Novel heterocyclic compound or salt thereof and intermediate compound thereof

FIELD: chemistry.

SUBSTANCE: described is a compound of general formula: [1], where R1 denotes an optionally substituted C2-C12 alkyl, aryl or heterocyclic group which can be a mono- or bicyclic 5-11-member radical, where the heteroatoms can be nitrogen, oxygen or sulphur; X1 denotes C2-C4 an alkylene group; X2 denotes a bond; X3 denotes a group of general formula NR3 or CR4R5NR3 (where R3 denotes a hydrogen atom, optionally substituted lower alkyl group or imino-protective group) and R4 and R5 are identical or different, and each denotes a hydrogen atom or a lower alkyl group or bond; X4 denotes a lower alkylene or lower alkenylene or lower alkynylene group, which can be substituted with one or more oxo groups or a bond; X5 denotes a sulphur atom or bond; Y1 denotes an optionally substituted divalent 4-, 5- or 6-member alicyclic hydrocarbon residue or an optionally subsituted divalent 5- or 6-member alicyclic amine residue, where the heteroatoms can be nitrogen or oxygen; Z1, Z2, Z3, Z4, Z5 and Z6 are identical or different, and each denotes a nitrogen atom or a group of general formula CR7 (where R7 denotes a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted amino group, or an amino group substituted with one or more C1-6 alkyl groups, a lower alkyl group, a cycloalkyl, a lower alkoxy group or a monocyclic 5-member heterocyclic group which can be substituted with one or more halogen atoms, where the heteroatoms can be nitrogen, acid or sulphur or a group of general formula Q1CO2R10 (where R10 denotes a carboxyl-protective group and Q1 denotes a lower alkenylene group), provided that at least one of Z3, Z4, Z5 and Z6 denotes a nitrogen atom, or salt thereof. The invention also describes an antimicrobial agent based on said compound.

EFFECT: novel compounds which can be used as antimicrobial agents are obtained and described.

25 cl, 176 ex, 6 tbl

 

The technical field to which the invention relates

The present invention relates to new compounds or their salts that have high antimicrobial activity against gram-positive bacteria, gram-negative bacteria and resistant bacteria, and refers to antimicrobial agents containing such compounds or salts. The present invention also relates to intermediate compounds suitable for obtaining such compounds.

The level of technology

In clinical practice using different types of antibiotics and synthetic antimicrobial agents for the treatment of infectious diseases. However, recent reports of such resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and penicillin-resistant Streptococcus pneumoniae (PRSP), and therapeutic treatment of patients infected with resistant bacteria, is a critically important task. In addition, appeared resistant to many drugs bacteria that have developed resistance to several drugs. Infectious diseases associated with bacteria resistant to many drugs, not treated and are a serious problem throughout the world.

Development of Antibes is Oticon, effective against resistant bacteria, is very desirable, and, for example, publication of the application for international patent # WO 99/07682 (Patent document 1) describes a quinolone compounds that are effective against MRSA. Publication of an application for international patent # WO 2004/002490 (Patent document 2) and the publication of the application for international patent WO 2004/002992 (Patent document 3) describe compounds whose mechanisms of action are different from the mechanisms of traditional medicines.

Patent document 1: publication of an application for international patent # WO 99/07682.

Patent document 2: publication of an application for international patent # WO 2004/002490.

Patent document 3: publication of an application for international patent # WO 2004/002992.

Description of the invention

It is desirable to develop drugs that have a high antimicrobial activity against gram-positive bacteria, gram-negative bacteria and drug-resistant bacteria and having high safety. Additionally, intermediate connection, suitable for receiving this medication is highly desirable.

In these circumstances, the authors of the present invention conducted intensive studies and found that the compound represented by the General formula is [1]:

(where R1denotes optionally substituted C2-C12alkyl, aryl or heterocyclic group; X1denotes optionally substituted C2-C4alkylenes group; X2refers to a group represented by the General formula NR2(where R2denotes a hydrogen atom, optionally substituted lower alkyl group or imino-protective group, or a bond; X3refers to a group represented by the General formula NR3or CR4R5NR3(where R3denotes a hydrogen atom, optionally substituted lower alkyl group or imino-protective group; and R4and R5are the same or different and each represents a hydrogen atom or optionally substituted lower alkyl group, or R4and R5together form an oxo group)or a bond; X4denotes optionally substituted lower alkylenes, lower alkynylamino or lower alkynylamino group or a bond; X5denotes an oxygen atom, a sulfur atom, sulfinyl group, sulfonyloxy group, a group represented by the General formula NR6(where R6denotes a hydrogen atom, optionally substituted lower alkyl, lower alkenylphenol or lower alkylamino group or imino-protective group), isiswati; Y1denotes optionally substituted divalent alicyclic hydrocarbon residue or an optionally substituted divalent alicyclic amine residue; Z1, Z2, Z3, Z4, Z5and Z6are the same or different, and each of them represents a nitrogen atom or a group represented by the General formula CR7(where R7denotes a hydrogen atom, halogen atom, hydroxyl group, cyano group, nitro group, formyl group, optionally protected or substituted amino group, optionally substituted lower alkyl, cycloalkyl, aryl, lower alkoxy, cycloalkane, aralkylated, alkanoyloxy, ureido or monocyclic heterocyclic group, or a group represented by the General formula Q1CONR8R9, Q1CO2R10or Q1CN (where R8and R9are the same or different and each represents a hydrogen atom, optionally substituted lower alkyl, cycloalkyl, Uralkaliy, aryl, lower alkoxy, alkanesulfonyl or monocyclic heterocyclic group, or they form together with the nitrogen atom, which is associated with R8and R9, optionally substituted cyclic amino group; R10denotes a hydrogen atom or carboxyl protection is the Rupp; and Q1denotes optionally substituted lower alkylenes or lower alkynylamino group or Association)), provided that at least one of the Z3, Z4, Z5and Z6represents a nitrogen atom), or its salt, which has a high antimicrobial activity and high safety; and that the connection represented by the General formula [2]:

(where X1adenotes optionally substituted C1-C3alkylenes group; Y2represents optionally protected carbonyl group; Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as described above; and at least one of the Z3, Z4, Z5and Z6denotes a nitrogen atom), and the compound represented by the General formula [3]:

(where R7cdenotes a halogen atom, hydroxyl group, cyano group, nitro group, formyl group, optionally protected or substituted amino group, optionally substituted lower alkyl, cycloalkyl, aryl, lower alkoxy, cycloalkane, aralkylated, alkanoyloxy, ureido or monocyclic heterocyclic group, or a group represented by the General formula Q1CONR8R9, Q1CO2R10or Q1CN (where R8, R9R 10and Q1have the same meanings as described above); Z2aand Z6aare the same or different, and each of them represents a nitrogen atom or a group represented by the General formula CR7(where R7has the same meaning as described above), are suitable for use as intermediates for obtaining the compounds of General formula [1]. The present invention is completed appropriately.

The compound of General formula [1] or its salt has a high antimicrobial activity against gram-positive bacteria, gram-negative bacteria and drug-resistant bacteria and has high safety, and for this reason is suitable as an excellent antimicrobial agent.

Compounds of General formulas [2] and [3] are suitable as intermediates for obtaining the compounds of General formula [1].

The best way of carrying out the invention

The compound of the present invention will be described in detail.

In the present description, unless otherwise specified, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; an alkyl group denotes, for example, C1-12alkyl group with straight chain or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, image is Teal, tert-butyl, pentyl, hexyl and octyl; C2-C12alkyl group denotes, for example, C2-12alkyl group with straight chain or branched chain, such as ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl and octyl; a lower alkyl group refers to, for example, C1-6alkyl group with straight chain or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl and isopentyl; Alchemilla group denotes, for example, C2-12alkenylphenol group with straight chain or branched chain, such as vinyl, allyl, propenyl, Isopropenyl, butenyl, Isobutanol, pentanol, hexanol, heptanol and octanol; lower Alchemilla group denotes, for example, C2-6alkenylphenol group with straight chain or branched chain, such as vinyl, allyl, propenyl, Isopropenyl, butenyl, Isobutanol, pentanol and hexanol; lower Alchemilla group denotes, for example, C2-6alkylamino group with straight chain or branched chain, such as ethinyl, 2-PROPYNYL and 2-butynyl.

Cycloalkyl group denotes, for example, C3-8cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; aryl group denotes, for example, such a group as phenyl, naphthyl, anthracene and phenanthrene; kalkilya gr what PLR means, for example, ar-C1-6alkyl group, such as benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl.

The lower alkoxy group denotes, for example, C1-6alkyloxy group with straight chain or branched chain, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentane; cycloalkane group denotes, for example, C3-8cycloalkane group, such as cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy; Arakelov group denotes, for example, ar-C1-6alkyloxy group, such as benzyloxy, penetrate; alkoxyalkyl group denotes, for example, C1-6alkyloxy C1-6alkyl group, such as methoxymethyl and 1-ethoxyethyl; aracelikarsaalyna group denotes, for example, ar-C1-6alkyloxy C1-6alkyl group, such as benzoyloxymethyl and penetrometer.

Lower Allenova group denotes, for example, C1-6alkylenes group such as methylene, ethylene, propylene, butylene, hexylen; C2-C4Allenova group denotes, for example, C2-4alkylenes group, such as ethylene, propylene and butylene; C1-C3Allenova group denotes, for example, C1-3alkylenes group such as methylene, ethylene and propylene; lower alkenylamine group is and means, for example, C2-6alkynylamino group, such as vinile, propylen, bouteillan and penttinen; lower akinlana group denotes, for example, C2-6alkynylamino group such as ethynylene, propylen, Butyrin and pentikinen.

Alcoolica group denotes, for example, C2-12alkanoyloxy group with straight chain or branched chain, such as acetyl, propionyl, butyryl, isovaleryl and pivaloyl; acyl group denotes, for example, formyl group, C2-12alkanoyloxy group with straight chain or branched chain, such as acetyl, propionyl, butyryl, isovaleryl and pivaloyl, ar-C1-6alkylcarboxylic group, such as benzylcarbamoyl, cyclic hydrocarbon-carbonyl group such as benzoyl and naphtol, heterocyclic carbonyl group, such as nicotinoyl, thenoyl, pyrrolidinecarbonyl and furoyl, succinimido group, glutaryl group, Malolo group, palolo group and α-aminoalcohol group with straight chain or branched chain, with optionally protected N-finish, which is derived from amino acids (the amino acid is, for example, glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine,, glutamine, arginine, lysine, histidine, hydroxylysine, Hairdryer shall lalani, tyrosine, tryptophan, Proline and hydroxyproline).

Acidalkaline group denotes, for example, such a group as acetylethyl, benzoylmethyl, p-nitrobenzoyl, p-bromobenzoyl, p-methoxybenzoyl and 1-benzoylethyl; acyloxy group denotes, for example, C2-6alkanoyloxy group with straight chain or branched chain, such as atomic charges, propionyloxy, and urologic group such as benzoyloxy; aryloxyalkyl group denotes, for example, such a group as acetoxymethyl, propionylacetate and pivaloyloxymethyl.

Allyloxycarbonyl group denotes, for example, C1-12allyloxycarbonyl group with straight chain or branched chain, such as methoxycarbonyl, etoxycarbonyl, 1,1-dimethylpropanolamine, isopropoxycarbonyl, 2-ethylhexyloxymethyl, tert-butoxycarbonyl and tert-pentyloxybenzoyl; aracelikarsaalyna group denotes, for example, ar-C1-6allyloxycarbonyl group, such as benzyloxycarbonyl and ventilatsioonil; aryloxyalkyl group denotes, for example, vinyloxycarbonyl group.

Alkylthio group denotes, for example, C1-6alkylthio group, such as methylthio, ethylthio, propylthio; aaltio group denotes, for example, phenylthio group; allylthiourea group denotes, for example, C1-6alkylthio C1-6 alkyl group, such as methylthiomethyl, ethylthiomethyl and propylthiouracil; artioukhina group denotes, for example, such a group as (phenylthio)methyl and 2-(p-nitrophenylthio)ethyl; alkanesulfonyl group denotes, for example, C1-6alkanesulfonyl group, such as methanesulfonyl, trifloromethyl, econsultancy and propanesulfonyl; arylsulfonyl group denotes, for example, such a group as benzazolyl, toluensulfonyl and naphthalenesulfonyl.

Arylsulfonyl group denotes, for example, p-toluensulfonyl group; alkanesulfonyl group represents C1-6alkanesulfonyl group, such as methanesulfonate, tripterocalyx, econsultancy; arylsulfonate group denotes, for example, such a group as benzosulfimide, toluensulfonate.

Lower alkylamino group denotes, for example, mono-C1-6alkylamino group, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamine, C3-6cyclooctylamino group, such as cyclopropylamino, cyclobutylamine, cyclopentylamine, and di-C1-6alkylamino group, such as dimethylamino, diethylamino, dipropylamino, dibutylamino; the cyclic amino group denotes, for example, such a group as piperazinil, piperid the Nile, morpholino and pyrrolidinyl; oxygen-containing heterocyclic group refers to, for example, such a group as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; sulfur-containing heterocyclic group refers to, for example, tetrahydropyranyloxy group.

Oxygen-containing heterocyclic alkyl group denotes, for example, 5-methyl-2-oxo-2H-1,3-dioxol-4-ylmethylene group; nitrogen-containing heterocyclic alkyl group denotes, for example, such a group as phthalimidomethyl and Succinimidyl; geterotsiklicheskikh group denotes, for example, such a group as 2-furfurylalcohol and 8-hinolincarbonova.

Cycloalkylcarbonyl group denotes, for example, such a group as cyclopentylamine and cyclohexylidene; aralkylamines group denotes, for example, such a group as benzylidene and naphthylmethyl; dialkylaminoalkyl group denotes, for example, such a group as N,N-dimethylaminomethylene and N,N-diethylaminomethyl; nitrogen-containing heterocyclic alkylidene group denotes, for example, 3-hydroxy-4-pyridylmethylene group.

Diarylphosphino group denotes, for example, diphenylphosphoryl group; di(aralkyl)phosphoryl group denotes, for example, dibenzoylresorcinol group; a substituted silyl group refers to, for example, such a group, ka is trimethylsilyl, triethylsilyl and tributyrin; alkylsalicylate group denotes, for example, 2-(trimethylsilyl)ethyl group.

Monocyclic heterocyclic group refers to, for example, such a group as furyl, furfuryl, thienyl, 2-thienyl, 2-pyrrolyl, imidazolyl, 3-pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, thiadiazolyl, personel, pyrrolidinyl, imidazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperazinil, 2-piperidyl, 3-piperidyl, 4-piperidyl, 2-piperazinil, 2-morpholinyl, 2-thiomorpholine and pyranyl; bicyclic heterocyclic group refers to, for example, such a group as benzofuranyl, isobenzofuranyl, benzothiazyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole, 1H-indazole, purinol, coumarinyl, bromanil, hinely, ethanolic, phthalazine, naphthyridine, honokalani, hintline, cinnoline, bromanil, isopropanol, hinokitiol, 1,3-benzodioxolyl, 1,4-benzodioxane, benzomorphans, benzomorphans, 2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl, 3,4-dihydro-2H-pyrido(4,3-b)(1,4)oxazin-7-yl, 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-yl, 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-yl, 3-oxo-3,4-dihydro-2H-benzothiazin-6-yl, 3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl, 3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-yl, (1,3)dioxolo(4,5-c)pyridine-6-yl, 6-oxide-2,3-dihydro(1,4)like(23-c)pyridin-7-yl, 7-oxo-5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl and 5,6,7,8-tetrahydroquinoxalin-2-yl; tricyclic heterocyclic group refers to, for example, such a group as tianren-2-yl, xanthene-2-yl, phenoxathiin-2-yl, 4aH-carbazole-2-yl, carbazole-2-yl, phenanthridine-3-yl, acridine-2-yl, pyrimidin-2-yl, phenanthrolin-3-yl, fenesin-1-yl, phenothiazines-2-Il, phenoxazin-2-yl and 2,3-dihydro-5-oxo-(1H,5H)-benzo(IJ)quinoline-6-yl; heterocyclic group refers to, for example, the above monocyclic heterocyclic, bicyclic or tricyclic heterocyclic heterocyclic group.

Protected carbonyl group denotes, for example, a group consisting of a carbonyl group and / or alcohol, such as (hydroxy)(methoxy)methylene, (hydroxy)(ethoxy)methylene, (hydroxy)(propoxy)methylene, (hydroxy)(isopropoxy)methylene, (hydroxy)(butoxy)methylene, (hydroxy)(pentyloxy)methylene, (hydroxy)(hexyloxy)methylene, (hydroxy)(heptyloxy)methylene, (hydroxy)(octyloxy)methylene, (hydroxy)(1,1-DIMETHYLPROPANE)methylene, dimethoxymethane, diethoxymethane, disproportionation, diisopropanolamine, diputaciones, bis(benzyloxy)methylene, 1,3-dioxolane-2-ilidene and 1,3-dioxane-2-ilidene group consisting of a carbonyl group and thiol, such as bis(methylthio)methylene, bis(ethylthio)methylene, bis(benzylthio)methylene, 1,3-ditiolan-2-ilidene and 1,3-dition-2-ilidene, and this is the Rupp, as oxazoline-2-ilidene, imidazolidin-2-ilidene, thiazolidin-2-ilidene.

The divalent alicyclic hydrocarbon residue indicates, for example, C3-8cycloalkenyl residue, such as 1,2-CYCLOBUTANE, 1,3-cyclobutyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexene and 1,4-cyclohexyl, and cross-linked C3-8cycloalkenyl residue such as bicyclo(3.2.1)octile, bicyclo(2.2.0)hexylen and bicyclo(5.2.0)Nonlin; divalent 4-, 5 - or 6-membered alicyclic hydrocarbon residue indicates, for example, C4-6cycloalkenyl residue, such as 1,2-CYCLOBUTANE, 1,3-cyclobutyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexene and 1,4-cyclohexyl, and cross-linked C4-6cycloalkenyl residue such as bicyclo(3.2.1)octile and bicyclo(2.2.0)hexalen.

Divalent alicyclic amine residue indicates, for example, 4-membered alicyclic amine residue, such as azetidin-1,2-diyl, azetidin-1,3-diyl, monocyclic 5-membered alicyclic amine residue, such as pyrrolidin-1,2-diyl and pyrrolidin-1,3-diyl, cross-linked 5-membered alicyclic amine residue, such as 3-azabicyclo(3.1.0)hexane-3,5-diyl, 3-azabicyclo(3.1.0)hexane-3,6-diyl, 8-azabicyclo(3.2.1)octane-3,8-diyl, octahydrocyclopenta(c)pyrrole-2,4-diyl, octahydrocyclopenta(c)Pirro is -2,5-diyl, octahedral(3,4-c)pyrrole-2,4-diyl and octahedral(3,4-c)pyrrole-2,5-diyl, monocyclic 6-membered alicyclic amine residue, such as piperidine-1,3-diyl, piperidine-1,4-diyl, piperazine-1,3-diyl, piperazine-1,4-diyl, morpholine-2,4-diyl and thiomorpholine-2,4-diyl, cross-linked 6-membered alicyclic amine residue, such as 3-azabicyclo(4.1.0)heptane-3,6-diyl, hexahydrobenzo(1,5-a)pyrazin-2,7-diyl, and homopiperazin-1,4-dialnow group.

Divalent 5-membered alicyclic amine residue indicates, for example, monocyclic 5-membered alicyclic amine residue, such as pyrrolidin-1,2-diyl and pyrrolidin-1,3-diyl, and cross-linked 5-membered alicyclic amine residue, such as 3-azabicyclo(3.1.0)hexane-3,5-diyl, 3-azabicyclo(3.1.0)hexane-3,6-diyl, 8-azabicyclo(3.2.1)octane-3,8-diyl, octahydrocyclopenta(c)pyrrole-2,4-diyl, octahydrocyclopenta(c)pyrrole-2,5-diyl, octahedral(3,4-c)pyrrole-2,4-diyl and octahedral(3,4-c)pyrrole-2,5-diyl; and divalent 6-membered alicyclic amine residue indicates, for example, monocyclic 6-membered alicyclic amine residue, such as piperidine-1,3-diyl, piperidine-1,4-diyl, piperazine-1,3-diyl, piperazine-1,4-diyl, morpholine-2,4-diyl and thiomorpholine-2,4-diyl, and cross-linked 6-membered alicyclic amine residue, such as 3-azabicyclo(4.1.0)heptane-3,6-diyl and hexahedron is data(1,5-a)pyrazin-2,7-diyl.

Examples of the imino-protective group include all groups that can generally be used as imino-protective group, for example, the groups described in W. Greene, et al., Protective Groups in Organic Synthesis, 3rd Ed., pp. 494-653, 1999, John Wiley & Sons, INC. More specific examples include an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, aryloxyalkyl group, aracelio group, alkoxyalkyl group, kalkylarksmall group, aaltio group, alkanesulfonyl group, arylsulfonyl group, diarylphosphino group, di(aralkyl)phosphoryl group, oxygen-containing heterocyclic alkyl group and a substituted silyl group.

Examples of the amino-protective group include all groups that can generally be used as an amino-protective group such as the groups described in W. Greene, et al., Protective Groups in Organic Synthesis, 3rd Ed., pp. 494-653, 1999, John Wiley & Sons, INC. More specific examples include an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, aryloxyalkyl group, aracelio group, alkoxyalkyl group, kalkylarksmall group, aaltio group, alkanesulfonyl group, arylsulfonyl group, dialkylaminoalkyl group, aralkylamines group, nitrogen-containing heterocyclic alkylidene group, qi is alkylidene group, diarylphosphino group, di(aralkyl)phosphoryl group, oxygen-containing heterocyclic alkyl group and a substituted silyl group.

Examples of the hydroxyl-protective group include all groups that can generally be used as the hydroxyl-protective group, for example, the groups described in W. Greene, et al., Protective Groups in Organic Synthesis, 3rd Ed., pp. 17-245, 1999, John Wiley & Sons, INC. More specific examples include an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, geterostrukturnogo group, alkyl group, alkenylphenol group, aracelio group, oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, alkoxyalkyl group, kalkylarksmall group, alkanesulfonyl group, arylsulfonyl group and a substituted silyl group.

Examples carboxyl-protective group include all groups that can generally be used as carboxyl-protective group such as the groups described in W. Greene, et al., Protective Groups in Organic Synthesis, 3rd Ed., pp. 369-453, 1999, John Wiley & Sons, INC. More specific examples include alkyl group, aryl group, aracelio group, arylalkyl group, alltoallw group, arylsulfonyl group, oxygen-containing heterocyclic group, alkylsulphonyl the group, aryloxyalkyl group, nitrogen-containing heterocyclic alkyl group, cycloalkyl group, alkoxyalkyl group, kalkylarksmall group, alkylthiomethyl group, alkenylphenol group and a substituted silyl group.

This group represents, for example, halogen atom, alkanesulfonyl group, arylsulfonate group, acyloxy group.

In General, the salt of the compounds of General formula [1] includes the famous salt formed by the basic group such as amino group, or an acid group such as hydroxyl group of the phenol or carboxyl group.

Examples of salts formed by the main group, include salts with mineral acids such as hydrochloric acid, Hydrobromic acid and sulfuric acid; salts with organic carboxylic acids as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and triperoxonane acid; and salts with sulfonic acids, as methanesulfonate acid, benzolsulfonat acid, p-toluensulfonate acid, mesitylenesulfonic acid and naphthalenesulfonate acid.

Examples of salts formed by the acid group, include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals, CA is calcium, and magnesium; ammonium salts and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine and N,N'-dibenziletilendiaminom.

In addition, among the above salts are pharmacologically acceptable salts are preferred as the salts of the compounds of General formula [1].

For example, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-he trihydrochloride is non-hygroscopic and is a particularly preferred salt.

Examples of substituents for C2-C12alkyl groups, aryl groups and heterocyclic groups, R1include one or more groups selected from halogen atom, optionally protected hydroxyl and carboxyl groups, lower alkyl, lower alkenyl, lower etkinlik and lower alkoxy groups which may be substituted by one or more halogen atoms, hydroxyimino group, acyl group, protected amino group, amino group, lower alkylamino group, alkylthio group, aryl group, monocyclic heterocyclic group, oxo group, and the like. Examples of preferred mandated the indicators include one or more groups, selected from halogen atom, optionally protected hydroxyl and carboxyl groups, lower alkyl, lower alkenyl, lower alkoxy groups which may be substituted by one or more halogen atoms, lower alkylamino group, aryl group, monocyclic heterocyclic group and oxo group. Examples of preferred substituents include one or more groups selected halogen atom, hydroxyl group, carboxyl group, methyl group, ethyl group, tert-butilkoi group, triptorelin group, vinyl group, a methoxy group, ethoxy group, triptoreline group, dimethylamino group, phenyl group, thienyl group, pyrrolidinyl group and oxo group. Examples of more preferred substituents include one or more groups selected from a halogen atom, methyl group, ethyl group, thienyl group and oxo group.

Examples of substituents for the lower alkyl groups, R2, R3, R4and R5for lower alkyl groups, lower alkenylphenol group and lower alkenylphenol group, R6include one or more groups selected from halogen atom, optionally protected hydroxyl and carboxyl groups, lower alkyl, lower alkenyl, lower alkinyl and lower alkoxy groups, which may be substituted by one or more atoms of halogen, lower alkyl, lower alkenylamine and lower alkenylamine groups which may be substituted by one or more aryl groups, the aryl group, a monocyclic heterocyclic group, and the like. Examples of preferred substituents include one or more groups selected from halogen atom, optionally protected hydroxyl and carboxyl groups, lower alkyl groups which may be substituted by one or more halogen atoms, and lower alkenylphenol group which may be substituted by one or more aryl groups. Examples of preferred substituents include one or more groups selected from a halogen atom, hydroxyl group, carboxyl group, methyl group, ethyl group, triptorelin group, 2-phenylethylene group and oxo group. Examples of more preferred substituents include a carboxyl group, and 2-phenylethylene group.

Examples of substituents for the lower alkyl group, cycloalkyl groups, aryl groups, lower alkoxy groups, cycloalkane group, aralkylated group, alkanoyloxy group, ureido group and monocyclic heterocyclic group, R7for Issa alkyl group and a lower alkoxy group, R 7afor the lower alkyl group and lower alkoxy group, R7bfor the lower alkyl group, cycloalkyl groups, aryl groups, lower alkoxy groups, cycloalkane group, aralkylated group, alkanoyloxy group, ureido group and monocyclic heterocyclic group, R7cfor the lower alkyl group and lower alkoxy group, R7dand lower alkyl groups, cycloalkyl group, aranceles groups, aryl groups, lower alkoxy groups, alkanesulfonyl group and monocyclic heterocyclic group, R8and R9include one or more groups selected from halogen atom, optionally protected hydroxyl and carboxyl groups, lower alkyl, lower alkenyl, lower etkinlik and lower alkoxy groups which may be substituted by one or more halogen atoms, hydroxyimino group, aryl group, monocyclic heterocyclic group, and the like. Examples of preferred substituents include one or more groups selected from halogen atom, optionally protected hydroxyl and carboxyl groups, lower alkyl and lower alkoxy groups which may be substituted by one or more halogen atoms and monocyclic heterocyclic group. Examples of more predpochtite is selected substituents include one or more groups, selected from a halogen atom, hydroxyl group, carboxyl group, methyl group and methoxy group.

Examples of the substituents for the amino group, R7include one or more groups selected from lower alkyl, lower alkenyl, lower etkinlik and lower alkoxy groups which may be substituted by one or more halogen atoms, acyl group, aryl group, monocyclic heterocyclic group, and the like. Examples of preferred substituents include one or more groups selected from lower alkyl and lower alkenyl groups which may be substituted by one or more halogen atoms, acyl group and aryl group. Examples of preferred substituents include one or more groups selected from methyl group, ethyl group, triptorelin group, vinyl group, formyl group, acetyl group, bentilee groups and phenyl groups. Examples of more preferred substituents include one or more groups selected from methyl group, ethyl group, acetyl group and a phenyl group.

Examples of substituents for the cyclic amino group formed by R8and R9together with the nitrogen atom to which they relate, include one the or more groups, selected from halogen atom, optionally protected hydroxyl and carboxyl groups, lower alkyl, lower alkenyl, lower etkinlik and lower alkoxy groups which may be substituted by one or more halogen atoms, hydroxyimino group, acyl group, amino group, lower alkylamino group, alkylthio group, aryl group, monocyclic heterocyclic group which may be substituted by one or more Uralkalij groups, oxo group, and the like. Examples of preferred substituents include one or more groups selected from halogen atom, optionally protected hydroxyl and carboxyl groups, lower alkyl, lower alkenyl, lower alkoxy groups which may be substituted by one or more halogen atoms, alkanoyloxy group, a lower alkylamino group, alkylthio group, aryl group, monocyclic heterocyclic group which may be substituted by one or more Uralkalij groups and oxo group. Examples of preferred substituents include one or more groups selected from a halogen atom, hydroxyl group, carboxyl group, methyl group, ethyl group, methoxy group, ethoxy group, dimethylamino group, a phenyl group is s, and oxo group.

Examples of substituents for the lower alkalinous group and lower alkynylamino group Q1include one or more groups selected from oxo group, optionally protected hydroxyl and carboxyl groups, lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a lower alkoxy group, aryl group, and the like. Examples of preferred substituents include one or more groups selected from oxo group, optionally protected hydroxyl and carboxyl groups, lower alkyl groups, lower alkoxy groups, and aryl groups. Examples of preferred substituents include one or more groups selected from oxo group, hydroxyl group, carboxyl group, methyl group, methoxy group and phenyl group.

Examples of substituents for C2-C4alkalinous group X1for C1-C3alkalinous group X1aand for the lower alkalinous group, lower alkynylamino group and lower alkynylamino group X4include one or more groups selected from oxo group, optionally protected hydroxyl and carboxyl groups, lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a lower alkoxy group, aryl group, and the like. An example of the preferred substituents include one or more groups, selected from oxo group and lower alkyl groups. Examples of preferred substituents include one or more groups selected from oxo group and a methyl group.

Examples of substituents for the divalent alicyclic hydrocarbon residue and the divalent alicyclic amine residue Y1include one or more groups selected from halogen atom, optionally protected hydroxyl and carboxyl groups, lower alkyl, lower alkenyl, lower etkinlik and lower alkoxy groups which may be substituted by one or more halogen atoms, hydroxyimino group, acyl group, amino group, lower alkylamino group, alkylthio group, aryl group, monocyclic heterocyclic group which may be substituted by one or more Uralkalij groups, oxo group and the like. Examples of preferred substituents include one or more groups selected from halogen atom, optionally protected hydroxyl and carboxyl groups, lower alkyl, lower alkenyl, lower alkoxy groups which may be substituted by one or more halogen atoms, alkanoyloxy group, a lower alkylamino group, alkylthio group, aryl group, monocyclic, heterotic the practical group, which may be substituted by one or more Uralkalij groups and oxo group. Examples of preferred substituents include one or more groups selected from a halogen atom, hydroxyl group, carboxyl group, methyl group, ethyl group, methoxy group, ethoxy group, dimethylamino group, phenyl group and oxo group.

In the compounds of the General formula [1] according to the present invention, examples of preferred compounds are as follows.

Preferred are compounds where R1represents optionally substituted aryl or heterocyclic group. More preferred are compounds where R1represents 3-fluoro-4-were, 3-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro-4-methylpyridyl, 5-fluoro-6-methylpyridyl, 4-ethylphenyl, naphthyl, benzo(b)thiophene-2-yl, benzo(b)thiophene-5-yl, benzo(b)thiophene-6-yl, 5-(thiophene-2-yl)isoxazol-2-yl, 2,3-dihydro-1,4-benzodithiol-6-yl, 2,3-dihydrobenzo(1,4)dioxin-6-yl, 2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl, 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-yl, 7-chloro-3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-yl, 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-yl or 3-oxo-3,4-dihydro-2H-benzothiazin-6-yl. Additional preferred compounds are compounds where R1represents a 2,3-dihydrobenzo(1,4)dioxin-6-yl, 23-dihydro(1,4)like(2,3-c)pyridin-7-yl or 3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl, and more preferred compounds are compounds where R1represents a 2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl.

Preferred are compounds where X1represents an optionally substituted ethylene group, and more preferred are compounds where X1represents an ethylene group.

Preferred are compounds where X2represents NH or a bond, and more preferred are compounds where X2that is the link.

Preferred are compounds where X3represents NH, CH2NH or a bond, and more preferred are compounds where X3represents NH or a bond, and more preferred compounds are compounds where X3represents NH.

Preferred are compounds where X4represents an optionally substituted lower alkylenes group or Association, and more preferred are compounds where X4represents the lowest alkylenes group, and more preferred compounds are compounds where X4represents a methylene group.

Preferred are compounds where X5represents an oxygen atom,a sulfur atom, NH or a bond, and more preferred are compounds where X5that is the link.

Preferred are compounds where Y1represents an optionally substituted divalent 4-, 5 - or 6-membered alicyclic hydrocarbon residue or an optionally substituted divalent 5 - or 6-membered alicyclic amine residue. More preferred are compounds where Y1represents an optionally substituted divalent 6-membered alicyclic hydrocarbon residue or an optionally substituted divalent 6-membered alicyclic amine residue, and more preferred compounds are compounds where Y1represents an optionally substituted cyclohexylamine, piperazinyl or piperidinyl group, and more preferred compounds are compounds where Y1is a piperidine-1,4-dialnow group (the nitrogen atom in the 1-position is bound to X2).

Preferred are compounds where Z1has the General formula CR7(where R7has the same meaning as described above), and more preferred are compounds where Z1has the General formula CR7a(where R7adenotes a hydrogen atom, halogen atom, hydro is a strong group, optionally substituted lower alkyl or lower alkoxy group), and more preferred compounds are compounds where Z1represents CH.

Preferred are compounds where Z2has the General formula CR7(where R7has the same meaning as described above), and more preferred are compounds where Z2represents a group represented by the General formula CR7a(where R7ahas the same meaning as described above), and more preferred compounds are compounds where Z2represents CH.

Preferred are compounds where Z3represents a nitrogen atom or a group represented by the General formula CR7a(where R7ahas the same meaning as described above), and more preferred are compounds where Z3represents a nitrogen atom or CH, and more preferred compounds are compounds where Z3represents a nitrogen atom.

Preferred are compounds where Z4represents a nitrogen atom or a group represented by the General formula CR7a(where R7ahas the same meaning as described above), and more preferred are compounds where Z4isone nitrogen atom or CH, and more preferred compounds are compounds where Z4represents CH.

Preferred are compounds where Z5has the General formula CR7(where R7has the same meaning as described above), and more preferred are compounds where Z5has the General formula CR7b(where R7bdenotes a hydrogen atom, halogen atom, optionally substituted lower alkyl or lower alkoxy group), and more preferred compounds are compounds where Z5has the General formula CR7d(where R7ddenotes a halogen atom, optionally substituted lower alkyl or lower alkoxy group), and more preferred compounds are compounds where Z5has the General formula CR7e(where R7edenotes a halogen atom, a lower alkyl group or lower alkoxy group).

Preferred are compounds where Z6represents a nitrogen atom or a group represented by the General formula CR7a(where R7ahas the same meaning as described above), and more preferred are compounds where Z6represents a nitrogen atom or CH.

Examples of most preferred compounds of the General formula [1] according to the present invention presented is Aut:

7-chloro-1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he,

1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-he,

1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he

5-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-he.

Examples of typical compounds of the General formula [1] according to the present invention are compounds shown in Tables 1A-3B.

Table 1A
Z3Z4Z5Z6R3RaX4-X5-R1
CHCHC(OCH3)NHH2,3-dihydro-1,4-benzodioxin-6-ylmethyl
CHCHC(OCH3) NHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
CHCHCHNHH2,3-dihydro-1,4-benzodioxin-6-ylmethyl
CHCHCHNHH7-chloro-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-on-6-ylmethyl
CHCHCHNHH2H-1,4-benzoxazin-3(4H)-on-6-ylmethyl
CHCHNCHHH1-benzothiophen-2-ylmethyl
CHCHNCHHH2-naphthylmethyl
CHCHNCHHH3-fluoro-4-methylbenzyl
CHCHNCHHH4-active compounds
CHCHNCHHH5-(2-thienyl)isoxazol-3-ylmethyl
CHCHNCHHH7-chloro-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-on-6-ylmethyl
CHCHNCHHH2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-on-6-ylmethyl
CHCHNCHHH 2,3-dihydro-1,4-benzodioxin-6-ylmethyl
CHCHNCHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
CHCHNCHHHCH2C≡CC6H5
CHCHNCHHH2H-1,4-benzoxazin-3(4H)-on-6-ylmethyl
CHCHNCHCH2C≡CC6H5HCH2C≡CC6H5
CHNCHCHHH2,3-dihydro-1,4-benzodioxin-6-ylmethyl
NCH C(OCH3)CHHH3-fluoro-4-methylbenzyl
NCHC(OCH3)CHHH3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]-oxazin-6-ylmethyl
NCHC(OCH3)CHHH2,3-dihydro(1,4)like(2,3-b)pyridin-7-ylmethyl
NCHC(OCH3)CHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHC(OCH3)CHHH5,6,7,8-tetrahydroquinoxalin-2-ylmethyl
NCHC(OCH3)CH CH2CO2HH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHC(OCH3)SNHCH32,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHC(OCH3)NHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCCH3CHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCHCHHH2,3-dihydro-1,4-benzodioxin-6-ylmethyl
NCHCHCHHH 2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCHCHHH2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-on-6-ylmethyl
NCHCCH=CHCO2C2H5CHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCClCHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCCNCHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCFCHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl

Table 1B
Z3Z4Z5Z6R3RaX4-X5-R1
NCHC(OCH3)CHHH(5-fluoro-2-methylpyridin-3-yl)methyl
NCHC(OCH3)CHHH4-fluoro-3-methylbenzyl
NCHC(OCH3)CHHH2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-on-6-yl
NCHC-ImCHHH2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl is etil
NCHC(OCH3)CHHH(5-fluoro-6-methylpyridin-3-yl)methyl
NCHC(OCH3)NHH(5-fluoro-6-methylpyridin-3-yl)methyl
NCHC(OCH3)NHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCFCHHH(5-fluoro-6-methoxypyridine-3-yl)methyl
NCHCFCHHH(5-fluoro-2,6-dimethylpyridin-3-yl)methyl
NCHCF CHHH(3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl)methyl
NCHCFCHHH(5-fluoro-6-methylpyridin-3-yl)methyl
NCHCFCHHH(3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-yl)methyl
NCHCFCHHH((1,3)dioxolo(4,5-c)pyridine-6-yl)methyl
NCHC(NHCH3)CHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCFCHHH(3,4-dihyd the on-2H-pyrido(4,3-b)(1,4)oxazin-7-yl)methyl
NCHCFCHHH3-(pyrazin-2-yl)prop-2-in-1-yl
NCHC(OCH3)CHHH(3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-yl)methyl
NCHC(OCH3)CHHH(6 oxido-2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)methyl
NCHC(OCH3)CHHH(5 ethylpyridine-2-yl)methyl
NCHCFCHHH3-fluoro-4-methylbenzoyl
NCHCF CHHH(2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)carbonyl
NCHC(OCH3)CHHH(7-oxo-5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)methyl
NCHC(OCH3)CHHH(4-methoxy-5-methylpyridin-2-yl)methyl
NCHC(OCH3)CHHH(5-ethyl-4-methoxypyridine-2-yl)methyl
NCHC(OCH3)CHHH(5-methoxy-4-methylpyridin-2-yl)methyl
NCHC(OCH3)CHH (5-(3-thienyl)isoxazol-3-yl)methyl
NCHC(OCH3)CHHH6-(3-thienyl)pyridine-2-yl)methyl
NCHC(OCH3)CHHH(5-fluoro-6-methoxypyridine-3-yl)methyl
NCHC(OCH3)CHHH(6-ethyl-5-herperidin-3-yl)methyl
NCHC(OCH3)CHHH(5-fluoro-6-(pyrrolidin-1-yl)pyridine-3-yl)methyl
NCHC(OCH3)CHHH(5-(2-furyl)isoxazol-3-yl)methyl
N/td> CHC(OCH3)CHHH(5-(2-thienyl)pyridine-3-yl)methyl
NCHC(OCH3)CHHH(6-(2-thienyl)pyridine-3-yl)methyl
NCHCFCHHH(5-(2-furyl)isoxazol-3-yl)methyl
NCHC(OCH3)CHHH(3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl)methyl
NCHC(OCH3)CHHH(5-(2-furyl)pyridine-3-yl)methyl
NCHC(OCHF2)CH HH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHC(OCH3)CHHH(1,5-naphthiridine-3-yl)methyl
NCHC(OCH3)CHHH(6-(2-furyl)pyrazin-2-yl)methyl
NCHC-OxaCHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHC-ThiaCHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCFCHHH(5,6,7,8-tetrahydroquinoxalin-2-yl)methyl
NCHCFCHHH(5-(2-furyl)-1,3-oxazol-2-yl)methyl
NCHCFCHHH(3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-yl)methyl
NCHC(OCH3)CHHH(3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-yl)methyl
NCHC(CF3)CHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCMeCFCHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCMe(OCH 3)CHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCFCHHH(2,3-dihydro(1,4)like(2,3-b)pyridin-7-yl)methyl
NCHCBrCHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHCNH2CHHH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHC(OCH3)CHHH(5-methyl-4-oxo-4H-Piran-2-yl)methyl
NCHC(OCH3)CHH H(5-aminopyridin-2-yl)methyl
Im: 1H-imidazol-1-yl, Oxa: 1,3-oxazol-2-yl, Thia: 1,3-thiazol-2-yl

CH
Table 2
Z3Z4Z5Z6X4-X5-R1
CHNCHCH2,3-dihydro-1,4-benzodioxin-6-ylmethyl
CHCHCHN2,3-dihydro-1,4-benzodioxin-6-ylmethyl
NCHCHCH2,3-dihydro-1,4-benzodioxin-6-ylmethyl
CHCHC(OCH3)N2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
CHNCH2,3-dihydro-1,4-benzodioxin-6-ylmethyl
CHCHC(OCH3)N2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-on-6-ylmethyl
NCHC(OCH3)CH3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl
CHCHCFN2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
NCHC(OCH3)CH2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
CHCHCNH2N2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
CHCHC-Tri N2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl
Tri: 1,2,4-triazole-1-yl

Table 3A

Table 3B

In the compounds of General formula [2] according to the present invention, examples of preferred compounds are as follows.

Preferred are compounds where X1arepresents a methylene group or ethylene group, and more preferred are compounds where X1arepresents a methylene group.

Preferred are compounds where Y2represents a 1,3-dioxolane-2-ridenow group, (hydroxy)(methoxy)methylene group, dimethoxymethylsilyl group or carbonyl group, and more preferred are compounds where Y2represents a 1,3-dioxolane-2-ridenow group, dimethoxymethylsilyl group or carbonyl group, and more preferred compounds are compounds where Y2represents dimethoxymethylsilyl group or carbonyl group, and more preferred compounds are compounds where Y2represents a carbonyl group.

Preferred are compounds where Z has the General formula CR7(where R7has the same meaning as described above), and more preferred are compounds where Z1represents a group represented by the General formula CR7a(where R7ahas the same meaning as described above), and more preferred compounds are compounds where Z1represents CH.

Preferred are compounds where Z2has the General formula CR7(where R7has the same meaning as described above), and more preferred are compounds where Z2represents a group represented by the General formula CR7a(where R7ahas the same meaning as described above), and more preferred compounds are compounds where Z2represents CH.

Preferred are compounds where Z3represents a nitrogen atom or a group represented by the General formula CR7a(where R7ahas the same meaning as described above), and more preferred are compounds where Z3represents a nitrogen atom or CH, and more preferred compounds are compounds where Z3represents a nitrogen atom.

Preferred are compounds where Z4presented yet a nitrogen atom or group, represented by the General formula CR7a(where R7ahas the same meaning as described above), and more preferred are compounds where Z4represents a nitrogen atom or CH, and more preferred compounds are compounds where Z4represents CH.

Preferred are compounds where Z5has the General formula CR7(where R7has the same meaning as described above), and more preferred are compounds where Z5has the General formula CR7a(where R7ahas the same meaning as described above), and more preferred compounds are compounds where Z5has the General formula CR7d(where R7dhas the same meaning as described above), and more preferred compounds are compounds where Z5has the General formula CR7e(where R7ehas the same meaning as above.)

Preferred are compounds where Z6represents a nitrogen atom or a group represented by the General formula CR7a(where R7ahas the same meaning as described above), and more preferred are compounds where Z6represents a nitrogen atom or CH.

Examples of typical compounds of the General formula [2] p the present invention are compounds, shown in tables 4A-4B.

CH
Table 4A
Z3Z5Z6Y2Z3Z5Z6Y2
NCHCHCONCHCH1,3-dioxolane-2-ilidene
NCFCHCONCFCH1,3-dioxolane-2-ilidene
NCCH3CHCONCCH3CH1,3-dio the Solan-2-ilidene
NC(OCH3)CHCONC(OCH3)CH1,3-dioxolane-2-ilidene
CHCHNCOCHCHN1,3-dioxolane-2-ilidene
CHCFNCOCHCFN1,3-dioxolane-2-ilidene
CHCCH3NCOCHCCH3N1,3-dioxolane-2-ilidene
CHC(OCH3)NCOC(OCH3)N1,3-dioxolane-2-ilidene
NCHNCONCHN1,3-dioxolane-2-ilidene
NCFNCONCFN1,3-dioxolane-2-ilidene
NCCH3NCONCCH3N1,3-dioxolane-2-ilidene
NC(OCH3)NCONC(OCH3)N1,3-dioxolane-2-ilidene

Table 4B
Z3Z5Z6Y2Z3Z5Z6Y2
NCHCHdimethoxymethylNCHCH(hydroxy)(methoxy)methylene
NCFCHdimethoxymethylNCFCH(hydroxy)(methoxy)methylene
NCCH3CHdimethoxymethylNCCH3CH(hydroxy)(the methods of the si)methylene
NC(OCH3)CHdimethoxymethylNC(OCH3)CH(hydroxy)(methoxy)methylene
CHCHNdimethoxymethylCHCHN(hydroxy)(methoxy)methylene
CHCFNdimethoxymethylCHCFN(hydroxy)(methoxy)methylene
CHCCH3NdimethoxymethylCHCCH3N(hydroxy)(methoxy)methylene
CHC(OCH3 )NdimethoxymethylCHC(OCH3)N(hydroxy)(methoxy)methylene
NCHNdimethoxymethylNCHN(hydroxy)(methoxy)methylene
NCFNdimethoxymethylNCFN(hydroxy)(methoxy)methylene
NCCH3NdimethoxymethylNCCH3N(hydroxy)(methoxy)methylene
NC(OCH3)Ndimethoxane the ilen NC(OCH3)N(hydroxy)(methoxy)methylene

In the compounds of the General formula [3] according to the present invention, examples of preferred compounds are as follows.

Preferred are compounds where R7crepresents a halogen atom or optionally substituted lower alkyl or lower alkoxy group.

Preferred are compounds where Z2ahas the General formula CR7(where R7has the same meaning as described above), and more preferred are compounds where Z2arepresents CH.

Preferred are compounds where Z6arepresents a nitrogen atom or CH.

Examples of typical compounds of the General formula [3] according to the present invention are compounds shown in Table 5.

Table 5
Z6aR7cZ6aR7c
CHF NF
CHCH3NCH3
CHOCH3NOCH3

Now will be described the methods of obtaining the compounds of the present invention.

Compounds of General formula [1] according to the present invention can be obtained by a combination of known methods. For example, the compound can be obtained in the following ways receipt.

[Method of obtaining 1]

(In the formulas, Y1adenotes optionally substituted divalent alicyclic amine residue, where one nitrogen atom in the ring is associated with a neighboring group, and the other atom in the ring is associated with X3; and R1X1aX3X4X5, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

Examples of known compounds of General formula [4a] include 4-((1-phenylethyl)amino)piperidine, tert-butyl (3-aminobenzyl)(4-piperidinyl)carbamate and phenyl N-(4-piperidinyl)carboxamide.

The compound of General formula [1a] m which can be obtained by the interaction of the compounds of General formula [2a] with the compound of General formula [4a] in the presence of a reducing agent.

This reaction can be carried out by a method described, for example, in the publication of applications for the international patent number WO 02/50061 and WO 02/56882, Jerry March, Advanced Organic Chemistry, 4th Ed., pp. 898-900, 1992, John Wiley & Sons, INC., or Richard C. Larock, Comprehensive Organic Transformations, pp. 421-425, 1989, VCH Publishers, INC., or a method in accordance with this method.

In this reaction may be any solvent which does not affect adversely on the reaction, and examples include alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers like dioxane, tetrahydrofuran, anisole, simple, dimethyl ether of ethylene glycol, simple, dimethyl ether of diethylene glycol, simple, diethyl ether of diethylene glycol and simple onomatology ether of ethylene glycol; such sulfoxidov as dimethyl sulfoxide; such esters as ethyl acetate; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and water. These solvents can be used in the form of a mixture.

Examples of the reducing agent used in this reaction include such complex hydride compounds as lithium aluminum hydride, triacetoxyborohydride sodium, cyanoborohydride sodium and sodium borohydride; borane, sodium is the first and the sodium amalgam. In addition to this can be used electrolytically with copper or platinum anode catalytic reduction using Raney Nickel, platinum oxide or palladium mobile or recovery using the reaction of the zinc-acid".

In this reaction the amount of compounds of General formula [4a] and the reducing agent can be 1-50-fold molar amount, preferably 1-5-fold molar amount, relative to the compound of General formula [2a].

This reaction can be carried out at 30-150°C, preferably at 0 to 100°C for from 10 minutes to 120 hours.

[Method of obtaining 2]

(In the formulas, X2arepresents a group represented by the General formula NR2a(where R2adenotes a hydrogen atom or optionally substituted lower alkyl group); and R1X1aX3X4X5, Y1, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

Examples of known compounds of General formula [4b] include 4-amino-1-(1-oxo-2-phenylethyl)piperidine and 4-amino-1-(2-phenylethyl)piperidine.

The compound of General formula [1b] can be produced by the interaction of the compounds of General formula [2a] with the compound of General formula [4b] in the presence of ostanavlevaysya agent. This reaction may be carried out in accordance with the method of obtaining 1.

[Method of obtaining 3]

(In the formulas, Y1bdenotes optionally substituted divalent alicyclic amine residue, where one nitrogen atom in the ring is associated with a neighboring group, and the other atom in the ring is associated with X2; and R1X1X2X4X5, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

Examples of known compounds of General formula [6] include 1,4-benzodioxan-6-carbaldehyde and (2,3-dihydro-1,4-benzodioxin-6-yl)acetaldehyde.

The compound of General formula [1c] can be produced by the interaction of the compounds of General formula [5] with the compound of General formula [6] in the presence of a reducing agent. This reaction may be carried out in accordance with the method of obtaining 1.

[Method 4]

(In the formulas, X3arepresents a group represented by the General formula NR3aor CR4R5NR3a(where R3adenotes a hydrogen atom or optionally substituted lower alkyl group; and R4and R5have the same meanings as described above); and R1X1X2X4X5, Y1, Z1, Z2, Z3 , Z4, Z5and Z6have the same meanings as above.)

The compound of General formula [1d] can be produced by the interaction of the compounds of General formula [7] with the compound of General formula [6] in the presence of a reducing agent. This reaction may be carried out in accordance with the method of obtaining 1.

