nitro, carboxyl group, sulfopropyl, optionally substituted alkyl groups, optionally substituted cycloalkyl group, optionally substituted alkenylphenol group, optionally substituted alkoxygroup, optionally substituted cycloalkanes, it is certainly substituted alkoxycarbonyl group, carbamoyl group, optionally substituted mono - or dialkylanilines group, optionally substituted carbamimidoyl group, optionally substituted allylthiourea, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, amino group, optionally substituted mono - or dialkylamino, optionally substituted alkanolamines, optionally substituted alkoxycarbonyl, optionally substituted alkylsulfonamides, optionally substituted mono - or dialkylanilines, saturated or unsaturated monocyclic or bicyclic heterocyclic carbonylation containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (provided the heterocyclic carbonylation optionally substituted), sulfamoyl group, optionally substituted mono - or dialkylamino group, optional substituted alkanoyloxy group, a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (this heterocyclic group optionally substituted), a saturated or unsaturated monocyclic or bicyclic heterocyclic oxy is the group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (provided the heterocyclic oxygraph optionally substituted), a saturated or unsaturated monocyclic or bicyclic heterocyclic carbonyl group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (specified heterocyclic carbonyl group is optionally substituted); and

R10means an aromatic ring optionally containing 1-3 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen, where the aforementioned aromatic ring optionally substituted by 1-4 substituents, selected from the following groups: halogen atom, carboxyl group, optionally substituted alkoxycarbonyl group, carbamoyl group, optionally substituted mono - or dialkylanilines group, optionally substituted alkyl groups, optionally substituted alkoxygroup, hydroxy-group, nitro group, ceanography, amino, optionally substituted mono - or dialkylamino, optionally substituted alkanoyloxy group, optionally substituted ancilliary and saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (in asana heterocyclic group optionally substituted).

Deputy (deputies) for optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted alkenylphenol group, optionally substituted alkoxygroup, optionally substituted cycloalkanes, optionally substituted alkoxycarbonyl group, optionally substituted mono - or dialkylanilines group, optionally substituted allylthiourea, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted mono - or dialkylamino, optionally substituted alkanolamines, optionally substituted alkoxycarbonyl, optionally substituted alkylsulfonamides, optionally substituted mono - or dialkylanilines, optionally substituted mono - or dialkylamino group, optionally substituted alkanoyloxy group, optionally substituted alkalinous group, saturated or unsaturated monocyclic or bicyclic heterocyclic carbonylation containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (provided the heterocyclic carbonylation optionally substituted), a saturated or unsaturated monocyclic or bicyclic of heteros Klionsky group, containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (this heterocyclic group optionally substituted), a saturated or unsaturated monocyclic or bicyclic heterocyclic actigraphy containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (provided the heterocyclic oxygraph optionally substituted), a saturated or unsaturated monocyclic or bicyclic heterocyclic carbonyl group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen (specified heterocyclic carbonyl group is optionally substituted), may be 1-5 groups selected from the following groups:

the halogen atom; ceanography; hydroxy-group; nitro group; carboxyl group; carbonyl group; tocography; sulfopropyl; cycloalkyl group, optionally substituted hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkoxycarbonyl group, optionally substituted hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; carbamoyl group; mono - or dialkyl baloiloi group, optionally substituted by a hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkyl groups, optionally substituted by a hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkanoyloxy group, optionally substituted hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkoxygroup, optionally substituted by a hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkanoyloxy, optionally substituted by halogen atom, hydroxy-group, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; allylthiourea, optionally substituted by halogen atom, hydroxy-group, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkylsulfonyl group, optionally substituted hydroxyl is POI, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkylsulfonyl group, optionally substituted hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; mono - or dialkylaminoalkyl group, optionally substituted hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; amino group; mono - or dialkylamino, optionally substituted by a hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; mono - or dialkylaminoalkyl, optionally substituted by a hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; mono - or dialkylamide, optionally substituted by a hydroxy-group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; and groups of formula:

where X1and X3means independently CH2, NH, O, S, SO or SO2; X2and X5means independently CH2, O, S, SO or SO2; X4indicates NH, O, S, SO or SO2; X6and X7means independently O or S; X8means S, CO or SO; and n, o, p, q and r is independently an integer of 1-4, where each group of the above formulas optionally substituted by 1-3 substituents selected from the following groups:

the halogen atom, carboxyl group, hydroxy-group, ceanography, carbonyl group, tocography, alkyl group, hydroxyalkyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkyl group, substituted with halogen, morpholinomethyl group, phenylalaline group, alkanoyloxy group, hydroxyalkanoates group, alkoxyalkanols group, alkoxygroup, fenilalanina, alkoxycarbonyl group, benzyloxycarbonyl group, mono - or dialkylamino, mono - or dialkylanilines group, mono - or dialkylamino group, alkylsulfonyl group and tetrazolyl group.

In addition, the "aromatic ring optionally containing 1-3 heteroatoms independently selected from oxygen atoms, sulfur and azo is a", means is preferably a group phenyl, naphthyl, pyridyl, hinely, ethanolic, furyl, pyrimidinyl, triazolyl or thienyl.

"Saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen"means preferably a group morpholinyl, thiomorpholine, piperazinil, pyrrolidinyl, piperidinyl, hexahydroazepin, pyrrolidyl, imidazolidinyl, oxazolidinyl, tetrahydropyranyl, tetrahydrofuranyl, DIOXOLANYL, oxiranyl, pyrimidinyl, pyridyl, triazolyl, tetrazolyl, oxadiazolyl, dihydropyrimidines, pyrazinyl, thiazolyl, oxazolyl, oxazolyl, pyridazinyl, imidazolyl, imidazolyl, pyrazinyl, thienyl, pyrrolyl, furyl or dihydroxyphenyl.

"Saturated or unsaturated monocyclic or bicyclic heterocyclic oxygraph containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen"means preferably a group of morpholinoethoxy, thiomorpholine, piperidinyloxy, pyrrolidinyloxy, piperidinyloxy, hexahydroazepin, pyrrolidinyloxy, imidazolidinone, oxazolidinone, tetrahydropyranyloxy, tetrahydropyranyloxy, DIOXOLANYL, oxyanions, pyrimidinone, pyridyloxy, triazolinone, tetrazolate, oxadiazolidine, digitrapper is midiyoke, pyrazinone, thiazolidone, oxazolidinone, oxazoline, pyridazinone, imidazolinone, imidazolinone, pyrazinone, titilate, pyrrolidone, forelocks or dihydroxyindole.

"Saturated or unsaturated monocyclic or bicyclic heterocyclic carbonyl group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen"means preferably a group morpholinylcarbonyl, thiomorpholine, piperazinylcarbonyl,

pyrrolidinylcarbonyl, piperidinylcarbonyl,

hexahydrobenzylcarbonate, pyrrolidinylcarbonyl,

imidazolidinedione, oxazolidinediones,

tetrahydropyranyloxy, tetrahydrofuranyl,

dioxyalkylene, oxiranylmethyl, pyrimidinylidene,

pyridylcarbonyl, triazolylmethyl, tetrachlorocarbon,

oxadiazolidine, dihydropyrimidinase,

PersonalCabinet, thiazolidinones, oxazolidinones,

oxazolidinones, pyridinylmethyl, imidazolylalkyl,

imidazolidinyl, PersonalCabinet, thienylboronic,

pyrrolidinone, fullcarbon or dihydroxyphenylethanol.

"Saturated or unsaturated monocyclic or bicyclic heterocyclic carbonylation containing 1-4 heteroatoms independently chosen is different from atoms of oxygen, sulfur and nitrogen"means preferably a group of morpholinylcarbonyl, dimorpholinyldiethyl,

piperazinylcarbonyl, pyrrolidinylcarbonyl,

piperidinylcarbonyl, hexahydrobenzylcarbonate,

pyrrolidinylcarbonyl, imidazolidinylideneamino,

oxazolidinecarboxylate, tetrahydropapaveroline,

tetrahydrofurfurylamine, dioxyalkylene,

oxiranylmethyl, pyrimidinecarbonitrile,

pyridylcarbonyl, thiazolecarboxamide,

tetrachloroaniline, oxadiazolidine,

dihydropyrimidinase, pyrazinecarboxamide,

thiazolecarboxamide, oxazolidinecarboxylate,

oxazolidinedione, pyridinecarboxamide,

imidazoledicarbonitrile, imidazolecarboxamide,

pyrazinecarboxamide, taylorsville,

pyrrolidinedione, shrinkability or

dihydroxyphenylethylamine.

In a preferred embodiment of the present invention R1means a hydrogen atom; alkoxycarbonyl group, optionally substituted by 1-5 substituents independently selected from ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup (this alkoxygroup optional for esena 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carboxyl group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), allylthiourea, alkylsulfonyl group, alkenylphenol group, amino group, mono - and dialkylamino, tetrazolyl group, carbamoyl group, mono - or dialkylanilines group (specified mono - or dialkylanilines group optionally substituted by 1-3 substituents, independently selected from carboxyl group and alkoxycarbonyl group), alkanolamines (this alkanolamines optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, a hydroxy-group and halogen atom), halogen atom, cycloalkyl group (specified cycloalkyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carbonyl group, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), phenyl group (this phenyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, Eminoglu the dust, mono - or dialkylamino, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), morpholinyl group, optionally substituted by exography, piperidinyloxy group (specified piperidinyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carbonyl group, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), pyrrolidinyl group (specified pyrrolidinyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, the halogen atom, carbonyl group, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), and pyrimidinyl group (specified pyrimidinyl group optionally substituted by 1-3 substituents, independently selected from carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl); carbamoyl gr the PPU, optionally substituted by alkoxygroup; dihydrooxazolo group, optionally substituted with 1-2 substituents independently selected from carboxyl group, alkoxycarbonyl groups, alkyl groups, carboxialkilnuyu group, alkoxycarbonyl group and hydroxyalkyl group; dihydroimidazolium group, optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl groups, alkyl groups, carboxialkilnuyu group, alkoxycarbonyl group and hydroxyalkyl group; dihydrooxazolo group, optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl groups, alkyl groups, carboxialkilnuyu group, alkoxycarbonyl group and hydroxyalkyl group; mono - or dialkylamino group, optionally substituted by 1-5 substituents, independently selected from halogen atom, hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup, amino, mono - or dialkylamino, morpholinyl group, peredelnoj group, cycloalkyl group (specified cycloalkyl group optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, aminor PPI and hydroxy-group) and phenyl group (this phenyl group optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxy-group); an alkyl group optionally substituted by 1-5 substituents independently selected from halogen atom, hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup, amino, mono - or dialkylamino, morpholinyl group, peredelnoj group, cycloalkyl group (specified cycloalkyl group optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxy-group) and phenyl group (this phenyl group optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxy-group); alkanoyloxy group, optionally substituted by 1-5 substituents independently selected from halogen atom, hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup, amino, mono - or dialkylamino, morpholinyl group, peredelnoj group, cycloalkyl group (specified cycloalkyl group optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxy-group) and phenyl group (this phenyl group optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxy-group); morpholinylcarbonyl group; piperazinylcarbonyl group optionally substituted alkyl group, carboxialkilnuyu group or alkoxycarbonyl group;

pyrrolidinylcarbonyl group, optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group and alkoxycarbonyl group; or piperidinylcarbonyl group, optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group and alkoxycarbonylmethyl group;

R5means saturated or unsaturated 5-8-membered heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen; where the specified heterocyclic group optionally substituted by 1-4 substituents, selected from the following groups:

the halogen atom;

the carbonyl group;

hydroxy-group;

ceanography;

nitro;

carboxyl group;

sulfopropyl;

alkyl group optionally substituted by a group selected from a halogen atom, ceanography, hydroxy-group, carboxyl group, alkoxy who arbonelli group, carbamoyl, cycloalkyl group optionally substituted by carboxyl or alkoxycarbonyl group, phenyl group (this phenyl group optionally substituted alkoxy, carboxyl or alkoxycarbonyl group), sulfopropyl, sulfamoyl group, mono - or dialkylanilines group, alkoxygroup (this alkoxygroup optionally substituted carboxyl, alkoxycarbonyl, hydroxy, alkoxy or phenyl group), alkanoyloxy group, alkanoyloxy, allylthiourea, alkylsulfonyl group, alkylsulfonyl group, amino group, mono - or dialkylamino, optionally substituted alkoxygroup, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, oxiranyl group, DIOXOLANYL group, optionally substituted alkyl group, pyrrolidinyl group (specified pyrrolidinyl group optionally substituted by exography, alkoxycarbonyl or a carboxyl group), piperidinyl group optionally substituted by carboxyl or alkoxycarbonyl group, piperazinilnom group, optionally substituted alkyl group, hexahydroazepin group optionally substituted by carboxyl or alkoxycarbonyl group, morpholine Inoi group and piperidinyloxy, optionally substituted alkyl group; alkenylphenol group, optionally substituted by a group selected from ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, benzyloxycarbonyl group and tetrazolyl group; alkoxygroup, optionally substituted by a group selected from a halogen atom, ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, carbamoyl group, cycloalkyl group optionally substituted by carboxyl or alkoxycarbonyl group, phenyl group (this phenyl group optionally substituted alkoxy, carboxyl or alkoxycarbonyl group), sulfopropyl, sulfamoyl group, alkoxygroup (this alkoxygroup optionally substituted carboxyl, alkoxycarbonyl, hydroxy, alkoxy or phenyl group), alkanoyloxy group, alkanoyloxy, allylthiourea, alkylsulfonyl group, alkylsulfonyl group, amino group, mono - or dialkylamino, replaced by alkoxygroup, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, oxiranyl group, DIOXOLANYL group, optionally substituted alkyl group, pyrrolidinyl group (specified pyrrolidinyl group long is correctly replaced by exography, alkoxycarbonyl or a carboxyl group), piperidinyl group optionally substituted by carboxyl or alkoxycarbonyl group, piperazinilnom group, optionally substituted alkyl group, hexahydroazepin group optionally substituted by carboxyl or alkoxycarbonyl group, morpholinyl group, piperidinyloxy, optionally substituted alkyl group, mono - or dialkylanilines group, optionally substituted hydroxy-group, pyrimidinyl group, peredelnoj group and morpholinylcarbonyl group; alkoxycarbonyl group, optionally substituted hydroxy-group, a carboxyl group, alkoxycarbonyl group or phenyl group; carbamoyl group; mono - or dialkylanilines group, optionally substituted by a group selected from carboxyl group, morpholinyl group, hydroxy-group and alkoxygroup; hydroxycarbonylmethyl group; allylthiourea, optionally substituted by a group selected from a hydroxy-group, carboxyl group and mono - or dialkylanilines group; alkylsulfonyl group; alkylsulfonyl group, optionally substituted by a group selected from a hydroxy-group, carboxyl group, alkoxycarbonyl group and mono - or dialkylanilines group; AMI is gruppy; mono - or dialkylamino, optionally substituted by a group selected from a hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup, mono - or dialkylamino and morpholinyl group; mono - or dialkanolamines, optionally substituted by a group selected from a hydroxy-group, alkoxygroup, carboxyl group, alkoxycarbonyl group and amino group; mono - or dialkylanilines, optionally substituted alkoxygroup; morpholinylcarbonyl; sulfamoyl group; mono - or dialkylaminoalkyl group; alkanoyloxy group, optionally substituted by a group selected from a hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup, mono - or dialkylamino and morpholinyl group; alkoxycarbonylmethyl, optionally substituted carboxyl group, a hydroxy-group or alkoxycarbonyl group; or a group selected from the following groups:

where X1and X3means independently CH2, NH, O, S, SO or SO2; X2and X5means independently CH2, O, S, SO or SO2; X4indicates NH, O, SO or SO2; and n, o, p, q and r independently is an integer of 1-4, where each group is given you the e formulas optionally substituted substituents, selected from the following groups:

carboxyl group, halogen atom, hydroxy-group, ceanography, carbonyl group, alkyl group, hydroxyalkyl group, alkoxycarbonyl group, carboxialkilnuyu group, morpholinomethyl group, phenylalaline group, alkanoyloxy group, hydroxyalkanoates group, alkoxyalkanols group, alkoxygroup, fenilalanina, alkoxycarbonyl group, benzyloxycarbonyl group, mono - or dialkylamino, mono - or dialkylanilines group, mono - or dialkylamino group, alkylsulfonyl group, dihydroxyethylene group, optionally substituted by exography and tetrazole group;

R6, R7and R8denote independently a hydrogen atom, a halogen atom, a hydroxy-group, a nitrogroup, cyano, alkyl group, alkoxygroup, alkoxycarbonyl group, benzyloxycarbonyl group, mono - or dialkylamino group or mono - or dialkylamino, where these groups alkyl, alkoxy, alkoxycarbonyl, benzyloxycarbonyl, mono - or dialkylamino and mono - or dialkylamino optionally substituted by 1-6 substituents, independently selected from halogen atom, hydroxy-group, alkoxygroup, allylthiourea, amino, nitro, ceanography, carbonyl group, carboxyl group, and oxycarbonyl group and mono - or dialkylamino; or

R6and R7or R7and R8may be combined at the ends with the formation of alkalinous group where the specified Allenova group optionally contains 1-3 heteroatoms independently selected from nitrogen atoms, sulfur and oxygen;

R10means an aromatic monocyclic ring, optionally containing 1-3 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen;

where the aforementioned monocyclic aromatic ring optionally substituted by 1-4 substituents, independently selected from halogen atom, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono - or dialkylanilines groups, alkyl groups, alkoxygroup, hydroxy-group, nitro group, ceanography, amino, mono - or dialkylamino, alkanoyloxy group, allylthiourea, tetrazolyl group and dihydrooxazolo group, where these alkyl group, alkoxygroup, mono - or dialkylamino, mono - or dialkylanilines group, alcoolica group and allylthiourea optionally substituted by substituent (substituents)independently selected from a halogen atom and the groups hydroxy, alkoxy, morpholinyl, piperidinyl, pyrrolidinyl, piperazinil, alkylpiperazine and alkanolamines.

In addition, in the above preferred compounds “aromatizes the second monocyclic ring, optionally containing 1-3 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen”represents a phenyl group, pyridyloxy group, pyrimidinyl group, follow group or thienyl group; and saturated or unsaturated 5-8-membered heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen”, is pyrimidinyl group, pyridyloxy group, triazolyl group, tetrazolyl group, oxadiazolyl group, dihydropyrimidinase group, personilnya group, thiazolidine group, oxazolidinyl group, imidazolidinyl group, dihydrooxazolo group, dihydropyrimidine group or pyrazolidine group.

In more preferred compounds, R1means a hydrogen atom; alkoxycarbonyl group substituted by 1-5 substituents independently selected from ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup (this alkoxygroup optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carboxyl group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), allylthiourea, alkylsulfonyl group, alkenylphenol GRU is dust, amino, mono - and dialkylamino, tetrazolyl group, carbamoyl group, mono - or dialkylanilines group (specified mono - or dialkylanilines group optionally substituted by 1-3 substituents, independently selected from carboxyl group and alkoxycarbonyl group), alkanolamines (this alkanolamines optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, a hydroxy-group and halogen atom), halogen atom, cycloalkyl group (specified cycloalkyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carbonyl group, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), phenyl group (this phenyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), morpholinyl group, optionally substituted by oxo is Ruppel, piperidinyloxy group (specified piperidinyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carbonyl group, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), pyrrolidinyl group (specified pyrrolidinyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carbonyl group, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), and pyrimidinyl group (specified pyrimidinyl group optionally substituted by 1-3 substituents, independently selected from carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl); dihydrooxazolo group, optionally substituted with 1-2 substituents independently selected from carboxyl group, alkoxycarbonyl groups, alkyl groups, carboxialkilnuyu group, alkoxycarbonyl group and hydroxyalkyl group; or a mono - or dialkylamino gr the PPU, optionally substituted by 1-5 substituents independently selected from halogen atom, hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup, amino, mono - or dialkylamino, morpholinyl group, peredelnoj group, cycloalkyl group (specified cycloalkyl group optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxy-group) and phenyl group (this phenyl group optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxy-group);

R2means alkyl group;

R3means a hydrogen atom;

R4means alkylenes group;

R5means heterocyclic group selected from pyrimidinyl group, peredelnoj group, triazolines group, tetrazolyl group, oxadiazolyl group, dihydropyrimidinase group, personalni group, thiazolidine group, oxazoline group, imidazolidine group, dihydrooxazolo group, pyrazolidine group and dihydropyridine group where the specified heterocyclic group substituted by 1-4 substituents, selected from the following groups:

the halogen atom is;

hydroxy-group;

the carbonyl group;

ceanography;

carboxyl group;

sulfopropyl;

alkyl group optionally substituted by a group selected from a halogen atom, ceanography, hydroxy-group, carboxyl group, alkoxygroup, optionally substituted by hydroxy or alkoxygroup, alkoxycarbonyl group, mono - or dialkylanilines group, mono - or dialkylamino, optionally substituted alkoxy or carboxypropyl, pyrrolidinyl group optionally substituted by carboxyl or alkoxycarbonyl group, piperidinyl group optionally substituted by carboxyl or alkoxycarbonyl group, piperazinilnom group, optionally substituted alkyl group, morpholinyl group, alkanoyloxy and alkylsulfonyl group;

alkenylphenol group, optionally substituted by a group selected from ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, benzyloxycarbonyl group and tetrazolyl group;

alkoxygroup, optionally substituted by a group selected from a halogen atom, ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono - or dialkylanilines group, optionally substituted hydroxy-group, alkoxygroup (shown is alkoxygroup optionally substituted by a hydroxy-group, carboxyl group or alkoxygroup), allylthiourea, alkylsulfonyl group, alkylsulfonyl group, mono - or dialkylamino, optionally substituted carboxyl group or alkoxygroup, morpholinyl group, pyrrolidinyl group (specified pyrrolidinyl group optionally substituted by carboxyl group, alkoxygroup or oxopropoxy), pyrimidinyl group optionally substituted by carboxyl group or alkoxygroup, optionally oxidized peredelnoj group, DIOXOLANYL group, substituted alkyl group, and morpholinylcarbonyl group;

cycloalkyl group optionally substituted by carboxyl group or alkoxycarbonyl group;

alkoxycarbonyl group optionally substituted phenyl group;

carbamoyl group;

mono - or dialkylanilines group, optionally substituted by a group selected from morpholinyl group, carboxyl group, hydroxy-group and alkoxygroup;

hydroxycarbonylmethyl group;

allylthiourea, optionally substituted by a group selected from a hydroxy-group, carboxyl group and mono - or dialkylanilines group;

alkylsulfonyl group, optionally substituted by a group selected from a hydroxy-group, alkoxycarbonyl group imono or dialkylanilines group;

amino group;

mono - or dialkylamino, optionally substituted by a group selected from a hydroxy-group, carboxyl group alkoxycarbonyl group, alkoxygroup, mono - or dialkylamino and morpholinyl group;

alkanolamines, optionally substituted by a group selected from a hydroxy-group, alkoxygroup, carboxyl group and amino group;

mono - or dialkylamide, optionally substituted alkoxygroup;

morpholinylcarbonyl;

morpholinyl group, optionally substituted by a group selected from a carbonyl group and carboxyl group;

piperazinilnom group, optionally substituted by a group selected from ceanography, alkyl group, hydroxyalkyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkanoyloxy group, alkoxyalkanols group, benzyloxycarbonyl group, mono - or dialkylanilines group, mono - or dialkylamino group, alkylsulfonyl group, tetrazolyl group and dihydroxyethylene group, optionally substituted by oxopropoxy;

piperidinyloxy group, optionally substituted by a group selected from carboxyl group, hydroxy-group, alkyl group, optionally substituted hydroxy-group or a carboxyl group, alkoxygroup, n is necessarily substituted phenyl group, alkoxycarbonyl group, carbonyl group and alkanoyloxy group;

pyrrolidinyloxy group, optionally substituted by a group selected from carboxyl group, alkoxycarbonyl group, carbonyl group and mono - or dialkylamino;

pyrrolidine group, optionally substituted by oxopropoxy;

hexahydroazepin group, optionally substituted alkanoyloxy group;

imidazolidinyl group, optionally substituted by oxopropoxy;

peredelnoj group optionally substituted by carboxyl group, hydroxy-group, alkanoyloxy group, alkyl group or hydroxyalkyl group (specified Peregrina group optionally optionally oxidized);

tetrazolyl group, optionally substituted alkyl group or hydroxyalkyl group;

dihydroxyethylene group, optionally substituted by oxopropoxy;

dihydroimidazole group;

dihydrooxazolo group;

oxazolidinyl group, optionally substituted by oxopropoxy;

tetrahydropyridine group, optionally substituted benzyl group;

pyrimidinyl group;

piperidinyloxy, optionally substituted alkyl group or a carboxyl group;

pyrrolidinyloxy, optionally substituted by a group selected from alkyl is Noah group, carboxyl group, alkoxycarbonyl group and alkanoyloxy group;

tetrahydropyranyloxy;

tetrahydropyranyloxy;

optional oxidized taylortype;

morpholinylcarbonyl group;

piperazinylcarbonyl group, optionally substituted by a group selected from alkanoyloxy groups and alkyl groups;

pyrrolidinylcarbonyl group optionally substituted by carboxyl group or alkoxycarbonyl group, and

piperidinylcarbonyl group optionally substituted by carboxyl group or alkoxycarbonyl group;

R6and R7denote independently a hydrogen atom, alkyl group, optionally substituted by a halogen atom, alkoxygroup, optionally substituted by halogen atom, hydroxy-group, a cyano or a mono - or dialkylamino; or

R6and R7may be combined at the ends with the formation of alkylenedioxy;

R8means a hydrogen atom;

R10means phenyl or pyridyloxy group, where the phenyl or Peregrina group optionally substituted by 1-4 substituents selected from a halogen atom, alkoxycarbonyl groups, alkyl groups, optionally substituted by a halogen atom, alkoxygroup, optionally substituted by halogen atom, hydroxy-group, ziang uppy, amino, mono - or dialkylamino and allylthiourea.

In the following preferred compounds, R1means alkoxycarbonyl group, optionally substituted by 1-5 substituents independently selected from hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup (this alkoxygroup optionally substituted by 1-3 substituents, independently selected from hydroxy-group, halogen atom, carboxyl group, alkoxycarbonyl group), alkenylphenol group, halogen atom, cycloalkyl group (specified cycloalkyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group and alkoxycarbonyl group), phenyl group (this phenyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group and alkoxycarbonyl group), piperidinyl group (specified piperidinyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group and alkoxycarbonylmethyl the th group), and pyrrolidinyloxy group (specified pyrrolidinyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group and alkoxycarbonyl group);

or dihydrooxazolo group optionally substituted by 1 or 2 substituents, independently selected from carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group and hydroxyalkyl group;

R5means pyrimidinyl group, pyridyloxy group, triazolyl group, tetrazolyl group, oxadiazolyl group, dihydropyrimidinase group, personilnya group, thiazolidine group, oxazolidinyl group, dihydrooxazolo group, pyrazolidine group or dihydropyrimidine group, where the group is substituted by 1-4 substituents, selected from the following groups:

the halogen atom;

hydroxy-group;

ceanography;

carboxyl group;

alkyl group optionally substituted by a group selected from a halogen atom, ceanography, hydroxy-group, carboxyl group, alkoxygroup, optionally substituted by hydroxy or alkoxygroup, alkoxycarbonyl group, mono - or dialkylanilines group, mono - or dialkyl is kinogruppy, optionally substituted alkoxy or carboxypropyl, pyrrolidinyl group optionally substituted by carboxyl or alkoxycarbonyl group, piperidinyl group optionally substituted by carboxyl or alkoxycarbonyl group, piperazinilnom group, optionally substituted alkyl group, morpholinyl group, alkanoyloxy and alkylsulfonyl group;

alkenylphenol group, optionally substituted by a group selected from ceanography, hydroxy-group and carboxyl group;

alkoxygroup, optionally substituted by a group selected from a halogen atom, ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono - or dialkylanilines group, optionally substituted hydroxy-group, alkoxygroup (this alkoxygroup optionally substituted by a hydroxy-group, a carboxyl group or alkoxygroup), allylthiourea, alkylsulfonyl group, alkylsulfonyl group, mono - or dialkylamino, optionally substituted carboxyl group or alkoxygroup, morpholinyl group, pyrrolidinyl group (specified pyrrolidinyl group optionally substituted by carboxyl group, alkoxygroup or oxopropoxy), pyrimidinyl group, optionally substituted CT is auxillou group or alkoxygroup, optional oxidized peredelnoj group, DIOXOLANYL group, substituted alkyl group, and morpholinylcarbonyl group;

cycloalkyl group optionally substituted by carboxyl group or alkoxycarbonyl group;

mono - or dialkylanilines group, optionally substituted by a group selected from morpholinyl group, carboxyl group, hydroxy-group and alkoxygroup;

hydroxycarbonylmethyl group;

allylthiourea, optionally substituted by a group selected from a hydroxy-group, carboxyl group and mono - or dialkylanilines group;

amino group;

mono - or dialkylamino, optionally substituted by a group selected from a hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup and morpholinyl group;

alkanolamines, optionally substituted by a group selected from a hydroxy-group, alkoxygroup, carboxyl group and amino group;

mono - or dialkylamide, optionally substituted alkoxygroup;

morpholinylcarbonyl;

morpholinyl group, optionally substituted by oxopropoxy;

piperazinilnom group, optionally substituted by a group selected from ceanography, alkyl group, hydroxyalkyl group, alkoxycarbonylmethyl group, the carb is cialiles group, alkanoyloxy group, alkoxyalkanols group, mono - or dialkylanilines group, mono - or dialkylamino group and alkylsulfonyl group;

piperidinyloxy group, optionally substituted by a group selected from carboxyl group, hydroxy-group, alkyl group, optionally substituted hydroxy-group or a carboxyl group, alkoxygroup, alkoxycarbonyl group, carbonyl group and alkanoyloxy group;

pyrrolidinyloxy group, optionally substituted by a group selected from a carbonyl group, carboxyl group, alkoxycarbonyl group and mono - or dialkylamino;

hexahydroazepin group, optionally substituted alkanoyloxy group;

peredelnoj group, optionally substituted hydroxy-group, carboxyl group, alkyl group or hydroxyalkyl group (specified Peregrina group optionally optionally oxidized);

tetrazolyl group, optionally substituted alkyl group or hydroxyalkyl group;

dihydroxyethylene group, optionally substituted by oxopropoxy;

oxazolidinyl group, optionally substituted by oxopropoxy;

tetrahydropyridine group, optionally substituted benzyl group;

pyrimidinyl group;

piperidinyloxy, optional the nutrient substituted alkyl group or a carboxyl group;

pyrrolidinyloxy, optionally substituted by a group selected from alkyl groups and alkanoyloxy group;

tetrahydropyranyloxy;

tetrahydropyranyloxy and

optional oxidized taylortype;

R10means phenyl or pyridyloxy group, where the phenyl or Peregrina group optionally substituted by 1-4 substituents selected from halogen atom, alkyl group, optionally substituted by a halogen atom, alkoxygroup, hydroxy-group, cyano, amino group and mono - or dialkylamino.

Another variant of implementation of the present invention includes compounds of formula (I), where R5means a group of the formula:

where ring a represents a saturated or unsaturated 5-8-membered heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen, and

R11means a group selected from the following groups:

the halogen atom;

hydroxy-group;

the carbonyl group;

ceanography;

carboxyl group;

sulfopropyl;

alkyl group optionally substituted by a group selected from a halogen atom, ceanography, hydroxy-group, carboxyl group, alkoxygroup, optionally substituted by hydroxy or alkoxygroup, alkoxycarbonyl gr is PPI, mono - or dialkylanilines group, mono - or dialkylamino, optionally substituted alkoxy or carboxypropyl, pyrrolidinyl group optionally substituted by carboxyl or alkoxycarbonyl group, piperidinyl group optionally substituted by carboxyl or alkoxycarbonyl group, piperazinilnom group, optionally substituted alkyl group, morpholinyl group, alkanoyloxy and alkylsulfonyl group;

alkenylphenol group, optionally substituted by a group selected from ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, benzyloxycarbonyl group and tetrazolyl group;

alkoxygroup, optionally substituted by a group selected from a halogen atom, ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono - or dialkylanilines group, optionally substituted hydroxy-group, alkoxygroup (this alkoxygroup optionally substituted by a hydroxy-group, a carboxyl group or alkoxygroup), allylthiourea, alkylsulfonyl group, alkylsulfonyl group, mono - or dialkylamino, optionally substituted carboxyl group or alkoxygroup, morpholinyl group, pyrrolidinyl group (specified Pirro is edinilsa group optionally substituted by carboxyl group, alkoxygroup or oxopropoxy), pyrimidinyl group optionally substituted by carboxyl group or alkoxygroup, optionally oxidized peredelnoj group, DIOXOLANYL group, substituted alkyl group, and morpholinylcarbonyl group;

cycloalkyl group optionally substituted by carboxyl group or alkoxycarbonyl group;

alkoxycarbonyl group optionally substituted phenyl group;

carbamoyl group;

mono - or dialkylanilines group, optionally substituted by a group selected from morpholinyl group, carboxyl group, hydroxy-group and alkoxygroup;

hydroxycarbonylmethyl group;

allylthiourea, optionally substituted by a group selected from a hydroxy-group, carboxyl group and mono - or dialkylanilines group;

alkylsulfonyl group, optionally substituted by a group selected from a hydroxy-group, alkoxycarbonyl group and mono - or dialkylanilines group;

amino group;

mono - or dialkylamino, optionally substituted by a group selected from a hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup, mono - or dialkylamino and morpholinyl group;

alkanolamines, optionally substituted by a group selected is of the hydroxy-group, alkoxygroup, carboxyl group and amino group;

mono - or dialkylamide, optionally substituted alkoxygroup;

morpholinylcarbonyl;

morpholinyl group, optionally substituted by a group selected from a carbonyl group and carboxyl group;

piperazinilnom group, optionally substituted by a group selected from ceanography, alkyl group, hydroxyalkyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkanoyloxy group, alkoxyalkanols group, benzyloxycarbonyl group, mono - or dialkylanilines group, mono - or dialkylamino group, alkylsulfonyl group, tetrazolyl group and dihydroxyethylene group, optionally substituted by oxopropoxy;

piperidinyloxy group, optionally substituted by a group selected from carboxyl group, hydroxy-group, alkyl group, optionally substituted hydroxy-group or a carboxyl group, alkoxygroup, optionally substituted phenyl group, alkoxycarbonyl group, carbonyl group and alkanoyloxy group;

pyrrolidinyloxy group, optionally substituted by a group selected from carboxyl group, alkoxycarbonyl group, carbonyl group and mono - or dialkylamino;

pyrrolidine group, not necessarily Thames is authorized by oxopropoxy;

hexahydroazepin group, optionally substituted alkanoyloxy group;

imidazolidinyl group, optionally substituted by oxopropoxy;

peredelnoj group optionally substituted by carboxyl group, hydroxy-group, alkanoyloxy group, alkyl group or hydroxyalkyl group (specified Peregrina group optionally optionally oxidized);

tetrazolyl group, optionally substituted alkyl group or hydroxyalkyl group;

dihydroxyethylene group, optionally substituted by oxopropoxy;

dihydroimidazole group;

dihydrooxazolo group;

oxazolidinyl group, optionally substituted by oxopropoxy;

tetrahydropyridine group, optionally substituted benzyl group;

pyrimidinyl group;

piperidinyloxy, optionally substituted alkyl group or a carboxyl group;

pyrrolidinyloxy, optionally substituted by a group selected from alkyl groups, carboxyl groups, alkoxycarbonyl group and alkanoyloxy group;

tetrahydropyranyloxy;

tetrahydropyranyloxy;

optional oxidized taylortype;

morpholinylcarbonyl group;

piperazinylcarbonyl group, optional samisen the th group, selected from alkanoyloxy groups and alkyl groups;

pyrrolidinylcarbonyl group optionally substituted by carboxyl group or alkoxycarbonyl group, and

piperidinylcarbonyl group optionally substituted by carboxyl group or alkoxycarbonyl group;

where the specified compound is shown by formula (I-A):

where each symbol has the meaning given above.