[Method of obtaining 5]

(In formulas L1denotes a leaving group; and R1X1X2X4X5, Y1b, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

Examples of known compounds of General formula [8] include 2-(3-oxo-3,4-dihydro-2H-benzothiazin-6-yl)ethyl methanesulfonate, 2-(benzo[1,3]dioxol-5-yl)ethyl methanesulfonate, 2-((2-bromacil)thio)thiophene and 2-bromo-N-(pyridin-2-yl)ndimethylacetamide.

The compound of General formula [1e] can be obtained by the interaction of the compounds of General formula [5] with the compound of General formula [8] in the presence or in the absence of base. This reaction can be performed in a manner described, for example, in U.S. patent No. 6603005, or method in accordance with this method.

In this reaction may be any solvent which does not affect adversely on the reaction, and examples include alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; galogenirovannyie hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers like dioxane, tetrahydrofuran, anisole, simple, dimethyl ether of ethylene glycol, simple, dimethyl ether of diethylene glycol, simple, diethyl ether of diethylene glycol and simple onomatology ether of ethylene glycol; such sulfoxidov as dimethyl sulfoxide; ketones such as acetone and 2-butanone; esters as ethyl acetate; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; and water. These solvents can be used in the form of their mixture.

In this reaction, examples of the bases used in accordance with necessity, include such organic bases as pyridine, dimethylaminopyridine and triethylamine; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate.

In this reaction the amount of compounds of General formula [8] and the base used in accordance with the need, can be 1 to 20-fold molar amount relative to the compound of the compounds of General formula [5].

This reaction can be carried out at 0 to 200°C, preferably at 0-150°C for from 30 minutes to 48 hours.

[Method of obtaining 6]

(In the formulas, R1L1 X1X2X3aX4X5, Y1, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

The compound of General formula [1f] can be obtained by the interaction of the compounds of General formula [7] with the compound of General formula [8] in the presence or in the absence of base. This reaction may be carried out in accordance with the method of obtaining 5.

[Method of obtaining 7]

(In formulas L2denotes a leaving group; and R1X1X2X3X4X5, Y1, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

Examples of known compounds of General formula [9] include 2-(4-(phenylacetyl)piperazine-1-yl)ethylchloride and 2-chloro-1-(4-feiticeira-1-yl)Etalon.

The compound of General formula [1] can be obtained by the interaction of the compounds of General formula [3a] with the compound of General formula [9] in the presence or in the absence of base.

In this reaction may be any solvent which does not affect adversely on the reaction, and examples include amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; such aromatice the Kie hydrocarbons, as benzene, toluene and xylene; ethers like dioxane, tetrahydrofuran, anisole, simple, dimethyl ether of ethylene glycol, simple, dimethyl ether of diethylene glycol, simple, diethyl ether of diethylene glycol and simple onomatology ether of ethylene glycol; such sulfoxidov as dimethyl sulfoxide; such esters as ethyl acetate; and water. These solvents can be used in the form of their mixture.

In this reaction, examples of the necessary amount used of the base include organic bases as pyridine, dimethylaminopyridine and triethylamine; and inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, sodium carbonate and cesium carbonate.

In this reaction, the required number of bases and compounds of General formula [9] can be 1-50-fold molar amount, preferably 1-5-fold molar amount relative to the compound of General formula [3a].

This reaction can be carried out at 30-150°C, preferably at 0 to 100°C for from 30 minutes to 48 hours.

Compounds of General formulas [1], [1a], [1b], [1c] [1d], [1e] [1f], obtained using the methods of obtaining 1-7, or their salts, can be converted into other compounds of General formula [1] or their salts by known reactions, such as condensation, accession the Oia, oxidation, reduction, rearrangement, substitution, halogenation, degidrirovaniya or hydrolysis, or a combination of such reactions.

For compounds in the above methods of preparation, when there are isomers (e.g. enantiomers, geometric isomers or tautomers), these isomers may also be used. In addition, there may be used a solvate, hydrates and various forms of crystals.

Compounds of General formula [2] according to the present invention can be obtained by a combination of known methods. For example, the compound can be obtained in the following ways receipt.

[Method of obtaining 8]

(In the formulas, Y2aindicates a protected carbonyl group; L3denotes a leaving group, and X1a, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

Examples of known compounds of General formula [10] include 2-(2-methyl bromide)-1,3-dioxolane, 2-(2-bromacil)-1,3-dioxolane and 2-(2-bromacil)-1,3-dioxane.

(8-1) the Compound of General formula [2b] can be obtained by the interaction of the compounds of General formula [3a] with the compound of General formula [10] in the presence or in the absence of base. This reaction may be carried out in accordance with the method of obtaining 7.

(8-2) the Compound of General formula [2a] can the t can be obtained by removing protection from the compounds of General formula [2b]. This reaction can be carried out by a method described, for example, in Protective Groups in Organic Synthesis, 3rd Ed., pp. 293-368, 1999, John Wiley & Sons, INC., or method in accordance with this method.

[Method of obtaining 9]

(In the formulas, R16denotes a chlorine atom, a bromine atom, an iodine atom or optionally substituted, alkanesulfonyl group; R17denotes carboxyl-protective group, and X1a, Y2a, Z3, Z4, Z5and Z6have the same meanings as above.)

Example compounds of General formula [11] is a 2-chloro-N-(2,2-dimethoxymethyl)pyridine-3-amine.

Examples of compounds of General formula [12] include methyl acrylate, acrylate and tert-butyl acrylate.

(9-1) the Compound of General formula [13] can be obtained by the interaction of the compounds of General formula [11] with a compound of General formula [12] in the presence of a catalyst, in the presence or in the absence of a base and in the presence or in the absence of ligand. This reaction can be carried out by a method described, for example, in Tsuji et al., Sen-i Kinzoku ga Hiraku Yuki Gosei (organic synthesis using transition metal), pp. 19-22, 1997, Maruzen and Chem. Pharm. Bull., vol. 33, pp. 4764-4768, 1985, or the method in accordance with this method.

In this reaction may be any solvent which does not affect adversely on the reaction, and examples VK is ucaut such alcohols, as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons like methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers like dioxane, tetrahydrofuran, anisole, simple, dimethyl ether of ethylene glycol, simple, dimethyl ether of diethylene glycol, simple, diethyl ether of diethylene glycol and simple onomatology ether of ethylene glycol; such sulfoxidov as dimethyl sulfoxide; such ketones, such as acetone and 2-butanone; esters as ethyl acetate; NITRILES such as acetonitrile; and water. These solvents can be used in the form of their mixtures. This reaction can be carried out in the absence of solvent.

Examples of catalysts used in this reaction include tetrakis(triphenylphosphine)palladium(0), palladium(II)acetate, palladium(II)chloride, bis(tri-tert-butylphosphine)palladium(0) and Tris(dibenzylideneacetone)dipalladium(0).

In this reaction, examples of the necessary amount used of the base include organic bases as pyridine, dimethylaminopyridine, triethylamine, N,N-dimethylbenzylamine, sodium acetate and potassium acetate; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, carbon is tons of potassium and sodium carbonate.

In this reaction, examples of the ligand used in accordance with necessity, include such trialkylphosphine as trimethylphosphine and three-tert-butylphosphine; such tricyclohexylphosphine as tricyclohexylphosphine; such triarylphosphine as triphenylphosphine and trailerteen; such trialkylphosphine as trimethylphosphite, triethylphosphite and tributylphosphite; such tricyclohexylphosphine as tricyclohexylphosphine; such triarylphosphite as triphenylphosphite; such salt imidazole as 1,3-bis(2,4,6-trimetilfenil)imidazole chloride; diketones such as acetylacetone and activerelation; amines such as trimethylamine, triethylamine, Tripropylamine and triisopropanolamine; and 1,1'-bis(diphenylphosphino)ferrocene, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 2-(di-tert-butylphosphino)-2',4',6'-triisopropylphenyl and 2-(di-tert-butylphosphino)biphenyl. These ligands can be used in the form of their combinations.

In this reaction, the amount of compounds of General formula [12] can be 1-10-fold molar amount, preferably 1-5-fold molar amount relative to the compound of General formula [11].

In this reaction, the amount of the catalyst is 0.001 to 10-fold molar amount, preferably 0.01 to 2-fold molar amount, from which oseney to the compound of General formula [11].

In this reaction, the amount of base used in accordance with necessity, is 1-10 times the molar quantity, preferably 1-5-fold molar amount relative to the compound of General formula [11].

In this reaction, the amount of ligand used in accordance with necessity, is within 0.00001-1-fold molar amount, preferably 0,001-0,1-fold molar amount relative to the compound of General formula [11].

This reaction can be carried out at 30-200°C, preferably at 0 to 100°C for from 30 minutes to 48 hours.

(9-2) the Compound of General formula [2c] can be obtained by shorting ring compounds of General formula [13] in the presence or in the absence of base. This reaction can be carried out by a method described, for example, in Chem. Pharm. Bull., vol. 33, pp. 4764-4768, 1985, or the method in accordance with this method.

In this reaction may be any solvent which does not affect adversely on the reaction, and examples include alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; aromatic hydrocarbons such as benzene, toluene and xylene; ethers like dioxane, tetrahydrofuran, anisole, simple, dimethyl ether of ethylene glycol, simple, dimethyl ether, diethyl what glycole, simple diethyl ether of diethylene glycol and simple onomatology ether of ethylene glycol; such sulfoxidov as dimethyl sulfoxide; ketones such as acetone and 2-butanone; esters as ethyl acetate; NITRILES such as acetonitrile; and water. These solvents can be used in the form of their mixture.

In this reaction, examples of the necessary amount used of the base include organic bases as pyridine, dimethylaminopyridine and triethylamine; and inorganic bases such as sodium methoxide, ethoxide sodium, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate and sodium carbonate.

In this reaction, the amount of base used in accordance with necessity, may be 1 to 20-fold molar amount relative to the compound of General formula [13].

This reaction can be carried out at 0 to 200°C, preferably at 0-150°C for from 30 minutes to 48 hours.

(9-3) the Compound of General formula [2d] can be obtained by removing protection from the compounds of General formula [2c]. This reaction may be carried out in accordance with the method of obtaining 8-2.

[Method 10]

(In the formulas, R7fdenotes a hydrogen atom or optionally substituted lower alkyl, cycloalkyl or aryl group; R18denotes an atom in Dorada or carboxyl-protective group; X1a, Y2a, Z3, Z4, Z5and Z6have the same meanings as above.)

Example compounds of General formula [15] is ethylglycine. In this reaction, the compound of General formula [15] can constitute its hydrate (hemiacetal). An example of a hydrate (hemiacetal) compounds of General formula [15] is acylglycerol hemiacetal.

(10-1) the Compound of General formula [2A] can be obtained by the interaction of the compounds of General formula [14] with a compound of General formula [15]. This reaction can be carried out by a method described, for example, in J. Chem. Soc., pp. 5156-5166, 1963, or in a manner in accordance with this method.

(10-2), the Compound of General formula [2f] can be obtained by removing protection from the compounds of General formula [2e]. This reaction may be carried out in accordance with the method of obtaining 8-2.

Compounds of General formula [3] according to the present invention can be obtained by combining known methods. For example, the compound can be obtained in the following ways receipt.

[Method of obtaining 11]

(In the formulas, R7c, R16, R17and Z6ahave the same meanings as above.)

Examples of compounds of General formula [16] include 3-amino-2-chloro-5-methoxypyridine and 3-amino-2-chloro-5-methoxypyrazine.

(11-1) Connection about the formula [17] can be obtained by the interaction of the compounds of General formula [16] with the compound of General formula [12] in the presence of a catalyst and in the presence or in the absence of base. This reaction may be carried out in accordance with the method of obtaining 9-1.

(11-2) the Compound of General formula [3b] can be obtained by shorting ring compounds of General formula [17] in the presence or in the absence of base. This reaction may be carried out in accordance with the method of obtaining 9-2.

[Method of obtaining 12]

(In the formulas, R7c, R18and Z6ahave the same meanings as above.)

The compound of General formula [3c] can be obtained by the interaction of the compounds of General formula [18] with a compound of General formula [15a]. This reaction may be carried out in accordance with the method of obtaining 10-1.

[Method of obtaining 13]

(In the formulas, Z2a, Z6aand R7chave the same meanings as above.)

(13-1), the Compound of General formula [33] can be obtained by oxidation of compounds of General formula [32].

This reaction can be carried out by a method described, for example, Heterocycles, vol. 32, pp. 1579-1586, 1991 or in Heterocycles, vol. 34, pp. 1055-1063, 1992, or the method in accordance with this method.

In this reaction may be any solvent which does not affect adversely on the reaction, and examples include halogenated hydrocarbons like methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such, it is to benzene, toluene and xylene; such sulfoxidov as dimethyl sulfoxide; and water. These solvents can be used in the form of their mixture.

Examples of the oxidizing agent used in this reaction, are m-chloroperbenzoic acid and peracetic acid.

In this reaction, the amount of oxidant may be 1-10-fold molar amount relative to the compound of General formula [32].

This reaction can be carried out at 0 to 200°C, preferably at 0-50°C, for from 30 minutes to 48 hours.

(13-2), the Compound of General formula [3] can be obtained by the interaction of the compounds of General formula [33] sulphonylchloride, and then hydrating the resulting product.

This reaction can be carried out by a method described, for example, Heterocycles, vol. 32, pp. 1579-1586, 1991, or in Heterocycles, vol. 34, pp. 1055-1063, 1992, or the method in accordance with this method.

In this reaction may be any solvent which does not affect adversely on the reaction with water, and its examples include halogenated hydrocarbons like methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; such sulfoxidov as dimethyl sulfoxide; NITRILES such as acetonitrile. These solvents can be used in the form of their mixture.

Examples of sulphonylchloride used in this reaction include ina p-toluensulfonate and benzosulphochloride.

In this reaction, the number of sulphonylchloride may be 1-10-fold molar amount relative to the compound of General formula [33].

This reaction can be carried out at 0 to 200°C, preferably at 0-50°C, for from 30 minutes to 48 hours.

Compounds of General formula [1] according to the present invention can also be obtained in the following ways receipt.

[Method of obtaining 14]

(In the formulas, Y1cdenotes optionally substituted divalent alicyclic hydrocarbon residue, where one carbon atom of the ring or substituent is substituted by oxo group, or denotes optionally substituted divalent alicyclic amine residue, where one carbon atom of the ring or substituent is substituted by oxo group; and R1X1X2X3aX4X5, Y1, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

An example of known compounds of General formula [6a] is a 1-(2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)methanamine.

The compound of General formula [1f] can be obtained by the interaction of the compounds of General formula [5b] with the compound of General formula [6a] in the presence of a reducing agent. This reaction may be carried out in accordance with the method of receiving the Oia 1.

Next will be described the methods of obtaining compounds of General formulas [5], [7] and [14], which are starting materials for producing the compounds of General formulas [1], [2] and [3] according to the present invention. These compounds can be obtained by a combination of known methods. For example, the compound can be obtained in the following ways receipt.

[Method of receiving A]

(In the formulas, R16, R17, Z3, Z4, Z5and Z6have the same meanings as above.)

Examples of compounds of General formula [16a] include 3-amino-2-chloro-5-methoxypyridine and 3-amino-2-chloro-5-methoxypyrazine.

(A-1) a Compound of General formula [17a] can be obtained by the interaction of the compounds of General formula [16a] with the compound of General formula [12] in the presence of a catalyst and in the presence or in the absence of base. This reaction may be carried out in accordance with the method of obtaining 9-1.

(A-2) a Compound of General formula [3d] can be obtained by shorting ring compounds of General formula [17a] in the presence or in the absence of base. This reaction may be carried out in accordance with the method of obtaining 9-2.

[Method of obtaining B]

(In the formulas, R7f, R18, Z3, Z4, Z5and Z6have the same meanings as described is use.)

The compound of General formula [3e] can be obtained by the interaction of the compounds of General formula [18a] with the compound of General formula [15]. This reaction may be carried out in accordance with the method of obtaining 10-1.

[Method of obtaining C]

(In the formulas, R19denotes an imino-protective group; L4denotes a leaving group, and X1X2, Y1b, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

An example of known compounds of General formula [19] is a 1-tert-butyl-4-ethyl-4-(2-(methanesulfonate)ethyl)-1,4-piperidinecarboxylate.

(C-1) a Compound of General formula [20] can be obtained by the interaction of the compounds of General formula [3a] with the compound of General formula [19] in the presence or in the absence of base. This reaction may be carried out in accordance with the method of obtaining 7.

(C-2) a Compound of General formula [5] can be obtained by removing protection from the compounds of General formula [20]. This reaction can be carried out by a method described, for example, in Protective Groups in Organic Synthesis, 3rd Ed., pp. 494-653, 1999, John Wiley & Sons, INC., or method in accordance with this method.

[Method of obtaining D]

(In the formulas, R20denotes an imino-protective group; L5denotes a leaving group; X1, 2X3a, Y1, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

An example of known compounds of General formula [21] represents a tert-butyl((1-(2-chloroacetyl)-4-(3-(trifluoromethyl)phenyl)-4-piperidyl)methyl)(methyl)carbamate.

(D-1) Compound of General formula [22] can be obtained by the interaction of the compounds of General formula [3a] with the compound of General formula [21] in the presence or in the absence of base. This reaction may be carried out in accordance with the method of obtaining 7.

(D-2) a Compound of General formula [7] can be obtained by removing protection from the compounds of General formula [22]. This reaction may be carried out in accordance with the method of obtaining C-2.

[Method of obtaining E]

(In the formulas, R21denotes an imino-protective group; Y1cdenotes optionally substituted divalent alicyclic amine residue, where the two nitrogen atom in the ring together adjacent group; and X1a, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

Examples of compounds of General formula [23] include 1-(tert-butoxycarbonyl)piperazine and methyl-4-(tert-butoxycarbonyl)piperazine-2-carboxylate.

(E-1) a Compound of General formula [20] can be obtained mutual is the action of compounds of General formula [2a] with the compound of General formula [23] in the presence of a reducing agent. This reaction may be carried out in accordance with the method of obtaining 1.

(E-2) the Compound of General formula [5a] can be obtained by removing protection from the compounds of General formula [20a]. This reaction may be carried out in accordance with the method of obtaining C-2.

[Method of obtaining F]

(In the formulas, R22denotes an imino-protective group; X1aX3a, Y1a, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

Example compounds of General formula [24] represents a 4-((benzyloxycarbonyl)amino)-4-methylpiperidin.

(F-1) Compound of General formula [22a] can be obtained by the interaction of the compounds of General formula [2a] with the compound of General formula [24] in the presence of a reducing agent. This reaction may be carried out in accordance with the method of obtaining 1.

(F-2) a Compound of General formula [7a] can be obtained by removing protection from the compounds of General formula [22a]. This reaction may be carried out in accordance with the method of obtaining C-2.

[Method of obtaining G]

(In the formulas, R23denotes an imino-protective group; and R1X4X5and Y1chave the same meanings as above.)

(G-1) Compound of General formula [26] can be obtained by interaction of soy is inane General formula [25] with the compound of General formula [6] in the presence of a reducing agent. This reaction may be carried out in accordance with the method of obtaining 1.

(G-2) the Compound of General formula [4c] can be obtained by removing protection from the compounds of General formula [26]. This reaction may be carried out in accordance with the method of obtaining C-2.

[Method of obtaining H]

(In the formulas, R24denotes an imino-protective group; and R1X3aX4X5and Y1ahave the same meanings as above.)

(H-1) Compound of General formula [28] can be obtained by the interaction of the compounds of General formula [27] with the compound of General formula [6] in the presence of a reducing agent. This reaction may be carried out in accordance with the method of obtaining 1.

(H-2), the Compound of General formula [4d] can be obtained by removing protection from the compounds of General formula [28]. This reaction may be carried out in accordance with the method of obtaining C-2.

[Method of obtaining I]

(In the formulas, Y2a, Z3, Z4, Z5and Z6have the same meanings as above.)

Examples of compounds of General formula [29] include a 3-nitropyridine-2-amine and 3-amino-2-nitropyridine.

Examples of compounds of General formula [30] include 2,2-dimethoxyacetate and 2,2-diethoxyacetate.

(I-1) Compound of General formula [31] can bytevalue by the interaction of the compounds of General formula [29] with a compound of General formula [30] in the presence of a reducing agent. This reaction may be carried out in accordance with the method of obtaining 1.

(I-2) Compound of General formula [14a] can be obtained by reduction of compounds of General formula [31]. This reaction can be carried out by a method described, for example, in Richard C. Larock, Comprehensive Organic Transformations, pp. 411-415, 1989, VCH Publishers, INC., or method in accordance with this method.

[Method of obtaining J]

(In the formulas, X1bdenotes optionally substituted methylene or ethylene group or a bond, and R17X1a, Y2a, Z3, Z4, Z5and Z6have the same meanings as above.)

The compound of General formula [13] can be obtained by the interaction of the compounds of General formula [17a] with the compound of General formula [30b] in the presence of a reducing agent. This reaction may be carried out in accordance with the method of obtaining 1.

[Method of obtaining K]

(In the formulas, Y1ddenotes optionally substituted divalent alicyclic hydrocarbon residue, where one carbon atom of the ring or substituent is an atom from a protected carbonyl group, or denotes optionally substituted divalent alicyclic amine residue, where one carbon atom of the ring or of the Deputy is from the battle of the atom, protected carbonyl group; and R17X1X1aX2, Y1c, Z1, Z2, Z3, Z4, Z5and Z6have the same meanings as above.)

(K-1) Compound of General formula [13b] can be obtained by the interaction of the compounds of General formula [17b] with the compound of General formula [30a] in the presence of a reducing agent. This reaction may be carried out in accordance with the method of obtaining 1.

(K-2) the Compound of General formula [5c] can be obtained by shorting ring compounds of General formula [13b] in the presence or in the absence of base. This reaction may be carried out in accordance with the method of obtaining 9-2.

(K-3) a Compound of General formula [5b] can be obtained by removing protection from the compounds of General formula [5c] in the presence or in the absence of base. This reaction may be carried out in accordance with the method of obtaining 8-2.

Compounds obtained by the methods of obtaining 1-14 and ways to get A-K, can be converted into other compounds known reactions, such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenoalkane, de-hydration or hydrolysis, or by using an appropriate combination of such reactions.

When imino, amino, hydroxyl or carboxyl group exists in the connection of eniah, obtained in the methods of obtaining 1-14 and how to get the A-K and their intermediate compounds, the reaction can be carried out with the help of such groups, suitably protected by protective groups.

In the methods of obtaining 1-14 and how to get the A-K when the compound having a carbonyl group is used in the reaction, the compound having a protected carbonyl group, can be used instead of the compound having the carbonyl group.

When the compound of General formula [1] according to the present invention is used as a medicine, as a rule, additives to the drug, with the compound can suitably be mixed, for example, a filler, a carrier and a diluent, which is used in the preparation. These compounds can be entered in the usual manner, orally or parenterally, for example in the form of tablets, capsules, powder, syrup, granules, pills, suspensions, emulsions, solutions, powder medication, suppositories, eye drops, nose drops, ear drops, plasters, ointments or injections. Method, dose and frequency of injection can be determined appropriately depending on the age, body weight and symptoms of the patient. Typically, the compound can be administered to adults oral or parenteral (e.g., by injection, infusion of Il is the introduction into the anus) in an amount of from 0.01 to 1000 mg/kg / day, at one time or in several divided doses.

The compound of General formula [1] according to the present invention has a high antimicrobial activity, for example against gram-positive bacteria, including resistant bacteria are resistant to many drugs Staphylococcus aureus resistant to many drugs Pneumococcus and resistant to vancomycin Enterococcus, against gram-negative bacteria, anaerobic bacteria, or atypical mycobacteria.

More specifically, the compound of General formula [1] according to the present invention has a high antimicrobial activity against, for example, bacteria, selected from Staphylococcus aureus (Staphylococcus aureus Smith, Staphylococcus aureus F-3095 (MDRSA) and Staphylococcus aureus F-2161 (MDRSA)), Pneumococcus (Streptococcus pneumoniae IID553, Streptococcus pneumoniae D-1687 (QRSP) and Streptococcus pneumoniae D-4249 (MDRSP)), Enterococcus faecalis (Enterococcus faecalis ATCC29212, Enterococcus faecalis IID682, Enterococcus faecalis D-2648 (VCM-R) and Enterococcus faecalis EF-210 (VanA)), Enterococcus faecium (Enterococcus faecium NBRC 13712 and Enterococcus faecium EF-211 (VanA)), Corynebacterium diphtheriae (Corynebacterium diphtheriae ATCC 27010), Escherichia coli (Escherichia coli NIHJ), Serratia marcescens (Serratia marcescens IID 5218), Haemophilus influenzae (Haemophilus influenzae ATCC 49247), Moraxella catarrhalis (Moraxella catarrhalis ATCC 25238), Pseudomonas aeruginosa (Pseudomonas aeruginosa IFO3445), Enterobacter cloacae (Enterobacter cloacae IID 977), Citrobacter freundii (Citrobacter freundii NBRC 12681), Gardnerella vaginalis (Gardnerella vaginalis ATCC 14018), Neisseria gonorrhoeae (Neisseria gonorrhoeae ATCC 19424), Peptostreptococcus asaccharolyticus (Peptostreptococcus asaccharolyticus ATCC 14963), Propionibacterium acnes (Propionibacterium acnes JCM 6425), Closridium perfringens (Clostridium perfringens ATCC 13124), Bacteroides fragilis (Bacteroides fragilis ATCC 25285), Porphyromonas gingivalis (Porphyromonas gingivalis JCM 8525), Prevotella intermedia (Prevotella intermedia JCM 7365), Fusobacterium nucleatum (Fusobacterium nucleatum JCM 8532), Legionella pneumophilia (Legionella pneumophilia ATCC33153, Legionella pneumophilia subsp. pneumophilia ATCC33155, Legionella pneumophilia subsp. pneumophilia ATCC33215 and Legionella pneumophilia subsp. fraseri ATCC33216), Mycoplasma pneumoniae (Mycoplasma pneumoniae ATCC15531), and the like.

The compound of General formula [1] according to the present invention has excellent security. Security can be assessed using various studies, for example, selected from the study of cytotoxicity, research selectivity towards gyrase human DNA and various bacteria, research selectivity with respect to the topoisomerase IV man and various bacteria, hERG research, studies of toxicity with repeated dosing studies of inhibiting the activity of cytochrome P450 (CYP), studies of inhibition of metabolic dependence studies of the mouse micronucleus in vivo studies UDS rat liver in vivo, and the like.

The compound of General formula [1] according to the present invention has excellent metabolic stability. Metabolic stability can be assessed using a variety of research, for example by using different types of stability studies, chosen from the study of metabolic stability to human liver microsomes, IP is to study the stability of S9 person, and the like.

In particular, the compounds of Examples 2, 4, 77 and 85 of the present invention exhibit higher antimicrobial activity and safety and, in addition, a higher metabolic stability, and tissue distribution.

In addition, the usefulness of the compounds of the General formula [1] according to the present invention will now be described with reference to the following examples of research.

Example study 1:Study of susceptibility 1

The analyte is first dissolved in dimethyl sulfoxide. Antibacterial activity (MICs) of these compounds is determined using the method of microrasbora, in accordance with the recommendations of the Japanese society of chemotherapy.

Staphylococcus aureus (S. aureus FDA209P, F-3095) is used as the investigated organism. Bacteria cultured in the cups with the agar Mullane-Hinton (MHA), at 35°C during the night, suspended in sterile physiological saline at a concentration that is equivalent to 0.5 to Macfarland. Bacterial inoculum prepare 10-fold dilutions of this suspension. Approximately 0,005 ml of bacterial inoculum inoculant in broth Mueller-Hinton with stabilized cationic composition (CAMHB, 100 μl/well)containing the test substance and incubated at 35°C during the night. The lowest concentration studies the target substance, if which is not observed macroscopic bacterial growth is defined as the MIC. Table 6 shows the results.

Table 6
The test substance
(No. of example)
MIC (mcg/ml)
S.aureus FDA209PS.aureus F-3095
20,03130,0313
40,03130,0313
80,03130,0313
100,01560,0156
170,00390,0313
300,03130,0313
330,03130,0313
350,03130,0313
440,03130,0313
450,03130,0625
550,00390,0078
770,03130,0625
790,00780,0156
800,00780,0156
850,03130,0313
900,03130,0313
930,06250,0313
950,03130,0625
960,06250,0625
1030,06250,0625
1180,06250,0625
119B0,06250,0625
1230,03130,125
1330,00780,0156
1370,03130,0625
1400,01560,0156
1410,03130,0313
1430,03130,0313
1440,03130,0313
1460,06250,0625
1470,03130,0625
1490,03130,0313
1510,03130,125
1520,06250,0625
1620,03130,0625
1630,03130,0313

Example research 2: An experiment with the I S. aureus

Use the mouse ICR (males grade SPF, age 4 weeks, five mice per group). Bacterial inoculum prepare suspendirovanie Staphylococcus aureus (S. aureus Smith), which is cultivated in a Cup of agar Mueller-Hinton at 37°C overnight in a sterile physiological saline solution, preparing a bacterial solution of about 4×108CFU/ml and diluting the solution 10-fold in 5.6% of the mucin-phosphate buffer. The ICR mice injected intraperitoneally bacterial inoculum (approximately 2×107CFU/mouse) to induce infection. Analyte dissolved in 10% hydroxypropyl-β-cyclodextrin and 0.05 mol/l hydrochloric acid. Each of the solutions of the analyte subcutaneously injected once in the amount of 3 mg/kg to mice 1 hour after infection. The number of surviving mice register within 5 days after infection.

As a result, all mice from the control group, which is not administered the test substance, die. However, all mice from the group introduction Examples№№2, 4, 68, 77, 93, 103, 119B, 140, 149 and 151 survive. Similarly, the compound of Example 85 enter in the quantity of 1 mg/kg as a result, four of five mice survive.

A case study 3:The study of cytotoxicity

Each test substance was dissolved in dimethyl sulfoxide and prepared for each concentration along with E-MEM, which contains Asim 10% FBS, and then 0.1 ml of this solution is distributed into each well of 96-well microplate. The Vero cell suspension containing 3×104cells/ml, prepared together with E-MEM containing 10% FBS, and 0.1 ml of suspension inoculant in each well. After incubation in 5% CO2at 37°C for 3 days, 50 μl of E-MEM containing 1 mg/ml inner salt, monosodium salt 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazole (Templ) and 25 μm phenazine of methosulfate (PMS), added to each well. After about 2 hours, measure the absorbance at 450 nm using a reader microplate.

Calculate the ratio of the absorbance for each well, which administered the test substance, and to control not containing the analyte of interest, and calculate the concentration of each connection, when cell proliferation is inhibited by 50% (CC50; µg/ml).

As a result, the values of CC50for all compounds of Examples№№ 2, 4, 8, 10, 30, 33, 35, 55, 68, 77, 79, 80, 85, 90, 93, 95, 96 and 103 constitute a 51.2 μg/ml or more.

The present invention will hereinafter be described with reference to Comparative examples and Examples; however the present invention is not limited to these Examples.

Unless approved otherwise, the media used for column chromatography on silica gel is a silica gel B. W., BW-127ZH pressed IMY Fuji Silysia Chemical Ltd.; the media used for column chromatography on basic silica gel is a silica gel produced FL100D, Fuji Silysia Chemical Ltd.; the medium used in column chromatography on silica gel with reversed phase, is an ODS-AM120-S50 manufactured by YMC Co., Ltd.

Column flash chromatography is carried out using a liquid chromatograph medium pressure, YFLC-Wprep2XY. N manufactured by YAMAZEN CORPORATION. If not stated otherwise, the column containing silica gel is a column Hi-Flash, W001, W002, W003 or W004 manufactured by YAMAZEN CORPORATION; and the column with the alkaline silica gel is a column Hi-Flash, W091, W092 or W093 manufactured by YAMAZEN CORPORATION.

The mixing ratio for the eluent is specified as the volume ratio.

In the Examples relevant abbreviations are used for the following values:

Ac: acetyl, Boc: tert-butoxycarbonyl, Bu: butyl, Et: ethyl, Me: methyl, MOM: methoxymethyl, Tf: trifloromethyl, THP: tetrahydro-2H-Piran-2-yl, Z: benzyloxycarbonyl and DMSO-d6: deuterated dimethyl sulfoxide.

Comparative example 1

To 1.0 g of 2-chloro-5-methoxypyridine-3-amine type of 0.82 ml of ethyl acrylate and 4.2 ml of triethylamine and 0.16 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred at an external temperature of 150-160°C for 6 hours in a sealed tube. The reaction to shift the ü cooled to room temperature and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of chloroform:methanol = 100:0-90:10, with the receipt of 0.41 g of ethyl (2E)-3-(3-amino-5-methoxypyridine-2-yl)acrylate and 0.25 g of 7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of solid products, light brown color.

Ethyl (2E)-3-(3-amino-5-methoxypyridine-2-yl)acrylate

1H-NMR (CDCl3) δ: of 1.32 (3H, t, J=7.2 Hz), 3,83 (3H, s), 3.96 points-Android 4.04 (2H, m), 4,25 (2H, square, J=7,2 Hz), 6,46 (1H, d, J=2.7 Hz), 6,78 (1H, d, J=15.1 Hz), 7,74 (1H, d, J=15.1 Hz), 7,83 (1H, d, J=2.7 Hz)

7-methoxy-1,5-naphthiridine-2(1H)-he

1H-NMR (DMSO-d6) δ: 3,88 (3H, s), is 6.54 (1H, d, J=9.8 Hz), 7,13 (1H, d, J=2.6 Hz), 7,86 (1H, d, J=9.8 Hz), 8,21 (1H, d, J=2.6 Hz), 11,78 (1H, s)

Comparative example 2

To a solution of 0.51 g of ethyl (2E)-3-(3-amino-5-methoxypyridine-2-yl)acrylate in 6 ml of methanol is added at room temperature of 0.53 g of a 28% solution of sodium methoxide/methanol and the mixture is heated under reflux, with stirring, for 2 hours and 20 minutes. It additionally adds to 0.53 g of a 28% solution of sodium methoxide/methanol and the mixture is heated under reflux, with stirring, for 1 hour 45 minutes. It additionally adds to 0.53 g of a 28% solution of sodium methoxide/methanol and the mixture is heated under reflux, with stirring, for 1 hour and 15 minutes. The reaction mixture is cooled to room temperature is, the solvent is then distilled off under reduced pressure and the resulting residue loaded with ethyl acetate and water and adjusted pH to 7.2 with 1 mol/l hydrochloric acid. The solvent is distilled off under reduced pressure, and the solid product filtered and washed with water and simple diethyl ether, to obtain 0.25 g of 7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of a solid light brown color.

Comparative example 3

To a suspension of 0.23 g of 7-methoxy-1,5-naphthiridine-2(1H)-it's in 3 ml of N,N-dimethylformamide added at room temperature 79 mg of 60% sodium hydride, the temperature was raised to 50°C and the mixture is stirred for 15 minutes. It adds 0,41 ml of 2-methyl bromide-1,3-dioxolane, the temperature of the reaction mixture increased to 90-100°C and the reaction mixture is stirred for 3 hours. The reaction mixture is cooled to room temperature and to it was added water and ethyl acetate. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue purified using flash column-chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 100:0 to 33:67, then gradient elution of chloroform:methanol = 1000-90:10, to obtain 0.11 g of 1-(1,3-dioxolane-2-ylmethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of a solid light brown color.

1H-NMR (CDCl3) δ: 3,83-4,07 (4H, m), of 3.97 (3H, s), 4,50 (2H, d, J=4,1 Hz), 5,20 (1H, t, J=4,1 Hz), 6,77 (1H, d, J=9.8 Hz), 7,40 (1H, d, J=2.4 Hz), 7,86 (1H, d, J=9.8 Hz), of 8.28 (1H, d, J=2,4 Hz

Comparative example 4

To 0.11 g of 1-(1,3-dioxolane-2-ylmethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is added to 6.0 ml of 80% aqueous solution triperoxonane acid and the mixture was stirred at 60-70°C for 1 hour. To it was added to 4.0 ml of 80% aqueous solution triperoxonane acid and the mixture was stirred at 60-70°C for 1 hour. The reaction mixture is cooled to room temperature and the solvent is distilled off under reduced pressure. The resulting residue loaded with ethyl acetate and water and adjusted pH to 7.0 with 1 mol/l aqueous solution of sodium hydroxide. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts are combined and the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.11 g (7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in the form of foam light brown color.

1H-NMR (DMSO-d6) δ: to 3.92 (3H, s), 5,28 (2H, s)6,70 (1H, d, J=9.6 Hz), was 7.36 (1H, d, J=2.4 Hz), 7,94 (1H, d, J=9.6 Hz), 8,29 (1H, d, J=2.4 Hz), 9,68 (1H, s)

Comparative example 5

To 0,99 g of 2-bromo-5-herperidin-3-amine type of 0.67 ml of ethyl acrylate, 3.5 ml of triethylamine and 0.13 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred at an external temperature of 145 to 150°C for 5 hours in a sealed tube. The reaction mixture is cooled to room temperature and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of chloroform:methanol = 100:0-90:10, with the receipt of 0.37 g of ethyl (2E)-3-(3-amino-5-herperidin-2-yl)acrylate and 0.15 g of 7-fluoro-1,5-naphthiridine-2(1H)-it is in the form of solid products, light brown color.

Ethyl (2E)-3-(3-amino-5-herperidin-2-yl)acrylate

1H-NMR (CDCl3) δ: of 1.33 (3H, t, J=7,1 Hz), was 4.02-4,12 (2H, usher.), 4,27 (2H, square, J=7,1 Hz), of 6.71 (1H, DD, J=9,8, 2.4 Hz), 6,85 (1H, d, J=15.1 Hz), 7,71 (1H, d, J=15.1 Hz), 7,94 (1H, d, J=2.4 Hz)

7-fluoro-1,5-naphthiridine-2(1H)-he

1H-NMR (DMSO-d6) δ: 6,72 (1H, DD, J=9,8, 1.7 Hz), 7,47 (1H, DD, J = 9,6, 2,5 Hz), 7,94 (1H, d, J=9.8 Hz), and 8.50 (1H, d, J=2.5 Hz), 11,99 (1H, s)

Comparative example 6

To a solution of 0.36 g of ethyl (2E)-3-(3-amino-5-herperidin-2-yl)acrylate in 3 ml of methanol, and 0.37 g of a 28% solution of sodium methoxide/methanol added at room temperature and the mixture is heated under reflux, with stirring, for 2 hours 40 minutes. To it was added 72 mg of a 28% solution of sodium methoxide/methane and the mixture is heated under reflux, under stirring, for 1 hour. The reaction mixture is cooled to room temperature, the solvent is then distilled off under reduced pressure and the resulting residue loaded with ethyl acetate and water and adjusted pH to 6.7 with 1 mol/l hydrochloric acid. The solvent is distilled off under reduced pressure, the solid product is filtered off and washed with water and simple diethyl ether to obtain 0.17 g of 7-fluoro-1,5-naphthiridine-2(1H)-it is in the form of a solid light brown color.

1H-NMR (DMSO-d6) δ: 6,72 (1H, d, J=9.8 Hz), 7,47 (1H, DD, J=a 9.6, 2.4 Hz), 7,94 (1H, d, J=9.8 Hz), and 8.50 (1H, d, J=2.4 Hz), 11,99 (1H, users)

Comparative example 7

To a suspension of 0.32 g of 7-fluoro-1,5-naphthiridine-2(1H)-it's in 3 ml of N,N-dimethylformamide add 0.12 g of 60% sodium hydride at room temperature and the mixture was stirred at 50-60°C for 1 hour. It adds to 0.60 ml of 2-methyl bromide-1,3-dioxolane, the temperature was raised to 85-95°C, and the reaction mixture is stirred for 4 hours. The reaction mixture is cooled to room temperature, and then to it was added water and ethyl acetate. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue is added chloroform, the firmness of the print product is filtered and purified using flash column-chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 100:0 to 30:70, with the receipt of 0.23 g of 1-(1,3-dioxolane-2-ylmethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it is in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 3,84-3,93 (2H, m), 3.96 points-of 4.05 (2H, m), of 4.45 (2H, d, J=4, 2 Hz), 5,19 (1H, t, J=4, 2 Hz), to 6.88 (1H, d, J=9.8 Hz), 7,69 (1H, DD, J=10,5, 2.4 Hz), of 7.90 (1H, d, J=9.8 Hz), to 8.41 (1H, d, J=2.4 Hz)

Comparative example 8

To 0.21 g of 1-(1,3-dioxolane-2-ylmethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it add 3 ml of 80% aqueous solution triperoxonane acid and the mixture is stirred at room temperature for 20 minutes and then stirred at 50-60°C for 1 hour. To it was added 3 ml of 80% aqueous solution of triperoxonane acid, the mixture was stirred at 80-90°C for 1 hour and 45 minutes, then additionally add 3 ml of 80% aqueous solution triperoxonane acid and the mixture was stirred at the same temperature for 1 hour. The reaction mixture is cooled to room temperature, and then the solvent is distilled off under reduced pressure. The resulting residue loaded chloroform and water and the pH adjusted to 7.4 with 20% aqueous sodium hydroxide solution. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.20 g of 7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)AC is maldehyde in the form of a yellow oily substance color.

1H-NMR (CDCl3) δ: 5,12 (2H, s), 6,93 (1H, d, J=9.9 Hz),? 7.04 baby mortality (1H, DD, J=9,6, and 2.3 Hz), 7,98 (1H, d, J=9.9 Hz), 8,46 (1H, d, J=2.3 Hz), made up 9.77 (1H, s)

Comparative example 9

Using the same technology as in Comparative example 21, 0,22 g (A) 1-benzyl-N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)-2-methylpiperidin-4-amine as a colorless oily substance and 0.13 g (B) 1-benzyl-N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)-2-methylpiperidin-4-amine as a colorless oily substance get of 0.24 g of 1-benzyl-2-methylpiperidin-4-it and 0.20 g of 1-(2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)methanamine.

(A)1H-NMR (CDCl3) δ with 1.07 (3H, d, J=6.6 Hz), 1,40-of 1.85 (4H, m), 2,40-2,60 (2H, m), 2,80-3,00 (2H, m), 3,42 (1H, d, J=13,7 Hz), 3,69-3,82 (3H, m), 4,24 is 4.35 (4H, m), 6,83 (1H, s), 7,18 and 7.36 (5H, m), 8,10 (1H, s)

(B)1H-NMR (CDCl3) δ: 1,19-of 1.40 (2H, m)to 1.22 (3H, d, J=6,1 Hz), 1,76-of 1.84 (1H, m), 1,86-of 1.97 (2H, m), 2,20-of 2.30 (1H, m), 2.40 a is 2.55 (1H, m), of 2,75 2,85 (1H, m), 3,14 (1H, d, J=13.5 Hz), of 3.78 (2H, s)4,07 (1H, d, J=13.5 Hz), 4,24-4,34 (4H, m), for 6.81 (1H, s), 7,20-7,40 (5H, m), of 8.09 (1H, s)

Comparative example 10

Using the same technology as in Comparative example 61, tert-butyl (1-benzyl-2-methylpiperidin-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate is obtained from 1-benzyl-N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)-2-methylpiperidin-4-amine.

1H-NMR (CDCl3) δ: 1.00 and is 1.13 (3H, m), 1,35-of 1.65 (12H, s), 1,78-of 1.92 (1H, m), 2,48-2,60 (2H, m), 3,09-3,20 (H, m)of 3.48 (1H, d, J=13.5 Hz)and 3.59 (1H, d, J=13.5 Hz), 4,20-4,66 (7H, m), of 6.73 (1H, s), 7,20-7,30 (5H, m), with 8.05 (1H, s)

Comparative example 11

To a suspension of 6.0 g of 1,7-naphthiridine-2(1H)-she's in 60 ml of N,N-dimethylformamide at room temperature, add 2.5 g of 60% sodium hydride and the mixture was stirred at 50-60°C for 1 hour. To it was added 6.4 ml of 2-methyl bromide-1,3-dioxolane, the temperature was raised to 90-95°C and the reaction mixture is stirred for 2 hours and 30 minutes. Temperature increases up to 95-100°C and the mixture is stirred for 4 hours. It adds 0,82 g of 60% sodium hydride and 2.1 ml of 2-methyl bromide-1,3-dioxolane and the mixture is additionally stirred at the same temperature for 2 hours. It adds 0,49 g of 60% sodium hydride and 1.3 ml of 2-methyl bromide-1,3-dioxolane and the mixture was stirred at 90-100°C for 2 hours. It additionally adds 0,49 g of 60% sodium hydride and 1.3 ml of 2-methyl bromide-1,3-dioxolane and the mixture was stirred at the same temperature for 4 hours. The reaction mixture is cooled to 5°C, and then to it was added ethyl acetate and ice water. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue purified using flash column-chromatography on what silicagel using a gradient elution of hexane:ethyl acetate = 100:0-0:100, and then, using a gradient elution of chloroform:methanol = 100:0-90:10, to obtain 3.1 g of 1-(1,3-dioxolane-2-ylmethyl)-1,7-naphthiridine-2(1H)-it is in the form of a solid brown color.

1H-NMR (CDCl3) δ: 3,85-of 3.94 (2H, m), 3,99-4,08 (2H, m), 4,58 (2H, d, J=4.5 Hz), from 5.29 (1H, t, J=4.5 Hz), 6,91 (1H, d, J=9.4 Hz), 7,41 (1H, d, J=5,1 Hz), to 7.67 (1H, d, J=9.4 Hz), to 8.45 (1H, d, J=5,1 Hz), 9,05 (1H, s)

Comparative example 12

(1) To 3.1 g of 1-(1,3-dioxolane-2-ylmethyl)-1,7-naphthiridine-2(1H)-it add 30 ml of 80% aqueous solution triperoxonane acid and the mixture was stirred at 70-80°C for 2 hours. The reaction mixture is cooled to room temperature, then add 30 ml of 80% aqueous solution triperoxonane acid, the mixture was stirred at 70-80°C for 3 hours and 30 minutes, and the temperature was raised to 75-85°C and the mixture is stirred for 2 hours. It additionally add 30 ml of 80% aqueous solution triperoxonane acid and the mixture is stirred at 80-90°C for 2 hours and 30 minutes. The reaction mixture is cooled to room temperature, and then leave overnight. The solvent is distilled off under reduced pressure and the resulting residue loaded chloroform and water and the pH adjusted to 10.4 with 20% aqueous sodium hydroxide solution. To it was added sodium chloride, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and extrac the combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 2.5 g of (2-oxo-1,7-naphthiridine-1(2H)-yl)acetaldehyde in the form of an oily yellow substance.

(2) To a solution of 2.5 g of (2-oxo-1,7-naphthiridine-1(2H)-yl)acetaldehyde in 25 ml of dichloromethane added 2.6 g of tert-butyl (piperidine-4-yl)carbamate and 0,76 ml of acetic acid, and 4.2 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 4 hours and then left overnight. To it was added chloroform and the pH of the reaction mixture was adjusted to 9.1 with saturated aqueous sodium bicarbonate solution and 20% aqueous sodium hydroxide solution. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and extracts are combined and the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue, add a simple diethyl ether, and the solid product filtered off to obtain 2.8 g of tert-butyl (1-(2-(2-oxo-1,7-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 1,35-is 1.51 (2H, m)of 1.44 (9H, s), 1,89-to 1.98 (2H, m), 2,23 of-2.32 (2H, m), 2,67-to 2.74 (2H, m), 2,90 are 2.98 (2H, m), 3,41-3,55 (1H, m), 4,37-4,50 (3H, m), 6.89 in (1H, d, J=9.5 Hz), 7,42(1H, d, J=5.0 Hz), the 7.65 (1H, d, J=9.5 Hz), to 8.45 (1H, d, J=5.0 Hz), 8,89 (1H, s)

Comparative example 13

To a solution of 2.8 g of tert-butyl (1-(2-(2-oxo-1,7-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 20 ml of ethanol at room temperature, add 60 ml of 6.2 mol/l solution of hydrochloric acid/ethanol and the mixture is stirred for 2 hours. It additionally add 60 ml of 6.2 mol/l solution of hydrochloric acid/ethanol and the mixture is stirred for 4 hours and then allowed to stand for 4 days. The solvent is distilled off under reduced pressure, to the obtained residue, add a simple diethyl ether, and the solid product filtered off to obtain 2.8 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it is in the form of a solid yellow color.

1H-NMR (D2O) δ: 1,94-of 2.09 (2H, m), 2,36 at 2.45 (2H, m), 3,23-3,37 (2H, m), 3,54-3,70 (3H, m), 3,92-a 4.03 (2H, m), 4,81-to 4.87 (2H, m), 7,25 (1H, d, J=9.6 Hz), to 8.20 (1H, d, J=9.6 Hz), of 8.27 (1H, d, J=5,9 Hz), 8,64 (1H, d, J=5,9 Hz), 9,18 (1H, s)

Comparative example 14

To a solution of 1.1 g of 1-(1,3-dioxolane-2-yl)methanamine in 10 ml of N,N-dimethylformamide at room temperature, add 1.6 ml of triethylamine and 2.0 g of 2-chloro-6-methoxy-3-nitropyridine and the mixture was stirred at 55-65°C for 1 hour. The reaction mixture is cooled to room temperature, and then to it was added ethyl acetate and water. The organic layer is separated and the aqueous layer was extragere the t with ethyl acetate. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 2.7 g of N-(1,3-dioxolane-2-ylmethyl)-6-methoxy-3-nitropyridine-2-amine in the form of a solid yellow color.

1H-NMR (CDCl3) δ: 3,90 (2H, DD, J=5,6, 3.5 Hz), 3,92-3,99 (2H, m), of 3.97 (3H, s), 4,01-4,10 (2H, m)to 5.17 (1H, t, J=3.5 Hz), 6,07 (1H, d, J=9.1 Hz), 8,31 (1H, d, J=9.1 Hz), 8,76 cent to 8.85 (1H, user.)

Comparative example 15

To a solution of 2.7 g of N-(1,3-dioxolane-2-ylmethyl)-6-methoxy-3-nitropyridine-2-amine in 30 ml ethanol add 0,81 g 10% palladium on coal at room temperature and the mixture was stirred at 40°C for 2 hours and 30 minutes in hydrogen atmosphere. The reaction mixture is cooled to room temperature, nerastvorimaya substance is filtered off and the residue from the filtration was washed with simple diethyl ether. The solvent is distilled under reduced pressure to obtain 2.4 g of 3-amino-2-(1,3-dioxolane-2-ylmethyl)amino-6-methoxypyridine in the form of a solid purple color.

1H-NMR (CDCl3) δ: 2,30-2,80 (2H, usher.), 3,62 is 3.76 (2H, m), of 3.84 (3H, s), 3,86-4,08 (4H, m), 4,30-5,10 (1H, usher.), further 5.15 (1H, t, J=4.4 Hz), to 5.93 (1H, d, J=7.8 Hz), 6,91 (1H, d, J=7,8 Hz)

Comparative example 16

To a solution of 0.20 g of 3-amino-2-(13-dioxolane-2-ylmethyl)amino-6-methoxypyridine in 2 ml of dioxane is added to 0.22 g 45-50% solution in toluene of ethyloxazole and the mixture is stirred at room temperature for 2 hours, and then leave overnight. To it was added 36 mg of 60% sodium hydride and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture are added water and ethyl acetate. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 100:0-50:50, to obtain 36 mg of 4-(1,3-dioxolane-2-ylmethyl)-6-methoxypurine (2,3-b)pyrazin-3(4H)-it is in the form of a solid light brown color.