The preferred option includes the compounds of formula (I), where R1means a hydrogen atom; alkoxycarbonyl group substituted by 1-5 substituents independently selected from ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup (this alkoxygroup optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carboxyl group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), allylthiourea, alkylsulfonyl group, alkenylphenol group, amino group, mono - and dialkylamino, tetrazolyl group, carbamoyl group, mono - or dialkylanilines group (specified mono - or dialkylanilines group optionally substituted by 1-3 substituents, independently selected from CT is auxillou group and alkoxycarbonyl group), alkanolamines (this alkanolamines optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, a hydroxy-group and halogen atom), halogen atom, cycloalkyl group (specified cycloalkyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carbonyl group, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), phenyl group (this phenyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), morpholinyl group, optionally substituted by exography, piperidinyloxy group (specified piperidinyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carbonyl group, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu gr is PPI, alkoxycarbonylmethyl group, carboxitherapy and alkoxycarbonylmethyl), pyrrolidinyl group (specified pyrrolidinyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, amino group, mono - or dialkylamino, halogen atom, carbonyl group, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl), and pyrimidinyl group (specified pyrimidinyl group optionally substituted by 1-3 substituents, independently selected from carboxialkilnuyu group, alkoxycarbonyl group, carboxitherapy and alkoxycarbonylmethyl); dihydrooxazolo group, optionally substituted with 1-2 substituents independently selected from carboxyl group, alkoxycarbonyl groups, alkyl groups, carboxialkilnuyu group, alkoxycarbonyl group and hydroxyalkyl group; or a mono - or dialkylamino group, optionally substituted by 1-5 substituents independently selected from halogen atom, hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup, amino, mono - or dialkylamino, morpholinyl group, peredelnoj group, cycloalkyl group (pointed to by the I cycloalkyl group optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxy-group) and phenyl group (this phenyl group optionally substituted by 1-3 substituents, independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, amino group and hydroxy-group);

R2means alkyl group;

R3means a hydrogen atom;

R4means alkylenes group;

ring a and R11mean the same groups as defined above;

R6and R7denote independently a hydrogen atom, alkyl group, optionally substituted by a halogen atom, alkoxygroup, optionally substituted by halogen atom, hydroxy-group, a cyano or a mono - or dialkylamino; or

R6and R7may be combined at the ends with the formation of alkylenedioxy;

R8means a hydrogen atom;

R10means phenyl or pyridyloxy group, where the phenyl or Peregrina group optionally substituted by 1-4 substituents selected from a halogen atom, alkoxycarbonyl groups, alkyl groups, optionally substituted by a halogen atom, alkoxygroup, optionally substituted by halogen atom, hydroxy-group, ceanography, amino, mono - or dialkylamino and allylthiourea.

D. the natives preferred option includes the compounds of formula (I), where ring a represents a saturated or unsaturated 5-8-membered heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen, and R11means a group selected from the following groups:

the halogen atom;

hydroxy-group;

the carbonyl group;

ceanography;

carboxyl group;

sulfopropyl;

alkyl group optionally substituted by a group selected from ceanography, hydroxy-group, carboxyl group, alkoxygroup, optionally substituted by a hydroxy-group, alkoxycarbonyl group, mono - or dialkylanilines group, mono - or dialkylamino, optionally substituted alkoxygroup, pyrrolidinyloxy group, piperidinyl group, piperazinilnom group, optionally substituted alkyl group, morpholinyl group, alkanoyloxy and alkylsulfonyl group;

alkenylphenol group, optionally substituted by a group selected from ceanography, hydroxy-group, carboxyl group, benzyloxycarbonyloxy group and tetrazolyl group;

alkoxygroup, optionally substituted by a group selected from a hydroxy-group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono - or dialkylanilines group, optionally substituted hydroxy-group, alkoxygroup, long is correctly substituted hydroxy-group, allylthiourea, alkylsulfonyl group, alkylsulfonyl group, mono - or dialkylamino, morpholinyl group, pyrrolidinyl group, optionally substituted by exography, pyrimidinyl group, optionally oxidized peredelnoj group, DIOXOLANYL group, substituted alkyl group, and morpholinylcarbonyl group;

alkoxycarbonyl group optionally substituted phenyl group;

carbamoyl group;

mono - or dialkylanilines group, optionally substituted by a group selected from morpholinyl group and alkoxygroup;

hydroxycarbonylmethyl group;

allylthiourea, optionally substituted by a group selected from a hydroxy-group, carboxyl group and mono - or dialkylanilines group;

alkylsulfonyl group, optionally substituted by a group selected from a hydroxy-group, alkoxycarbonyl group and mono - or dialkylanilines group;

amino group;

mono - or dialkylamino, optionally substituted by a group selected from a hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup, mono - or dialkylamino and morpholinyl group;

alkanolamines, optionally substituted by a group selected from a hydroxy-group, alkoxygroup and amino;

mono - and who and dialkylamides, optionally substituted by alkoxygroup;

morpholinylcarbonyl;

morpholinyl group, optionally substituted by a group selected from a carbonyl group and carboxyl group;

piperazinilnom group, optionally substituted by a group selected from ceanography, alkyl group, hydroxyalkyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkanoyloxy group, alkoxyalkanols group, benzyloxycarbonyl group, mono - or dialkylanilines group, mono - or dialkylamino group, alkylsulfonyl group, tetrazolyl group and dihydroxyethylene group, optionally substituted by oxopropoxy;

piperidinyloxy group, optionally substituted by a group selected from carboxyl group, hydroxy-group, alkyl group, optionally substituted hydroxy-group or a carboxyl group, alkoxygroup, optionally substituted phenyl group, alkoxycarbonyl group, carbonyl group and alkanoyloxy group;

pyrrolidinyloxy group, optionally substituted by a group selected from a carbonyl group and mono - or dialkylamino;

pyrrolidine group, optionally substituted by oxopropoxy;

hexahydroazepin group, optionally substituted alkanoyloxy group;

imidazolidinyl group, not battelino replaced by oxopropoxy;

peredelnoj group optionally substituted by carboxyl group, hydroxy-group, alkyl group or hydroxyalkyl group (specified Peregrina group optionally optionally oxidized);

tetrazolyl group, optionally substituted alkyl group or hydroxyalkyl group;

dihydroxyethylene group, optionally substituted by oxopropoxy;

dihydroimidazole group;

dihydrooxazolo group;

oxazolidinyl group, optionally substituted by oxopropoxy;

tetrahydropyridine group, optionally substituted benzyl group;

pyrimidinyl group;

piperidinyloxy, optionally substituted alkyl group;

pyrrolidinyloxy, optionally substituted by a group selected from alkyl groups and alkanoyloxy group;

tetrahydropyranyloxy;

tetrahydropyranyloxy;

optional oxidized taylortype;

morpholinylcarbonyl group;

piperazinylcarbonyl group, optionally substituted by a group selected from alkanoyloxy groups and alkyl groups, and

pyrrolidinylcarbonyl group.

The preferred option includes the compounds of formula (I), where R1means alkoxycarbonyl group optionally substituted group is, selected from hydroxy-group and alkoxygroup;

R2means alkyl group;

R3means a hydrogen atom;

R4means alkylenes group;

ring a and R11mean the same groups as defined above;

R6and R7denote independently a hydrogen atom, alkyl group, optionally substituted by a halogen atom, alkoxygroup, optionally substituted by a halogen atom, a cyano or a mono - or dialkylamino, or

R6and R7may be combined at the ends with the formation of alkylenedioxy;

R8means a hydrogen atom;

R10means phenyl or pyridyloxy group, where the phenyl or Peregrina group optionally substituted by 1-4 substituents selected from a halogen atom, alkoxycarbonyl groups, alkyl groups, optionally substituted by a halogen atom, alkoxygroup, optionally substituted by halogen atom, hydroxy-group, ceanography, amino, mono - or dialkylamino and allylthiourea.

Examples of ring a include pyrimidinyl group, pyridyloxy group, triazolyl group, tetrazolyl group, oxadiazolyl group, dihydropyrimidinase group, personilnya group, thiazolidine group, oxazolidinyl group, dihydrooxazolo group, pyrazolidine group, dihydropyrazine the optimum group, etc.

More preferred compounds include compounds in which the ring And means pyrimidinyl group, tetrazolyl group or pyridyloxy group; and R11means a group selected from:

alkyl group optionally substituted by a group selected from carboxyl group, hydroxyalkoxy, mono - or dialkylanilines group, mono - or dialkylamino, optionally substituted alkoxygroup, amino, mono - or dialkylanilines group and morpholinyl group;

alkenylphenol group, optionally substituted hydroxy-group, carboxyl group, or cyano;

alkoxygroup, optionally substituted by a group selected from a hydroxy-group, carboxyl group, carbamoyl group, alkoxycarbonyl group, mono - or dialkylanilines group, optionally substituted hydroxy-group, hydroxyalkoxy, carboxitherapy, alkylsulfonyl group, alkylsulfonyl group, mono - or dialkylamino, morpholinyl group, oxopyrrolidin group, optionally oxidized peredelnoj group and morpholinylcarbonyl group;

carbamoyl group;

allylthiourea, optionally substituted hydroxy-group or mono - or dialkylanilines group;

mono - or dialkylamino, optional samisen the th hydroxy-group, carboxyl group or alkoxygroup;

alkanolamines, optionally substituted hydroxy-group or alkoxygroup;

mono - or dialkylamide, optionally substituted alkoxygroup;

morpholinyl group;

piperazinilnom group, optionally substituted by a group selected from alkyl groups, hydroxyalkyl groups, alkoxycarbonyl group, carboxialkilnuyu group, alkanoyloxy group and mono - or dialkylanilines group;

piperidinyloxy group, optionally substituted by a group selected from carboxyl group, alkoxycarbonyl group, a hydroxy-group, hydroxyalkyl group, carboxialkilnuyu group and the carbonyl group;

pyrrolidinyloxy group, optionally substituted by a group selected from a carboxyl group and mono - or dialkylamino;

peredelnoj group, which is substituted by hydroxyalkyl group or oxidized;

tetrazolyl group, optionally substituted alkyl group or hydroxyalkyl group;

oxodegradable group;

pyrimidinyl group;

pyrrolidinyloxy, optionally substituted alkanoyloxy group, and

optional oxidized taylortype;

R6means a hydrogen atom, alkyl group, optionally substituted by a halogen atom alkoxygroup, the cyano or mono - or dialkylamino;

R10means a phenyl group which is substituted by 1-3 substituents selected from halogen atom, alkyl group, optionally substituted by a halogen atom, alkoxygroup and ceanography.

Even more preferred compounds include compounds where R1means alkoxycarbonyl group, optionally substituted by 1-5 substituents independently selected from hydroxy-group, carboxyl group, alkoxycarbonyl group, alkoxygroup (this alkoxygroup optionally substituted by 1-3 substituents, independently selected from hydroxy-group, halogen atom, carboxyl group and alkoxycarbonyl group), alkenylphenol group, halogen atom, cycloalkyl group (specified cycloalkyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group and alkoxycarbonyl group), phenyl group (this phenyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group, carboxialkilnuyu group and alkoxycarbonylmethyl GRU is p), piperidinyloxy group (specified piperidinyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group and alkoxycarbonyl group) and pyrrolidinyloxy group (specified pyrrolidinyl group optionally substituted by 1-3 substituents, independently selected from hydroxy-group, halogen atom, carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group and alkoxycarbonyl group); or dihydrooxazolo group optionally substituted by 1 or 2 substituents, independently selected from carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group, alkoxycarbonyl group and hydroxyalkyl group;

R11means a group selected from:

alkyl group optionally substituted by carboxyl group, alkoxycarbonyl group or hydroxy-group;

carboxyaniline group;

alkoxygroup, optionally substituted by a group selected from ceanography, hydroxy-group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono - or dialkylanilines group, mono - or dialkylanilines group substituted by a hydroxy-group, hydroxyalkoxy, alcalali Niley group, alkylsulfonyl group, mono - or dialkylamino and oxopyrrolidin group;

mono - or dialkylamino, optionally substituted by carboxyl group;

alkanolamines, optionally substituted hydroxy-group or alkoxygroup;

morpholinyl group;

piperazinilnom group, optionally substituted by a group selected from alkyl groups, alkanoyloxy group and mono - or dialkylanilines group;

piperidinyloxy group, optionally substituted carboxyl group, alkoxycarbonyl group, a hydroxy-group, carboxialkilnuyu group or hydroxyalkyl group;

pyrrolidinyloxy group, optionally substituted mono - or dialkylamino;

peredelnoj group, which is substituted by hydroxyalkyl group or oxidized;

tetrazolyl group, optionally substituted hydroxyalkyl group;

pyrimidinyl group;

pyrrolidinyloxy, optionally substituted alkyl group or alkanoyloxy group, and

optionally substituted oxidized taylortype; and

R10means a phenyl group which is substituted by 1-3 substituents selected from alkyl group optionally substituted by a halogen atom, alkoxygroup and ceanography.

Even more preferred compounds include the up connections, where R1means alkoxycarbonyl group, optionally substituted by 1-5 substituents independently selected from carboxyl group, alkoxycarbonyl group, halogen atom, hydroxy-group and cycloalkyl group; R11means alkyl group optionally substituted by carboxyl group; carboxyaniline group; alkoxygroup, optionally substituted by a group selected from ceanography, hydroxy-group, carboxyl group, allylthiourea and alkylsulfonyl group; mono - or dialkylamino, optionally substituted by carboxyl group; hydroxyalkanoates; morpholinyl group; piperazinilnom group optionally substituted alkyl group or alkanoyloxy group, or piperidinyloxy group optionally substituted by carboxyl group or a hydroxy-group;

R6means alkyl group, optionally substituted by a halogen atom, alkoxygroup or mono - or dialkylamino; and

R7means a hydrogen atom.

Especially preferred compounds include compounds where R1means ethoxycarbonyl group, hydroxyethoxyethyl group, 2-forecastable group, 2,2-diplomaticcarbon group or 2,2,2-triftoratsetofenona group; R2means ethyl group; R10 represents a phenyl group, substituted by 1-2 substituents selected from ceanography and triptorelin group; R6means a methoxy group or triptorelin group. In this regard, other examples of particularly preferred compounds include compounds where R1means carboxy(C2-10alkoxy)carbonyl group or alkoxycarbonyl(C2-10alkoxy)carbonyl group, and R2, R10and R6have the above specified values.

Even more preferred compounds include compounds where R1means ethoxycarbonyl group or hydroxyethoxyethyl group; R2means ethyl group; R10means a phenyl group substituted by 1-2 substituents selected from ceanography and triptorelin group; and R6means a methoxy group.

The most preferred compounds include the compounds listed below.

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-hydroxyethylpiperazine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-methylpiperidin-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]is aftereden-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(hydroxyacetylamino)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methylsulfonylmethane)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2,3-dihydroxypropane)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyvinyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl](5-{[methyl-(2-carboxyethyl)]amino}pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypeptidase-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypeptidase-1-yl)pyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxymethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropanoyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxymethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[5-(2-carboxyethyl)pyrimidine-2-yl]-(3-cyano-5-trifloromethyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-[(3-cyano-5-trifloromethyl)-(5-{[methyl)-(2-carboxyethyl)]amino}pyrimidine-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-6-dimethylamino-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[5-4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropanoyl)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2,2,2-triptoreline ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypeptidase-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-perately ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypeptidase-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

1-metaliteracy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypeptidase-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

(2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-1-((R)-4,5-dihydrooxazolo-2-yl)-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid, or

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic KIS is the notes; or

their pharmaceutically acceptable salt.

The following examples of preferred compounds include:

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether (R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-cyanopropionic)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-cyanopropionic)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-cyanopropionic)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridin the-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-cyanopropionic)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-cyanopropionic)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-dimethylaminopyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-dimethylaminopyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-dimethylaminopyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-dimethylaminopyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-dimethylaminopyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carbon is howling acid;

3-carboxypropanoyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic what Islami;

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridin-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimido the-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-cyanopropionic)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-cyanopropionic)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-cyanopropionic)pyrimidine-2-yl]}amino-2-e is Il-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-cyanopropionic)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-cyanopropionic)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-dimethylaminopyridine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-dimethylaminopyridine-2-yl)}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-dimethylaminopyridine-2-yl)}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-dimethylaminopyridine-2-yl)}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-dimethylaminopyridine-2-yl)}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-trif ormetal-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxitherapy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

3-carboxypropanoyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-triptime the Il-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

5-carboxypentyl (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;

4-carboxybutyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid, or

2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid; or pharmaceutically acceptable salt.

This compound (I) or its pharmaceutically acceptable salt can be administered orally or parenterally, and can be prepared in the form of pharmaceutical preparations with conventional pharmaceutically acceptable carriers used for this purpose.

Pharmaceutically acceptable salts of compound (I) can include, for example, alkali metal salts such as lithium salt, sodium or potassium; salts of alkaline earth metals such as calcium salt or magnesium; salts with zinc or aluminium, salts with organic bases, such as ammonium, choline, diethanolamine, lysine, Ethylenediamine, t-butylamine, tert-octylamine, Tris(hydroxymethyl)aminomethane, N-methylglucamine, triethanolamine or degidro(abIe)tiemin; salts with inorganic acids such as chlorite is Todorova acid, itestosterone acid, sulfuric acid, nitric acid or phosphoric acid; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid or toluensulfonate acid; or salts derived from acidic amino acid such as aspartic acid or glutamic acid.

In addition, pharmaceutically acceptable salts of compound (I) include, for example, Quaternary salts formed between a compound of formula (I) and alkylhalogenide or phenylalkylamines.

A preferred pharmaceutical composition for oral administration of this compound (I) or its pharmaceutically acceptable salts include solid forms such as tablets, granules, capsules or powders; and liquid forms such as solutions, suspensions or emulsions. Preferred pharmaceutical compositions for parenteral administration include injection or infusion solutions prepared with distilled water suitable for injection, saline solution or aqueous glucose solution; suppositories or drug inhalation.

The criminal code is related to pharmaceutical compositions containing the compound (I) of the present invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, which is usually used for oral or parenteral administration. Pharmaceutically acceptable carriers for oral administration include, for example, binding agent (syrup, Arabian gum, gelatin, sorbitol, tragakant, polyvinylpyrrolidone and the like), excipient (lactose, sugar, corn starch, potassium phosphate, sorbitol, glycine and the like), lubricating agents (magnesium stearate, talc, polyethylene glycol, silicon dioxide, and the like), disintegrity agent (potato starch and the like) and moisturizer (anhydrous sodium dodecyl sulfate and the like). Pharmaceutically acceptable carriers for parenteral administration include, for example, distilled water for injection, physiological salt solution and an aqueous solution of glucose.

The dose of compound (I) of the present invention or its pharmaceutically acceptable salts varies depending on the method of administration, age, weight, medical condition/severity of the patient's condition. However, it can typically be in the range of about 0.001 to 1000 mg/kg/day, preferably in the range of about 0.01 to 100 mg/kg/day.

Compounds of the present invention have inhibitory activity against SETR and detect actions increase HDL cholesterol and reduce LDL cholesterol. Thus, they are useful in the prevention or treatment the AI of the subject (in particular, mammal, including humans)suffering from arteriosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, cerebral infarction, diabetes, vascular complications of diabetes, thrombotic diseases, obesity, endotoxemia or similar

In addition, the compounds of the present invention can be used in combination with other drugs used to treat such diseases. For example, the compound of the present invention can be used in combination with an inhibitor of cholesterol synthesis, such as an inhibitor of HMG-CoA reductase inhibitor, an inhibitor of cholesterol absorption, such as anion-exchange resin, fibrin, lowering triglycerides agent such as Niacin, or other lowering cholesterol agent such as an inhibitor of ACAT.

Compounds of the present invention have superior bioavailability and is useful as an inhibitor SER. Above all, preferred are compounds having a carboxyl group in the terminal position of the respective batch is of Italy R 1-R11especially compounds having a carboxyl group in the terminal position R1and/or R5or R1and/or R11.

The compound (I) of the present invention can be obtained in the following ways :

Method 1

The compound (I) of the present invention can be obtained by condensation of compounds of formula (II):

where the symbols are as defined above, with a compound of formula (III):

R10-R4-Z1(III)

where Z1means tsepliaeva group, and other symbols have the above specified values.

The condensation can be carried out in the presence of a base in a suitable solvent.

Tsepliaeva group includes a halogen atom including chlorine atom, bromine atom, iodine atom, and substituted sulfonyloxy, including methysulfonylmethane, toluensulfonate and triftormetilfullerenov.

Conventional base can be used as a base, and, for example, can preferably be used a hydride of an alkali metal including sodium hydride, potassium hydride; an alkali metal hydroxide including sodium hydroxide, potassium hydroxide; alkali earth metal hydroxide, including barium hydroxide; alkali metal alkoxide including sodium methoxide, ethoxide sodium, atoxic potassium tert-butok the ID of potassium; the alkaline carbonate metalla, including sodium carbonate, potassium carbonate, cesium carbonate; bicarbonate of an alkali metal including sodium bicarbonate, potassium bicarbonate; amines including triethylamine, diisopropylethylamine, methylpiperidin, dimethylaniline, 1,8-diazabicyclo[5.4.0]undecene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]nonan; pyridine, including pyridine, dimethylaminopyridine etc.

Any solvent which does not disturb the reaction can be preferably used, and such a solvent includes, for example, hydrocarbons including pentane, hexane; aromatic hydrocarbons, including benzene, toluene, nitrobenzene; halogenated hydrocarbons including dichloromethane, chloroform; ethers, including diethyl ether, tetrahydrofuran; amides including dimethylformamide, N-organic, 1,3-dimethylimidazolidin-2-he; sulfoxidov, including dimethyl sulfoxide; alcohols, including methanol, ethanol, methyl ethyl ketone; NITRILES including acetonitrile; water, or a mixed of them solvent.

The reaction is carried out at a temperature from low to high, preferably from -78°C to 200°C, more preferably from -30°C to 100°C.

Method 2

Among the compounds of formula (I-A) a compound of the formula (I-b):

where the symbols are as defined above values can be obtained

(a) Ziani is of the compounds of formula (II-A):

where the symbols are as defined above values, obtaining the compounds of formula (II-B):

where the symbols are as defined above values

(b) reaction of the compound (II-B) with hydroxylamine or its salt to obtain the compounds of formula (II-C):

where the symbols are as defined above values

(C) alkanolamines of compound (II-C) to obtain the compounds of formula (II-D):

where the symbols are as defined above values, and then

(d) cyclization of the compound (II-D) base.

Cyanide in method (a) can be carried out by reaction of the halogenated CYANOGEN in the presence of a base in a suitable solvent.

As halogenated CYANOGEN is preferable cyanogenmod.

As can be preferably used a common basis, and preferably can be used carbonate of an alkali metal including sodium bicarbonate.

Can be used any solvent which does not disturb the reaction, and preferably can be used a solvent, referenced in method 1.

The reaction with hydroxylamine in the method (b) can be carried out in the presence of a base in a suitable solvent.

As the warping can be used preferably tertiary alkylamines followed, including triethylamine, diisopropylethylamine etc.

Can be used any solvent which does not interfere with the specified reaction, and preferably can be used a solvent, referenced in method 1.

Alkanolamine in method (C) can be carried out by alkanolamines in the presence of a base in a suitable solvent.

As can be used a normal basis, and preferably can be used amines including triethylamine or diisopropylethylamine, or pyridine, including pyridine, 4-dimethylaminopyridine.

Can be used any solvent which does not interfere with the specified reaction, and preferably can be used a solvent, referenced in method 1.

In cyclization in method (d) as a base can be used a normal basis, and preferably can be used amines including triethylamine or diisopropylethylamine; pyridine, including pyridine, 4-dimethylaminopyridine; a carbonate of an alkali metal, including potassium carbonate; or an alkoxide of an alkali metal including sodium methoxide.

Can be used any solvent which does not interfere with the specified reaction, and preferably can be used a solvent, referenced in method 1.

Additionally, the cyclization after Alka is milirovanie can also be performed in situ.

The reaction is carried out under conditions of from cooling to heating, preferably from -50°C to 100°C, more preferably from 0°C. to 50°C.

Method 3

Among the compounds of formula (I-A) a compound of the formula (I-C):

where the symbols are as defined above values can be obtained by reaction of compounds of formula (II-B):

where the symbols are as defined above, with sodium azide.

The above reaction is carried out in the presence of ammonium chloride in a suitable solvent.

Can be used any solvent which does not interfere with the specified reaction, and preferably can be used a solvent, referenced in method 1.

The reaction is carried out at a temperature from low to high, preferably from -50°C to 150°C, more preferably from 20°C. to 100°C.

In addition, the substituent(s) of the compound (I) of the present invention may(may) be transformed(s) other(s) various(e) the Deputy(s) in the amount of the compound (I) in accordance with the following methods as desired.

In each of the following method as a base can be used a normal basis, and, if no other instructions, may preferably be used a solvent, referenced in method 1.

In addition, in each of the following ways as acid can be used acid, and, if no other instructions, may preferably be used a mineral acid such as hydrochloric acid, nitric acid, sulfuric acid, or organic acid represented sulfonic acids (for example, methanesulfonic acid, p-toluensulfonate acid, triftormetilfullerenov acid)or carboxylic acids (e.g. acetic acid, triperoxonane acid).

Further, each following method may be used any solvent which does not prevent specified reactions, and as such a solvent may preferably be used a solvent, referenced in method 1.

Tsepliaeva group includes a halogen atom such as chlorine atom, bromine atom, iodine atom, and substituted sulfonyloxy, such as methanesulfonamido, triftormetilfullerenov and toluensulfonate.

In addition, in each subsequent method “saturated or unsaturated monocyclic or bicyclic heterocyclic group having 1-4 heteroatoms independently selected from oxygen atom, sulfur atom and a nitrogen atom”, in R5called the “heterocyclic group”.

(1) Among the compounds (I-A), a compound in which the ring And means tetrazolyl group, and R11means optional samisen the Yu alkyl group, can be obtained by alkylation of compounds in which the ring And means tetrazolyl group, and R11means a hydrogen atom.

Alkylation of the compounds can be carried out by reaction with the compound of the formula:

R11A-Z2

where R11Ameans optionally substituted alkyl group, and Z2means tsepliaeva group, in a suitable solvent in the presence or in the absence of a base or by reaction with the compound of the formula:

R11A-HE

where the symbols have the above meanings, in a suitable solvent in the presence of a phosphine and an azodicarboxylic ester.

This reaction proceeds more preferably, when add a catalytic amount of an iodide of an alkali metal (e.g. potassium iodide and the like).

As phosphines, and azodicarboxylic esters that are commonly used in reactions of Mitsunobu, can be preferably used. Phosphines include, for example, triphenylphosphine, tributylphosphine etc., and azodicarboxylic esters include diethylazodicarboxylate, diisopropylethylamine etc.

(2) Among the compounds (I-A), a compound in which the ring a represents 2-oxopiperidine group, and R11means optionally substituted alkyl group, can be obtained by alkylation of compounds where ring a represents 2-hydroxyp remedially group, and R 11means a hydrogen atom, with a compound of the formula:

R11A-Z2

where the symbols have the above specified values.

The above reaction can also be conducted in the same manner as (1).

(3) Connection, where R5means heterocyclic group substituted by an optionally substituted amino group or a group of the formula:

where the symbols are as defined above values can be obtained by the reaction of a combination of compounds, where R5means heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, with a corresponding amine or a compound of the formula:

where the symbols have the above specified values.

The specified reaction mix can be carried out in the presence of palladium catalyst and in the presence or in the absence of a base in a suitable solvent.

As the palladium catalyst may preferably be used a conventional palladium catalyst, including

the palladium acetate, tetrakis(triphenylphosphine)palladium

Tris(dibenzylideneacetone)dipalladium,

dichlorobis(triphenylphosphine)palladium

dichlorobis(tri-o-tolylphosphino)palladium or

acetate bis(triphenylphosphine)palladium, etc.

As the base can be used g is droxia alkali metal, including sodium hydroxide, potassium hydroxide; alkali earth metal hydroxide, including barium hydroxide; alkali metal alkoxide including sodium methoxide, ethoxide sodium, atoxic potassium tert-piperonyl potassium; alkaline carbonate metalla, including sodium carbonate, potassium carbonate, cesium carbonate; bicarbonate of an alkali metal including sodium bicarbonate, potassium bicarbonate; a phosphate of an alkali metal, including potassium phosphate; amines including triethylamine, diisopropylethylamine, methylpiperidin, dicyclohexylmethane; pyridine, including pyridine, 4-dimethylaminopyridine, etc.

In addition, this reaction can be added phosphines. As phosphines can be preferably used triphenylphosphine, tributylphosphine,

tetrafluoroborate three-tert-butylphosphine,

1,3-bis(diphenylphosphino)propane,

2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,

1,1'-bis(diphenylphosphino)ferrocene,

2-(di-tert-butylphosphino)biphenyl,

2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl,

2-(dicyclohexylphosphino)biphenyl, etc.

(4) the Compound, where R5means heterocyclic group substituted by an optionally substituted amino group or a group of the formula

where the symbols are as defined above values can also be obtained by reaction of the compound where R5means courtesans is a cyclic group, substituted by a halogen atom or optionally substituted alkylsulfonyl group with a corresponding amine or a compound of the formula:

where the symbols have the above specified values.

The above reaction can be optional addition of copper catalyst in the presence or in the absence of a base in a suitable solvent.

As the copper catalyst can be preferably used copper iodide, copper bromide, copper acetate, triftorbyenzola copper, etc.

Preferably can be used the same basis, to which reference is made in (3).

In addition, the reaction proceeds more preferably adding N,N'-dimethylethylenediamine, 1,10-phenanthroline, ethylene glycol, phenylphenol or similar

(5) the Compound, where R5means heterocyclic group substituted by an optionally substituted amino group, can be obtained by linking compounds, where R5means heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, with the compound of the formula:

(R20)3Sn-NR21R22

where R20means alkyl group, and NR21R22means optionally substituted by an amino group.

The reaction mix can be performed is in the presence of a palladium catalyst and in the presence or in the absence of a base in a suitable solvent.

Preferably can be used such as a palladium catalyst, a base and phosphines, referred to in (3).

(6) Connection, where R5means heterocyclic group, substituted by cyano, can be obtained by cyanide compounds, where R5means heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates.

Cyanide can be carried out by reaction of the parent compound with cyanide metal, including sodium cyanide, potassium cyanide or cyanide zinc, in the presence of palladium catalyst in a suitable solvent.

Preferably can be used the same palladium catalyst as described in (3).

(7) the Compound, where R5means heterocyclic group substituted by an optionally substituted alkoxycarbonyl group, can be obtained by reaction of the compound where R5means heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, with a corresponding alkilany alcohol in an atmosphere of carbon monoxide using a palladium catalyst in the presence of a base in a suitable solvent.

Preferably can be used such as palladium catalyst and a base, as described in (3).

In addition, azanuy the reaction may preferably be carried out with addition of ligand, and as a ligand can be preferably used phosphines, referred to in (3).

(8) the Compound, where R5means heterocyclic group substituted by an optionally substituted alkenylphenol group, can be obtained by reaction of the compound where R5means heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, with the corresponding alkene.

The specified reaction mix can be carried out in the presence of palladium catalyst and in the presence or in the absence of a base in a suitable solvent.

Preferably can be used the same basis, to which reference is made in (3), and can be also used silver carbonate.

In addition, the above reaction can preferably be carried out with addition of ligand, and the ligand can be preferably used phosphines, referred to in (3).

(9) the Compound, where R5means heterocyclic group substituted by an optionally substituted alkoxygroup, can be obtained by alkoxysilane compounds, where R5means heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates.

Alkoxysilane can be optional by adding the edno catalyst for the reaction of the starting compound with an appropriate alcohol in a suitable solvent or in undiluted form in the presence of a base.

Preferably can be used the same basis as described above in (3), in particular, preferably can be used cesium carbonate.

In addition, this reaction proceeds more preferably adding 1,10-phenanthroline, 2-aminopyridine, etc.

(10) the Compound, where R5means heterocyclic group substituted by an optionally substituted alkoxygroup, can be obtained by reaction of the compound where R5means heterocyclic group, substituted alkylsulfonyl group, with the appropriate alkali metal alkoxide in a suitable solvent. The corresponding alkali metal alkoxide can be obtained by treating the corresponding Olkiluoto alcohol alkali metal hydride or alkali metal.

(11) the Compound wherein R5means heterocyclic group substituted by an optionally substituted alkylthiol, can be obtained by reaction of the compound where R5means heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, with the corresponding alkylthio.

The above reaction can be conducted in the same manner as described previously in (9), and it is facilitated between 1,10-phenanthroline or ethylene glycol.

(12) the Compound wherein R5means heterocyclic group, semese the ing optionally substituted heterocyclic group, can be obtained by the reaction of a combination of compounds, where R5means heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, with the appropriate heterocyclic Bronevoy acid or a corresponding heterocyclic ether Bronevoy acid.

This combination can be carried out in the presence of palladium catalyst and in the presence or in the absence of a base in a suitable solvent.

The above reaction can also be conducted in the same manner as (3).

(13) the Compound, where R5means heterocyclic group substituted by optionally substituted heterocyclic group, can be obtained by the reaction of a combination of compounds, where R5means heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, with the appropriate heterocyclic compound alkalolu.

The above reaction can also be conducted in the same manner as (5).

(14) the Compound, where R5means heterocyclic group, substituted alkoxycarbonylmethyl group, can be obtained by the reaction of a combination of compounds, where R5means heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, salt of the alkali metal is alkoxycarbonylmethyl acid.

Salt of an alkali metal alkoxycarbonylmethyl acid can be obtained according to the method described, for example, in Baskin et al., Tetrahedron Lett., 43, 8479 (2002).

In addition, the above reaction can be carried out in the presence of a copper catalyst in a suitable solvent according to the Method described in the literature reference.

Can be used the same copper catalyst as described in (4), and, in particular, preferably can be used iodide of copper.

(15) the Compound having a group of the formula:

where the symbols are as defined above values, as a substituent on R5can be obtained by condensation of compounds having the hydroxy-group as a substituent on R5with a compound of the formula:

where X11means OF, SO, SO2or NRp(Rpmeans a protective group), and q is an integer of 1-4, and, if necessary, removing the protective group for amino group.

As a protective group may be used a conventional protective group, including benzyloxycarbonyloxy group, tert-butoxycarbonyl group, etc.

The above reaction can be carried out in a suitable solvent in the presence of phosphines and esters of azodicarboxylic acid. The above reaction can also be conducted in the same manner as (1)

The removal of the protective group can be performed in the usual way, including catalytic reduction, treatment with an acid, and the like, depending on the type of the protective group.

(16) a Compound that aminoalkyl group as a substituent on R5can be obtained by catalytic reduction of compound having a cyano or cyanoaniline group as a substituent on R5.

Catalytic reduction can be carried out with the use of the catalyst in hydrogen atmosphere in a suitable solvent in accordance with generally accepted way. The catalyst includes palladium catalyst such as palladium on coal, Nickel catalyst such as Raney Nickel, platinum catalyst such as platinum on charcoal, and so on

(17) the Compound having optionally substituted mono - or dialkylaminoalkyl group as a substituent on R5can be obtained by the reaction of compounds having aminoalkyl group as a substituent on R5with the appropriate halogenated mono - or dialkylamino.

The above reaction can be carried out in a suitable solvent in the presence of a base.

(18) the Compound having optionally substituted monoalkanolamines group as a substituent on R5may be recip is but the reaction of the compound, having aminoalkyl group as a substituent on R5with the appropriate alkylsulfonates in a suitable solvent.

(19) the Compound having a group of the formula:

where R12means alkyl group, and other symbols are as defined above values, as a substituent on R5can be obtained by reaction of the compound having a group of the formula:

where the symbols are as defined above values, as a substituent on R5with the appropriate alkylsulfonates (R12NCO). The above reaction can also be conducted in the same manner as (18).

(20) the Compound having optionally substituted mono - or dialkylanilines as a substituent on R5can be obtained by condensation of compounds having an amino group as a substituent on R5with optionally substituted mono - or dialkylamino using Carboniferous agent in a suitable solvent in the presence or in the absence of base.

Can be used generally accepted carbonyloxy agent, such as carbonyldiimidazole, phosgene, triphosgene etc.

(21) a Compound that morpholinylcarbonyl as a substituent on R5can be obtained by condensation of compounds having the amino group in which the quality of substituents on R 5with morpholine using Carboniferous agent in a suitable solvent. The above reaction can also be conducted in the same manner as (20).

(22) the Compound having a group of the formula:

where X12means O or NH, as a substituent at R5can be obtained by treating compound having a group of the formula:

N-X12-SN2-CONH-

where the symbols are as defined above values, as a substituent on R5with carbonyliron agent in a suitable solvent.

The above reaction can also be conducted in the same manner as (20).

(23) a Compound having optionally substituted karbamoilnuyu group as a substituent on R5can be obtained by condensation of compounds having carboxyl group as a substituent on R5the desired amine.

The condensation can be performed using a condensing agent in a suitable solvent. Preferably can be used conventional condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole etc.

In addition, the condensation can be performed preferably with the addition of the activating agent, including 1-hydroxybenzotriazole, 1-hydroxysuccinimide etc.

(24) Soy is inania having a group of the formula:

where the symbols are as defined above values, as a substituent on R5can be obtained by condensation of compounds having carboxyl group as a substituent on R5with a compound of the formula:

where the symbols are defined above value.

The above reaction can also be conducted in the same manner as (23).

(25) a Compound containing tetrazolyl group as a substituent on R5can be obtained by the reaction of compounds containing the cyano as a substituent at R5with an alkali metal azide in the presence of acid in a suitable solvent.