1H-NMR (CDCl3) δ: a 3.87-of 3.96 (2H, m), Android 4.04 (3H, s), 4,06-to 4.15 (2H, m), 4,60 (2H, d, J=5,1 Hz), to 5.57 (1H, t, J=5,1 Hz), was 6.73 (1H, d, J=8,8 Hz), 8,01 (1H, d, J=8,8 Hz), 8,18 (1H, s)

Comparative example 17

To 0.21 g of 4-(1,3-dioxolane-2-ylmethyl)-6-methoxypurine(2,3-b)pyrazin-3(4H)-it add 10 ml of 80% aqueous solution triperoxonane acid and the mixture is stirred at room temperature for 5 hours and then left overnight. The solvent is distilled off under reduced pressure. The resulting residue loaded with ethyl acetate and water and adjusted pH to 7.0 with 1 mol/l aqueous solution of sodium hydroxide. The PR is anceschi layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.18 g (6-methoxy-3-occupied(2,3-b)pyrazin-4(3H)-yl)acetaldehyde in the form of foam light brown color.

1H-NMR (CDCl3) δ: of 3.94 (3H, s), with 5.22 (2H, s)6,76 (1H, d, J=8,8 Hz), 8,07 (1H, d, J=8,8 Hz), 8,24 (1H, s)to 9.70 (1H, s)

Comparative example 18

To a solution of 1.2 g of 1,8-naphthiridine-2(1H)-she's in 18 ml of N,N-dimethylformamide added 0.36 g of 60% sodium hydride and the mixture was stirred at 50-60°C for 7 minutes. It adds to 0.94 ml of 2-methyl bromide-1,3-dioxolane and the mixture was stirred at 95-105°C for 3 hours. The reaction mixture is cooled to room temperature, then add water and ethyl acetate and the organic layer separated. The aqueous layer was extracted with ethyl acetate and chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 1:1, to obtain 1.2 g of 1-(1,3-dioxolane-2-ylmethyl)-1,8-naphthiridine-2(1H)-it is in the form of a solid white product.

1H-NMR (CDCl3) δ: 3,83-3,93 (2H, m), 3.95 to to 4.17 (2H, m), 4.72 in (1H, d, J=5,1 Hz)to 5.56 (1H, t, J=5,1 Hz), 6,72 (1H, d, J=9.5 Hz), 7,17 (1H, DD, J7,6, the 4.7 Hz), to 7.64 (1H, d, J=9.5 Hz), 7,86 (1H, DD, J=7,6, 1.8 Hz), to 8.57 (1H, DD, J=4,7, 1.8 Hz)

Comparative example 19

To 1.1 g of 1-(1,3-dioxolane-2-ylmethyl)-1,8-naphthiridine-2(1H)-it add 11 ml of 90% aqueous solution triperoxonane acid and the mixture is stirred at room temperature for 2 hours. Then, there was added 1.1 ml of water and the mixture is stirred for 13 hours, and additionally add 1.1 ml of water and the mixture is stirred for 3 hours and 30 minutes, and stirred at 50-70°C for 1 hour and 30 minutes. The solvent is distilled off under reduced pressure, and the obtained residue is added saturated aqueous sodium bicarbonate solution, water and chloroform. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.75 g (2-oxo-1,8-naphthiridine-1(2H)-yl)acetaldehyde in the form of a solid yellow color.

1H-NMR (CDCl3) δ: are 5.36 (2H, s), to 6.80 (1H, d, J=9.5 Hz), 7,20 (1H, DD, J=7,6, 4,8 Hz), 7,72 (1H, d, J=9.5 Hz), to $ 7.91 (1H, DD, J=7,6, 1.8 Hz), 8,51 (1H, DD, J=4,8, 1.8 Hz), 9,72 (1H, s)

Comparative example 20

To a solution of 1.0 g of 1,6-naphthiridine-2(1H)-it in 10 ml of N,N-dimethylformamide added to 0.30 g of 60% hydride soda is I and the mixture was stirred at 50-60°C for 1 hour. It adds to 0.78 ml of 2-methyl bromide-1,3-dioxolane, and the reaction mixture is stirred at 90-100°C for 30 minutes. It additionally adds to 0.30 g of 60% sodium hydride and 0.78 ml of 2-methyl bromide-1,3-dioxolane and the mixture was stirred at 90-108°C for 5 hours and 30 minutes. The reaction mixture is cooled to room temperature, then add water and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 100:1, receipt of 0.60 g of 1-(1,3-dioxolane-2-ylmethyl)-1,6-naphthiridine-2(1H)-it is in the form of a solid yellow color.

1H-NMR (CDCl3) δ: 3,84-of 3.94 (2H, m), 3,98-4,07 (2H, m), 4,48 (2H, d, J=4.3 Hz), 5,23 (1H, t, J=4.3 Hz), to 6.75 (1H, d, J=9.5 Hz), 7,47 (1H, d, J=6.2 Hz), 7,78 (1H, d, J=9.5 Hz), 8,58 (1H, d, J=6.2 Hz), 8,76 (1H, s)

Comparative example 21

To a solution of 0.29 g (2-oxo-1,8-naphthiridine-1(2H)-yl)acetaldehyde in 10 ml of methylene chloride added to 0.30 g of tert-butyl (piperidine-4-yl)carbamate and 87 μl of acetic acid, the mixture is stirred for 10 minutes, and then to the reaction mixture of 0.48 g triacetoxy the reed sodium and the mixture is stirred at room temperature for 4 hours. To it add water, saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and extracts are combined and the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 100:1 to obtain 0.27 g of tert-butyl (1-(2-(2-oxo-1,8-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of an oily material light brown color.

1H-NMR (CDCl3) δ: 1,36-1,51 (11H, m), 1,88 is 1.96 (2H, m), 2,19-of 2.28 (2H, m), 2,66-of 2.72 (2H, m), 2,98-of 3.06 (2H, m), 3,41 of 3.56 (1H, m), 4,50-4,60 (1H, m), 4,65-4,70 (2H, m), 6,74 (1H, d, J=9.5 Hz), 7,17 (1H, DD, J=7,7, 4,8 Hz), 7,63 (1H, d, J=9.5 Hz), 7,86 (1H, DD, J=7,7, 1.8 Hz), 8,58 (1H, DD, J=4,8, 1.8 Hz)

Comparative example 22

To a solution of 0.26 g of tert-butyl (1-(2-(2-oxo-1,8-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 4 ml of dichloromethane is added 2 ml triperoxonane acid and the mixture is stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, added to the obtained residue, water and simple diethyl ether and the aqueous layer was separated and washed with simple diethyl ether, and then added 20% aqueous p is the target sodium hydroxide, and the reaction mixture was adjusted to pH 13-14. To it was added dichloromethane and sodium chloride, the organic layer is separated and the aqueous layer was extracted with chloroform, and the implementation of vysalivaniya. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.15 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,8-naphthiridine-2(1H)-it is in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: 1,31 was 1.43 (2H, m), 1.77 in is 1.91 (4H, m), 2,13-2,22 (2H, m), 2,62-by 2.73 (3H, m), 3,03-3,10 (2H, m), of 4.66-4.72 in (2H, m), 6,74 (1H, d, J=9.4 Hz), 7,17 (1H, DD, J=7,6, 4.6 Hz), 7,63 (1H, d, J=9.4 Hz), 7,86 (1H, DD, J=7,6, 1.9 Hz), 8,59 (1H, DD, J=4,6, 1.9 Hz)

Comparative example 23

To a solution of 1.2 g of 1,5-naphthiridine-2(1H)-she's in 24 ml of N,N-dimethylformamide type of 0.82 g of 60% sodium hydride at 60°C and the mixture was stirred at the same temperature for 20 minutes and then stirred at 55-80°C for 30 minutes. To it add 1.3 ml of 2-methyl bromide-1,3-dioxolane at 60°C, the temperature of the reaction mixture was raised to 100°C for 4 hours, and the reaction mixture is added 2.3 g of potassium carbonate and the mixture was stirred at the same temperature for 3 hours. After she left during the night, it adds to 0.85 ml of 2-methyl bromide-1,3-dioxolane and 0.33 g of 60% sodium hydride and the mixture was stirred at 70-75°C for 1 hour and 30 minutes. The reaction is th the mixture is cooled to room temperature, then add water, sodium chloride and chloroform, and the organic layer separated. The aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 49:1 to obtain 1.1 g of 1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-it is in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 3,82-of 3.94 (2H, m), 3.96 points-of 4.05 (2H, m)to 4.52 (2H, d, J=4, 2 Hz), with 5.22 (1H, t, J=4,2 Hz)6,94 (1H, d, J=9.8 Hz), was 7.45 (1H, DD, J=8,6, and 4.5 Hz), of 7.90-7,98 (2H, m), 8,54 (1H, DD, J=4,5, 1.2 Hz)

Comparative example 24

To 1.0 g of 1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-it add 5 ml of 80% aqueous solution triperoxonane acid and the mixture was stirred at 60-70°C for 30 minutes and then stirred at 70 to 90°C for 4 hours. It additionally add 5 ml of 80% aqueous solution triperoxonane acid and the mixture is stirred for 2 hours. The solvent is distilled off under reduced pressure, the obtained residue is added saturated aqueous solution of sodium bicarbonate, sodium chloride and chloroform, and the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine received the initial solution is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.73 g of (2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in the form of oily substances orange color.

1H-NMR (CDCl3) δ: 5,15 (2H, s), of 6.99 (1H, d, J=10.0 Hz), 7,43-7,49 (1H, m), of 7.96-8,03 (2H, m), 8,56-to 8.62 (1H, m), 9,76 (1H, s)

Comparative example 25

To a solution of 0.24 g of tert-butyl (1-benzyl-2-methylpiperidin-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate in 3 ml of methanol, add 90 µl of acetic acid and 0.32 g of 20% palladium hydroxide. The reaction mixture is stirred for 4 hours 30 minutes in a hydrogen atmosphere. Nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure to obtain 0.16 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(2 methylpiperidin-4-yl)carbamate in the form of a yellow foam.

1H-NMR (CDCl3) δ: 1,36-of 1.45 (9H, m)of 1.50 (3H, d, J=6.8 Hz), 1,67 is 1.75 (1H, m), 1,86-of 1.95 (1H, m), 2,03 with 2.14 (1H, m), 2,18-of 2.30 (1H, m), 3.04 from-3,17 (1H, m), 3,26-to 3.35 (1H, m), 3,83-3,93 (1H, m), 4,27-4,51 (7H, m), of 6.71-6,83 (1H, m), 8,08 (1H, s), 9,40-a 9.60 (1H, m)

Comparative example 26

(1) using the same technology as in Comparative example 61, tert-butyl (1-benzyl-2-methylpiperidin-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate is obtained from 1-benzyl-N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)-2-methylpiperidin-4-amine.

(2) using the same technology as in Comparative example 25, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(2 methylpiperidin-4-yl)carbamate obtained from tert-butyl (1-benzo is l-2-methylpiperidin-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate.

1H-NMR (CDCl3) δ: 1,27-1,57 (14H, m), 1,82 is 2.00 (2H, m), 2,83-of 2.97 (1H, m), 3,14-of 3.27 (1H, m), 3,40-of 3.53 (1H, m), 4.26 deaths-br4.61 (7H, m), 6,62-7,02 (1H, m), 8,05-8,13 (1H, m), 9,84-10,06 (1H, m)

Comparative example 27

Using the same technology as in Comparative example 3, 1-(1,3-dioxolane-2-ylmethyl)pyrido(3,4-b)pyrazin-2(1H)-he obtained from pyrido(3,4-b)pyrazin-2(1H)-it 2-methyl bromide-1,3-dioxolane.

1H-NMR (CDCl3) δ: 3,84-was 4.02 (4H, m), of 4.44 (2H, d, J=4.0 Hz), of 5.24 (1H, t, J=4.0 Hz), the 7.43 (1H, d, J=6.0 Hz), with 8.33 (1H, s), 8,63 (1H, d, J=6.0 Hz), 9,07 (1H, s)

Comparative example 28

To a solution of 3.2 g of 7-chloro-1,8-naphthiridine-2(1H)-she's in 32 ml of N,N-dimethylformamide added 3.7 g of potassium carbonate and the mixture was stirred at 50-60C° for 23 minutes and then there was added 2.2 ml of 2-methyl bromide-1,3-dioxolane and the mixture was stirred at 60-78°C for 25 minutes. To it was added 16 ml of N,N-dimethylformamide and 1.1 ml of 2-methyl bromide-1,3-dioxolane, and the mixture was stirred at 90-95°C for 2 hours and 15 minutes, there was added 3.7 g of potassium carbonate and the mixture is stirred for 20 minutes. The reaction mixture is cooled to room temperature, then add water and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. P the obtained residue is purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 1:1 to obtain 3.6 g of 7-chloro-1-(1,3-dioxolane-2-ylmethyl)-1,8-naphthiridine-2(1H)-it is in the form of a yellow solid product color.

1H-NMR (CDCl3) δ: 3,86-of 3.96 (2H, m), 4,10-4,20 (2H, m), 4,63 (2H, t, J=5.4 Hz), the ceiling of 5.60 (1H, t, J=5.4 Hz), to 6.75 (1H, d, J=9.6 Hz), 7,17 (1H, d, J=8.0 Hz), a 7.62 (1H, d, J=9.6 Hz), 7,79 (1H, d, J=8.0 Hz)

Comparative example 29

To a solution of 2.5 g of 7-chloro-1-(1,3-dioxolane-2-ylmethyl)-1,8-naphthiridine-2(1H)-she's in 30 ml of methanol added to 5.4 g of a 28% solution of sodium methoxide/methanol and the mixture is heated under reflux, with stirring, for 3 hours and 40 minutes. The reaction mixture is cooled to room temperature, then add water, and then the solvent is distilled off under reduced pressure. To the obtained residue, add water, a saturated aqueous solution of ammonium chloride and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and extracts are combined and the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 2.9 g of 1-(1,3-dioxolane-2-ylmethyl)-7-methoxy-1,8-naphthiridine-2(1H)-it is in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: 3,84-of 3.94 (2H, m)4,00 (3H, s), 4,05-to 4.15 (2H, m)and 4.65 (2H, d, J=5,1 Hz)to 5.56 (1H, t, J=5,1 Hz), 6,55 (1H, d, J=9.3 Hz), to 6.57 (1H, d, J=8.6 Hz), 7,55 (1H, d, J=9.3 Hz), 7,69 (1H, d, J=8.6 Hz)

Comparative example 30

To 2.8 g of 1-(1,3-dioxolane-2-ylmethyl)-7-methoxy-1,8-naphthas who ridin-2(1H)-it add 20 ml of 80% aqueous solution triperoxonane acid and the mixture was stirred at 60-72°C for 3 hours and 20 minutes and at 80-85°C for 2 hours and 20 minutes, then there was added 4 ml of water, and the mixture is additionally stirred for 4 hours. The reaction mixture is cooled to room temperature and then left overnight and the solvent is distilled off under reduced pressure. To the obtained residue is added saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 1.8 g (7-methoxy-2-oxo-1,8-naphthiridine-1(2H)-yl)acetaldehyde in the form of a solid yellow color.

1H-NMR (CDCl3) δ: to 3.92 (3H, s), 5,23 (2H, d, J=0.7 Hz), 6,63 is 6.67 (2H, m), 7,66 (1H, d, J=9.5 Hz), 7,78 (1H, d, J=8,3 Hz), 9,65-9,67 (1H, m)

Comparative example 31

To a solution of 1.6 g (7-methoxy-2-oxo-1,8-naphthiridine-1(2H)-yl)acetaldehyde in 70 ml of dichloromethane added 1.5 g of tert-butyl (piperidine-4-yl)carbamate and 0.42 ml of acetic acid, the mixture is stirred for 20 minutes, then the reaction mixture is added 2.3 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 2 hours and 10 minutes. To it add water, saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and e is strict unite, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 50:1 to obtain 2.8 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,8-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of a white foam.

1H-NMR (CDCl3) δ: 1,38-1,51 (11H, m), 1,88-to 1.98 (2H, m), 2,22-2,31 (2H, m), 2,69 is 2.75 (2H, m), 2,98-of 3.06 (2H, m), 3,41-to 3.52 (1H, m)to 4.01 (3H, s), to 4.38-4,47 (1H, m), br4.61-of 4.66 (2H, m), to 6.57 (1H, d, J=9.3 Hz), is 6.61 (1H, d, J=8.5 Hz), 7,56 (1H, d, J=9.3 Hz), 7,72 (1H, d, J=8,5 Hz)

Comparative example 32

To 2.8 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,8-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate are added 50 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 29 hours. The solvent is distilled off under reduced pressure, ethyl acetate is added to the thus obtained solid product, and the crystals are filtered and washed with ethyl acetate to obtain 2.3 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,8-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 1,90-of 2.05 (2H, m), 2,34 is 2.43 (2H, m), 3,17-3,30 (2H, m), 3,55-to 3.67 (3H, m), 3,93-was 4.02 (2H, m), Android 4.04 (3H, s), 4,88-4,94 (2H, m), 6,62 (1H, d, J=9.5 Hz), 6,83 (1H, d, J=8.5 G is), to 7.93 (1H, d, J=9.5 Hz), 8,01 (1H, d, J=8,5 Hz)

Comparative example 33

Using the same technology as in Comparative example 14, N-(1,3-dioxolane-2-ylmethyl)-3-nitropyridine-2-amine obtained from 2-bromo-3-nitropyridine and 1-(1,3-dioxolane-2-yl)methanamine.

1H-NMR (CDCl3) δ: 3,90-4,10 (6H, m)to 5.17 (1H, t, J=3,4 Hz), 6,64-6,69 (1H, m), at 8.36-8,44 (3H, m)

Comparative example 34

Using the same technology as in Comparative example 15, 3-amino-2-(1,3-dioxolane-2-ylmethyl)aminopyridine is obtained from N-(1,3-dioxolane-2-ylmethyl)-3-nitropyridine-2-amine.

1H-NMR (CDCl3) δ: 3,20-of 3.60 (2H, usher.), 3,70-3,74 (2H, m), a 3.87-4,08 (4H, m), 4,76-4,88 (1H, usher.), 5,16 (1H, t, J=4,1 Hz), 6,55 (1H, DD, J=7,4, 5,2 Hz)6,86 (1H, DD, J=7,4, 1.3 Hz), of 7.70 (1H, DD, J=5,2, 1.3 Hz)

Comparative example 35

To a solution of 0.20 g of 3-amino-2-(1,3-dioxolane-2-ylmethyl)aminopyridine in 2 ml ethanol add 0.25 g of 45-50% solution of ethyloxazole in toluene and the mixture is heated under reflux, with stirring, for 1 hour 30 minutes. The reaction mixture is cooled to room temperature and to it was added water and ethyl acetate. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous alpacamania and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of chloroform:methanol = 100:0-90:10 to obtain 0.16 g of 4-(1,3-dioxolane-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-it is in the form of a solid light brown color.

1H-NMR (CDCl3) δ: 3,85-of 3.95 (2H, m), 4,06-4,16 (2H, m), of 4.66 (2H, d, J=5,2 Hz)to 5.56 (1H, t, J=5,2 Hz), 7,33 (1H, DD, J=7,9, 4,7 Hz), 8,17 (1H, DD, J=7,9) and 1.7 Hz), 8,35 (1H, s), at 8.60 (1H, DD, J=4,7) and 1.7 Hz)

Comparative example 36

Using the same technology as in Comparative example 4, (3 occupied(2,3-b)pyrazin-4(3H)-yl)acetaldehyde is obtained from 4-(1,3-dioxolane-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-it.

1H-NMR (CDCl3) δ: 5,33 (2H, s), 7,35 (1H, DD, J=7,9, 4,7 Hz), by 8.22 (1H, DD, J=7,9) and 1.7 Hz), 8,40 (1H, s), charged 8.52 (1H, DD, J=4,7) and 1.7 Hz), of 9.75 (1H, s)

Comparative example 37

Using the same technology as in Comparative example 42, tert-butyl (1-(2-(2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate is obtained from (2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and tert-butyl (piperidine-4-yl)carbamate.

1H-NMR (CDCl3D2O) δ: 1,24-1,46 (11H, m), 1,90-to 1.98 (2H, m), 2.21 are of 2.30 (2H, m), 2,62 of 2.68 (2H, m), 2,88-of 2.97 (2H, m), 4,35-4,55 (3H, m), 6,92 (1H, d, J=9.7 Hz), 7,47 (1H, DD, J=8,5, and 4.5 Hz), 7,74 for 7.78 (1H, m), 7,92 (1H, d, J=9.7 Hz), 8,55 (1H, DD, J=4,5, 1,1 Hz)

Comparative example 38

Using the same technology the technology, as in Comparative example 13, 1-(2-(4-aminopiperidin-1-yl)ethyl)1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (1-(2-(2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 1,80-2,10 (2H, m), 2.26 and-2,48 (2H, m), 3,10 is 3.40 (2H, m), 3,53-3,70 (3H, m), 3,90-4,10 (2H, m), 4,84-of 4.90 (2H, m), 7,31 (1H, d, J=10.0 Hz), 8,21 (1H, DD, J=9,0, 5,5 Hz), compared to 8.26 (1H, d, J=10.0 Hz), 8,72 (1H, d, J=9.0 Hz), 8,81 (1H, d, J=5,5 Hz)

Comparative example 39

To a suspension of 3.8 g of pyridine-2,3-diamine in 100 ml of dioxane is added to 7.1 g 45-50% solution of ethyloxazole in toluene and the mixture is stirred at room temperature for 1 hour and then heated under reflux, with stirring, for 1 hour. The reaction mixture was cooled in an ice bath and to it was added a simple diethyl ether. The solid product is filtered off with getting a 3.9 g of pyrido(2,3-b)pyrazin-2(1H)-it is in the form of a solid light brown color.

1H-NMR (DMSO-d6) δ: 7,58 (1H, DD, J=8,2, 4.5 Hz), 7,73 (1H, DD, J=8,2, 1,6 Hz), of 8.37 (1H, s), 8,53 (1H, DD, J=4,5, 1,6 Hz)

Comparative example 40

Using the same technology as in Comparative example 3, 1-(1,3-dioxolane-2-ylmethyl)pyrido(2,3-b)pyrazin-2(1H)-he obtained from pyrido(2,3-b)pyrazin-2(1H)-it 2-methyl bromide-1,3-dioxolane.

1H-NMR (CDCl3) δ: 3,83-4,00 (4H, m), of 4.49 (2H, d, J=4.0 Hz), 5,23 (1H, t, J=4.0 Hz), 7,52 (1H, DD, J=8,5, 4,4 Hz), to 7.99 (1H, DD, J=8,, 1.5 Hz), 8,56 (1H, s), 8,66 (1H, DD, J=4,4, 1.5 Hz)

Comparative example 41

Using the same technology as in Comparative example 3 4-(1,3-dioxolane-2-ylmethyl)pyrido(3,4-b)pyrazin-3(4H)-he obtained from pyrido(3,4-b)pyrazin-3(4H)-it 2-methyl bromide-1,3-dioxolane.

1H-NMR (CDCl3) δ: 3,85-of 4.05 (4H, m), a 4.53 (2H, d, J=4, 2 Hz), from 5.29 (1H, t, J=4, 2 Hz), 7,73 (1H, d, J=5,2 Hz), 8,49 (1H, s), 8,59 (1H, d, J=5,2 Hz), 9,05 (1H, s)

Comparative example 42

To a solution of 0.18 g (6-methoxy-3-occupied(2,3-b)pyrazin-4(3H)-yl)acetaldehyde in 4 ml of dichloromethane added 0.16 g of tert-butyl (piperidine-4-yl)carbamate and 47 μl of acetic acid and 0.26 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 3 hours. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue, add a simple diethyl ether, methanol and hexane, and the solid product is filtered off with getting to 0.23 g of tert-butyl (1-(2-(6-methoxy-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate in the form of a solid PR is the product of light brown color.

1H-NMR (CDCl3) δ: of 1.25 to 1.47 (2H, m)of 1.44 (9H, s), 1,86-of 1.95 (2H, m), 2,18-of 2.28 (2H, m), 2,70-2,77 (2H, m), 2,93-to 3.02 (2H, m), 3,38-to 3.52 (1H, usher.), as 4.02 (3H, s), 4,35-of 4.44 (1H, m), 4.53-in-4,59 (2H, m), of 6.73 (1H, d, J=8,8 Hz), 8,01 (1H, d, J=8,8 Hz), 8,15 (1H, s)

Comparative example 43

To a suspension of 0.23 g of tert-butyl (1-(2-(6-methoxy-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate in 3 ml of ethyl acetate added to 4.0 ml of 4.0 mol/l solution of hydrochloric acid/ethyl acetate at room temperature. The mixture was stirred at the same temperature for 5 hours and then left overnight. The solvent is distilled off under reduced pressure, to the obtained residue, add a simple diethyl ether, and the solid product is filtered off with getting to 0.23 g of 4-(2-(4-aminopiperidin-1-yl)ethyl)-6-methoxypurine(2,3-b)pyrazin-3(4H)-she hydrochloride in the form of a solid light brown color.

1H-NMR (D2O) δ: 1,88-2,03 (2H, m), 2,32 is 2.43 (2H, m), 3,18-of 3.32 (2H, m), 3,52-3,74 (3H, m), 3,91-Android 4.04 (2H, m), 4,07 (3H, s), 4,87-is 4.93 (2H, m), 6,98 (1H, d, J=8,9 Hz), 8,17 (1H, d, J=8,9 Hz), 8,18 (1H, s)

Comparative example 44

Using the same technology as in Comparative example 1, 7-methyl-1,5-naphthiridine-2(1H)-he obtained from 2-chloro-5-methylpyridin-3-amine and acrylate.

1H-NMR (DMSO-d6) δ: 2,39 (3H, s), of 6.66 (1H, d, J=9.8 Hz), 7,43-7,47 (1H, m), 7,89 (1H, d, J=9.8 Hz), 8,32-to 8.34 (1H, m), 11,81-11,85 (1H, user.)

Comparative example 45

Using the same technology as in Comparative example 3, 1-(1,3-dioxolane-2-ylmethyl)-7-methyl-1,5-naphthiridine-2(1H)-he obtained from 7-methyl-1,5-naphthiridine-2(1H)-it 2-methyl bromide-1,3-dioxolane.

1H-NMR (CDCl3) δ: 2,50 (3H, s), 3,84-3,93 (2H, m), 3,97-4,07 (2H, m), 4,50 (2H, d, J=4, 2 Hz), with 5.22 (1H, t, J=4, 2 Hz), 6.87 in (1H, d, J=9.8 Hz), 7,69-7,73 (1H, m), 7,89 (1H, d, J=9.8 Hz), scored 8.38 (1H, d, J=1.5 Hz)

Comparative example 46

Using the same technology as in Comparative example 4, (7-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde is obtained from 1-(1,3-dioxolane-2-ylmethyl)-7-methyl-1,5-naphthiridine-2(1H)-it.

1H-NMR (DMSO-d6) δ: 2,41 (3H, in), 5.25 (2H, s), 6,83 (1H, d, J=9.8 Hz), 7,73 for 7.78 (1H, m), of 7.97 (1H, d, J=9.8 Hz), scored 8.38-8,42 (1H, m)to 9.70 (1H, s)

Comparative example 47

Using the same technology as in Comparative example 39, 7 bromperidol(2,3-b)pyrazin-2(1H)-he obtained from 5-bromopyridine-2,3-diamine and ethyloxazole.

1H-NMR (DMSO-d6) δ: 7,86 (1H, d, J=2.2 Hz), 8,39 (1H, s), at 8.60 (1H, d, J=2.2 Hz), 12,56-12,64 (1H, user.)

Comparative example 48

To a suspension of 4.0 g of 7-bromperidol(2,3-b)pyrazin-2(1H)-she's in 40 ml of N,N-dimethylformamide type of 8.2 g of a 28% solution of sodium methoxide/methanol and 0.25 g of copper bromide (I) at room temperature and the mixture was stirred at 80-90°C for 3 hours in nitrogen atmosphere. The reaction mixture is cooled to 55°C, to which she added to 2.8 ml of 2-methyl bromide-1,3-dioxolane and the mixture was stirred at 80-90°C for 1 hour and 30 minutes in nitrogen atmosphere. The reaction mixture is cooled to room temperature, and then leave overnight. The mixture is additionally stirred at 80-90°C for 1 hour and then stirred at 90-100°C for 1 hour and 30 minutes. The reaction mixture is cooled to room temperature, and then to it was added ethyl acetate and water. Nerastvorimaya substance is filtered off, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate, and the solvent is then distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of chloroform:methanol = 100:0-95:5, ethyl acetate is added to thus obtained orange oily substance, and the solid product filtered off to obtain 0.12 g of 1-(1,3-dioxolane-2-ylmethyl)-7-methoxypurine(2,3-b)pyrazin-2(1H)-it is in the form of a solid product of orange color.

1H-NMR (CDCl3) δ: 3,84-3,93 (2H, m), 3,93-was 4.02 (2H, m)to 3.99 (3H, s), 4,47 (2H, d, J=3.8 Hz), to 5.21 (1H, t, J=3.8 Hz), 7,39 (1H, d, J=2.7 Hz), at 8.36 (1H, d, J=2.7 Hz), scored 8.38 (1H, s)

Comparative example 49

Using the same technology as in Comparative example 4 (7-methoxy-2-occupied(2,3-b)pyrazin-1(2H)-yl)acetaldehyde is obtained from 1-(1,3-dioxolane-2-ylmethyl)-7-methoxypurine(2,3-)pyrazin-2(1H)-it.

1H-NMR (DMSO-d6) δ: of 3.94 (3H, s), 5,31 (2H, s), of 7.48 (1H, d, J=2.7 Hz), 8,32 (1H, s), with 8.33 (1H, d, J=2.7 Hz), 9,68 (1H, s)

Comparative example 50

To a solution of 0.50 g of 2,6-dichloro-3-nitropyridine in 5 ml of acetonitrile add 0,43 g of potassium carbonate, there was added a solution of 0.24 ml of 2-aminomethyl-1,3-dioxolane in 3 ml of acetonitrile under cooling on ice and the mixture is stirred for 2 hours while cooling on ice. It additionally add 80 ál of 2-aminomethyl-1,3-dioxolane and the mixture is stirred for 2 hours while cooling on ice. To it was added water and ethyl acetate while cooling on ice, the organic layer is separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using as eluent hexane:ethyl acetate = 20:1 with the receipt of 0.44 g of 6-chloro-N-(1,3-dioxolane-2-ylmethyl)-3-nitropyridine-2-amine in the form of a solid yellow color.

1H-NMR (CDCl3) δ: 3,90-4,00 (2H, m), 4,00-4,12 (2H, m), 5,16 (1H, t, J=3.3 Hz), 6,63 (1H, d, J=8.7 Hz), 8,35 (1H, d, J=8.7 Hz), 8,40 at 8.60 (1H, user.)

Comparative example 51

To a suspension of 13 g of iron powder in 650 ml of ethanol and 350 ml of water is added 14 g of sodium chloride and the mixture is heated with reverse holodilniki is, with stirring, for 20 minutes. To it was added 10 g of 6-chloro-N-(1,3-dioxolane-2-ylmethyl)-3-nitropyridine-2-amine at 65°C and the mixture is heated under reflux, with stirring, for 30 minutes. Nerastvorimaya substance is filtered off, the solvent is distilled under reduced pressure to obtain 300 ml, to it was added ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using the eluent of ethyl acetate to obtain 6.5 g of 3-amino-6-chloro-2-(1,3-dioxolane-2-ylmethyl)aminopyridine in the form of a solid light purple color.

1H-NMR (CDCl3) δ: 3.15 in (2H, s), 3,68 (2H, DD, J=6,0, 4,2 Hz), 3,88-3,98 (2H, m), 3,98-4,06 (2H, m), 4,50-4,60 (1H, m), 5,14 (1H, t, J=4, 2 Hz), 6,51 (1H, d, J=7,7 Hz), to 6.80 (1H, d, J=7,7 Hz)

Comparative example 52

Using the same technology as in Comparative example 16, 6-chloro-4-(1,3-dioxolane-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-he obtained from 3-amino-6-chloro-2-(1,3-dioxolane-2-ylmethyl)aminopyridine and ethyloxazole.

1H-NMR (CDCl3) δ: a 3.87-of 3.96 (2H, m), 4,08-4,18 (2H, m), 4,56 (2H, d, J=5.4 Hz), to 5.58 (1H, t, J=5.4 Hz), 7,30 (1H, d, J=8,3 Hz), 8,10 (1H, d, J=8,3 Hz), 8,32 (1H)

Comparative example 53

To a solution of 0.10 g of 6-chloro-4-(1,3-dioxolane-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-it's in 3 ml of N,N-dimethylformamide type of 0.57 g of cesium fluoride and the mixture is stirred at 90-100°C for 1 hour 10 minutes. It additionally adds 0,57 g of cesium fluoride and the mixture is stirred at 90-100°C for 1 hour and 30 minutes. To it was added ethyl acetate and water, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was successively washed with diluted hydrochloric acid and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 50:1 to receive 60 mg of 4-(1,3-dioxolane-2-ylmethyl)-6-torpedo(2,3-b)pyrazin-3(4H)-it is in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 3,86-of 3.96 (2H, m), 4,06-4,16 (2H, m), a 4.53 (2H, d, J=5.4 Hz), 5,54 (1H, t, J=5.4 Hz), 6,91 (1H, DD, J=8,4, 2.4 Hz), of 8.25 (1H, DD, J=8,4, 7,3 Hz), 8,30 (1H, s)

Comparative example 54

Using the same technology as in Comparative example 4, (6-fluoro-3-occupied(2,3-b)pyrazin-4(3H)-yl)acetaldehyde is obtained from 4-(1,3-dioxolane-2-ylmethyl)-6-torpedo(2,3-b)pirate is -3(4H)-it.

1H-NMR (CDCl3) δ: 5,27 (2H, s), 6,93 (1H, DD, J=8,5, 2.4 Hz), 8,30 (1H, DD, J=8,5, 7,1 Hz), a 8.34 (1H, s), of 9.75 (1H, s)

Comparative example 55

Using the same technology as in Comparative example 4, (6-chloro-3-occupied(2,3-b)pyrazin-4(3H)-yl)acetaldehyde is obtained from 6-chloro-4-(1,3-dioxolane-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-it.

1H-NMR (CDCl3) δ: 5,31 (2H, s), 7,32 (1H, d, J=8,3 Hz), 8,15 (1H, d, J=8,3 Hz), at 8.36 (1H, s), 9,76 (1H, s)

Comparative example 56

To a solution of 0.30 g of 6-chloro-4-(1,3-dioxolane-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-she and 78 mg of 1,2,4-triazole in 9 ml of N,N-dimethylformamide added 48 mg of 60% sodium hydride and the mixture was stirred at 40-50°C for 1 hour and 30 minutes. It is additionally added 78 mg of 1,2,4-triazole and 48 mg of 60% sodium hydride and the mixture was stirred at 40-50°C for 1 hour and 30 minutes, and stirred at 60-70°C for 20 minutes. The reaction mixture was loaded mixed solution of ethyl acetate and water and neutralized with 2.0 mol/l hydrochloric acid, and nerastvorimaya substance is filtered off. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure the AI. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 80:20-30:70, and washed with simple diisopropyl ether to obtain 77 mg of 4-(1,3-dioxolane-2-ylmethyl)-6-(1H-1,2,4-triazole-1-yl)pyrido(2,3-b)pyrazin-3(4H)-it is in the form of a solid product light red color.

1H-NMR (CDCl3) δ: 3,86-of 3.96 (2H, m), 4.04 the-4,14 (2H, m), of 4.67 (2H, d, J=4.9 Hz), vs. 5.47 (1H, t, J=4.9 Hz), to 7.93 (1H, d, J=8.5 Hz), 8,16 (1H, s), 8.34 per-of 8.37 (2H, m), 9,19 (1H, s)

Comparative example 57

To a solution of 1.0 g of monoethoxylate in 14 ml of dichloromethane type of 0.47 g of 5,6,7,8-tetrahydroquinoxaline, 91 μl of concentrated sulfuric acid, 1.7 g of sodium persulfate and a suspension of 60 mg of silver nitrate in 14 ml of water and the mixture is heated under reflux, with stirring, for 1 hour 30 minutes. To the reaction mixture additionally add 1.7 g sodium persulfate and 60 mg of silver nitrate and the mixture is heated under reflux for 1 hour and 50 minutes. The reaction mixture was loaded chloroform and the pH adjusted to 7.5 with saturated aqueous sodium bicarbonate solution, nerastvorimaya substance is filtered off and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced on the no. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 90:10-67:33 to obtain 0.16 g of ethyl 5,6,7,8-tetrahydroquinoxalin-2-carboxylate as an oily yellow substance.

1H-NMR (CDCl3) δ: the 1.44 (3H, t, J=7,1 Hz), 1,92 is 2.00 (4H, m), 3.00 and-3,10 (4H, m), 4,50 (2H, square, J=7,1 Hz), of 9.02 (1H, s)

Comparative example 58

To a solution of 0.16 g of ethyl 5,6,7,8-tetrahydroquinoxalin-2-carboxylate in 1.5 ml of tetrahydrofuran added while cooling on ice 29 mg of lithium aluminum hydride, the mixture is stirred for 45 minutes, it additionally added 29 mg of lithium aluminum hydride and the mixture is stirred for 30 minutes. To it was added ethyl acetate and water, nerastvorimaya substance is filtered off, the filtrate add sodium chloride, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.10 g (5,6,7,8-tetrahydroquinoxalin-2-yl)methanol in the form of a solid brown color.

1H-NMR (CDCl3) δ: 1,89-to 1.98 (4H, m), 2,92-a 3.01 (4H, m), was 4.76 (2H, s), with 8.33 (1H, s)

Comparative example 59

Using the same technology as in Comparative example 67, 5,6,7,8-tetrahydroquinoxalin-2-carbaldehyde is obtained from (5,6,7,8-tetrahydroquinoxalin-2-yl)methanol.

1H-NMR (CDCl3) δ: 1,96 is 2.01 (4H, m), 3,03-3,10 (4H, m), 8,91 (1H, s), of 10.09 (1H, s)

Comparative example 60

To a suspension of 1.0 g of 1-(TRIFLUOROACETYL)piperidine-4-amine hydrochloride in 20 ml of dichloromethane added 0.71 g of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 0.25 ml of acetic acid and the mixture is stirred at room temperature for 2 hours. To the reaction mixture of 1.37 g of triacetoxyborohydride sodium and the mixture was stirred at the same temperature for 30 minutes. The solvent is distilled off under reduced pressure, then to it was added water and ethyl acetate, and the pH of the mixture was adjusted to 1.5 using 1 mol/l hydrochloric acid. The aqueous layer was separated and washed with ethyl acetate, to it was added ethyl acetate, and the pH of the aqueous layer was adjusted to 7.8 with saturated aqueous sodium bicarbonate solution. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 1.4 g of N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1-(TRIFLUOROACETYL)PI is uridin-4-amine as a colorless oily substance.

1H-NMR (CDCl3) δ: 1,35 of 1.50 (2H, m), 1,90-2,00 (2H, m), 2,80-is 2.88 (1H, m), 3,02-of 3.12 (1H, m), 3,18 of 3.28 (1H, m), 3,71 (2H, s), 3,90-4,00 (1H, m), 4,25 (4H, s), 4,25-4,32 (1H, m), 6.75 in-6,83 (3H, m)

Comparative example 61

To a solution of 1.4 g of N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1-(TRIFLUOROACETYL)piperidine-4-amine in 20 ml of dichloromethane added 0.88 g of di-tert-BUTYLCARBAMATE and the mixture is stirred at room temperature for 30 minutes. Added to it, and 0.28 ml of triethylamine, the mixture was stirred at the same temperature for 10 minutes, and then add of 0.44 g of di-tert-BUTYLCARBAMATE and the mixture is stirred for 10 minutes. After stirring at 40°C for 30 minutes, the solvent is distilled off under reduced pressure and the resulting residue purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 1:1 to obtain 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-(1-(TRIFLUOROACETYL)piperidine-4-yl) carbamate in the form of a white foam.

1H-NMR (CDCl3) δ: the 1.44 (9H, s), 1.60-to is 1.82 (4H, m), 2,60 is 2.80 (1H, m)3,00-3,20 (1H, m), 3.95 to of 4.05 (1H, m), 4,15-and 4.40 (3H, m), 4,25 (4H, s), 4,50 with 4.65 (1H, m), 6,60 to 6.75 (2H, m), 6,70-of 6.73 (1H, m), 6,79 (1H, d, J=8,3 Hz)

Comparative example 62

To a solution of 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate in 20 ml of methanol, add 5 ml of water and 0,53 g Carbo is ATA potassium and the mixture is stirred at room temperature for 1 hour and 15 minutes. The solvent is distilled off under reduced pressure, and to it was added ethyl acetate and water. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 1.0 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidine-4-yl)carbamate as a pale yellow oily material color.

1H-NMR (CDCl3) δ: of 1.42 (9H, s), 1,35 is 1.70 (4H, m), 2,55-2,70 (2H, m), 3,05 is 3.15 (2H, m), 4,15-of 4.35 (3H, m), 4,24 (4H, s), 6,66-of 6.71 (1H, m), 6.73 x to 6.75 (1H, m), is 6.78 (1H, d, J=8,3 Hz)

Comparative example 63

Using the same technology as in Comparative example 60 N-(2,3-dihydro-1,4-like(2,3-c)pyridine-7-ylmethyl)-1-(TRIFLUOROACETYL)piperidine-4-amine is obtained from 1-(TRIFLUOROACETYL)piperidine-4-amine hydrochloride and 2,3-dihydro-1,4-like(2,3-c)pyridine-7-carbaldehyde.

1H-NMR (CDCl3) δ: 1,39-is 1.51 (2H, m), 1.93 and is 2.01 (2H, m), 2,79-is 2.88 (1H, m), 3,02-3,10 (1H, m), 3,19-of 3.27 (1H, m), 3,80 (2H, s), 3,90-to 3.99 (1H, m), 4,25 is 4.35 (5H, m), to 6.80 (1H, s), 8,11 (1H, s)

Comparative example 64

Using the same technology as in Comparative example 61, tert-butyl (2,3-dihydro-1,4-like(2,3-c)pyridine-7-ylmethyl) (1-(TRIFLUOROACETYL)piperidine-4-yl)carb the Mat is obtained from N-(2,3-dihydro-1,4-like(2,3-c)pyridine-7-ylmethyl)-1-(TRIFLUOROACETYL)piperidine-4-amine.

1H-NMR (CDCl3) δ: USD 1.43 (9H, s), 1,37-of 1.84 (4H, m), 2,60 is 2.80 (1H, m)3,00-3,20 (1H, m), 3,98-4,06 (1H, m), 4,25-to 4.41 (7H, m), 4,54-to 4.62 (1H, m), 6,74 (1H, s), with 8.05 (1H, s)

Comparative example 65

Using the same technology as in Comparative example 62, tert-butyl (2,3-dihydro-1,4-like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate obtained from tert-butyl (2,3-dihydro-1,4-like(2,3-c)pyridine-7-ylmethyl) (1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: of 1.39 (9H, s), 1,34-1,71 (4H, m), 2,52-2,70 (2H, m), 3.04 from-3,11 (2H, m), 4,11-4,48 (7H, m), of 6.75 (1H, s), with 8.05 (1H, s)

Comparative example 66

To a solution of 0.11 kg disodium salt of 5-hydroxy-2-(hydroxymethyl)-1,4-dihydropyridines-4-it is in 600 ml of dimethyl sulfoxide add 0.25 kg of potassium carbonate and 81 ml of 1-bromo-3-chloropropane and the mixture was stirred at 80-90°C for 3 hours and 20 minutes at 90-100°C for 45 minutes, and optionally, at 80-95°C for 5 hours. The reaction mixture is cooled to room temperature, then add water and chloroform, and nerastvorimaya substance is filtered off. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography is as silica gel using eluent chloroform:methanol = 10:1 to obtain 31 g of (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-yl)methanol in the form of oily substance brown.

1H-NMR (CDCl3) δ: 2,23-of 2.30 (2H, m), 4,24-to 4.28 (2H, m), 4,33-4,37 (2H, m), 4,63 (2H, s), PC 6.82 (1H, s), 8,19 (1H, s)

Comparative example 67

To a solution of 13 g of (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-yl)methanol in 250 ml of chloroform, add 13 g of manganese dioxide and the mixture is stirred at room temperature for 30 minutes. It additionally add on parts 20 g of manganese dioxide, the mixture is then stirred at room temperature for 20 minutes and at 60-70°C for 1 hour and 30 minutes. The reaction mixture is cooled to room temperature, nerastvorimaya substance is then filtered off and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 1:1 to obtain 2.2 g of 3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridine-8-carbaldehyde in the form of solid product is a light yellowish-white in color.

1H-NMR (CDCl3) δ: 2,28 to 2.35 (2H, m), 4,36-4,43 (4H, m), 7,53 (1H, s), at 8.36 (1H, s), 9,94 (1H, s)

Comparative example 68

Using the same technology as in Comparative example 60 N-(3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)-1-(TRIFLUOROACETYL)piperidine-4-amine is obtained from 1-(TRIFLUOROACETYL)piperidine-4-amine hydrochloride and 3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridine-8-carbaldehyde.

1H-NMR (CDCl3) δ: 1,39-of 1.52 (2H, m), 1.93 and is 2.01 (2H, m), 2,12-of 2.30 (2H, m), 2,80-is 2.88 (1H, m), 3,01-3,11 (1H, m), 3,18 of 3.28 (1H, m), 3,81 (2H, s), 3,90-to 3.99 (1H, m), 4,21-to 4.38 (5H, m), 6,85 (1H, s), 8,18 (1H, s)

Comparative example 69

Using the same technology as in Comparative example 61, tert-butyl (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl) (1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate obtained from N-(3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)-1-(TRIFLUOROACETYL)piperidine-4-amine.

1H-NMR (CDCl3) δ: of 1.41 (9H, s), 1,55-1,90 (4H, m), 2,20-of 2.30 (2H, m), 2,65 is 2.80 (1H, m), 3.04 from-is 3.21 (1H, m), 3,70-4,50 (8H, m), 4,55 with 4.64 (1H, m), 6,78 (1H, s), 8,13 (1H, s)

Comparative example 70

Using the same technology as in Comparative example 62, tert-butyl (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl) (piperidine-4-yl)carbamate obtained from tert-butyl (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl) (1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,40-1,72 (13H, m), 2,17-of 2.28 (2H, m), 2,50-2,70 (2H, m), 3,01-3,11 (2H, m), 4,10-4,50 (7H, m), 6,79 (1H, s), 8,13 (1H, s)

Comparative example 71

Using the same technology as in Comparative example 1, ethyl (2E)-3-(3-amino-5-chloropyridin-2-yl)acrylate and ethyl (2E)-3-(6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)acrylate are obtained from 2,5-dichloropyridine-3-amine and acrylate.

Ethyl (2E)-3-(3-amino-5-chloropyridin-2-yl)and is relat

1H-NMR (CDCl3) δ: of 1.33 (3H, t, J=7,1 Hz), Android 4.04 (2H, s), 4,27 (2H, square, J=7,1 Hz)6,91 (1H, d, J=15.2 Hz), 7,01 (1H, d, J=2.0 Hz), 7,71 (1H, d, J=15.2 Hz), 8,00 (1H, d, J=2.0 Hz)

Ethyl (2E)-3-(6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)acrylate

1H-NMR (DMSO-d6) δ: of 1.28 (3H, t, J=7,1 Hz), 4,22 (2H, square, J=7,1 Hz), 6,77 (1H, d, J=16.0 Hz), 6,78 (1H, d, J=9.5 Hz), of 7.75 (1H, d, J=16.0 Hz), 7,80-to 7.84 (1H, m), 7,94 (1H, d, J=9.5 Hz), 8,82-8,87 (1H, m), 11,98 (1H, s)

Comparative example 72

Using the same technology as in Comparative example 3 ethyl (2E)-3-(5-(1,3-dioxolane-2-ylmethyl)-6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)acrylate are obtained from ethyl (2E)-3-(6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)acrylate and 2-methyl bromide-1,3-dioxolane.

1H-NMR (CDCl3) δ: to 1.38 (3H, t, J=7,1 Hz), 3,84-3,93 (2H, m), 3.96 points-4,06 (2H, m), 4,32 (2H, square, J=7,1 Hz), a 4.53 (2H, d, J=4,1 Hz), 5,20 (1H, t, J=4,1 Hz), 6,63 (1H, d, J=16.1 Hz), of 6.96 (1H, d, J=9.8 Hz), to 7.77 (1H, d, J=16.1 Hz), to $ 7.91 (1H, d, J=9.8 Hz), 8,03-of 8.06 (1H, m), 8,68 (1H, d, J=1.7 Hz)

Comparative example 73

Using the same technology as in Comparative example 4 ethyl (2E)-3-(6-oxo-5-(2-oxoethyl)-5,6-dihydro-1,5-naphthiridine-3-yl)acrylate are obtained from ethyl (2E)-3-(5-(1,3-dioxolane-2-ylmethyl)-6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)acrylate.

1H-NMR (CDCl3) δ: of 1.36 (3H, t, J=7.2 Hz), 4,30 (2H, square, J=7,2 Hz), 5,19 (2H, s), 6,59 (1H, d, J=16.1 Hz), 7,00 (1H, d, J=9.8 Hz), 7,34-7,38 (1H, m), 7,71 (1H, d, J=16.1 Hz), to 7.99 (1H, d, J=9.8 Hz), 8,72 (1H, d, J=1,5 Hz), 9,79 (1H, s)

Comparative example 74

Using the same technology as in Comparative example 2, 7-chloro-1,5-naphthiridine-2(1H)-he obtained from ethyl (2E)-3-(3-amino-5-chloropyridin-2-yl)acrylate.

1H-NMR (DMSO-d6) δ: 6,77 (1H, d, J=9.8 Hz), 7,70-7,73 (1H, m), 7,94 (1H, d, J=9.8 Hz), 8,49 (1H, d, J=2.2 Hz), 11,95 a 12.05 (1H, user.)

Comparative example 75

Using the same technology as in Comparative example 3 7-chloro-1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-he obtained from 7-chloro-1,5-naphthiridine-2(1H)-it 2-methyl bromide-1,3-dioxolane.

1H-NMR (CDCl3) δ: 3,84-4,06 (4H, m), 4,46 (2H, d, J=4, 2 Hz), 5,20 (1H, t, J=4, 2 Hz), 6,92 (1H, d, J=9.8 Hz), 7,89 (1H, d, J=9.8 Hz), of 7.96 (1H, d, J=2.0 Hz), 8,46 (1H, d, J=2.0 Hz)

Comparative example 76

Using the same technology as in Comparative example 4 (7-chloro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde obtained from 7-chloro-1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-it.

1H-NMR (CDCl3) δ: 5,13 (2H, s), of 6.96 (1H, d, J=9.9 Hz), 7,31-7,33 (1H, m), of 7.96 (1H, d, J=9.9 Hz), 8,51 (1H, d, J=2.0 Hz), 9,78 (1H, s)

Comparative example 77

To a solution of 0.16 g (7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in 2 ml of dichloromethane, 0.14 g of tert-butyl (piperidine-4-yl) carbamate type 41 μl of acetic acid and 0.23 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 1 hour and 30 minutes. The reaction mixture C is Gruaud chloroform and saturated aqueous sodium bicarbonate and the pH adjusted to 8.5, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 19:1 with the receipt of 0.23 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: 1,36 is 1.48 (2H, m)of 1.45 (9H, s), 1,91 of 1.99 (2H, m), 2,22-2,31 (2H, m), 2,61 of 2.68 (2H, m), 2,90-of 2.97 (2H, m), 3,42-of 3.54 (1H, m), 3,98 (3H, s), 4,32-4,47 (3H, m), 6,74 (1H, d, J=9.8 Hz), 7,18 (1H, d, J=2.3 Hz), to 7.84 (1H, d, J=9.8 Hz), of 8.28 (1H, d, J=2.3 Hz)

Comparative example 78

To a solution of 0.23 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 5 ml of ethanol is added at room temperature, 5 ml of 6.0 mol/l solution of hydrochloric acid/ethanol and the mixture is stirred for 1 hour. The solvent is distilled off under reduced pressure, to the obtained residue, add a simple diethyl ether, and the solid product is filtered off with getting to 0.22 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid product light is on yellow.

1H-NMR (D2O) δ: 1,93-2,07 (2H, m), 2,34 is 2.44 (2H, m), 3,20-to 3.33 (2H, m), 3,57-to 3.67 (3H, m), 3,90-4,01 (2H, m), of 4.05 (3H, s), 4,73-4,85 (2H, m), 6.89 in (1H, d, J=9.8 Hz), to 7.50 (1H, d, J=2.3 Hz), of 8.06 (1H, d, J=9.8 Hz), 8,42 (1H, d, J=2.3 Hz)

Comparative example 79

To a solution of 0.15 g of 1,8-naphthiridine-2(1H)-it is in 2 ml of N,N-dimethylformamide add 45 mg of 60% sodium hydride and the mixture was stirred at 50-65°C for 1 hour. To it was added a solution of 0.44 g of 1-tert-butyl-4-ethyl-4-(3-((methylsulphonyl)oxy)propyl)piperidine-1,4-in primary forms in 1.2 ml of N,N-dimethylformamide and the reaction mixture is stirred at 80-90°C for 1 hour and 30 minutes and cooled to room temperature, and then to it was added water and ethyl acetate. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 3:2 with the receipt of 0.29 g of 1-tert-butyl-4-ethyl-4-(3-(2-oxo-1,8-naphthiridine-1(2H)-yl)propyl)piperidine-1,4-in primary forms in the form of a colorless oily substance.

1H-NMR (CDCl3) δ: 1,22 (3H, t, J=7,1 Hz), 1,32-of 1.41 (2H, m)of 1.44 (9H, s), 1,65-1,72 (4H, m), 2.05 is-2,11 (2H, m), 2,80-3,00 (2H, m), 3.75 to 4.00 points (2H, m), 4,13 (2H, square, J=7,1 Hz),4,43-4,48 (2H, m), 6,72 (1H, d, J=9.5 Hz), 7,18 (1H, DD, J=7,7, a 4.7 Hz), the 7.65 (1H, d, J=9.5 Hz), 7,88 (1H, DD, J=7,7, 1.8 Hz), to 8.57 (1H, DD, J=4,7, 1.8 Hz)

Comparative example 80

To a solution of 0.53 g of 1-tert-butyl-4-ethyl-4-(3-(2-oxo-1,8-naphthiridine-1(2H)-yl)propyl)piperidine-1,4-in primary forms in 6 ml of chloroform, add 25 ml triperoxonane acid and the mixture is stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, the obtained residue is added saturated aqueous sodium bicarbonate solution and the mixture is neutralized, and then to it was added chloroform. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to get to 0.47 g of ethyl 4-(3-(2-oxo-1,8-naphthiridine-1(2H)-yl)propyl)piperidine-4-carboxylate as a colorless oily substance.

1H-NMR (CDCl3) δ: 1,22 (3H, t, J=7,1 Hz), 1,45-and 1.54 (2H, m), 1,64-1,71 (4H, m), 2,12-of 2.20 (2H, m), 2,67-2,78 (2H, m), 3,02-is 3.08 (2H, m), 4,14 (2H, square, J=7,1 Hz), to 4.41-4,47 (3H, m), of 6.73 (1H, d, J=9.5 Hz), 7,17 (1H, DD, J=7,6, 4,7 Hz), to 7.64 (1H, d, J=9.5 Hz), 7,87 (1H, DD, J=7,6, 1.7 Hz), to 8.57 (1H, DD, J=4,7) and 1.7 Hz)

Comparative example 81

Using the same technology as in Comparative example 79, 1-tert-butyl 4-ethyl 4-3-(2-oxo-1,7-naphthiridine-1(2H)-yl)propyl)piperidine-1,4 -, in primary forms derived from 1,7-naphthiridine-2(1H)-it 1-tert-butyl-4-ethyl-4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-in primary forms.

1H-NMR (CDCl3) δ: 1,20-1,74 (9H, m)of 1.44 (9H, s), is 2.05 and 2.13 (2H, m), 2,74-2,95 (2H, m), of 3.77-of 3.95 (2H, m), 4,14 (2H, square, J=7,1 Hz), 4.26 deaths-or 4.31 (2H, m), 6.89 in (1H, d, J=9.5 Hz), the 7.43 (1H, d, J=5,1 Hz), the 7.65 (1H, d, J=9,5 Hz), to 8.45 (1H, d, J=5,1 Hz), a total of 8.74 (1H, s)

Comparative example 82

To a solution of 0.50 g of 1-tert-butyl 4-ethyl 4-(3-(2-oxo-1,7-naphthiridine-1(2H)-yl)propyl)piperidine-1,4-in primary forms in 3 ml ethanol add 3.0 ml of 4.0 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 1 hour. To it was added 2.0 ml of 4.0 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 1 hour. The solid product is filtered off with getting to 0.29 g of ethyl 4-(3-(2-oxo-1,7-naphthiridine-1(2H)-yl)propyl)piperidine-4-carboxylate hydrochloride in the form of solid product is a light yellow color.

1H-NMR (DMSO-d6) δ: 1,11 (3H, t, J=7,1 Hz), 1,48 is 1.58 (2H, m), 1,62-1,72 (4H, m), 2,03-2,11 (2H, m), 2,70-2,82 (2H, m), 3,14-of 3.25 (2H, m), 4,07 (2H, square, J=7,1 Hz), 4,24-4,30 (2H, m), 7,03 (1H, d, J=9.5 Hz), 8,02 (1H, d, J=5.4 Hz), of 8.09 (1H, d, J=9.5 Hz), 8,54 (1H, d, J=5.4 Hz), 8,88-9,07 (2H, m), 9,17 (1H, s)

Comparative example 83

To a solution of 1.2 ml of Diisopropylamine in 20 ml of tetrahydrofuran, 5.8 ml is added dropwise a 1.6 mol/l solution bouthillette/hexane at -78°C and the mixture was stirred at the same temperature for 1 hour. To it was added dropwise a solution of 2.0 g of 1-tert-butyl-4-ailpipe the one-1,4-in primary forms in 2 ml of tetrahydrofuran and the mixture is stirred for 1 hour. To it was added 1.7 ml of a simple benzyl-3-bromopropionic ether, and the temperature of the reaction mixture was raised to room temperature and the mixture is stirred for 10 hours. A mixture of loads of water and the pH adjusted to 2.0 with 6 mol/l hydrochloric acid. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 10:1 to obtain 2.0 g of 1-tert-butyl 4-ethyl 4-(3-(benzyloxy)propyl)piperidine-1,4-in primary forms in the form of a colorless oily substance.

1H-NMR (CDCl3) δ: of 1.25 (3H, t, J=7.2 Hz), 1,25-1,45 (2H, m)of 1.45 (9H, s), 1,50-of 1.65 (4H, m), 2.05 is-of 2.15 (2H, m), 2,75-3,00 (2H, m), 3,42 (2H, t, J=6,1 Hz), 3.75 to of 3.95 (2H, m)to 4.16 (2H, square, J=7,2 Hz), 4,47 (2H, s), 7,26-7,37 (5H, m)

Comparative example 84

To a solution of 2.0 g of 1-tert-butyl 4-ethyl 4-(3-(benzyloxy)propyl)piperidine-1,4-in primary forms in 20 ml of ethanol is added a suspension of 0.30 g of 10% palladium on coal in 2 ml of ethanol and the mixture is stirred for 4 hours in hydrogen atmosphere. Nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure obtained with the eating of 1.7 g of 1-tert-butyl-4-ethyl-4-(3-hydroxypropyl)piperidine-1,4-in primary forms in the form of a colorless oily substance.

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=7.2 Hz), 1,23-of 1.62 (6H, m)of 1.45 (9H, s), 2,05-of 2.15 (2H, m), 2,80-2,95 (2H, m), to 3.58-3,63 (2H, m), 3.75 to of 3.95 (2H, m), 4,18 (2H, square, J=7,2 Hz)

Comparative example 85

To a solution of 1.7 g of 1-tert-butyl 4-ethyl 4-(3-hydroxypropyl)piperidine-1,4-in primary forms in 20 ml of tetrahydrofuran type of 0.82 ml of triethylamine and of 0.58 ml methanesulfonyl chloride at 5°C and the mixture is stirred at room temperature for 1 hour. To it was added ethyl acetate and water. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 1.9 g of 1-tert-butyl-4-ethyl-4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-in primary forms in the form of a colorless oily substance.

1H-NMR (CDCl3) δ: 1.25 and about 1.75 (6H, m)of 1.28 (3H, t, J=7.2 Hz), a 1.45 (9H, s), 2,05-of 2.15 (2H, m), 2,80-2,95 (2H, m)of 3.00 (3H, s), 3,80-of 3.95 (2H, m), 4,19 (2H, square, J=7,2 Hz), 4,15-4,22 (2H, m)

Comparative example 86

In 184 ml of 80% triperoxonane acid are dissolved 4,60 g of 1-(1,3-dioxolane-2-ylmethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she, and the resulting solution was stirred at room temperature for 11 hours and at 60°C for 3.5 hours. The reaction mixture was loaded chloro what Orme and alkalinized with 10% aqueous sodium hydroxide solution while cooling on ice. The organic layer is separated and washed with an aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain (7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in the form of a solid yellow color.

In 58 ml of chloroform is dissolved received (7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde, add 2.67 g of tert-butyl (piperidine-4-yl)carbamate and 0.80 g of acetic acid and the mixture is stirred at room temperature for 1.5 hours. To the reaction mixture to 4.23 g triacetoxyborohydride sodium and the mixture is stirred for 15 hours. To it was added a saturated aqueous solution of sodium bicarbonate and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Silica Gel 60N, production KANTO CHEMICAL CO., INC. and eluent chloroform:methanol = 10:1 to receive 4,36 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of a solid white product.

1H-NMR (CDCl3) δ: 1,38-of 1.44 (2H, m)of 1.45 (9H, s), 1,90-2,00 (2H, m), 2.21 are of 2.30 (2H, m), 2,59-2,70 (2H, m), 2,87-to 2.99 (2H, m), 3.43 points-of 3.54 (1H, m), 3,98 (3H, s), 4,29-to 4.38 (2H, m), 4,40-of 4.49 (1H, m), 6,74 (1H, d, J=9.6 Hz), 7,16-7,19 (1H, m), to 7.84 (1H, d, J=9.6 Hz), of 8.28 (1H, d, J=2.3 Hz)

Comparative example 87

To a solution 4,36 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 50 ml of chloroform, add 10 ml triperoxonane acid and the mixture is stirred at room temperature for 1 hour. After that, the solvent is distilled off under reduced pressure, the reaction mixture is alkalinized with saturated aqueous sodium bicarbonate solution, then the solvent is distilled off under reduced pressure and the resulting residue purified by column chromatography on silica gel using silica gel: Chromatorex-NH production of Fuji Silysia Chemical Ltd., and eluent chloroform:methanol = 10:1 to obtain 2.16 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: 1,39 (4H, m), 1,81 is 1.86 (2H, m), 2,17-of 2.24 (2H, m), 2,63-by 2.73 (3H, m), 2.95 and 3.00 for (2H, m), 3,98 (3H, s), 4,34-4,39 (2H, m), of 6.75 (1H, d, J=9.6 Hz), 7.23 percent (1H, d, J=2.3 Hz), to 7.84 (1H, d, J=9.6 Hz), 8,28 (1H, d, J=2.3 Hz)

Comparative example 88

In 50 ml of chloroform is dissolved to 5.00 g of 3-bromo-1,5-naphthiridine, they added 6,40 g of m-chloroperbenzoic acid and the mixture is stirred at room temperature for 1.5 hours. To the reaction mixture are added 5% aqueous sodium thiosulfate solution and chloroform, and the organic layer on the make, sequentially washed with 5% aqueous sodium hydroxide solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Chromatorex-NH, the production of Fuji Silysia Chemical Ltd. and eluent ethyl acetate:hexane = 1:1, receipt of 1.95 g of 3-bromo-1,5-naphthiridine-5-oxide in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: at 7.55 (1H, DD, J=8,7, 6,0 Hz), to 7.99 (1H, d, J=8.7 Hz), 8,55 (1H, d, J=6.0 Hz), 9,04 (1H, d, J=2.3 Hz), 9,23 (1H, d, J=2.3 Hz)

Comparative example 89

To a solution of 0.50 g of 3-bromo-1,5-naphthiridine-5-oxide in 10 ml of chloroform added 0.51 g of p-toluensulfonate, 1.04 g of potassium carbonate and 3 ml of water and the mixture is stirred at room temperature overnight. To it was added water and chloroform, and the solid product filtered off to obtain 0.39 g of 7-bromo-1,5-naphthiridine-2(1H)-it is in the form of a solid white product.

1H-NMR (DMSO-d6) δ: 6,77 (1H, d, J=9.6 Hz), the 7.85-7,87 (1H, m), of 7.90 (1H, d, J=9.6 Hz), 8,53 (1H, d, J=1,8 Hz), of 11.69-12,50 (1H, m)

Comparative example 90

In 5 ml of N,N-dimethylformamide is dissolved 770 mg of 7-bromo-1,5-naphthiridine-2(1H)-add 278 mg of 60% sodium hydride and the mixture is stirred at room temperature in the course is 1 hour. To it was added within 4 days of 1.1 ml of 2-methyl bromide-1,3-dioxolane at 110°C. the Reaction mixture is cooled to room temperature, and then add ethyl acetate and 1 mol/l hydrochloric acid. The organic layer was separated, sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Silica Gel 60 manufactured KANTO CHEMICAL CO., INC. and eluent ethyl acetate:hexane 2:1 to receive 467 mg of 7-bromo-1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-it is in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: a 3.87-3,91 (2H, m), 4,00-a 4.03 (2H, m), 4,46 (2H, d, J=4,1 Hz), 5,20 (1H, t, J=4,1 Hz)6,94 (1H, d, J=9.6 Hz), 7,86-7,89 (1H, m), 8,11 (1H, d, J=1,8 Hz), 8,56 (1H, d, J=1,8 Hz)

Comparative example 91

In 10 ml of suspended 1-methyl-2-pyrrolidinone, 358 mg of 7-bromo-1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-she and 183 mg of copper cyanide, and the suspension is heated under reflux for 70 minutes. The reaction mixture is cooled to room temperature, then to it was added ethyl acetate, the mixture was sequentially washed with water and saturated aqueous saline solution and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. According to the scientists the residue purified by column chromatography on silica gel using silica gel: Silica Gel 60 manufactured KANTO CHEMICAL CO., INC. and eluent ethyl acetate:hexane 1:1 to obtain 145 mg of 7-cyano-1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-it is in the form of a solid yellow color.

1H-NMR (CDCl3) δ: a 3.87-are 3.90 (2H, m), 3,98-was 4.02 (2H, m), of 4.49 (2H, d, J=4,1 Hz)to 5.17 (1H, t, J=4,1 Hz), 7,06 (1H, d, J=9.6 Hz), 7,95 (1H, d, J=9.6 Hz), 8,23-8,24 (1H, m), 8,72 (1H, d, J=1,8 Hz)

Comparative example 92

In 5 ml of 90% triperoxonane acid are dissolved 215 mg of 7-cyano-1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-she, and the resulting solution was stirred at 60°C for 7 hours. After cooling the reaction mixture to room temperature and alkalizing with 10% aqueous sodium hydroxide solution, the solvent is then distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Silica Gel 60 manufactured KANTO CHEMICAL CO., INC. and eluent ethyl acetate:hexane = 1:1, and washed with water to obtain 90 mg of (7-cyano-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 5,19 (2H, s), 7,09-7,11 (1H, m), 7,52-7,53 (1H, m), 8,02 (1H, d, J=9.6 Hz), 8,76 (1H, d, J=1.4 Hz), 9,83 (1H, s)

Comparative example 93

To a solution of 83 mg of (7-cyano-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and 80 mg of tert-butyl piperidine-4-yl-carbamate in 10 ml of chloroform, add 24 ál of acetic acid ismes stirred at room temperature for 1.5 hours. To the reaction mixture are added 136 mg triacetoxyborohydride sodium and the mixture is stirred for 1.5 hours. To the reaction mixture is added saturated aqueous sodium bicarbonate solution and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Chromatorex-NH production Fuji Silysia Chemical Ltd. and eluent ethyl acetate:hexane = 1:1 to obtain 76 mg of tert-butyl (1-(2-(7-cyano-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of a solid brown color.

1H-NMR (CDCl3) δ: 1,33-of 1.39 (2H, m)of 1.44 (9H, s), 1,92-of 1.97 (2H, m), 2,22-of 2.28 (2H, m), 2,64 of 2.68 (2H, m), 2,85-2,90 (2H, m), 3.46 in-3,51 (1H, m), 4,30 is 4.35 (2H, m), to 4.41 is 4.45 (1H, m), 7,05 (1H, d, J=9.6 Hz), 7,94 (1H, d, J=9.6 Hz), 8,12-of 8.15 (1H, m), 8,72 (1H, d, J=1.4 Hz)

Comparative example 94

To a solution of 3.15 g of 3-chloro-6-methoxypyrazine-2-amine in 20 ml of triethylamine added to 2.6 ml of ethyl acrylate and 0.50 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred at an external temperature of 120-130°C for 2 hours in a sealed tube. It additionally add 5 ml of triethylamine and the mixture was stirred at the same temperature for 4 hours and 50 minutes. The reaction mixture is cooled to room temperature and left overnight, then add 0.5 ml of ethyl acrylate and 0.25 g of bis(tri-tert-butylphosphine)palladium(0) and a mixture of AC who're asked when the external temperature of 115-125°C for 9 hours and 20 minutes in a sealed tube. The reaction mixture is cooled to room temperature, then add water and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 4:1 to obtain 2.55 g of ethyl (2E)-3-(3-amino-5-methoxypyrazine-2-yl)acrylate in the form of a solid yellow color.

1H-NMR (CDCl3) δ: of 1.32 (3H, t, J=7,1 Hz), 3,91 (3H, s), 4.26 deaths (2H, square, J=7,1 Hz), 4.72 in (2H, s), of 6.73 (1H, d, J=15.1 Hz), to 7.61-to 7.68 (2H, m)

Comparative example 95

To a solution of 0.85 g of ethyl (2E)-3-(3-amino-5-methoxypyrazine-2-yl)acrylate in 40 ml of ethanol is added 2.20 g of 28% solution of sodium methoxide/methanol and the mixture is heated under reflux, with stirring, for 7 hours and 30 minutes. The reaction mixture is cooled to room temperature, then the solvent is distilled off under reduced pressure, and to the obtained residue, add water, a saturated aqueous solution of ammonium chloride and chloroform, the organic layer is separated, and the aqueous layer add sodium chloride, and extracted with chloroform. The organic layer and EXT the act unite, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue, add a simple diethyl ether, and the solid product filtered off and washed with simple diethyl ether to obtain 0.64 g of 3-methoxypyridine(2,3-b)pyrazin-6(5H)-it is in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 4,06 (3H, s), 6,72 (1H, d, J=9.8 Hz), 7,92 (1H, d, J=9.8 Hz), 8,13 (1H, s)9,68 (1H, s)

Comparative example 96

To a solution of 0.30 g of 3-methoxypyridine(2,3-b)pyrazin-6(5H)-she's in 6 ml N,N-dimethylformamide added 0.35 g of potassium carbonate and the mixture was stirred at 65-75°C for 10 minutes. It adds to 0.21 ml of 2-methyl bromide-1,3-dioxolane and the mixture was stirred at 95-100°C for 1 hour and 30 minutes. It additionally add 0.05 ml of 2-methyl bromide-1,3-dioxolane and 120 mg of potassium carbonate and the mixture was stirred at 95-100°C for 2 hours and 15 minutes. The reaction mixture is cooled to room temperature, and then to it was added water and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts are combined and the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. the received residue purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 2:1 with the receipt of 0.13 g of 5-(1,3-dioxolane-2-ylmethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-it is in the form of a solid product yellow.

1H-NMR (CDCl3) δ: 3,88-to 3.92 (2H, m), 4,06-4,12 (5H, m), 4,63 (2H, d, J=5,1 Hz), the 5.51 (1H, t, J=5,1 Hz), 6,78 (1H, d, J=9.8 Hz), the 7.85 (1H, d, J=9.8 Hz), to 8.12 (1H, s)

Comparative example 97

To 0.12 g of 5-(1,3-dioxolane-2-ylmethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-it add 5 ml of 90% aqueous solution triperoxonane acid and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction mixture is added saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.12 g (3-methoxy-6-occupied(2,3-b)pyrazin-5(6H)-yl)acetaldehyde in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 3,99 (3H, s), of 5.24 (2H, s), PC 6.82 (1H, d, J=9.8 Hz), 7,94 (1H, d, J=9.8 Hz), 8,15 (1H, s), 9,71 (1H, s)

Comparative example 98

Using the same technology as in Comparative example 60, 1-(4-benzylmorphine-2-yl)-N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)methanamine obtained from 1-(4-benzylmorphine-2-yl)methanamine and 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde.

Using the same technology as in eunicella example 61, tert-butyl ((4-benzylmorphine-2-yl)methyl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate is obtained from 1-(4-benzylmorphine-2-yl)-N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)methanamine.

1H-NMR (CDCl3) δ: 1,34-for 1.49 (9H, m), 1,81-of 1.93 (1H, m), 2,09-to 2.18 (1H, m), 2,56-of 2.66 (1H, m), 2,70-2,77 (1H, m), 3,20-of 3.85 (7H, m), 4,23-of 4.35 (4H, m), 4,37 with 4.64 (2H, m), 6,68-6,74 (1H, m), 7,20 and 7.36 (5H, m), 8,07 (1H, s)

Comparative example 99

Using the same technology as in Comparative example 25, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(morpholine-2-ylmethyl)carbamate is obtained from tert-butyl ((4-benzylmorphine-2-yl)methyl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate.

1H-NMR (CDCl3) δ: 1,35-of 1.57 (9H, m), 2,75-3,10 (2H, m), 3.25 to of 3.56 (4H, m), 3,93-4,19 (3H, m), 4,25-of 4.44 (4H, m), 4,46-of 4.67 (2H, m), 6,70-6,92 (1H, m), 8,10-8,19 (1H, m), 9,80 is 10.4 (1H, user.)

Comparative example 100

To a solution of 0.62 g of 2,6-dichloro-3-fluoro-5-((methoxyethoxy)methyl)pyridine in 18 ml of N,N-dimethylformamide added 0.54 ml of triethylamine, 0.15 ml of formic acid and 0.15 g of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 90-100°C for 4 hours and 30 minutes in nitrogen atmosphere. To it was added water and ethyl acetate, nerastvorimaya substance is filtered off, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine received rastvorosmesitelnoj washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 8:1 to obtain 0.39 g of 2-chloro-5-fluoro-3-((methoxyethoxy)methyl)pyridine as a colorless oily substance.

1H-NMR (CDCl3) δ: 3.43 points (3H, s)and 4.65 (2H, d, J=0.8 Hz), 4,80 (2H, s), 7,66 (1H, DD, J=8,4, 3.0 Hz), 8,18 (1H, d, J=3.0 Hz)

Comparative example 101

To a solution of 0.10 g of 2-chloro-5-fluoro-3-((methoxyethoxy)methyl)pyridine in 3 ml of dioxane is added 0.20 g of potassium carbonate, 68 μl of trimethylboroxine and 56 mg of tetrakis(triphenylphosphine)palladium(0) and the mixture heated under reflux, with stirring, for 2 hours in nitrogen atmosphere. To it was added 0.20 g of potassium carbonate, 68 μl of trimethylboroxine and 56 mg of tetrakis(triphenylphosphine)palladium(0) and the mixture heated under reflux, with stirring, for 2 hours in nitrogen atmosphere. To it was added 0.20 g of potassium carbonate, 68 μl of trimethylboroxine and 56 mg of tetrakis(triphenylphosphine)palladium(0) and the mixture heated under reflux, with stirring, for 1 hour in nitrogen atmosphere. Nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 100:1 to obtain 93 mg bestv what these oily substances. The substance is purified by column chromatography on basic silica gel using the eluent of chloroform to obtain 64 mg of 5-fluoro-3-((methoxyethoxy)methyl)-2-methylpyridine as a colorless oily substance.

1H-NMR (CDCl3) δ: 2.49 USD (3H, s), 3,42 (3H, s), 4,58 (2H, s), was 4.76 (2H, s), 7,47 (1H, DD, J=9,2, 2.7 Hz), of 8.27 (1H, d, J=2.7 Hz)

Comparative example 102

To a solution of 0.49 g of 5-fluoro-3-((methoxyethoxy)methyl)-2-methylpyridine in 20 ml of dioxane is added 10 ml of 6.0 mol/l hydrochloric acid and the mixture is stirred at 30-40°C for 1 hour. To it was added water and ethyl acetate, and the pH of the mixture was adjusted to 5.5 with 20% aqueous sodium hydroxide solution and saturated aqueous sodium bicarbonate solution. The organic layer is separated and the aqueous layer was extracted with ethyl acetate twice. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to get 0,41 g (5-fluoro-2-methylpyridin-3-yl)methanol as a pale yellow oily material color.

1H-NMR (CDCl3) δ: 2,40 (1H, t, J=5,2 Hz), the 2.46 (3H, s), 4.72 in (2H, d, J=5,2 Hz), 7,53 (1H, DD, J=9,1, 2.6 Hz), 8,24 (1H, d, J=2,6 Hz)

Comparative example 103

To a solution of 32 mg (5-fluoro-2-methylpyridin-3-yl)methanol is in 2 ml of dichloromethane added 80 mg of molecular sieve 3A and 40 mg of 4-methylmorpholine N-oxide and the mixture is stirred at room temperature for 30 minutes. To it was added 6.0 mg of tetrapropylammonium of perruthenate and the mixture is stirred at room temperature for 1 hour and 30 minutes. Nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 100:1 to receive 20 mg of 5-fluoro-2-methylnicotinamide in the form of a colorless oily substance.

1H-NMR (CDCl3) δ: 2,87 (3H, d, J=1.0 Hz), 7,81 (1H, DD, J=8.0 a, 3,0 Hz), 8,56 (1H, d, J=3.0 Hz), 10,33 (1H, d, J=2.2 Hz)

Comparative example 104

To a suspension of 77 mg of sodium hydride in 2 ml of N,N-dimethylformamide type of 0.13 g of imidazole and the mixture is stirred at room temperature for 10 minutes. To the reaction mixture in parts add 0.20 g of 7-bromo-1-((1,3-dioxolane-2-yl)methyl)-1,5-naphthiridine-2(1H)-it, and then there was added 18 mg of copper oxide (II). The reaction mixture was stirred at 135-140°C for 30 minutes. The reaction mixture is cooled to room temperature, then to it was added chloroform and water, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue, add the mixed solvent is simple diethyl ether:ethyl acetate (3:1), and the solid product filtered off to obtain 0.12 g of 1-((1,3-dioxolane-2-yl)methyl)-7-(1H-imidazol-1-yl)-1,5-naphthiridine-2(1H)-it is in the form of a solid yellow color.

1H-NMR (CDCl3) δ: 3,86-4,20 (4H, m), 4,55 (2H, d, J=4.0 Hz), is 5.18 (1H, t, J=4.0 Hz), 6,97 (1H, d, J=9.9 Hz), 7,32 (1H, s), 7,40 (1H, s), 7,95 (1H, d, J=9.9 Hz), 7,98 (1H, s), 8,01 (1H, d, J=2.1 Hz), 8,65 (1H, d, J=2.1 Hz)

Comparative example 105

To 0.12 g of 1-((1,3-dioxolane-2-yl)methyl)-7-(1H-imidazol-1-yl)-1,5-naphthiridine-2(1H)-it add 2 ml of 80% aqueous solution triperoxonane acid at room temperature and the mixture was stirred at 50-60°C for 1 hour and 30 minutes. The reaction mixture is cooled to room temperature, and then the solvent is distilled off under reduced pressure. The resulting residue loaded chloroform and water and the pH adjusted to 7.8 using 20% aqueous sodium hydroxide solution. The organic layer is separated and the aqueous layer was extracted with chloroform, and then further extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.12 g (7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in the form of a solid yellow color.

1H-NMR (DMSO-d6) δ: to 5.35 (2H, s), 6,92 (1H, d, J=9.8 Hz), 7,20 (1H, s), 7,22 (1H, s), of 8.00 (1H, s), with 8.05 (1H, d, J=9.8 Hz), to 8.12 (1H, d, J=2.2 Hz), 8,96 (1H, d, J=22 Hz), to 9.70 (1H, s)

Comparative example 106

Using the same technology as in Comparative example 60, benzyl (3R,4R)-4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-3-hydroxypiperidine-1-carboxylate is obtained from benzyl (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate and 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde.

Using the same technology as in Comparative example 61, benzyl (3R,4R)-4-((tert-butoxycarbonyl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-3-hydroxypiperidine-1-carboxylate is obtained from benzyl (3R,4R)-4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-3-hydroxypiperidine-1-carboxylate.

Using the same technology as in Comparative example 25, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)((3R,4R)-3-hydroxypiperidine-4-yl)carbamate obtained from benzyl (3R,4R)-4-((tert-butoxycarbonyl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-3-hydroxypiperidine-1-carboxylate.

1H-NMR (CDCl3) δ: 1,28-of 1.57 (9H, m), 1,90-to 2.40 (2H, m), 2,70-3,10 (2H, m), 3.43 points-of 3.80 (2H, m), 4,00 is 4.35 (2H, m), 4,40-4,86 (6H, m), 7,20-7,40 (1H, m), 8,23-8,39 (1H, m), 9,10-9,90 (2H, m)

Comparative example 107

Using the same technology as in Comparative example 42, tert-butyl (1-(2-(3-methoxy-6-occupied(2,3-b)pyrazin-5(6H)-yl)ethyl)piperidine-4-yl)carbamate is obtained from (3-methoxy-6-occupied(2,3-b)PI is Azin-5(6H)-yl)acetaldehyde and tert-butyl piperidine-4-ylcarbamate.

1H-NMR (CDCl3) δ: 1,30-1,50 (11H, m), 1,87 is 1.96 (2H, m), 2,18-of 2.30 (2H, m), 2,66-to 2.74 (2H, m), 2,94-of 3.06 (2H, m), 3,39-to 3.52 (1H, m)4,06 (3H, s), 4,34-to 4.46 (1H, m), 4.53-in-br4.61 (2H, m), 6,76 (1H, d, J=9.6 Hz), to 7.84 (1H, d, J=9.6 Hz), 8,11 (1H, s)

Comparative example 108

Using the same technology as in Comparative example 65, 5-(2-(4-aminopiperidin-1-yl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-he hydrochloride is obtained from tert-butyl (1-(2-(3-methoxy-6-occupied(2,3-b)pyrazin-5(6H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (DMSO-d6) δ: 1,88-of 2.20 (4H, m), 3,05-3,19 (2H, m), 3,20-3,68 (3H, m), 3,71-3,82 (2H, m), 4,11 (3H, s), 4,68-4,78 (2H, m), 6,77 (1H, d, J=9.6 Hz), 8,01 (1H, d, J=9.6 Hz), 8,29 (1H, s), 8,30 is 8.38 (3H, usher.), of 10.58-10,70 (1H, user.)

Comparative example 109

To 2.9 g of 5-chloro-2-methoxypyridine-4-amine type of 2.35 ml of ethyl acrylate, 18 ml of triethylamine and 0.46 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture is stirred at ambient temperature 115-130°C for 5 hours in a sealed tube. It additionally add 5 ml of triethylamine, 0,30 g of bis(tri-tert-butylphosphine)palladium(0) and 0.5 ml of ethyl acrylate, and the mixture was stirred at an external temperature of 120-130°C for 6 hours and 30 minutes in a sealed tube. The reaction mixture is cooled to room temperature and to it was added water and ethyl acetate. The organic layer is separated and the aqueous layer was extracted with chloroform and ethyl acetate. Organic SL the St and the extract combined the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 1:1 with the receipt of 0.89 g of ethyl (2E)-3-(4-amino-2-methoxypyridine-5-yl)acrylate in the form of a solid yellow color.

1H-NMR (CDCl3) δ: of 1.33 (3H, t, J=7,1 Hz), of 3.95 (3H, s), 4.26 deaths (2H, square, J=7,1 Hz), the 5.45 (2H, s), 6,28 (1H, d, J=16.1 Hz), EUR 7.57 (1H, d, J=16.1 Hz), 8,29 (1H, s)

Comparative example 110

To a solution of 0.87 g of ethyl (2E)-3-(4-amino-2-methoxypyridine-5-yl)acrylate in 50 ml of methanol add 2,31 g of a 28% solution of sodium methoxide/methanol at room temperature and the mixture is heated under reflux, with stirring, for 4 hours. The reaction mixture is cooled to room temperature, and then the solvent is distilled off under reduced pressure. To the obtained residue is added saturated aqueous solution of ammonium chloride and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The thus obtained solid product is washed with simple diethyl ether to obtain 0.55 g of 2-methoxypyridine(2,3-d)pyrimidine-7(8H)-she's in VI is e solid yellow color.

1H-NMR (CDCl3) δ: 4,07 (3H, s), 6,56 (1H, d, J=9.5 Hz), to 7.68 (1H, d, J=9.5 Hz), 8,68 (1H, s), to 9.32 (1H, s)

Comparative example 111

To a suspension of 0.50 g of 2-methoxypyridine(2,3-d)pyrimidine-7(8H)-she's in 7.5 ml of N,N-dimethylformamide type of 0.59 g of potassium carbonate at room temperature, the temperature was raised up to 60-80°C and the mixture is stirred for 1 hour. To it was added 0.35 ml of 2-methyl bromide-1,3-dioxolane at 80°C, the temperature of the reaction mixture increased to 103°C and the mixture is stirred for 3 hours 30 minutes. The reaction mixture is cooled to room temperature and to it was added water and chloroform. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 75:1 with the receipt of 0.60 g of 8-(1,3-dioxolane-2-ylmethyl)-2-methoxypyridine(2,3-d)pyrimidine-7(8H)-it is in the form of a solid yellow color.

1H-NMR (CDCl3) δ: a 3.87-of 3.95 (2H, m), 4,05 is 4.13 (2H, m), 4.09 to (3H, s), 4,59 (2H, d, J=5,1 Hz), 5,52 (1H, d, J=5,1 Hz), 6,60 (1H, d, J=9.5 Hz), a 7.62 (1H, d, J=9.5 Hz), 8,65 (1H, s)

Comparative example 112

To 0.20 g of 8-(1,3-d is oxolan-2-ylmethyl)-2-methoxypyridine(2,3-d)pyrimidine-7(8H)-it add 5 ml of 80% aqueous solution triperoxonane acid and the mixture is stirred at room temperature for 8 hours. To the reaction mixture is added saturated aqueous sodium bicarbonate solution and chloroform. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.21 g (2-methoxy-7-occupied(2,3-d)pyrimidine-8(7H)-yl)acetaldehyde in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: Android 4.04 (3H, in), 5.25 (2H, s), only 6.64 (1H, d, J=9.5 Hz), 7,72 (1H, d, J=9.5 Hz), 8,71 (1H, s), 9,72 (1H, s)

Comparative example 113

To a solution of 0.65 g of tert-butyl 3-(aminomethyl)piperidine-1-carboxylate in 5 ml of dichloromethane added 0.50 g (2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde and 0.17 ml of acetic acid. Then added 0.96 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 1 hour and 15 minutes. The reaction mixture was loaded chloroform and the pH adjusted to 8.6 with saturated aqueous sodium bicarbonate solution and 20% aqueous sodium hydroxide solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous is magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 1.3 g of tert-butyl 3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)piperidine-1-carboxylate as an oily yellow substance.

1H-NMR (CDCl3) δ: 1,12-of 1.92 (5H, m)of 1.45 (9H, s), 2,20-of 2.72 (3H, m), 2,80-2,90 (1H, m), of 3.78 (2H, s), 3,78-3,98 (2H, m), 4,22 is 4.35 (4H, m), at 6.84 (1H, s), 8,10 (1H, s)

Comparative example 114

To a solution of 1.3 g of tert-butyl 3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)piperidine-1-carboxylate in 10 ml of methanol is added 0.54 ml of ethyltryptamine and the mixture is stirred at room temperature for 2 hours and then stirred at 40-45°C for 3 hours. To it was added 0.54 ml of ethyltryptamine and the mixture is heated under reflux, with stirring, for 3 hours. The mixture is cooled to room temperature, and then the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 1:1 with the receipt of 0.47 g of tert-butyl 3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(TRIFLUOROACETYL)amino)methyl)piperidine-1-carboxylate as a colorless oily substance.

1H-NMR (CDCl3) δ: 1,07 is 2.10 (5H, m)of 1.44 (9H, s), 2,58-of 2.66 (1H, m), 2,70-and 2.79 (1H, m), 3,20-3,50 (2H, m), of 3.80-4.00 points (2H, m), 4.26 deaths is 4.36 (4H, m), 4,58-and 4.68 (2H, m), of 6.66 (1H, s), 8,11 (1H, s)

Comparative example 115

To a solution of 0.43 g of tert-butyl 3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(TRIFLUOROACETYL)-amino)methyl)piperidine-1-carboxylate in 3 ml of chloroform DOB is given in 3 ml triperoxonane acid and the mixture is stirred at room temperature for 1 hour and 40 minutes. The solvent is distilled off under reduced pressure. The resulting residue loaded chloroform and water and the pH adjusted to 8.0 with aqueous sodium bicarbonate solution and 20% aqueous sodium hydroxide solution. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.15 g of N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)-2,2,2-Cryptor-N-(piperidine-3-ylmethyl)ndimethylacetamide in the form of a light yellow oily material color.

1H-NMR (CDCl3) δ: 1,08-of 1.26 (1H, m), 1,48-of 1.62 (1H, m), 1,68-of 2.15 (3H, m), 2,32-2,47 (1H, m), 2,54-of 2.66 (1H, m), 3.00 and-of 3.12 (2H, m), 3,22-3,30 (1H, m), 3,32-3,44 (1H, m), 4,24 is 4.36 (4H, m), br4.61 (2H, s), to 6.67 (1H, s), 8,11 (1H, s)

Comparative example 116

To a solution of 1.5 g of methyl 2,6-dichloro-5-fornicating in 12 ml of methanol is added dropwise to 1.3 g of a 28% solution of sodium methoxide/methanol 3 ml of methanol and the mixture is stirred at room temperature for 40 minutes. To it was added water and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous with what LifeCam magnesium and the solvent is distilled off under reduced pressure to obtain 1.2 g of methyl 2-chloro-5-fluoro-6-methoxynicotinate in the form of a solid white product.

1H-NMR (CDCl3) δ: to 3.92 (3H, s), 4.09 to (3H, s), 7,92 (1H, d, J=9.8 Hz)

Comparative example 117

To a solution of 1.5 g of methyl 2-chloro-5-fluoro-6-methoxynicotinate in 15 ml of N,N-dimethylformamide type of 0.38 g of tetrakis(triphenylphosphine)palladium(0), and 1.4 ml of triethylamine and 0.38 ml of formic acid at room temperature and the mixture was stirred at 50-60°C for 1 hour in nitrogen atmosphere, and then stirred at 90-100°C for 2 hours and 20 minutes. It is additionally added to 1.4 ml of triethylamine, 0,38 g of tetrakis(triphenylphosphine)palladium(0) and 0.38 ml of formic acid at room temperature and the mixture was stirred at 90-100°C for 1 hour. After cooling to room temperature the reaction mixture is poured with ethyl acetate and water and adjusted pH to 4.8 with 2 mol/l hydrochloric acid. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts are combined and the resulting solution was washed with saturated aqueous sodium chloride. A mixed solvent of chloroform:methanol added to the organic layer for dissolution of nerastvorimogo substances and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The ethyl acetate added to the obtained residue, and the solid product is filtered off with getting to 0.30 g of methyl 5-fluoro-6-methoxynicotinate in view of the solid yellow color.

1H-NMR (CDCl3) δ: to 3.92 (3H, s), 4.09 to (3H, s), 7,88 (1H, DD, J=10,5, 2.0 Hz), 8,61 (1H, d, J=2.0 Hz)

Comparative example 118

To a suspension of 0.24 g of lithium aluminum hydride in 6 ml of tetrahydrofuran is added dropwise a solution of 0.58 g of methyl 5-fluoro-6-methoxynicotinate in 3.5 ml of tetrahydrofuran while cooling on ice. After heating to room temperature, the mixture is stirred for 30 minutes. Thereto is added dropwise a saturated aqueous sodium bicarbonate solution while cooling on ice, after stirring for 10 minutes, the reaction mixture was filtered through celite and the residue from filtration washed with ethyl acetate and water. The organic layer of the filtrate was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.55 g (5-fluoro-6-methoxypyridine-3-yl)methanol in the form of oily substance brown.

1H-NMR (CDCl3) δ: 1,72 (1H, t, J=5.7 Hz), a 4.03 (3H, s)and 4.65 (2H, d, J=5.7 Hz), 7,40 (1H, DD, J=10,7, 2.0 Hz), 7,89 (1H, d, J=2.0 Hz)

Comparative example 119

To a solution of 0.54 g (5-fluoro-6-methoxypyridine-3-yl)methanol in 5 ml of dichloromethane added 1.5 g of manganese dioxide. The mixture paramesh what happens at room temperature for 3 hours, then there was added to 0.89 g of manganese dioxide and 4 ml of dichloromethane and the mixture is stirred for 1 hour. It additionally add 1.5 g of manganese dioxide and 2 ml of dichloromethane and the mixture is stirred at room temperature for 2 hours and 30 minutes. After her leave to stand over night, nerastvorimaya substance is filtered off and the residue from the filtration was washed with chloroform. The solvent is distilled under reduced pressure to get to 0.48 g of 5-fluoro-6-methoxynicotinate in the form of a solid yellow color.

1H-NMR (CDCl3) δ: 4,13 (3H, s), 7,78 (1H, DD, J=9,8, 1.8 Hz), 8,42 (1H, d, J=1,8 Hz), becomes 9.97 (1H, d, J=2.7 Hz)

Comparative example 120

Using the same technology as in Comparative example 101, 3-fluoro-5-((methoxyethoxy)methyl)-2,6-dimethylpyridin derived from 2,6-dichloro-3-fluoro-5-((methoxyethoxy)methyl)pyridine.

1H-NMR (CDCl3) δ: 2,47 (3H, s), 2,48 (3H, d, J=2.7 Hz), 3,42 (3H, s)4,55 (2H, s), to 4.73 (2H, s), 7,35 (1H, d, J=9.8 Hz)

Comparative example 121

Using the same technology as in Comparative example 102, (5-fluoro-2,6-dimethylpyridin-3-yl)methanol obtained from 3-fluoro-5-((methoxyethoxy)methyl)-2,6-dimethylpyridine.

1H-NMR (CDCl3) δ: 1,99-of 2.20 (1H, usher.), of 2.45 (3H, s), 2,48 (3H, d, J=2,9 Hz), and 4.68 (2H, s), 7,40 (1H, d, J=9.8 Hz)

Comparative example 122

Using the same technology as in Comparative example 103, 5-fluoro-2,6-diethylnicotinamide obtained from (5-fluoro-2,6-dimethylpyridin-3-yl)methanol.

1H-NMR (CDCl3) δ: 2.57 m (3H, d, J=2,9 Hz), 2,82 (3H, d, J=1.0 Hz), 7,72 (1H, d, J=9.0 Hz), 10,28 (1H, d, J=2.2 Hz)

Comparative example 123

To a solution of 0.25 g of (3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl)methanol in 7.5 ml of chloroform added 0.66 g of manganese dioxide and the mixture is heated under reflux, with stirring, for 4 hours and 50 minutes. The reaction mixture is cooled to room temperature, nerastvorimaya substance is then filtered off and the solvent is distilled off under reduced pressure to obtain 0.24 g of 3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-carbaldehyde in the form of an oily material light yellow color.

1H-NMR (CDCl3) δ: 2,04-2,11 (2H, m), 2,85 (2H, t, J=6.5 Hz), 4,32 (2H, t, J=5,1 Hz), 7,72 (1H, s), of 8.27 (1H, s), 9,94 (1H, s)

Comparative example 124

Using the same technology as in Comparative example 60, tert-butyl (3S)-3-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)pyrrolidin-1-carboxylate is obtained from tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate and 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde.

1H-NMR (CDCl3) δ: USD 1.43 (9H, s), 1,54-of 1.64 (1H, m), 2,18-to 2.42 (2H, m), 2,50-of 2.86 (3H, m), 3,62 (2H, s), 4,10-4,22 (1H, usher.), 4,25 is 4.36 (4H, m), 4,86-4,94 (1H, m), 686 (1H, C), 8,10 (1H, s)

Comparative example 125

Using the same technology as in Comparative example 13, (3S)-N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)pyrrolidin-3-amine hydrochloride is obtained from tert-butyl (3S)-3-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)pyrrolidin-1-carboxylate.

1H-NMR (DMSO-d6) δ: 2,03-and 2.14 (1H, m), 2,30-to 2.40 (1H, m), 3,30-and 3.72 (4H, m), 3,92-of 4.05 (1H, m), 4,32-4,43 (4H, m), of 4.45 (2H, s), 7,19 (1H, s), by 8.22 (1H, s)

Comparative example 126

To 2.2 g of 1-(1,3-dioxolane-2-ylmethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it add 20 ml of 80% aqueous solution triperoxonane acid and the mixture is stirred at 80-90°C for 3 hours. To it was added 10 ml of 80% aqueous solution triperoxonane acid and the mixture is stirred at 80-90°C for 2 hours, then further add 10 ml of 80% aqueous solution triperoxonane acid and the mixture was stirred at the same temperature for 9 hours. The reaction mixture is cooled to room temperature, and then the solvent is distilled off under reduced pressure. To the obtained residue, add 2 mol/l aqueous sodium hydroxide solution and adjusted the pH to 8.0, and to it was added chloroform and methanol. The organic layer is separated and the aqueous layer was extracted with a mixed solution of chloroform and methanol twice. The organic layer and extracts are combined to receive the config solution is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue, add a simple diethyl ether and hexane, and the solid product filtered off to obtain 1.5 g of 7-fluoro-1-(2-hydroxy-2-methoxyethyl)-1,5-naphthiridine-2(1H)-it is in the form of a solid light brown color.

1H-NMR (DMSO-d6) δ: 3,21 (3H, s), 4,19-or 4.31 (2H, m), 4,72-rate 4.79 (1H, m), 6,53 (1H, d, J=7,1 Hz), at 6.84 (1H, d, J=9.8 Hz), of 7.97 (1H, d, J=9.8 Hz), 8,03 (1H, DD, J=11,5, 2.4 Hz), 8,55 (1H, d, J=2.4 Hz)

Comparative example 127

Using the same technology as in Comparative example 77, tert-butyl (1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate obtained from 7-fluoro-1-(2-hydroxy-2-methoxyethyl)-1,5-naphthiridine-2(1H)-she and tert-butyl (piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1.32 to-1,49 (2H, m)of 1.44 (9H, s), 1,89 of 1.99 (2H, m), 2,20-of 2.30 (2H, m), 2,61 of 2.68 (2H, m), 2,86-2,95 (2H, m), 3,42-of 3.54 (1H, m), 4,27 is 4.35 (2H, m), of 4.38-4,47 (1H, m)6,86 (1H, d, J=9.8 Hz), of 7.48-of 7.55 (1H, m), 7,89 (1H, d, J=9.8 Hz), 8,42 (1H, d, J=2.4 Hz)

Comparative example 128

Using the same technology as in Comparative example 78, 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 1,92-of 2.08 (2H, m), 2,34 at 2.45 (2H, m), 3,17-to 3.35 (2H, m), 3,56-3,68 (3H, m), 3,91-a 4.03 (2H, m), 4,71-4,78 (2H, m), of 6.99 (1H, d, J=9.9 Hz), of 7.96 (1H, DD, J=10,0, 2,1 Hz), of 8.09 (1H, d, J=9.9 Hz), to 8.57 (1H, d, J=2.1 Hz)

Comparative p is emer 129

To a suspension of 0.40 g of 7-bromo-1-((1,3-dioxolane-2-yl)methyl)-1,5-naphthiridine-2(1H)-she's in 4 ml of dioxane is added 0.18 g of tert-BUTYLCARBAMATE, 0,59 g of cesium carbonate, 22 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 18 mg of Tris(dibenzylideneacetone)diplegia(0) at room temperature and the mixture was stirred at 90-95°C for 4 hours and 15 minutes. After cooling to room temperature, to the reaction mixture are added chloroform and water, the organic layer is separated and washed with water and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, to the obtained residue, add a simple diethyl ether, and the solid product is filtered off with getting to 0.29 g of tert-butyl (5-(1,3-dioxolane-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)carbamate in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: of 1.55 (9H, s), 3,86-of 3.94 (2H, m), as 4.02 is 4.13 (2H, m), 4,46 (2H, d, J=4.6 Hz), 5,33 (1H, t, J=4.6 Hz), to 6.80 (1H, d, J=9.6 Hz), 6,91 (1H, s), 7,83 (1H, d, J=9.6 Hz), 8,29 (1H, d, J=2.0 Hz), 8,43 (1H, )

Comparative example 130

To a solution of 0.15 g of tert-butyl (5-(1,3-dioxolane-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)carbamate in 2 ml of N,N-dimethylformamide added 21 mg of 60% sodium hydride and 32 μl of methyliodide and the mixture is stirred at room temperature in ECENA 2 hours and 20 minutes. It is additionally added 9 mg of 60% sodium hydride and 13 μl of methyliodide and the mixture is stirred at room temperature for 1 hour. To the reaction mixture are added ethyl acetate and water and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 1:1-3:7 receipt of 0.13 g of tert-butyl (5-(1,3-dioxolane-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)(methyl)carbamate in the form of oily substance brown.

1H-NMR (CDCl3) δ: 1.50 in (9H, s)to 3.38 (3H, s), 3,85-of 3.94 (2H, m), 3,97-of 4.05 (2H, m), 4,48 (2H, d, J=4.3 Hz), with 5.22 (1H, t, J=4.3 Hz), 6.87 in (1H, d, J=9.8 Hz), 7,84-7,89 (2H, m), 8,51 (1H, d, J=2.0 Hz)

Comparative example 131

To a solution of 10 g of 5-(benzyloxy)-2-(hydroxymethyl)pyridin-4(1H)-she's in 58 ml of pyridine added 4.6 ml of acetylchloride while cooling on ice and the mixture was stirred at 60-70°C for 3 hours. The solvent is distilled off from the mixture under reduced pressure, water is added and the mixture is stirred while cooling on ice. The solid product is filtered off, there was added chloroform, and the obtained product is dried over anhydrous magnesium sulfate, the solvent is distilled off from the mixture under reduced pressure. It adds a simple diethyl ether, and the solid product is filtered off with obtaining 9.2 grams (5-(benzyloxy)-4-oxo-1,4-dihydropyridines-2-yl)acetate in the form of a solid light brown color.