Azide of an alkali metal includes sodium azide, lithium azide, etc.

As acid is preferred ammonium salt of halogenated hydrogen, including ammonium chloride.

(26) a Compound containing tetrazolyl group as a substituent on R5can be obtained by alkylation of compounds having tetrazolyl group as a substituent on R5.

The alkylation can be conducted in the same manner as (1).

(27) a Compound that optionally is substituted by an amino group or a group of the formula:

where the symbols are as defined above values, as the Deputy is and R 5can be obtained by reaction of the compound having a halogen atom or optionally substituted alkylsulfonate as a substituent on R5, with a corresponding amine or a compound of the formula:

where the symbols are defined above value.

The above reaction can be preferably carried out in the presence or absence of a base in a suitable solvent.

(28) a Compound that is not necessarily replaced by alkylamino or a group of the formula:

where R13means alkyl group, optionally substituted hydroxy-group, alkoxycarbonyl group, morpholinyl group or phenyl group, and n is above a certain value, as a substituent at R5can be obtained by reaction of the compound having an amino group or a group of the formula:

where the symbols are defined above is, as a substituent on R5with the appropriate alkylhalogenide or appropriate alkilany ether sulfonic acid.

Preferably can be used alkilany ether sulfonic acid, including ester methanesulfonic acid, ether toluensulfonate acid, ether triftormetilfullerenov acid, etc.

The reaction can be carried out in p is outstay or in the absence of a base in a suitable solvent.

(29) the Compound having a group of the formula:

where X1means O or NH, and other symbols are as defined above values, as a substituent on R5can be obtained by shorting ring compounds having a group of the formula:

Z3-(CH2)n-X13-CH2-CONH-

where Z3means tsepliaeva group and other symbols are as defined above values, as a substituent on R5.

The reaction is preferably carried out in the presence or absence of a base in a suitable solvent.

(30) the Compound containing a carboxyl group as a substituent on R5can be obtained by hydrolysis of compounds having alkoxycarbonyl group as a substituent on R5.

The hydrolysis can be carried out by treatment of the parent compound base or acid in a suitable solvent in a conventional manner. As can be preferably used an alkali metal hydroxide.

(31) the Compound containing a carboxyl group as a substituent on R5can be obtained by hydrolysis of compounds containing the cyano as a substituent at R5.

The hydrolysis can be carried out by treatment of the parent compound acid in a suitable of rest retele.

(32) a Compound containing karbamoilnuyu group as a substituent on R5can be obtained by hydrolysis of compounds containing the cyano as a substituent at R5.

The hydrolysis can be carried out by treatment of the parent compound acid in a suitable solvent.

(33) a Compound that carboxialkilnuyu group as a substituent on R5can also be obtained by catalytic reduction of compound having carboxyaniline group, benzyloxycarbonylamino group or benzyloxycarbonylamino as a substituent on R5.

Catalytic reduction can be performed in the same way as (16).

(34) the Compound containing a hydroxy-group as a substituent on R5can be obtained by hydrolysis of compounds having alkanoyloxy, as a substituent at R5.

The hydrolysis can be conducted in the same manner as (30).

(35) the Compound containing Surfin (SO) or the sulfoxide (SO2in the Deputy for R5can be obtained by oxidation of compounds having S Deputy in R5(for example, compounds having thiomorpholine group or allylthiourea as a substituent on R5).

Specified the oxidation can be carried out by treatment of the parent compound oxidizing agent in a suitable races is varicela.

As the oxidizing agent can be preferably used peroxides such as hydrogen peroxide, m-chlorbenzene acid, acetylhydrolase etc.

(36) a Compound containing N-oxide in the Deputy for R5can be obtained by oxidation of compounds having N Deputy for R5(for example, compounds having pyridyloxy group as a substituent on R5).

Specified oxidation can be performed in the same way as (35).

(37) a Compound having a 1,2-dihydroxyethylene group as a substituent on R5can be obtained by treating compound having alkyl group, a substituted mono - or dialkylanilines group as a substituent on

R5that acid in a suitable solvent.

Strongly acidic resin can be preferably used as the acid along with the above-described acids.

(38) the Compound having an alkyl group substituted by a hydroxy-group, or optionally substituted alkoxygroup as substituents on R5can be obtained by the reaction of compounds having oxiranylmethyl group as a substituent on R5with alkali metal salt of the corresponding alcohol in a suitable solvent.

Salt of an alkali metal alcohol includes a lithium salt, sodium salt, potassium salt, etc.

(39) the Compound having an alkyl group substituted by a hydroxy-group or amino group, or alkyl group substituted by a hydroxy-group, and optionally substituted mono - or dialkylamino, as a substituent at R5can be obtained by the reaction of compounds having auxiliarily group as a substituent on R5with ammonia or the corresponding mono - or dialkylamino in a suitable solvent.

(40) a Compound that hydroxycarbonylmethyl group as a substituent on R5can be obtained by reaction of the compound having a cyano as a substituent at R5with hydroxylamine or its salt in a suitable solvent.

The above reaction can be carried out in the presence of a base in a suitable solvent.

(41) a Compound that oxodegradable group as a substituent on R5can be obtained by the reaction of compounds having hydroxycarbonylmethyl group as a substituent on R5with carbonyliron agent in a suitable solvent in the presence or in the absence of base.

Can be used the same carbonyloxy agent as described in (20).

(42) a Compound that alphagroup as a substituent on R5can be obtained by hydrolysis of compounds having alkoxy bonillachacin group as a substituent on R 5.

The hydrolysis can be conducted in the same manner as (30).

(43) a Compound that sulfamoyl group as a substituent on R5can be obtained by condensation of compounds having alphagroup as a substituent on R5the desired amine.

The condensation can be carried out by treating compound having alphagroup as a substituent on R5, halogenation agent in a suitable solvent, followed by reaction of the compounds with the desired amine in the presence or in the absence of base.

Can be used conventional halogenation agent, including thionylchloride, oxychlorine phosphorus or the like

(44) the Compound having a hydroxyalkyl group as a substituent on R5can be obtained by reduction of compounds having carboxialkilnuyu group as a substituent on R5or conversion of carboxyl groups in the anhydride or ester of carboxylic acid, and recovering the obtained compound.

The transformation of the carboxylic acid anhydride may be carried out by reaction of the starting compound with a halogenated alkylphosphates in a suitable solvent in the presence of a base.

Turning in the air can be made by reaction of the starting compound with an alcohol in the presence of a condensing agent in the approach is the total solvent. This method can be performed in the same way as (23), except that instead of the amine used alcohol.

Recovery can be carried out by treatment of the compounds obtained regenerating agent in a suitable solvent.

As the reducing agent can be used preferably borhydride (sodium borohydride, DIBORANE, complex, borane-dimethyl sulfide and the like), aluminum hydrides (sociallyengaged, diisobutylaluminium etc).

(45) the Compound having a hydroxyalkyl group as a substituent on R5can be obtained by reduction of compounds having alkoxycarbonylmethyl group as a substituent on R5.

Recovery can be performed in the same way as (44).

(46) the Compound wherein R10is an aromatic group substituted by cyano, optionally having one to three heteroatoms independently selected from oxygen atom, sulfur atom and nitrogen atom (hereinafter referred to as “aromatic group”), can be obtained by cyanide compounds, where R10is an aromatic group substituted by a halogen atom.

Cyanide can also be conducted in the same manner as (6).

(47) Connection, where R1is a hydrogen atom, can be obtained by treatment with an acid or restoring the link is, where R1is tert-butoxycarbonyl group or benzyloxycarbonyl group.

The acid treatment can be conducted in the same manner as (37), and recovery can be performed in the same way as (33).

(48) the Compound wherein R1optionally substituted alkoxycarbonyl group or optionally substituted carbamoyl group, can be obtained by reaction of the compound where R1is a hydrogen atom, with Carboniferous agent together with the desired alcohol or desired amine in a suitable solvent.

The reaction can be conducted in the same manner as (20).

(49) the Compound having iodine atom as a substituent at R5can be obtained by moderowaniem connection with the bromine atom as a substituent at R5.

Iodination can be carried out by reaction of the corresponding alkali metal iodide in a suitable solvent with the addition of a copper catalyst, if desired.

Can be used the same copper catalyst as described in (4).

In addition, this reaction proceeds more preferably adding N,N'-dimethylethylenediamine, 1,10-phenanthroline, ethylene glycol or the like

(50) the Compound having an amino group as a substituent on R5can be obtained by reaction of the compound having carboxyl group as the substituent at R 5in terms of the rearrangement reaction of kurzius.

The rearrangement reaction of kurzius can be performed using conventional aidarous agent (for example, diphenylphosphinite) in a suitable solvent in the presence of a base.

The reaction may also be carried out by adding an alcohol to obtain compounds having optionally replaced alkoxycarbonylmethyl as a substituent on R5with the subsequent removal alkoxycarbonyl group.

Remove alkoxycarbonyl group can be performed in a conventional manner, such as treatment with an acid or recovery, depending on the type you want to remove alkoxycarbonyl group. The acid treatment can be conducted in the same manner as (37), and recovery can be performed in the same way as (33).

(51) the Compound having a hydroxy-group as a substituent on R5can be obtained by catalytic reduction of compound having benzyloxy as a substituent on R5. Recovery can be performed in the same way as (33).

(52) a Compound that oxoprop as a substituent on R5can be obtained by oxidation of compounds having the hydroxy-group as a substituent on R5.

Oxylene can be performed using an oxidizing agent in the approach is General solvent.

As the oxidizing agent can be used conventional oxidant such as complex chromate-pyridine, chlorproma pyridinium, pyridinium dichromate, reagent dessa-Martin (1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one), dimethyl sulfoxide, etc.

(53) a Compound containing optionally substituted by alkoxygroup as a substituent on R5can be obtained by alkylation of compounds containing a hydroxy-group as a substituent on R5.

The alkylation can be performed using the appropriate connection in the same way as (1).

(54) Connection, with optional substituted alkanolamines as a substituent on R5can be obtained by condensation of compounds having an amino group as a substituent on R5with the appropriate carboxylic acid or its reactive derivative.

Condensation with the corresponding carboxylic acid may preferably be carried out in a suitable solvent in the presence of a condensing agent. The above reaction can also be conducted in the same manner as (23).

In addition, condensation with a reactive derivative of the corresponding carboxylic acid can be carried out in a suitable solvent or neat in the presence or in the absence of base.

Reactions osobne derived includes gelegenheid acid, the carboxylic acid anhydride, activated ester, activated amide, etc.

(55) the Compound having a group of the formula:

where R14means alkanoyloxy group, optionally substituted hydroxy-group or alkoxygroup and n is above a certain value, as a substituent at R5can be obtained by condensation of compounds having a group of the formula:

where the symbols are as defined above values, as a substituent on R5with the appropriate carboxylic acid or its reactive derivative.

The reaction can be conducted in the same manner as (54).

(56) a Compound that maleimido group as a substituent on R5can be obtained by reaction of the compound having an amino group as a substituent on R5with maleic anhydride. The reaction can be carried out in a suitable solvent.

(57) a Compound having the alkyl group, substituted peredelnoj group and a hydroxy-group, as a substituent at R5can be obtained by reaction of the compound having as a substituent at R5alkyl group, a substituted peredelnoj group, the nitrogen atom of which is oxidized triperoxonane anhydride. The above reaction is carried out in a suitable solvent.

(58) Connected to the tion, having a halogen atom as a substituent at R5can be obtained by treating compound having a hydroxy-group as a substituent on R5, halogenation agent.

As the halogenation agent can be preferably used conventional halogenation agent, including thionyl chloride, phosphorus oxychloride, and tetravalent carbon (e.g. carbon tetrachloride, tetrabromide carbon and the like) and phosphines (e.g. triphenylphosphine, trailerforum, triethylphosphine etc).

(59) a Compound that cyanoaniline group as a substituent on R5can be obtained by reduction of compounds having cyanoacetylene group as a substituent on R5.

The specified recovery can be carried out by treatment of the parent compound regenerating agent or catalytic restore the original agent in a suitable solvent.

Can be used any reducing agent provided that it restores only the double bond without affecting the cyano. For example, preferably can be used bis(2-methoxyethoxy)aluminiumhydride sodium in the presence of copper bromide.

Catalytic reduction can be performed in the same way as (33).

(60) a Compound having a hydroxyalkyl group at the ka is este substituent on R 5can be obtained by reduction of compounds having formyl group as a substituent on R5.

The specified recovery can be carried out by treatment of the parent compound regenerating agent in a suitable solvent.

The reaction can be conducted in the same manner as in the recovery method (45).

(61) Connection, where R6is a hydroxy-group, can be obtained by demethylation of the compound where R6is a methoxy group.

Demethylation can be carried out by treatment of the parent compound demetrious agent in a suitable solvent.

As demetrious agent can be used a common agent, including trimethylsilylmethyl, hydrogen bromide/acetic acid, tribromide boron, sulfuric acid, etc.

(62) Connection, where R6optionally substituted by alkoxygroup, can be obtained by alkylation of compounds, where R6is a hydroxy-group.

The alkylation can be conducted in the same manner as (1).

(63) Connection, where R6optionally substituted by alkylsulfonamides, can be obtained by alkylsulfonamides compounds, where R6is a hydroxy-group.

Alkylsulfonamides can be carried out by reaction of the corresponding alkylhalogenide or the corresponding anhydride alkylsulfonyl acid in a suitable solvent in the presence or in the absence of base.

(64) the Compound wherein R6is cyano, can be obtained by cyanide compounds, where R6optionally substituted by alkylsulfonamides.

(65) the Compound wherein R6is aminoalkyl group, can be obtained by reduction of compounds, where R6is cyano.

Recovery can be performed in the same way as (16).

(66) the Compound wherein R6is an alkyl group, can be obtained by alkylation of compounds, where R6optionally substituted by alkylsulfonamides.

The alkylation can be carried out by reaction alkylamine in the presence of a palladium catalyst, of a silver catalyst and a copper catalyst in a suitable solvent.

Preferably can be used tetrakis(triphenylphosphine)palladium as palladium catalyst, silver carbonate as a silver catalyst, copper chloride (I) as a copper catalyst.

(67) the Compound having imidazolylalkyl group or oxazolidinyl group as a substituent on R5can be obtained (i) by reaction of the compound that contains the cyano as a substituent at R5with the desired alcohol in the presence of acid in a suitable solvent or neat with obtaining compounds containing alkoxy is carbamimidoyl group as a substituent on R 5and (ii) the reaction of compounds containing carbamimidoyl group as a substituent on R5with 2 aminoethanol or Ethylenediamine in a suitable solvent or neat.

(68) the Compound having a carboxyl group as a substituent on R1can be obtained (i) by oxidation of compounds containing hydroxyalkyl group as a substituent on R1in the same way, as (52), with compounds containing ecogroup as a substituent on R1and (ii) the oxidation of compounds containing oxoprop as a substituent on R1.

Oxidation for the second stage can be performed using an oxidizing agent in a suitable solvent. As the oxidizing agent preferably may be used sodium chlorite, silver oxide (I), periodate sodium, etc.

(69) a Compound having a carboxyl group as a substituent on R1can be directly obtained by oxidation of compounds containing hydroxyalkyl group as a substituent on R1.

The oxidation may be used as oxidant Jones reagent, potassium permanganate, etc.

(70) Compound, where R1is a hydrogen atom, can be obtained by treating compound, where R1is ethoxycarbonyl group, siling what legendary or base. Trimethylsilylmethyl can be preferably used as silicalite. As the base preferably may be used sodium hydroxide.

(71) Among compounds (I-A), a compound where R11is a hydroxyl group, can be obtained (i) by reaction of the compound where R11is a halogen atom, with DIBORANE or borane with obtaining compounds, where R11is esters Bronevoy acid, and (ii) reaction of the compound where R11is esters Bronevoy acid, peroxides.

As the peroxides can be preferably used hydroxide solution is hydrogen, m-chloroperbenzoic acid or OXONE™ (manufactured DuPont).

Each method of obtaining the compounds of formula (I)described above, when required to protect the functional group contained in any connection, the specified protection you can do the conventional way, when you need it. General description relating to protective groups and their use, are given Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.

When the amino group is protected benzyloxycarbonyloxy group specified protective group can be removed by catalytic regeneration in hydrogen atmosphere in a suitable solvent.

When the hydroxy-group-protected benzyl group specified protective group mo is et to be removed by catalytic regeneration, as explained above.

When the amino group is protected tert-butoxycarbonyl group specified protective group can be removed by treatment with an acid (e.g. hydrochloric acid, triperoxonane acid, toluensulfonate acid and the like) in a suitable solvent.

When the hydroxy-group is protected tetrahydropyranyloxy group specified protective group can be removed by treatment with acid as described above.

Reactions (1)-(71) for the conversion of R1, R5, R6or R11can be similarly applied for the conversion of another Deputy of this compound (I)when it is necessary.

The original compound (II) is a novel compound and can be obtained by condensation of compounds of formula (V):

where the symbols are as defined above, with a compound of formula (IV):

R5-Z4(IV)

where Z4means tsepliaeva group, and R5is above a certain value.

Tsepliaeva group includes a halogen atom including chlorine atom, bromine atom, iodine atom, and substituted sulfonyloxy, including methysulfonylmethane, triftormetilfullerenov and toluensulfonate.

The above reaction can be carried out in a suitable solvent (such as 1,4-dioxane, dimethylformamide, 1,2-dimetil is iasolution and the like) in the presence or in the absence of a base (for example, diisopropylethylamine and the like) at a temperature of from room temperature to the reaction when heated.

The above reaction can also be carried out by adding a palladium catalyst (such as Tris(dibenzylideneacetone)diplodia), and phosphine (e.g. triphenylphosphine, tributylphosphine or 2-(di-tert-butylphosphino)biphenyl] at room temperature in the presence of a base (for example, tert-butoxide sodium), if desired.

The compound (V) is a novel compound and can be obtained in accordance with the following scheme:

where R15means a protective group for the amino group and the other symbols have the above specified values.

Conventional protective group, including benzyloxycarbonyloxy group, can be used as a protective group for amino group. In addition, optically active compound (V) can be obtained by protecting the amino group of the optically active protective group for amino group (for example, optically active α-protected benzyloxycarbonyloxy group having a chiral center in the position of the benzyl, such as α-methylbenzyloxycarbonyl group), separation of the diastereomers in the method of producing compound (VI) or compound (VII) and the removal of the protective group.

The compound of formula (IX) may be obtained is by eakley benzotriazole, the compounds of formula (XI) and the aldehyde of formula (X) in a suitable solvent (e.g. toluene) at room temperature.

The compound of formula (VII) can be obtained by reaction of compounds of formula (IX) with the compound of the formula (VIII) in the presence of an acid catalyst (for example, organic acids, including p-toluensulfonate acid, acetic acid, methanesulfonate acid, or a Lewis acid including a complex of boron TRIFLUORIDE-diethyl ether, titanium tetrachloride, aluminum chloride)in a suitable solvent (e.g. toluene, methylene chloride, tetrahydrofuran and the like) when heated or at room temperature (for example, 0°C.-150°C., preferably 25°C.-120°C).

The compound of formula (VI) can be obtained by alkanolamines, alkoxycarbonylmethyl, alkylation, etc. of compounds of formula (VII), if necessary.

The compound of formula (V) can be obtained by removing the protective group for the amino acids of the compounds of formula (VI). The removal of the protective group can be an accepted way, including treatment with an acid, the processing base, recovery, etc. depending on the type of protective group. When using benzyloxycarbonyloxy group or α-substituted benzyloxycarbonyl group they can be removed by catalytic regeneration in a suitable solvent (for example, ethanol is, methanol, tetrahydrofuran, acetic acid and the like) in an atmosphere of hydrogen. The removal of the protective group for the amino group of compounds of formula (VII) can be performed in the same manner as the removal of the protective group for the amino acids of the compounds of formula (VI).

When using optically active protective group, such as α-substituted benzyloxycarbonyl group as a protective group for amino group separation of the diastereomers can be conventional method such as recrystallization or column chromatography.

The compound of formula (VII) can also be obtained by reaction of compounds of formula (VIII) with the compound of the formula (XII):

The above reaction can also be conducted in the same manner as the reaction of the compound of formula (VIII) with the compound of the formula (IX).

Furthermore, respective substituents R1, R5, R7and R8can be converted into the desired substituents in accordance with any of the methods(1)-(71).

The compound of the formula (II-A) can be obtained by condensation of compounds of formula (V) with the compound of the formula (III):

R10-R4-Z1(III)

where the symbols have the above specified values.

The condensation can be conducted in the same manner as described in WO00/17165 or in method 1 above.

Many of the starting compounds and reagents to obtain to enter the mentioned compounds are either commercially available, or described in the literature or can be easily obtained by the method as described in the literature or used in organic synthesis.

As used in this description, "3,4-dihydro-2H-naphthiridine" means the same structure as "1,2,3,4-tetrahydronaphthalen".

Experiment

Inhibitory activity of the compounds of the present invention against SETR tested in this experiment.

Preparation of acceptor microemulsions

A solution of 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (3.5 mg), cholesterolaemia (3 mg) and triolein (0.7 mg) in chloroform were mixed, and the lipid was dried in air in an atmosphere of nitrogen gas to remove solvent. Then was added dioxane (0.25 ml) and the resulting mixture was stirred for dissolution. The obtained lipid solution (0.2 ml) was slowly injected with a Hamilton syringe under the surface of the buffer solution of Tris-saline-EDTA (TSE) [10 mm Tris/HCl (pH 7.4), 0,15M NaCl, 2 mm EDTA] (10 ml)with sonication in a bath with ice. After 1-hour treatment with ultrasound in a bath with ice, the solution was stored at 4°C.

Preparation of donor microemulsions

The solution of phosphatidylcholine (PC) eggs (0.33 ml) and BODIPY-CE (0,62 mg) were mixed in chloroform. After removal of the solvent by drying the lipid in the air in the atmosphere of nitrogen was added TSE-buffer solution (3 ml) and the floor is obtained, the solution was treated with ultrasound in a bath with ice. The resulting solution was filtered for sterilization through a 0.22 μm filter and stored at 4°C.

Inhibitory activity against SETR in vitro

The test solution was prepared using dimethyl sulfoxide as a solvent. The plasma of healthy volunteers was diluted to 0.64% TSE-buffer and the resulting solution plasma (187 μl) was added to the test solution (3 µl) only a solvent, followed by incubation at 37°C for 24 hours. After adding TSE buffer solution (10 μl)containing 5% donor microemulsion and 5% acceptor microemulsion, the resulting mixture was incubated at 37°C for 3 hours. Before and after incubation the fluorescence intensity was measured at a wavelength of excitation (Ex) 550 nm/wavelength emission (Em) 600 nm. Activity SETR was determined as the difference between measurements obtained before incubation and after incubation. The speed reducing this difference in the sample was determined as the rate of inhibiting the activity SER. IC50for each sample was calculated from the rate of inhibiting the activity SETR.

Results

EXAMPLES

The present invention is illustrated in more detail by examples, but should not be construed as limited by these examples.

In the examples of the compounds having the structure of formula:

indicate that their configuration is the configuration of (2R*,4S*). In addition, Me means methyl group.

Example 1

(1) a Solution of 5-amino-2-methoxypyridine (10 g) in toluene (20 ml) is added dropwise to a suspension of benzotriazole (9.6 g) in toluene (150 ml). Then add dropwise a solution of propionic aldehyde (6,35 ml) in toluene (20 ml) at 30°C or below and the mixture was stirred at room temperature overnight. The suspension is filtered and the obtained crystals are washed with ether to obtain (1-benzotriazol-1-ylpropyl)-(6-methoxypyridine-3-yl)amine (19.7 g). TPL: 109,3-110,3°C.

(2) (1-benzotriazol-1-ylpropyl)-(6-methoxypyridine-3-yl)amine (15 g) and benzyl ether, N-vinylcarbazole acid (9.4 g) was dissolved in toluene (200 ml), then add monohydrate p-toluensulfonate acid (100 mg) and the mixture was stirred at 80°C for 4 hours in a stream of nitrogen. After cooling to room temperature the reaction solution is added to a mixture of saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. The resulting solution was purified column chromatography (silica gel; hexane:ethyl acetate=8:1→4:1) to give the benzyl ether of (2R*,4S*)-(2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine-4-yl)ka is benovoy acid (14,31 g). MC (m/z): 342 [M+H]+.

(3) Benzyl ether of (2R*,4S*)-(2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine-4-yl)carbamino acid (5.1 g) and pyridine (18 ml) dissolved in methylene chloride (150 ml), then added dropwise to ethylchloride (14,3 ml) while cooling on ice and the mixture is stirred at the same temperature for 30 minutes. To the reaction solution was added an aqueous solution of citric acid. The organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→2:1) to give the ethyl ester of (2R*,4S*)-4-benzyloxycarbonylamino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5,58 g). MC (m/z): 414 [M+H]+.

(4) Ethyl ester of (2R*,4S*)-4-benzyloxycarbonylamino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5.5 g) and ammonium formate (2,09 g) dissolved in methanol (50 ml), add 10% palladium on coal (550 mg) in a stream of nitrogen and the resulting mixture was stirred at 40°C for 30 minutes. The catalyst was removed by filtration and then the filtrate is concentrated under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution and methylene chloride. The organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrate in on igenom pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=90:1→20:1) to give the ethyl ester of (2R*,4S*)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3.88 g) MS (m/z): 280 [M+H]+.

5) Ethyl ester of (2R*,4S*)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2 g) and 5-bromo-2-chloropyrimidine (of 3.46 g) was dissolved in N,N-dimethylformamide (20 ml) and the resulting mixture is heated to 150°C and stirred for 5 hours. After cooling to room temperature, to the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=19:1→7:3) to give the ethyl ester of (2R*,4S*)-4-(5-bromopyrimidine-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.08 g). MS (m/z): 436/438 (M+N+).

(6) Ethyl ester of (2R*,4S*)-4-(5-bromopyrimidine-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in N,N-dimethylformamide, and then to the solution was added sodium hydride (17 mg, 62.7 percent) at room temperature and the resulting mixture is stirred for 10 minutes. After adding 3,5-bis(trifluoromethyl)benzylbromide 158 mg) the mixture was stirred at room temperature for 10 minutes. To the reaction mixture are added water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=49:1→3:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (190 mg). MC (m/z): 622/664 [M+H]+.

Example 2

(1) (S)-1-phenethyl alcohol (16.1 g) and pyridine (10,7 ml) dissolved in chloroform (100 ml) and the resulting solution was added a solution (100 ml) p-nitrophenylphosphate (26,6 g) in chloroform. The reaction solution was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=85:15→70:30) to give p-nitrophenyl-(S)-1-phenylethylamine (35,6 g).

(2) Ethyl ester of (2R*,4S*)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (34.3 g), p-nitrophenyl-(S)-1-phenylethylamine (35,3 g) and triethylamine (17,1 ml) dissolved in acetonitrile (250 ml) and the resulting mixture is refluxed for 3 hours. The reaction solution was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The PR is anceschi layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:hexane:ethyl acetate=10:10:1) to give the ethyl ester of (2R*,4S*)-2-ethyl-6-methoxy-4-[(S)-1-phenylethanolamine]-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (44,0 g). MC (m/z): 428 [M+H]+.

(3) Ethyl ester of (2R*,4S*)-2-ethyl-6-methoxy-4-[(S)-1-phenylethanolamine]-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (44,0 g) is recrystallized from hexane (100 ml) to give the ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-[(S)-1-phenylethanolamine]-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (13,83 g). MC (m/z): 428 [M+H]+.

(4) 10% palladium on coal (2.0 g) are added to a solution of ethyl ester (2R,4S)-2-ethyl-6-methoxy-4-[(S)-1-phenylethanolamine]-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (8,49 g) in ethanol and stirred under reduced pressure for 4 hours. Palladium on coal is removed by filtration and the filtrate concentrated under reduced pressure to obtain ethyl ester (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5,56 g). MC (m/z): 280 [M+H]+.

(5) Ethyl ester of (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5.49 g) and 5-bromo-2-chloropyrimidine (9.5 g) was dissolved in 1,4-dioxane (100 ml), then to the solution was added N,N-diisopropyl the ethylamine (8,55 ml) and the resulting mixture is refluxed for 5 hours. The reaction solution is concentrated under reduced pressure and the residue purified column chromatography (silica gel; hexane:ethyl acetate=95:5→80:20) to give the ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-(5-bromopyrimidine-2-yl)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (8,29 g). MC (m/z): 436/438 [M+H]+.

(6) Ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-(5-bromopyrimidine-2-yl)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (8,20 g) dissolved in N,N-dimethylformamide (75 ml), then to the solution was added sodium hydride

(62,7%, 942 mg) under cooling on ice and the resulting mixture is stirred for 30 minutes. After adding 3,5-bis(trifluoromethyl)benzylbromide (8.7 g) and the resulting mixture was stirred for 30 minutes. To the reaction solution was added water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure (silica gel; hexane:ethyl acetate=95:5→80:20) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (8,01 g). MC (m/z): 662/664 [M+H]+.

Example 3

(1) (S)-1-phenethyl ester (2R,4S)-(2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine-4-yl)carbamino acid (840 mg) and pyridine (0,956 ml) dissolved in methylene chloride (5 ml). After adding dropwise a solution (5 ml) e is illifaut (1.13 ml) in methylene chloride while cooling on ice, the resulting mixture was stirred at room temperature for one hour. The reaction solution was washed with 1N. aqueous solution of sodium hydroxide, 1N. hydrochloric acid and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=90:1→60:40) to give the ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-[(S)-1-phenylethanolamine]-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1,00 g). MC (m/z): 428 [M+H]+.

(2) 10% palladium on coal (100 mg) are added to a solution (10 ml) of ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-[(S)-1-phenylethanolamine]-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1,00 g) in ethanol and the mixture is stirred for 3 hours in hydrogen atmosphere. Palladium on coal is removed by filtration and the filtrate concentrated under reduced pressure to obtain ethyl ester (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (619 mg). MC (m/z): 280 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid and 5-bromo-2-chloropyrimidine (1.06 g) was dissolved in 1,4-dioxane (5 ml), then to the solution was added N,N-diisopropylethylamine (0,951 ml) and the resulting mixture refluxed overnight. The reaction solution is concentrated under reduced pressure and the residue purified column chromatography (Seeley is aqel; hexane:ethyl acetate=95:5→80:20) to give the ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-(5-bromopyrimidine-2-yl)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (853 mg). MC (m/z): 436 [M+H]+.

(4) Ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-(5-bromopyrimidine-2-yl)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (735 mg) was dissolved in N,N-dimethylformamide (5 ml), add sodium hydride (62.7 percent, 84 mg) under cooling on ice and the mixture is stirred for 30 minutes. After adding 3,5-bis(trifluoromethyl)benzylbromide (0,463 ml) the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=95:5→75:25) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (950 mg). MC (m/z): 662 [M+H]+.

Example 4

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (scored 8.38 g) is dissolved in 1,4-dioxane (36 ml), and then to the solution was added sodium iodide (11.4 g), copper iodide (360 mg) and N,N'-dimethylethylenediamine (420 μl) and the mixture per mesilat at 105°C for 24 hours in a stream of nitrogen. After cooling to room temperature, to the reaction mixture, water is added, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated salt solution, dried over magnesium sulfate, and then add a small amount of NH-silica gel and filtered. The filtrate is concentrated under reduced pressure. To the obtained residue is added isopropyl ether and ethyl acetate and the precipitated solid substance produce by filtration to obtain ethyl ester (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (of 7.23 g). MC (m/z): 710 [M+H]+.

Example 5

The corresponding starting compound is treated analogously to example 4 to provide the above compounds. MC (m/z): 710 [M+H]+.

Example 6

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (6 g) dissolved in N,N-dimethylformamide (20 ml) and to the solution was added palladium acetate (200 mg), 1,1'-bis(diphenylphosphino)ferrocene (1 g), benzyl alcohol (18.6 ml) and triethylamine (12,6 ml). The resulting mixture was bubbled with carbon monoxide at room temperature for 5 minutes, heated to 90°C. and stirred in an atmosphere of carbon monoxide in techeneenii. The reaction solution is cooled to room temperature, then add saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=8:1, then NH-silica gel; hexane:ethyl acetate=10:1) to give the ethyl ester of (2R*,4S*)-4-{(5-benzyloxycarbonylamino-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5,64 g). MC (m/z): 718 [M+H]+.

Example 7

Ethyl ester of (2R*,4S*)-4-{(5-benzyloxycarbonylamino-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (752 mg) dissolved in a mixed solution of tetrahydrofuran (18 ml) and methanol (6 ml), and then to the solution was added 10% palladium on coal (300 mg) and the resulting mixture was stirred at room temperature for 4 hours and 30 minutes in a hydrogen atmosphere. The reaction solution is filtered and concentrated under reduced pressure to obtain ethyl ester (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxyamide-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (564 mg). MC (m/z): 342 [M+H]+.

Example 8

Ethyl EPE is (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxyamide-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in N,N-dimethylformamide (4 ml) and to the solution was added morpholine (0,03 ml) and 1-hydroxybenzotriazole (50 mg) at room temperature. To the resulting mixture add monohydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide while cooling on ice, is added dropwise a triethylamine (0.04 ml) and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1 → 1:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-carbonyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (142 mg). MC (m/z): 697 [M+H]+.

Examples 9-13

The corresponding starting compound is treated analogously to example 8 to obtain the compounds listed in table 1.

Table 1
Example No.RPhysical properties, etc.
9MS (m/z): 681 [M+H]+
10MS (m/z): 710 [M+H]+
11MS (m/z): 738 [M+H]+
12MS (m/z): 685 [M+H]+
13MS (m/z): 740 [M+H]+

Example 14

(1) Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxyamide-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3 g) dissolved in toluene (100 ml), then the solution is added triethylamine (2 ml), diphenylphosphoryl (1.5 ml) and benzyl alcohol (0.5 ml) at room temperature, obtained the mixture is heated to 90°C and stirred for 4 hours. The reaction solution is cooled to room temperature, then add saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=17:3→7:3) to give the ethyl ester of (2R*,4S*)-4-{(5-benzyloxycarbonylamino-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,27 g). MC (m/z): 733 [M+H]+.

(2) Ethyl ester of (2R*,4S*)-4-{(5-benzyloxycarbonylamino-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,27 g) dissolved in a mixed solution of tetrahydrofuran (60 ml). After adding methanol (40 ml), 10% palladium on coal (400 mg) and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours. The reaction solution is filtered and concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R*,4S*)-4-{(5-aminopyridin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1,46 g). MC (m/z): 599 [M+H]+.

Example 15

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (250 mg) is dissolved in toluene (2 ml) and to the solution was added Tris(dibenzylideneacetone)dipalladium (6.9 mg), tert-piperonyl sodium (54,8 mg), 2-(di-tert-butylphosphino)biphenyl (9.0 mg) and pyrrolidine (47 μl). The resulting mixture was stirred at room temperature for 45 minutes in a stream of nitrogen, then heated to 80°C and stirred for 18 hours. After cooling to room temperature, to the reaction solution was added the ester. The mixture is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyrrolidin-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (158,5 mg). MC (m/z): 653 [M+H]+.

Examples 16-30

The corresponding starting compound is treated analogously to example 15 to obtain the compounds listed in table 2.

MC (m/z):
657 [M+H]+
Table 2-1
Example No.ConfigurationR RN-Physical properties, etc.
16(2R*4S*)MC (m/z):
696 [M+H]+
17(2R,4S)MC (m/z):
696 [M+H]+
18(2R*4S*)
19(2R*4S*)MC (m/z):
671 [M+H]+
20(2R*4S*)MC (m/z):
715 [M+H]+
21(2R*4S*)MC (m/z):
669 [M+H]+
22(2R,4S)MC (m/z):
669 [M+H]+
23(2R,4S)MC (m/z):
712 [M+H]+

Table 2-2
Example No.ConfigurationR RN-Physical properties, etc.
24(2R,4S) MC (m/z):
627 [M+H]+
25(2S,4R)MC (m/z):
669 [M+H]+
26(2R*4S*)MC (m/z):
739 [M+H]+
27(2R*4S*)MC (m/z):
739 [M+H]+
28(2R*4S*)MC (m/z):
773 [M+H]+
29(2R,4S)MC (m/z):
773 [M+H]+
30(2R*4S*)MC (m/z):
667 [M+H]+

Example 31

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-CT is about acid (120 mg) is dissolved in ethyl acetate (1 ml) and to the solution was added 4n. HCl/ethyl acetate (0,09 ml). The solvent is concentrated under reduced pressure, add ether and hexane, and the precipitated powder is filtered to obtain hydrochloride of the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (112 mg). MC (m/z): 669 [M+H]+.