1H-NMR (CDCl3) δ: of 2.08 (3H, s), 4,89 (2H, s)to 5.00 (2H, s), 6,63 (1H, s), 7,28 (5H, s)to 7.50 (1H, s)

Comparative example 132

To a solution of 6.1 g of (5-(benzyloxy)-4-oxo-1,4-dihydropyridines-2-yl)acetate in 50 ml of dimethyl sulfoxide add 5.0 g of tert-butyl (2-bromacil)carbamate and 10 g of potassium carbonate and the mixture was stirred at 80-90°C for 6 hours and 30 minutes. The reaction mixture is cooled to room temperature and then to it was added ethyl acetate and water. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of chloroform:methanol = 99:1-98:2 to obtain 3.8 g (5-(benzyloxy)-4-(2-((tert-butoxycarbonyl)amino)ethoxy)pyridine-2-yl)acetate as an oily material brown color.

1H-NMR (CDCl3) δ: of 1.45 (9H, s), of 2.15 (3H, s)to 3.58 (2H, square, J=5.3 Hz), of 4.13 (2H, t, J=5.3 Hz), 4,96 (1H, s), 5,10 (2H, s), 5,16 (2H, s), 6.89 in (1H, s), 7,30 was 7.45 (5H, m), 8,16 (1H, s)

Comparative example 133

To a solution of 3.8 g (5-(benzyloxy)4-(2-((tert-butoxycarbonyl)amino)ethoxy)pyridine-2-yl)acetate in 91 ml of ethanol is added 1.1 g of 10% palladium on coal and the mixture is stirred at room temperature for 5 hours in an atmosphere of hydrogen. Nerastvorimaya substance is filtered off and the solvent is distilled off from the mixture under reduced pressure. To it was added chloroform and simple diethyl ether, and the solid product filtered off to obtain 2.1 g of (4-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-hydroxypyridine-2-yl)acetate in the form of a solid light brown color.

1H-NMR (CDCl3) δ: of 1.45 (9H, s), of 2.15 (3H, s), 3,61 (2H, square, J=4,8 Hz), is 4.21 (2H, t, J=4,8 Hz), 5,20 (2H, s), to 5.35 (1H, s)6,94 (1H, s), compared to 8.26 (1H, s)

Comparative example 134

To a solution of 1.0 g (4-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-hydroxypyridine-2-yl)acetate in 15 ml of dichloromethane add 0,86 ml of triethylamine and 0.78 ml triftormetilfullerenov anhydride while cooling on ice and the mixture is stirred for 30 minutes. To it was added a saturated aqueous solution of sodium bicarbonate and water and the organic layer is separated and washed with saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 66:34 to 50:50 to obtain 1.3 g (4-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-(((trifluoromethyl)-sulfonyl)oxy)pyridine-2-yl)acetate as a colorless oily what about the substance.

1H-NMR (CDCl3) δ: of 1.45 (9H, s), measuring 2.20 (3H, s), of 3.60 (2H, square, J=5,2 Hz)to 4.23 (2H, t, J=5,2 Hz), of 5.05 (1H, s), is 5.18 (2H, s),? 7.04 baby mortality (1H, s), 8,35 (1H, s)

Comparative example 135

To a solution of 1.0 g (4-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-(((trifluoromethyl)sulfonyl)oxy)pyridine-2-yl)acetate in 5.0 ml of dioxane is added 1.0 g of cesium carbonate, 58 mg of Tris(dibenzylideneacetone)diplegia(0) and 76 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and the mixture is heated under reflux, with stirring, for 2 hours. To the reaction mixture are added ethyl acetate, nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 60:40-0:100 with getting to 0.29 g of tert-butyl 7-((acetoxy)methyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazin-4-carboxylate in the form of a solid brown color.

1H-NMR (CDCl3) δ: of 1.56 (9H, s), and 2.14 (3H, s), 3,85-to 3.89 (2H, m), 4,29-4,32 (2H, m), 5,11 (2H, s)6,86 (1H, s), 8,88 (1H, s)

Comparative example 136

To a solution of 0.11 g of tert-butyl 7-((acetoxy)methyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazin-4-carboxylate in a mixture of 1.7 ml of tetrahydrofuran and 1.7 ml of water is added to 0.36 ml of 2.0 mol/l aqueous sodium hydroxide solution and the mixture was stirred at room is based temperature for 1 hour. The reaction solution is saturated with potassium carbonate, and then added ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 90 mg of tert-butyl 7-(hydroxymethyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazin-4-carboxylate in the form of oily substance brown.

1H-NMR (CDCl3) δ: of 1.56 (9H, s), 3,32-to 3.41 (1H, m), 3,86-to 3.89 (2H, m), 4,29-4,32 (2H, m), with 4.64 (2H, s)6,76 (1H, s), 8,82-8,89 (1H, m)

Comparative example 137

Using the same technology as in Comparative example 67, tert-butyl 7-formyl-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazin-4-carboxylate is obtained from tert-butyl 7-(hydroxymethyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazin-4-carboxylate.

1H-NMR (CDCl3) δ: was 1.58 (9H, s), 3,91-of 3.94 (2H, m), 4,34-4,37 (2H, m), of 7.48 (1H, s), 9,12-of 9.21 (1H, m), 9,96 (1H, s)

Comparative example 138

To a solution of 0.30 g of 8-(2-hydroxyethyl)-1,4-dioxaspiro(4,5)decane-8-La in 5 ml of dichloromethane add 0,76 g periodinane dessa-Martin while cooling on ice and the mixture is stirred at room temperature for 1 hour. To the reaction mixture, water is added while cooling on ice and organic is Loy separated and the aqueous layer was extracted with chloroform. The organic layer and extracts are combined and the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, there was added chloroform, and nerastvorimaya substance is filtered off. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 35:65-25:75 obtaining 0,19 g (8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)acetaldehyde in the form of an oily material light yellow color.

1H-NMR (CDCl3) δ: 1,53-of 1.64 (2H, m), 1,68 (2H, TD, J = 13,1, a 4.3 Hz), 1,79-1,89 (2H,m), 1,95 (2H, dt, J = 12,7 4,3 Hz), 2,54 at 2.59 (1H, usher.), to 2.65 (2H, d, J = 1.5 Hz), 3,90-4,00 (4H, m), 9,88 (1H, t, J = 1.5 Hz)

Comparative example 139

To a solution of 150 g of 2-chloro-5-herperidin-3-amine in 600 ml of N,N-dimethylformamide is added in a flow of nitrogen 190 ml of butyl acrylate and 287 ml of triethylamine and the mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to 58°C, there was added to 13.1 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred at 110-120°C for 40 minutes. The reaction mixture was cooled to 57°C, there was added to 13.1 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred at 110-120°C for 3 hours. The reaction mixture is cooled to room temperature and to it was added water and ethyl the Etat. Nerastvorimaya substance is filtered off, the organic layer of the filtrate was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue, add cyclohexane and ethyl acetate, and the solid product filtered off to obtain 200 g of butyl (2E)-3-(3-amino-5-herperidin-2-yl)acrylate in the form of a solid light brown color.

1H-NMR (CDCl3) δ: of 0.95 (3H, t, J=7,3 Hz), to 1.38 to 1.48 (2H, m), 1,64-1,72 (2H, m), of 4.13 (2H, s), is 4.21 (2H, t, J=6,7 Hz), of 6.71 (1H, DD, J=9,8, and 2.3 Hz), 6,86 (1H, d, J=15.3 Hz), 7,72 (1H, d, J=15.3 Hz), 7,94 (1H, d, J=2.3 Hz)

Comparative example 140

To a solution of 90 mg of butyl (2E)-3-(3-amino-5-herperidin-2-yl)acrylate in 5 ml of dichloromethane added 90 mg (8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)acetaldehyde and 33 μl of acetic acid and the mixture is stirred at room temperature for 4 hours and left overnight. To the reaction mixture is added 80 mg of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 1 hour. To it was added a saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organization is practical layer and the extract combined the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 60:40 to 50:50 to obtain 82 mg of butyl (2E)-3-(5-fluoro-3-((2-(8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)ethyl)amino)pyridin-2-yl)acrylate in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: of 0.95 (3H, t, J=7.4 Hz), to 1.38 to 1.48 (2H, m), 1.55V is 2.00 (10H, m), 3,22-3,30 (2H, m), 3,90-was 4.02 (6H, m), 4,20 (2H, t, J=6.6 Hz), 5.40 to-5,47 (1H, m), 6,63 (1H, DD, J=11,2, 2.4 Hz), 6,83 (1H, d, J=15.2 Hz), 7,71 (1H, d, J=15.2 Hz), 7,82 (1H, d, J=2.4 Hz)

Comparative example 141

To a solution of 80 mg of butyl (2E)-3-(5-fluoro-3-((2-(8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)ethyl)amino)pyridin-2-yl)acrylate in 4 ml of a mixture of methanol and tetrahydrofuran (1:1) are added at room temperature to 55 mg of a 28% solution of sodium methoxide/methanol and the mixture is heated under reflux, with stirring, for 1 hour. The reaction mixture is cooled to room temperature, then to it was added ethyl acetate and water and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain the 65 mg of 1-(2-(8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: 1,70-1,80 (4H, m), 1,87 is 1.96 (4H, m), 2,48-of 2.56 (2H, m), 3,92-4,00 (4H, m), 3,98 (3H, s), of 4.38 is 4.45 (2H, m), 6,76 (1H, d, J=9.8 Hz), 7.24 to to 7.32 (1H, m), 7,87 (1H, d, J=9.8 Hz), 8,30 (1H, d, J=2.4 Hz)

Comparative example 142

To 60 mg of 1-(2-(8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it add 3 ml of 80% aqueous solution triperoxonane acid at room temperature and the mixture is stirred for 8 hours and 30 minutes. The solvent is distilled off under reduced pressure, the obtained residue is added saturated aqueous sodium bicarbonate solution and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts are combined and the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue purified using flash column-chromatography on silica gel using a gradient elution of chloroform:methanol = 100:0-99:1 to obtain 41 mg of 1-(2-(1-hydroxy-4-oxocyclohexyl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of a solid yellow color.

1H-NMR (CDCl3) δ: 1,60-2,12 (6H, m), 2,22-of 2.30 (2H, m), 2,73-and 2.83 (2H, m), 3,67 is 3.76 (1H, usher.), of 4.00 (3H, s), 4,47 (2H, t, J=6,7 Hz), to 6.80 (1H, d, J=9.6 Hz), 7,16 (1H, d, J=2.3 Hz), to 7.93 (1H, d, J=9.6 Hz), 8,35 (1H, d, J=2.3 Hz)

Comparative example 143

To a solution of 0.50 g of 1-(TRIFLUOROACETYL)piperidine-4-amine in 10 ml of mixed solvent of N,N-dimethylformamide and tetrahydrofuran (1:1), of 0.41 g of potassium carbonate type of 0.42 ml of propargylamine and the mixture is heated under reflux, with stirring, for 2 hours. To it was added water and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to get to 0.60 g of N-(2-propyne-1-yl)-1-(TRIFLUOROACETYL)piperidine-4-amine in the form of a crude product (crude product (A). On the other hand, the solution to 0.70 g of 1-(TRIFLUOROACETYL)piperidine-4-amine 7.2 ml of a mixed solvent of N,N-dimethylformamide and tetrahydrofuran (1:1)add a 0.59 g of potassium carbonate and 0.30 ml of propargylamine and the mixture is heated under reflux, with stirring, over 1 hour 50 minutes. To it was added water and ethyl acetate and mixed with a 0.60 g of A crude product obtained above, and the pH of the mixture was adjusted to 1 with 6 mol/l hydrochloric acid. The aqueous layer was separated and washed with ethyl acetate, the ethyl acetate there was added, and the aqueous layer was saturated with potassium carbonate. The organic layer is separated, washed with saturated aqueous chloride NAT the Oia and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 1.0 g of N-(2-propyne-1-yl)-1-(TRIFLUOROACETYL)piperidine-4-amine in the form of oily substance brown.

1H-NMR (CDCl3) δ: 1,36 is 1.48 (2H, m), 1,90-to 1.98 (2H, m), of 2.23 (1H, t, J=2.3 Hz), 3,03-to 3.34 (3H, m), 3,48 (2H, d, J=2.3 Hz), 3,90-3,98 (1H, m), 4,22-or 4.31 (1H, m)

Comparative example 144

(1) To a solution of 0.60 g of N-(2-propyne-1-yl)-1-(TRIFLUOROACETYL)piperidine-4-amine 5.2 ml of dioxane is added 0.56 g of di-tert-BUTYLCARBAMATE and the mixture is stirred at room temperature for 1 hour and 45 minutes. The solvent is distilled off under reduced pressure and the resulting residue purified by column chromatography on silica gel using elution with hexane:ethyl acetate = 3:1 with obtaining 0,70 g of tert-butyl (2-propyne-1-yl)(1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate as a colorless oily substance.

(2) To a solution of 0.20 g of tert-butyl (2-propyne-1-yl)(1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate in 6.0 ml of triethylamine added 59 μl of godperson, 0,57 mg of copper iodide (I) and 4.2 mg dichlorobis(triphenylphosphine)palladium(II) under nitrogen atmosphere and the mixture was stirred at 60-70°C for 4 hours and 30 minutes. Nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 60:40 to 50:50 to obtain 0.17 g of tert-butyl (3-(pyrazin-2-yl)-2-propyne-1-yl)(1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate as a colourless m is kanistha substances.

1H-NMR (CDCl3) δ: rate of 1.51 (9H, s), 1,76-2,02 (4H, m), 2,72-2,84 (1H, m), 3,12-up 3.22 (1H, m), 4,08-4.26 deaths (4H, m), with 4.64-4.72 in (1H, m), 8,49 (1H, d, J=2.7 Hz), 8,53-8,56 (1H, m), at 8.60 (1H, d, J=1.2 Hz)

Comparative example 145

Using the same technology as in Comparative example 62, tert-butyl (piperidine-4-yl)(3-pyrazin-2-yl)-2-propyne-1-yl)carbamate obtained from tert-butyl (3-(pyrazin-2-yl)-2-propyne-1-yl)(1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: rate of 1.51 (9H, s), 1,72-of 1.92 (4H, m), 2,66 was 2.76 (2H, m), 3,17-3,24 (2H, m), 3.96 points-4,30 (3H, m), of 8.47 (1H, d, J=2.4 Hz), 8,51-8,54 (1H, m), to 8.62 (1H, d, J=1.2 Hz)

Comparative example 146

Using the same technology as in Comparative example 140, ethyl (2E)-3-(3-((2-(8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)ethyl)amino)-5-methoxypyrazine-2-yl)acrylate are obtained from 8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)acetaldehyde and ethyl (2E)-3-(3-amino-5-methoxypyrazine-2-yl)acrylate.

1H-NMR (CDCl3) δ: is 1.31 (3H, t, J=7.2 Hz), 1,71-1,90 (8H, m), 3,60-the 3.65 (2H, m), 3,90-4,00 (6H, m), of 3.94 (3H, s), 4,24 (2H, square, J=7,2 Hz), 5,80-5,94 (1H, m), of 6.68 (1H, d, J=15.1 Hz), 7,51 (1H, s), 7,63 (1H, d, J=15.1 Hz)

Comparative example 147

Using the same technology as in Comparative example 2, 5-(2-(8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-he obtained from ethyl (2E)-3-(3-((2-(8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)ethyl)amino)-5-methoxypyrazine-2-yl) - Christ.crylate.

1H-NMR (CDCl3) δ: 1,50-1,80 (6H, m), 1,90-2,00 (4H, m), 2.40 a is 2.44 (1H, usher.), the 3.89-3,99 (4H, m), 4,08 (3H, s), 4,58-to 4.62 (2H, m), is 6.78 (1H, d, J=9.6 Hz), 7,87 (1H, d, J=9.6 Hz), 8,14 (1H, s)

Comparative example 148

Using the same technology as in Comparative example 142, 5-(2-(1-hydroxy-4-oxocyclohexyl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-he obtained from 5-(2-(8-hydroxy-1,4-dioxaspiro(4,5)DECA-8-yl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-it.

1H-NMR (CDCl3) δ: 1,79 (2H, TD, J=13,8, a 4.9 Hz), 2,04 (2H, t, J=6.8 Hz), 2,03-2,12 (2H, m), 2,20-to 2.29 (2H, m), 2,80 (2H, TD, J=13,8, 6.2 Hz), 3,30 is-3.45 (1H, usher.), 4.09 to (3H, s)and 4.65 (2H, t, J=6.8 Hz), for 6.81 (1H, d, J=9.6 Hz), 7,92 (1H, d, J=9.6 Hz), 8,18 (1H, s)

Comparative example 149

To a solution of 0.28 g of tert-butyl 3-(aminomethyl)pyrrolidin-1-carboxylate in a mixture of 7 ml of methanol and 20 ml of dichloromethane added to 0.23 g of 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde and 0.50 g of molecular sieves 3Å, the mixture is stirred at room temperature for 3 hours and then the reaction mixture was loaded 79 mg sodium borohydride and stirred at room temperature for 5 hours and 30 minutes. Her water is added while cooling on ice, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous Sul is an atom of magnesium and the solvent is distilled off under reduced pressure to get to 0.48 g of tert-butyl 3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)-pyrrolidin-1-carboxylate as a colorless oily substance.

1H-NMR (CDCl3) δ: of 1.45 (9H, s), 1,50-3,60 (9H, m), of 3.77 (2H, s), 4.26 deaths is 4.36 (4H, m), for 6.81 (1H, s), 8,11 (1H, s)

Comparative example 150

Using the same technology as in Comparative example 13, 1-(2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)-N-(pyrrolidin-3-ylmethyl)methanamine hydrochloride is obtained from tert-butyl 3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)pyrrolidin-1-carboxylate.

1H-NMR (D2O) δ: 1,76-1,89 (1H, m), 2,31-to 2.41 (1H, m), 2,73-2,87 (1H, m), 3,02-3,11 (1H, m), 3,28 is 3.40 (3H, m), 3.45 points-of 3.54 (1H, m)to 3.64 (1H, DD, J=11.8 in, and 8.2 Hz), to 4.41 figure-4.49 (4H, m), 4,54-4,60 (2H, m), 7,35-7,46 (1H, m), 8.30 to-at 8.36 (1H, m)

Comparative example 151

A solution of 2.0 g of 7-methyl-1,8-naphthiridine-2(1H)-she's in 150 ml of ethanol is added 1.0 g of 5% palladium on coal and the mixture is stirred at 40-50°C for 17 hours in an atmosphere of hydrogen. The reaction mixture is cooled to room temperature, nerastvorimaya substance is filtered off and the residue from the filtration was washed with methanol. The solvent is distilled off under reduced pressure and the resulting residue purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 1:1 with the receipt of 0.92 g of 7-methyl-3,4-dihydro-1,8-naphthiridine-2(1H)-it is in the form of a solid white product.

1H-NMR (CDCl3) δ: 2,52 (3H, s), 2,61 of 2.68 (2H, m), 2,86-to 2.94 (2H, m), is 6.78 (1H, d, J=7,6 Hz), was 7.36 (1H, d, J=7,6 Hz), 9,86 (1H, s)

The comparator is the first example 152

A solution of 0.90 g of 7-methyl-3,4-dihydro-1,8-naphthiridine-2(1H)-she's in 150 ml of dioxane is heated under reflux, adding in parts of 25.7 g of selenium dioxide and the mixture is stirred for 10 days. Nerastvorimaya substance is filtered off with celite and the solvent is distilled off under reduced pressure. To the obtained residue, add 2-propanol, and the solid product filtered off. Thus obtained solid product was then purified using column chromatography on silica gel using eluent chloroform:methanol = 20:1 and to it was added ethyl acetate, and the solid product is filtered off with getting to 0.48 g of 7-oxo-7,8-dihydro-1,8-naphthiridine-2-carbaldehyde in the form of a solid light orange color.

1H-NMR (CDCl3) δ: 6.87 in (1H, d, J=9.6 Hz), 7,80 (1H, d, J=9.6 Hz), the 7.85 (1H, DD, J=7,8, 1.0 Hz), 8,07 (1H, d, J=7.8 Hz), 10,11 (1H, s)

Comparative example 153

To a solution of 0.53 g of 1-(TRIFLUOROACETYL)piperidine-4-amine in 100 ml of dichloromethane type of 0.47 g of 7-oxo-7,8-dihydro-1,8-naphthiridine-2-carbaldehyde and 0.16 ml of acetic acid and the mixture is stirred at room temperature for 45 minutes. The reaction mixture was added to 0,86 g triacetoxyborohydride sodium and stirred at the same temperature for 5 hours. To it add water, a saturated aqueous solution of bicarbonate is the atrium and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. Additionally added to the aqueous layer, sodium chloride, and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 20:1 with the receipt of 0.59 g of 7-(((1-(TRIFLUOROACETYL)piperidine-4-yl)amino)methyl)-1,8-naphthiridine-2(1H)-it foam light orange color.

1H-NMR (CDCl3) δ: 1,42-of 1.56 (2H, m), 1,98-of 2.08 (2H, m), 2,85-to 2.94 (1H, m), 3,01-3,11 (1H, m), 3,19-3,29 (1H, m), 3,93-was 4.02 (1H, m)4,06 (2H, s), 4,29-to 4.38 (1H, m), 6,70 (1H, d, J=9.4 Hz), 7,24 (1H, d, J=7.8 Hz), 7,72 (1H, d, J=9.4 Hz), 7,86 (1H, d, J=7,8 Hz)

Comparative example 154

To a solution of 0.58 g of 7-(((1-(TRIFLUOROACETYL)piperidine-4-yl)amino)methyl)-1,8-naphthiridine-2(1H)-she's in 25 ml of chloroform type of 0.43 g of di-tert-BUTYLCARBAMATE and the mixture is stirred at room temperature for 3 days. To the reaction mixture, water is added, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, the to it was added a mixed solvent of hexane:ethyl acetate (1:1), and the solid product filtered off to obtain 0.56 g of tert-butyl ((7-oxo-7,8-dihydro-1,8-naphthiridine-2-yl)methyl)(1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate as a pale pink solid white product.

1H-NMR (CDCl3) δ: 1,29 is 2.00 (13H, m), 2,67-2,84 (1H, m), 3,06-3,24 (1H, m), 4,06-4,20 (2H, m), 4,35-of 4.67 (3H, m), 6,69 (1H, d, J=9.5 Hz),? 7.04 baby mortality-7,19 (1H, m), of 7.70 (1H, d, J=9.5 Hz), the 7.85 (1H, d, J=8.0 Hz), RS 9.69 (1H, s)

Comparative example 155

To a solution of 0.30 g of tert-butyl ((7-oxo-7,8-dihydro-1,8-naphthiridine-2-yl)methyl)(1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate in 40 ml of methanol, add 0.10 g of 10% palladium on coal and the mixture is stirred at 45-50°C for 9 hours and 30 minutes in hydrogen atmosphere. The reaction mixture is cooled to room temperature, nerastvorimaya substance is filtered off and the residue from the filtration was washed with methanol. The solvent is distilled off under reduced pressure and the resulting residue purified by column chromatography on silica gel using eluent chloroform:methanol = 100:3 to obtain 0.18 g of tert-butyl ((7-oxo-5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)methyl)(1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate as a colourless foam.

1H-NMR (CDCl3) δ: 1,24-1,88 (13H, m), 2,59-of 2.81 (3H, m), 2,87 are 2.98 (2H, m), 3.04 from-3,20 (1H, m), 3,98-4,08 (1H, m), 4.26 deaths-4,48 (3H, m), 4,54-4,63 (1H, m), 6,76-6,92 (1H, m), the 7.43 (1H, d, J=7,6 Hz), 8,20 at 8.60 (1H, user.)

Comparative example 156

To a solution of 0.30 g of tert-butyl ((7-oxo-5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)methyl)(1-(TRIFLUOROACETYL)piperidine-4-yl)carbamate in 12 ml of methanol, add 0.10 g of potassium carbonate and 3 ml of water and the mixture is stirred at room temperature for 7 hours and 30 minutes. To the reaction mixture add water, saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated, and the aqueous layer add sodium chloride and extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.24 g of tert-butyl ((7-oxo-5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)methyl)(piperidine-4-yl)carbamate as a colourless foam.

1H-NMR (CDCl3) δ: 1,28-1,78 (13H, m), 2,55-of 2.72 (4H, m), 2,87-of 2.97 (2H, m), 3,02-of 3.12 (2H, m), 4,15-4,50 (3H, m), 6,80-6,91 (1H, m), 7,41 (1H, d, J=7,6 Hz), 8,00-8,30 (1H, user.)

Comparative example 157

To a solution of 0.13 g of (4-methoxy-5-methylpyridin-2-yl)methanol in 2 ml of dichloromethane added 0.14 g of manganese dioxide. The mixture is stirred for 6 hours, with additional add-on parts 0.36 g of manganese dioxide at room temperature. Nerastvorimaya substance is filtered off, the solvent is distilled off under reduced pressure, and the obtained residue on imaut using column flash chromatography using a gradient elution of hexane:ethyl acetate = 9:1-4:1 to obtain 77 mg of 4-methoxy-5-methylpyridin-2-carbaldehyde in the form of a solid white product.

1H-NMR (CDCl3) δ: of 2.26 (3H, s), of 3.95 (3H, s), the 7.43 (1H, s), 8,42 (1H, s), 10,00 (1H, s)

Comparative example 158

To a solution of 49 mg (5-ethyl-4-methoxypyridine-2-yl)methanol in 1 ml dichloromethane added to 0.13 g of manganese dioxide. The mixture is stirred at room temperature for 1 hour and 30 minutes, then there was added to 0.13 g of manganese dioxide and the mixture is stirred for 1 hour 30 minutes. Chloroform is added to the reaction mixture, nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure to obtain 54 mg of 5-ethyl-4-methoxypyridine-2-carbaldehyde in the form of oily substance brown.

1H-NMR (CDCl3) δ: 1,24 (3H, t, J=7.5 Hz), 2,70 (2H, square, J=7.5 Hz), of 3.95 (3H, s), 7,45 (1H, s), 8,43 (1H, s), 10,00 (1H, s)

Comparative example 159

To a suspension of 8.3 g of 2-(hydroxymethyl)-5-methoxypyridine-4(1H)-she's in 30 ml of pyridine, is added dropwise to 5.7 ml acetylchloride while cooling on ice. After heating to room temperature, the mixture was stirred at 55-60°C for 2 hours and 30 minutes. After cooling to room temperature the solvent is distilled off under reduced pressure and the resulting residue purified using flash column-chromatography on silica gel using a gradient elution of chloroform:methanol = 95:1-80:20 to obtain 6.7 g (5-methoxy-4-oxo-1,4-Digi retiredin-2-yl)acetate in the form of a brown foam.

1H-NMR (CDCl3) δ: 2,15 (3H, s), 3,86 (3H, s), of 5.15 (2H, s), 6,83 (1H, s), to 7.68 (1H, s)

Comparative example 160

To a solution of 4.6 g of (5-methoxy-4-oxo-1,4-dihydropyridines-2-yl)acetate in 120 ml of dichloromethane added to 6.5 ml of triethylamine, is added dropwise to 5.9 ml triftormetilfullerenov anhydride while cooling on ice and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture are added water and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 4:1-4:6 receipt of 5.2 g of (5-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)pyridine-2-yl)acetate in the form of a solid yellow color.

1H-NMR (CDCl3) δ: 2,16 (3H, s), a 4.03 (3H, s), is 5.18 (2H, s), 7,26 (1H, s), 8,43 (1H, s)

Comparative example 161

To a solution of 0.50 g of (5-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)pyridine-2-yl)acetate in 5 ml of dioxane is added to 0.63 g of potassium carbonate, to 0.21 ml trimethylboroxine and 0.18 g of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 70 to 90°C for 3 cha is s in nitrogen atmosphere. The mixture is heated under reflux, with additional stirring for 3 hours, After cooling to room temperature, to the reaction mixture are added water and ethyl acetate and the organic layer separated. The aqueous layer was extracted with ethyl acetate, the organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 80:20-50:50 with getting 0,22 g (5-methoxy-4-methylpyridin-2-yl)acetate as an oily yellow substance.

1H-NMR (CDCl3) δ: 2,13 (3H, s), of 2.23 (3H, s)to 3.92 (3H, s), 5,12 (2H, s), to 7.15 (1H, s)to 8.14 (1H, s)

Comparative example 162

To a solution of 0.21 g of (5-methoxy-4-methylpyridin-2-yl)acetate in 2 ml of methanol type of 0.64 ml of 20% aqueous sodium hydroxide solution and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure, the obtained residue is added water and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure shall obtain 0.16 g of (5-methoxy-4-methylpyridin-2-yl)methanol in the form of a solid white product.

1H-NMR (CDCl3) δ: 2,24 (3H, s)to 3.92 (3H, s), of 4.66 (2H, s), 7,02 (1H, s), of 8.09 (1H, s)

Comparative example 163

Using the same technology as in Comparative example 67, 5-methoxy-4-methylpyridin-2-carbaldehyde is obtained from (5-methoxy-4-methylpyridin-2-yl)methanol.

1H-NMR (CDCl3) δ: to 2.29 (3H, s), a 4.03 (3H, s), 7,80 (1H, s), 8,31 (1H, s), 9,96 (1H, s)

Comparative example 164

To a solution of 30 mg (5-(3-thienyl)isoxazol-3-yl)methanol in 5 ml of dichloromethane added 84 mg periodinane dessa-Martin while cooling on ice and the mixture is stirred at room temperature for 1 hour and 30 minutes. It additionally adds 40 mg periodinane dessa-Martin and the mixture is stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture add a simple diethyl ether, nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure to obtain 30 mg of 5-(3-thienyl)isoxazol-3-carbaldehyde in the form of a solid yellow color.

1H-NMR (CDCl3) δ: 6.75 in (1H, s), 7,42-7,49 (2H, m), 7,88 (1H, DD, J=2,8, 1.3 Hz), 10,18 (1H, s)

Comparative example 165

To a solution of 0.85 g of 2,6-dichloro-3-fluoro-5-((methoxyethoxy)methyl)pyridine in 8 ml of N,N-dimethylformamide added at room temperature 0.45 g of lithium chloride, one piece of 2,6-di-tert-b is Tyl-4-METHYLPHENOL, the 1.04 ml tributyl(vinyl)tin, and add at room temperature, 50 mg dichloride bis(triphenylphosphine)palladium (II). In nitrogen atmosphere, the mixture was stirred at 40-50°C for 1 hour and stirred at 50-60°C for 1 hour and 30 minutes, and then stirred at 70-80°C for 1 hour. After cooling to room temperature the solvent is distilled off under reduced pressure and the resulting residue purified using flash column-chromatography on silica gel using eluent chloroform:methanol = 9:1 to obtain 0.51 g of a crude product of 2-chloro-5-fluoro-3-((methoxyethoxy)methyl)-6-vinylpyridine) - derivatives in the form of oily substance slightly yellow in color.

Comparative example 166

To a solution of 0.47 g of a crude product of 2-chloro-5-fluoro-3-((methoxyethoxy)methyl)-6-vinylpyridine) - derivatives obtained in Comparative example 165, 5 ml of methanol is added 0.24 g of 10% palladium on coal and the mixture is stirred at 40°C for 1 hour in a hydrogen atmosphere. Nerastvorimaya substance is filtered off, the solvent is distilled off under reduced pressure and the resulting residue purified using flash column-chromatography on silica gel using eluent chloroform:methanol = 19:1 to obtain 0.36 g of a crude product of 2-chloro-6-ethyl-5-fluoro-3-((methoxyethoxy)methyl)pyridine as a colorless oily substance.

Comparative note the p 167

To a solution of 0.33 g of a crude product of 2-chloro-6-ethyl-5-fluoro-3-((methoxyethoxy)methyl)pyridine obtained in Comparative example 166, in 3 ml of N,N-dimethylformamide added 0.16 g tetrakis(triphenylphosphine)palladium(0) and 0.98 ml of triethylamine at room temperature, and thereto is added dropwise with 0.27 ml of formic acid. The mixture was stirred at 70-80°C for 45 minutes under nitrogen atmosphere. After cooling to room temperature, to the reaction mixture are added water and ethyl acetate, nerastvorimaya substance is filtered off, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using eluent chloroform:methanol = 9:1 to obtain 0.11 g of 2-ethyl-3-fluoro-5-((methoxyethoxy)methyl)pyridine as a colorless oily substance.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7,6 Hz), 2,87 (2H, CVD, J=7,6, and 2.3 Hz), to 3.41 (3H, s), 4,59 (2H, s), 4,71 (2H, s), 7,35 (1H, DD, J=10,0, 1.7 Hz), 8,31 (1H, s)

Comparative example 168

To a solution of 0.11 g of 2-ethyl-3-fluoro-5-((methoxyethoxy)methyl)pyridine in 2 ml of 1,4-dioc the Ana add 1 ml of 6 mol/l hydrochloric acid and the mixture is stirred at 30-40°C for 1 hour. After cooling to room temperature the reaction mixture is loaded with water and ethyl acetate and the pH adjusted to 7.9 with 20% aqueous sodium hydroxide solution and saturated aqueous sodium bicarbonate solution. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 87 mg of (6-ethyl-5-herperidin-3-yl)methanol as a pale yellow oily material color.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7,6 Hz), 1.93 and-2,05 (1H, usher.), 2,87 (1H, CVD, J=7,6, and 2.3 Hz), 4.72 in (2H, d, J=3,4 Hz), 7,39 (1H, DD, J=10,1, 1,6 Hz), 8,30 (1H, s)

Comparative example 169

Using the same technology as in Comparative example 67, 6-ethyl-5-fioricetonline obtained from (6-ethyl-5-herperidin-3-yl)methanol.

1H-NMR (CDCl3) δ: of 1.34 (3H, t, J=7,6 Hz), of 2.97 (2H, t, J=7,6, 2.4 Hz), to 7.77 (1H, DD, J=9,0, 1.7 Hz), 8,80 (1H, s), of 10.09 (1H, d, J=2.2 Hz)

Comparative example 170

To a solution of 2.0 g of 5-hydroxy-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-4-it in 20 ml of dichloromethane added to 2.1 ml of triethylamine, is added dropwise 1.9 ml triftormetilfullerenov anhydride while cooling on ice and the mixture premesis the Ute for 40 minutes. To the reaction mixture are added water and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using as eluent hexane:ethyl acetate = 2:1 to obtain 2.9 g of 4-oxo-6-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-3-yl triftoratsetata in the form of a solid light brown color.

1H-NMR (CDCl3) δ: 1,53-1,90 (6H, m), 3,55-3,62 (1H, m), of 3.77-of 3.85 (1H, m), to 4.38 (1H, DD, J=14,9, 0.7 Hz), of 4.57 (1H, DD, 14,9, 0.7 Hz), 4,74 (1H, t, J=3.2 Hz), of 6.66 (1H, s), with 8.05 (1H, s)

Comparative example 171

To a solution of 1.0 g 4-oxo-6-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-3-yl triftoratsetata in 10 ml of dioxane is added 1.2 g of potassium carbonate, 0.4 ml of trimethylboroxine and 0.33 g of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 70-80°C for 2 hours in argon atmosphere. After cooling to room temperature, to the reaction mixture are added water and ethyl acetate and the organic layer separated. The aqueous layer was extracted with ethyl acetate, the organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified polosukhina chromatography on silica gel using as eluent hexane:ethyl acetate = 1:1 with the receipt of 0.62 g of 5-methyl-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-4-it is in the form of oily substance brown.

1H-NMR (CDCl3) δ: 1,20-of 1.66 (6H, m)of 1.66 (3H, s), of 3.25 to 3.35 (1H, m), 3,53-3,63 (1H, m)4,06 (1H, d, J=14.4 Hz), 4,25 (1H, d, J=14.4 Hz), 4,47 (1H, t, J=3.3 Hz), 6,16 (1H, s), the 7.43 (1H, s)

Comparative example 172

To a solution of 0.61 g of 5-methyl-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-4-it is in 3 ml of methanol add 0,03 ml of concentrated hydrochloric acid and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added 0.5 g of potassium carbonate and chloroform and the mixture is stirred for 30 minutes. Nerastvorimaya substance is filtered off, the solvent is distilled off under reduced pressure and the resulting residue purified by column chromatography on silica gel using eluent chloroform:methanol = 9:1 to obtain 0.26 g of 2-hydroxymethyl-5-methyl-4H-Piran-4-it is in the form of a solid white product.

1H-NMR (CDCl3) δ: 1,92 (3H, d, J=1.1 Hz), 3,03 (1H, t, J=6,7 Hz), 4,47 (2H, d, J=6,7 Hz), to 6.43 (1H, s), 7,66 (1H, d, J=1.1 Hz)

Comparative example 173

Using the same technology as in Comparative example 67, 5-methyl-4-oxo-4H-Piran-2-carbaldehyde is obtained from 2-hydroxymethyl-5-methyl-4H-Piran-4-it.

1H-NMR (CDCl3) δ: 1,99 (3H, d, J=1.2 Hz), 6.89 in (1H, s), 7,80 (1H, s), 9,67 (1H, s)

Comparative example 174

To a solution of 1.5 g of methyl 2,6-dichloro-5-fornicating in 15 ml of N,N-di is malformed type of 0.93 ml of triethylamine at room temperature, and thereto is added dropwise to 0.56 ml pyrrolidine. The mixture was stirred at the same temperature for 1 hour, add additional 56 μl of pyrrolidine and the mixture is stirred for 50 minutes. After her leave to stand overnight, the reaction mixture are added ethyl acetate and water. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 1.7 g of methyl 2-chloro-5-fluoro-6-(pyrrolidin-1-yl)nicotinate as a solid white product.

1H-NMR (CDCl3) δ: 1,90 of 1.99 (4H, m), 3,66-3,74 (4H, m), 3,86 (3H, s), 7,73 (1H, DD, J=13,0, 0.6 Hz)

Comparative example 175

To a solution of 1.7 g of methyl 2-chloro-5-fluoro-6-(pyrrolidin-1-yl)nicotinate in 15 ml of N,N-dimethylformamide added at room temperature of 0.38 g of tetrakis(triphenylphosphine)palladium(0) and 1.4 ml of triethylamine and thereto is added dropwise and 0.37 ml of formic acid. The mixture was stirred at 80-90°C for 2 hours and 30 minutes in nitrogen atmosphere. After cooling to room temperature, to the reaction mixture are added water and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts are combined and the resulting solution was prom which provide a saturated aqueous solution of sodium chloride. To the organic layer, add a mixed solvent of chloroform:methanol, the organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue, add mixed solvent simple diethyl ether:ethyl acetate (1:2), nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using the eluent of chloroform to obtain 1.3 g of methyl 5-fluoro-6-(pyrrolidin-1-yl)nicotinate as a solid product is a light yellow color.

1H-NMR (CDCl3) δ: 1,95 of 1.99 (4H, m), 3,69 of 3.75 (4H, m), 3,86 (3H, s), the 7.65 (1H, d, J=14,0, 1.8 Hz), 8,56 (1H, t, 1.8 Hz)

Comparative example 176

To a solution of 0.24 g of lithium aluminum hydride in 5 ml of THF is added dropwise a solution 0,70 g of methyl 5-fluoro-6-(pyrrolidin-1-yl)nicotinate in 5 ml of tetrahydrofuran while cooling on ice. After heating to room temperature, the mixture is stirred for 45 minutes, and thereto is added dropwise a saturated aqueous sodium bicarbonate solution while cooling on ice and the mixture is stirred for 10 minutes. The reaction mixture is filtered and the residue on the filter is washed with ethyl acetate and water. The organic layer of the filtrate was separated and the aqueous layer was extracted with ethyl acetate. Organic the sky layer and the extract combined the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.68 g (5-fluoro-6-(pyrrolidin-1-yl)pyridine-3-yl)methanol in the form of oily substance brown.

1H-NMR (CDCl3) δ: 1,52-of 1.57 (1H, m), 1,92-to 1.98 (4H, m), 3,61-3,66 (4H, m), to 4.52-4,56 (2H, m), 7,21 (1H, DD, J=13,9, 1.8 Hz), 7,87 (1H, t, J=1,8 Hz)

Comparative example 177

Using the same technology as in Comparative example 67, 5-fluoro-6-(pyrrolidin-1-yl)nicotinamide obtained from (5-fluoro-6-(pyrrolidin-1-yl)pyridine-3-yl)methanol.

1H-NMR (CDCl3) δ: 1,97-2,03 (4H, m), 3,74-of 3.80 (4H, m), 7,56 (1H, DD, J=13,5, 1.8 Hz), 8,32 (1H, t, J=1,8 Hz), 9,76 (1H, d, J=3.2 Hz)

Comparative example 178

Using the same technology as in Comparative example 58, (5-(2-furyl)isoxazol-3-yl)methanol obtained from methyl 5-(2-furyl)isoxazol-3-carboxylate.

1H-NMR (CDCl3) δ: 1,94 of 1.99 (1H, m), to 4.81 (2H, d, J=6.4 Hz), 6,50 (1H, s), is 6.54 (1H, DD, J=3,6, and 1.6 Hz), 6,91 (1H, d, J=3.6 Hz), 7,53-7,56 (1H, m)

Comparative example 179

Using the same technology as in Comparative example 164, 5-(2-furyl)isoxazol-3-carbaldehyde is obtained from (5-(2-furyl)isoxazol-3-yl)methanol.

1H-NMR (CDCl3) δ: return of 6.58 (1H, DD, J=3,6, 1.7 Hz), to 6.80 (1H, s), 7,01 (1H, d, J=3.6 Hz), and 7.6 (1H, d, J=1.7 Hz), 10,18 (1H, s)

Comparative example 180

To a solution of 0.11 kg of sodium hydroxide in 1000 ml of water, add 1.4 kg 12% aqueous solution of sodium hypochlorite and 0.40 kg of 2-chloro-5-fioricetonline and the mixture is stirred at room temperature for 2 hours and 30 minutes. The reaction mixture is heated to 45°C and stirred for 4 hours. The reaction mixture is cooled to room temperature and to it was added ethyl acetate, and 6 mol/l aqueous solution of hydrochloric acid. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract, combine, add anhydrous magnesium sulfate and activated charcoal and the mixture is stirred at room temperature for 30 minutes. Nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure to get 0,29 kg of 2-chloro-5-herperidin-3-amine in the form of a solid brown color.

1H-NMR (CDCl3) δ: 4,22 (2H, s), 6,79 (1H, DD, J=9,3, 2.7 Hz), to 7.67 (1H, d, J=2.7 Hz)

Comparative example 181

To a solution of 1.2 g of 2-chloro-5-herperidin-3-amine in 5 ml of pyridine add 0,86 ml of 2-methylacrylic chloride while cooling on ice and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture are added water and ethyl acetate, the organic layer is separated and the command layer is extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 100:0-50:50 to obtain 1.1 g of N-(2-chloro-5-herperidin-3-yl)-2-methylacrylamide in the form of a colorless oily substance.

1H-NMR (CDCl3) δ: 2,11 (3H, DD, J=1.5 and 1.0 Hz), the ceiling of 5.60-5,63 (1H, m), 5,93-5,96 (1H, m), 7,99-8,02 (1H, m), 8,15 (1H, s), 8,72 (1H, DD, J=9,9, 2,8 Hz)

Comparative example 182

To a solution of 1.1 g of N-(2-chloro-5-herperidin-3-yl)-2-methylacrylamide in 10 ml of N,N-dimethylformamide add 1.5 ml of triethylamine and 0.13 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred at 110°C for 3 hours and 40 minutes in a stream of nitrogen. It is additionally added to 0.13 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture is stirred for 2 hours. It is additionally added to 0.13 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture is stirred for 2 hours. The reaction mixture is cooled to room temperature, then the solvent is distilled off under reduced pressure, and to the obtained residue, add a simple diisopropyl ether and ethyl acetate, the solid product otfit byvaut and washed with ethyl acetate, to the thus obtained solid product add water, chloroform, and methanol, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue, add a simple diisopropyl ether, and the solid product filtered off to obtain 0.25 g of 7-fluoro-4-methyl-1,5-naphthiridine-2(1H)-it is in the form of a solid light brown color.

1H-NMR (CDCl3) δ: 2,45 (3H, d, J=1.0 Hz), 6,61-only 6.64 (1H, m), 7,45 (1H, DD, J=9,6, and 2.6 Hz), 8,51 (1H, d, J=2.6 Hz), 11,78-11,83 (1H, user.)

Comparative example 183

Using the same technology as in Comparative example 3, 1-(1,3-dioxolane-2-ylmethyl)-7-fluoro-4-methyl-1,5-naphthiridine-2(1H)-he obtained from 7-fluoro-4-methyl-1,5-naphthiridine-2(1H)-it 2-methyl bromide-1,3-dioxolane.

1H-NMR (CDCl3) δ: 2,54 (3H, d, J=1.2 Hz), 3,82-4,06 (4H, m), 4,43 (2H, d, J=4,1 Hz), is 5.18 (1H, t, J=4,1 Hz), 6.75 in-is 6.78 (1H, m), to 7.67 (1H, DD, J=10,6, 2.4 Hz), to 8.41 (1H, d, J=2.4 Hz)

Comparative example 184

Using the same technology as in Comparative example 4, (7-fluoro-4-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde is obtained from 1-(1,3-dioxolane-2-ylmethyl)-7-fluoro-4-methyl-1,5-naphthiridine-2(1H)-it.

1H-NMR (CDCl3) δ: 2,58 (3H, s), 5,11 (2H, s), to 6.80 (1H, s), 7,02 (1H, DD, J=9,6, 2,3 is C), to 8.45 (1H, d, J=2.3 Hz), of 9.75 (1H, s)

Comparative example 185

To a solution of 0.10 g (5-bromopyridin-3-yl)methanol in 5 ml of dioxane is added at room temperature 72 mg of 2-Farnborough acid, 67 mg of lithium chloride, 0.51 g of cesium carbonate, 5.4 mg of palladium acetate and 20 mg of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and the mixture is heated under reflux for 1 hour 30 minutes in nitrogen atmosphere. The reaction mixture is cooled to room temperature, and then the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of chloroform:methanol = 95:5 to 90:10 to obtain 39 mg (5-(2-furyl)pyridine-3-yl)methanol in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: 1,50-1,80 (1H, usher.), 4,78 (2H, s), of 6.52 (1H, DD, J=3,4, 1.7 Hz), 6,77 (1H, d, J=3,4 Hz), 7,53 (1H, d, J=1.7 Hz), 7,98 (1H, s), of 8.47 (1H, d, J=1,8 Hz), cent to 8.85 (1H, d, J=1,8 Hz)

Comparative example 186

Using the same technology as in Comparative example 164, 5-(2-furyl)nicotinamide obtained from (5-(2-furyl)pyridine-3-yl)methanol.

1H-NMR (CDCl3) δ: 6,56 (1H, DD, J=3.3, which is 1.7 Hz), to 6.88 (1H, d, J=3.3 Hz), 7,58 (1H, d, J=1.7 Hz), 8,39 (1H, t, J=1.9 Hz), of 8.95 (1H, d, J=1.9 Hz), to 9.15 (1H, d, J=1.9 Hz), 10,16 (1H, s)

Comparative example 187

To a suspension of 0.50 G1-(1,3-dioxolane-2-ylmethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it's in 3 ml of tetrahydrofuran, add 3 ml of 20% aqueous sodium hydroxide solution and the mixture is heated under reflux, under stirring, for 1 hour. To it was added 3 ml of water and the mixture is heated under reflux, with stirring, for 3 hours 30 minutes. To it was added 3 ml of 20% aqueous sodium hydroxide solution and the mixture is heated under reflux, with stirring, for 4 hours. The tetrahydrofuran is distilled off under reduced pressure, and then the mixture is heated under reflux, with stirring, for 1 hour 30 minutes. After cooling to room temperature, to the reaction mixture are added 2 mol/l hydrochloric acid and bring the pH to 5. To it was added ethyl acetate, the organic layer is separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue, add a simple diethyl ether, and the solid product filtered off to obtain 0.32 g of 1-(1,3-dioxolane-2-ylmethyl)-7-hydroxy-1,5-naphthiridine-2(1H)-it is in the form of a solid yellow color.

1H-NMR (DMSO-d6) δ: 3,76-3,86 (2H, m), 3,92-4,06 (2H, m), 4,32 (2H, d, J=4.6 Hz), to 5.08 (1H, t, J=4.6 Hz), is 6.61 (1H, d, J=9.6 Hz), 7,37 (1H, d, J=2.2 Hz), to 7.84 (1H, d, J=9.6 Hz), 8,14 (1H, d, J=2.2 Hz), 10,6-11,0 (1H, user.)

Comparative example 188

To a suspension of 0.15 g of 1-(1,3-dioxo the EN-2-ylmethyl)-7-hydroxy-1,5-naphthiridine-2(1H)-she's in 1.5 ml of toluene was added 1 ml of 40% aqueous sodium hydroxide solution, 97 mg of tetrabutylammonium bromide and 0.25 ml of 10 mol/l chlorine(debtor)methane in N,N-dimethylformamide, the mixture is stirred for 50 minutes, then add 1 ml of a solution of 10 mol/l chlorine(debtor)methane in N,N-dimethylformamide and the mixture is stirred for 3 hours and 40 minutes. To the reaction mixture are added water and toluene, the organic layer is separated and the aqueous layer was extracted with toluene. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 95 mg of 7-(deformedarse)-1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-it is in the form of a solid light brown color.

1H-NMR (CDCl3) δ: 3,83-Android 4.04 (4H, m), 4,47 (2H, d, J=4, 2 Hz), 5,20 (1H, t, J=4, 2 Hz), of 6.65 (1H, t, J=72,2 Hz), make 6.90 (1H, d, J=9.9 Hz), to 7.77 (1H, d, J=2.2 Hz), of 7.90 (1H, DD, J=9,9, 0.7 Hz), 8,40 (1H, d, J=2.2 Hz)

Comparative example 189

Using the same technology as in Comparative example 4, (7-(deformedarse)-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde obtained from 7-(deformedarse)-1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-it.

1H-NMR (CDCl3) δ: 5,13 (2H, s), 6,63 (1H, t, J=71,9 Hz)6,94 (1H, d, J=9.8 Hz), to 7.09 (1H, d, J=2.2 Hz), 7.95 is-8,00 (1H, m), to 8.45 (1H, d, J=2.2 Hz), made up 9.77 (1H, s)

Comparative example 190

To a solution of 0.26 g of 3-methyl-1,5-naphthiridine in 4 ml of benzene added 0.35 g of N-bromosuccinimide and 29 mg azobisisobutyronitrile and the mixture is heated under reflux, with stirring, for 2 hours and 15 minutes. It is additionally added to 0.13 g of N-bromosuccinimide and the mixture is heated under reflux, with stirring, for 30 minutes. After cooling to room temperature, 0.50 g of a solution of hexamethylenetetramine in 1.5 ml of water is added dropwise to the reaction mixture while cooling on ice, add 1.5 ml of acetic acid and the mixture is heated under reflux, with stirring, for 1 hour and 20 minutes. After cooling to room temperature, to the reaction mixture are added chloroform and 20% aqueous sodium hydroxide solution, and the pH of the mixture was adjusted to 8.5. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue purified using flash column-chromatography on silica gel using as eluent hexane:ethyl acetate = 1:1, to obtain 25 mg of 1,5-naphthiridine-3-carbaldehyde in the form of a solid product is slightly yellow in color.

1H-NMR (CDCl3) δ: 7,80 (1H, d is, an 8.5 and 4.2 Hz), 8,49-charged 8.52 (1H, m), 8,82 cent to 8.85 (1H, m), 9,12 (1H, DD, J=4.2, and 1.5 Hz), 9,46 (1H, d, J=2.2 Hz), 10,35 (1H, s)

Comparative example 191

To a solution of 0.10 g of methyl 6-chloropyrazine-2-carboxylate in 2.9 ml of dioxane is added 65 mg of 2-Farnborough acid, 74 mg of lithium chloride, or 0.57 g of cesium carbonate, 21 mg, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and 24 mg of Tris(dibenzylideneacetone)diplegia(0) and the mixture heated under reflux for 2 hours. To the reaction mixture are added water and ethyl acetate, the organic layer is separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is then distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of hexane:ethyl acetate = 87:13-83:17 to obtain 74 mg of methyl 6-(2-furyl)pyrazin-2-carboxylate in the form of a solid white product.

1H-NMR (CDCl3) δ: of 4.05 (3H, s), 6,60 (1H, DD, J=3,5, 1.8 Hz), 7,30-to 7.32 (1H, m), 7,62-the 7.65 (1H, m), 9,12 (1H, s), 9,12 (1H, s)

Comparative example 192

Using the same technology as in Comparative example 58, 6-(2-furyl)pyrazin-2-yl)methanol obtained from methyl 6-(2-furyl)pyrazin-2-carboxylate.

1H-NMR (CDCl3) δ: is 3.08-3.24 in (1H, m), a 4.86 (2H, s), 6,59 (1H, DD, J=3,4, 1.7 Hz), 7,18 (1H, d, J=3,4 Hz), 7,58 to 7.62 (1H, m), 8,46 (1H, is), 8,89 (1H, s)

Comparative example 193

Using the same technology as in Comparative example 67, 6-(2-furyl)pyrazin-2-carbaldehyde is obtained from (6-(2-furyl)pyrazin-2-yl)methanol.

1H-NMR (CDCl3) δ: 6,63 (1H, DD, J=3,4, 1.7 Hz), 7,30 (1H, DD, J=3,4, 0.7 Hz), 7,66 (1H, DD, J=1,7, 0.7 Hz), 8,99 (1H, s), 9,16 (1H, s), 10,18 (1H, s)

Comparative example 194

Using the same technology as in Comparative example 58, (5-(2-furyl)-1,3-oxazol-2-yl)methanol obtained from ethyl 5-(2-furyl)-1,3-oxazol-2-carboxylate.

1H-NMR (CDCl3) δ: 4,78 (2H, s), 6,50 (1H, DD, J=3,4, 2.0 Hz), only 6.64 (1H, d, J=3,4 Hz), 7,21 (1H, s), 7,46-of 7.48 (1H, m)

Comparative example 195

Using the same technology as in Comparative example 164, 5-(2-furyl)-1,3-oxazol-2-carbaldehyde is obtained from (5-(2-furyl)-1,3-oxazol-2-yl)methanol.

1H-NMR (CDCl3) δ: to 6.57 (1H, DD, J=3,5, 1.8 Hz), 6,94 (1H, d, J=3.5 Hz), 7,53 (1H, s), 7,56-7,58 (1H, m), of 9.75 (1H, s)

Comparative example 196

To a solution of 16 g of 4-oxo-6-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-3-yl triftoratsetata in 100 ml of acetonitrile is added in nitrogen atmosphere of 5.1 ml propargilovyh ethanol, 18 ml of triethylamine, and 0.62 g dichlorobis(triphenylphosphine)palladium(II) and 0.42 g of copper iodide (I) and the mixture is stirred at room temperature for 2 hours. Nerastvorim is Eesa substance is filtered off and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of chloroform:methanol = 100:0-97:3 to obtain 6.2 g of 5-(3-hydroxy-1-propyne-1-yl)-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-4-it is in the form of oily substance brown.

1H-NMR (CDCl3) δ: 1,51-1,90 (6H, m), 2,27-2,40 (1H, usher.), 3,52-of 3.60 (1H, m), 3,78-3,86 (1H, m), 4,34 (1H, d, J=14,9 Hz), 4,50 (2H, s), of 4.54 (1H, d, J=14,9 Hz), to 4.73 (1H, t, J=3.3 Hz), 6,51 (1H, s), of 8.00 (1H, s)

Comparative example 197

Using the same technology as in Comparative example 151, 5-(3-hydroxypropyl)-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-4-one is obtained from 5-(3-hydroxy-1-propyne-1-yl)-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-4-it.

1H-NMR (CDCl3) δ: 1,52-of 1.92 (8H, m), of 2.51 (2H, t, J=7.0 Hz), 2,85-3,17 (1H, usher.), 3,52-of 3.60 (1H, m), of 3.57 (2H, t, J=5,9 Hz), 3,80-3,88 (1H, m)to 4.33 (1H, d, J=14.4 Hz), a 4.53 (1H, d, J=14.4 Hz), to 4.73 (1H, t, J=3.2 Hz), 6,46 (1H, s), of 7.70 (1H, s)

Comparative example 198

To a solution of 1.2 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-4-it is in 5 ml ethanol add 16 ml of 25% aqueous ammonia and the mixture is heated under reflux, with stirring for 9 hours and 30 minutes. The solvent is distilled off under reduced pressure and the resulting residue purified using flash column-chromatography on silica gel with and the use of gradient elution of chloroform:methanol = 95:5-90:10 with receipt of 0.42 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-Piran-2-yloxy)methyl)pyridin-4(1H)-it is in the form of oily substance brown.

1H-NMR (CDCl3) δ: 1,52-of 1.92 (8H, m)of 2.64 (2H, t, J=6.5 Hz), 3,51 (2H, t, J=5.6 Hz), 3,55-3,62 (1H, m), 3,93-was 4.02 (1H, m), 4,55-and 4.68 (3H, m), of 6.31 (1H, s), 7,47 (1H, s)

Comparative example 199

(1) To a solution of 0.42 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-Piran-2-yloxy)methyl)pyridin-4(1H)-she's in 8 ml of tetrahydrofuran added 0.54 g of triphenylphosphine and 0,89 g of 40% solution of diethylazodicarboxylate/toluene and the mixture is stirred for 10 minutes. The solvent is distilled under reduced pressure to obtain 7-((tetrahydro-2H-Piran-2-yloxy)methyl)-3,4-dihydro-2H-pyrano(3,2-c)pyridine in the form of oily substance brown.

(2) using the same technology as in Comparative example 172, (3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-yl)methanol hydrochloride is obtained from 7-((tetrahydro-2H-Piran-2-yloxy)methyl)-3,4-dihydro-2H-pyrano(3,2-c)pyridine.

1H-NMR (DMSO-d6) δ: 1,99 (2H, Quint., J=5.8 Hz), 2,84 (2H, t, J=6.2 Hz), to 4.46 (2H, t, J=5,2 Hz), 4,70 (2H, s), 6,06-6,36 (1H, usher.), 7,22 (1H, s), 8,48 (1H, s)

Comparative example 200

Using the same technology as in Comparative example 123, 3,4-dihydro-2H-pyrano(3,2-c)pyridine-7-carbaldehyde is obtained from (3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-yl)methanol hydrochloride.

1H-NMR (CDCl3) δ: of 2.08 (2H, Quint., J=5.8 Hz), 2,85 (2H, t, J=6.4 Hz), 4,30 (2H, t, J=5,1 Hz), was 7.36 (1H, s), scored 8.38 (1H, s), becomes 9.97 (1H, s)

Comparative example 201

To a solution of 1.8 g of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine in 8 ml of tetrahydrofuran added while cooling on ice 2.0 ml triethyl 1,1,2-acontracorriente and 0.63 g of 60% sodium hydroxide and the mixture is stirred at room temperature for 2 hours. To it was added water and ethyl acetate, the organic layer is separated and washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 3.5 g of triethyl 1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)ethane-1,1,2-tricarboxylate in the form of oily substance brown.

1H-NMR (CDCl3) δ: 1,20 of 1.28 (9H, m), of 3.57 (2H, s), 4,10 (2H, square, J=7,2 Hz), 4,25 (4H, square, J=7,2 Hz), 8,64-8,67 (1H, m), 8,96-8,99 (1H, m)

Comparative example 202

(1) To a solution of 3.5 g of triethyl 1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)ethane-1,1,2-tricarboxylate in a mixture of 35 ml of ethanol and 8.8 ml of water is added 0.27 g of ammonium chloride and 1.6 g of iron powder and the mixture is heated under reflux, with stirring, for 2 hours and 20 minutes. After cooling to room temperature nerastvorimaya substance is filtered off and washed with ethyl acetate and water. To it add the sodium chloride, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed us is placed in an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain a residue in the form of oily substance brown.

(2) To a solution of the obtained residue in (1) in 8 ml of dioxane is added to 8.0 ml of hydrochloric acid and the mixture is heated under reflux, with stirring, for 1 hour 30 minutes. The solvent is distilled off under reduced pressure, there was added ethanol and simple diethyl ether and the precipitate is filtered off with obtaining of 0.44 g of 7-(trifluoromethyl)-3,4-dihydro-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid light brown color.

1H-NMR (DMSO-d6) δ: to 2.65 (2H, t, J=7,7 Hz), of 3.13 (2H, t, J=7,7 Hz), 7,46 (1H, d, J=1.3 Hz), 8,46 (1H, d, J=1.3 Hz), 10,43 (1H, s)

Comparative example 203

Using the same technology as in Comparative example 3, 1-(2,2-dimethoxymethyl)-7-(trifluoromethyl)-3,4-dihydro-1,5-naphthiridine-2(1H)-he obtained from 7-(trifluoromethyl)-3,4-dihydro-1,5-naphthiridine-2(1H)-she hydrochloride and 2-bromo-1,1-dimethoxyethane.

1H-NMR (CDCl3) δ: 2,82 (2H, t, J=7.5 Hz), up 3.22 (2H, t, J=7.5 Hz), 3.43 points-of 3.46 (6H, m), 3,99 (2H, d, J=5,1 Hz), br4.61 (1H, t, J=5,1 Hz), 7,89-a 7.92 (1H, m), 8,45-8,48 (1H, m)

Comparative example 204

To a solution of 0.11 g of 1-(2,2-dimethoxymethyl)-7-(trifluoromethyl)-3,4-dihydro-1,5-naphthiridine-2(1H)-she's in 2 ml of dioxane is added 0.16 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone and the mixture is heated under reflux, with stirring, for 3 hours. To it was added water and ethyl acetate, the pH of the mixture was adjusted to 12 using 2.0 mol/l of water is of astora sodium hydroxide and the organic layer separated. The organic layer was washed with aqueous solution of sodium hydroxide and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 90 mg of 1-(2,2-dimethoxymethyl)-7-(trifluoromethyl)-1,5-naphthiridine-2(1H)-it is in the form of a solid brown color.

1H-NMR (CDCl3) δ: 3,44 (6H, s), to 4.38 (2H, d, J=5,1 Hz), 4,63 (1H, t, J=5,1 Hz), 7,03 (1H, d, J=9.8 Hz), 7,98 (1H, d, J=9.8 Hz), 8,24 (1H, s), is 8.75 (1H, d, J=1.0 Hz)

Comparative example 205

To a solution of 90 mg of 1-(2,2-dimethoxymethyl)-7-(trifluoromethyl)-1,5-naphthiridine-2(1H)-it is in 0.72 ml of methyl ethyl ketone type 38 μl of concentrated hydrochloric acid and the mixture is heated under reflux, with stirring, for 1 hour 30 minutes. The reaction mixture is cooled to room temperature, there was added chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 67 mg (2-oxo-7-(trifluoromethyl)-1,5-naphthiridine-1(2H)-yl)acetaldehyde in the form of oily substance brown.

1H-NMR (CDCl3) δ: to 5.21 (2H, s), to 7.09 (1H, d, J=9.8 Hz), 7,49 (1H, s), of 8.04 (1H, d, J=9.8 Hz), 8,79-8,82 (1H, m), 9,82 (1H, s)

Comparative example 206

To a suspension of 10 g of 2,6-dichloro-5-fornicating acid in 30 ml of toluene added 8.5 g of thionyl chloride and 0.10 ml of N,N-dimethylformamide and the mixture was stirred at 72°C for 1 hour and 30 minutes. The reaction mixture is cooled to room temperature and the solvent is distilled off under reduced pressure. The resulting residue is added dropwise to 30 ml of 25% aqueous solution of ammonium at -20°C. the Temperature was raised to 5C° and the mixture is stirred for 30 minutes. The solid product is filtered off with getting to 9.9 g of 2,6-dichloro-5-fornicating in the form of a solid white product.

1H-NMR (DMSO-d6) δ: 7,94 (1H, s), 8,11 (1H, s)8,23 (1H, d, J=7,8 Hz)

Comparative example 207

Using the same technology as in Comparative example 101, 2-chloro-5-fluoro-6-nicotine amide derived from 2,6-dichloro-5-fioricetonline.

1H-NMR (CDCl3) δ: 2,56 (3H, d, J=2,9 Hz), 5,91 (1H, s), 6,85 (1H, s), of 8.00 (1H, d, J=8,5 Hz)

Comparative example 208

Using the same technology as in Comparative example 180, 2-chloro-5-fluoro-6-methylpyridin-3-amine obtained from 2-chloro-5-fluoro-nicotine amide.

1H-NMR (CDCl3) δ: 2,37 (3H, d, J=2.7 Hz), Android 4.04 (2H, s), is 6.78 (1H, d, J=9.5 Hz)

Comparative example 209

Using the same technology as in Comparative example 1, butyl (2E)-3-(3-amino-5-fluoro-6-m is terpyridine-2-yl)acrylate are obtained from 2-chloro-5-fluoro-6-methylpyridin-3-amine and butyl acrylate.

1H-NMR (CDCl3) δ: of 0.95 (3H, t, J=7,3 Hz), of 1.40 to 1.48 (2H, m), 1,68 (2H, Quint., J=6.8 Hz), is 2.40 (3H, d, J=2.7 Hz), 3,93 (2H, s), is 4.21 (2H, t, J=6.8 Hz), to 6.67 (1H, d, J=10,2 Hz), 6.87 in (1H, d, J=15.2 Hz), 7,71 (1H, d, J=15.2 Hz)

Comparative example 210

Using the same technology as in Comparative example 2, 7-fluoro-6-methyl-1,5-naphthiridine-2(1H)-he obtained from butyl (2E)-3-(3-amino-5-fluoro-6-methylpyridin-2-yl)acrylate.

1H-NMR (DMSO-d6) δ: 2.49 USD (3H, d, J=2,9 Hz), of 6.68 (1H, d, J=9.8 Hz), 7,41 (1H, J=10,2 Hz), 7,89 (1H, d, J=9.8 Hz), 11,9 (1H, s)

Comparative example 211

To a solution of 0.74 g of 7-fluoro-6-methyl-1,5-naphthiridine-2(1H)-it is in 5 ml of N,N-dimethylformamide add 2.0 g of cesium carbonate and 0.84 g of 2-bromo-1,1-dimethoxyethane, the temperature was raised to 90-100°C and the mixture is stirred for 2 hours and 30 minutes. The reaction mixture is cooled to room temperature, there was added ethyl acetate, nerastvorimaya substance is filtered, and the solvent is then distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 100:1 with obtaining 0,69 g of 1-(2,2-dimethoxymethyl)-7-fluoro-6-methyl-1,5-naphthiridine-2(1H)-it is in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 2,58 (3H, d, J=2.7 Hz), 3.43 points (6H, s), 4,28 (2H, d, J=5,2 Hz), with 4.64 (1H, t, J=5,2 Hz), 6,83 (1H, d, J=9.8 Hz), to 7.64 (1H, d, J=11.2 Hz), 7,86 (1H, d, J=9.8 Hz)

Comparative example 212

The solution to 0.69 g of 1-(2,2-dimethoxymethyl)-7-fluoro-6-methyl-1,5-naphthiridine-2(1H)-she's in 6 ml of methyl ethyl ketone added 0.35 ml of concentrated hydrochloric acid, and the temperature was raised to 74°C and the mixture is stirred for 2 hours and 50 minutes. The reaction mixture is cooled to room temperature and the solvent is distilled off under reduced pressure. To the obtained residue is added ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate to obtain 0.52 g (7-fluoro-6-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 2,59 (3H, d, J=2.7 Hz), 5,10 (2H, s), 6.89 in (1H, d, J=10.0 Hz), 7,00 (1H, dt, J=10.0 Hz), 7,92 (1H, d, J=9.8 Hz), of 9.75 (1H, s)

Comparative example 213

To a mixed solution of 0.17 g of tert-butyl (5-(methyl bromide)pyrazin-2-yl)carbamate in 4 ml DMSO and 2 ml of dichloromethane added while cooling on ice 0.26 g of trimethylamine N-oxide dihydrate and the mixture is stirred for 2 hours. To it was added water and chloroform, the organic layer is separated and washed with saturated aqueous sodium bicarbonate, water and saturated aq is m solution of sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.10 g of tert-butyl (5-formylpyridine-2-yl)carbamate in the form of a solid white product.

1H-NMR (CDCl3) δ: 1,55-to 1.59 (9H, m), 7,63-of 7.70 (1H, usher.), 8,82 (1H, d, J=1.2 Hz), 9,44 (1H, dt, J=1.2 Hz), 10,07 (1H, s)

Comparative example 214

To a solution of 1.66 g of (7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in 42 ml of chloroform added to 1.61 g of tert-butyl (piperidine-4-yl)carbamate and of 0.48 g of acetic acid and the mixture is stirred at room temperature for 7.5 hours. To the reaction mixture of 2.56 g of triacetoxyborohydride sodium and the mixture is stirred for 10 hours. To it was added a saturated aqueous solution of sodium bicarbonate and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. Ethanol is added to the obtained residue, and the solid product is filtered off with getting a 0.59 g of tert-butyl (1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of a solid white product.

1H-NMR (CDCl3) δ: 1,31-1,49 (11H, m), 1,84-2,04 (2H, m), 2,14-is 2.37 (2H, m), 2,56-a 2.71 (2H, m), 2,82 was 3.05 (2H, m), 3,35-of 3.60 (1H, m), 4,20-to 4.52 (3H, m), 6,79-6,93 (1H, m), 7,44-7,58 (1H, m), 7,79-of 7.96 (1H, m), of 8.37-8,48 (1H, m,)

Comparison is sustained fashion example 215

A solution of 0.59 g of tert-butyl (1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 30 ml of 2 mol/l solution of hydrochloric acid/ethanol was stirred at room temperature for 18 hours. To the reaction mixture add 2 ml of chloroform and the mixture is stirred at 40°C for 4 hours, and stirred at room temperature for 18 hours. In the reaction mixture and the solvent is distilled off under reduced pressure, the mixture is neutralized with saturated aqueous sodium bicarbonate solution, and then the solvent is distilled off under reduced pressure. The obtained residue was washed with ethanol and, in the mother liquid, the solvent is distilled off under reduced pressure and the resulting residue purified by column chromatography on silica gel using silica gel: Chromatorex-NH production Fuji Silysia Chemical Ltd. and eluent chloroform:methanol = 10:1 with obtaining 421 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it is in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 1,30-1,45 (2H, m), and 1.54 (2H, s), a 1.75-to 1.87 (2H, m), 2,11-of 2.24 (2H, m), 2,60 was 2.76 (3H, m), 2,86-to 2.99 (2H, m), 4,25-4,39 (2H, m)6,86 (1H, d, J=9.6 Hz), of 7.48-of 7.60 (1H, m), 7,89 (1H, d, J=9.6 Hz), at 8.36-8,49 (1H, m)

Comparative example 216

To a solution of 1.00 g of 3-bromo-1,5-naphthiridine in 5 ml of 1,4-dioxane add to 0.67 g of tert-BUTYLCARBAMATE, 2,18 g of the carbonate as what I 44 mg of Tris(benzylideneacetone)diplodia and 83 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and the mixture is stirred at 80°C for 12.5 hours in argon atmosphere. To the reaction mixture are added water and chloroform and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Silica Gel 60N production KANTO CHEMICAL CO., INC. and eluent chloroform:methanol, 10:1, receipt of 1.03 g of tert-butyl 1,5-naphthiridine-3-ylcarbamate in the form of an oily yellow substance.

1H-NMR (DMSO-d6) δ: 1,53 (9H, s), 7,60-the 7.65 (1H, m), 8,32 (1H, d, J=4,1 Hz), charged 8.52 (1H, s), 8,90-8,93 (1H, m), 8,97-9,00 (1H, m), 10,08 (1H, s)

Comparative example 217

To a solution of 1.00 g of tert-butyl 1,5-naphthiridine-3-ylcarbamate in 6 ml of methanol was added 1 ml of 12 mol/l aqueous solution of hydrogen chloride and the mixture is stirred for 30 minutes. To the reaction mixture add 5 ml of methanol and 1 ml of 12 mol/l aqueous solution of hydrogen chloride and the mixture is stirred at 40°C for 40 minutes and at 80°C for 40 minutes. In the reaction mixture and the solvent is distilled off under reduced pressure, the mixture is neutralized with saturated aqueous sodium bicarbonate solution, is then the solvent is distilled off under reduced pressure. The obtained residue was washed with ethanol and, in the mother liquid, the solvent is distilled off under reduced pressure and the resulting residue purified by column chromatography on silica gel using silica gel: Chromatorex-NH production Fuji Silysia Chemical Ltd. and eluent chloroform:methanol = 10:1 to obtain 0.50 g of 1,5-naphthiridine-3-amine in the form of a solid yellow color.

1H-NMR (CDCl3) δ: 4,18 (2H, s), 7,31-7,42 (1H, m), 7,43-7,50 (1H, m), 8,21-8,30 (1H, m), 8,51-to 8.62 (1H, m), 8,77-8,88 (1H, m)

Comparative example 218

To 2 ml of hydrogen fluoride/pyridine added 145 mg 1,5-naphthiridine-3-amine at 0°C, the reaction mixture are added 76 mg of sodium nitrite and stirred at 0°C for 1 hour. The reaction mixture was stirred at 60°C for 1 hour and neutralized with saturated aqueous sodium bicarbonate solution at 0°C, then to it was added chloroform and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Silica Gel 60N production KANTO CHEMICAL CO., INC. and eluent chloroform:methanol = 20:1 to obtain 77 mg of 3-fluoro-1,5-naphthiridine in the form of solid product is a light yellow color.

1/sup> H-NMR (CDCl3) δ: 7,62-to 7.67 (1H, m), 8,03-8,08 (1H, m), 8,42-of 8.47 (1H, m), 8,90-to 8.94 (1H, m), 8,98-9,03 (1H, m)

Comparative example 219

To a solution of 76 mg of 3-fluoro-1,5-naphthiridine in 3 ml of chloroform added 136 mg of m-chloroperbenzoic acid and the mixture is stirred at room temperature for 2.5 hours. To it was added 27 mg of m-chloroperbenzoic acid and the mixture is stirred at room temperature for 1 hour. To the reaction mixture are added 5% aqueous sodium thiosulfate solution and chloroform, the organic layer separated and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Silica Gel 60N production KANTO CHEMICAL CO., INC. and eluent chloroform:methanol = 50:1 to receive 60 mg of 7-fluoro-1,5-naphthiridine 1-oxide in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 7,53 (1H, DD, J=8,7, 6,0 Hz), of 8.04 (1H, d, J=8.7 Hz), 8,59 (1H, d, J=6.0 Hz), 8,66-8,77 (1H, m), 8,91-of 9.02 (1H, m)

Comparative example 220

To a solution of 60 mg of 7-fluoro-1,5-naphthiridine 1-oxide in 1.6 ml of chloroform added 84 mg p-toluensulfonate, 171 mg of potassium carbonate and 0.5 ml of water and the mixture is stirred at room temperature overnight. The solid product is filtered off, purified by using column chromate is graphy on silica gel using silica gel: Chromatorex-NH production Fuji Silysia Chemical Ltd. and eluent chloroform:methanol = 10:1 to obtain 14 mg of 7-fluoro-1,5-naphthiridine-2(1H)-it is in the form of a solid white product.

1H-NMR (CDCl3) δ: of 6.71 (1H, d, J=10.1 Hz), 7.29 trend-EUR 7.57 (1H, m), 7,94 (1H, d, J=10.1 Hz), and 8.50 (1H, d, J=2.3 Hz), 12,00 (1H, s)

Comparative example 221

To 20,02 g of 7-bromo-1-(1,3-dioxolane-2-ylmethyl)-1,5-naphthiridine-2(1H)-it add 400 ml of 80% aqueous solution triperoxonane acid and the mixture was stirred at 90°C for 3.5 hours. The reaction mixture is cooled to room temperature, and then the solvent is distilled off under reduced pressure. the pH of the resulting residue was adjusted to 7.7 with 2 mol/l aqueous solution of sodium hydroxide. Then the precipitate is filtered off with getting 13,43 g (7-bromo-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in the form of a solid brown color.

1H-NMR (CDCl3) δ: 5,13 (2H, s), 6,98 (1H, d, J=9.6 Hz), 7,49 (1H, d, J=1.4 Hz), 7,95 (1H, d, J=9.6 Hz), at 8.60 (1H, d, J=1.4 Hz), 9,78 (1H, s)

Example 1

To 0.11 g (7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde add 0.15 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate in 4 ml of dichloromethane, 24 μl of acetic acid and 0.13 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 1 hour. To the reaction mixture are added chloroform and a saturated aqueous solution of bicarbonate n is sodium, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue purified using flash column-chromatography on basic silica gel using a gradient elution of hexane:ethyl acetate = 100:0 to 20:80, and then a gradient eluent chloroform:methanol = 100:0-90:10 to obtain 0.18 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate foam light yellow color.

1H-NMR (CDCl3) δ: of 1.39 (9H, s), 1,40-1,72 (4H, m), 2.06 to to 2.25 (2H, m), 2.57 m-of 2.64 (2H, m), 2,96 was 3.05 (2H, m), of 3.96 (3H, s), 4,05-4,18 (1H, m), 4,23-4,50 (8H, m), of 6.73 (1H, d, J=9.8 Hz), was 6.73 (1H, s), 7,17 (1H, d, J=2.3 Hz), 7,83 (1H, d, J=9.8 Hz), with 8.05 (1H, s), of 8.27 (1H, d, J=2.3 Hz)

Example 2

To a solution of 0.17 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 3 ml of ethyl acetate added at room temperature to 6.0 ml of 4.0 mol/l solution of hydrochloric acid/ethyl acetate. The mixture was stirred at the same temperature for 1 hour and the solvent is distilled off under reduced pressure. To the obtained residue, add a simple diethyl ether, and t is erdy the product is filtered to obtain 0.16 g of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 1,98-to 2.13 (2H, m), 2,50-2,60 (2H, m), 3,21-to 3.34 (2H, m), 3,60-of 3.77 (3H, m), 3.95 to 4,08 (2H, m), of 4.05 (3H, s), 4,42-of 4.49 (4H, m), 4.53-in-4,59 (2H, m), 4,72-to 4.87 (2H, m), 6.89 in (1H, d, J=9.6 Hz), 7,37 (1H, ), of 7.48-7,53 (1H, m), of 8.06 (1H, d, J=9.6 Hz), 8,31 (1H, s), 8,40-8,44 (1H, m)

Example 3

To 0.11 g (7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde add solution to 0.19 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl(piperidine-4-yl)carbamate in 3 ml of dichloromethane, 31 μl of acetic acid and 0.17 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 1 hour, and then leave overnight. To it was added chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 19:1 to obtain 0.21 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of a white foam.

1H-NMR (CDCl3) δ: of 1.39 (9H, s), 1,33-1,71 (4H, m), 2,08-of 2.24 (2H, m), 2.57 m) 2.63 in (2H, m), 2,94-3,01 (H, m), was 4.02-4,18 (1H, m), 4,23-4,46 (8H, m), of 6.73 (1H, s), at 6.84 (1H, d, J=9.8 Hz), 7,47 (1H, DD, J=10,1, 2.4 Hz), 7,87 (1H, d, J=9.8 Hz), with 8.05 (1H, s), to 8.41 (1H, d, J=2.4 Hz)

Example 4

To a solution of 0.21 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 4 ml of ethanol is added at room temperature, 4 ml of 6.0 mol/l solution of hydrochloric acid/ethanol and the mixture is stirred for 1 hour 30 minutes. The solvent is distilled off under reduced pressure, to the obtained residue, add a simple diethyl ether, and the solid product filtered off to obtain 0.21 g of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 2,00-of 2.16 (2H, m), 2,52-2,61 (2H, m), 3,23-to 3.35 (2H, m), 3,61-to 3.67 (2H, m), 3,69-of 3.80 (1H, m), 3,98-4,07 (2H, m), 4,46-4,51 (2H, m), a 4.53 (2H, s), 4,58-4,63 (2H, m), 4,71-4,96 (2H, m), 7,00 (1H, d, J=9.8 Hz), 7,47 (1H, s), 7,93-to 7.99 (1H, m), 8,10 (1H, d, J=9.8 Hz), of 8.37 (1H, s), 8,56-8,58 (1H, m)

Example 4(2)

To a suspension of 0.30 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 1.8 ml of isopropyl alcohol added to 0.23 ml of concentrated hydrochloride and the mixture is heated under reflux, with stirring, over 1 hour 50 minutes. React the mixture was cooled to 5°C, and the solid product filtered off to obtain 0.28 g of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she trihydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 2,00-of 2.16 (2H, m), 2,52-2,61 (2H, m), 3,23-to 3.35 (2H, m), 3,61-to 3.67 (2H, m), 3,69-of 3.80 (1H, m), 3,98-4,07 (2H, m), 4,46-4,51 (2H, m)to 4.52 (2H, s), 4,55-4,63 (2H, m), 4,71-4,96 (2H, m), of 6.99 (1H, d, J=9.8 Hz), 7,44 (1H, s), 7,93-to 7.99 (1H, m), 8,10 (1H, d, J=9.8 Hz), at 8.36 (1H, s), to 8.57 (1H, d, J=2.2 Hz)

Example 5

Using the same technology as in Example 1, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)-2-methylpiperidin-4-yl)carbamate is obtained from (7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(2 methylpiperidin-4-yl)carbamate.

1H-NMR (CDCl3) δ: 0,99-1,10 (3H, m), 1,33-1,83 (13H, m), 2.57 m-2,78 (4H, m), 3,14 is 3.23 (1H, m), of 3.96 (3H, s), 4,13-4,53 (9H, m), of 6.73 (1H, s), of 6.73 (1H, d, J=9.6 Hz), 7,19 (1H, d, J=2.2 Hz), 7,83 (1H, d, J=9.6 Hz), 8,05 (1H, s), of 8.27 (1H, d, J=2.2 Hz)

Example 6

Using the same technology as in Example 2, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-2-methylpiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)-2-methylpiperidin-4-yl)carbama the A.

1H-NMR (CDCl3) δ: of 1.03 (3H, d, J=6.6 Hz), 1,20-1,90 (4H, m), 2,66-is 2.88 (5H, m), 2.95 and was 3.05 (1H, m), of 3.77 (2H, d, J=2.7 Hz), of 3.97 (3H, s), 4,25-4,43 (6H, m), 6,74 (1H, d, J=9.6 Hz), PC 6.82 (1H, s), 7,20-of 7.25 (1H, m), 7,84 (1H, d, J=9.6 Hz), 8,10 (1H, s), of 8.27 (1H, d, J=2.4 Hz)

To a solution of 53 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-2-methylpiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she's in 1 ml of ethyl acetate added at room temperature to 0.23 ml of 4.0 mol/l solution of hydrochloric acid/ethyl acetate, and after stirring the solid product is filtered off to obtain 40 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-2-methylpiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (DMSO-d6-D2O) δ: of 1.03 (3H, d, J=6.6 Hz), from 2.00 to 2.35 (4H, m), 3,12-of 3.60 (5H, m), 3,90-4,30 (3H, m), 4,07 (3H, s), 4,33 is 4.45 (4H, m), 4,58-a 4.86 (2H, m), 6,72 (1H, d, J=9.5 Hz), 7,22 (1H, s), 7,66 to 7.75 (1H, m), of 7.96 (1H, d, J=9.5 Hz), compared to 8.26 (1H, s), a 8.34 (1H, d, J=1.9 Hz)

Example 7

To a suspension of 0.20 g of 1-(2-(4-(aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride in 3 ml of methanol is added at room temperature 66 mg cyanoborohydride sodium, 64 μl of 3-fluoro-4-methylbenzaldehyde and 0.12 ml of acetic acid and the mixture was stirred at the same temperature for 1 hour and 30 minutes. It adds a 64 μl of 3-fluoro-4-methylbenzaldehyde and the mixture was stirred at the same temperature for 1 hour and 30 min is so It is additionally added 33 mg of cyanoborohydride sodium and 64 μl of 3-fluoro-4-methylbenzaldehyde and the mixture was stirred at the same temperature for 3 hours and then left overnight. Mix download chloroform and the pH adjusted to 9.9 with saturated aqueous sodium bicarbonate solution and 1 mol/l aqueous solution of sodium hydroxide. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 10:1 to obtain 0.16 g of 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it is in the form of oily substance slightly yellow in color.

1H-NMR (CDCl3) δ: 1,37-1,49 (2H, m), 1,87-of 1.95 (2H, m), 2,17 was 2.25 (2H, m), and 2.26 (3H, d, J=1.7 Hz), 2,48-to 2.57 (1H, m), 2,68-to 2.74 (2H, m), 2,97 totaling 3.04 (2H, m), of 3.78 (2H, s), 4,45-4,51 (2H, m), 6.90 to (1H, d, J=9.5 Hz), 6,97-7,02 (2H, m), 7,10-to 7.15 (1H, m), the 7.43 (1H, d, J=5,1 Hz), 7,66 (1H, d, J=9.5 Hz), 8,46 (1H, d, J=5,1 Hz), of 8.92 (1H, s)

Example 8

To a solution of 0.16 g of 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it's in 3 ml of ethyl acetate add 5 ml of 4.0 mol/l solution of the hydrochloric acid/ethyl acetate at room temperature. To it was added 2 ml of ethyl acetate, the mixture was stirred at the same temperature for 10 minutes and the solvent is distilled off under reduced pressure. The ethyl acetate added to the obtained residue, and the solid product filtered off to obtain 0.18 g of 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 1,98-2,11 (2H, m), 2,28 (3H, d, J=1.5 Hz), 2,50-of 2.58 (2H, m), 3,22-to 3.33 (2H, m), 3,60-3,70 (3H, m), 3,97-of 4.05 (2H, m), 4,30 (2H, s), 4,81-to 4.87 (2H, m), 7,17-7,22 (2H, m), 7,20 (1H, d, J=9.5 Hz), was 7.36 (1H, t, J=7,7 Hz), 8,17 (1H, d, J=5,9 Hz), 8,17 (1H, d, J=9.5 Hz), 8,61 (1H, d, J=5,9 Hz), 9,12 (1H, s)

Example 9

To a solution of 0.16 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate in 3 ml of dichloromethane added 0.10 g (6-methoxy-3-occupied(2,3-b)pyrazin-4(3H)-yl)acetaldehyde, 26 μl of acetic acid and 0.15 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The floor is built the residue purified using flash column-chromatography on basic silica gel using the eluent of chloroform to obtain 0.15 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(6-methoxy-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate in the form of an oily material light brown color.

1H-NMR (CDCl3) δ: to 1.38 (9H, s), 1,40-1,70 (4H, m), 2,03-of 2.23 (2H, m), 2,66-by 2.73 (2H, m), 3,02-3,10 (2H, m)4,00 (3H, s), a 4.03-4,20 (1H, m), 4,23-to 4.46 (6H, m), 4,48-4,55 (2H, m), of 6.71 (1H, s), 6,72 (1H, d, J=8.5 Hz), 8,01 (1H, d, J=8.5 Hz), of 8.04 (1H, s)to 8.14 (1H, s)

Example 10

To a solution of 0.14 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(6-methoxy-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate in 3.0 ml of ethanol is added at room temperature, 3 ml of 6.0 mol/l solution of hydrochloric acid/ethanol. The mixture was stirred at the same temperature for 3 hours and the solvent is distilled off under reduced pressure. To the obtained residue, add a simple diethyl ether, and the solid product filtered off to obtain 0.11 g of 4-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-6-methoxypurine(2,3-b)pyrazin-3(4H)-she hydrochloride in the form of a solid light brown color.

1H-NMR (D2O) δ: 1,97-2,12 (2H, m), 2,49-of 2.58 (2H, m), 3,20-to 3.34 (2H, m), 3,66-of 3.78 (3H, m), 3,97-4,08 (2H, m), 4,07 (3H, s), of 4.44 figure-4.49 (2H, m), of 4.49 (2H, s), 4,55-4,60 (2H, m), 4,88-4,94 (2H, m), 6,98 (1H, d, J=8,9 Hz), 7,41 (1H, s), 8,18 (1H, d, J=8,9 Hz), 8,19 (1H, s), a 8.34 (1H, s)

Example 11

Using the same technology as in Example 7, 1-(2-(4-((4-active compounds)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-NAF is iridin-2(1H)-she hydrochloride and 4-ethylbenzaldehyde.

1H-NMR (CDCl3) δ: of 1.23 (3H, t, J=7,6 Hz), 1,37-1,49 (2H, m), 1,87-of 1.95 (2H, m), 2,16-of 2.24 (2H, m), 2,49-of 2.58 (1H, m), 2.63 in (2H, square, J=7,6 Hz), 2,67-by 2.73 (2H, m), 2,96-3,03 (2H, m), of 3.78 (2H, s), of 4.44-4,50 (2H, m), 6.89 in (1H, d, J=9.5 Hz), to 7.15 (2H, d, J=8.0 Hz), 7.23 percent (2H, d, J=8.0 Hz), 7,41 (1H, d, J=5,1 Hz), the 7.65 (1H, d, J=9.5 Hz), 8,44 (1H, d, J=5,1 Hz), 8,91 (1H, s)

Example 12

Using the same technology as in Example 8, 1-(2-(4-((4-active compounds)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-((4-active compounds)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it.

1H-NMR (D2O) δ: to 1.21 (3H, t, J=7,7 Hz), 1,99-2,12 (2H, m), 2,50 at 2.59 (2H, m), 2,68 (2H, square, J=7,7 Hz), 3,22-to 3.33 (2H, m), to 3.58-3,71 (3H, m), 3,97-4,06 (2H, m), 4,30 (2H, s), 4,81-to 4.87 (2H, m), 7,24 (1H, d, J=9.8 Hz), 7,38 (2H, d, J=8,2 Hz), 7,42 (2H, d, J=8,2 Hz), 8,19 (1H, d, J=9.8 Hz), 8,24 (1H, d, J=5,9 Hz), 8,63 (1H, d, J=5,9 Hz), 9,16 (1H, s)

Example 13

To a solution of 0.75 g (2-oxo-1,8-naphthiridine-1(2H)-yl)acetaldehyde in 40 ml of dichloromethane added 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidine-4-yl)carbamate, 0,23 ml of acetic acid and 1.3 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 2 hours. To it add water, saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous chlorine is IDA sodium and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 200:3 to obtain 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,8-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of a white foam.

1H-NMR (CDCl3) δ: of 1.41 (9H, s), 1,55-1,70 (4H, m), 2.05 is was 2.25 (2H, m), 2,62 of 2.68 (2H, m), is 3.08-3,14 (2H, m), 4,00-4,18 (1H, m), 4,21-4,27 (6H, m), 4,62-of 4.67 (2H, m), 6,64-6,70 (1H, m), 6,72 (1H, d, J=1.7 Hz), 6,72 (1H, d, J=9.5 Hz), 6,77 (1H, d, J=8,3 Hz), to 7.15 (1H, DD, J=7,7, a 4.7 Hz), to 7.61 (1H, d, J=9.5 Hz), to 7.84 (1H, DD, J=7,7, 1.9 Hz), 8,56 (1H, DD, J=4,7, 1.9 Hz)

Example 14

To 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1-(2-(2-oxo-1,8-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate are added 50 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 1 day. The solvent is distilled off under reduced pressure, there was added ethanol and the solvent is distilled off under reduced pressure. To the obtained residue is added ethyl acetate, and after stirring the solid product is filtered off with obtaining 1.2 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-1-yl)ethyl)-1,8-naphthiridine-2(1H)-she hydrochloride in the form of a solid white product.

1H-NMR (D2O) δ: 1,93-2,07 (2H, m), 2,48-of 2.58 (2H, m), 3,18 to be 3.29 (2H, m), 3,57-of 3.78 (3H, m), a 4.03-4,10 (2H, m), 4,20-4,27 (2H, m), 4,30-and 4.40 (4H, m), 4,90-of 4.95 (2H, m), 6,85 (1H, d, J=9.5 Hz), 6,9-7,06 (3H, m), 7,47 (1H, DD, J=7,7, 4,8 Hz), of 8.06 (1H, d, J=9.5 Hz), 8,24 (1H, d, J=7,7 Hz), to 8.70 (1H, d, J=4,8 Hz)

Example 15

(1) of 0.60 g of 1-(1,3-dioxolane-2-ylmethyl)-1,6-naphthiridine-2(1H)-it add 6 ml of 90% aqueous solution triperoxonane acid and the mixture is stirred at room temperature for 12 hours. To it was added 1.0 ml of water and the mixture is stirred for 1 hour, and stirred at 55-75°C for 3 hours and 30 minutes. The solvent is distilled off from the mixture under reduced pressure, there was added a saturated aqueous sodium bicarbonate solution and chloroform and the mixture is stirred at room temperature for 1 hour and 30 minutes. Then the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain (2-oxo-1,6-naphthiridine-1(2H)-yl)acetaldehyde.

(2) To a solution of 0.38 g (2-oxo-1,6-naphthiridine-1(2H)-yl)acetaldehyde in 14 ml of dichloromethane added 0.35 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidine-4-yl)carbamate and 0.12 ml of acetic acid, the mixture is stirred for 5 minutes and then the reaction mixture is added 0.32 g of triacetoxyborohydride sodium and the mixture is stirred for 4 hours and 20 minutes. To the reaction mixture is added saturated aqueous bicarbonate NAT the Oia and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 100:1 to obtain 0.36 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,6-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate as a colorless oily substance.

1H-NMR (CDCl3) δ: USD 1.43 (9H, s), 1,61 is 1.70 (4H, m), 2,09-of 2.23 (2H, m), 2,58-2,63 (2H, m), 2,98 totaling 3.04 (2H, m), 3.95 to 4,35 (9H, m), 6,64-6,70 (1H, m), of 6.73 (1H, d, J=9.5 Hz), 6,74 (1H, d, J=2.4 Hz), 6,78 (1H, d, J=8,3 Hz), from 7.24 (1H, d, J=5,9 Hz), 7,73 (1H, d, J=9.5 Hz), 8,58 (1H, d, J=5,9 Hz), 8,77 (1H, s)

Example 16

To 0.15 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1-(2-(2-oxo-1,6-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate add 10 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 2 hours and 30 minutes. It additionally add 5 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate mixture interacts at room temperature for 20 hours and the solvent is distilled off under reduced pressure. The mixture is dissolved in 8 ml of 6 mol/l hydrochloric acid, and ZAT is m the solvent is distilled off under reduced pressure. Ethanol added to the obtained residue, and the solvent is distilled off under reduced pressure, and then to the obtained residue is added ethyl acetate, and the solid product is filtered off with obtaining of 0.13 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-1-yl)ethyl)-1,6-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 2,02-and 2.14 (2H, m), 2,52 at 2.59 (2H, m), 3.27 to to 3.36 (2H, m), 3,64-3,70 (3H, m), 3,99-4,07 (2H, m), 4,24-4.26 deaths (2H, m), 4,35 (4H, s), 4.80 to the 4.90 (2H, m), 6,98-7,07 (3H, m), was 7.08 (1H, d, J=9.8 Hz), of 8.06 (1H, d, J=7,3 Hz), of 8.25 (1H, d, J=9.8 Hz), 8,79 (1H, d, J=7,1 Hz), 9,23 (1H, s)

Example 17

Using the same technology as in Example 8, 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she.

1H-NMR (D2O) δ: 1,96-2,10 (2H, m), of 2.28 (3H, s), 2,48-to 2.57 (2H, m), 3,18-and 3.31 (2H, m), 3,59-3,68 (3H, m), 3.95 to 4,06 (2H, m), Android 4.04 (3H, s), the 4.29 (2H, s), 4,74 of 4.83 (2H, m), 6.87 in (1H, d, J=9.8 Hz), 7,17-7,22 (2H, m), of 7.36 (1H, t, J=7.8 Hz), 7,44 (1H, d, J=2.2 Hz), of 8.06 (1H, d, J=9.8 Hz), 8,40 (1H, d, J=2.2 Hz)

Example 18

To a solution of 0.32 g (2-oxo-1,7-naphthiridine-1(2H)-yl)acetaldehyde in 10 ml of dichloromethane type of 0.59 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidine-4-yl)carbamate and 97 μl of acetic acid, and then to the reaction mixture of 0.54 g triacetoxy is Orhidea sodium and the mixture is stirred at room temperature for 2 hours and 30 minutes. To it add water, saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 100:1 to obtain 0.15 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,7-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate as a colorless oily substance.

1H-NMR (CDCl3) δ: of 1.42 (9H, s), 1,62-1,72 (4H, m), 2,12-of 2.26 (2H, m), 2,63-2,69 (2H, m), 3.00 and-a 3.06 (2H, m), 3,98-to 4.15 (1H, m), 4,22-4,33 (6H, m), to 4.41-to 4.46 (2H, m), 6,67-of 6.71 (1H, m), 6,74 (1H, d, J=2.0 Hz), 6,78 (1H, d, J=8,3 Hz), 6.89 in (1H, d, J=9.5 Hz), the 7.43 (1H, d, J=5.0 Hz), 7,66 (1H, d, J=9.5 Hz), 8,44 (1H, d, J=5.0 Hz), 8,87 (1H, s)

Example 19

To 0.15 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1-(2-(2-oxo-1,7-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate add 8 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate mixture interacts at room temperature for 21 hours and the solvent is distilled off under reduced pressure. To the obtained residue is added ethanol, the solvent is distilled off under reduced pressure, and then to receive the resultant residue is added ethyl acetate, and the solid product filtered off to obtain 0.15 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride in the form of a solid yellow color.

1H-NMR (D2O) δ: 2,01-to 2.13 (2H, m), 2,52-of 2.58 (2H, m), 3,26-to 3.35 (2H, m), 3,61-and 3.72 (3H, m), 4,00-4,07 (2H, m), 4,25 (2H, s), 4,35 (4H, s), 4,82-4,89 (2H, m), 6,69-7,07 (3H, m), 7,27 (1H, d, J=9.0 Hz), by 8.22 (1H, d, J=9.8 Hz), of 8.28 (1H, d, J=5.7 Hz), 8,65 (1H, d, J=5.7 Hz), 9,19 (1H, s)

Example 20

To a solution of 0.07 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,8-naphthiridine-2(1H)-it's in 3 ml of dichloromethane added 57 mg of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-carbaldehyde and 14 μl of acetic acid, the mixture is stirred for 10 minutes and then the reaction mixture are added 79 mg triacetoxyborohydride sodium, and the mixture interacts within 1 day. It additionally add 7 µl of acetic acid, the mixture is stirred for 35 minutes and then add 7 µl of acetic acid and 26 mg triacetoxyborohydride sodium, and the mixture interacts within 20 minutes. To the reaction mixture add water, saturated aqueous sodium bicarbonate solution, the chloroform and sodium chloride, the organic layer is separated and the aqueous layer was extracted with chloroform in the implementation of vysalivaniya. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent from onaut under reduced pressure. The resulting residue is dissolved in 5 ml of 6 mol/l hydrochloric acid and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography with reversed-phase silica gel using the eluent from the water to obtain 71 mg of 7-chloro-6-(((1-(2-(2-oxo-1,8-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-she hydrochloride in the form of a solid light gray color.

1H-NMR (D2O) δ: 2,03-2,19 (2H, m), 2,56-of 2.66 (2H, m), 3,22-to 3.34 (2H, m), 3,59-of 3.85 (5H, m), a 4.03-to 4.15 (2H, m), 4,56 (2H, s), 4,70-5,02 (2H, m), 6,83 (1H, d, J=9.4 Hz), 7,44-7,49 (1H, m), to 7.93 (1H, s), with 8.05 (1H, d, J=9.4 Hz), by 8.22 (1H, d, J=7.8 Hz), 8,68-8,73 (1H, m)

Example 21

To a solution of 83 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,8-naphthiridine-2(1H)-she's in 15 ml of dichloromethane in parts added 54 mg of 3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carbaldehyde, 86 μl of acetic acid and 0.36 g of triacetoxyborohydride sodium when carrying out the reaction at room temperature for 1.5 days. To the reaction solution was added water, saturated aqueous sodium bicarbonate solution, the chloroform and sodium chloride, the organic layer is separated and the aqueous layer was extracted with chloroform in the implementation of vysalivaniya. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The obtained OST is OK purified by column chromatography on silica gel using eluent chloroform:methanol = 5:1, and the resulting residue is dissolved in 5 ml of 6 mol/l hydrochloric acid, and then the solvent is distilled off under reduced pressure. To the obtained residue, add a simple diethyl ether, and the solid product filtered off to obtain 0.12 g of 6-(((1-(2-(2-oxo-1,8-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)-2H-1,4-benzoxazin-3(4H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 1,94-of 2.09 (2H, m), 2,50-of 2.58 (2H, m), 3,18-to 3.34 (2H, m), 3,59-3,70 (3H, m), 3,98-4,11 (2H, m), 4,27 (2H, s), 4,71 (2H, s), 4,91 is equal to 4.97 (2H, m), 6,85 (1H, d, J=9.5 Hz), 7,06-7,11 (2H, m), to 7.15 (1H, DD, J=to 8.4, 1.8 Hz), 7,47 (1H, DD, J=7,8, and 4.8 Hz), 8,07 (1H, d, J=9.5 Hz), 8,23 compared to 8.26 (1H, m), 8,68-8,72 (1H, m)

Example 22

To a solution of 0.62 g of (2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in 20 ml of dichloromethane added 1.5 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidine-4-yl)carbamate and to 0.19 ml of acetic acid and the mixture is stirred at room temperature for 30 minutes and then the reaction mixture is added 1.0 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 4 days. To it add water, saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled at bonigen the m pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 75:1 with obtaining 0,70 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of an oily material light brown color.