Example 32

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in isopropanol (1 ml), and then to the solution was added copper iodide (2.7 mg), ethylene glycol (31 μl), potassium phosphate (119 mg) and 2-methylaminoethanol (20 µl), the resulting mixture was heated to 80°C in a stream of nitrogen and stirred for 20 hours. After adding distilled water, the mixture extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→3:7) to give the ethyl ester of (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[methyl-(2-hydroxyethyl)]aminopyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid with (58.2 mg). MC (m/z): 657 [M+H]+.

Examples 33 and 34

The corresponding starting compound is treated similarly is the example 32 to obtain compounds listed in table 3.

Table 3
Example No.R RN-Physical properties, etc.
33MC (m/z): 643 [M+H]+
34MC (m/z): 687 [M+H]+

Example 35

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (500 mg) dissolved in toluene (2 ml) and to the solution was added copper iodide (7.2 mg), 2-phenylphenol (of 25.5 mg), potassium phosphate (318,4 mg) and (±)-piperidine-3-ylmethanol (to 172.8 mg). The mixture is heated to 80°C in a stream of nitrogen and stirred for 5 days. After adding distilled water, the mixture extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-guide oxymethylphenyl-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (of 22.8 mg). MC (m/z): 697 [M+H]+.

Example 36

To a solution of ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylpyrimidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (245 mg) in ethanol (2 ml) is added an aqueous solution of 2n. sodium hydroxide (of 0.332 ml) and the resulting mixture was refluxed at 50°C for 1 hour. The reaction solution was diluted with ethyl acetate and acidified with 1N. hydrochloric acid. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform: chloroform:methanol=90:10) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypeptidase-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (210 mg). MC (m/z): 711 [M+H]+.

Example 37

The corresponding starting compound is treated analogously to example 36 to provide the above compounds. MC (m/z): 711 [M+H]+.

Example 38

To a solution of (1.5 ml) ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylpyrimidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (120 mg) in tetrahydrofuran the e add diisobutylaluminium (1M solution in toluene, 0,486 ml) while cooling on ice and the mixture is stirred for 1 hour. To the reaction solution was added saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=80:20→70:30) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-hydroxyethylpiperazine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (110 mg). MC (m/z): 697 [M+H]+.

Example 39

To a solution of ethyl ester of (2R*,4S*)-4-{[5-(4-benzyloxypyridine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (700 mg) in ethanol (10 ml) is added 10% palladium on coal (100 mg) and the resulting mixture is stirred in hydrogen atmosphere overnight. Palladium on coal is removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=80:20→ 0:50) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-hydroxypiperidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (313 mg). MC (m/z): 683 [M+H]+

Example 40

The corresponding starting compound is treated analogously to example 39 to provide the above compounds. MC (m/z): 683 [M+H]+.

Example 41

To a solution (1 ml), ethyl ether (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-hydroxypiperidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (100 mg) added 1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-he (74 mg) and the resulting mixture was stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=90:10→60:40) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-oxopiperidin-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (51 mg). MC (m/z): 681 [M+H]+.

Example 42

To a solution (2 ml) ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-hydroxypiperidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (140 mg) in N,N-dimethylformamide added sodium hydride (62.7 percent, and 9.4 mg) and the resulting mixture was stirred at room temperature within 10 minutes. Add methyliodide is 0.019 ml) and the mixture is stirred at room temperature for the of 2 hours. Add water and ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=90:10→60:40) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-methoxypiperidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (71 mg). MC (m/z): 697 [M+H]+.

Examples 43-47

The corresponding starting compound is treated analogously to example 15 to obtain the compounds listed in table 4.

Table 4
Example No.ConfigurationR-Physical properties, etc.
43(2R*4S*)MC (m/z):
802 [M+H]+
44(2R,4S)MC (m/z):
802 [M+H]+
45MC (m/z):
740 [M+H]+
46(2R*4S*)MC (m/z):
682 [M+H]+
47(2R,4S)MC (m/z):
682 [M+H]+

Example 48

Ethyl ester of (2R*,4S*)-4-{[5-(4-benzyloxycarbonylamino-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (938 mg) was dissolved in a mixed solvent of tetrahydrofuran:methanol (1:1) (6 ml), then add 10% palladium on coal (300 mg) and the resulting mixture was stirred at room temperature in a stream of nitrogen for 13 hours. The catalyst was removed by filtration and the filtrate concentrated. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=10:0→9:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(piperazine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (786 mg). MC (m/z): 668 [M+H]+.

Example 49

The corresponding source the connection is treated analogously to example 48 to obtain the above compound. MC (m/z): 668 [M+H]+.

Example 50

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(piperazine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (110 mg) is dissolved in methylene chloride (1 ml), then the solution is added triethylamine (0.1 ml) and acetylchloride (19 μl) and the mixture was stirred at room temperature a stream of nitrogen for 2 hours. After adding distilled water, the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=9:1) to give the ethyl ester of (2R*,4S*)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (103,6 mg) MS (m/z): 710 [M+N]+.

Examples 51-55

The corresponding starting compound is treated analogously to example 50 to obtain the compounds listed in table 5.

Table 5
Example No.ConfigurationR-b> Physical properties, etc.
51(2R,4S)MS (m/z):
710 [M+H]+
52(2R*4S*)MS (m/z):
740 [M+H]+
53(2R,4S)MS (m/z):
740 [M+H]+
54(2R*4S*)MS (m/z):
746 [M+H]+
55(2R*4S*)MS (m/z):
775 [M+H]+

Example 56

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(piperazine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in N,N-dimethylformamide (1 ml), and then to the solution was added 2-ionatana (26 μl) and excess potassium carbonate, the resulting mixture is heated to 50°C in a stream of nitrogen and stirred for 5 hours. After EXT is the exercise of distilled water, the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=19:1→9:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-[4-(2-hydroxyethyl)piperazine-1-yl]pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (128 mg) MC (m/z): 712 [M+H]+.

Examples 57 and 58

The corresponding starting compound is treated analogously to example 56 to obtain the compounds listed in table 6.

Table 6
Example No.R-Physical properties, etc.
57MS (m/z): 754 [M+H]+
58MS (m/z): 768 [M+H]+

Examples 59 and 60 of

The corresponding starting compound is treated analogously to example 36 to obtain the compounds listed in table 7.

/p>

Table 7
Example No.R-Physical properties, etc.
59MS (m/z): 754 [M+H]+
60MS (m/z): 740 [M+H]+

Example 61

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(piperazine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (110 mg) is dissolved in methylene chloride (1 ml), the solution is added triethylamine (0.1 ml) and utilizationa (20 ml) and stirred at room temperature in a stream of nitrogen in for 2 hours. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethylcarbodiimide-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (104,4 mg). MC (m/z): 739 [M+H]+.

Example 62

<> Ethyl ester of (2R*,4S*)-4-{(5-aminopyridin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in N,N-dimethylformamide (4 ml), then the solution add acetylchloride (0,02 ml) and triethylamine (0.1 ml) and the resulting mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R*,4S*)-4-{(5-acetylaminophenol-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (132 mg). MC (m/z): 641 [M+H]+.

Examples 63-65

The corresponding starting compound is treated analogously to example 62 to obtain the compounds listed in table 8.

Table 8
Example No.R-MS (m/z):
63 MS (m/z): 671 [M+H]+
64MS (m/z): 703/705 [M+H]+
65MS (m/z): 705/707 [M+H]+

Example 66

Ethyl ester of (2R*,4S*)-4-{(5-aminopyridin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (500 mg) is dissolved in N,N-dimethylformamide (4 ml), the solution add carbobenzoxy (210 mg) and 1-hydroxybenzotriazole (170 mg) at room temperature, add the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (240 mg) under cooling on ice, is added dropwise a triethylamine (0.15 ml) and then stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R*,4S*)-4-({5-[(2-benzyloxycarbonylamino)acetylamino]pyrimidine-2-yl}-[3,5-bis(trifluoromethyl)benzyl])amino-2-ethyl-6-m the toxi-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (631 mg). MC (m/z): 790 [M+H]+.

Examples 67 and 68

The corresponding starting compound is treated analogously to example 66 to obtain the compounds listed in table 9.

Table 9
Example No.R-Physical properties, etc.
67MS (m/z): 657 [M+H]+
68MS (m/z): 791 [M+H]+

Example 69

Ethyl ester of (2R*,4S*)-4-({5-[(2-benzyloxycarbonylamino)acetylamino]pyrimidine-2-yl}-[3,5-bis(trifluoromethyl)benzyl])amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (631 mg) dissolved in methanol (10 ml)and added to a solution of 10% palladium on coal (100 mg) and then the resulting mixture was stirred at room temperature in the atmosphere hydrogen for 30 minutes. The reaction solution is filtered and concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give the ethyl ester of (2R*,4S*)-4-{[5-(2-what aminoazotoluene)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (463 mg). MC (m/z): 626 [M+H]+.

Example 70

The corresponding starting compound is treated analogously to example 39 to provide the above compounds. MC (m/z): 701 [M+H]+.

Example 71

Ethyl ester of (2R*,4S*)-4-{(5-aminopyridin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in methylene chloride (4 ml), the solution add carbodiimides (60 mg) and triethylamine (0.1 ml) and the resulting mixture was stirred at room temperature for 1 hour. To the reaction solution was added morpholine (0.05 ml) and the mixture is stirred at room temperature for 2 hours and 30 minutes. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=7:3→1:1→0:1) with obtaining the ethyl ester of (2R*,4S*)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{[(morpholine-4-yl)carbonyl]amino}pyrimidine-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (154 mg). MC (m/z): 712 [M+H]+.

Example 72

The corresponding starting compound is srabatyvayut analogously to example 71 to provide the above compounds. MC (m/z): 700 [M+H]+.

Example 73

Ethyl ester of (2R*,4S*)-4-{[5-(2-aminoethylamino)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in N,N-dimethylformamide (4 ml), then the solution add carbodiimides (40 mg) and triethylamine (0,08 ml) and the resulting mixture was stirred at room temperature for 3 hours and 30 minutes. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=3:2→3:7) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2,5-dioxoimidazolidin-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (126 mg). MC (m/z): 682 [M+H]+.

Example 74

The corresponding starting compound is treated analogously to example 73 to provide the above compounds. MC (m/z): 683 [M+H]+.

Example 75

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-chloroethylamino)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (283 mg) dissolve Aut in N,N-dimethylformamide (4 ml), then to the solution was added sodium hydride (18 mg) under cooling on ice and the resulting mixture was stirred at room temperature overnight. To the reaction solution was added water and extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=7:3→1:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-oxopyrrolidin-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (132 mg). MC (m/z): 667 [M+H]+.

Example 76

The corresponding starting compound is treated analogously to example 75 to provide the above compounds. MC (m/z): 669 [M+H]+.

Example 77

(1) Ethyl ester of (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(2-hydroxyethoxy)acetylamino]pyrimidinyl-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (90 mg) is dissolved in chloroform (4 ml), then the solution add methylchloride (0.1 ml) and triethylamine (0.2 ml) under cooling on ice and the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution was added water and extracted with chloroform. The organic layer was washed with saturated is the first salt solution, dried over magnesium sulfate and concentrated under reduced pressure to obtain ethyl ester (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(2-methanesulfonylaminoethyl)acetylamino]pyrimidinyl-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (143 mg).

(2) Ethyl ester of (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(2-methanesulfonylaminoethyl)acetylamino]pyrimidinyl-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (143 mg) was dissolved in tetrahydrofuran (4 ml), added to a solution of tert-piperonyl sodium (48 mg) and then the resulting mixture was stirred at room temperature for 4 hours and 20 minutes. To the reaction solution was added a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-exmortis-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (51 mg). MC (m/z): 683 [M+H]+.

Example 78

Ethyl ester of (2R*,4S*)-4-{(5-aminopyridin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic sour is s (300 mg) is dissolved in toluene (10 ml), then to the solution was added maleic anhydride (150 mg) and the resulting mixture is refluxed for 1 hour and 30 minutes. After cooling to room temperature, to the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2,5-dioxo-2,5-dihydropyrrol-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (77 mg). MC (m/z): 679 [M+H]+.

Example 79

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3.50 g) was dissolved in toluene (10 ml), then to the solution was added benzyl alcohol (1,02 ml), copper iodide (94 mg), 1,10-phenanthroline (178 mg) and cesium carbonate (1,61 g) and the resulting mixture was stirred at 100°C. in a stream of nitrogen for 6 hours. Mixture is allowed to cool to room temperature, then add benzyl alcohol (0.51 ml), copper iodide (94 mg), 1,10-phenanthroline (178 mg), cesium carbonate (0,80 g) and toluene (2 ml) and the resulting mixture was stirred at 100°C. in a stream of nitrogen in those who tell the night. The reaction mixture is allowed to cool to room temperature, then add benzyl alcohol (0.1 ml), copper iodide (94 mg), 1,10-phenanthroline (178 mg) and cesium carbonate (0,80 g) and the resulting mixture was stirred at 100°C. in a stream of nitrogen for 5 hours. The mixture is allowed to cool to room temperature, the reaction solution was added water and ethyl acetate and insoluble substances are removed by filtration on Celite™. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. To the obtained residue is added copper iodide (94 mg), 1,10-phenanthroline (178 mg), cesium carbonate (1,61 g) and toluene (5 ml) and stirred at 100°C. in a stream of nitrogen overnight. After cooling to room temperature, to the reaction solution was added water and ethyl acetate and insoluble substances are removed by filtration on Celite™. The organic layer of the filtrate was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=10:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-benzyloxypyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2.25 mg). MC (m/z): 690 [M+H]+.

Examples 80 and 81

The corresponding source connection amrabat who live analogously to example 79 with obtaining compounds, listed in table 10.

Table 10
Example No.ConfigurationR-Physical properties, etc.
80(2R,4S)MS (m/z): 690 [M+H]+
81(2R*,4S*)MS (m/z): 713 [M+H]+

Example 82

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-benzyloxypyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.52 g) was dissolved in methanol (270 ml), and then to the solution was added 10% palladium on coal and the resulting mixture was stirred at room temperature in hydrogen atmosphere for 30 minutes. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to obtain ethyl ester (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1,33 g). MC (m/z): 600 [M+H]+.

Note the p 83

The corresponding starting compound is treated analogously to example 82 to provide the above compounds. MC (m/z): 600 [M+H]+.

Example 84

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in N,N-dimethylformamide (1 ml), and then to the solution was added sodium hydride (63%, 11 mg) under cooling on ice and the resulting mixture was stirred at 0°C in within 30 minutes. Add methyliodide (23 μl) and the resulting mixture is stirred for 2 hours while cooling on ice. To the reaction mixture is added 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer of the filtrate was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methoxypyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (129 mg). MC (m/z): 614 [M+H]+.

Examples 85-88

The corresponding starting compound is treated analogously to example 84, from obtaining the compounds listed in table 11.

Table 11
Example No.R-Physical properties, etc.
85MS (m/z): 686 [M+H]+
86MS (m/z): 657 [M+H]+
87MS (m/z): 672 [M+H]+
88MS (m/z): 658 [M+H]+

Example 89

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in N,N-dimethylformamide (1 ml), and then to the solution was added sodium carbonate (200 mg) and 2-bromoethanol (162 μl) and the mixture was stirred at 60°C throughout the night. To the reaction mixture is added 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. Received OS is atok purified column chromatography (silica gel; hexane:ethyl acetate=2:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (95 mg). MC (m/z): 644 [M+H]+.

Examples 90-92

The corresponding starting compound is treated analogously to example 89 to obtain the compounds listed in table 12.

Table 12
Example No.ConfigurationR-Physical properties, etc.
90(2R,4S)MS (m/z): 644 [M+H]+
91(2R*,4S*)MS (m/z): 658 [M+H]+
92(2R*,4S*)MS (m/z): 688 [M+H]+

Example 93

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-d the hydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in tetrahydrofuran (1 ml), then to the solution was added pyrimidine-2-ylmethanol (41 mg) and triphenylphosphine (98 mg). After adding dropwise of a solution of 40% diethylazodicarboxylate-toluene (163 ml) while cooling on ice, the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyrimidine-2-ylethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (118 mg). MC (m/z): 692 [M+H]+.

Examples 94-107

The corresponding starting compound is treated analogously to example 93 to obtain the compounds listed in table 13.

Table 13-1
Example No.ConfigurationR-Physical properties, etc.
94(2R*,4S*) MS (m/z): 690 [M+H]+
95(2R,4S)MS (m/z):
705 [M+H]+
96(2R*4S*)MS (m/z):
684 [M+H]+
97(2R,4S)MS (m/z):
670 [M+H]+
98(2R*4S*)MS (m/z):
697 [M+H]+
99(2R*4S*)MS (m/z):
697 [M+H]+
100(2R,4S)MS (m/z):
683 [M+H]+
101(2R*4S*)MS (m/z):
759 [M+H]+

Table 13-2
Example No.ConfigurationR-Physical properties, etc.
102(2R*4S*)MS (m/z):
711 [M+H]+
103(2R,4S)MS (m/z):
714 [M+H]+
104(2R*4S*)MS (m/z):
671 [M+H]+
105(2R,4S)MS (m/z):
671 [M+H]+
106(2R*4S*)MS (m/z):
674 [M+H]+
107(2R*4S*) MS (m/z):
714 [M+H]+

Example 108

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxycarbonylpyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) dissolved in methanol (3 ml), and then to the solution was added 1M aqueous sodium hydroxide solution (2 ml) and the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture is added 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=19:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxymethylaminomethyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (100 mg). MC (m/z): 658 [M+H]+.

Example 109

The corresponding starting compound is treated analogously to example 108 to provide the above compounds. MC (m/z): 686 [M+H]+.

Example 110

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxymethylaminomethyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in N,N-dim is telharmonic (1 ml), then to the solution was added morpholine (30 μl). After adding monohydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (66 mg) and hydrate of 1-hydroxybenzotriazole while cooling on ice, the resulting mixture was stirred at room temperature for 4 hours. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=19:1) to give the ethyl ester of (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(morpholine-4-yl)-2-accoutability-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (138 mg). MC (m/z): 727 [M+H]+.

Examples 111-113

The corresponding starting compound is treated analogously to example 110 to obtain the compounds listed in table 14.

tr>
Table 14
Example No.R-Physical properties, etc.
111MS (m/z):
671 [M+H]+
112MS (m/z):
685 [M+H]+
113MS (m/z):
701 [M+H]+

Example 114

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methylsulfonylmethane)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) dissolved in chloroform (1 ml), then added to a solution of m-chloroperbenzoic acid (60 mg) and the resulting mixture was stirred at room temperature for 2 hours. After adding a saturated aqueous solution of sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=19:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methylsulfonylmethane)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (125 mg). MC (m/z): 690 [M+H]+.

Example 115

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methylsulfonylmethane)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-digitron-[1,5]naphthiridine-1-carboxylic acid (226 mg) dissolved in chloroform (1.5 ml), then add to a solution of m-chloroperbenzoic acid (248 mg) and the resulting mixture was stirred at room temperature for 40 minutes. Add saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=19:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methansulfonate)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (182 mg). MC (m/z): 706 [M+H]+.

Example 116

The corresponding starting compound is treated analogously to example 115 with receipt of the above compounds. MC (m/z): 706 [M+H]+.

Example 117

To a solution (10 ml), ethyl ether (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-[2-(pyridin-2-yl)ethoxy]pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) in chloroform add m-chloroperbenzoic acid (79 mg) and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is cidaut column chromatography (NH-silica gel; hexane:ethyl acetate=75:25→0:100) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-[2-(1-oxypyridine-2-yl)ethoxy]pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (173 mg). MC (m/z): 721 [M+H]+.

Example 118

A mixture of ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-[2-(1-oxypyridine-2-yl)ethoxy]pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (115 mg), triperoxonane anhydride (0,226 ml) and N,N-dimethylformamide (5 ml) was stirred at room temperature overnight. The reaction solution was distributed between ethyl acetate and aqueous saturated sodium bicarbonate solution. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by thin-layer chromatography (hexane:ethyl acetate=1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-{5-[2-hydroxy-2-(pyridin-2-yl)ethoxy]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (24 mg). MC (m/z): 721 [M+H]+.

Example 119

Ethyl ester of (2R*,4S*)-4-({5-[((S)-1-benzylpyrrolidine-3-yl)oxy]pyrimidine-2-yl}-[3,5-bis(trifluoromethyl)benzyl])amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (280 mg) was dissolved in methanol (5 ml), then the solution dobavlaut% palladium on coal (50 mg) and the resulting the mixture is stirred at room temperature in hydrogen atmosphere overnight. The reaction solution is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=4:1→3:1→0:1) with obtaining the ethyl ester of (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[((S)-1-benzylpyrrolidine-3-yl)oxy]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (168 mg). MC (m/z): 669 [M+H]+.

Example 120

The corresponding starting compound is treated analogously to example 50 to provide the above compounds. MC (m/z): 711 [M+H]+.

Example 121

Ethyl ester of (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (147 mg) was dissolved in tetrahydrofuran (2 ml), then to the solution was added 1N. hydrochloric acid (2 ml) and the resulting mixture is stirred over night. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=3:2→3:7) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)b is nzyl]-[5-(2,3-dihydroxypropane)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (72 mg). MC (m/z): 674 [M+H]+.

Example 122

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) dissolved in 2-methoxyethanol (1.0 ml), and then to the solution was added copper iodide (21 mg), 1,10-phenanthroline (41 mg) and cesium carbonate (368 mg) and the resulting mixture stirred at 110°C in a stream of nitrogen for 15 hours. After cooling to room temperature, to the reaction mixture, water is added, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate, add a small amount of NH-silica gel, the mixture is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=3:1) to obtain 2-methoxyethanol ether ethyl-(2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxyethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (38 mg). MC (m/z): 688 [M+H]+.

Example 123

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (400 mg) is dissolved in isopropyl alcohol (2 ml), then to the solution was added 2-mercaptoethanol (96 ml), copper iodide (20 mg), ethylene glycol (62 μl) and potassium carbonate (156 m is) and the resulting mixture was stirred at 80°C in a stream of nitrogen overnight. After cooling to room temperature, to the reaction mixture, water is added, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate, add a small amount of NH-silica gel, the mixture is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1→1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyarylalkyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (110 mg). MC (m/z): 600 [M+H]+.

Example 124

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (400 mg) is dissolved in isopropyl alcohol (2 ml), then to the solution was added methyl ester of thioglycolic (120 ml), copper iodide (20 mg), ethylene glycol (62 μl) and potassium carbonate (120 µl) and the resulting mixture was stirred at 80°C in a stream of nitrogen overnight. After cooling to room temperature, to the reaction mixture, water is added, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in methanol (6 ml),then added to a solution of 1M aqueous sodium hydroxide solution (3 ml) and tetrahydrofuran (6 ml) and the resulting mixture was stirred at room temperature for 10 minutes. 10%aqueous citric acid solution is added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1→1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-karboksimetilsellulozdan-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (153 mg). MC (m/z): 674 [M+H]+.

Example 125

The corresponding starting compound is treated analogously to example 110 to provide the above compounds. MC (m/z): 687 [M+H]+.

Examples 126 and 127

The corresponding starting compound is treated analogously to example 115 with obtaining the compounds listed in table 15.

Table 15
Example No.RPhysical properties, etc.
126MS (m/z):
692 [M+H]+
127 MS (m/z):
719 [M+H]+

Example 128

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxyamide-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (400 mg) dissolved in tetrahydrofuran (2 ml), then the solution add ethylchloride (0,02 ml) and triethylamine (0.04 ml) while cooling on ice and the resulting mixture is stirred for 30 minutes. The reaction solution was filtered and to the filtrate add sodium borohydride (18 mg) and the mixture is stirred for 1 hour and 40 minutes. To the reaction solution was added 1N. hydrochloric acid and extracted with ethyl acetate. The organic layer is washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(hydroxymethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (80 mg). MC (m/z): 614 [M+H]+.

Example 129

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(hydroxymethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carbon is acid (150 mg) is dissolved in tetrahydrofuran (4 ml), then to the solution was added sodium hydride (12 mg) and methyliodide (0,02 ml) while cooling on ice and the resulting mixture was stirred at room temperature for 3 hours and 30 minutes. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxymethyleneamino-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (92 mg). MC (m/z): 628 [M+H]+.

Example 130

The corresponding starting compound is treated analogously to example 129 to provide the above compounds. MC (m/z): 656 [M+H]+.

Example 131

(1) Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(hydroxymethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) is dissolved in N,N-dimethylformamide (4 ml), then added to a solution of sodium hydride (28 mg) under cooling on ice and the resulting mixture is stirred for 30 minutes. To the reaction solution was added 2-(2-bromoethoxy)tetrahydropyran (0.15 ml) and poluchenno the mixture was stirred at room temperature for 2 hours and 30 minutes. After adding sodium hydride (28 mg) and 2-(2-bromoethoxy)tetrahydropyran (0.15 ml) the resulting mixture was stirred at 50°C for 2 hours and 30 minutes. After cooling to room temperature, to the reaction solution was added saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R*,4S*)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{2-[(tetrahydropyran-2-yl)oxy]ethoxymethyl}pyrimidine-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (201 mg). MC (m/z):

742 [M+H]+.

(2) Ethyl ester of (2R*,4S*)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{2-[(tetrahydropyran-2-yl)oxy]ethoxymethyl}pyrimidine-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) dissolved in methanol (5 ml), then to the solution was added 1N. hydrochloric acid (1 ml) and the mixture is stirred for 1 hour and 30 minutes. After adding a saturated aqueous solution of sodium bicarbonate, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The floor is obtained residue purified column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(2-hydroxy)ethoxymethyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (124 mg). MC (m/z): 658 [M+H]+.

Example 132

(1) Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(hydroxymethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1 g) dissolved in methylene chloride (20 ml), then added to a solution of triphenylphosphine (855 mg) and tetrabromide carbon (1.35 g) and the resulting mixture is stirred for 3 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(methyl bromide)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (690 mg). MC (m/z): 676 [M+H]+.

(2) Morpholine (0,02 ml) dissolved in N,N-dimethylformamide (2 ml), then to the solution was added sodium hydride (9 mg) under cooling on ice and the resulting mixture is stirred for 30 minutes. Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)b is nzyl]-[5-(methyl bromide)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (112 mg) is added to the reaction solution while cooling on ice and the resulting mixture was stirred at room temperature within 1 hour and 30 minutes. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=3:1→1:1) to give the ethyl ester of (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(morpholine-4-yl)methyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (33 mg). MC (m/z): 683 [M+H]+.

Examples 133-136

The corresponding starting compound is treated analogously to example 132 to obtain the compounds listed in table 16.

Table 16
Example No.RPhysical properties, etc.
133MS (m/z):
667 [M+H]+
134MS (m/z):
696 [M+H]+
135 MS (m/z):
671 [M+H]+
136MS (m/z):
681 [M+H]+

Example 137

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (367 mg), benzyl ester of acrylic acid (180 mg), Tris(dibenzylideneacetone)dipalladium (61 mg), dicyclohexylmethane (162 mg) and tetrafluoroborate three-tert-butylphosphine (39 mg) was dissolved in 1,4-dioxane (4 ml) and the resulting mixture was stirred at room temperature in a stream of nitrogen for 3 days. To the reaction solution was added an aqueous citric acid solution and ethyl acetate and the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=23:2→3:2) to give the ethyl ester of (2R*,4S*)-4-{[5-(2-benzyloxycarbonylamino]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (372 mg). MC (m/z): 744 [M+H]+.

Examples 138-139

The corresponding starting compound is treated analogously to example 137 with obtaining the compounds listed in the table is e 17.

Table 17
Example No.ConfigurationR-Physical properties, etc.
138(2R,4S)MS (m/z):
744 [M+H]+
139(2R*4S*)MS (m/z):
635 [M+H]+

Example 140

Ethyl ester of (2R,4S)-4-{[5-(2-benzyloxycarbonylamino)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,02 g) dissolved in a mixture of tetrahydrofuran (50 ml) and methanol (9 ml). After adding 10% palladium on coal (600 mg) the mixture was stirred at room temperature in hydrogen atmosphere for 2 hours and 30 minutes. The reaction solution is filtered and concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=3:2→0:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-ka is baxevanis)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.7 g). MC (m/z): 654 [M+H]+.

Example 141

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyvinyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (500 mg) dissolved in a mixed solution of tetrahydrofuran (15 ml) and methanol (5 ml), then added to a solution of 10% palladium on coal (160 mg) and the resulting mixture was stirred at room the temperature in hydrogen atmosphere for 3 hours and 30 minutes. The reaction solution is filtered and concentrated under reduced pressure to obtain ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (498 mg). MC (m/z): 656 [M+H]+.

Example 142

The corresponding starting compound is treated analogously to example 141 to provide the above compounds. MC (m/z): 656 [M+H]+.

Example 143

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyvinyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in tetrahydrofuran (4 ml), then the solution add ethylchloride (0.04 ml) and triethylamine (0.06 ml) while cooling on ice and the resulting mixture is stirred for 30 minutes. The reaction solution is filtered, then add sodium borohydride (5 mg) and the resulting mixture is stirred for 1 hour and 30 minutes while cooling on ice. To the reaction solution was added 1N. hydrochloric acid and extracted with ethyl acetate. The organic layer is washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-hydroxypropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (155 mg). MC (m/z): 640 [M+H]+.

Example 144

The corresponding starting compound is treated analogously to example 143 to provide the above compounds. MC (m/z): 642 [M+H]+.

Example 145

The corresponding starting compound is treated analogously to example 110 to provide the above compounds. MC (m/z): 669 [M+H]+.

Example 146

To a suspension (1 ml) of copper bromide (227 mg) in tetrahydrofuran is added dropwise 65% solution (982 mg), bis(2-methoxyethoxy)aluminiumhydride sodium in toluene while cooling on ice and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction solution is cooled to -78°C and add 2-butanol (0,29 ml). Then add the dropwise a solution (0.5 ml) ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-cyanophenyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (100 mg) in tetrahydrofuran and the resulting mixture stirred at the same temperature for 2 hours. After heating to room temperature, the mixture is stirred for additional two hours. To the reaction solution was added saturated aqueous solution of ammonium chloride and the mixture is distributed by the addition of ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by thin-layer chromatography on silica gel (hexane:ethyl acetate=2:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-cyanoethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (74 mg). MC (m/z): 637 [M+H]+.

Example 147

A mixture of ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-cyanophenyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (385 mg), sodium azide (99 mg), ammonium chloride (81 mg) and N,N-dimethylformamide (5 ml) was stirred at 100°C during the night. The mixture is distributed between ethyl acetate and a saturated solution of salt. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=5:1) to give the ethyl ester of (2R*,4S*)-4-([3,5-bis(triptime who yl)benzyl]-{5-[2-(tetrazol-5-yl)vinyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (155 mg). MC (m/z): 679 [M+H]+.

Example 148

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (250 mg) is dissolved in N,N-dimethylformamide (2 ml), then to the solution was added pyridine-4-Bronevoy acid (87 mg), tetrakis(triphenylphosphine)palladium (81 mg) and sodium carbonate potassium (117 mg) and the mixture was stirred at 100°C. in a stream of nitrogen for 2 hours. After cooling to room temperature, to the reaction mixture, water is added, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=4:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyridin-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (131 mg). MC (m/z): 661 [M+H]+.

Examples 149 and 150

The corresponding starting compound is treated analogously to example 148 to obtain the compounds listed in table 18.

Table 18
Example No.Proc is the tenant R-Physical properties, etc.
149(2R*4S*)MS (m/z):
661 [M+H]+
150(2R,4S)MS (m/z):
662 [M+H]+

Example 151

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in toluene (2 ml), then to the solution was added 2-tributylstannyl (105 μl) and tetrakis(triphenylphosphine)palladium (16 mg) and the mixture was stirred at 100°C. in a stream of nitrogen throughout the night. After cooling to room temperature, to the reaction mixture is added 10% aqueous solution of potassium fluoride, followed by extraction with ethyl acetate. The organic layer is washed sequentially with 10% aqueous solution of potassium fluoride and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyridine-2-Yeremey-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (138 mg). MC (m/z): 661 [M+H]+.

Example 152

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (250 mg) is dissolved in N,N-dimethylformamide (2 ml), then to the solution was added pinacolone ether 5-formylpyridine-3-Bronevoy acid (164 mg), tetrakis(triphenylphosphine)palladium (81 mg) and sodium carbonate (90 mg) and the mixture was stirred at 100°C overnight in a stream of nitrogen. After cooling to room temperature, to the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=2:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-formylpyridine-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (119 mg). MC (m/z): 689 [M+H]+.

Example 153

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-formylpyridine-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (118 mg) was dissolved in tetrahydrofuran (1.5 ml), and then to the solution was added dropwise a solution of 1M diisobutylaluminium-tetrahydro the furan (0.33 ml) and the resulting mixture is stirred for 1 hour in a stream of nitrogen while cooling on ice. To the reaction mixture is added a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-hydroxymethyluracil-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (84 mg). MC (m/z): 691 [M+H]+.

Example 154

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (350 mg) was dissolved in 1,4-dioxane (1 ml), then the solution add pyrrolidin-2-he (100 mg), Tris(dibenzylideneacetone)dipalladium (23 mg), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (21 mg) and cesium carbonate (241 mg) and the mixture was stirred at 100°C. in a stream of nitrogen overnight. After cooling to room temperature, to the reaction mixture, water is added, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate, and then add a small amount of NH-silica gel, the mixture is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column of chromatogr is FIA (silica gel; hexane:ethyl acetate=4:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(pyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (105 mg). MC (m/z): 584 [M+H]+.

Example 155

(1) a Mixture of ethyl ester of (2R*,4S*)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg), 2-chloro-4,6-dimethoxypyrimidine (468 mg), N,N-diisopropylethylamine (0,467 ml) and 1,4-dioxane (5 ml) is refluxed for 2 days. The reaction solution is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=80:20→60:40) to give the ethyl ester of (2R*,4S*)-4-(4,6-dimethoxypyrimidine-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (280 mg). MC (m/z): 418 [M+H]+.

(2) Ethyl ester of (2R*,4S*)-4-(4,6-dimethoxypyrimidine-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (260 mg) was dissolved in N,N-dimethylformamide (1 ml), and then to the solution was added sodium hydride (62.7 percent, 31 mg) under cooling on ice and the resulting mixture is stirred for 15 minutes. Then add 3,5-bis(trifluoromethyl)benzylbromide (0,171 ml) and the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, the organic layer was washed with saturated salt solution, dried over with what LifeCam magnesium and concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=90:10→60:40) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4,6-dimethoxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (285 mg) MS (m/z): 644 [M+H]+.

Example 156

(1) Ethyl ester of (2R,4S)-4-(5-bromopyridin-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (250 mg) is dissolved in N,N-dimethylformamide (3 ml), and then to the solution was added sodium hydride (28 mg) under cooling on ice and the resulting mixture is stirred for 30 minutes. To the reaction mixture was added 1-methyl bromide-3,5-xylene (171 mg) and the resulting mixture was stirred at room temperature for one day. To the reaction solution was added water and extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R*,4S*)-4-[(5-bromopyrimidine-2-yl)-(3,5-dimethylbenzyl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (268 mg). MC (m/z): 554/556 [M+H]+.

(2) Ethyl ester of (2R*,4S*)-4-[(5-bromopyrimidine-2-yl)-(3,5-dimethylbenzyl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic sour is s (268 mg) dissolved in toluene (10 ml), then to the solution was added Tris(dibenzylideneacetone)dipalladium (44 mg), tert-piperonyl sodium (70 mg), 2-(di-tert-butylphosphino)biphenyl (57 mg) and morpholine (0.06 ml) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction solution is heated to 50°C. and stirred for 1 hour. To the reaction solution was added NH-silica gel and the mixture is filtered. To the filtrate is added a saturated aqueous solution of sodium bicarbonate and extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=3:1→1:1) to give the ethyl ester of (2R*,4S*)-4-{(3,5-dimethylbenzyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (168 mg). MC (m/z): 561 [M+H]+.

Example 157

The corresponding starting compound is treated analogously to example 156-(1) to obtain the above compound. MC (m/z): 551/553 [M+H]+.

Example 158

The corresponding starting compound is treated analogously to example 156-(2) to obtain the above compound. MC (m/z): 558 [M+H]+.

Example 159

The corresponding starting compound is treated analogously to example 137 to provide the above compounds. MC (m/z): 633 [M+H]+.

Example 160

The corresponding starting compound is treated analogously to example 141 to provide the above compounds. MC (m/z): 545 [M+H]+.

Examples 161-176

The corresponding starting compound is treated analogously to example 156 to obtain the compounds listed in table 19.

Table 19-1
Example No.RPhysical properties, etc.
161MS (m/z):
593 [M+H]+
162MS (m/z):
563 [M+H]+
163MS (m/z):
567/569
[M+H]+
164MS (m/z):
601 [M+H]+
165MS (m/z):
551 [M+H]+
166MS (m/z):
599 [M+H]+
167MS (m/z):
617 [M+H]+

Table 19-2
Example No.RPhysical properties, etc.
168MS (m/z):
591 [M+H]+
169MS (m/z):
547 [M+H]+
170MS (m/z):
569 [M+H]+
171MS (m/z):
585/587
[M+H]+
172 MS (m/z):
619 [M+H]+
173MS (m/z):
587 [M+H]+

Table 19-3
Example No.RPhysical properties, etc.
174MS (m/z):
601/603
[M+H]+
175MS (m/z):
615 [M+H]+
176MS (m/z):
656 [M+H]+

Example 177

(1) Ethyl ester of (2R*,4S*)-4-(5-bromopyridin-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1 g), Tris(dibenzylideneacetone)dipalladium (210 mg), tert-piperonyl sodium (661 mg), 2-(di-tert-butylphosphino)biphenyl (137 mg) and morpholine (400 μl) dissolved in toluene (10 ml) and the resulting mixture was stirred at 40°C in a stream of nitrogen for 19 hours. After cooling on the room temperature to the reaction mixture is added a saturated salt solution and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→2:1) to give the ethyl ester of (2R*,4S*)-2-ethyl-6-methoxy-4-[5-(morpholine)pyrimidine-2-yl]amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (560 mg). MC (m/z): 443 [M+H]+.

(2) Ethyl ester of (2R*,4S*)-2-ethyl-6-methoxy-4-[5-(morpholine)pyrimidine-2-yl]amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (118 mg) was dissolved in N,N-dimethylformamide (2 ml), to the solution was added sodium hydride (62.7 percent, 13 mg) in a stream of nitrogen while cooling on ice and the resulting mixture was stirred at room temperature for 30 minutes. After adding 4-ftorangidridy (86 ml) while cooling on ice, the resulting mixture was stirred at room temperature overnight. To the mixture are added water and ethyl acetate, the mixture is washed with saturated salt solution, the organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1→1:1) to give the ethyl ester of (2R*,4S*)-2-ethyl-4-{(4-terbisil)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (93 mg). MC (m/z): 551 [M+H]+.

Examples 178-183

Accordingly the corresponding starting compound is treated analogously to example 177-(2) to obtain the compounds listed in table 20.

Example 20
Example No.RPhysical properties, etc.
178MS (m/z):
569 [M+H]+
179MS (m/z):
619 [M+H]+
180MS (m/z):
611/613
[M+H]+
181MS (m/z):
601/603
[M+H]+
182MS (m/z):
565 [M+H]+
183MS (m/z):
633 [M+H]+

Example 184

Trimethylsilane (4.6 liters) is added dropwise to a suspension of ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2.4 g), sodium iodide (5.4 g) and acetonitrile (50 ml) at 80°C. After addition, the reaction solution is cooled to room temperature and add saturated aqueous sodium thiosulfate solution and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1→0:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (988 mg). MC (m/z): 655 [M+H]+.

Example 185

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (207 g) dissolved in N,N-dimethylformamide (3 ml), and then to the solution was added sodium hydride (62.7 percent, 15 mg) under cooling on ice and the resulting mixture is stirred at room temperature for 30 minutes. After adding ethyliodide (50 ml) while cooling on ice, the resulting mixture was stirred at room temperature for 2 hours. To the mixture are added water and ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography the raffia (silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-ethoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (141 mg). MC (m/z): 683 [M+H]+.

Example 188

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (100 mg), cesium carbonate (55 mg) and methyl ester of 2-chloro-2,2-DIPEROXY acid (44 mg) was dissolved in N,N-dimethylformamide (1 ml) and stirred at 75°C for 17 hours. The reaction solution is cooled to room temperature and added dropwise an aqueous solution of citric acid and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-deformedarse-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (101 mg). MC (m/z): 705 [M+H]+.

Example 187

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (775 mg) and pyridine (287 μl) dissolved in methylene chloride (5 ml), then R is the target is added dropwise triftormetilfullerenov anhydride (240 ml) while cooling on ice and the resulting mixture was stirred at the same temperature for 4 hours. To the reaction solution was added an aqueous solution of citric acid, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=6:1→2:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (567 mg). MC (m/z): 787 [M+H]+.

Example 188

A mixture of ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (732 mg), tetrakis(triphenylphosphine)palladium (catalytic amount), cyanide zinc (142 mg) and N,N-dimethylformamide (10 ml) was stirred at 95°C in a stream of nitrogen for 8 hours. After cooling to room temperature, to the reaction solution was added water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→2:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]natteri the Jn-1-carboxylic acid (572 mg). MC (m/z): 664 [M+H]+.

Example 189

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (458 mg) was dissolved in ethanol (5 ml), then to the solution was added a catalytic amount of Raney Nickel and the mixture was stirred at room temperature under nitrogen atmosphere for 5 hours. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=1:2→0:1) to give the ethyl ester of (2R,4S)-6-aminomethyl-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (211 mg). MC (m/z): 668 [M+H]+.

Example 190

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (250 mg) is dissolved in 1,4-dioxane (3 ml) and to the solution was added a catalytic amount of tetrakis(triphenylphosphine)palladium, a catalytic amount of silver carbonate and a catalytic amount of copper chloride (I) in a stream of nitrogen. After adding dropwise the solution of trimethylaluminum-hexane (1M, 480 μl) the mixture was stirred at 60°C for 30 minutes. After cooling to room is based temperature to the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (153 mg). MC (m/z): 653 [M+H]+.

Example 191

(1) 5-amino-2-methoxypyridine (5.0 g) is dissolved in methylene chloride (100 ml) and to the solution add sodium sulfate (3.5 g). The reaction solution is cooled to -25°C, then add acetaldehyde (and 2.26 ml) and the resulting mixture was stirred at the same temperature for 2 hours and 30 minutes. The sodium sulfate is removed by filtration and the filtrate is cooled to -25°C. After addition of the benzyl ester of N-vinylcarbazole acid (7,12 g) and a complex of boron TRIFLUORIDE-diethyl ether (0.51 ml) the resulting mixture was stirred at the same temperature for 1 hour and then at room temperature overnight. The reaction solution is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→3:1) to give the benzyl ether of (2R*,4S*)-(6-methoxy-2-methyl-1,2,3,34-tetrahydro[1,5]naphthiridine-4-yl)carbamino acid (8,56 g). MC (m/z): 328 [M+H]+.

(2) Benzyloxyethyl (2R*,4S*)-(6-methoxy-2-methyl-1,2,3,4-tetrahydro[1,5]naphthiridine-4-yl)carbamino acid (8,55 g) and pyridine (10,6 ml) dissolved in methylene chloride (75 ml) then the solution is added dropwise ethylchloride (12.5 ml) under cooling on ice and the resulting mixture was stirred at the same temperature for 2 hours. To the reaction solution was added an aqueous solution of citric acid, the organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→3:1) to give the ethyl ester of (2R*,4S*)-4-benzyloxycarbonylamino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (6,18 g). MC (m/z: 400 [M+H]+.

(3) Ethyl ester of (2R*,4S*)-4-benzyloxycarbonylamino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (of 5.83 g) was dissolved in a mixed solvent of ethanol (60 ml) and tetrahydrofuran (60 ml), then to the solution was added 10% palladium on coal (500 mg) and the resulting mixture was stirred at room temperature in hydrogen atmosphere for 7 hours. The catalyst was removed by filtration, the filtrate is concentrated under reduced pressure to obtain ethyl ester (2R*,4S*)-4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3,85 g). MC (m/z): 266 [M+H]+.

(4) Ethyl ester of (2R*,4S*)-4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3.80 g), 5-bromo-2-chloropyrimidine (6,92 g) and N,N-diisopropylethylamine (6,23 ml) dissolved in 1,4-dioxane (50 ml) and the resulting mixture is boiled with reverse what holodilniki for 4 hours. After cooling to room temperature the reaction solution is partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→6:4) to give the ethyl ester of (2R*,4S*)-4-(5-bromopyrimidine-2-yl)amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (of 5.92 g). MC (m/z): 422/424 [M+H]+.

(5) Ethyl ester of (2R*,4S*)-4-(5-bromopyrimidine-2-yl)amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5.9 g) was dissolved in N,N-dimethylformamide (60 ml), then to the solution was added sodium hydride (62.7 percent, 697 mg) at room temperature and the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution was added water and ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is crystallized from diisopropyl ether and hexane to obtain ethyl ester (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (6,1 g). MC (m/z): 648/650 [M+H]+.

Examples 192-195 (in Russian)

Match is their starting compound is treated analogously to example 15 with obtaining compounds, listed in table 21.

Table 21
Example No.RPhysical properties, etc.
192MS (m/z):
655 [M+H]+
193MS (m/z):
668 [M+H]+
194MS (m/z):
696 [M+H]+
195MS (m/z):
710 [M+H]+

Example 196

Ethyl ester of (2R*,4S*)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3 g), 2,5-dibromopyridine (5,09 g), Tris(dibenzylideneacetone)dipalladium (196 mg), tert-piperonyl sodium (2.1 g), 2-cyclohexylamino-2'-(N,N-dimethylamino)biphenyl (169 mg) was dissolved in toluene (30 ml) and the resulting mixture stirred at room temperature in a stream of nitrogen overnight. To the reaction solution was added a saturated solution of salt, utilized the t and the organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→8:1) to give the ethyl ester of (2R*,4S*)-4-(5-bromopyrimidine-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (306 mg). MC (m/z): 435/437 [M+H]+.

(2) the resulting product is treated as in example 1-(6) to obtain the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (207 mg). MC (m/z): 661/663 [M+H]+.

Example 197

The corresponding starting compound is treated analogously to example 196 to obtain the above compound. MC (m/z): 661/663 [M+H]+.

Examples 198-199

The corresponding starting compound is treated analogously to example 15 to obtain the compounds listed in table 22.

Table 22
Example No.ConfigurationPhysical properties, etc.
198(2R*4S*)MS (m/z):
668 [M+H]+
199(R,4S) MS (m/z):
668 [M+H]+

Example 200

Ethyl ester of (2R*,4S*)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3.3 g), 6-chloronicotinamide (4.9 g) and N,N-diisopropylethylamine (4,1 ml) dissolved in 1,4-dioxane (25 ml) and the mixture is stirred at the boil under reflux for 24 hours. To the reaction solution was added a saturated salt solution and ethyl acetate, the organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1) to give the ethyl ester of (2R*,4S*)-4-(5-cyano-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (4,13 g). MC (m/z): 382 [M+H]+.

(2) the resulting product is treated as in example 1-(6) to obtain the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-cyano-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (207 mg). MC (m/z): 608 [M+H]+.

Example 201

The corresponding starting compound is treated analogously to example 147 to provide the above compounds. MC (m/z): 651 [M+H]+.

Example 202

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(tetrazol-5-yl)pyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]h is pteridine-1-carboxylic acid (120 mg), potassium carbonate (51 mg) and excess 2-bromoethanol dissolved in N,N-dimethylformamide (3 ml) and the resulting mixture was stirred at 50°C for 2 hours. To the reaction solution was added water and ethyl acetate and the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1→1:1) to give the ethyl ester of (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]pyridine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (119 mg). MC (m/z): 695 [M+H]+.

Example 203

A suspension of ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-cyano-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (127 mg) and concentrated hydrochloric acid (2 ml) stirred at the boil under reflux for 2 hours. To the reaction solution was added water and ethyl acetate, the organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=19:1→9:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxypentyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydr what-2H-[1,5]naphthiridine-1-carboxylic acid (48 mg). MC (m/z): 627 [M+H]+.

Example 204

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-cyano-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.5 g) dissolved in ethanol (30 ml) and to the solution is added dropwise acetylchloride (14 ml) at 0°C. After adding dropwise, the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→1:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxycarbonylmethylene-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (221 mg), MC (m/z): 654 [M+H]+, ethyl ester (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carbamoylation-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (404 mg), MC (m/z): 626 [M+H]+and ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxycarbonylpyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (596 mg), MC (m/z): 655 [M+H]+.

Example 205

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxycarbonyl eilperin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (100 mg) and Ethylenediamine (150 μl) dissolved in ethanol (3 ml) and the resulting mixture is stirred at the boil under reflux for 4 hours. After cooling to room temperature, to the reaction solution was added a saturated salt solution and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=1:1→1:2) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4,5-dihydro-1H-imidazol-2-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (96 mg). MC (m/z): 651 [M+H]+.

Example 206

The corresponding starting compound is treated analogously to example 205 to provide the above compounds. MC (m/z): 652 [M+H]+.

Example 207

(1) Ethyl ester of (2R*,4S*)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,13 g) is dissolved in 1,4-dioxane (40 ml), then the solution add diisopropylethylamine (4 ml) and benzyl ether 5-chloropyrazine-2-carboxylic acid (1.9 g), the mixture was heated to 110°C in a stream of nitrogen and stirred for 20 hours. After adding distilled water, the mixture extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl is Etat=4:1→1:1) to give the ethyl ester of (2R*,4S*)-4-(5-benzyloxycarbonylamino-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2.24 g). MC (m/z): 492 [M+H]+.

(2) Ethyl ester of (2R*,4S*)-4-(5-benzyloxycarbonylamino-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2.2 g) is dissolved in N,N-dimethylformamide (20 ml), then to the solution was added sodium hydride (62.7 percent, 223 mg) under cooling on ice and the resulting mixture is stirred for 10 minutes. After adding 3.5-bistrifluormethylbenzene (1 ml), the mixture is extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R*,4S*)-4-{(5-benzyloxycarbonylamino-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,39 g). MC (m/z): 718 [M+H]+.

Example 208

The corresponding starting compound is treated analogously to example 7 to provide the above compounds. MC (m/z): 628 [M+H]+.

Example 209

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-carboxypropyl-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1 g) dissolved in toluene (8 ml), then the solution is added triethylamine (of 0.67 ml) and diphenylphosphoryl (0,52 ml) and the resulting mixture was stirred at on the th temperature in a stream of nitrogen for 1 hours. After adding saturated aqueous sodium hydrogen carbonate solution the mixture is stirred at room temperature for 2 hours. The mixture is extracted with ether, the organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in toluene (8 ml) and stirred at 80°C for 5 days. After adding water, the mixture extracted with ether. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R*,4S*)-4-{(5-aminopyridin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (540 mg). MC (m/z): 599 [M+H]+.

Example 210

Ethyl ester of (2R*,4S*)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5 g) dissolved in toluene (50 ml), then to the solution was added Tris(dibenzylideneacetone)dipalladium (293 mg), tert-piperonyl sodium (3.8 g), 2-(di-tert-butylphosphino)biphenyl (376 mg) and 2,6-dichloropyrazine (4.7 g) and the resulting mixture was stirred at room the temperature in a stream of nitrogen for 23 hours. After adding a saturated aqueous solution of sodium bicarbonate, the mixture is extracted with ether. The organic layer was washed with saturated salt solution, dried over sulfate is Agnes and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=6:1→3:1) to give the ethyl ester of (2R*,4S*)-4-(6-chloropyrazine-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5.3g). MC (m/z): 392 [M+H]+.

(2) Ethyl ester of (2R*,4S*)-4-(6-chloropyrazine-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.1 g) is dissolved in N,N-dimethylformamide (15 ml), then to the solution was added sodium hydride (62.7 percent, 139,7 mg) under cooling on ice and the mixture is stirred for 15 minutes. After adding 3.5-bistrifluormethylbenzene (0,94 ml) the mixture was stirred at room temperature for 20 hours. After adding distilled water, the mixture extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(6-chloropyrazine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (900 mg). MC (m/z): 618/620 [M+H]+.

Example 211

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(6-chloropyrazine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) was dissolved in 1,3-dimethylimidazolidine (2 ml), the m to the solution add diisopropylethylamine (0,13 ml) and morpholine (0.6 ml), the resulting mixture was heated to 100°C. and stirred for 3 days. After adding distilled water, the mixture extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[6-(morpholine-4-yl)pyrazin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (223,2 mg). MC (m/z): 669 [M+H]+.

Examples 212 and 213

The corresponding starting compound is treated analogously to example 211 to obtain the compounds listed in table 23.

Table 23
Example No.RPhysical properties, etc.
212MS (m/z):
657 [M+H]+
213MS (m/z):
671 [M+H]+

Example 214

(1) Ethyl ester of (2R*,4S*)-4-amino-2-stor is l-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5 g) dissolved in isopropanol (5 ml), then to the solution was added copper iodide (10.3 ml), ethylene glycol (0,12 ml), potassium phosphate (454 mg) and 4-(5-iodopyrimidine-2-yl)morpholine (311,5 mg) and the resulting mixture heated to 80°C. and stirred in a stream of nitrogen for 20 hours. After adding distilled water, the mixture extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=17:3→3:1) to give the ethyl ester of (2R*,4S*)-2-ethyl-6-methoxy-4-[2-(morpholine-4-yl)pyrimidine-5-yl]amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (122,2 mg). MC (m/z): 443 [M+H]+.

(2) Ethyl ester of (2R*,4S*)-2-ethyl-6-methoxy-4-[2-(morpholine-4-yl)pyrimidine-5-yl]amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (50 mg) dissolved in acetonitrile (0.5 ml), and then to the solution was added sodium hydride (62.7 percent, 5.4 mg) at room temperature and the mixture is stirred for 10 minutes. After adding 3,5-bis(trifluoromethyl)benzylbromide (27 μl) the mixture is stirred for 22 hours. After adding distilled water, the mixture extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; Gex is n:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[2-(morpholine-4-yl)pyrimidine-5-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (24,8 mg). MC (m/z): 669 [M+H]+.

Example 215

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (250 mg) is dissolved in 1,4-dioxane (3 ml) and to the solution was added a catalytic amount of tetrakis(triphenylphosphine)palladium, a catalytic amount of silver carbonate and a catalytic amount of copper chloride (I) in a stream of nitrogen. After adding dropwise the solution triethylaluminium-hexane (1M, 480 μl) and the resulting mixture was stirred at 60°C for 30 minutes. After cooling to room temperature, to the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2,6-diethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (77 mg). MC (m/z): 639 [M+H]+.

Example 216

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (18 g) is dissolved in N,N-dimethylformamide(60 ml) and to the solution was added palladium acetate (611 mg), 1,1'-bis(diphenylphosphino)ferrocene (3,02 g), ethanol (31.7 ml) and triethylamine (37,9 ml). The resulting mixture was bubbled with carbon monoxide at room temperature for 10 minutes, then heated at 90°C and stirred overnight in an atmosphere of carbon monoxide. The reaction solution is cooled to room temperature, add a saturated solution of salt and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=8:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxycarbonylpyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (12.4 g). MC (m/z): 656 [M+H]+.

Example 217

The corresponding original connection is treated analogously to example 36 to obtain the connection 217. MC (m/z): 628 [M+H]+.

Example 218

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxyamide-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in N,N-dimethylformamide (2 ml) and to the solution add triethylamine (53 μl), hydrochloride tert-butyl ester 3-methylaminopropane acid (101,14 mg), hydrate 1-hydroxybenzo the asola (65 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (92 mg) under cooling on ice. The mixture is stirred at room temperature for 21 hours. The reaction solution is concentrated under reduced pressure, then the residue partitioned between saturated aqueous sodium bicarbonate and ethyl acetate and the organic layer concentrated under reduced pressure. The resulting residue is dissolved in a solution (2 ml), 4n. hydrochloric acid in 1,4-dioxane and stirred at room temperature for 1 hour. To the reaction solution was added an excess amount of saturated aqueous sodium bicarbonate solution and the mixture is neutralized 1H. HCl, then extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give the ethyl ester of (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(2-carboxyethyl)methylcarbamoyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (223 mg). MC (m/z): 713 [M+H]+.

Example 219

The corresponding initial connection process as in example 218 with obtaining connection 219. MC (m/z): 725 [M+H]+.

Example 220

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxyamide-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in N,N-dimethyl who formamide (2 ml) and to the solution add triethylamine (53 μl), hydrochloride methyl ester 3-aminopropionic acid (67 mg), hydrate of 1-hydroxybenzotriazole (65 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (92 mg) under cooling on ice. The mixture is stirred for 21 hours. The reaction solution is concentrated under reduced pressure, then the residue partitioned between saturated aqueous sodium bicarbonate and ethyl acetate and the organic layer concentrated under reduced pressure. The resulting residue is dissolved in methanol (2 ml)solution was added 5N. aqueous NaOH solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added 6N. HCl (0,85 ml), then extracted with ethyl acetate and the organic layer concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give the ethyl ester of (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(2-carboxyethyl)carbarnoyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (190 mg). MC (m/z): 699 [M+H]+.

Examples 221-222

The corresponding starting compound is treated analogously to example 220 to obtain the compounds listed in table 24.

That the face 24
Example No.RPhysical properties, etc.
221MS (m/z): 685 [M+H]+
222MS (m/z): 699 [M+H]+

Example 223

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxyamide-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in N,N-dimethylformamide (2 ml) and to the solution is added triethylamine (67 μl), methyl ester O-(tert-butyldimethylsilyl)serine (112,02 mg), hydrate 1-hydroxybenzotriazole (64,86 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (92,02 mg). The resulting mixture was stirred at room temperature for 2.5 hours. The reaction solution is concentrated under reduced pressure, then the residue partitioned between saturated aqueous sodium bicarbonate and ethyl acetate and the organic layer concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (2 ml), to the solution was added 1M solution of 1M tetrabutylammonium fluoride-tetrahydrofuran (0,55 ml) and the resulting mixture was stirred at room is based temperature for 10 minutes. The reaction solution is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxy-1-methoxycarbonylaminophenyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (of 229.5 mg). MC (m/z): 729 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxy-1-methoxycarbonylaminophenyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (220 mg) is dissolved in methanol (3 ml), to the solution was added 2n. aqueous NaOH solution (3 ml) and the mixture is stirred at room temperature for 23 hours. The reaction solution is partitioned between 6N. HCl (1 ml) and chloroform and the organic layer is dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=49:1→19:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-carboxy-2-hydrooximethylcarbamil)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (133,5 mg). MC (m/z): 713 [M+H]+.

Example 224

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-arbonboy acid (300 mg) is dissolved in toluene (5 ml) and to the solution was added Tris(dibenzylideneacetone)dipalladium (41 mg), tert-piperonyl sodium (65 mg), 2-(di-tert-butylphosphino)biphenyl (54 mg) and tert-butyl methyl ether 3-methylaminopropane acid (108 mg). The resulting mixture is stirred overnight in a stream of nitrogen at room temperature. The reaction solution is cooled to room temperature, and then distributed between ethyl acetate and a saturated solution of salt. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane-ethyl acetate=9:1→3:1) to give the ethyl ester of (2R,4S)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{[methyl-(2-tert-butoxycarbonylmethyl)]amino}pyrimidine-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (106 mg). MC (m/z): 741 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{[methyl-(2-tert-butoxycarbonylmethyl]amino}pyrimidine-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (100 mg) is dissolved in a solution of 4n. HCl/ethyl acetate (1 ml) and stirred at room temperature for 30 minutes. The reaction solution is partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure and the obtained estato is purified column chromatography (silica gel; hexane-ethyl acetate=4:1→0:1) to give the ethyl ester of (2R,4S)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{[methyl-(2-carboxyethyl)]amino}pyrimidine-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (55 mg). MC (m/z): 685 [M+H]+.

Example 225

The corresponding original connection is treated analogously to example 224 getting connection 225. MC (m/z): 729 [M+H]+.

Example 226

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxyamide-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1 g) dissolved in toluene (25 ml) and to the solution add triethylamine (0,66 ml), diphenylphosphoryl (0,52 ml) and benzyl alcohol (0.2 ml). The mixture is heated at 90°C and stirred overnight. The reaction solution is cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane-ethyl acetate=4:1→3:2) to give the ethyl ester of (2R,4S)-4-{(5-benzyloxycarbonylamino-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.1 g). MC (m/z): 733 [M+H]+/sup> .

(2) Ethyl ester of (2R,4S)-4-{(5-benzyloxycarbonylamino-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.1 g) is dissolved in N,N-dimethylformamide (15 ml) and to the solution was added 63% sodium hydride (69 mg) under cooling on ice. The reaction mixture is stirred for 30 minutes, add ethyl-4-bromobutyrate (0.33 ml) while cooling on ice and the resulting mixture was stirred at room temperature for 2.5 hours. The mixture is partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane-ethyl acetate=9:1→7:3) to give the ethyl ester of (2R,4S)-4-({5-[benzyloxycarbonyl(3-ethoxycarbonylphenyl)]aminopyrimidine-2-yl}-[3,5-bis(trifluoromethyl)benzyl])amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (898 g). MC (m/z): 847 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-({5-[benzyloxycarbonyl(3-ethoxycarbonylphenyl)]aminopyrimidine-2-yl}-[3,5-bis(trifluoromethyl)benzyl])amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) dissolved in methanol (12 ml) and to the solution was added 1N. aqueous NaOH solution (2 ml). The resulting mixture was stirred at to the room temperature for 1 day. To the mixture is added 1N. HCl and the reaction solution was concentrated under reduced pressure. The remainder is distributed by the addition of ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane-ethyl acetate=1:0→9:1) to give the ethyl ester of (2R,4S)-4-({5-[benzyloxycarbonyl(3-carboxypropyl)]aminopyrimidine-2-yl}-[3,5-bis(trifluoromethyl)benzyl])amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (219 g). MC (m/z): 819 [M+H]+.

(4) Ethyl ester of (2R,4S)-4-({5-[benzyloxycarbonyl(3-carboxypropyl)]aminopyrimidine-2-yl}-[3,5-bis(trifluoromethyl)benzyl])amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (154 mg) was dissolved in methanol (5 ml) and to the solution was added 10% palladium on coal (25 mg). The resulting mixture was stirred for 1.5 hours in an atmosphere of hydrogen. The reaction solution is filtered and then concentrated under reduced pressure. The resulting solution was purified column chromatography (silica gel; chloroform:methanol=9:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropyl)aminopyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (98 mg). MC (m/z): 685 [M+H]+.

Example 227

The corresponding original connection is treated analogously to example 226 getting connection 227. MC (m/z): 599 [M+H]+.

Example 228

The corresponding original connection is treated analogously to example 14 with the connection 228. MC (m/z): 657 [M+H]+.

Example 229

Ethyl ester of (2R,4S)-4-{(5-aminopyridin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (500 mg) dissolved in acetonitrile (10 ml) and to the solution add oxetan-2-he (0,08 ml). The resulting mixture was refluxed for 3 days. The reaction solution is cooled to room temperature and concentrate under reduced pressure. The resulting solution was purified column chromatography (silica gel; chloroform:methanol=1:0→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethyl)aminopyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (199 mg). MC (m/z): 671 [M+H]+.

Example 230

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethyl)aminopyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) dissolved in a mixture of tetrahydrofuran (5 ml) and methanol (1 ml) and to the solution was added 2.0m solution trimethylsilyldiazomethane in hexane (0, ml). The resulting mixture was stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel; hexane-ethyl acetate=7:3→3:2) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylethyl)aminopyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (232 g). MC (m/z): 685 [M+H]+.

Example 231

(1) Ethyl ester of (2R,4S)-4-{(5-benzyloxycarbonylamino-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) is dissolved in tetrahydrofuran (5 ml) and to the solution was added 63% sodium hydride (20 mg) under cooling on ice. The resulting mixture was stirred for 30 minutes and to the solution add methyliodide (30 ml) while cooling on ice. The resulting mixture is stirred over night at room temperature and then partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane-ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{[methyl(benzyloxycarbonyl)]amino}pyrimidine-2-yl)]amino-2-ethyl-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (275 mg). MC (m/z): 747 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{[methyl(benzyloxycarbonyl)]amino}pyrimidine-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1,34 g) dissolved in methanol (20 ml) and to the solution was added 10% palladium on coal (250 mg). The resulting mixture is stirred for 3 hours in hydrogen atmosphere. The reaction solution is filtered and then the filtrate is concentrated under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane-ethyl acetate=17:3→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methylaminopropyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (698 mg). MC (m/z): 613 [M+H]+.

Example 232

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methylaminopropyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in N,N-dimethylformamide (5 ml) and to the solution was added ethyl-4-bromobutyrate (13 μl) and potassium carbonate (50 mg). The resulting mixture is heated at 50°C and stirred for 2 hours. The reaction solution is cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then conc the shape under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane-ethyl acetate=9:1→3:2) to give the ethyl ester of 4-(2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(3-ethoxycarbonylphenyl)methyl]aminopyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (85 mg). MC (m/z): 727 [M+H]+.

Example 233

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) is dissolved in toluene (4 ml) and to the solution was added Tris(dibenzylideneacetone)dipalladium (42 mg), tert-piperonyl sodium (65 mg), 2-(di-tert-butylphosphino)biphenyl (54 mg) and piperidine-4-elatinaceae (116 mg). The resulting mixture is stirred over night at room temperature in a stream of nitrogen and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane-ethyl acetate=9:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylmethylene-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (125 mg). MC (m/z): 753 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trif ormetal)benzyl]-[5-(4-ethoxycarbonylmethylene-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (106 mg) was dissolved in methanol (8 ml) and to the solution was added 1N. aqueous NaOH solution (3 ml). The resulting mixture was stirred at room temperature for 3.5 hours and add 1N. HCl and ethyl acetate for distribution. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxymethyllysine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (70 mg). MC (m/z): 725 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxymethyllysine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (62 mg) was dissolved in ethanol (3 ml) and to the solution was added 1N. an aqueous solution of NaOH (84 μl). The resulting mixture was stirred at room temperature for 5 minutes. The reaction solution is concentrated under reduced pressure to obtain sodium salt of the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxymethyllysine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (56 mg). MC (m/z): 723 [M+H]+.

Examples 234-235

The corresponding starting compound is treated analogously to example 233 (1)-(2) getting connected is th, listed in table 25.

Table 25
Example No.R RN-Physical properties, etc.
234MS (m/z): 711 [M+H]+
235MS (m/z): 713 [M+H]+

Example 236

The corresponding original connection is treated analogously to example 233 (2)-(3) with connection 236. MC (m/z): 697 [M-Na]-.

Examples 237-238

The corresponding starting compound is treated analogously to example 233 (3) to obtain the compounds listed in table 26.

Table 26
Example No.R RN-Physical properties, etc.
237MS (/z): 711 [M+H] +
238MS (m/z): 669 [M-Na]-

Example 239

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(piperazine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in ethanol (3 ml) and to the solution was added sodium bicarbonate (to 76.4 mg) and cyanogenmod (35 mg). The resulting mixture was stirred at room temperature for 13 hours and partitioned between water and diethyl ether to the reaction solution. The resulting mixture was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-cyanopiperidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (183 mg). MC (m/z): 693 [M+H]+.

Example 240

(1), hydroxylamine Hydrochloride (45,2 mg) dissolved in dimethyl sulfoxide (1.5 ml) and to the solution add triethylamine (90,6 µl). To the reaction solution was added a tetrahydrofuran insoluble matter is removed by filtration and the filtrate is evaporated to remove the tetrahydrofuran under reduced pressure the AI. To the resulting solution was added ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-cyanopiperidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (80 mg), the mixture is heated at 75°C and stirred for 15 hours. The reaction solution is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain crude ethyl ester (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[4-(N-hydroxycarbamoyl)piperazine-1-yl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid. MC (m/z): 726 [M+H]+.

(2) the Crude ethyl ester of (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[4-(N-hydroxycarbamoyl)piperazine-1-yl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid is dissolved in acetonitrile (1 ml) and to the solution add carbodiimides (29 mg). The resulting mixture is heated at 60°C and stirred for 17 hours. The reaction solution is cooled to room temperature and add 1N. HCl and ethyl acetate for distribution. The resulting solution was washed with water and saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. Received about who headed the remainder of the purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give the ethyl ester of (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[4-(5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)piperazine-1-yl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (42 mg). MC (m/z): 752 [M+H]+.

Example 241

The corresponding original connection is treated analogously to example 147 with obtaining connection 241. MC (m/z): 736 [M+H]+.

Example 242

(1) Ethyl ester of (2R,4S)-4-{(5-aminopyridin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in N,N-dimethylformamide (4 ml) and to the solution was added 4-tert-butyl-(S)-2-tert-butoxycarbonylmethylene (123 mg) and 1-hydroxybenzotriazole (68 mg)were then added while cooling on ice monohydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (96 mg) and triethylamine (0.06 ml). The resulting mixture was stirred at room temperature for 2 hours and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(triform the Teal)benzyl]-[5-((S)-3-tert-butoxycarbonyl-2-tert-butoxycarbonylmethylene)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (242 mg). MC (m/z): 870 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-((S)-3-tert-butoxycarbonyl-2-tert-butoxycarbonylmethylene)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (235 mg) was dissolved in dichloromethane (10 ml) and to the solution add triperoxonane acid (1 ml). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=9:1→0:1) to give the ethyl ester of (2R,4S)-4-{[5-((S)-2-amino-3-carboxymethylamino)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (103 mg). MC (m/z): 712 [M-N]-.

Example 243

(1) Ethyl ester of (2R,4S)-4-{(5-aminopyridin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (273 mg) was dissolved in N,N-dimethylformamide (5 ml) and to the solution was added methyl-3-chlororespiration (67 μl) and triethylamine (0,19 ml) under cooling on ice. The resulting mixture was stirred at room temperature for 1 hour and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The floor is built the residue purified column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-methoxycarbonylpropionyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (138 mg) as a crude product. MC (m/z): 713 [M+H]+.

(2) the Crude product (130 mg), ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-methoxycarbonylpropionyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid is treated analogously to example 233 (2) to obtain ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxymethylamino)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (121 mg). MC (m/z): 699 [M+H]+.

Example 244

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxamidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (500 mg) dissolved in toluene (10 ml) and to the solution add triethylamine (0,66 ml), diphenylphosphoryl (0,52 ml) and methanol (1 ml). The resulting mixture is heated at 60°C and stirred for 2 days. The reaction solution is cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated the ri reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methoxycarbonylaminophenyl-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (25 mg). MC (m/z): 657 [M+H]+.

Example 245

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-aminopyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (400 mg) dissolved in dichloromethane (5 ml) and to the solution was added N,N'-carbonyldiimidazole (162 mg) and triethylamine (0,28 ml). The resulting mixture was stirred at room temperature for 1.5 hours, then dobavlayet-1,2-diol (75 μl). The mixture is stirred for 3 days and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyacetanilide)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (222 mg). MC (m/z): 687 [M+H]+.

Examples 246-248

The corresponding starting compound is treated analogously to example 245 obtaining compounds, re olenych in table 27.

Table 27
Example No.R-Physical properties, etc.
246MS (m/z): 701 [M+H]+
247MS (m/z): 715 [M+H]+
248MS (m/z): 757 [M+H]+

Example 249

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyacetanilide)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (192 mg) dissolved in acetone (5 ml) and to the solution add 2,M oxide chromium (VI) in dilute sulfuric acid solution (320 ml) while cooling on ice. The resulting mixture was stirred for 4.5 hours and partitioned between sodium bisulfite, water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified speakers chromatog what afia (silica gel; chloroform:methanol=9:0→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxymethylaminomethyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (78 mg). MC (m/z): 701 [M+H]+.

Examples 250-251

The corresponding starting compound is treated analogously to example 249 obtaining the compounds listed in table 28.

Example 28
Example No.R-Physical properties, etc.
250MS (m/z): 715 [M+H]+
251MS (m/z): 729 [M+H]+

Example 252

The corresponding original connection is treated analogously to example 121 obtaining connection 252. MC (m/z): 717 [M+H]+.

Example 253

The corresponding original connection is treated analogously to example 243 getting connection 253. MC (m/z): 727 [M+H]+.

Example 254

img src="https://img.russianpatents.com/888/8884259-s.jpg" height="43" width="72" />

The corresponding original connection is treated analogously to example 233 (2) with connection 254. MC (m/z): 713 [M+H]+.

Example 255

The corresponding original connection is treated analogously to example 62 with obtaining connection 255. MC (m/z): 727 [M+H]+.

Example 256

The corresponding original connection is treated analogously to example 233 getting connection 256. MC (m/z): 711 [M-Na]-.

Example 257

(1) Ethyl ester of (2R,4S)-4-{(5-aminopyridin-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) is dissolved in N,N-dimethylformamide (4 ml) and to the solution was added methyl-3-chlorocarbonate (116 μl) and triethylamine (280 μl). The resulting mixture was stirred at room temperature for 4 hours and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methoxycarbonylaminophenyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic to the slots (247 mg). MC (m/z): 657 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methoxycarbonylaminophenyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (238 mg) is treated analogously to example 226 (2) and (3) to give the ethyl ester of (2R,4S)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{(3-carboxypropyl)-(methoxycarbonyl)]amino}pyrimidine-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (187 mg). MC (m/z): 743 [M+H]+.

Example 258

The corresponding original connection is treated analogously to example 233 (3) to obtain the compound 258. MC (m/z): 741 [M-Na]-.