1H-NMR (CDCl3) δ: USD 1.43 (9H, s), 1,61-1,72 (4H, m), 2,10-of 2.21 (2H, m), 2,61 (2H, t, J=7,3 Hz), 2,97-3,03 (2H, m), 3,97-to 4.15 (1H, m), 4,20-to 4.38 (8H, m), 6,65-6,76 (2H, m), is 6.78 (1H, d, J=8,3 Hz), make 6.90 (1H, d, J=9.8 Hz), was 7.45 (1H, DD, J=8,6, and 4.5 Hz), of 7.75 (1H, d, J=8.6 Hz), of 7.90 (1H, d, J=9.8 Hz), 8,53 (1H, d, J=4.5 Hz)

Example 23

To 0,69 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1-(2-(2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate add 25 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 42 hours. The solvent is distilled off under reduced pressure, to the obtained residue, add mixed solution of ethyl acetate and ethanol (5:1), and the solid product is filtered off with getting a 0.59 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 1,98-2,12 (2H, m), 2,46-of 2.58 (2H, m), 3,21-to 3.36 (2H, m), 3,56-3,70 (3H, m), 3,97-4,07 (2H, m), 4,20-of 4.25 (2H, m)to 4.33 (4H, s), 4.80 to the ceiling of 5.60 (2H, m), of 6.96-7,05 (3H, m), 7,24 (1H, d, J=10.0 Hz), of 8.09 (1H, DD, J=8,9, 5,2 Hz), by 8.22 (1H, d, J=10.0 Hz), 8,54 (1H, is, J=8,9 Hz), 8,77 (1H, d, J=5,2 Hz)

Example 24

Using the same technology as in Example 7, 1-(2-(4-((2-naphthylmethyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride and 2-naphthaldehyde.

1H-NMR (CDCl3) δ: 1.41 to a rate of 1.51 (2H, m), 1,91 of 1.99 (2H, m), 2,16 was 2.25 (2H, m), 2,54-2,62 (1H, m), 2,68-by 2.73 (2H, m), 2,98 totaling 3.04 (2H, m)to 3.99 (2H, s), 4,45-4,50 (2H, m), 6.89 in (1H, d, J=9.5 Hz), 7,42 (1H, d, J=5.0 Hz), 7,43-of 7.48 (3H, m), the 7.65 (1H, d, J=9.5 Hz), 7,76 (1H, s), 7,79-to 7.84 (3H, m), 8,44 (1H, d, J=5.0 Hz), 8,91 (1H, s)

Example 25

Using the same technology as in Example 8, 1-(2-(4-((2-naphthylmethyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-((2-naphthylmethyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it.

1H-NMR (DMSO-d6) δ: 2,08-2,22 (2H, m), 2.40 a-2,48 (2H, m), is 3.08-3,20 (2H, m), 3,28-a 3.87 (5H, m), 4,34-4,43 (2H, m), 4,70-rate 4.79 (2H, m), 7,01 (1H, d, J=9.5 Hz), 7,56-7,63 (2H, m), 7,78 (1H, d, J=8,3 Hz), of 7.90-8,04 (4H, m), 8,09 (1H, d, J=9.5 Hz), 8,14 (1H, s), 8,55 (1H, d, J=5.4 Hz), 9,26 (1H, s), 9,78-becomes 9.97 (2H, m), 10,82-10,96 (1H, m)

Example 26

To a suspension of 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride in 6 ml of methanol added 99 mg cyanoborohydride sodium and 0.40 g of molecular sieves 3Å and the mixture is stirred at room temperature for 15 minutes. To it was added 68 mg of phenylpropionaldehyde and the mixture was stirred at whom atoi temperature for 1 hour and 30 minutes. To it was added 68 mg of phenylpropionaldehyde and the mixture is stirred at room temperature for 2 hours. To it was added 68 mg of phenylpropionaldehyde and the mixture is stirred at room temperature for 1 hour and 30 minutes. To it was added a saturated aqueous sodium bicarbonate solution and chloroform, and nerastvorimaya substance is filtered off. The organic layer was separated, sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 50:1 to obtain 0.11 g of 1-(2-(4-(bis(3-phenyl-2-PROPYNYL)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it is in the form of an oily material light yellow color.

1H-NMR (CDCl3) δ: 1,59-1,72 (2H, m), 1,99-2,07 (2H, m), 2,18-of 2.26 (2H, m), 2,66 is 2.75 (3H, m), 3,06-3,14 (2H, m), a-3.84 (4H, s), 4,45-to 4.52 (2H, m), 6.89 in (1H, d, J=9.5 Hz), 7,27-7,46 (11H, m), the 7.65 (1H, d, J=9.8 Hz), 8,44 (1H, d, J=5,1 Hz), 8,91 (1H, s)

Example 27

Using the same technology as in Example 8, 1-(2-(4-(bis(3-phenyl-2-PROPYNYL)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-(bis(3-phenyl-2-PROPYNYL)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it.

1H-NMR (DMSO-d6) δ: 2,10-of 2.25 (2H, m), 2,38-of 2.50 (2H, is), 3,18-3,30 (2H, m), 3,38-to 3.92 (5H, m), 4,32 was 4.42 (4H, m), 4,71-rate 4.79 (2H, m),? 7.04 baby mortality (1H, d, J=9.5 Hz), 7,34-rate of 7.54 (10H, m), 7,98 (1H, d, J=5.4 Hz), 8,11 (1H, d, J=9.5 Hz), 8,58 (1H, d, J=5.4 Hz), 9,31 (1H, s)

Example 28

Using the same technology as in Example 7, 1-(2-(4-((1-benzothiophen-2-ylmethyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride and 1-benzothiophen-2-carbaldehyde.

1H-NMR (CDCl3) δ: 1,39 of 1.50 (2H, m), 1,89-of 1.97 (2H, m), 2,15-of 2.24 (2H, m), 2.57 m)-2,66 (1H, m), 2,68-by 2.73 (2H, m), 2,97 totaling 3.04 (2H, m), 4,11 (2H, d, J=0.8 Hz), of 4.44-4,50 (2H, m), 6.89 in (1H, d, J=9.5 Hz), 7,14 (1H, s), 7,27-7,34 (2H, m), 7,42 (1H, d, J=5,1 Hz), the 7.65 (1H, d, J=9.5 Hz), to 7.67-7,72 (1H, m), 7,79 (1H, d, J=7,6 Hz), 8,44 (1H, d, J=5,1 Hz), of 8.90 (1H, s)

Example 29

Using the same technology as in Example 8, 1-(2-(4-((1-benzothiophen-2-ylmethyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-((1-benzothiophen-2-ylmethyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it.

1H-NMR (DMSO-d6) δ: 2,02-of 2.16 (2H, m), 2,38 is 2.46 (2H, m), 3,11-up 3.22 (2H, m), 3,35-of 3.46 (3H, m), 3,79-3,88 (2H, m), 4,58 (2H, s), 4,69-4,78 (2H, m), 7,06 (1H, d, J=9.6 Hz), 7,40-7,46 (2H, m), 7,72 (1H, s), 7,88-7,94 (1H, m), 8,00-with 8.05 (2H, m), 8,13 (1H, d, J=9.6 Hz), 8,59 (1H, d, J=5.4 Hz), 9,31 (1H, s)

Example 30

To a suspension of 0.10 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride in 3 ml of methanol, add 0.15 ml of 28% solution of sodium methoxide/methanol and 15 µl of the UKS the red acid. To it was added 51 mg of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-carbaldehyde and 0.20 g of molecular sieves 3Å and the mixture is stirred at room temperature for 30 minutes. To it was added 33 mg of cyanoborohydride sodium and the mixture is stirred at room temperature for 1 hour and 30 minutes. To it was added 51 mg of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-carbaldehyde and the mixture is stirred at room temperature for 2 hours. Nerastvorimaya substance is filtered off, and to it was added chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated and sequentially washed with water and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 10:1 to obtain 97 mg of 7-chloro-6-(((1-(2-(2-oxo-1,7-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-it is in the form of a solid white product.

1H-NMR (CDCl3) δ: 1,43-to 1.60 (2H, m), 1,88 is 1.96 (2H, m), 2,18-of 2.26 (2H, m), 2,50-of 2.58 (1H, m), 2,69 was 2.76 (2H, m), 2,97 was 3.05 (2H, m), of 3.48 (2H, s), of 3.95 (2H, s), of 4.44-4,50 (2H, m), 6.90 to (1H, d, J=9.5 Hz), 7,42 (1H, d, J=a 4.9 Hz), 7,60 (1H, s), the 7.65 (1H, d, J=9.5 Hz), 8,17 (1H, s), to 8.45 (1H, d, J=4.9 Hz), of 8.92 (1H, s)

Example 31

Using the same technology as in Example 30, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride and 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde.

1H-NMR (CDCl3) δ: 1,40-of 1.52 (2H, m), 1,87-of 1.95 (2H, m), 2,16 was 2.25 (2H, m), 2,49-to 2.57 (1H, m), 2,67-to 2.74 (2H, m), 2,97 totaling 3.04 (2H, m), 3,80 (2H, s), 4.26 deaths is 4.36 (4H, m), of 4.44-4,51 (2H, m), 6,83 (1H, s), 6.89 in (1H, d, J=9.5 Hz), 7,42 (1H, d, J=5,1 Hz), the 7.65 (1H, d, J=9.5 Hz), 8,11 (1H, s), to 8.45 (1H, d, J=5,1 Hz), 8,91 (1H, s)

Example 32

Using the same technology as in Example 8, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it.

1H-NMR (D2O) δ: 1,98-2,11 (2H, m), 2,49-to 2.57 (2H, m), 3,23-to 3.33 (2H, m), 3,62-and 3.72 (3H, m), 3.96 points-of 4.05 (2H, m), to 4.38 (2H, s), 4,39-of 4.44 (2H, m), 4,46-4,51 (2H, m), 4.80 to a 4.86 (2H, m), 7,19 (1H, d, J=9.5 Hz), 7,22 (1H, ), of 8.15 (1H, d, J=5.7 Hz), 8,17 (1H, d, J=9.5 Hz), 8,23 (1H, s), at 8.60 (1H, d, J=5.7 Hz), 9,10 (1H, s)

Example 33

Using the same technology as in Example 30, 6-(((1-(2-(2-oxo-1,7-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride and 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-kerbal is degidi.

1H-NMR (CDCl3) δ: 1,39-is 1.51 (2H, m), 1,86-of 1.95 (2H, m), 2,16 was 2.25 (2H, m), 2,47-to 2.57 (1H, m), 2,68-to 2.74 (2H, m), 2,97 totaling 3.04 (2H, m), of 3.48 (2H, s), 3,83 (2H, s), of 4.44-4,50 (2H, m), 6.89 in (1H, d, J=9.4 Hz), 6,98 (1H, d, J=7,8 Hz), 7,42 (1H, d, J=5,1 Hz), EUR 7.57 (1H, d, J=7.8 Hz), the 7.65 (1H, d, J=9.4 Hz), 8,02-8,10 (1H, usher.), to 8.45 (1H, d, J=5,1 Hz), 8,91 (1H, s)

Example 34

Using the same technology as in Example 30, 1-(2-(4-(((5-(2-thienyl)isoxazol-3-yl)methyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride and 5-(2-thienyl)isoxazol-3-carbaldehyde.

1H-NMR (CDCl3) δ: 1,38-1,49 (2H, m), 1,88 is 1.96 (2H, m), 2,17-of 2.26 (2H, m), 2,52-2,62 (1H, m), 2,68-to 2.74 (2H, m), 2,97 totaling 3.04 (2H, m), 3,91 (2H, s), of 4.44-4,50 (2H, m), 6,40 (1H, s), 6.89 in (1H, d, J=9.5 Hz), 7,12 (1H, DD, J=5,1, and 3.7 Hz), 7,40-7,46 (2H, m)to 7.50 (1H, DD, J=3,7, 1.0 Hz), the 7.65 (1H, d, J=9.5 Hz), 8,44 (1H, d, J=5,1 Hz), of 8.90 (1H, s)

Example 35

Using the same technology as in Example 8, 1-(2-(4-(((5-(2-thienyl)isoxazol-3-yl)methyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-(((5-(2-thienyl)isoxazol-3-yl)methyl)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it.

1H-NMR (DMSO-d6) δ: 2,05-to 2.18 (2H, m), 2,36 is 2.46 (2H, m), 3,10-up 3.22 (2H, m), 3,35 is 3.40 (3H, m), 3,60-3,88 (2H, m), of 4.38-to 4.46 (2H, m), 4,70-rate 4.79 (2H, m), 7,02 (1H, d, J=9.5 Hz), to 7.15 (1H, s), 7,28 (1H, DD, J=5,1, and 3.7 Hz), 7,74 (1H, d, J=3,7 Hz), 7,89 (1H, d, J=5,1 Hz), 7,94 (1H, d, J=5,1 Hz), 8,10 (1H, d, J=9.5 Hz), 8,56 (1H, d, J=5,1 Hz), 9,27 (1H, s), 10,20-the 10.40 (2H, usher.), of 10.73-10,90 (1H, user.)

Example 36/p>

Using the same technology as in Example 30, 1-(2-(4-((3-phenyl-2-PROPYNYL)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride and phenylpropionaldehyde.

1H-NMR (CDCl3) δ: 1,40-of 1.52 (2H, m), 1,88 is 1.96 (2H, m), 2,22 is 2.33 (2H, m), 2,70-to 2.85 (3H, m), 2,99-of 3.07 (2H, m), 3,68 (2H, s), 4,46-to 4.52 (2H, m), 6.89 in (1H, d, J=9.5 Hz), 7,28-to 7.32 (3H, m), 7,38-7,44 (3H, m), the 7.65 (1H, d, J=9.5 Hz), 8,44 (1H, d, J=5,1 Hz), of 8.92 (1H, s)

Example 37

Using the same technology as in Example 8, 1-(2-(4-((3-phenyl-2-PROPYNYL)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-((3-phenyl-2-PROPYNYL)amino)piperidine-1-yl)ethyl)-1,7-naphthiridine-2(1H)-it.

1H-NMR (DMSO-d6) δ: 2.00 in to 2.13 (2H, m), 2,32-to 2.41 (2H, m), 3,14-3,26 (2H, m), 3,35 of 3.75 (3H, m), 3,80-3,86 (2H, m), 4,20-to 4.28 (2H, m), 4,70-4,78 (2H, m), 7,01 (1H, d, J=9.5 Hz), 7,42-of 7.48 (3H, m), 7,51-7,56 (2H, m), 7,92 (1H, d, J=5.4 Hz), of 8.09 (1H, d, J=9.5 Hz), 8,56 (1H, d, J=5,1 Hz), 9,26 (1H, s), 9,99-10,08 (2H, m), 10,70-was 10.82 (1H, m)

Example 38

Using the same technology as in Example 30, 6-(((1-(2-(2-oxo-1,7-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)-2H-1,4-benzoxazin-3(4H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthiridine-2(1H)-she hydrochloride and 3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carbaldehyde.

1H-NMR (DMSO-d6) δ: 1,13-1,25 (2H, m), 1.70 to to 1.79 (2H, m), 1,97-to 2.06 (2H, m), 2,28-is 2.37 (1H, m), 2,46-to 2.57 (2H, m), 284-2,92 (2H, m)and 3.59 (2H, s), 4,35 was 4.42 (2H, m), 4,50 (2H, s), for 6.81-6.90 to (4H, m), to 7.67 (1H, d, J=5.0 Hz), 7,94 (1H, d, J=9.5 Hz), 8,40 (1H, d, J=5.0 Hz), of 8.92 (1H, s), 10,61 (1H, s)

Example 39

(1) using the same technology as in Example 1, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)-2-methylpiperidin-4-yl)carbamate is obtained from (7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(2 methylpiperidin-4-yl)carbamate.

(2) using the same technology as in Example 54, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-2-methylpiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)-2-methylpiperidin-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,11 (3H, d, J=6,1 Hz), 1,22-of 1.44 (2H, m), 1,84-to 1.98 (2H, m), 2,28 is 2.44 (1H, m), 2,56-2,61 (2H, m), 2,68-2,90 (1H, m), 2,97-of 3.07 (1H, m), is 3.08-and 3.16 (1H, m), with 3.79 (2H, s), of 3.97 (3H, s), 4,16-4,20 (1H, m), 4,34-to 4.38 (4H, m), 4,55-4,59 (1H, m), 6,74 (1H, d, J=9.6 Hz), for 6.81 (1H, s), 7,24 (1H, d, J=2.3 Hz), to 7.84 (1H, d, J=9.6 Hz), 8,10 (1H, s), of 8.27 (1H, d, J=2.3 Hz)

Example 40

To a solution of 0.13 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 2.6 ml of N,N-dimethylformamide add 75 mg of 5,6,7,8-tetrahydroquinoxalin-2-carbaldehyde, of 0.26 ml of acetic acid, of 0.21 ml of triethylamine and 98 mg triacetic is iborhead sodium and the mixture is stirred at room temperature for 9 hours and 40 minutes. To it add water, saturated aqueous sodium bicarbonate solution and ethyl acetate, and the pH of the reaction mixture was adjusted to 11.5 with 20% aqueous sodium hydroxide solution, then the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 10:1, and added ethyl acetate and 4 mol/l solution of hydrochloric acid/ethyl acetate. The solvent is distilled from the mixture under reduced pressure, it adds a simple diethyl ether, and the solid product filtered off to obtain 92 mg of 7-methoxy-1-(2-(4-((5,6,7,8-tetrahydroquinoxalin-2-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid light brown color.

1H-NMR (D2O) δ: 1,87-of 1.95 (4H, m), 2,01 with 2.14 (2H, m), of 2.51-2,60 (2H, m), 2,92-of 3.00 (4H, m), 3,19-to 3.34 (2H, m), 3,59-of 3.78 (3H, m), 3,97-4,06 (2H, m), Android 4.04 (3H, s), 4,47 (2H, s), 4,76-rate 4.79 (2H, m), to 6.88 (1H, d, J=9.8 Hz), 7,47 (1H, d, J=2.1 Hz), of 8.06 (1H, d, J=9.8 Hz), 8,39 (1H, s), to 8.41 (1H, d, J=2.1 Hz)

Example 41

(1) To 95 mg of 1-(1,3-dioxolane-2-ylmethyl)pyrido(3,4-b)pyrazin-2(1H)-it is added to 4.0 ml of 80% aqueous process is as triperoxonane acid and the mixture is stirred at room temperature for 2 hours, and then leave overnight. To it was added to 4.0 ml of 80% aqueous solution triperoxonane acid and the mixture was stirred at 50-70°C for 6 hours. The reaction mixture is cooled to room temperature and the solvent is distilled off under reduced pressure. The resulting residue loaded chloroform and water and adjusted pH to 7.0 with 1 mol/l aqueous solution of sodium hydroxide. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 40 mg (2 occupied(3,4-b)pyrazin-1(2H)-yl)acetaldehyde in the form of an oily material light brown color.

(2) To a suspension of 40 mg (2 occupied(3,4-b)pyrazin-1(2H)-yl)acetaldehyde in 2 ml of dichloromethane added a solution of 74 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidine-4-yl) carbamate in 2 ml of dichloromethane and 12 μl of acetic acid and the mixture is stirred at room temperature for 10 minutes. To it was added 67 mg of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and extracts are combined according to the scientists, the solution washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of chloroform:methanol = 100:0-90:10 to 80 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl(1-(2-(2-occupied(3,4-b)pyrazin-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of an oily material light brown color.

1H-NMR (CDCl3) δ: of 1.42 (9H, s), 1,54-1,72 (4H, m), 2.05 is-of 2.23 (2H, m), 2,59-of 2.66 (2H, m), 2.91 in is 3.00 (2H, m), 3.95 to to 4.14 (1H, m), 4,20-4,30 (8H, m), 6,64-6,70 (1H, m), of 6.73 (1H, d, J=2.0 Hz), 6,78 (1H, d, J=8,3 Hz), 7.23 percent (1H, d, J=5,9 Hz), 8,30 (1H, s), 8,61 (1H, d, J=5,9 Hz), the remaining 9.08 (1H, s)

Example 42

Using the same technology as in Example 2, 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-1-yl)ethyl)pyrido(3,4-b)pyrazin-2(1H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-occupied(3,4-b)pyrazin-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 1,83-to 1.98 (2H, m), 2,34 at 2.45 (2H, m), 3,09-is 3.21 (2H, m), 3,40 of 3.56 (3H, m), 3,82-are 3.90 (2H, m), 4,10 (2H, s), is 4.21 (4H, s), 4,50-4,80 (2H, m), 6,85-6,92 (3H, m), 7,86 (1H, d, J=6.8 Hz), 8,40 (1H, s), 8,69 (1H, d, J=6.8 Hz), 9,16 (1H, s)

Example 43

To a solution of 0.20 g (7-methoxy-2-oxo-1,8-naphthiridine-1(2H)-yl)acetaldehyde in 20 ml of dichloromethane added 0.32 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidine-4-yl)carbamate and 53 μl of acetic acid and the mixture is stirred at room temperature T. the value of 15 minutes. To the reaction mixture of 0.29 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 1 hour and 40 minutes. To it add water, saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 50:1 to obtain 0.50 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl(1-(2-(7-methoxy-2-oxo-1,8-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of a white foam.

1H-NMR (CDCl3) δ: of 1.41 (9H, s), 1,59-1,72 (4H, m), 2,09 was 2.25 (2H, m), 2,64-of 2.72 (2H, m), 3,07-3,14 (2H, m)to 3.99 (3H, s), 4,00-to 4.15 (1H, m), 4,20-4,34 (6H, m), 4,57-4,63 (2H, m), 6,56 (1H, d, J=9.4 Hz), 6,60 (1H, d, J=8,3 Hz), 6,64-6,69 (1H, m), of 6.71-6.73 x (1H, m), 6,77 (1H, d, J=8,3 Hz), 7,55 (1H, d, J=9.4 Hz), 7,71 (1H, d, J=8,3 Hz)

Example 44

To 0.50 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl(1-(2-(7-methoxy-2-oxo-1,8-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate add 15 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 43 hours. The solvent banished is under reduced pressure, methanol is added to the obtained residue, and the solvent is distilled off under reduced pressure. Then to the resulting residue is added ethyl acetate, and the solid product is filtered off with getting 0,41 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,8-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 1,92-of 2.08 (2H, m), 2,45-of 2.58 (2H, m), 3,16-and 3.31 (2H, m), 3,56-and 3.72 (3H, m), 3.96 points-4,10 (2H, m), of 4.05 (3H, s), 4,17-to 4.28 (2H, m)to 4.33 (4H, s), 4,82-to 4.98 (2H, m), only 6.64 (1H, d, J=9.3 Hz), 6,85 (1H, d, J=8,4 Hz), 6,95-7,06 (3H, m), of 7.96 (1H, d, J=9.3 Hz), of 8.04 (1H, d, J=8,4 Hz)

Example 45

To a solution of 0.20 g of 1-(2-(4-(aminopiperidin-1-yl)ethyl)-7-methoxy-1,8-naphthiridine-2(1H)-she hydrochloride in 4 ml of methanol is added 0.21 g of 28% sodium methoxide, 88 mg of 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde, 30 μl of acetic acid and 67 mg of cyanoborohydride sodium and the mixture is stirred at room temperature for 6 hours and 45 minutes. To it was added 27 mg of 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde and 9 μl of acetic acid and the mixture is stirred for 1 hour 30 minutes. After her leave to stand overnight, the mixture is stirred at room temperature for 2 hours, added 27 mg of 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde and 9 μl of acetic acid and the mixture is stirred for 2 hours and 30 minutes. To reaction the th mixture, water is added, 1 mol/l aqueous sodium hydroxide solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 5:1, the oily substance thus obtained, dissolved in 4 mol/l solution of hydrochloric acid/ethyl acetate and methanol, and the solvent is then distilled off under reduced pressure. To the obtained residue is added ethyl acetate, and the solid product filtered off to obtain 0.18 g of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,8-naphthiridine-2(1H)-she hydrochloride in the form of a solid white product.

1H-NMR (D2O) δ: 2.00 in to 2.13 (2H, m), 2,52-2,62 (2H, m), 3,21-to 3.33 (2H, m), 3,64-a 3.83 (3H, m), 3,98-to 4.15 (5H, m), 4,49-of 4.54 (2H, m), 4,59 (2H, s), with 4.64-and 4.68 (2H, m), 4,89-4,94 (2H, m), of 6.65 (1H, d, J=9.5 Hz), 6,86 (1H, d, J=8.6 Hz), 7,56 (1H, s), of 7.97 (1H, d, J=9.5 Hz), with 8.05 (1H, d, J=8.6 Hz), 8,43 (1H, s)

Example 46

To a solution of 0.13 g (3 occupied(2,3-b)pyrazin-4(3H)-yl)acetaldehyde, a 0.23 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidine-4-yl)carbamate in 4 ml of dichloromethane added 38 μl of acetic acid and 0.21 g of triacetoxyborohydride sodium and the mixture is peremeshivayte at room temperature for 3 hours. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of chloroform:methanol = 100:0-90:10 to obtain 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate as a pale brown oily material color.

1H-NMR (CDCl3) δ: of 1.41 (9H, s), 1,50-of 1.66 (4H, m), 1,98-of 2.20 (2H, m), 2,64-of 2.72 (2H, m), 3,01-3,10 (2H, m), 3.95 to to 4.14 (1H, m), 4,18-4,30 (6H, m), 4,54-br4.61 (2H, m), 6,63 of 6.68 (1H, m), 6,69-6,72 (1H, m), 6,77 (1H, d, J=8,3 Hz), 7,31 (1H, DD, J=8,0, 4.6 Hz), 8,16 (1H, DD, J=8.0 a, 1,6 Hz), 8,31 (1H, s), 8,56 (1H, DD, J=4,6, 1,6 Hz)

Example 47

Using the same technology as in Example 2, 4-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-1-yl)ethyl)pyrido(2,3-b)pyrazin-3(4H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 1,90-of 2.05 (2H, m), 2,45 is 2.55 (2H, m), 3,16-of 3.32 (2H, m), 3,55-3,71 (3H, m), 3.96 points to 4.0 (2H, m), is 4.21 (2H, s)to 4.33 (4H, s), 4,88-is 4.93 (2H, m), 6,95? 7.04 baby mortality (3H, m), 7,58 (1H, DD, J=8.0 a, 4,8 Hz), 8,35 (1H, DD, J=8,0, 1.5 Hz), 8,39 (1H, s)8,71 (1H, DD, J=4,8, 1.5 Hz)

Example 48

Using the same technology as in Example 1, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate is obtained from (2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3-D2O) δ: 1,34-of 1.52 (9H, m), 1,60-1,70 (4H, m), 2,08-2,22 (2H, m), 2,58-2,63 (2H, m), 2.95 and totaling 3.04 (2H, m), 4,00-4,20 (1H, m), 4,24-and 4.40 (8H, m), 6,74 (1H, s)6,91 (1H, d, J=9.8 Hz), 7,46 (1H, DD, J=8,6, and 4.5 Hz), 7,76 (1H, d, J=8.6 Hz), to $ 7.91 (1H, d, J=9.8 Hz), with 8.05 (1H, s), 8,53-8,56 (1H, m)

Example 49

Using the same technology as in Example 2, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (DMSO-d6-D2O) δ: 2,02-to 2.18 (2H, m), a 2.36-2,48 (2H, m), 3,12-3,24 (2H, m), 3,30-3,50 (3H, m), 3.72 points-3,88 (2H, m), 4,36-to 4.46 (4H, m), a 4.53 (2H, s), 4,65-to 4.73 (2H, m), 7,00 (1H, d, J=9.8 Hz), a 7.62 (1H, s), 7,76 (1H, DD, J=8,6, and 4.6 Hz), 8,08 (1H, d, J=9.8 Hz), 8,42 (1H, d, J=8.6 Hz), and 8.50 (1H, s), 8,65 (1H, d, J=4,6 Hz)

Example 50

Using the same technology as in Example 30, 6-(((1-(2-(2-oxo-1,5-is aftereden-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthiridine-2(1H)-she hydrochloride and 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-carbaldehyde.

1H-NMR (CDCl3-D2O) δ: 1,36 of 1.50 (2H, m), 1,82-of 1.92 (2H, m), 2,12-of 2.20 (2H, m), 2,44-of 2.54 (1H, m), 2,60-of 2.64 (2H, m), 2,90-of 3.00 (2H, m), 3,44 (2H, s), with 3.79 (2H, s), 4,34-4,39 (2H, m), 6.89 in (1H, d, J=9.6 Hz), 6,94 (1H, d, J=7,8 Hz), 7,44 (1H, DD, J=8,5, 4,4 Hz), 7,54 (1H, d, J=7.8 Hz), 7,78 (1H, d, J=8.5 Hz), 7,89 (1H, d, J=9.6 Hz), charged 8.52 (1H, d, J=4.4 Hz)

Example 51

Using the same technology as in Example 41, (2 occupied(2,3-b)pyrazin-1(2H)-yl)acetaldehyde is obtained from 1-(1,3-dioxolane-2-ylmethyl)pyrido(2,3-b)pyrazin-2(1H)-she. Tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-occupied(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidine-4-yl)carbamate is obtained from (2-occupied(2,3-b)pyrazin-1(2H)-yl)acetaldehyde and tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: of 1.42 (9H, s), 1,53-1,72 (4H, m), 2,02-of 2.23 (2H, m), 2,49-of 2.66 (2H, m), 2,90-of 3.00 (2H, m), 3,94 is 4.13 (1H, m), 4,20 is 4.35 (8H, m), 6,64-to 6.80 (3H, m)to 7.50 (1H, DD, J=8,6, and 4.5 Hz), to 7.77 (1H, DD, J=8,6, 1.3 Hz), 8,53 (1H, s), 8,66 (1H, DD, J=4,5, 1.3 Hz)

Example 52

Using the same technology as in Example 2, 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-1-yl)ethyl)pyrido(2,3-b)pyrazin-2(1H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-occupied(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (DMSO-d6) δ: 1,94-2,12 (2H, m), 2,27-to 2.40 (2H, m), 3.00 and-3,86 (7H, m), as 4.02 is 4.13 (2H, m), 4,25 (4H, s), 4,60-4,69 (2H, m)6,91 (1H, d, J=8,3 Hz), 7,00-7,07 (1H, m), to 7.15 (1H, s), 66-7,79 (1H, m), 8,32 is 8.38 (1H, m), and 8.50 (1H, s), 8,63 (1H, d, J=4.4 Hz), 9,40-9,60 (2H, usher.), 10,65-10,85 (1H, user.)

Example 53

Using the same technology as in Example 41, (3 occupied(3,4-b)pyrazin-4(3H)-yl)acetaldehyde is obtained from 4-(1,3-dioxolane-2-ylmethyl)pyrido(3,4-b)pyrazin-3(4H)-she. Tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-occupied(3,4-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate is obtained from (3-occupied(3,4-b)pyrazin-4(3H)-yl)acetaldehyde and tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: of 1.41 (9H, s), 1,53 was 1.69 (4H, m), 2.06 to and 2.26 (2H, m), 2,65-of 2.72 (2H, m), 2,93-to 3.02 (2H, m), 3.96 points-of 4.12 (1H, m), 4,12-4,34 (6H, m), 4,34-and 4.40 (2H, m), 6,63-to 6.80 (3H, m), 7,74 (1H, d, J=5,1 Hz), to 8.45 (1H, s), 8,58 (1H, d, J=5,1 Hz), 8,87 (1H, s)

Example 54

To a solution of 10 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-occupied(3,4-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate in 1 ml of dichloromethane add 1.0 ml triperoxonane acid at room temperature. The mixture was stirred at the same temperature for 4 hours and the solvent is distilled off under reduced pressure. The resulting residue loaded chloroform and water and the pH adjusted to 0.5 with 1 mol/l hydrochloric acid, and the aqueous layer was separated. To the aqueous layer add chloroform, and the pH of the aqueous layer was adjusted to 12 with 1 mol/l aqueous solution of sodium hydroxide. Organically the layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 2 mg of 4-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-1-yl)ethyl)pyrido(3,4-b)pyrazin-3(4H)-it is in the form of an oily material light brown color.

1H-NMR (CDCl3) δ: of 1.35 to 1.48 (2H, m), 1,83-of 1.95 (2H, m), 2,13-of 2.23 (2H, m), 2,50-to 2.65 (1H, m), 2,69 is 2.75 (2H, m), 2.91 in is 3.00 (2H, m), 3,71 (2H, s), 4,24 (4H, s), 4,37-of 4.44 (2H, m), 6,76-6,86 (3H, m), 7,74 (1H, d, J=5,1 Hz), to 8.45 (1H, s), 8,58 (1H, d, J=5,1 Hz), of 8.90 (1H, s)

Example 55

To a suspension of 0.21 g of 4-(2-(4-aminopiperidin-1-yl)ethyl)-6-methoxypurine(2,3-b)pyrazin-3(4H)-she hydrochloride in 5 ml of methanol added to 0.22 g of a 28% solution of sodium methoxide/methanol, 0.11 g of 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-carbaldehyde, 32 μl of acetic acid and 70 mg of cyanoborohydride sodium and the mixture is stirred at room temperature for 3 hours. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. Received the STATCOM purified by column chromatography on basic silica gel using eluent chloroform:methanol = 10:1. To the obtained residue, add a simple diethyl ether and hexane, and the solid product is filtered off with obtaining of 0.13 g of 6-(((1-(2-(6-methoxy-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-it is in the form of a solid light brown color.

1H-NMR (CDCl3) δ: of 1.34 to 1.47 (2H, m), 1,82-of 1.93 (2H, m), 2,12-2,22 (2H, m), 2,46-of 2.56 (1H, m), 2.71 to 2,78 (2H, m), 3.00 and-is 3.08 (2H, m), of 3.46 (2H, s), 3,83 (2H, s), a 4.03 (3H, s), 4,54-br4.61 (2H, m), 6,72 (1H, d, J=8.7 Hz), 6,97 (1H, d, J=7.8 Hz), 7,56 (1H, d, J=7.8 Hz), 8,01 (1H, d, J=8.7 Hz), 8,14 (1H, s), 8,60-8,80 (1H, user.)

Example 56

Using the same technology as in Example 1, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate is obtained from (7-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: of 1.39 (9H, s), 1,40-1,72 (4H, m), 2,08 was 2.25 (2H, m), 2.49 USD (3H, s), 2,56-2,63 (2H, m), 2,97-of 3.06 (2H, m), as 4.02-4,20 (1H, m), 4,24-4,48 (8H, m), of 6.73 (1H, s), 6,83 (1H, d, J=9.6 Hz), 7,50-rate of 7.54 (1H, m), 7,86 (1H, d, J=9.6 Hz), with 8.05 (1H, s), at 8.36-8,39 (1H, m)

Example 57

Using the same technology as in Example 2, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methyl-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methyl-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 2,02-of 2.16 (2H, m), of 2.51 2.63 in (2H, m), 2,65 (3H, s), 3.25 to 3,37 (2H, m), 3,63 at 3.69 (2H, m), 3,71-3,82 (1H, m), 3,99-4,08 (2H, m), 4,46-4,51 (2H, m), of 4.54 (2H, s), 4,59-4,63 (2H, m), 4,76-a 4.86 (2H, m), 7,17 (1H, d, J=9.9 Hz), of 7.48 (1H, s), 8,18 (1H, d, J=9.9 Hz), scored 8.38 (1H, s), 8,40 (1H, s)8,64 (1H, m)

Example 58

Using the same technology as in Example 1, tert-butyl (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)(1-(2-(7-methoxy-2-occupied(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidine-4-yl)carbamate is obtained from (7-methoxy-2-occupied(2,3-b)pyrazin-1(2H)-yl)acetaldehyde and tert-butyl (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,29-1,72 (4H, m)to 1.37 (9H, s), 2.06 to 2,28 (4H, m), 2,58-of 2.66 (2H, m), 2.91 in-a 3.01 (2H, m)to 3.99 (3H, s), 4,06-4,16 (1H, m), 4,20-to 4.38 (8H, m), 6,77 (1H, s), 7,15-7,21 (1H, m), 8,13 (1H, s), with 8.33 (1H, s), at 8.36 (1H, d, J=2.7 Hz)

Example 59

To a solution of 87 mg of tert-butyl (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)(1-(2-(7-methoxy-2-occupied(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 2 ml of dichloromethane is added 2 ml triperoxonane acid and the mixture is stirred at room temperature for 1 hour. The solvent is distilled from the mixture under reduced pressure and to it was added chloroform and water. The aqueous layer was separated and the pH adjusted to 13.1 using 20% aqueous sodium hydroxide solution. To it was added chloroform, the organic layer is separated and the aqueous layer is xtraceroute chloroform. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 54 mg of 1-(2-(4-((3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxypurine(2,3-b)pyrazin-2(1H)-it is in the form of an oily material yellowish-brown color.

1H-NMR (CDCl3) δ: 1,36 is 1.48 (2H, m), 1,86-of 1.95 (2H, m), 2,13-of 2.28 (2H, m), of 2.25 (2H, Quint., J=5.8 Hz), 2,48 at 2.59 (1H, m), 2,64-2,70 (2H, m), 2.91 in are 2.98 (2H, m), 3,80 (2H, s), of 4.00 (3H, s), 4,24 (2H, t, J=5.8 Hz), 4,28 is 4.36 (2H, m)to 4.33 (2H, t, J=5.8 Hz), 6,85 (1H, s), 7.24 to 7,28 (1H, m), 8,18 (1H, C)to 8.34 (1H, s), at 8.36 (1H, d, J=2.7 Hz)

Example 60

Using the same technology as in Example 8, 1-(2-(4-((3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxypurine(2,3-b)pyrazin-2(1H)-he hydrochloride is obtained from 1-(2-(4-((3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxypurine(2,3-b)pyrazin-2(1H)-it.

1H-NMR (D2O) δ: 1,97-2,10 (2H, m), 2,31 (2H, Quint., J=5.7 Hz), 2,49-to 2.57 (2H, m), 3,21-and 3.31 (2H, m), 3,61-3,71 (3H, m), 3.95 to Android 4.04 (2H, m), of 4.05 (3H, s), 4,36 (2H, t, J=5,9 Hz), 4,37 (2H, s), 4,48 (2H, t, J=5,9 Hz), 4,73-to 4.87 (2H, m), 7,20 (1H, s), 7,49 (1H, d, J=2.6 Hz), of 8.28 (1H, s), a 8.34 (1H, s), 8,42 (1H, d, J=2,6 Hz)

Example 61

To a solution and 0.46 g of ethyl 4-(3-(2-oxo-1,8-naphthiridine-1(2H)-yl)propyl)Pieper is DIN-4-carboxylate in 10 ml of N,N-dimethylformamide type of 0.37 g of potassium carbonate and 0.31 g of 2-((2-bromacil)thio)thiophene and the mixture was stirred at 50-70°C for 2 hours and 10 minutes. The reaction mixture is cooled to room temperature, then add water and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 50:1 to obtain 0.39 g of ethyl 4-(3-(2-oxo-1,8-naphthiridine-1(2H)-yl)propyl)-1-(2-(2-tianity)ethyl)piperidine-4-carboxylate as an oily yellow substance.

1H-NMR (CDCl3) δ: of 1.20 (3H, t, J=7,1 Hz), 1,42-of 1.52 (2H, m), 1,60 was 1.69 (4H, m), 2.00 in and 2.14 (4H, m), 2,52-of 2.58 (2H, m), 2,64-a 2.71 (2H, m), 2,85-only 2.91 (2H, m), 4,10 (2H, square, J=7,1 Hz), 4,42-4,47 (2H, m), of 6.71 (1H, d, J=9.4 Hz), 6,93-6,97 (1H, m), 7,08-7,10 (1H, m), to 7.15 (1H, DD, J=7,6, 4.6 Hz), 7,30-7,33 (1H, m), to 7.61 (1H, d, J=9.4 Hz), to 7.84 (1H, DD, J=7,6, 1.7 Hz), 8,55 (1H, DD, J=4,6) and 1.7 Hz)

Example 62

To a solution of 0.30 g of ethyl 4-(3-(2-oxo-1,8-naphthiridine-1(2H)-yl)propyl)-1-(2-(2-tianity)ethyl)piperidine-4-carboxylate in 5 ml ethanol add 1.7 ml of 20% aqueous sodium hydroxide solution at room temperature and the mixture is heated under reflux, with stirring, for 7 hours. It additionally add 0.3 ml of 20% aqueous sodium hydroxide solution and the mixture is stirred for 1 hour and then cooled to room is temperature and the solvent is distilled off under reduced pressure. The resulting residue loaded with water and pH adjusted to 6.5 using 1 mol/l hydrochloric acid. The solid product is filtered off with getting to 0.22 g of 4-(3-(2-oxo-1,8-naphthiridine-1(2H)-yl)propyl)-1-(2-(2-tianity)ethyl)piperidine-4-carboxylic acid in the form of a solid white product.

1H-NMR (DMSO-d6) δ: 1,24 is 1.34 (2H, m), 1,45-to 1.59 (4H, m), 1,86-to 1.98 (4H, m), 2,42-2,47 (2H, m), 2,55-2,62 (2H, m), 2,87 of 2.92 (2H, m), 4,30 is 4.35 (2H, m), 6,69 (1H, d, J=9.5 Hz), 7,03 (1H, DD, J=5,1, 3.6 Hz), 7,15-7,17 (1H, m), to 7.32 (1H, DD, J=7,6, 4,8 Hz), to 7.59 (1H, d, J=5,1 Hz), 7,95 (1H, d, J=9.5 Hz), 8,16-to 8.20 (1H, m), 8,63-8,66 (1H, m)

Example 63

Using the same technology as in Example 61, ethyl 4-(3-(2-oxo-1,7-naphthiridine-1(2H)-yl)propyl)-1-(2-(2-tianity)ethyl)piperidine-4-carboxylate is obtained from ethyl 4-(3-(2-oxo-1,7-naphthiridine-1(2H)-yl)propyl)piperidine-4-carboxylate and 2-(2-brometalia)thiophene.

1H-NMR (CDCl3) δ: to 1.21 (3H, t, J=7.2 Hz), of 1.40 and 1.80 (6H, m), 2.00 in to 2.18 (4H, m), 2,50-2,60 (2H, m), 2,62-to 2.74 (2H, m), 2,84 of 2.92 (2H, m), of 4.12 (2H, square, J=7,2 Hz), 4,24-or 4.31 (2H, m), to 6.88 (1H, d, J=9.5 Hz), to 6.95 (1H, DD, J=5,3, 3.6 Hz), 7,10 (1H, DD, J=3,6, 1.2 Hz), 7,32 (1H, DD, J=5,3, 1.2 Hz), 7,42 (1H, d, J=5.0 Hz), to 7.64 (1H, d, J=9.5 Hz), 8,44 (1H, d, J=5.0 Hz), a total of 8.74 (1H, s)

Using the same technology as in Example 62, 4-(3-(2-oxo-1,7-naphthiridine-1(2H)-yl)propyl)-1-(2-(2-tianity)ethyl)piperidine-4-carboxylic acid is obtained from ethyl 4-(3-(2-oxo-1,7-naphthiridine-1(2H)-yl)propyl)-1-(2-(2-tianity)ethyl)piperidine-4-carboxylate.

1H-NMR (DMSO-d6) δ: 1,22-of 1.36 (2H, m), 1,48-1,60 (H, m), 1,86-2,02 (4H, m), 2.40 a-2,63 (4H, m), 2,86-of 2.93 (2H, m), 4,22-to 4.28 (2H, m), 6,85 (1H, d, J=9.5 Hz), 7,03 (1H, DD, J=5,4, 3.5 Hz), 7,16 (1H, DD, J=3,5, 1.1 Hz), 7,58 (1H, DD, J=5,4, 1.1 Hz), 7,69 (1H, d, J=5.0 Hz), 7,95 (1H, d, J=9.5 Hz), 8,42 (1H, d, J=5.0 Hz), 8,93 (1H, s)

Example 64

Using the same technology as in Example 1, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(6-fluoro-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate and (6-fluoro-3-occupied(2,3-b)pyrazin-4(3H)-yl)acetaldehyde.

1H-NMR (CDCl3) δ: 1,30-1,70 (4H, m)to 1.38 (9H, s), 2.00 in to 2.15 (2H, m), 2,64-2,70 (2H, m), 3,01-is 3.08 (2H, m), as 4.02-4,16 (1H, m), 4,25-4,33 (6H, m), 4,42-4,48 (2H, m), of 6.71 (1H, s), 6.89 in (1H, DD, J=8,4, 2,8 Hz), 8,03 (1H, s), 8,21-of 8.27 (2H, m)

Example 65

To a solution of 90 mg of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(6-fluoro-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate in 1 ml of methanol was added 1 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 1 hour. The solid product is filtered off to obtain 76 mg of 4-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-6-torpedo(2,3-b)pyrazin-3(4H)-she hydrochloride.

1H-NMR (DMSO-d6) δ: 1,97-of 2.09 (2H, m), 2,28-is 2.37 (2H, m), 3.00 and-3,14 (2H, m), 3,26-to 3.36 (1H, m), 3,39 is 3.57 (2H, m), of 3.80-4.00 points (2H, m), 4,19-4,27 (2H, m), 4,33 is 4.45 (4H, m), 455-4,63 (2H, m)to 7.25 (1H, DD, J=8,5 and 2.2 Hz), 7,32 (1H, s), compared to 8.26 (1H, s), with 8.33 (1H, s), 8,46-8,51 (1H, m), 9,70-9,90 (2H, usher.), 10,35-10,55 (1H, user.)

Example 66

Using the same technology as in Example 1, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-occupied(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidine-4-yl)carbamate is obtained from (7-methoxy-2-occupied(2,3-b)pyrazin-1(2H)-yl)acetaldehyde and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,34 is 1.70 (4H, m)of 1.39 (9H, s), 2,08-of 2.24 (2H, m), 2,60-of 2.66 (2H, m), 2,92-of 3.00 (2H, m)to 3.99 (3H, s), a 4.03-to 4.15 (1H, m), 4,23-4,37 (8H, m), of 6.73 (1H, s), 7,18 (1H, d, J=2.4 Hz), with 8.05 (1H, s), with 8.33 (1H with), at 8.36 (1H, d, J=2.4 Hz)

Example 67

Using the same technology as in Example 59, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxypurine(2,3-b)pyrazin-2(1H)-he obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-occupied(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,37 is 1.48 (2H, m), 1,86 of 1.99 (2H, m), 2,13-of 2.23 (2H, m), 2,48-of 2.58 (1H, m), 2,64-2,69 (2H, m), 2.91 in are 2.98 (2H, m), of 3.78 (2H, s), of 4.00 (3H, s), 4,25 is 4.35 (6H, m), for 6.81 (1H, s), 7,26 (1H, d, J=2.6 Hz), 8,10 (1H, s), a 8.34 (1H, s), at 8.36 (1H, d, J=2,6 Hz)

Example 68

Using the same technology as in Example 8, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)these who)-7-methoxypurine(2,3-b)pyrazin-2(1H)-he hydrochloride is obtained from 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxypurine(2,3-b)pyrazin-2(1H)-it.

1H-NMR (D2O) δ: 1,96-2,10 (2H, m), 2,49-to 2.57 (2H, m), 3,21-of 3.32 (2H, m), 3,61-and 3.72 (3H, m), 3.95 to Android 4.04 (2H, m)4,06 (3H, s), 4,39 (2H, s), 4,40-of 4.54 (4H, m), 4.75 V-to 4.81 (2H, m), 7,25 (1H, s)of 7.48-7,51 (1H, m), 8,24 (1H with), to 8.34 (1H, s), to 8.41-8,44 (1H, m)

Example 69

Using the same technology as in Example 1, tert-butyl (1-(2-(6-chloro-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate and (6-chloro-3-occupied(2,3-b)pyrazin-4(3H)-yl)acetaldehyde.

1H-NMR (CDCl3) δ: to 1.38 (9H, s), 1,40-of 1.65 (4H, m), 1,97-of 2.15 (2H, m), 2,64-2,70 (2H, m), 3,03-3,10 (2H, m), as 4.02-to 4.14 (1H, m), 4,25-4,34 (6H, m), 4,46-to 4.52 (2H, m), 6,70 (1H, s), 7,26 (1H, d, J=8,2 Hz), 8,02 (1H, s), 8,09 (1H, d, J=8,2 Hz), of 8.28 (1H, s)

Example 70

To a solution of 0.11 g of tert-butyl (1-(2-(6-chloro-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate in 3 ml of dioxane is added 25 mg of tert-butyl carbamate and 82 mg of cesium carbonate. To add 2.5 mg of Tris(dibenzylideneacetone)diplegia(0) and 3.1 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in argon atmosphere. The mixture was stirred at 80-90°C for 2 hours in argon atmosphere. Nerastvorimaya substance is filtered off and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography is and alkaline silica gel using eluent chloroform:methanol = 20:1 to obtain 78 mg of tert-butyl (1-(2-(6-((tert-butoxycarbonyl)amino)-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate in the form of an oily material light brown color.

1H-NMR (CDCl3) δ: 1,35 is 1.70 (4H, m)to 1.38 (9H, s), and 1.56 (9H, s), 2,03-2,19 (2H, m), 2,58-of 2.64 (2H, m), 3.00 and totaling 3.04 (2H, m), 4,06-4,19 (1H, m), 4,24-to 4.38 (6H, m), 4,40-4,48 (2H, m), 6,72 (1H, s), 7,37 (1H, s), of 7.96 (1H, d, J=8,8 Hz), with 8.05 (1H, s), of 8.09 (1H, d, J=8,8 Hz), 8,15 (1H, s)

Example 71

Using the same technology as in Example 65, 6-amino-4-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)pyrido(2,3-b)pyrazin-3(4H)-he hydrochloride is obtained from tert-butyl (1-(2-(6-((tert-butoxycarbonyl)amino)-3-occupied(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate.

1H-NMR (DMSO-d6-D2O) δ: 1,85-of 1.97 (2H, m), 2,32-to 2.41 (2H, m), 3.04 from-3,14 (2H, m), 3.33 and-of 3.48 (3H, m), 3,92-4,00 (2H, m), 4.26 deaths (2H, s), 4,35-to 4.46 (4H, m), 4,54-4,60 (2H, m), 6,56 (1H, d, J=8,8 Hz), 7,31 (1H, s), 7,83 (1H, d, J=8,8 Hz), 7,87 (1H, s), 8,30 (1H, s)

Example 72

(1) To 98 mg of 4-(1,3-dioxolane-2-ylmethyl)-6-(1H-1,2,4-triazole-1-yl)pyrido(2,3-b)pyrazin-3(4H)-it add 3 ml of 80% aqueous solution triperoxonane acid and the mixture is stirred at room temperature for 6 hours and 30 minutes. To it was added water and ethyl acetate, and the mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium hydroxide. The organic layer is separated, and the aqueous layer add sodium chloride, and the mixture is extracted with chloroform. Organic the sky layer and the extract combined the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.12 g (3-oxo-6-(1H-1,2,4-triazole-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde in the form of a solid product light red color.

(2) To a solution of 48 mg of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate in 2 ml of methanol are added 50 mg (3-oxo-6-(1H-1,2,4-triazole-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde, 2.5 ml of dichloromethane and 20 ml of acetic acid and the mixture is stirred at room temperature for 40 minutes. To the reaction mixture are added 9.0 mg of cyanoborohydride sodium and the mixture is stirred at room temperature for 1 hour and 30 minutes. To it was added a saturated aqueous sodium bicarbonate solution and chloroform, the organic layer was separated, sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 50:1 to obtain 35 mg of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(3-oxo-6-(1H-1,2,4-triazole-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate in the form of an oily material light yellow color.