Example 259

(1) Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in tetrahydrofuran (2 ml) and to the solution add metallated (174 mg) and triphenylphosphine (438 mg), then add dropwise a solution of (0,73 ml) 40% of diethylazodicarboxylate in toluene while cooling with water. The resulting mixture was stirred at room temperature for 3 hours and add water. The resulting solution was extracted with ethyl acetate and the organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. To the obtained residue, add methi anchored, isopropyl ether and hexane, the precipitated insoluble substances are removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=6:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (157 mg). MC (m/z): 686 [M+H]+.

(2) Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (154 mg) was dissolved in tetrahydrofuran (2 ml) and to the solution is added dropwise a solution of 1.12 ml) of 1M diisobutylaluminium in toluene while cooling on ice and the resulting mixture is stirred at 0°C for 3 hours. To the reaction mixture is added 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxy-1-methylethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (88 mg). MC (m/z): 658 [M+H]+ .

Examples 260-264

The corresponding starting compound is treated analogously to example 250 (1) to obtain the compounds listed in table 29.

Table 29
Example No.R-Physical properties, etc.
260MS (m/z): 688 [M+H]+
261MS (m/z): 700 [M+H]+
262MS (m/z): 714 [M+H]+
263MS (m/z): 714 [M+H]+
264MS (m/z): 754 [M+H]+

Example 265

The corresponding original connection is treated analogously to example 114 by receiving connection 265. MC (m/z): 716 [M+H]+.

Examples 266-27

The corresponding starting compound is treated analogously to example 121 to obtain the compounds listed in table 30.

Table 30
Example No.R-Physical properties, etc.
266MS (m/z): 674 [M+H]+
267MS (m/z): 674 [M+H]+

Example 268

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (170 mg) is dissolved in methylene chloride (3 ml) and to the solution was added 4-methoxycarbonylpropionyl acid (51 mg), copper acetate (II) (52 mg), triethylamine (79 μl) and molecular sieves 4Å (170 mg). The resulting mixture is stirred over night at room temperature. Insoluble substances are removed by filtration and the filtrate is distributed between ethyl acetate and a saturated solution of salt. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and is eat concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→3:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-methoxycarbonylbenzyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (132 mg). MC (m/z): 734 [M+H]+.

Example 269

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in tetrahydrofuran (3 ml) and to the solution was added at room temperature tert-piperonyl potassium (28 mg) and β-propiolactone (16 μl). The reaction solution is stirred over night at room temperature and then added ethyl acetate and 1N. HCl for distribution. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) and LC/MS (CAPCEL PAK MFII (SHISEIDO), water:methanol=60:40 → 0:100, 40 ml/min) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxymethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (12 mg). MC (m/z): 672 [M+H]+.

Example 270

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidine-2-yl)}amino-2-etil-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3.5 g) and ethyl-4-bromobutyrate (928 mg) is dissolved in N,N-dimethylformamide (20 ml) and to the solution was added potassium carbonate (969 mg). The resulting mixture is stirred over night at 50°C. the Reaction solution is cooled to room temperature and distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→3:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3.77 g). MC (m/z): 714 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3,71 g) dissolved in ethanol (35 ml) and to the solution was added 2n. aqueous NaOH solution (7.8 ml). The mixture is stirred over night at room temperature. The reaction solution is concentrated under reduced pressure and the residue is added ethyl acetate and 1N. HCl for distribution. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropyl is C)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3.55 g). MC (m/z): 686 [M+H]+.

Example 271

The corresponding original connection is treated analogously to example 270 obtaining connection 271. MC (m/z): 700 [M+H]+.

Examples 272-275

The corresponding starting compound is treated analogously to example 270 (1) to obtain the compounds listed in table 31.

Table 31
Example No.R-Physical properties, etc.
272MS (m/z): 728 [M+H]+
273MS (m/z): 742 [M+H]+
274MS (m/z): 756 [M+H]+
275MS (m/z): 684 [M+H]+

Examples 276-280

The corresponding starting compound is treated analogously to example 270 (2) to obtain the connection, read the IP table 32.

Table 32
Example No.R-Physical properties, etc.
276MS (m/z): 726 [M+H]+
277MS (m/z): 720 [M+H]+
278MS (m/z): 700 [M+H]+
279MS (m/z): 714 [M+H]+
280MS (m/z): 728 [M+H]+

Example 281

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-oxitetraciclina-3-yloxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg) is dissolved in ethanol (1 ml) and to the solution was added 2n. aqueous NaOH solution (1 ml). The resulting mixture was stirred at room temperature for 3 hours and EXT the keys 1H. HCl (2 ml) and ethyl acetate for distribution. The organic layer is concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=19:1→9:1). The resulting residue is dissolved in ethanol (1 ml) and to the solution was added 2n. aqueous NaOH solution (81 ml), then concentrated under reduced pressure to obtain sodium salt of the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-carboxy-3-hydroxypropoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (114 mg). MC (m/z): 700 [M-Na]-.

Example 282

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxycarbonylpyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1 g) dissolved in tetrahydrofuran (7 ml) and to the solution add a solution of 1M diisobutylaluminium-tetrahydrofuran (3,36 ml) under cooling on ice. The mixture is stirred at room temperature for 2 hours. To the reaction solution was added saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→2:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bistritei)benzyl]-(5-hydroxyethylpyrrolidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (760 mg). MC (m/z): 614 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxyethylpyrrolidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (735 mg) was dissolved in chloroform (5 ml) and to the solution was added manganese dioxide (2 g). The mixture is stirred over night at room temperature. Manganese dioxide is removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-formylpyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (450 mg). MC (m/z): 612 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-formylpyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (185 mg), tert-butyl ester of L-Proline (62 mg), acetic acid (35 μl) dissolved in 1,2-dichloroethane (3 ml) and to the solution add triacetoxyborohydride sodium (128 mg). The mixture is stirred at room temperature for 2 hours and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column items is matography (silica gel; hexane:ethyl acetate=9:1→1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-(S)-tert-butoxycarbonylamino-1-ylmethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg). MC (m/z): 767 [M+H]+.

Example 283

The corresponding original connection is treated analogously to example 224 (2) to obtain the compound 283. MC (m/z): 711 [M+H]+.

Example 284

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxyamide-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (335 mg) was dissolved in methylene chloride (2 ml) and to the solution add oxalicacid (70 μl) and a drop of N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, the residue is dissolved in tetrahydrofuran (1 ml) and acetonitrile (1 ml) and added trimethylamine (93 μl) and a solution of 2M trimethylsilyldiazomethane-hexane (587 μl). The mixture is stirred over night at room temperature. The reaction solution is concentrated under reduced pressure and to the residue is added 2,6-lutidine (500 ml) and benzyl alcohol (500 ml). The resulting mixture was stirred at 150°C for 15 minutes. The reaction solution is cooled to room temperature and extracted with ethyl is the Etat and 1H. HCl. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→3:1) to give the ethyl ester of (2R,4S)-4-{(5-benzyloxycarbonylamino-2-yl)-[3,5-bis(trifluoromethyl)benzyl]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (60 mg). MC (m/z): 732 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{(5-benzyloxycarbonylamino-2-yl)-[3,5-bis(trifluoromethyl)benzyl]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (53 mg) was dissolved in ethanol (0.5 ml) and to the solution was added 10% palladium on coal (10 mg). The mixture is stirred in hydrogen atmosphere at room temperature for 3 hours. Palladium on coal is filtered and then the filtrate is concentrated under reduced pressure to obtain ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxymethylaminomethyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (44 mg) MS (m/z): 642 [M+H]+.

Example 285

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxyethylpyrrolidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (130 mg) was dissolved in acetone (2.5 ml) and the solution domavladelec potassium (108 mg) and ethylbromoacetate (0,129 ml). The mixture is stirred at room temperature for 6 days. The reaction solution is concentrated under reduced pressure and water is added. The mixture is stirred for 40 hours and distribute by adding chloroform to the reaction solution. The organic layer is dried over magnesium sulfate, and then concentrated under reduced pressure to obtain ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-karboksimetoksimetilguanina-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (to 33.8 mg). MC (m/z): 672 [M+H]+.

Example 286

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxyethylpyrrolidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (170 mg) was dissolved in dimethyl sulfoxide (45 ml) and to the solution was added 5N. aqueous NaOH solution (5 μl) and tert-butyl ester of acrylic acid (0,14 ml). The mixture is stirred at room temperature for 1 hour and partitioned between water and diethyl ether. The organic layer is dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-tert-butoxycarbonyloxyimino)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carbon is howling acid (161 mg). MC (m/z): 742 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-tert-butoxycarbonyloxyimino)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (155 mg) is dissolved in a solution (3 ml), 4n. HCl in 1,4-dioxane and the mixture is stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxylatomethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (145 mg). MC (m/z): 686 [M+H]+.

Example 287

The corresponding original connection is treated analogously to example 233 (3) to obtain the compound 287. MC (m/z): 656 [M+H]+.

Example 288

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxyethylpyrrolidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (526 mg) dissolved in chloroform (3 ml) and to the solution was added manganese dioxide (1.5 g). The mixture is stirred at room temperature for 19 hours. The reaction solution is filtered through Celite™ and the filtrate concentrated under reduced pressure to obtain ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)be the ZIL]-(5-formylpyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (500 mg). MC (m/z): 612 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-formylpyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in toluene (3 ml) and to the solution was added methyl ether, benzyloxycarbonylamino(diethoxyphosphoryl)acetic acid (238 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene (98 µl). The mixture is stirred at room temperature for 18 hours and add 1N. HCl and ethyl acetate for distribution. The organic layer is washed with water and saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel: hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R,4S)-4-{[5-((Z)-2-benzyloxycarbonylamino-2-methoxycarbonylbenzyl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (209 mg). MC (m/z): 817 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-{[5-((Z)-2-benzyloxycarbonylamino-2-methoxycarbonylbenzyl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) dissolved in methanol (4 ml) and to the solution was added 10% palladium on coal (140 mg). The mixture is stirred in hydrogen atmosphere at room temperature for 22 hours. The reaction solution is filtered and Phi is Trat concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give the ethyl ester of (2R,4S)-4-{[5-(2-amino-2-methoxycarbonylethyl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (118 mg). MC (m/z): 685 [M+H]+.

Example 289

The corresponding original connection is treated analogously to example 233 (2) to obtain the compound 289. MC (m/z): 671 [M+H]+.

Example 290

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-hydroxypropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (940 mg) was dissolved in dichloromethane (20 ml) and to the solution was added triphenylphosphine (850 mg) and tetrabromide carbon (1.0 g). The mixture is stirred at room temperature for 1 hour and partitioned between water and chloroform. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-bromopropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (576 mg) as a crude product. MC (m/z): 704/706 [M+H]+

(2) the Crude product (150 mg), ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-bromopropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid is dissolved in N,N-dimethylformamide (4 ml) and to the solution was added morpholine (60 μl). The mixture is stirred at room temperature for 2 days and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-{5-[3-(morpholine-4-yl)propyl]pyrimidine-2-ml}]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (114 mg). MC (m/z): 711 [M+H]+.

Example 291

(1) the Crude product (230 mg), ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-bromopropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid is dissolved in tetrahydrofuran (4 ml) and to the solution add 15% solution methanolate sodium (0.3 ml). The mixture is stirred at room temperature for 4.5 hours and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced is the making. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-methylsulfinylpropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (216 mg) as a crude product. MC (m/z): 672 [M+H]+.

(2) the Crude product (210 mg), ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-methylsulfinylpropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid is dissolved in chloroform (4 ml) and to the solution was added m-chloroperbenzoic acid (160 mg). The mixture is stirred at room temperature for 2 hours and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=7:3→2:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-methanesulfonyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (63 mg). MC (m/z): 704 [M+H]+.

Example 292

The corresponding original connection is treated analogously to example 137 to receive the drug connection 292. MC (m/z): 635 [M+H]+.

Example 293

The copper bromide (I) (746 mg) is suspended in tetrahydrofuran (5 ml), the solution is added dropwise 65% solution in toluene (3,23 g) bis(2-methoxyethoxy)aluminiumhydride sodium when cooled on ice under nitrogen atmosphere and the resulting mixture is stirred for 30 minutes. The reaction solution is cooled to -78°C and add 2-butanol (954 μl) and ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-cyanophenyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (330 mg). The resulting mixture was stirred at the same temperature for 2 hours and then stirred at room temperature for 2 hours. To the reaction solution was added saturated aqueous solution of ammonium chloride, the insoluble matter is removed by filtration through Celite™ and the obtained filtrate is distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-cyanoethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (254 mg). MC (m/z): 637 [M+H]+.

Example 294

The corresponding original connection is treated analogously to example 147 with obtaining connection 294. MC (m/z): 680 [M+H]+.

Example 295

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-hydroxypropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1 g) and triphenylphosphine (491 mg) was dissolved in dichloromethane (10 ml) and to the solution add tetrabromide carbon (775 mg). The resulting mixture is stirred over night at room temperature. The reaction solution is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-bromopropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (955 mg). MC (m/z): 704/706

[M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-bromopropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (946 mg) and 3-methoxy-3-oxoprop-1-sulfinate sodium (281 mg) was dissolved in dimethyl sulfoxide (8 ml) and the resulting mixture is stirred over night in a stream of nitrogen at room temperature. To the reaction solution was added water and ethyl acetate and the organic layer was washed with saturated salt solution, then dried over sulfate magnify concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1→1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-{5-[3-(2-methoxycarbonylaminophenyl)propyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (801 mg). MC (m/z):

776 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-{5-[3-(2-methoxycarbonylaminophenyl)propyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) and 2n. an aqueous solution of NaOH (516 μl) dissolved in ethanol (3 ml) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution was added 2n. an aqueous solution of HCl (520 μl) and the resulting mixture is stirred over night. To the reaction mixture are added ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-sulfopropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (96 mg). MC (m/z): 704 [M+H]+.

Example 296

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-sulfopropyl)pyrimidine-2-yl]}amino-2-ethyl-6-labels and-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (125 mg) is dissolved in thionyl chloride (3 ml) and stirred at 80°C for 2 hours. The reaction solution is cooled to room temperature and then concentrated under reduced pressure. To the obtained residue is added chloroform (3 ml), then add a solution (2 ml) 7h. ammonia in methanol while cooling on ice. The resulting mixture was stirred at room temperature for 3 hours. To the reaction solution was added water and ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-methoxycarbonylpropionyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (29 mg), MC (m/z): 720 [M+H]+and ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-sulfamoylbenzoyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (10 mg), MC (m/z): 705 [M+H]+.

Example 297

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-cyanoethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (500 mg) is dissolved in ethanol (5 ml) and to the solution was added sodium carbonate (292 mg) and hydroxylamine hydrochloride (192 mg). The resulting mixture is heated at 80°C and stirred for 31,5 h the owls. The reaction solution is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-{5-[2-(N-hydroxycarbamoyl)ethyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (297 mg) MS (m/z): 670 [M+H]+and ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carbamoylethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (140 mg), MC (m/z): 655 [M+H]+.

Example 298

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-{5-[2-(N-hydroxycarbamoyl)ethyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (140 mg) is dissolved in acetonitrile (1 ml) and to the solution add carbodiimides (51 mg). The mixture is heated at 60°C and stirred for 25,5 hours. The reaction solution is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chronochromie (silica gel; chloroform:methanol=1:0→19:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-{5-[2-(5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)ethyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (84 mg). MC (m/z): 696 [M+H]+.

Example 299

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2.0 g), cyanide zinc (352 mg) and tetrakis(triphenylphosphine)palladium (347 mg) was dissolved in N,N-dimethylformamide (10 ml) and stirred under nitrogen atmosphere at 100°C for 4 hours. The reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→3:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-cyanopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1,69 g). MC (m/z): 609 [M+H]+.

Example 300

The corresponding original connection is treated analogously to example 147 with obtaining connection 300. MC (m/z): 652 [M+H]+.

Example 301

The corresponding original connection handling is up analogously to example 202 with receiving a connection 301. MC (m/z): 696 [M+H]+.

Example 302

Hydroxylamine hydrochloride (285 mg) was dissolved in dimethyl sulfoxide (4 ml) and to the solution add triethylamine (0,57 ml). To the reaction solution was added a tetrahydrofuran insoluble matter is removed by filtration and the filtrate is evaporated to remove the tetrahydrofuran under reduced pressure. To the resulting solution was added ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-cyanopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (500 mg), the mixture was heated at 75°C and stirred for 1 hour. The reaction solution is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure to obtain solution of ethyl (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-(N-hydroxycarbamoyl)pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (510 mg). MC (m/z): 642 [M+H]+.

Example 303

The corresponding initial connection process as in example 298 getting connection 303. MC (m/z): 668 [M+H]+.

Example 304

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-Digi the ro-2H-[1,5]naphthiridine-1-carboxylic acid (250 mg) is dissolved in N,N-dimethylformamide (2 ml) and to the solution was added tetrakis(triphenylphosphine)palladium (81 mg), pyridine-3-Bronevoy acid (87 mg) and potassium carbonate (117 mg). The resulting mixture was stirred in a stream of nitrogen at 100°C for 2 hours. After cooling to room temperature, to the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-{5-[pyridin-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (96 mg) MS (m/z): 661 [M+H]+.

Example 305

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyridin-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (812 mg) and benzylbromide (292 μl) dissolved in acetonitrile (8 ml) and stirred at 50°C for 6 hours. The reaction solution is concentrated under reduced pressure, the residue is crystallized and washed with isopropyl ether to obtain 1-benzyl-3-(2-{[3,5-bis(trifluoromethyl)benzyl]-((2R,4S)-1-etoxycarbonyl-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine-4-yl)}aminopyrimidine-5-yl)pyridinylamino (1.01 g). MC (m/z): 661 [M+H-PhCH2Br]+.

(2) 1-benzyl-3-(2-{[3,5-bis(trifluoromethyl)benzyl]-((2R,4S)-1-etoxycarbonyl-2-ethyl-6-labels and-1,2,3,4-tetrahydro[1,5]naphthiridine-4-yl)}aminopyrimidine-5-yl)pyridineboronic (117 mg) was dissolved in methanol (2 ml) and to the solution add tetrahydroborate sodium (11 mg). The resulting mixture was stirred in a stream of nitrogen at room temperature for 10 minutes. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, the organic layer was washed with saturated salt solution, then dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→2:1) to give the ethyl ester of (2R,4S)-4-{[5-(1-benzyl-1,2,5,6-tetrahydropyridine-3-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (65 mg). MC (m/z): 755 [M+H]+.

Example 306

Ethyl ester of (2R,4S)-4-{[5-(1-benzyl-1,2,5,6-tetrahydropyridine-3-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (432 mg) dissolved in methanol (10 ml), the solution is added catalytic amount of 10% palladium on coal and the mixture is stirred overnight in a hydrogen atmosphere at room temperature. The catalyst (10% palladium on coal) is removed by filtration and then the filtrate is concentrated under reduced pressure. The precipitate purified column chromatography (NH-silica gel; hexane:ethyl acetate=1:2→0:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(piperidine-3-yl)pyrimidine-2-yl]}amine is-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (177 mg). MC (m/z): 667 [M+H]+.

Example 307

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(piperidine-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (143 mg) and triethylamine (45 μl) dissolved in dichloromethane (2 ml)to the solution add acetylchloride (23 ml) at 0°C and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added an aqueous solution of citric acid and dichloromethane. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:2→0:1) to give the ethyl ester of (2R,4S)-4-{[5-(1-acetylpiperidine-3-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (134 mg). MC (m/z): 709 [M+H]+.

Example 308

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyridin-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (402 mg) was dissolved in dichloromethane (5 ml)solution was added m-chloroperbenzoic acid (210 mg) under cooling on ice and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous solution of sodium bicarbonate. Organic is the cue layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→49:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-oxypyridine-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (361 mg). MC (m/z): 677 [M+H]+.

Example 309

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-oxypyridine-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (272 mg) was dissolved in acetic anhydride (3 ml) and stirred at the boil under reflux for 3 days. The reaction solution is cooled to room temperature and concentrate under reduced pressure. The resulting residue is dissolved in methanol, added to a solution of concentrated aqueous ammonia solution and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure and the resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:2→0:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxypyridine-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg). MC (m/z): 677 [M+H]+.

Example 310

(1) Atila the initial ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) is dissolved in N,N-dimethylformamide (2.5 ml) and to the solution was added tetrakis(triphenylphosphine)palladium (98 mg), pinacolyl ether 5-formylpyridine-3-Bronevoy acid (197 mg) and sodium carbonate (108 mg). The mixture is stirred overnight in a stream of nitrogen at 100°C. After cooling to room temperature, to the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure to obtain ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-formylpyridine-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (69 mg). MC (m/z): 689 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-formylpyridine-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (65 mg) was dissolved in tert-butyl alcohol (of 0.67 ml), to the solution was added water (0,18 ml), 2-methyl-2-butene (44 μl) and the dihydrate Mononitrate (15 mg) and slowly add the sodium chlorite (36 mg) under cooling with water. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture is added 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified the column chromatography (silica gel; hexane:ethyl acetate=19:1→9:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-carboxypentyl-3-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (54 mg). MC (m/z): 705 [M+H]+.

Example 311

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (100 mg) dissolved in chloroform (1.5 ml)solution was added m-chloroperbenzoic acid (48 mg) and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over magnesium sulfate. Acid contamination is removed using a small number NH-silica gel, and the organic layer concentrated under reduced pressure. To the obtained residue is added diethyl ether and isopropyl ether, and the precipitated crystals are removed by filtration to obtain ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-exmortis-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (89 mg). MC (m/z): 685 [M+H]+.

Example 312

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl][5-(3-hydroxypropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (750 mg) is dissolved in chloroform (15 ml) and to the solution was added m-chloroperbenzoic acid (303 mg) under cooling on ice. The mixture is stirred at room temperature for 2 hours and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=7:3→2:3) to give the ethyl ester of (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[1-(3-chlorobenzoyloxy)-2,3-dihydroxypropyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (677 mg) as a crude product. MC (m/z): 812 [M+H]+.

(2) the Crude product (360 mg), ethyl ester (2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[1-(3-chlorobenzoyloxy)-2,3-dihydroxypropyl]pyrimidine-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid is dissolved in methanol (10 ml), to the solution was added 1N. aqueous NaOH solution (5 ml) and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure and distribute the addition of ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=1:0→9:1) to obtain the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1,2,3-trihydroxy)propylpyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (184 mg). MC (m/z): 674 [M+H]+.

Example 313

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) is dissolved in 1,4-dioxane (1 ml) and to the solution was added cesium carbonate (205 mg), pyrrolidin-2-he (41 μl), 4,5-bis(diphenylphosphino)-9,9-Xanten (81 mg) and Tris(dibenzylideneacetone)dipalladium at 41.5 mg). The mixture is heated at 90°C and stirred for 15 hours. The reaction solution is cooled to room temperature and partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-oxopyrrolidin-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (126,6 mg). MC (m/z): 667 [M+H]+.

Example 314

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-iodopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg), 3-methoxy-3-oxoprop-1-sulfinate sodium (221 mg) and copper iodide (I) (242 mg) was dissolved in dimethyl sulfoxide (2 ml). The resulting mixture was stirred in a stream of nitrogen at 110°C for 3 hours. Reaktionarsten cooled to room temperature and the solution was added water and ethyl acetate. After removal of precipitated insoluble substances by filtration through Celite™ organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→2:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylaminophenyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (286 mg). MC (m/z): 734 [M+H]+.

Example 315

Ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylaminophenyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (141 mg) and 2n. an aqueous solution of NaOH

(384 ml) dissolved in ethanol (3 ml) and the resulting mixture was stirred at 50°C for 30 minutes. To the reaction solution was added 2n. an aqueous solution of HCl (385 μl) and stirred over night. To the reaction mixture are added ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-sulfapyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carbon is th acid (64 mg). MC (m/z): 662 [M+H]+.

Example 316

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2 g), 3-methoxy-3-oxoprop-1-sulfinate sodium (2,63 g) and copper iodide (I) (2,88 g) dissolved in dimethyl sulfoxide (25 ml) and the resulting mixture stirred in a stream of nitrogen at 110°C for 6 hours. The reaction solution is cooled to room temperature and the solution was added water and ethyl acetate. After removal of precipitated insoluble substances by filtration through Celite™ organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→2:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylaminophenyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.92 g). MC (m/z): 734 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylaminophenyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.9 g) and 2n. an aqueous solution of NaOH (2.6 ml) dissolved in ethanol (20 ml) and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution we use the t 2n. an aqueous solution of HCl (2.7 ml) and a solution of hydrogen peroxide (10 ml) and the resulting mixture is stirred over night. To the reaction mixture chloroform, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-sulfapyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.68 g). MC (m/z): 662 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-sulfapyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in thionyl chloride (2 ml) and stirred at 120°C for 2 hours. The reaction solution is cooled to room temperature and then concentrated under reduced pressure. To the obtained residue is added toluene (2 ml), then add a solution (15 ml) 0.5m ammonia in 1,4-dioxane while cooling on ice and the resulting mixture is stirred over night at room temperature. The reaction solution is concentrated under reduced pressure, and then to the resulting residue is added water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated when s is low pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=3:1→2:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-sulfanilamide-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (75 mg). MC (m/z): 663 [M+H]+.

Example 317

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-sulfapyridine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (927 mg) is dissolved in thionyl chloride (10 ml) and heated at 100°C for 2 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is dissolved in toluene (10 ml). To the resulting mixture hydrochloride tert-butyl ester of glycine (468 mg) and triethylamine (389 ml) while cooling on ice and the reaction mixture is stirred for 5 hours, giving to gradually heated from a temperature under cooling on ice to room temperature. The reaction mixture was partitioned between saturated salt solution and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=6:1→2:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(tert-butoxycarbonylmethylene)pyrim the DIN-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (235 mg).

MC (m/z): 777 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(tert-butoxycarbonylmethylene)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (230 mg) was dissolved in ethyl acetate (6 ml) and to the solution was added a solution (4 ml) 4h. HCl/ethyl acetate. The resulting mixture is stirred over night at room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:0→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-karboksimetilsellulozdan-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (135 mg). MC (m/z): 721 [M+H]+.

Examples 318-319

The corresponding starting compound is treated analogously to example 156 (1) to obtain the compounds listed in table 33.

td align="center">
Example No.RR'Physical properties, etc.
318MS (m/z):
619/621 [M+H]+
319MS (m/z):
586/588 [M+H]+

Example 320

Ethyl ester of (2R,4S)-4-[(5-bromopyrimidine-2-yl)-(3-cyano-5-trifloromethyl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) is dissolved in toluene (4 ml) and to the solution was added Tris(dibenzylideneacetone)dipalladium (44 mg), tert-piperonyl sodium (70 mg), 2-(di-tert-butylphosphino)biphenyl (58 mg) and acetylpiperidine (93 mg). The resulting mixture was stirred at room temperature for 1 hour in a stream of nitrogen, then heated at 50°C., stirred for 5.5 hours and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:1→0:1) to give the ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-(3-cyano-5-trifloromethyl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic key is lots (177 mg). MC (m/z): 667 [M+H]+.

Example 321

The corresponding original connection is treated analogously to example 320 obtaining connection 321. MC (m/z): 634 [M+H]+.

Example 322

(1) Ethyl ester of (2R,4S)-4-[(5-bromopyrimidine-2-yl)-(3-cyano-5-trifloromethyl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3 g) is dissolved in 1,4-dioxane (30 ml) and to the solution was added benzyl ester of acrylic acid (1,57 g), Tris(dibenzylideneacetone)dipalladium (665 mg), dicyclohexylmethane (1.42 g) and tetrafluoroborate three-tert-butylphosphine (420 mg). The resulting mixture was stirred at room temperature for 3 days in a stream of nitrogen and partitioned between aqueous citric acid solution and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3→3:2) with obtaining the ethyl ester of (2R,4S)-4-{[5-(2-benzyloxycarbonylamino)pyrimidine-2-yl]-(3-cyano-5-trifloromethyl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1,82 mg). MC (m/z): 701 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[5-(2-benzyloxycarbonylamino)pyrimidine-2-yl]-(3-cyano-5-trifloromethyl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]nafti the one-1-carboxylic acid (800 mg) dissolved in a mixture of tetrahydrofuran (16 ml) and methanol (4 ml) and to the solution was added 10% palladium on coal (230 mg). The resulting mixture is stirred for 9 hours in an atmosphere of hydrogen. The reaction solution is filtered and then the filtrate is concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:0→9:1) to give the ethyl ester of (2R,4S)-4-{[5-(2-carboxyethyl)pyrimidine-2-yl]-(3-cyano-5-trifloromethyl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (317 mg) MS (m/z): 613 [M+H]+.

Example 323

The corresponding original connection is treated analogously to example 322 obtaining connection 323. MC (m/z): 580 [M+H]+.

Examples 324-325

The corresponding starting compound is treated analogously to example 143 from obtaining the compounds listed in table 34.

Table 34
Example No.RR'Physical properties, etc.
324MS (m/z):
599 [M+H]+
325 MS (m/z):
566 [M+H]+

Example 326

The corresponding original connection is treated analogously to example 156 (2) to obtain the connection 326. MC (m/z): 626 [M+H]+.

Example 327

Ethyl ester of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (315 mg) was dissolved in methanol (9 ml) and to the solution was added 1N. aqueous NaOH solution (1 ml). The resulting mixture was stirred at room temperature for 1 day and add 1N. HCl and ethyl acetate for distribution. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=7:3→3:7→0:1) with obtaining the ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-{(3-methoxycarbonyl-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (54 mg). MC (m/z): 659 [M+H]+.

Example 328

Ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-{(3-methoxycarbonyl-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (86 mg dissolved in methanol (9 ml) and N,N-dimethylformamide (1 ml) and to the solution was added 1N. aqueous NaOH solution (3 ml). The resulting mixture was stirred at room temperature for 1.5 hours and add 1N. HCl and ethyl acetate for distribution. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified by thin-layer chromatography on silica gel (silica gel; chloroform:methanol=9:1) to give the ethyl ester of (2R,4S)-4-{(3-carboxy-5-trifloromethyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (25 mg). MC (m/z): 645 [M+H]+.

Example 329

The corresponding original connection is treated analogously to example 177 (2) to obtain the connection 329. MC (m/z): 689/691 [M+H]+.

Example 330

Ethyl ester of (2R*,4S*)-4-{(3,5-dibromobenzyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in N,N-dimethylformamide (4 ml) and to the solution add cyanide zinc (75 mg), a catalytic amount of tetrakis(triphenylphosphine)palladium. The resulting mixture is heated at 110°C and stirred for 2 hours in a stream of nitrogen. The reaction solution is cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Organic SL is th is washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=7:3→1:1) to give the ethyl ester of (2R*,4S*)-4-{(3,5-dicyanovinyl)-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (134 mg). MC (m/z): 583 [M+H]+.

Example 331

(1) Ethyl ester of (2R,4S)-4-[(5-bromopyrimidine-2-yl)-(3-cyano-5-trifloromethyl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg), ethyl ester isonipecotic acid (109 ml), tert-piperonyl sodium (70 mg) and 2-(di-tert-butylphosphino)biphenyl (58 mg) was dissolved in toluene (5 ml) and to the solution was added Tris(dibenzylideneacetone)dipalladium (44 mg). The resulting mixture is stirred overnight under nitrogen atmosphere at room temperature and distributed between ethyl acetate and a saturated solution of salt. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→3:2) to give the ethyl ester of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(4-ethoxycarbonylpyrimidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (125 mg). MC (m/z): 696 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{(3-cyano-5-trifloromethyl)-[5-(4-ethoxycarbonylpyrimidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (120 mg) is treated analogously to example 36 to obtain ethyl ester (2R,4S)-4-{[5-(4-carboxypeptidase-1-yl)pyrimidine-2-yl]-(3-cyano-5-trifloromethyl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (65 mg). MC (m/z): 668 [M+H]+.

Example 332

The corresponding original connection is treated analogously to example 224 (1) to obtain the connection 332. MC (m/z): 698 [M+H]+.

Example 333

The corresponding original connection is treated analogously to example 224 (2) to obtain the connection 333. MC (m/z): 642 [M+H]+.

Example 334

Ethyl ester of (2R,4S)-4-[(5-bromopyrimidine-2-yl)-(3-cyano-5-trifloromethyl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (10 g) is treated analogously to example 4 with obtaining the ethyl ester of (2R,4S)-4-[(3-cyano-5-trifloromethyl)-(5-modeminizin-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (8,18 g). MC (m/z): 667 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-[(3-cyano-5-trifloromethyl)-(5-modeminizin-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) is dissolved N,N-dimethylformamide (2.5 ml) and to the solution was added tetrakis(triphenylphosphine)palladium (104 mg), pyrimidine-5-Bronevoy acid (112 mg) and sodium carbonate (114 mg). The resulting mixture was stirred at 100°C for 4 hours in a stream of nitrogen. After cooling to room temperature, to the reaction mixture, water is added. The mixture is extracted with ethyl acetate and the organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=2:1) to give the ethyl ester of (2R,4S)-4-[([5,5']bipyridinyl-2-yl)-(3-cyano-5-trifloromethyl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (116 mg). MC (m/z): 619 [M+H]+.

Example 335

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (100 mg) dissolved in dimethyl sulfoxide (2 ml) and to the solution was added 2M solution (300 ál) of dimethylamine in tetrahydrofuran while cooling on ice. The resulting mixture was stirred at 40°C for 72 hours in a closed vessel and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:this is laatat=4:1→2:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-6-dimethylamino-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (78 mg). MC (m/z): 682 [M+H]+.

Example 336

The corresponding initial connection process as in example 335 obtaining connection 336. MC (m/z): 668 [M+H]+.

Example 337

(1) To a suspension of ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3,45 g), sodium iodide (4.6 g) and acetonitrile (50 ml) is added dropwise trimethylsilane (3.8 ml) at 80°C. After add dropwise, the reaction solution is cooled to room temperature and add saturated aqueous sodium thiosulfate solution and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=49:1→19:1) to give the ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3,09 g). MC (m/z): 696 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[5-(4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3,05 g) and pyridine (1,06 ml) dissolved in methylene chloride (20 ml) and to the solution add the keys dropwise triftormetilfullerenov anhydride (885 μl) under cooling on ice. The mixture is stirred at the same temperature for 4 hours and the solution is added an aqueous solution of citric acid. The organic layer was washed with saturated aqueous sodium bicarbonate, then brine, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:2→0:1) to give the ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,39 g). MC (m/z): 828 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in dimethyl sulfoxide (4 ml) and to the solution was added 2M solution of dimethylamine in tetrahydrofuran (1.2 ml) under cooling on ice. The mixture is stirred at 40°C for 48 hours in a closed vessel. To the reaction solution was added water and ethyl acetate, then the organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:2→0:1) to give the ethyl ester of (2R,4S)-4-{[-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-6-dimethylamino-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (163 mg). MC (m/z): 723 [M+H]+.

Example 338

Ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (250 mg), palladium acetate (34 mg), 1,1'-bis(diphenylphosphino)ferrocene (84 mg) and triethylamine (126 μl) dissolved in N,N-dimethylformamide (2 ml) and to the solution was added formic acid (28 μl). The mixture is stirred at 60°C for 1 hour in a stream of nitrogen. To the reaction solution was added water and ethyl acetate, then the organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=1:2→0:1) to give the ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (195 mg). MC (m/z): 680 [M+H]+.

Example 339

Ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) is dissolved in 1,4-dioxane (2 ml) and to the solution is added dropwise a catalytic amount of tetrakis(triphenylphosphine)palladium, silver carbonate and chloride copper (I) and 1M solution (362 μl) trim illumine in hexane in a stream of nitrogen. The mixture is stirred at 60°C for 1 hour. The reaction solution is cooled to room temperature and add water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=1:2→0:1) to give the ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (142 mg). MC (m/z): 694 [M+H]+.

Example 340

Ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg), a catalytic amount of tetrakis(triphenylphosphine)palladium cyanide zinc (37 mg) was dissolved in N,N-dimethylformamide (2 ml) and the mixture was stirred at 100°C for 6 hours in a stream of nitrogen. The reaction solution is cooled to room temperature and add water and ethyl acetate. The mixture was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=3:7→0:1) to give the ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-yl)pyrimidine-2-yl]-[3,bis(trifluoromethyl)benzyl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (149 mg). MC (m/z): 705 [M+H]+.

Example 341

The corresponding original connection is treated analogously to example 337 (1) to obtain the connection 341. MC (m/z): 700 [M+H]+.

Example 342

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.5 g) and pyridine (519 μl) dissolved in methylene chloride (10 ml) and to the solution add triftormetilfullerenov anhydride (432 ml) while cooling on ice in a nitrogen atmosphere. The mixture is stirred for 1 hour and is distributed between methylene chloride and saturated aqueous citric acid. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→3:2) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.56 g). MC (m/z): 832 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.27 g) dissolve Aut in N,N-dimethylformamide (10 ml) and to the solution was added palladium acetate (34 mg), 1,1'-bis(diphenylphosphino)ferrocene (169 mg), benzyl alcohol (and 3.16 ml) and triethylamine (2,13 ml). The mixture is bubbled with carbon monoxide at room temperature for 5 minutes, then heated at 80°C and stirred for 1.5 hours in an atmosphere of carbon monoxide. The reaction solution is cooled to room temperature and add a saturated solution of salt. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=19:1→3:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-6-benzyloxycarbonyl-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (520 mg), MC (m/z): 818 [M+H]+and ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (330 mg), MC (m/z): 684 [M+H]+.

Example 343

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-6-benzyloxycarbonyl-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (500 mg) is dissolved in ethanol (2 ml) and to the solution was added 10% palladium on coal (50 mg). The mixture was stirred at the room for the Noah temperature for 1.5 hours in an atmosphere of hydrogen. Palladium on coal is removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:7) to give 1-ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1,6-dicarboxylic acid (323 mg). MC (m/z): 728 [M+H]+.

(2) 1-ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1,6-dicarboxylic acid (300 mg) and TRIFLUORIDE bis(2-methoxyethyl)aminocore (1.6 ml) is stirred overnight at 80°C. the Reaction solution is cooled to room temperature and add ethyl acetate to dilution. The mixture is then poured into a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with 1N. HCl and saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified by thin-layer chromatography on silica gel (hexane:ethyl acetate=2:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthiridine-1,6-dicarboxylic acid (77 mg), MC (m/z): 752 [M+H]+and ethyl ester of (2R,4S)-6-[bis((2-methoxyethyl)carbarnoyl)-4-[3,5-bis(trifluoromethyl)be the ZIL]-[5-(3-ethoxycarbonylmethoxy)pyrimidine-2-yl]}amino-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1,6-dicarboxylic acid (184 mg), MC (m/z): 843 [M+H]+.

Examples 344-346

The corresponding starting compound is treated analogously to example 36 to obtain the compounds listed in table 35.

Table 35
Example No.RR'Physical properties, etc.
344MS (m/z):
724 [M+H]+
345MS (m/z):
815 [M+H]+
346MS (m/z):
656 [M+H]+

Example 347

(1) To aqueous solution (650 ml) of sodium azide (101,4 g) is added dropwise a solution (390 ml) of acid chloride of acrylic acid (117,7 ml) in toluene while cooling on ice and the mixture is stirred at the same temperature for 1 hour. Then BA is Yu water with ice is removed and the mixture is stirred until cooling to room temperature. Solution the reaction mixture was washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate. The resulting solution in toluene is added dropwise to a mixture of (R)-1-phenethyl alcohol (173 ml), pyridine (52,6 ml) and hydroquinone (of 7.90 g), which is heated to 85°C., and the mixture was stirred at the same temperature for 1 hour. The reaction mixture is cooled to room temperature. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=10:1→9:1) to give (R)-1-phenethyl ether vinylcarbazole acid (167,3 g). MC (m/z): 191 [M+H]+.

(2) {[1-(benzotriazol-1-yl)propyl]-(6-methoxypyridine-3-yl)}amine (212,5 g), (R)-1-phenethyl ether vinylcarbazole acid (143,4 g) and monohydrate p-toluensulfonate acid (1,43 g) dissolved in toluene (2,80 l) and the resulting mixture was stirred at 85°C for 3 hours. After cooling to room temperature when standing, the reaction mixture was washed with saturated aqueous sodium bicarbonate, water and saturated salt solution. The organic layer is dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified colonoscopy because it allows the Noah chromatography (silica gel; hexane:ethyl acetate=4:1). To the residue is added a mixture of hexane/ethyl acetate (9:1) and precipitated crystals are removed by filtration. To the resulting mixture of diastereomers add ether, the resulting mixture is stirred and the precipitated crystals are removed by filtration. To the resulting crystals add a mixture of hexane/ethyl acetate (4:1) and the resulting mixture is stirred. The resulting crystals are removed by filtration to obtain (R)-1-phenethyl ester (2R,4S)-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine-4-yl)carbamino acid (38,7 g). MC (m/z): 356 [M+H]+.

(3) (R)-1-phenethyl ester (2R,4S)-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine-4-yl)carbamino acid (200 mg) is dissolved in tetrahydrofuran (3 ml) and to the solution was added di-tert-BUTYLCARBAMATE (395 mg). The mixture is stirred overnight at 70°C. After cooling to room temperature when standing to the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=6:1→4:1) to give tert-butyl ester (2R,4S)-2-ethyl-6-methoxy-4-((R)-1-fenilalaninammonii)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (270 mg). MC (m/z): 456 [M+H]sup> +.

(4) Tert-butyl ester (2R,4S)-2-ethyl-6-methoxy-4-((R)-1-fenilalaninammonii)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (39,00 g) dissolved in methanol (550 ml) and to the solution was added 10% palladium on coal (20,0 g). The mixture is stirred at room temperature for 2 hours in a stream of nitrogen. The resulting mixture was filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:1→chloroform:methanol=9:1) to give tert-butyl ester (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (24,87, MC (m/z): 308 [M+H]+.

(5) Tert-butyl ester (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (24,80 g) is dissolved in 1,4-dioxane (450 ml) and to the solution was added 5-bromo-2-chloropyrimidine (39,01 g) and N,N-diisopropylethylamine (35.1 ml). The resulting mixture is stirred over night at 80°C. After cooling to room temperature when standing the mixture is concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=6:1) to give tert-butyl ester (2R,4S)-4-(5-bromopyrimidine-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (27,48 g). MC (m/z): 466/464 [M+H]+.

(6) Tert-butyl ester (2R,4S)-4-(5-bromopyrimidine-2-yl)amino-2-ethyl-6-labels and-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (20,00 g) dissolved in N,N-dimethylformamide (150 ml) and to the solution was added sodium hydride (62.7 percent, 2,46 mg) under cooling on ice. The mixture is stirred at the same temperature for 30 minutes. Then added to the mixture of 3,5-bis(trifluoromethyl)benzylbromide (11.8 ml) and the mixture is stirred at room temperature for 1 hour. After neutralizing the reaction solution by adding 10% aqueous citric acid solution, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. To the obtained residue is added ether and hexane. The precipitated crystals are removed by filtration to obtain tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (28,13 g). MC (m/z): 692/690 [M+H]+.

(7) Tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (6,00 g) dissolved in toluene (60 ml) and to the solution was added Tris(dibenzylideneacetone)dipalladium (796 mg), 2-(di-tert-butylphosphino)biphenyl (1.04 g), morpholine (1,52 ml) and tert-piperonyl sodium (1,67 g). The mixture is stirred at room temperature for 7 hours in a stream of nitrogen. After neutralization of the reaction mixture by adding 10% aqueous citric acid solution, the mixture is extracted with ethyl acetate. The organic layer industry is with water and saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1) to give tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (lower than the 5.37 g). MC (m/z): 697 [M+H]+.

(8) Tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid is dissolved in 1,4-dioxane (15 ml) and to the solution was added a solution (40 ml) 4h. HCl/1,4-dioxane while cooling in a water bath. The mixture is stirred at room temperature for 3 hours. After neutralization of the reaction mixture by addition of a saturated aqueous solution of sodium bicarbonate, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure to obtain (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine (4,48 g). MC (m/z): 597 [M+H]+.

(9) (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine (233 mg) was dissolved in methylene chloride (2 ml) and to the solution was added triethyl is in (65 μl), then add triphosgene (46 mg) under cooling in a water bath. The mixture is stirred at the same temperature for 30 minutes. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. To the obtained residue, add tetrahydrofuran (2 ml), ethylene glycol (1.0 ml), triethylamine (0,40 ml) and dimethylaminopyridine (10 mg) and the resulting mixture was stirred at room temperature for 5 days. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:2) to give 2-hydroxyethylamide ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro[1,5]naphthiridine-1-carboxylic acid (192 mg). MC (m/z): 685 [M+H]+.

Examples 348-353

The corresponding starting compound is treated analogously to example 347 (9) to obtain the compounds listed in table 36.

Table 36
Example No.RR'Physical properties, etc.
348MS (m/z):
699 [M+H]+
349MS (m/z):
695 [M+H]+
350MS (m/z):
723 [M+H]+
351MS (m/z):
715 [M+H]+
352MS (m/z):
747 [M+H]+
353MS (m/z):
726 [M+H]+

(1) Tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3.00 g) was dissolved in 1,4-dioxane (25 ml) and to the solution was added Tris(dibenzylideneacetone)dipalladium (596 mg), complex three-tert-butylphosphino-tetrafluoroborate (378 mg), methyl acrylate (0,78 ml) and N,N-dicyclohexylamine (1.27 g). The resulting mixture was stirred at 40°C for 7 hours in a stream of nitrogen. To the reaction mixture is added 10% aqueous citric acid solution and then extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1) to give tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylbenzyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,93 g). MC (m/z): 696 [M+H]+.

(2) Tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylbenzyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,92 g) dissolved in methanol (60 ml) and to the solution was added 10% palladium on coal (3.00 g). The mixture is stirred at room temperature for 2 hours in a stream of nitrogen. The reaction mixture Phi is trout and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=8:1→6:1) to give tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,19 g). MC (m/z): 698 [M+H]+.

(3) Tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,18 g) is dissolved in 1,4-dioxane (5 ml) and to the solution was added a solution (10 ml), 4n. HCl in 1,4-dioxane. The mixture is stirred at room temperature for 1.5 hours. After neutralizing the reaction solution by addition of a saturated aqueous solution of sodium bicarbonate, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure to obtain (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine (1.90 g). MC (m/z): 598 [M+H]+.

(4) (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine (220 mg) is dissolved in methylene chloride (1.5 ml) and to the solution add triethylamine (62 μl), then add triphosgene (44 mg) when Oh is Adeney in a water bath. The mixture is stirred at the same temperature for 30 minutes. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. To the obtained residue, add tetrahydrofuran (2.5 ml), ethylene glycol (1.0 ml), triethylamine (0,40 ml) and dimethylaminopyridine (10 mg) and the resulting mixture is stirred over night at room temperature in a stream of nitrogen. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:2) to give 2-hydroxyethylamide ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (145 mg). MC (m/z): 686 [M+H]+.

(5) 2-hydroxyethyloxy ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonylethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (141 mg) was dissolved in 1,4-dioxane (3 ml) and to the solution was added 1N. aqueous NaOH solution (1 ml). The mixture is stirred at room temperature for 1 hour. After acidification of reaction the solution by adding 10% aqueous citric acid solution, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 2-hydroxyethylamide ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (138 mg). MC (m/z): 672 [M+H]+.

Examples 355-357

The corresponding starting compound is treated analogously to example 354 (4)-(5) to obtain the compounds listed in table 37.

Table 37
Example No.RR'Physical properties, etc.
355MS (m/z):
682 [M+H]+
356MS (m/z):
710 [M+H]+
357 MS (m/z):
702 [M+H]+

Example 358

(1) Tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (4,00 g) dissolved in toluene (40 ml) and to the solution was added Tris(dibenzylideneacetone)dipalladium (530 mg), 2-(di-tert-butylphosphino)biphenyl (691 mg), 4-ethoxycarbonylpyrimidine (1,37 g) and tert-piperonyl sodium (835 mg). The resulting mixture is stirred over night at room temperature in a stream of nitrogen. After neutralization of the reaction mixture by adding 10% aqueous citric acid solution, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→6:1) to give tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylpyrimidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2.16 g). MC (m/z): 767 [M+H]+.

(2) Tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylpyrimidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,03 g) is dissolved in 1,4-dioxane (6 ml) and to the solution add Rast is PR (15 ml) 4h. HCl in 1,4-dioxane. The resulting mixture was stirred at room temperature for 1 hour. After neutralizing the reaction solution by addition of a saturated aqueous solution of sodium bicarbonate, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure to obtain (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylpyrimidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine (1,79 g). MC (m/z): 667 [M+H]+.

(3) (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylpyrimidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine (130 mg) was dissolved in methylene chloride (2 ml) and to the solution was added pyridine (47 μl)and then added dropwise to propylchloride (77 μl) under cooling on ice. The mixture is stirred at the same temperature for 2 hours in a stream of nitrogen. To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is dissolved in ethanol (1 ml) and to the solution was added 2M aqueous NaOH solution (1 ml). The mixture is stirred at 60°C for 1 hour. After adding 10% aqueous RA the creators of citric acid to the reaction mixture, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=19:1) to obtain the propyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypeptidase-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (115 mg) MS (m/z): 725 [M+H]+.

Example 359

The corresponding original connection is treated analogously to example 358 getting 359 connection. MC (m/z): 723 [M+H]+.

Example 360

Tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonylpyrimidine-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (120 mg) is dissolved in 1,4-dioxane (1 ml) and to the solution was added 1M aqueous NaOH solution (1 ml). The mixture is stirred at 50°C for 1 hour. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=19:1) to give tert-butyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypeptidase-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic what Islami (77 mg) MS (m/z): 739 [M+N] +.

Examples 361-364

The corresponding starting compound is treated analogously to example 354 (4)-(5) to obtain the compounds listed in table 38.

Table 38
Example No.RR'Physical properties, etc.
361MS (m/z):
729 [M+H]+
362MS (m/z):
725 [M+H]+
363MS (m/z):
765 [M+H]+
364MS (m/z):
737 [M+H]+

Example 365

(1) (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(is orfelin-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-2H-[1,5]naphthiridine (100 mg) is dissolved in methylene chloride (1.0 ml) and to the solution is added triethylamine (28 μl), then add triphosgene (20 ml) under cooling with water. The mixture is stirred at the same temperature for 5 minutes in a stream of nitrogen. The reaction mixture was concentrated under reduced pressure and to the residue is added methylene chloride (1.5 ml), triethylamine (28 μl) and 2-aminoethanol (24 μl). The resulting mixture is stirred over night at room temperature in a stream of nitrogen. To the reaction mixture is added a saturated salt solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:0→19:1) to give (2-hydroxyethyl)amide (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (97 mg). MC (m/z): 684 [M+H]+.

Example 366

(2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-2H-[1,5]naphthiridine (150 mg) is dissolved in toluene (2.0 ml) and to the solution was added 2-chlorotriazine (40 mg). The mixture is stirred at 60°C for 9 hours in a stream of nitrogen. To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated of rest the rum salt, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1→1:9) to give (2-chloroethyl)amide (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (160 mg). MC (m/z): 702/704 [M+H]+.

Example 367

(2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-2H-[1,5]naphthiridine (250 mg) is dissolved in methylene chloride (2.0 ml) and to the solution add triethylamine (118 μl), then add triphosgene (50 mg) under cooling in a water bath. The mixture is stirred at the same temperature for 30 minutes in a stream of nitrogen. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is dissolved in a mixture of tetrahydrofuran (2.5 ml) and N,N-dimethylformamide (1 ml) and to the solution was added the hydrochloride of O-methylhydroxylamine (70 mg) and triethylamine (230 μl). The resulting mixture was stirred at room temperature for 4 days in a stream of nitrogen. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over with what LifeCam magnesium and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1→chloroform:methanol=19:1) to produce methoxyamine (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (57 mg). MC (m/z): 670 [M+H]+.

Example 368

(2-chloroethyl)amide and (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (147 mg) was dissolved in acetonitrile (2.0 ml) and to the solution add 40% potassium fluoride dioxide aluminum (121 mg). The mixture is stirred over night at 50°C. the Reaction mixture was filtered through Celite™ and the filtered insoluble matter is washed with ethyl acetate. The filtrate and washing are combined and concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:1→chloroform:methanol=19:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-1-(4,5-dihydrooxazolo-2-yl)-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine (51 mg). MC (m/z): 666 [M+H]+.

Example 369

(2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-2H-[1,5]naphthiridine (250 mg) is dissolved in methylene chloride (2.0 ml) and to the solution add triethylamine (118 μl), the m add triphosgene (50 mg) under cooling in a water bath. The mixture is stirred at the same temperature for 30 minutes in a stream of nitrogen. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is dissolved in a mixture of tetrahydrofuran (2.5 ml) and N,N-dimethylformamide (1 ml) and to the solution was added the hydrochloride of the methyl ether Of tert-butyl-L-serine (178 mg) and triethylamine (230 μl). The resulting mixture was stirred at room temperature for 4 days in a stream of nitrogen. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1) to give ((S)-2-tert-butoxy-1-methoxycarbonylethyl)amide (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (309 mg). MC (m/z): 798 [M+H]+.

(2) To ((S)-2-tert-butoxy-1-methoxycarbonylethyl)amide (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid type solution (5 ml) 4h. HCl in 1,4-dioxane. The resulting mixture was stirred pikantnoi temperature for 5 hours. After neutralization of the reaction mixture by addition of a saturated aqueous solution of sodium bicarbonate, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:1→0:1) to give ((S)-2-hydroxy-1-methoxycarbonylethyl)amide (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (237 mg). MC (m/z): 742 [M+H]+.

(3) ((S)-2-hydroxy-1-methoxycarbonylethyl)amide and (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (214 mg) was dissolved in methylene chloride (3.0 ml) and to the solution was added pyridine (28 μl), then add triftormetilfullerenov anhydride (58 μl) at -20°C. the Mixture is stirred at the same temperature for 40 minutes in a stream of nitrogen. To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:1→1:9) Paul is rising (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1-((S)-4-methoxycarbonyl-4,5-dihydrooxazolo-2-yl)-3,4-dihydro-2H-[1,5]naphthiridine (172 mg). MC (m/z): 724 [M+H]+.

(4) (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1-((S)-4-methoxycarbonyl-4,5-dihydrooxazolo-2-yl)-3,4-dihydro-2H-[1,5]naphthiridine (84 mg) was dissolved in tetrahydrofuran (2.0 ml) and the solution slowly added 1M solution (0.4 ml) in diisobutylaluminium tetrahydrofuran while cooling on ice. The mixture is stirred at the same temperature for 30 minutes in a stream of nitrogen. To the reaction mixture is added a saturated solution of salt, the mixture is stirred at room temperature for 1 hour and then extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=19:1) to give (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-1-((R)-4-hydroxymethyl-4,5-dihydrooxazolo-2-yl)-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine (61 mg). MC (m/z): 696 [M+H]+.

Example 370

(1) (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-2H-[1,5]naphthiridine (200 mg) is dissolved in methylene chloride (1.5 ml) and to the solution was added pyridine (54 μl), then add chlorocatechol (40 ml) under cooling in a water bath. The mixture is stirred at room is the temperature for 1 hour in a stream of nitrogen. To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1→1:1) to give (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-1-chloroacetyl-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine (156 mg). MC (m/z): 675/673 [M+H]+.

(2) (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-1-chloroacetyl-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine (80 mg) was dissolved in N,N-dimethylformamide (1.5 ml) and to the solution was added morpholine (52 μl) and potassium carbonate (49 mg). The resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture is added a saturated salt solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:0→19:1) to give (2R,4S)-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1-(morpholine-4-yl)acetyl-3,4-dihydro-2H-[1,5]naphthiridine (60 mg). MC (m/z): 724 [M+H]+.

Example 371

The corresponding initial connection process as in example 370 (1) to obtain compound 371. MC (m/z): 703 [M+H]+.

Example 372

(2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-2H-[1,5]naphthiridine (300 mg) is dissolved in N,N-dimethylformamide (3 ml) and to the solution was added sodium hydride (62.7 percent, 21 mg) under cooling on ice, and then 1 hour later add acilitated (71 μl). The mixture is stirred at room temperature for 24 hours. The reaction solution is partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on NH-column (silica gel; hexane:ethyl acetate=9:1→4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-1-ethoxycarbonylmethyl-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine (107 mg). MC (m/z): 683 [M+H]+.

Example 373

The corresponding initial connection process as in example 370 (1) and example 36 to obtain compounds 373. MC (m/z): 709 [M+H]+.

Example 374

The corresponding original connection is treated analogously to example 322 (1) what rucenim connection 374. MC (m/z): 730 [M+H]+.

Example 375

The corresponding original connection is treated analogously to example 322 (2) to obtain the connection 375. MC (m/z): 642 [M+H]+.

Example 376

The corresponding original connection is treated analogously to example 143 from obtaining connection 376. MC (m/z): 628 [M+H]+.

Example 377

The corresponding original connection is treated analogously to example 15 (1) to obtain compound 377. MC (m/z): 725 [M+H]+.

Example 378

The corresponding original connection is treated analogously to example 36 to obtain the connection 378. MC (m/z): 697 [M+H]+.

Example 379

The corresponding original connection is treated analogously to example 200 to obtain compounds 379. MC (m/z): 608 [M+H]+.

Example 380

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-cyano-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg), chloride of hydroxylamine (170 mg) and triethylamine (340 μl) dissolved in ethanol (2 ml) and the mixture is stirred at the boil under reflux for 2 hours. The reaction solution is cooled to room temperature and add water and ethylacetophenone layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure to obtain ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[N-hydroxycarbonylmethyl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (360 mg). MC (m/z): 641 [M+H]+.

Example 381

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[N-hydroxycarbonylmethyl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (193 mg) and trimethylamine (126 μl) dissolved in dichloromethane (3 ml) and to the solution add triphosgene (268 mg) at 0°C. the Mixture is stirred at room temperature for 30 minutes. To the reaction solution was added water and dichloromethane and the organic layer was washed with a saturated solution of salt. Then the organic layer is dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:0→97:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (33 mg). MC (m/z): 667 [M+H]+.

Example 382

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-bromopyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (276 mg), Tris(dibenzyl graceton)dipalladium (76 mg), tert-piperonyl sodium (80 mg), 2-(di-tert-butylphosphino)biphenyl (50 mg) and utilizedabated (131 mg) was dissolved in toluene (3 ml) and the resulting mixture was stirred at room temperature for 22 hours in a stream of nitrogen. To the reaction solution was added water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4-etoxycarbonyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (109 mg). MC (m/z): 738 [M+H]+.

Example 383

The corresponding original connection is treated analogously to example 36 to obtain compounds 383. MC (m/z): 710 [M+H]+.

Example 384

(1) Ethyl ester of (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (10 g) dissolved in toluene (100 ml) and to the solution was added 2-bromopyridine (6.8 ml), Tris(dibenzylideneacetone)dipalladium (328 mg), 2-(di-tert-butylphosphino)biphenyl (282 mg) and tert-piperonyl sodium (6.9 g). The mixture is stirred at room temperature for 3.5 hours under nitrogen atmosphere, then heated at 80°C and stirred for 4 hours. auktsionnyi the solution is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to obtain (6.4 g) of the crude ethyl ester (2R,4S)-2-ethyl-6-methoxy-4-(pyridin-2-yl)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid. MC (m/z): 357 [M+H]+.

(2) the Crude ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-(pyridin-2-yl)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid is dissolved in methylene chloride (80 ml) and add N-bromosuccinimide (3.15 g). The resulting mixture was stirred at room temperature for 15 minutes. The reaction solution is concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-(5-bromopyridin-2-yl)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5.0 g). MC (m/z): 435/437 [M+H]+.

(3) Ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-(5-bromopyridin-2-yl)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3 g) dissolved in N,N-dimethylformamide (20 ml) and to the solution was added sodium hydride (62.7 percent, 580 mg) under cooling on ice. The mixture is stirred for 30 minutes and then add 3,5-bis(trimethyl)benzylbromide (3.2 ml). The mixture is stirred at room temperature is 24 hours and partitioned between water and ethyl acetate while cooling on ice. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.7 g). MC (m/z): 661/663 [M+H]+.

(4) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.7 g) dissolved in toluene (15 ml) and to the solution was added morpholine (0.45 ml), Tris(dibenzylideneacetone)dipalladium (238 g), 2-(di-tert-butylphosphino)biphenyl (152 mg) and tert-piperonyl sodium (494 mg). The mixture is stirred at room temperature for 85 minutes in nitrogen atmosphere, then heated at 80°C for 3.5 hours. The reaction solution is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine--carboxylic acid (1.26 g). MC (m/z): 668 [M+H]+.

(5) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.25 g) and sodium iodide (1.68 g) was dissolved in acetonitrile (15 ml). Then the resulting mixture is heated at 80°C. is added dropwise trimethylsilane (1,4 ml) under nitrogen atmosphere and the resulting mixture is stirred for 19.5 hours. The reaction solution is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:1→0:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (642 mg). MC (m/z): 654 [M+H]+.

(6) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (585 mg) is dissolved in methylene chloride (5 ml) and to the solution was added pyridine (218 μl) and triftormetilfullerenov anhydride (180 ml) under nitrogen atmosphere while cooling on ice. The reaction solution is stirred for 75 minutes and partitioned between saturated aqueous Rast is a PR citric acid and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (657 mg). MC (m/z): 786 [M+H]+.

(7) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-tripterocalyx-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (650 mg) was dissolved in dimethyl sulfoxide (20 ml) and to the solution add triethylamine (1 ml) and 2M solution (20 ml) of methylamine in tetrahydrofuran. The resulting mixture is heated at 100°C and stirred for 5 hours in a sealed tube under nitrogen atmosphere. The reaction solution is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-morpholine-4-yl)pyridine-2-yl]}amino-2-ethyl-6-methylamino-3,4-dihydro-2H-[1,5]naphthiridine-1-carbon is Oh acid (45 mg). MC (m/z): 667 [M+H]+.

Example 385

(1) Ethyl ester of (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2 g), ethyl ester of 2-chlorocresol-4-carboxylic acid (3.77 g) and diisopropylethylamine (2.5 ml) was dissolved in 1,4-dioxane (15 ml) and the resulting mixture is stirred for 9 hours at the boil under reflux. The reaction solution is cooled to room temperature and add water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→2:1) to give the ethyl ester of (2R,4S)-4-(4-ethoxycarbonylmethyl-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2.85 g). MC (m/z): 419 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-(4-ethoxycarbonylmethyl-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2,75 g) dissolved in N,N-dimethylformamide (30 ml) and to the solution was added sodium hydride (62.7 percent, 315 mg) under cooling on ice. The resulting mixture was stirred at room temperature for 30 minutes. To the mixture is added 3,5-bis(trifluoromethyl)benzylbromide (1.8 ml) under cooling on ice and the resulting mixture is stirred over night at room temperature. To the reaction solution we use the t water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4-ethoxycarbonylmethyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3,53 g). MC (m/z): 645 [M+H]+.

Example 386

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4-ethoxycarbonylmethyl-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg) and the monohydrate of lithium hydroxide (78 mg) dissolved in a mixture of methanol (3 ml) and water (500 μl) and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution is acidified by adding 2n. aqueous HCl, then add ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure to obtain ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4-carboxykinase-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (190 mg). MC (m/z): 617 [M+H]+.

Example 387

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4-carboxykinase-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic to the slots (200 mg) and the hydrate of 1-hydroxybenzotriazole (53 mg) was dissolved in N,N-dimethylformamide (3 ml) and to the solution was added the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (311 mg). The mixture is stirred at room temperature for 20 minutes. To the obtained mixture is added a mixture of concentrated ammonia-water (3 ml) under cooling on ice and the resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture are added water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrated under reduced pressure to obtain ethyl ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4-carbamoylation-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (200 mg). MC (m/z): 616 [M+H]+.

Example 388

(1) Ethyl ester of (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3.0 g) dissolved in 1,2-dichloroethane (50 ml) and to the solution was added 3,5-bis(trifluoromethyl)benzaldehyde (1.9 ml). The resulting mixture was stirred at room temperature for 1 hour, then add 95% triacetoxyborohydride sodium (4.6 g). The resulting mixture was stirred for 17 hours and partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifter ethyl)benzyl]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (4.92 in). MC (m/z): 506 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (4.9 g) was dissolved in ethanol (30 ml) and to the solution was added sodium bicarbonate (2.5 g) and cyanogenmod (1.1 g). The resulting mixture was stirred at room temperature for 16 hours and partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→13:7) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]cyano}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (4,35 mg) MS (m/z): 531 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]cyano}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (3 g) dissolved in N,N-dimethylformamide (30 ml) and to the solution was added ammonium chloride (3 g) and sodium azide (3.7 g). The resulting mixture is heated at 100°C and stirred for 24 hours. The reaction solution is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The obtained residue PTS who participate column chromatography (silica gel; chloroform:methanol=1:0→19:1) and the eluate concentrated, followed by recrystallization (hexane:isopropanol) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(tetrazol-5-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1.2 g). MC (m/z): 574 [M+H]+.

Example 389

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(tetrazol-5-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (230 mg) was dissolved in tetrahydrofuran (3 ml) and to the solution was added methyl ether 3-hydroxy-2,2-dimethylpropionic acid (58 ml), a solution of 0.18 ml) 40% of diethylazodicarboxylate in toluene and triphenylphosphine (121 mg). The resulting mixture was stirred at room temperature for 19 hours and partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[2-(2-methoxycarbonyl-2-methylpropyl)-2H-tetrazol-5-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (243 mg). MC (m/z): 688 [M+H]+.

Example 390

The corresponding original connection is treated similarly p is the iMER 386 obtaining connection 390. MC (m/z): 674 [M+H]+.

Example 391

The corresponding original connection is treated analogously to example 240 getting 391 connection. MC (m/z): 590 [M+H]+.

Example 392

(1) Ethyl ester of (2R,4S)-4-{(N-hydroxycarbamoyl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (513 mg) and diisopropylethylamine (317 μl) dissolved in dichloroethane (5 ml) and to the solution add acetoxyacetyl (127 μl) at 0°C. the resulting mixture is stirred over night at room temperature. To the reaction solution was added saturated aqueous solution of citric acid and the organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R,4S)-4-{[(acetylacetonate)amino(acetyloxyacetylacetone)iminomethyl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (330 mg). MC (m/z): 764 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[(acetylacetonate)amino(acetyloxyacetylacetone)iminomethyl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (320 mg) and potassium carbonate (579 mg) suspender is in ethanol (5 ml) and the resulting mixture is stirred over night at room temperature. To the reaction solution was added water and ethyl acetate, the organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=2:1→0:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxymethyl-[1,2,4]oxadiazol-3-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (52 mg). MC (m/z): 604 [M+H]+.

Example 393

(1) Ethyl ester of (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5.0 g) dissolved in 1,2-dichloroethane (90 ml) and to the solution is added triethylamine (7.5 ml) and 4,6-dichloropyrimidine (5.3g). The resulting mixture is heated at 80°C and stirred for an 18.5 hours. The reaction solution is cooled to room temperature and then concentrated under reduced pressure and add 1N. HCl and diethyl ether for distribution. The organic layer is washed with water, saturated aqueous sodium bicarbonate, water and saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→1:1) to give the ethyl ester of (2R,4S)-4-(6-chloropyrimidine-4-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridin the-1-carboxylic acid (of 5.92 g). MC (m/z): 392/394 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-(6-chloropyrimidine-4-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (4.0 g) dissolved in acetonitrile (50 ml) and to the solution was added sodium hydride (62.7 percent, 428,7 mg) under cooling on ice. The mixture is stirred for 5 minutes and then add 3,5-bis(trifluoromethyl)benzylbromide (2.8 ml). The resulting mixture was stirred at room temperature for 14 hours and partitioned between water and diethyl ether while cooling on ice. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(6-chloropyrimidine-4-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (5.1 g). MC (m/z): 618/620 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(6-chloropyrimidine-4-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (140 mg) was dissolved in 1,3-dimethyl-2-imidazolidinone (2 ml) and to the solution add diisopropylethylamine (0.4 ml) and tert-butyl methyl ether 3-methylaminopropane acid (150 mg). The resulting mixture is heated at 80°C and stirred for 56,5 hours. The reaction solution is cooled to on the th temperature and partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[6-(2-tert-butoxycarbonylmethyl)methylaminopropyl-4-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (of 113.2 mg). MC (m/z): 741 [M+H]+.

(4) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[6-(2-tert-butoxycarbonylmethyl)methylaminopropyl-4-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (100 mg) is dissolved in 2n. the solution (2 ml) HCl/1,4-dioxane and the resulting mixture was stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:0→9:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[6-(2-carboxyethyl)methylaminopropyl-4-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (29 mg). MC (m/z): 685 [M+H]+.

Example 394

The corresponding initial connection process as in example 393 (3) to obtain the compound 394. MC (m/z): 667 [M+H]+.

Example 395

The corresponding initial connection process as in example 393 (3) to obtain the compound 395. MC (m/z): 699 [M+H]+.

Example 396

The corresponding original connection is treated analogously to example 36 to obtain compounds 396. MC (m/z): 671 [M+H]+.

Example 397

Ethyl ester of 4-chloro-2-methylsulfonylamino-5-carboxylic acid (5 g) dissolved in ethanol (100 ml) and to the solution was added sodium carbonate (11.4 g) and 2-methylaminoethanol (4.6 ml). The mixture is heated at 80°C and stirred for 3 hours. The reaction solution is cooled to room temperature and partitioned between water and chloroform. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give 9-methyl-2-methylsulfanyl-8,9-dihydro-7H-pyrimido[4,5-e][1,4]oxazepine-5-it (2,92 g). MC (m/z): 226 [M+H]+.

(2) 9-methyl-2-methylsulfanyl-8,9-dihydro-7H-pyrimido[4,5-e]oxazepine-5-he (1 g) dissolved in tetrahydrofuran (50 ml) and to the solution add metallocarborane acid (1 g) under cooling on ice. The mixture is stirred at room temperature for 20 hours and partitioned between saturated aqueous bicarbonate Natrii chloroform. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) to obtain 2-methanesulfonyl-9-methyl-8,9-dihydro-7H-pyrimido[4,5-e][1,4]oxazepine-5-it (765 mg) MS (m/z): 242 [M+H]+.

(3) Ethyl ester of (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (931 mg) is dissolved in 1,4-dioxane (30 ml) and to the solution add diisopropylethylamine (2.7 ml) and 2-methanesulphonyl-9-methyl-8,9-dihydro-7H-pyrimido[4,5-e][1,5]oxazepan-5-it (750 mg). The resulting mixture was heated to 80°C. and stirred for 19 hours. The reaction solution is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The obtained residue is washed with a mixture of hexane:ethyl acetate to obtain unrefined (1.13 g) in ethyl ether (2R,4S)-2-ethyl-6-methoxy-4-(9-methyl-5-oxo-5,7,8,9-tetrahydropyrimido[4,5-e][1,4]oxazepine-2-yl)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid. MC (m/z): 457 [M+H]+.

(4) Untreated (500 mg), ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-(9-methyl-5-oxo-5,7,8,9-tetrahydropyrimido[4,5-e][1,4]oxazepine-2-yl)amino-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic keys which the notes are dissolved in N,N-dimethylformamide (10 ml) and to the solution was added sodium hydride (62.7 percent, 46 mg) under cooling on ice. The mixture is stirred for 10 minutes and then add 3,5-bis(Cryptor)benzylbromide (0.3 ml). The resulting mixture was stirred at room temperature for 15 hours. The reaction solution is partitioned between water and diethyl ether while cooling on ice. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=1:1→1:4) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(9-methyl-5-oxo-5,7,8,9-tetrahydropyrimido[4,5-e][1,4]oxazepine-2-yl)amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (331,3 mg). MC (m/z): 683 [M+H]+.

Example 398

The corresponding original connection is treated analogously to example 36 to obtain compound 398. MC (m/z): 701 [M+H]+.

Example 399

(1) 5-bromo-2,4-dichloropyrimidine (500 mg) dissolved in tetrahydrofuran (10 ml) and to the solution was added sodium hydride (62.7 percent, 92,2 mg) under cooling on ice. The mixture is stirred for 10 minutes and add benzyl alcohol (236,8 mg) and a few drops of N,N-dimethylformamide. The mixture is stirred at room temperature for 21 hours, then heated at 80°C and stirred for 3.5 hours. The reaction Rast is the PR cooled to room temperature and partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) and the eluate is dried under reduced pressure, then the residue is dissolved in 1,4-dioxane (10 ml) and add ethyl ester (2R,4S)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (300 mg) and diisopropylethylamine (0,52 ml). The resulting mixture is heated at 80°C and stirred for 4 hours. The reaction solution is cooled to room temperature and partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3), the eluate is dried under reduced pressure, then the residue is dissolved in acetonitrile (6 ml) and to the solution was added sodium hydride (62.7 percent, 23 mg) under cooling on ice. The mixture is stirred for 10 minutes and then add 3,5-bis(Cryptor)benzylbromide (0.15 ml). The resulting mixture was stirred at room temperature for a period of 14.5 hours. The reaction solution is partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over sulfate m is fester and concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give the ethyl ester of (2R,4S)-4-{(4-benzyloxy-5-bromopyrimidine-2-yl)-[3,5-bis(trifluoromethyl)benzyl]]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (45 mg). MC (m/z): 768/770 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{(4-benzyloxy-5-bromopyrimidine-2-yl)-[3,5-bis(trifluoromethyl)benzyl]]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (40 mg) dissolved in toluene (1 ml) and to the solution was added morpholine (10,6 μl), Tris(dibenzylideneacetone)dipalladium (11.0 mg), 2-(di-tert-butylphosphino)biphenyl (14.3 mg) and tert-piperonyl sodium (11.6 mg). The resulting mixture was stirred at room temperature for 30 minutes in nitrogen atmosphere, then heated at 80°C for 7 hours. The reaction solution is cooled to room temperature and partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by NH-column chromatography (silica gel; hexane:ethyl acetate=9:1→3:1) to give the ethyl ester of (2R,4S)-4-{[4-benzyloxy-5-(morpholine-4-Yeremey-2-yl)-[3,5-bis(trifluoromethyl)benzyl]]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (12.6 mg). MC (m/z): 775 [M+H]+.

(3) Ethyl e is Il (2R,4S)-4-{[4-benzyloxy-5-(morpholine-4-Yeremey-2-yl)-[3,5-bis(trifluoromethyl)benzyl]]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (10 mg) is dissolved in a solution (1 ml) mixture of tetrahydrofuran:methanol=1:1 and the solution add 10% palladium on coal (5 mg). The resulting mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. The reaction solution is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[4-hydroxy-5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (8.3 mg/). MC (m/z): 685 [M+H]+.

Example 400

The corresponding original connection is treated analogously to example 322 obtaining connection 400. MC (m/z): 672 [M+H]+.

Example 401

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethyl)-4-hydroxypyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (155 mg) was dissolved in tetrahydrofuran (2.5 ml) and to the solution add triethylamine (192 μl) and ethylchloride (132 ml) while cooling on ice. The mixture is stirred at room temperature for 1.5 hours and then add sodium borohydride (87,3 mg) under cooling on ice. The mixture is stirred at room temperature for 2 hours. The reaction solution is partitioned between water and methylene chloride while cooling on ice. The organic layer washed the t 1H. HCl and saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[4-ethoxycarbonyl-5-(3-hydroxypropoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (59 mg). MC (m/z): 730 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[4-ethoxycarbonyl-5-(3-hydroxypropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (50 mg) dissolved in ethanol (1 ml) and to the solution was added 5N. aqueous NaOH solution (1 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution distribute, adding 6N. HCl while cooling on ice, and concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=7:3→1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[4-hydroxy-5-(3-hydroxypropyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (24 mg). MC (m/z): 658 [M+H]+.

Example 402

Ethyl ester of (2R,4S)-4-{(4-benzyloxy-5-bromopyrimidine-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine--carboxylic acid (300 mg) is dissolved in toluene (2 ml) and to the solution was added 2-methylaminoethanol (73 μl), Tris(dibenzylideneacetone)dipalladium (82 mg), 2-(di-tert-butylphosphino)biphenyl (107 mg) and tert-piperonyl sodium (109 mg). The resulting mixture was stirred at room temperature for 30 minutes in nitrogen atmosphere, then heated at 80°C and stirred for 17.5 hours. The reaction solution is cooled to room temperature and add water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→1:1) to obtain crude (130 mg), ethyl ester (2R,4S)-4-{(4-benzyloxypyridine-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid. MC (m/z): 690 [M+H]+.

(2) Untreated (120 mg), ethyl ester of (2R,4S)-4-{(4-benzyloxypyridine-2-yl)-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid is dissolved in a solution (10 ml) mixture of tetrahydrofuran:methanol=1:1 and to the solution was added 10% palladium on coal (60 mg). The mixture is stirred at room temperature for at 34.5 hours in hydrogen atmosphere. The reaction solution is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=:0→9:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4-hydroxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (72.4 mg). MC (m/z): 600 [M+H]+.

Example 403

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4-hydroxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (85 mg) was dissolved in acetone (3 ml) and to the solution was added potassium carbonate (98,1 mg) and paratoluenesulfonyl (32.4 mg). The mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in 1,4-dioxane (3 ml) and to the solution add diisopropylethylamine (0.5 ml) and (2-methoxyethyl)methylamine (br15.15 mg). The resulting mixture is heated at 50°C and stirred for 3 hours, then heated at 100°C and stirred for 16.5 hours. The reaction solution is cooled to room temperature and add 1N. HCl and diethyl ether for distribution. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-{4-[(2-methoxyethyl)methylamino]pyrimidine-2-yl})amino-2-e is Il-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (68 mg). MC (m/z): 671 [M+H]+.

Example 404

The corresponding initial connection process as in example 403 obtaining connection 404. MC (m/z): 741 [M+H]+.

Example 405

The corresponding original connection is treated analogously to example 242 (2) to obtain the connection 405. MC (m/z): 685 [M+H]+.

Example 406

The corresponding original connection is treated analogously to example 270 obtaining connection 406. MC (m/z): 686 [M+H]+.

Example 407

The corresponding initial connection process as in example 93 to obtain connection 407. MC (m/z): 674 [M+H]+.

Example 408

(1) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (10 g) dissolved in toluene (50 ml) and to the solution was added Tris(dibenzylideneacetone)dipalladium (1.4 g), 2-(di-tert-butylphosphino)biphenyl (901 mg), tert-piperonyl sodium (3.1 g) and morpholine (2.6 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution is partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrated p and reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (9,84 g). MC (m/z): 669 [M+H]+.

(2) Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (2.5 g) dissolved in a mixture of tetrahydrofuran:ethanol (1:1, 20 ml) and to the solution add sodium hydroxide (1.5 g). The mixture is stirred at 85°C for 16 hours. The reaction solution is cooled to room temperature and then partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (NH-silica gel; hexane:ethyl acetate=9:1→7:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine (1.45 g). MC (m/z): 597 [M+H]+.

(3) (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro[1,5]naphthiridine (160 mg) was dissolved in dichloromethane (1.5 ml) and to the solution add triethylamine (93 μl) and triphosgene (62 mg). The mixture is stirred is at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure and add diethyl ether. Insoluble substances are removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (1.5 ml) and to the solution was added 60% sodium hydride (32 mg) and ethyl ester of 2,2-debtor-3-hydroxypropionic acid (123 mg) under cooling on ice. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution is partitioned between water and diethyl ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The crude product is dissolved in a mixture of tetrahydrofuran:methanol (1:1, 3 ml) and to the solution was added 2n. aqueous NaOH solution (0.5 ml). The mixture is stirred at room temperature for 1 hour. To the reaction solution was added 1N. HCl (1.0 ml). The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give 2-carboxy-2,2-diferetiable ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (150 mg). MC (m/z): 749 M+H] +.

Example 409

The corresponding initial connection process as in example 408 obtaining connection 409. MC (m/z): 741 [M+H]+.

Example 410

(1) (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-2H-[1,5]naphthiridine (290 mg) was dissolved in dichloromethane (1.5 ml) and to the solution add triethylamine (203 ml) and triphosgene (145 mg). The resulting mixture was stirred at room temperature for 15 minutes. The reaction solution is concentrated under reduced pressure and then the insoluble matter is removed by filtration with the use of tetrahydrofuran and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (1.5 ml) and to the solution was added 60% sodium hydride (20 mg) and tert-butyl methyl ether 3-hydroxypropionic acid (72 ml) under cooling on ice. The mixture is stirred at room temperature for 1.5 hours. The reaction solution is partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give 2-tert-butoxycarbonylamino ester (2R,4S)-4-{[3,5-bis(cryptomite is)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (180 mg). MC (m/z): 769 [M+H]+.

(2) To 2-tert-butoxycarbonylamino ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (165 mg) is added a solution of 4n. HCl-ethyl acetate (2 ml) and the resulting mixture is stirred for 1.5 hours. The reaction solution is concentrated and the resulting residue partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; chloroform:methanol=1:0→9:1) to obtain 2-carboxycellulose ester (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (145 mg). MC (m/z): 713 [M+H]+.

Reference example 1

2-(benzyloxy)ethanol (0.75 ml) dissolved in N,N-dimethylformamide (3 ml) and added dropwise to a solution of sodium hydride (400 mg) in N,N-dimethylformamide while cooling on ice. The mixture is stirred for 40 minutes. To the reaction solution was added Chloroacetic acid (500 mg) under cooling on ice and the resulting mixture was stirred at room temperature for 1 day. To the reaction solution was added a mixture of ice water and extracted with ethyl acetate. Water cloudbased 6N. HCl, the solution is brought to pH 2 and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrated under reduced pressure to obtain 2-(benzyloxy)toxicmonkey acid (895 mg). MC (m/z): 211 [M+H]+.

Reference example 2

(1) 5-bromo-2-chloropyrimidine (5 g) is dissolved in 1,4-dioxane (100 ml) and to the solution add diisopropylethylamine (0,81 ml) and morpholine (4.5 ml). The resulting mixture is heated at 60°C in a stream of nitrogen and stirred for 4 hours. To the resulting mixture add distilled water and extracted with ether. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=19:1→9:1) to obtain 4-(5-bromopyrimidine-2-yl)research (6,74 g). MC (m/z): 244/246 [M+H]+.

(2) 4-(5-bromopyrimidine-2-yl)morpholine (3 g) is dissolved in 1,4-dioxane (60 ml) and to the solution was added copper iodide (700 mg), sodium iodide (22 g), N,N'-dimethylated-1,2-diamine (0.8 ml). The resulting mixture is heated at 110°C and stirred for 6 days. To the mixture of distilled water and extracted with ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. Received about who headed the remainder of the purified column chromatography (silica gel; hexane:ethyl acetate=19:1→7:3) as eluting solvent to obtain 4-(5-iodopyrimidine-2-yl)research (2,33 g). MC (m/z): 292 [M+H]+.

Reference example 3

(S)-1-phenethyl alcohol (1.0 g) and 1,1'-carbonyldiimidazole (1,33 g) dissolved in tetrahydrofuran (20 ml) and the resulting mixture was stirred at 80°C for 2 hours. To the reaction solution was added ethyl ether (2R*,4S*)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (1,91 g) and triethylamine (1,14 ml) and the resulting mixture was refluxed for 3 days. The reaction solution was distributed between ethyl acetate and saturated aqueous sodium bicarbonate solution, then the organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue is purified column chromatography (silica gel; hexane:ethyl acetate=90:10→70:30). The mixture of diastereomers is recrystallized from hexane to obtain ethyl ester (2R,4S)-2-ethyl-6-methoxy-4-((S)-1-phenylethanolamine)-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (345 mg). The physical properties are the same as for compound obtained in example 2 (3).

Reference example 4

(1) To aqueous solution (1000 ml) of sodium azide (157,6 g) is added dropwise a solution (605 ml) gililland (182,4 ml) in toluene at about the ladanyi on ice. The resulting mixture was stirred at the same temperature for 3 hours. To the mixture is added saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated salt solution and dried over magnesium sulfate. The resulting solution in toluene is added dropwise to a mixture of (S)-1-phenethyl alcohol (268 ml), pyridine (81,5 ml) and hydroquinone (12,21 g), which is heated to 85°C., and the mixture was stirred at the same temperature for 2 hours. To the obtained mixture is added saturated aqueous sodium bicarbonate solution and the organic layer was washed with saturated salt solution, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=10:1→8:1) to give (S)-1-phenethyl ether vinylcarbazole acid (240,2 g). MC (m/z): 191 [M+H]+.

(2) {[1-(benzotriazol-1-yl)propyl]-6-methoxypyridine-3-yl)}amine (218 g), (S)-1-phenethyl ether vinylcarbazole acid (147,1 g) and monohydrate p-toluensulfonate acid (1.47 g) was dissolved in toluene (2,88 l) and the resulting mixture is stirred overnight at 85°C. After cooling to room temperature when standing to the mixture is added saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with saturated salt solution, dried over sulfate magney then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=3:1→1:1). To the resulting mixture of diastereomers add a mixture of hexane/ethyl acetate (4:1). Mixture is allowed to stand and the precipitated crystals are filtered to obtain (S)-1-phenethyl ester (2R,4S)-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-2H-[1,5]naphthiridine-4-yl)carbamino acid (69,0 g). MC (m/z): 356 [M+H]+.

The filtrate is concentrated under reduced pressure to use in the next process (3).

(3) Concentrate (194,7 g)obtained in (2)described above, and pyridine (183 ml) dissolved in methylene chloride (1.65 l). To the mixture is added dropwise a solution (540 ml) ethylchloride (180 ml) in methylene chloride while cooling on ice and stirred at the same temperature for 2 hours. The reaction solution was washed with 10% aqueous citric acid solution and saturated salt solution, then dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=4:1) and the compound obtained is recrystallized from hexane (350 ml) to give the ethyl ester of (2R,4S)-2-ethyl-6-methoxy-4-((S)-1-phenylethanolamine)-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (133 g). The physical properties are the same as for compound obtained in example 2 (3).

With Ilony example 5

Tert-butyl acrylate (4.4 ml) dissolved in methanol (5 ml) and to the solution was added 2-methoxyethylamine (3.1 ml). The resulting mixture was stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure. The resulting residue is purified by distillation under reduced pressure to obtain tert-butyl 3-(2-methoxyethylamine)propionate (4.61 in). BP. 98,0-102,0°C (5.8 mm Hg). MC (m/z): 204 [M+H]+.

Reference example 6

Ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (8.0 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (265 mg), potassium acetate (of 3.56 g) and bis(pinacolato)LIBOR (4.6 g) was dissolved in dimethyl sulfoxide (50 ml)the mixture is heated at 80°C. in a nitrogen atmosphere and stirred for 1 hour. After cooling to room temperature the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (80 ml) and to the solution is added dropwise 30% hydrogen peroxide solution (80 ml) under cooling on ice. After 1 hour to the mixture is added saturated aqueous sodium thiosulfate solution under cooling on ice for destruction of excess the and of hydrogen peroxide. The resulting mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography (silica gel; hexane:ethyl acetate=19:1→3:1) to give the ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidine-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid (to 4.41 g). The physical properties are the same as for compound obtained in example 83.

1. The compound of formula (I)

where R1means1-6alkoxycarbonyl group, optionally substituted by 1-5 substituents independently selected from hydroxy-group, carboxyl group,
With1-6alkoxygroup,1-6allylthiourea,1-6alkylsulfonyl group2-6alkenylphenol group1-6alkanolamines, halogen atom and C3-10cycloalkyl group;
karbamoilnuyu group, optionally substituted C1-6alkoxygroup;
dihydrooxazolo group, optionally substituted by 1-2 hydroxy, C1-6alkyl groups;
mono - or di-C1-6alkylcarboxylic group, optionally substituted by 1-5 substituents, independently selected from a halogen atom and a hydroxy-group;
With alkyl group, optionally substituted by 1-51-6alkoxycarbonyl groups; or
With1-6alkanoyloxy group, optionally substituted by 1-5 morpholinyl groups;
R2means1-6alkyl group;
R3means a hydrogen atom;
R4means1-4alkylenes group;
R5means unsaturated 5-8-membered heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms and nitrogen,
where unsaturated 5-8-membered heterocyclic group containing 1-4 heteroatoms independently selected from oxygen atoms and nitrogen, is pyrimidinyl group, pyridyloxy group, tetrazolyl group, oxadiazolyl group, personilnya group or oxazolidinyl group;
where specified heterocyclic group optionally substituted by 1-4 substituents, selected from the following groups:
the halogen atom;
the carbonyl group;
hydroxy-group;
ceanography;
carboxyl group;
sulfopropyl;
With1-6alkyl group optionally substituted by a group selected from ceanography, hydroxy-group, carboxyl group, With1-6alkoxycarbonyl group, carbamoyl, sulfopropyl, sulfamoyl group, mono - or di - C1-6alkylcarboxylic group1-6alkoxygroup (specified With1-6alkoxy is the SCP optionally substituted by carboxyl or hydroxy group), With1-6alkanoyloxy,1-6alkylsulfonyl group, amino group, mono - or di-C1-6alkylamino, optionally substituted C1-6alkoxygroup, pyrrolidinyloxy group (specified pyrrolidinyl group optionally substituted C1-6alkoxycarbonyl or a carboxyl group), piperidinyl group, piperazinilnom group, optionally substituted C1-6alkyl group, and morpholinyl group;
With2-6alkenylphenol group, optionally substituted by a group selected from ceanography, hydroxy-group, carboxyl group, benzyloxycarbonyloxy group and tetrazolyl group;
C1-6alkoxygroup, optionally substituted by a group selected from a hydroxy-group, carboxyl group, With1-6alkoxycarbonyl group, carbamoyl group1-6alkoxygroup (specified With1-6alkoxygroup optionally substituted hydroxy group), With1-6allylthiourea,1-6alkylsulfonyl group, C1-6alkylsulfonyl group, DIOXOLANYL group, optionally substituted C1-6alkyl group, pyrrolidinyl group (specified pyrrolidinyl group optionally substituted by oxopropoxy), mono - or di - C1-6alkylcarboxylic group, optionally substituted hydroxy-group, pyrimidinyl group is s, peredelnoj group and morpholinylcarbonyl group;
With1-6alkoxycarbonyl group;
carbamoyl group;
mono - or di - C1-6alkylcarboxylic group, optionally substituted by a group selected from carboxyl group, morpholinyl group, a hydroxy-group and C1-6alkoxygroup;
hydroxycarbonylmethyl group;
With1-6allylthiourea, optionally substituted by a group selected from a hydroxy-group, carboxyl group and mono - or di - C1-6alkylcarboxylic group;
With1-6alkylsulfonyl group, optionally substituted by a group selected from a hydroxy-group, With1-6alkoxycarbonyl group and mono-or di - C1-6alkylcarboxylic group;
amino group;
mono - or di-C1-6alkylamino, optionally substituted by a group selected from a hydroxy-group, carboxyl group, With1-6alkoxycarbonyl group and morpholinyl group; mono - or di-C1-6alkanolamines, optionally substituted by a group selected from a hydroxy-group, With1-6alkoxygroup, carboxyl group and amino group;
mono - or di - C1-6allylcarbamate amino group, optional
replaced With1-6alkoxygroup;
morpholinylcarbonyl;
sulfamoyl group;
With1-6alkanoyloxy group;
With1-6ALCO is starveillance, optionally substituted
a carboxyl group, a hydroxy-group or1-6alkoxycarbonyl group; or
group selected from the following groups:
,,,,
,,,
and
where X1and X3means independently CH2, NH or O;
X2and X5means independently CH2;
X4indicates NH, O or SO;
n, o, p, q and r is independently an integer of 1-3, where each group of the above formulas optionally substituted by substituents selected from the following groups:
carboxyl group, a hydroxy-group, ceanography, the carbonyl group, C1-6alkyl group, hydroxys1-6alkyl group, a C1-6alkoxycarbonyl1-6alkyl group, carboxy1-6alkyl group, panels1-6alkyl group, a C1-6alkanoyloxy group1-6alkoxyl1-6alkanoyloxy group1-6alkoxygroup, panels1-6alkoxygroup,1-6alkoxycarbonyl group, benzyloxycarbonyl group, mono - or di-C1-6alkylamino, mono - or di-C1-6alkylcarboxylic group, mono - is whether di-C 1-6alkylsulfonyl group1-6alkylsulfonyl group, dihydrooxazolo group, optionally substituted by exography, and tetrazolyl group; R6, R7and R8denote independently a hydrogen atom, a hydroxy-group, cyano, C1-6alkyl group, a C1-6alkoxygroup, mono - or di - C1-6alkylcarboxylic group or mono - or di-C1-6alkylamino, where these groups With1-6alkyl, C1-6alkoxy, mono - or di - C1-6allylcarbamate and mono - or di-C1-6alkylamino optionally substituted by 1-6 substituents, independently selected from a halogen atom, a C1-6alkoxygroup and amino;
R10means phenyl group,
where specified phenyl group optionally substituted with 1-2 substituents independently selected from a halogen atom, karboksilnoj group1-6alkoxycarbonyl group1-6alkyl group, a C1-6alkoxygroup, ceanography and C1-6ancilliary where specified1-6alkyl group, a C1-6alkoxygroup and C1-6allylthiourea optionally substituted by halogen atoms; or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1means1-6alkoxycarbonyl group, optionally substituted by 1-5 substituents independently selected from carboxy who enoy group, of halogen atom, hydroxy-group and C3-10cycloalkyl group;
where R5means a group of the formula:

ring And means pyrimidinyl, tetrazolyl group or pyridyloxy group;
R11means1-6alkyl group optionally substituted by carboxyl group, carboxy2-6alkenylphenol group; C1-6alkoxygroup, optionally substituted by a group selected from a hydroxy-group, carboxyl group, With1-6ancilliary and C1-6alkylsulfonyl group; mono - or di - C1-6alkylamino, optionally substituted by carboxyl group; hydraxis1-6alkanolamines; morpholinyl group; piperazinilnom group, optionally substituted C1-6alkyl group or a C1-6alkanoyloxy group; or piperidinyloxy group optionally substituted by carboxyl group or a hydroxy-group; R6means1-6alkyl group optionally substituted by a halogen atom, a C1-6alkoxygroup or mono - or di - C1-6alkylamino; and R7means a hydrogen atom;

3. The compound according to claim 2, where R1means ethoxycarbonyl group, hydroxyethoxyethyl group, 2-forecastable group, 2,2-diplomaticcarbon group or 2,2,2-triptoreline CARBONYLS the th group;
R2means ethyl group;
R10means a phenyl group substituted by 1-2 substituents selected from ceanography and triptorelin group; and R6means a methoxy group or triptorelin group.

4. The compound according to claim 2, where R1means carboxy(C1-6alkoxy)carbonyl group;
R2means ethyl group;
R10means a phenyl group substituted by 1-2 substituents selected from ceanography and triptorelin group; and
R6means a methoxy group or triptorelin group.

5. A compound selected from the following compounds, or pharmaceutically acceptable salt:
ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;
ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methylsulfonylmethane)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;
ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-carboxypeptidase-1-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;
ethyl ester of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxymethoxy)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;
ethyl ester of (2R,4S)-4-{[5-(4-acetylpiperidine-1-the l)pyrimidine-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-6-dimethylamino-2-ethyl-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;
2,2,2-triptoreline ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethyl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid;
2-carboxy-2-methylpropionyl ether of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholine-4-yl)pyrimidine-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthiridine-1-carboxylic acid.

6. The method of obtaining the derived tetrahydronaphthalene formula (I)

where the symbols R1, R2, R3, R4, R5, R6, R7, R8and R10have the meanings defined in claim 1, and not containing primary and secondary amino groups, involving the condensation of the compounds of formula (II)

where each symbol has the meaning as defined above, with a compound of formula (III):

where Z1means tsepliaeva group selected from a halogen atom, methysulfonylmethane, toluensulfonate and triftormetilfullerenov, and other symbols have the above specified values.

7. The method of obtaining a mixture of diastereomers of the formula (VII-a)

where R15'means benzyloxycarbonyloxy group containing a chiral center in the position of the benzyl;
R6means a hydrogen atom, a C1-6alkyl group, neobyazatelnostyu a halogen atom, With1-6alkoxygroup, cyano or mono-or di - C1-6alkylamino;
and the symbols R2, R3, R7and R8have the same meanings as defined in claim 1, involving the reaction of the compound of formula (IX)

where each symbol has the same meanings as defined above, with a compound of formula (VIII-a):

where each symbol has the same meanings as defined above.

8. A method of obtaining optically active compounds of the formula (VII-b)

where the symbols R2, R3, R7and R8have the same meanings as defined in claim 1, and R6has the same meaning as defined in claim 7, involving the reaction of the compound of formula (IX):

where each symbol has the same meanings as defined above, with a compound of formula (VIII-a):

where R15'means optically active protective group for amino group selected from benzyloxycarbonyl groups containing a chiral center in the position of the benzyl, such as α-methylbenzyloxycarbonyl group, and the symbol R3has the same meanings as defined above, separation of the mixture of diastereomers of the formula (VII-a)

where each symbol has the same the values, as defined above, and removing the optically active protective group for amino group.

9. The method according to claim 7, where the compound of formula (XII)

where the symbols R2, R7and R8have the same meanings as defined in claim 1, and R6has the same meaning as defined in claim 7, is used instead of the compound (IX)

where each symbol has the same meanings as defined above.

10. The method of claim 8 where the compound of formula (XII)

where the symbols R2, R7and R8have the same meanings as defined in claim 1, and R6has the same meaning as defined in claim 7, is used instead of the compound (IX)

where each symbol has the same meanings as defined above.

11. Method of inhibiting protein transfer cholesterolemia ether comprising contacting a specified protein with an effective amount of a compound according to any one of claims 1 to 5.

12. The use of compounds according to any one of claims 1 to 5, or its pharmaceutically acceptable salt for the manufacture of a pharmaceutical composition having inhibitory activity against protein transfer cholesterolemia ether.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzodiazine of the formula (1), which possess properties of inhibiting proliferative action and can be used during treatment of hyper-proliferative diseases like cancer. In formula (I) G1 and G2 each independently representing a halogen; X1 -R1 selected C1-C6-alkoxy, X2 represents a simple bond; Q1 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, where Q1 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different , selected from cyano, carbamoyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkyl-sulfinyl C1-C6-alkyl-sulfonyl, N-C1-C6-alkyl-carbamoyl N,N-di-[C1-C6-alkyl]carbamoyl, C1-C6-alkanoyl, sulfamoyl, N-C1-C6-alkyl-sulfamoyl, N,N-di-[C1-C6-alkyl-]sulfamoyl, carbamoyl C1-C6-alkyl, N-C1-C6-alkyl-carbamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]carbamoylC1-C6-alkyl, sulfamoylC1-C6-alkyl, N-C1-C6-alkyl-sulfamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]sulfamoylC1-C6-alkyl, C1-C6-alkanoylC1-C6-alkyl, or from the group with the formula: Q2 -X3-, where X3 represents CO and Q2 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular nitrogen heteroatom and not necessarily 1 or 2 heteroatoms, selected from nitrogen and sulphur, and where. Q2 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different, selected from halogens, C1-C4-alkyl, and where any C1-C6-alkyl and C2-C6-alkaloid groups within the limits of Q1 does not necessarily have one or more substitute groups, which can be similar or different, selected from hydroxy and C1-C6-alkyl and/or not necessarily a substitute selected from cyano, C1-C6-alkoxy, C2-C6-alkanoxy and NRaRb, where Ra represents hydrogen or C1-C4-alkyl and Rb represents hydrogen or C1-C4-alkyl, or Ra and Rb together with a nitrogen atom, to which they are attached, they form a 4-, 5- or 6- member non-aromatic saturated monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, which not necessarily have 1 or 2 substitutes, which can be similar or different, on the available carbon atom, and selected from halogens and C1-C3-alkilenedioxy.

EFFECT: obtaining new derivatives benzodiazine, which possess properties of inhibiting proliferative action and can be used during the treatment of hyper-proliferative diseases such as cancer

27 cl, 73 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of noscapine of the general formula (1) or its racemates, optical isomers, or their pharmaceutically acceptable salts and/or hydrates possessing anticarcinogenic activity, and to a pharmaceutical composition as tablets, capsules or injection formulations placed into pharmaceutically acceptable package, ant to methods for their synthesis, and to a method for inhibition of proliferation by their using. In compounds of the formula (1) R1 represents a substitute of amino-group chosen from alkyl; R2 represents a substitute of cyclic system chosen from possibly substituted alkyl wherein substitutes are chosen from possibly substituted amino-group or azaheterocycle comprising possibly oxygen (O), sulfur (S) or nitrogen (N) atoms as an additional heteroatom, and added to alkyl group by nitrogen atom, possibly substituted aryl possibly substituted and possibly condensed heteroaryl comprising at least one heteroatom chosen from nitrogen, sulfur and oxygen atoms, possibly substituted sulfamoyl. Except for, invention relates to 3-(9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 5-(4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-9-carbaldehyde (or -9-carbonitrile, or -9-sulfonyl chloride, or -9-carboxylic acid) and 3-(9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, and method for their synthesis. Also, invention relates to combinatory and focused libraries.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 5 tbl, 9 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

The invention relates to new proizvodnim quinoline of formula (I), where R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl; R4is hydrogen and pharmaceutically acceptable inorganic or organic anion; R5is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, chlorine, bromine, CF3and coxFywhere x=0-2, y=1-3, provided that x+y=3; R6is hydrogen; R5and R6taken together, constitute methylendioxy

The invention relates to new substituted benzo/a/acridinium formula (II), where R1and R2are independently IT, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy, or R1and R2together represent-OCH2O-; R3represents H; R5and R6are independently H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy, or R5and R6together represent-co2O-; R7represents H or (C1-C8)alkyl, or R1, R2, R3, R5, R6independently represent H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy; R1and R2together represent-OCH2O-; R2and R3together represent-co2O-; R5and R6together represent-OCH2O-; R7represents H or (C1-C8)alkyl, provided that one of R1and R2is (C1-C8)alkoxy, or R1and R2together represent-co2O-, or R1, R5and R6independently represent H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy; R2

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new annelated asaheterocycles include pyrimidine fragment of general formula I in the form of free bases or pharmaceutically acceptable salts. Compounds of this invention possess properties of PI3 kinase inhibitors. In general formula I X represents oxygen atom or sulphur atom; Z represents oxygen atom, R1 represents hydrogen atom or optionally substituted C1-C6alkyl, or Z represents nitrogen atom together with bound carbon atom forming through Z and R1 optionally substituted annelated imidazoline cycle; R2 represents optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, possibly annelated with 5-6-term heterocyclyl containing heteroatoms chosen from oxygen and nitrogen, optionally substituted 5-6-term heterocyclyl containing heteroatoms chosen from nitrogen, oxygen and/or sulphur, possibly annelated with phenyl ring. Invention also concerns method of production of compounds, pharmaceutical compositions and medical products.

EFFECT: effective application for preparation of medical products for oncologic therapy.

14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds consistent with the general formula (I) or the general formula (II) where: R1 = H; Z = O or S; P1 = CR5R6, P2 = CR7R8, Q = CR9R10; each of R5, R6, R7, R8, R9 and R10 denotes H; Y = CR12R13-CO, where R12, R13 is selected from C0-7-alkyl; C3-6-cycloalkyl or phenyl-C0-7-alkyl; and where the phenyl ring doesn't have to be substituted R19, specified below; in the group (X)0, X = CRI4R15, where R14 and R15 are independently selected from C0-7-alkyl, and o represents a number from zero to three; (W)n, W = O, S, C(O), S(O) or S(O)2 or NR16, where R16 denotes H, and n equals zero or one; (V)m, V = C(O), NHC(O), C(O)NH or CR17R18, where R17 and R18 denotes H, and m represents a number from zero to three, on condition that, when m is more than one, (V)m contains a maximum of one carbonyl group; U = a stable 5-7-member monocyclic or 8-11-member dicyclic ring, which is saturated or non-saturated and which has from zero to four heteroatoms selected from: , where R19 represents: C0-7-alkyl, C3-6-cycloclkyl, Ar-C0-7-alkyl, O-C0-7-aklyl, NH-C0-7-alkyl, N(C0-7-alkyl)2, O-phenyl, S-phenyl; or, as a part of CHR19 or CR19 group, R19 can represent a halogen; where Ar represents a stable 5- or 6- member monocyclic or stable 9- or 10- member dicyclic ring, which is unsaturated as determined earlier for U, and where Ar doesn't have to be substituted R19, which is of importance specified above; C0-7-alkyl represents a stable linear or a branched aliphatic carbon chain, which contains from 0 to 7 carbon atoms, which doesn't have to be substituted with one, two or three halogen atoms and doesn't have to contain one or few heteroatoms selected from O, N and S, where the heteroatom is present only when C0-7-alkyl contains as a minimum one carbon atom; C3-6-cycloalkyl relates to C0-7-alkyl, certainly higher than the additionally contained carboxyl ring, which doesn't have to be substituted with one or more halogens, selected from F, Cl, Br and I or heteroatoms, selected from N, O, S; A represents O; B, D and G are independently selected from: CR19, where R19 is as specified above or N; E represents O or S; J, L, M, R, T, T2, T3 and T4 which are independently selected from: CR19 and N, where R19 is as specified above; T5 represents N; q represents a number from one to three, determining in this way a 5-, 6- or 7- member ring or its salt, hydrate or solvate. The bonds of the general formula (I) or the general formula (II), represent cruzipain inhibitors and inhibitors of other cisteinproteases and can be used as therapeutic agents, for example, in cases of Chagas disease or for confirmation of target oriented therapeutic bonding.

EFFECT: new bonds which posses helpful biological properties have been discovered.

27 cl, 156 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to heterocycle-substituted tricyclic compounds of the formula (I): or their pharmaceutically acceptable salts wherein R means hydrogen atom; R1 and R2 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R3 means hydrogen atom; n1 and n2 = 0-3 independently under condition that they both do not mean 0; Het means pyridyl wherein pyridyl is added to B through cyclic carbon atom and it comprises from 1 to 4 substitutes (W) chosen independently from group comprising -NR4R5, -NHCOR26, -NHSO2R16; R21 means aryl and R21 means heteroaryl wherein heteroaryl represents furyl, thienyl, pyridyl, thiazolyl, pyrrolidinyl, azethidinyl; R4 and R5 mean hydrogen atom or alkyl comprising 1-6 carbon atoms, or R4 and R5 mean in common -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)2NR7-(CH2)2- wherein R7 means hydrogen atom or alkyl comprising 1-6 carbon atoms; R8, R, R10 and R11 mean hydrogen atom; B means -(CH2)n4CR12=CR12a(CH2)n5 wherein n4 and n5 = 0-2 independently; R12 and R12a are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R21 means from 1 to 3 substitutes chosen independently from group comprising hydrogen atom, trifluoromethyl, trifluoromethoxy, halogen atom, cyano, alkyl comprising 1-6 carbon atoms, alkoxy group comprising 1-6 carbon atoms, or -CR29(=NOR28); R22 means -COR23, -S(O)R31, -S(O)2R31 or -COOR27; R23 means cycloalkyl comprising 3-7 carbon atoms, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, cycloalkyl comprising 3-7 carbon atoms containing from 1 to 3 substitutes chosen from group comprising halogen atom, (C1-C3)-alkoxy-(C1-C3)-alkyl, hydroxy group and alkoxy group comprising 1-6 carbon atoms, aryl, aryl-(C2-C6)-alkyl; R27 means alkyl comprising 1-6 carbon atoms, phenyl or benzyl; R28 and R29 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R31 means alkyl comprising 1-6 carbon atoms, halogenalkyl comprising 1-6 carbon atoms, aryl, aryl-(C1-C6)-alkyl. Also, invention relates to pharmaceutical compositions containing these substances and their using for preparing a drug used in treatment of thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, heart failure and cancer.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 11 tbl, 9 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides novel condensed furan compounds of general formula I: , wherein circle X represents benzene, pyridine, or the like; Y optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted piperidyl, oxo-substituted pyrrolydyl, or oxo-substituted morpholino group; R3 hydrogen and the like; and R4 is hydrogen, or a pharmaceutically acceptable salt thereof, which are useful as drugs, especially as inhibitor of activated blood coagulation factor A, as well as intermediate compounds.

EFFECT: expanded synthetic possibilities in furan series and increased choice of biologically active compounds.

16 cl, 85 tbl, 481 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of tetracyclic derivatives of isoquinolone. Invention describes a method for synthesis of derivatives of 3,5-dihydro-1,11-dimethylfuro[2',3':3,4]cyclohepta[c]isoquinoline-5-one of the general formula (1a-f): wherein (1a): R means hydrogen atom (H); R' means hydrogen atom (H); (1b): R means chlorine atom (Cl); R' means hydrogen atom (H); (1c): R means bromine atom (Br); R' means hydrogen atom (H); (1d): R means iodine atom (J); R' means hydrogen atom (H); (1e): R means methoxy-group (-OCH3); R' means hydrogen atom (H); (1f): R means -OCH3; R' means -OCH3. Method involves boiling derivatives of 3,5-dihydro-1,11-dimethylfuro[2',3':3,4]cyclohepta[c]isochromen-5-one in formamide medium in the ratio 0.01 mole of the parent substance per 45 ml of formamide for 25-120 min. Invention provides preparing new compounds that possess the potential useful biological properties.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 tbl, 6 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to compounds with formula I, active towards receptors, activated by peroxisome proliferators (PPAR), and can be used in medicine, formula I, where U, W, X and Y represent CH, V represents CR8; R1 represents-C(O)OR or a carboxylic acid isoster, where R is a hydrogen atom, substituted alkyl, aryl or heteroaryl; R2 represents -S(O)2R21; R6 and R7 represent a hydrogen atom, substituted alkyl or cycloalkyl; R8 represents a hydrogen atom, halogen, -OR9, substituted inferior alkyl, cycloalkyl, heterocycloalkyl, phenyl, benzyl, heteroaryl or heteroaralkyl; R9 represents a substituted alkyl or cycloalkyl; R21 represents a substituted heteroaryl or phenyl; n equals 1.

EFFECT: obtaining new biologically active compounds and pharmaceutically active compositions based on these compounds.

46 cl, 134 ex, 4 tbl

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