1H-NMR (CDCl3) δ: to 1.38 (9H), 1,30-1,70 (4H, m), 2.05 is-of 2.21 (2H, m), 2,69 is 2.75 (2H, m), 3.00 and-is 3.08 (2H, m), 4.04 the-4,16 (1H, m), 4,25-4,34 (6H, m), to 4.52-4,58 (2H, m), 6,70 (1H, s), 7,92 (1H, d, J=8.6 Hz), 8,02 (1H, s)to 8.14 (1H, s), 8,31 (1H, C), 8,35 (1H, d, J=8.6 Hz), which is 9.09 (1H, s)

Example 73

Using the same technology as in Example 65, 4-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-6-(1H-1,2,4-triazole-1-yl)pyrido(2,3-b)pyrazin-3(4H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(3-oxo-6-(1H-1,2,4-triazole-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (DMSO-d6) δ: 1,97-of 2.34 (4H, m), 3,02-3,14 (2H, m), 3,24-to 3.36 (1H, m), 3,40-3,50 (2H, m), of 3.80-4.00 points (2H, m), 4,19-4.26 deaths (2H, m), 4,30-4,45 (4H, m), 4.80 to a 4.83 (2H, m), 7,27 (1H, s), of 7.90 (1H, d, J=8,4 Hz), of 8.25 (1H, s), 8,35 (1H, s), to 8.41 (1H, s), charged 8.52 (1H, d, J=8,4 Hz), of 9.55-9,80 (2H, usher.), 9,94 (1H, s), 10,95-11,00 (1H, m)

Example 74

Using the same technology as in Example 1, ethyl (2E)-3-(5-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)acrylate are obtained from ethyl (2E)-3-(6-oxo-5-(2-oxoethyl)-5,6-dihydro-1,5-naphthiridine-3-yl)acrylate and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,30-1,75 (13H, m)to 1.38 (3H, t, J=7.2 Hz), 2,10-of 2.27 (2H, m), 2,58-to 2.65 (2H, m), 2,98-of 3.06 (2H, m), 4.04 the-4,20 (1H, m), 4,24-4,46 (10H, m), 6,62 (1H, d, J=16.2 Hz), 6,72-6,74 (1H, usher.), 6,93 (1H, d, J=9.8 Hz), of 7.75 (1H, d, J=16.2 G is), for 7.78 (1H, s), 7,89 (1H, d, J=9.8 Hz), with 8.05 (1H, s), 8,68 (1H, d, J=1.2 Hz)

Example 75

Using the same technology as in Example 54, ethyl (2E)-3-(5-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)acrylate are obtained from ethyl (2E)-3-(5-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)acrylate.

1H-NMR (CDCl3) δ: 1,35-and 1.54 (2H, m)to 1.37 (3H, t, J=7.2 Hz), 1.85 to a 2.00 (2H, m), 2,12-of 2.28 (2H, m), 2,46-to 2.74 (3H, m), 2,93 totaling 3.04 (2H, m), 3,80 (2H, s), 4,24-of 4.44 (8H, m), of 6.65 (1H, d, J=16.1 Hz), PC 6.82 (1H, s), 6,93 (1H, d, J=9.8 Hz), 7,76 (1H, d, J=16.1 Hz), 7,87-a 7.92 (1H, usher.), 7,89 (1H, d, J=9.8 Hz), 8,10 (1H, s), 8,68 (1H, d, J=1.7 Hz)

Example 76

Using the same technology as in Example 1, tert-butyl (1-(2-(7-chloro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate is obtained from (7-chloro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,35-1.55V (13H, m), 2,08-of 2.27 (2H, m), 2,58-to 2.65 (2H, m), 2,93-to 3.02 (2H, m), 4,05-4,20 (1H, m), 4,22-4,50 (8H, m), 6,72 (1H, s), to 6.88 (1H, d, J=9.8 Hz), 7,78-of 7.82 (1H, m), 7,86 (1H, d, J=9.8 Hz), with 8.05 (1H with), 8,46 (1H, d, J=2.0 Hz)

Example 77

Using the same technology as in Example 2, 7-chloro-1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)Piri is in-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (1-(2-(7-chloro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate.

1H-NMR (D2O) δ: 2,00-and 2.14 (2H, m), of 2.51-2,61 (2H, m), 3,22-to 3.36 (2H, m), 3,60-of 3.80 (3H, m), 3,97-4,07 (2H, m), 4,45-4,50 (2H, m)to 4.52 (2H, s), 4,57-to 4.62 (2H, m), 4.72 in-4,82 (2H, m), 7,03 (1H, d, J=9.8 Hz), 7,44 (1H, ), 8,08 (1H, d, J=9.8 Hz), 8,19 is 8.22 (1H, m), at 8.36 (1H, s), 8,61 (1H, d, J=1.7 Hz)

Example 78

To the suspension is 0.22 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 7 ml of methanol added 66 mg of cyanoborohydride sodium, 64 μl of 3-fluoro-4-methylbenzaldehyde, of 0.30 g of a 28% solution of sodium methoxide/methanol and 30 μl of acetic acid and the mixture is stirred at room temperature for 3 hours. To it was added 22 mg of 3-fluoro-4-methylbenzaldehyde and the mixture was stirred at the same temperature for 1 hour. It is additionally added 33 mg of cyanoborohydride sodium and the mixture was stirred at the same temperature for 1 hour. To it was added a saturated aqueous sodium bicarbonate solution and the solvent is distilled off under reduced pressure. They added chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel, and the use of eluent chloroform:methanol = 9:1 to obtain 20 mg of 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of a colorless oily substance.

1H-NMR (CDCl3) δ: 1,36-of 1.57 (2H, m), 1,86-of 1.94 (2H, m), 2,13-2,22 (2H, m), of 2.25 (3H, s), 2,48-of 2.56 (1H, m), 2,61 of 2.68 (2H, m), 2,94-a 3.01 (2H, m), of 3.77 (2H, s), of 3.97 (3H, s), 4,33-4,39 (2H, m), 6,74 (1H, d, J=9.6 Hz), 6,95-7,01 (2H, m), 7,11 (1H, t, J=8.0 Hz), 7.23 percent (1H, d, J=2.3 Hz), to 7.84 (1H, d, J=9.6 Hz), of 8.28 (1H, d, J=2.3 Hz)

Example 79

To a solution of 297 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she and 159 mg of 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-carbaldehyde in 4 ml of chloroform and 1 ml of methanol type of 0.11 ml of acetic acid and the mixture is stirred at room temperature for 16 hours. To the reaction mixture 299 mg triacetoxyborohydride sodium and the mixture is stirred for 1.5 hours. To it was added a saturated aqueous solution of sodium bicarbonate and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Silica Gel 60 manufactured KANTO CHEMICAL CO., INC. and eluent chloroform:methanol (mixed with 5% of 28% aqueous ammonium)= 87:13 to obtain 275 mg of 1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-yl)methylamino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of a yellow foam.

To a solution of 260 mg of 1-(2-(4-((3-oxo-3,4-dihydro-2H-p the Rideau(3,2-b)(1,4)oxazin-6-yl)methylamino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she's in 4 ml of ethyl acetate and 2 ml of methanol, add 3 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature within 12 minutes. The solvent is distilled off under reduced pressure, it adds a simple diethyl ether, and the solid product is filtered off with getting 304 mg of 1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-yl)methylamino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid white product.

1H-NMR (DMSO-d6) δ: 2,03-2,12 (2H, m), 2,37 is 2.44 (2H, m), is 3.08-and 3.16 (2H, m), 3.27 to to 3.33 (2H, m), 3,35-of 3.43 (1H, m), 3,78-3,82 (2H, m), 4,07 (3H, s), 4,19 (2H, t, J=5.5 Hz), 4,70-to 4.73 (4H, m), 6,72 (1H, d, J=9.6 Hz), 7.23 percent (1H, d, J=8,3 Hz), 7,46 (1H, d, J=8,3 Hz), 7,72 (1H, d, J=2.3 Hz), 7,94 (1H, d, J=9.6 Hz), a 8.34 (1H, d, J=2.3 Hz), 9,54-9,68 (2H, m), 11,30-11,63 (2H, m)

Example 80

To a solution of 150 mg of 1-(2-(4-(aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she and 82 mg of 2,3-dihydro(1,4)like(2,3-b)pyridine-7-carbaldehyde in 15 ml of chloroform added 60 mg of acetic acid and the mixture is stirred at room temperature for 16.5 hours. To the reaction mixture are added 158 mg triacetoxyborohydride sodium and the mixture is stirred for 2 hours. To it was added a saturated aqueous solution of sodium bicarbonate and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel with the use of what Finance silica gel: Silica Gel 60N production KANTO CHEMICAL CO., INC. and eluent chloroform:methanol = 10:1 to obtain 103 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-b)pyridin-7-yl)methylamino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of colorless viscous oily substance.

In a solution of 134 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-b)pyridin-7-yl)methylamino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she's in 1 ml of methanol and 5 ml of ethyl acetate is added 2 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature. The solid product is filtered off to obtain 159 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-b)pyridin-7-yl)methylamino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (DMSO-d6) δ: 2,02-2,11 (2H, m), 2,35-to 2.42 (2H, m), 3,07-3,17 (2H, m), 3,24-of 3.32 (3H, m), 3.75 to 3,82 (2H, m), 4,07 (3H, s), 4.09 to 4,19 (2H, m), 4,25-or 4.31 (2H, m), to 4.41-of 4.44 (2H, m), 4,67-4,74 (2H, m), 6,72 (1H, d, J=9,6 Hz), to 7.64 (1H, d, J=2.3 Hz), of 7.70 (1H, d, J=2.3 Hz), 7,92 (1H, d, J=2.3 Hz), 7,94 (1H, d, J=9.6 Hz), with 8.33 (1H, d, J=2.3 Hz), 9,59-9,78 (3H, m), of 11.26-to 11.52 (1H, m)

Example 81

To a solution of 150 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)methylamino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she and 85 mg of bromoacetate in 15 ml of acetonitrile was added 100 mg of potassium carbonate and the mixture is stirred at room temperature for 18 hours and stirred at 40°C for 4 hours. The solvent is distilled at p is low pressure, to it was added chloroform and water and the organic layer separated. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Silica Gel 60N production KANTO CHEMICAL CO., INC. and eluent chloroform:methanol = 20:1 to obtain 90 mg of ethyl ((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)acetate as an oily material brown color.

1H-NMR (CDCl3) δ: 1.26 in (3H, m), 1,52 is 1.60 (2H, m), 1,84-1,89 (2H, m), 2,08-of 2.15 (2H, m), 2,59-of 2.64 (2H, m), 2,65-a 2.71 (1H, m), 3,01-of 3.07 (2H, m), 3,40-of 3.43 (2H, m), 3,84-a 3.87 (2H, m), of 3.97 (3H, s), 4,12-4,17 (2H, m), 4.26 deaths-the 4.29 (2H, m), or 4.31-4,37 (4H, m), 6,72 to 6.75 (1H, m), 7,13-to 7.15 (1H, m), 7,19-7,21 (1H, m), 7,82-a 7.85 (1H, m), 8,05-8,07 (1H, m), 8,27-8,29 (1H, m)

Example 82

To a solution of 90 mg of ethyl ((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)acetate in 0.2 ml of methanol and 1 ml of tetrahydrofuran, add 0.2 ml of 10% aqueous sodium hydroxide solution and the mixture is stirred at room temperature for 2 hours. To the reaction mixture was added 1 mol/l aqueous solution of hydrochloric acid and neutralize it, and the solvent is distilled off under reduced pressure. The resulting residue is purified by means of resin; HP-20, manufacturing Mitsubihi Chemical Corporation, and eluent from acetone to obtain 54 mg of ((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)acetic acid in the form of solid product is a light yellow color.

1H-NMR (DMSO-d6) δ: of 1.26 to 1.34 (2H, m), 1,66-1,71 (2H, m), 1,74-of 1.78 (2H, m), 1,90-of 1.97 (2H, m), 2,94-a 3.01 (3H, m), to 3.58-3,62 (2H, m), 3,66 at 3.69 (2H, m), of 3.96 (3H, s), 4,25-to 4.28 (2H, m), or 4.31 is 4.35 (4H, m), of 6.65 (1H, d, J=9,6 Hz), was 7.08 (1H, s), 7,40 (1H, d, J=2.3 Hz), 7,86 (1H, d, J=9.6 Hz), of 7.96 (1H, s), of 8.27 (1H, d, J=2.3 Hz)

Example 83

To a solution of 75 mg of tert-butyl (1-(2-(7-cyano-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 5 ml of ethyl acetate, add 7 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 2 hours. The reaction mixture was alkalinized with saturated aqueous sodium bicarbonate solution, the solvent is distilled off under reduced pressure, and then the obtained residue is purified by column chromatography on silica gel using silica gel: Chromatorex-NH production Fuji Silysia Chemical Ltd., and eluent of chloroform to obtain 34 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-cyano-1,5-naphthiridine-2(1H)-it is in the form of solid product is a light yellow color.

To a solution of 32 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-cyano-(1,5-naphthiridine)-2(1H)-she and 16 mg of 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde in 5 ml of chloroform, add 9 ál of vinegar the first acid and the mixture is stirred at room temperature overnight. To the reaction mixture are added 34 mg of triacetoxyborohydride sodium and the mixture is stirred for 9 hours. To it was added a saturated aqueous sodium bicarbonate solution and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Chromatorex-NH production Fuji Silysia Chemical Ltd. and eluent of chloroform to obtain 39 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-cyano-1,5-naphthiridine-2(1H)-it is in the form of solid product is a light yellow color.

To a solution of 36 mg of 1-(2-(4-((2,3-dihydro (1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-cyano-1,5-naphthiridine-2(1H)-she's in 5 ml of acetic acid, add 0.5 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and 5 ml of ethyl acetate and the mixture is stirred at room temperature for 10 minutes. The solvent is distilled under reduced pressure to obtain 44 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-cyano-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid white product.

1H-NMR (CDCl3) δ: 2,03-of 2.09 (2H, m), 2,33-of 2.38 (2H, m), 3,07 is 3.15 (2H, m), 3,28-to 3.36 (3H, m), 3,76-3,81 (2H, m), 4,21-4,24 (2H, m), 4,34 is 4.36 (2H, m), 4,40-4,43 (2H, m), 4,62-of 4.66 (2H, m), to 7.09 (1H, d, J=9.6 Hz), 7,26 (1H, C)8,07 (1H, d, J=9.6 Hz), 8,23 (1H, s), 8,84 cent to 8.85 (1H, m), 8,96 (1H, d, J=1,8 Hz), 9,65-to 9.70 (2H, m), a 10.74-10,78 (1H, m)

Example 84

To a solution of 0.12 g (3-methoxy-6-occupied(2,3-b)pyrazin-5(6H)-yl)acetaldehyde in 5 ml of methylene chloride added 0.18 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate, 26 μl of acetic acid and 0.12 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 2 hours and 30 minutes. To the reaction mixture is added saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 20:1 to obtain 0.32 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(3-methoxy-6-occupied(2,3-b)pyrazin-5(6H)-yl)ethyl)piperidine-4-yl)carbamate as a colorless oily substance.

1H-NMR (CDCl3) δ: 1,27-1,72 (13H, m), 2,01-of 2.23 (2H, m), 2,59-2,69 (2H, m), 3,01-3,11 (2H, m), 3,98-4,18 (1H, m), a 4.03 (3H, s), 4,19-4,39 (6H, m), 4,46-4,56 (2H, m), of 6.71 (1H, s), 6,74 (1H, d, J=9.8 Hz), 7,83 (1H, d, J=9.8 Hz), of 8.04 (1H, s), 8,10 (1H, s)

Example 85

To 0.32 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(3-methoxy-6-occupied(2,3-b)the feast of the zine-5(6H)-yl)ethyl)piperidine-4-yl)carbamate add 15 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 2.5 days. The solvent is distilled off under reduced pressure, to the obtained residue, add 5 ml of ethyl acetate and the solid product filtered off to obtain 0.24 g of 5-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl-3-methoxypyridine(2,3-b)pyrazin-6(5H)-she hydrochloride in the form of a solid yellow color.

1H-NMR (D2O) δ: 1,98-to 2.13 (2H, m), 2,50 at 2.59 (2H, m), 3,19-to 3.35 (2H, m), 3,64-of 3.77 (3H, m), of 3.97-4.09 to (2H, m), 4,13 (3H, s), 4,45-to 4.52 (4H, m), 4,55-br4.61 (2H, m), 4,90-4,94 (1H, m), to 6.88 (1H, d, J=9.8 Hz), 7,40 (1H, ), 8,08 (1H, d, J=9.8 Hz), compared to 8.26 (1H, s), with 8.33 (1H, s)

Example 86

Using the same technology as in Example 1, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(4-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)morpholine-2-ylmethyl)carbamate is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(morpholine-2-ylmethyl)carbamate and (7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde.

1H-NMR (CDCl3) δ: 1,35-of 1.55 (9H, m), 1,95-2,10 (1H, m), 2,23 is 2.33 (1H, m), 2,58-a 2.71 (2H, m), 2,75-is 2.88 (2H, m), 3,17-3,50 (2H, m), 3,53-3,62 (1H, m), 3,65-with 3.79 (1H, m), 3,82-to 3.89 (1H, m), 3,98 (3H, s), 4,22-4,46 (7H, m), to 4.52-and 4.68 (1H, m), 6,69-6,77 (1H, m), 6,74 (1H, d, J=9.6 Hz), 7,18 (1H, d, J=2.2 Hz), the 7.85 (1H, d, J=9.6 Hz), 8,08 (1H, s), compared to 8.26-8,31 (1H, m)

Example 87

Using the same technology as in Example 2, 1-(2-(2-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)morpholine-4-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride on ucaut from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(4-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)morpholine-2-ylmethyl)carbamate.

1H-NMR (D2O) δ: 3,11-3,20 (1H, m), 3.27 to 3,39 (2H, m), 3.43 points-of 3.50 (1H, m), 3,65-3,74 (2H, m), 3,78-3,86 (1H, m), a 3.87-of 3.97 (2H, m), of 4.05 (3H, s), 4,21-4,32 (2H, m), of 4.44-4,51 (4H, m), 4,56-br4.61 (2H, m), 4,70 of 4.83 (2H, m), 6,89 (1H, d, J=9.8 Hz), 7,42 (1H, s), 7,49-7,53 (1H, m), 8,07 (1H, d, J=9.8 Hz), 8,35 (1H, s), 8,42 (1H, d, J=2.2 Hz)

Example 88

Using the same technology as in Example 78, 1-(2-(4-(((5-fluoro-2-methylpyridin-3-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and 5-fluoro-2-methylnicotinamide.

1H-NMR (CDCl3) δ: 1,39-is 1.51 (2H, m), 1,90 of 1.99 (2H, m), 2,17-of 2.28 (2H, m), 2,44-2,61 (1H, m), of 2.51 (3H, s), 2.63 in-a 2.71 (2H, m), 2,96 was 3.05 (2H, m), with 3.79 (2H, s), 3,98 (3H, s), 4,33 was 4.42 (2H, m), of 6.75 (1H, d, J=9.8 Hz), 7.23 percent (1H, s), 7,47 (1H, DD, J=9,0, 2.6 Hz), the 7.85 (1H, d, J=9.8 Hz), 8,23 (1H, d, J=2.6 Hz), of 8.28 (1H, d, J=2.2 Hz)

Example 89

To a suspension of 0.10 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 4 ml of methanol added 31 mg cyanoborohydride sodium, 44 μl of 4-fluoro-3-methylbenzaldehyde, 39 mg of a 28% solution of sodium methoxide/methanol and 42 μl of acetic acid and the mixture is stirred at room temperature for 1 hour and 15 minutes. To it add 44 μl of 4-fluoro-3-methylbenzaldehyde and 31 mg of cyanoborohydride sodium and the mixture was stirred at the same temperature for 45 minutes. It additionally add 44 μl of 4-fluoro-3-methylbenzaldehyde I mg cyanoborohydride sodium and the mixture was stirred at the same temperature for 30 minutes. To it was added a saturated aqueous solution of sodium bicarbonate and ethyl acetate and the organic layer is separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 10:1. The resulting residue is dissolved in 2 ml of ethyl acetate and thereto was added 1 ml of 4.0 mol/l solution of hydrochloric acid/ethyl acetate at room temperature. The solvent is distilled off under reduced pressure, the obtained residue is added ethyl acetate, and the solid product filtered off to obtain 54 mg of 1-(2-(4-((4-fluoro-3-methylbenzyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 1,95-of 2.09 (2H, m), 2,28 (3H, d, J=1.5 Hz), 2,47-of 2.56 (2H, m), 3,16-3,26 (2H, m), 3,55-of 3.64 (3H, m), 3,92-4,00 (2H, m), Android 4.04 (3H, s), 4,27 (2H, s), 4,70-of 4.90 (2H, m), 6.87 in (1H, d, J=9.8 Hz), 7,12-7,18 (1H, m), 7,28-7,39 (2H, m), 7,44 (1H, d, J=2.2 Hz), of 8.06 (1H, d, J=9.8 Hz), 8,40 (1H, d, J=2.3 Hz)

Example 90

Using the same technology as in Example 30, 6-(((1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and 3-OK, what about the-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-carbaldehyde.

1H-NMR (CDCl3) δ: 1,40-of 1.53 (2H, m), 1,87 is 1.96 (2H, m), 2,14-of 2.24 (2H, m), 2,47-of 2.58 (1H, m), 2,62-2,69 (2H, m), 2.95 and totaling 3.04 (2H, m), of 3.48 (2H, s), 3,83 (2H, s), 3,98 (3H, s), 4,33-to 4.41 (2H, m), 6,74 (1H, d, J=9.6 Hz), 6,97 (1H, d, J=7,7 Hz), 7,24 (1H, d, J=2.2 Hz), EUR 7.57 (1H, d, J=7,7 Hz), the 7.85 (1H, d, J=9.6 Hz), 8,13-8,23 (1H, usher.), of 8.28 (1H, d, J=2.2 Hz)

Example 91

To a solution of 0.12 g (7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in 1 ml dichloromethane added a solution of 0.14 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate in 1.4 ml of dichloromethane and 23 μl of acetic acid and 0.13 g of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 1 hour and 40 minutes. The reaction mixture was loaded chloroform and saturated aqueous sodium bicarbonate and the pH adjusted to 8.6, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of chloroform:methanol = 19:1-93:7 to obtain 0.12 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)is arbamate in the form of a solid product light yellow color.

1H-NMR (CDCl3) δ: 1.32 to 1,72 (13H, m), 2,10-of 2.27 (2H, m), 2,60-2,69 (2H, m), 2,94-3,03 (2H, m), 4,05-to 4.15 (1H, m), 4,24-and 4.40 (8H, m), 6,72 (1H, s), 6,93 (1H, d, J=9.8 Hz), 7,32 (1H, s), 7,39 (1H, s), of 7.75 (1H, s), to 7.93 (1H, d, J=9.8 Hz), of 7.97 (1H, s), of 8.04 (1H, s), 8,65 (1H, d, J=1.9 Hz)

Example 92

Using the same technology as in Example 4, 1-(2-(4-(((2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)methyl)amino)piperidine-1-yl)ethyl)-7-(1H-imidazol-1-yl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 1,90-of 2.15 (2H, m), 2,52-2,61 (2H, m), 3,24-to 3.36 (2H, m), 3,66-of 3.80 (3H, m), EUR 4.00-4.09 to (2H, m), 4,40-4,50 (2H, m), 4,50-of 4.54 (2H, m), 4,57-4,88 (4H, m), 7,16 (1H, d, J=9.9 Hz), 7,45 (1H, s), to 7.77 (1H, t, J=2.0 Hz), of 8.09 (1H, t, J=1.6 Hz), 8,19 (1H, d, J=9.9 Hz), at 8.36 (1H, s), 8,44 (1H, d, J=1.6 Hz), 8,93 (1H, d, J=2.0 Hz), 9,46 (1H, t, J=1.4 Hz)

Example 93

Using the same technology as in Example 78, 1-(2-(4-(((5-fluoro-6-methylpyridin-3-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and 5-fluoro-6-methylnicotinamide.

1H-NMR (CDCl3) δ: of 1.35 to 1.47 (2H, m), 1,86-of 1.95 (2H, m), 2,14-of 2.24 (2H, m), 2,47-of 2.56 (1H, m), of 2.51 (3H, d, J=2,9 Hz), 2,62 of 2.68 (2H, m), 2,94-to 3.02 (2H, m), 3,82 (2H, s), 3,98 (3H, s), 4,33-and 4.40 (2H, m), 6,74 (1H, d, J=9.8 Hz), 7,21 (1H, d, J=2.3 Hz), was 7.36 (1H, DD, J=9,9, 1,4 Hz), to 7.84 (1H, d, J=9.8 Hz), 8,23 (1H, s), of 8.28 (1H, d, J=23 Hz)

Example 94

Using the same technology as in Example 1, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)((3R,4R)-3-hydroxy-1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)((3R,4R)-3-hydroxypiperidine-4-yl)carbamate and (7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde.

1H-NMR (CDCl3) δ: 1,22-of 1.42 (9H, m), 1,55-of 1.85 (3H, m), 2,18-of 2.36 (2H, m), 2,67-and 2.79 (2H, m), 2,98-of 3.07 (1H, m), 3,26-to 3.36 (1H, m), 3,62-to 3.73 (1H, m), of 3.94 (3H, s), 4,00-to 4.52 (8H, m), 6,70-6,84 (2H, m), 7,13-7,17 (1H, m), 7,81-with 8.05 (2H, m), 8,24-8,32 (1H, m)

Example 95

To a solution of 75 mg of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)((3R,4R)-3-hydroxy-1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 3 ml of ethanol, add 3.0 ml of a solution of hydrochloric acid/ethanol at room temperature. The mixture was stirred at the same temperature for 1 hour and the solvent is distilled off under reduced pressure. To the obtained residue, add a simple diethyl ether and the solid product filtered off. To the solid product is added chloroform and water, and the aqueous layer was separated. The aqueous layer was loaded with chloroform and the pH adjusted to 12 with 1 mol/l aqueous solution of sodium hydroxide. The organic layer is separated, washed with saturated aqueous chloride into three and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 45 mg of 1-(2-((3R,4R)-4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-3-hydroxypiperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it.

1H-NMR (CDCl3) δ: of 1.35 to 1.47 (1H, m), 1,92-2,02 (1H, m), 2,07-of 2.23 (2H, m), 2,33-to 2.42 (1H, m), 2,65-by 2.73 (2H, m), 2.91 in-2,99 (1H, m), 3,14-up 3.22 (1H, m), 3,44-to 3.52 (1H, m), 3.72 points-of 3.84 (1H, m), 3,92-4,01 (1H, m), of 3.97 (3H, s), 4,25 was 4.42 (6H, m), of 6.73 (1H, d, J=9.8 Hz), 6,76 (1H, s), 7,18 (1H, d, J=2.4 Hz), to 7.84 (1H, d, J=9.8 Hz), of 8.09 (1H, s), of 8.27 (1H, d, J=2.4 Hz)

Example 96

Using the same technology as in Example 78, 5-(2-(4-(((5-fluoro-6-methylpyridin-3-yl)methyl)amino)piperidine-1-yl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-he obtained from 5-(2-(4-aminopiperidin-1-yl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-she hydrochloride and 5-fluoro-6-methylnicotinamide.

1H-NMR (CDCl3) δ: 1,31 was 1.43 (2H, m), 1,83-of 1.92 (2H, m), 2,12-2,22 (2H, m), 2,44 is 2.55 (1H, m), 2,50 (3H, d, J=2.7 Hz), 2,67-to 2.74 (2H, m), 2,99-is 3.08 (2H, m), 3,81 (2H, s)4,06 (3H, s), 4,55-to 4.62 (2H, m), 6,76 (1H, d, J=9.8 Hz), was 7.36 (1H, d, J=9.8 Hz), to 7.84 (1H, d, J=9.8 Hz), 8,11 (1H, s), by 8.22 (1H, s)

Example 97

To a solution of 0.33 g of (2-methoxy-7-occupied(2,3-d)pyrimidine-8(7H)-yl)acetaldehyde in 15 ml of dichloromethane add a solution of 0.53 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate in 5.3 ml of dichloromethane and 87 μl of acetic acid and the mixture is stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture are added 0.40 g of triacetoxyborohydride sodium and the mixture is stirred for 2 hours and 30 minutes. After her leave to stand overnight, the mixture is stirred at room temperature is re within 4 hours. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using a gradient elution of chloroform:methanol = 50:1 to 10:1 to obtain 0.55 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(2-methoxy-7-occupied(2,3-d)pyrimidine-8(7H)-yl)ethyl)piperidine-4-yl)carbamate in the form of foam a light yellow color.

1H-NMR (CDCl3) δ: 1.25 and 1.69 in (13H), 2,01-of 2.23 (2H, m), 2,61-2,69 (2H, m), 3,02-3,11 (2H, m), 3,63-a-3.84 (1H, m)4,06 (3H, s), 4,22-4,43 (6H, m), 4,45-a 4.53 (2H, m), to 6.57 (1H, d, J=9.4 Hz), of 6.71 (1H, s), 7,60 (1H, d, J=9.4 Hz), of 8.04 (1H, s)8,64 (1H, s)

Example 98

To a solution of 0.54 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(2-methoxy-7-occupied(2,3-d)pyrimidine-8(7H)-yl)ethyl)piperidine-4-yl)carbamate in 15 ml of dichloromethane add 5 ml triperoxonane acid and the mixture is stirred at room temperature for 2 hours. Add 2 mol/l aqueous sodium hydroxide solution while cooling on ice to bring the pH of the mixture to 13, there was added dichloromethane, org the organic layer is separated and the aqueous layer was extracted with dichloromethane. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 10:1 to obtain 0.34 g of 8-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-2-methoxypyridine(2,3-d)pyrimidine-7(8H)-it is in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: 1,31 was 1.43 (2H, m), 1,81-1,90 (2H, m), 2,08-2,19 (2H, m), 2,41 is 2.55 (1H, m), 2,64-of 2.72 (2H, m), 2,97-of 3.06 (2H, m), of 3.77 (2H, s)4,07 (3H, s), 4,23-4,34 (4H, m), 4,50-4,58 (2H, m), 6,56 (1H, d, J=9.5 Hz), to 6.80 (1H, s), to 7.59 (1H, d, J=9.5 Hz), 8,08 (1H, s), 8,63 (1H, s)

Example 99

To a solution of 0.15 g of N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)-2,2,2-Cryptor-N-(piperidine-3-ylmethyl)ndimethylacetamide in 2 ml of dichloromethane added 85 mg of (7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and 24 μl of acetic acid, then add 0,13 g triacetoxyborohydride sodium and the mixture is stirred at room temperature for 2 hours. To the reaction mixture are added chloroform and add saturated aqueous sodium bicarbonate solution while cooling on ice and the pH adjusted to 8.0. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and e is strict unite, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.21 g of N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)-2,2,2-Cryptor-N-(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-3-ylmethyl)ndimethylacetamide in the form of a solid yellow color. To 0.21 g of N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)-2,2,2-Cryptor-N-(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-3-ylmethyl)ndimethylacetamide add 3 ml of methanol and 0.7 ml of water and added 62 mg of potassium carbonate. The mixture is stirred at room temperature for 1 hour and 15 minutes, then stirred at 40-50°C for 1 hour and stirred at 50-60°C for 1 hour and 30 minutes. The solvent is distilled off under reduced pressure, the obtained residue is added chloroform and water, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of hexane:ethyl acetate = 92:8-88:12 to obtain 0.18 g of 1-(2-(3-(((2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl is ethyl)amino)methyl)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it is in the form of a light yellow oily material color.

1H-NMR (CDCl3) δ: 0,90-1,10 (1H, m), 1,45-of 1.92 (5H, m), 2.05 is with 2.14 (1H, m), 2,46-2,52 (2H, m), 2,60-of 2.66 (2H, m), 2,85 of 2.92 (1H, m), 2,98 was 3.05 (1H, m), 3,74 (2H, s), 4,25 is 4.35 (6H, m), for 6.81 (1H, s)6,86 (1H, d, J=9.8 Hz), 7,60 (1H, DD, J=10,4, 2.2 Hz), 7,88 (1H, d, J=9.8 Hz), 8,10 (1H, s), to 8.41 (1H, d, J=2.4 Hz)

Example 100

To a solution of 0.14 g of 1-(2-(3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she's in 4 ml of ethyl acetate was added 1 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 20 minutes. The solvent is distilled off under reduced pressure, to the obtained residue, add a simple diethyl ether, and the solid product filtered off to obtain 0.10 g of 1-(2-(3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 1,31 is 1.48 (1H, m), 1,76-1,90 (1H, m), 2.00 in and 2.14 (2H, m), 2,32 is 2.44 (1H, m), 2,86-3,26 (4H, m), 3,56-4,00 (4H, m), of 4.38-to 4.46 (4H, m), to 4.52-4,56 (2H, m), 4,74-4,84 (2H, m), of 6.99 (1H, d, J=10.4 Hz), 7,33 (1H with), 7,94 (1H, DD, J=10,4, 2,1 Hz), 8,10 (1H, d, J=10,2 Hz), 8,29 (1H, s), 8,56 (1H, d, J=2.1 Hz)

Example 101

To a suspension of 0.10 g of 1-(2-(4-(aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride in 2 ml of methanol, add 0.15 g of 28% solution of sodium methoxide/methanol, 39 mg of (5-fluoro-6-methoxy)nicotinanilide and 14 μl of acetic acid is acid. There was added 31 mg cyanoborohydride sodium and the mixture is stirred at room temperature for 3 hours. After her leave to stand overnight, the mixture is stirred at room temperature for 35 minutes, add 31 mg cyanoborohydride sodium and the mixture was stirred at the same temperature for 1 hour and 40 minutes. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution, the organic layer separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of chloroform:methanol = 95:5-92:8 to obtain 43 mg of 7-fluoro-1-(2-(4-(((5-fluoro-6-methoxypyridine-3-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-it is in the form of a solid white product.

1H-NMR (CDCl3) δ: 1,32 of 1.46 (2H, m), 1.85 to was 1.94 (2H, m), 2,13-2,22 (2H, m), 2,45 is 2.55 (1H, m), 2,62 of 2.68 (2H, m), 2.91 in-2,99 (2H, m in), 3.75 (2H, s)to 4.01 (3H, m), 4,28-4,34 (2H, m)6,86 (1H, d, J=9.8 Hz), 7,38 (1H, DD, J=10,9, 2.0 Hz), 7,50-of 7.55 (1H, m), 7,83 (1H, d, J=2.0 Hz), 7,88 (1H, d, J=9.8 Hz), 8,42 (1H, d, 2.4 Hz)

Example 102

Using the same technology as in Example 78, 7-fluoro-1-(2-(4-(((5-fluoro-2,6-dimethylpyridin-3-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he will get is from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and 5-fluoro-2,6-dimethylaminocinnamaldehyde.

1H-NMR (CDCl3) δ: 1,36 is 1.48 (2H, m), 1,87-of 1.97 (2H, m), 2,16-of 2.26 (2H, m), 2,42-2,59 (7H, m), 2,62-2,70 (2H, m), 2,92-a 3.01 (2H, m), 3,74 (2H, s), 4,29-4,37 (2H, m)6,86 (1H, d, J=9.5 Hz), 7,34 (1H, d, J=10.0 Hz), 7,54 (1H, DD, J=10,2, 2.0 Hz), 7,89 (1H, d, J=10.0 Hz), 8,42 (1H, d, J=2.2 Hz)

Example 103

To a suspension of 0.10 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and 61 mg of 3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-carbaldehyde in 2.5 ml of methanol added 62 mg cyanoborohydride sodium, 0.14 g of 28% solution of sodium methoxide/methanol and 86 μl of acetic acid and the mixture is stirred at room temperature for 1 hour 50 minutes. To it was added ethyl acetate, saturated aqueous sodium bicarbonate solution and 2 mol/l aqueous sodium hydroxide solution, the organic layer is separated and the aqueous layer was extracted with ethyl acetate twice. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 10:1. The resulting residue is dissolved in 1 ml methanol and 1 ml of ethyl acetate and add 0.5 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate at room temperature. The solvent is distilled off under reduced Yes the tion, to the obtained residue, add a simple diethyl ether, and the solid product filtered off to obtain 0.11 g of 1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride in the form of solid product is a light yellow color.

1H-NMR (D2O) δ: 2,00-2,12 (4H, m), 2,50 at 2.59 (2H, m), with 2.93 (2H, t, J=6.3 Hz), 3,22-of 3.32 (2H, m), 3,60 of 3.75 (1H, m), 3,63 (2H, t, J=5,9 Hz), 3.95 to 4,06 (2H, m), 4,33 is 4.36 (2H, m), of 4.44 (2H, s), 4,72 to 4.92 (2H, m), 6,99 (1H, d, J=9.9 Hz), 7,52 (1H, s), 7,95 (1H, DD, J=10,3, 2,1 Hz), 8,10 (1H, d, J=9.9 Hz), to 8.20 (1H, s), to 8.57 (1H, d, J=2.1 Hz)

Example 104

To a solution of 62 mg of (3S)-N-(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)pyrrolidin-3-amine hydrochloride in 3 ml of methanol is added at room temperature to 0.10 g of a 28% solution of sodium methoxide/methanol, 37 mg of (7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde, 60 μl of acetic acid, 0.12 g of molecular sieves 3Å and 11 mg cyanoborohydride sodium and the mixture was stirred at the same temperature 1 hour 10 minutes. To the reaction mixture is added saturated aqueous sodium bicarbonate solution and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. Received OS is atok purified by column chromatography on basic silica gel using eluent chloroform:methanol = 30:1, added ethyl acetate and 4 mol/l solution of hydrochloric acid/ethyl acetate, and the solid product filtered off to obtain 33 mg of 1-(2-((3S)-3-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)pyrrolidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid yellow color.

1H-NMR (D2O) δ: 2,16-of 2.34 (1H, m), 2,55-2,70 (1H, m), 3,35-of 3.95 (6H, m), 4,16-4.26 deaths (1H, m), 4,45-4,85 (8H, m), 6,98 (1H, d, J=10.0 Hz), 7,47 (1H, s), 7,94-7,98 (1H, m), 8,08 (1H, d, J=10.0 Hz), at 8.36 (1H, s), 8,56 (1H, C)

Example 105

Using the same technology as in Example 78, 7-fluoro-1-(2-(4-(((5-fluoro-6-methylpyridin-3-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and 5-fluoro-6-methylnicotinamide.

1H-NMR (CDCl3) δ: 1,33-to 1.45 (2H, m), 1.85 to was 1.94 (2H, m), 2,14-of 2.23 (2H, m), 2,46 is 2.55 (1H, m), of 2.51 (3H, d, J=2.7 Hz), 2,61 of 2.68 (2H, m), 2.91 in is 3.00 (2H, m), 3,81 (2H, s), 4,28 is 4.35 (2H, m)6,86 (1H, d, J=9.8 Hz), was 7.36 (1H, DD, J=10,1, 1,6 Hz), 7,53 (1H, DD, J=10,2, 2.3 Hz), 7,88 (1H, d, J=9.8 Hz), 8,23 (1H, s), 8,42 (1H, d, J=2.3 Hz)

Example 106

Using the same technology as in Example 1, tert-butyl (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate obtained from tert-butyl (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)(piperidine-4-yl)carbamate and (7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetal is degidi.

1H-NMR (CDCl3) δ: 1,28-1,74 (13H, m), 2,07-of 2.30 (4H, m), 2.57 m-to 2.65 (2H, m), 2,94-3,03 (2H, m), 4,06-4,18 (1H, m), 4,20-and 4.40 (8H, m), 6,77 (1H, s), 6,85 (1H, d, J=9.8 Hz), 7,47 (1H, DD, J=10,4, 2.3 Hz), 7,87 (1H, d, J=9.8 Hz), to 8.14 (1H, s), to 8.41 (1H, d, J=2.3 Hz)

Example 107

Using the same technology as in Example 2, 1-(2-(4-((3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 2,00-of 2.15 (2H, m), is 2.37 (2H, Quint., J=5,9 Hz), of 2.51-2,60 (2H, m), 3,20-to 3.35 (2H, m), 3,60-of 3.78 (3H, m), 3,97-4,07 (2H, m), 4,42 (2H, t, J=5,9 Hz), 4,48 (2H, s), 4,60 (2H, t, J=5,9 Hz), 4,71-to 4.87 (2H, m), of 6.99 (1H, d, J=10.0 Hz), 7,37 (1H, s), of 7.96 (1H, DD, J=10,1, 2,1 Hz), 8,10 (1H, d, J=10.0 Hz), of 8.37 (1H, s), to 8.57 (1H, d, J=2.1 Hz)

Example 108

Using the same technology as in Example 30, 1-(2-(4-(((1,3)dioxolo(4,5-c)pyridine-6-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and (1,3)dioxolo(4,5-c)pyridine-6-carbaldehyde.

1H-NMR (CDCl3) δ: 1,36 of 1.50 (2H, m), 1,80-of 1.97 (2H, m), 2.13 and amounts to 2.24 (2H, m), 2,47-to 2.57 (1H, m), 2,61 of 2.68 (2H, m), 2.91 in is 3.00 (2H, m), 3,83 (2H, s), 4,28 is 4.36 (2H, m), 6,03 (2H, s)6,86 (1H, d, J=9.8 Hz), to 6.88 (1H, s), 7,56 (1H, DD, J=10,2, 2,1 Hz), 7,88 (1H, DD, J=9,8, 0.5 Hz), 8,00 (1H, s), to 8.41 (1H, d, J=2.1 Hz)

Example 109

Using the same technology as in Example 8, 1-(2-(4-(((1,3)dioxolo(4,5-c)pyridine-6-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-((((1,3)dioxolo(4,5-c)pyridine-6-ylmethyl)amino)-piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it.

1H-NMR (D2O) δ: 2,00-and 2.14 (2H, m), 2,50-2,60 (2H, m), 3,20-to 3.35 (2H, m), 3,60-of 3.78 (3H, m), 3.96 points-4,07 (2H, m), 4,48 (2H, s), 4,70-4,88 (2H, m), 6,34 (2H, s), 7,00 (1H, d, J=9.9 Hz), 7,32 (1H, s), 7,93-to 7.99 (1H, m), 8,10 (1H, d, J=9.9 Hz), 8,16 (1H, s), to 8.57 (1H, d, J=2.2 Hz)

Example 110

To 0.12 g of tert-butyl ((5-(1,3-dioxolane-2-yl)methyl)-6-oxo-5,6-dihydro-1,5-naphthiridine-3-yl)(methyl)carbamate add 2 ml of 80% aqueous solution triperoxonane acid and the mixture is stirred at room temperature for 2 hours. After her leave to stand over night, there was added 2 ml of 80% aqueous solution triperoxonane acid and the mixture is stirred at room temperature for 1 hour and 30 minutes and stirred at 40-50°C for 35 minutes. The reaction mixture was loaded 20% aqueous sodium hydroxide solution and chloroform and the pH adjusted to 6.3. The organic layer is separated and the aqueous layer was extracted with chloroform. In addition, while maintaining the aqueous layer approximately neutral aqueous layer was extracted with a mixed solvent of chloroform:methanol (5:95). The organic layer and extracts are combined the resulting solution with the shat over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 76 mg (7-(methylamino)-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in the form of a solid yellow color.

To 76 mg (7-(methylamino)-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde add a solution of 0.11 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate in 2.5 ml dichloromethane and 19 μl of acetic acid and the mixture is stirred at room temperature for 5 minutes. To the reaction mixture add 0.10 g of triacetoxyborohydride sodium and the mixture was stirred at the same temperature for 2 hours and 20 minutes. To it was added chloroform and bring the pH of the reaction mixture to 8.3 with saturated aqueous sodium bicarbonate solution. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 19:1 to obtain 55 mg of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-(methylamino)-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate as a pale yellow oily material color.

1H-NMR (CDCl3) δ: 1,34-1,73 (13H, m), 2,10-of 2.26 (2H, m), 2,58-of 2.64 (2H, m), 2,96 (3H, d, J=5,1 Hz), 2,98 was 3.05 (2H, m), a 4.03-4,17 (1H, m), 4,25 is 4.45 (8H, m), to 6.57 (1H, d, J=9.8 Hz), 6,70-6,76 (2H, m), 7,74 (1H, d, J=9.8 Hz), 7,98 (1H, d, J=2.2 Hz, with 8.05 (1H, s)

Example 111

Using the same technology as in Example 4, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-(methylamino)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-(methylamino)-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 1,96-2,12 (2H, m), 2,48-to 2.57 (2H, m), 2,95 (3H, s), 3,20-of 3.32 (2H, m), 3,60-and 3.72 (3H, m), 3.95 to Android 4.04 (2H, m), 4,37-of 4.44 (4H, m), 4,47-to 4.52 (2H, m), 4,77 of 4.83 (2H, m), of 6.75 (1H, d, J=9.8 Hz), 7,05-was 7.08 (1H, m), 7.23 percent (1H, s), of 7.97 (1H, d, J=9.8 Hz), 8,16 (1H, d, J=2.2 Hz), 8,24 (1H, s)

Example 112

Using the same technology as in Example 78, tert-butyl 7-(((1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazin-4-carboxylate is obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and tert-butyl 7-formyl-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazin-4-carboxylate.

1H-NMR (CDCl3) δ: 1,38-1,49 (2H, m)to 1.59 (9H, s), 1,87-of 1.95 (2H, m), 2,13-of 2.23 (2H, m), 2,48-to 2.57 (1H, m), 2,61-of 2.66 (2H, m), 2,92 are 2.98 (2H, m), 3,81 (2H, s), 3,84-a 3.87 (2H, m), 4,28-4,34 (4H, m), PC 6.82 (1H, s)6,86 (1H, d, J=9.9 Hz), 7,55 (1H, DD, J=10,5, 2.2 Hz), 7,88 (1H, d, J=9.9 Hz), to 8.41 (1H, d, J=2.2 Hz), 8,79-8,87 (1H, m)

Example 113

Using the same technology as in Example 2, 1-(2-(4-((3,4-dihydro-2H-pyrido(4,3-b)(1,4)oxazin-7-ylmethyl)amino)piperidin the-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl 7-(((1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazin-4-carboxylate.

1H-NMR (D2O) δ: 2,00-2,12 (2H, m), 2,52-2,60 (2H, m), 3,23-to 3.36 (2H, m), 3,51 (2H, t, J=4.4 Hz), to 3.64 (2H, t, J=6.0 Hz), 3,68-of 3.78 (1H, m), 3,98-4,06 (2H, m), 4,48-of 4.54 (4H, m), 4,66 to 4.92 (2H, m), of 6.99 (1H, d, J=9,8 Hz), 7,30 and 7.36 (1H, m), 7,92-7,98 (1H, m), 8,01 (1H, s), 8,11 (1H, d, J=9.8 Hz), to 8.57 (1H, s)

Example 114

To a solution of 40 mg of 1-(2-(1-hydroxy-4-oxocyclohexyl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in 5 ml of dichloromethane added at room temperature of 25 mg of 1-(2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)methanamine and 11 μl of acetic acid, the mixture is stirred for 2 hours, then the reaction mixture is added 27 mg of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 1 hour. To it was added a saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 30:1 to obtain 10 mg (A) 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-1-hydroxycyclohexyl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of a solid product is light yellow in color and 9 mg (B) 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-1-hydroxycyclohexyl)ethyl)-7-methoxy-1,5-NAF is iridin-2(1H)-it is in the form of solid product is a light yellow color.

(A)1H-NMR (CDCl3) δ: 1,35-of 1.55 (4H, m), 1,80-2,20 (6H, m), 2,65 is 2.75 (1H, m), of 3.77 (2H, s), of 3.97 (3H, s), 4,25-to 4.46 (6H, m), of 6.75 (1H, d, J=9.6 Hz), to 6.80 (1H, s), 7,32 (1H, d, J=2.4 Hz), 7,86 (1H, d, J=9.6 Hz), 8,10 (1H, C)8,29 (1H, d, J=2.4 Hz)

(B)1H-NMR (CDCl3) δ: 1,40-1,60 (4H, m), 1,70-1,90 (6H, m), 2,48-of 2.58 (1H, m), 3,82 (2H, s), of 3.96 (3H, s), 4.26 deaths-of 4.44 (6H, m), 6,74 (1H, d, J=9.6 Hz), PC 6.82 (1H, s), 7,38 (1H, d, J=2.4 Hz), the 7.85 (1H, d, J=9.6 Hz), 8,11 (1H, C)8,28 (1H, d, J=2.4 Hz)

Example 115

Using the same technology as in Example 3 tert-butyl 1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(3-(pyrazin-2-yl)-2-propyne-1-yl)carbamate obtained from 7-fluoro-1-(2-hydroxy-2-methoxyethyl)-1,5-naphthiridine-2(1H)-she and tert-butyl (piperidine-4-yl)(3-(pyrazin-2-yl)-2-propyne-1-yl)carbamate.

1H-NMR (CDCl3) δ: 1.50 in (9H, s), 1,78-of 1.88 (4H, m), 2,16-of 2.28 (2H, m)to 2.66 (2H, t, J=7,1 Hz), 3,03-of 3.12 (2H, m), 4.04 the-of 4.25 (3H, m), 4,32 (2H, t, J=7,1 Hz)6,86 (1H, d, J=9.8 Hz), of 7.48-rate of 7.54 (1H, m), 7,88 (1H, d, J=9,8 Hz), to 8.41 (1H, d, J=2.4 Hz), 8,48 (1H, d, J=2.7 Hz), 8,51-8,54 (1H, m), to 8.62 (1H, d, J=1.2 Hz)

Example 116

To a solution of 96 mg of tert-butyl 1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(3-(pyrazin-2-yl)-2-propyne-1-yl)carbamate in 2 ml of chloroform added at room temperature 1 ml triperoxonane acid and the mixture is stirred for 1 hour 30 minutes. To it was added a saturated aqueous solution of sodium bicarbonate, the organic layer is separated and the aqueous layer was extracted with chloroform. Organic SL the St and the extract combined the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 20:1 to receive 20 mg of 7-fluoro-1-(2-(4-((3-(pyrazin-2-yl)prop-2-in-1-yl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-it is in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: 1,38-1,49 (2H, m), 1,86-of 1.95 (2H, m), 2.21 are of 2.30 (2H, m)to 2.67 (2H, t, J=7,1 Hz), was 2.76-of 2.86 (1H, m), 2,93-a 3.01 (2H, m), 3,76 (2H, s)to 4.33 (2H, t, J=7,1 Hz)6,86 (1H, d, J=9.8 Hz), 7,56 (1H, DD, J=10,3 and 2.2 Hz), 7,89 (1H, d, J=9.8 Hz), 8,42 (1H, d, J=2.2 Hz), 8,48 (1H, d, J=2.4 Hz), charged 8.52-8,55 (1H, m), 8,65 (1H, d, J=1.4 Hz)

Example 117

To 85 mg of 1-(2-(4-((3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride add chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained oily substance added at room temperature 2 ml of methanol and 83 mg of a 28% solution of sodium methoxide/methanol and the mixture is heated under reflux, while p is remesiana, within 4 hours. After cooling to room temperature, to the reaction mixture are added water and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting residue was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 53 mg of 1-(2-(4-((3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-ONU as a pale brown oily material color.

1H-NMR (CDCl3) δ: 1,38-of 1.52 (2H, m), 1,86-of 1.97 (2H, m), 2,13-of 2.28 (4H, m), 2,46 at 2.59 (1H, m), 2,61 of 2.68 (2H, m), 2,94-to 3.02 (2H, m), 3,78-a-3.84 (2H, m), of 3.97 (3H, s), 4,24 (2H, t, J=5.8 Hz), or 4.31-and 4.40 (4H, m), 6,74 (1H, d, J=9.8 Hz), 6,86 (1H, s), 7.23 percent-to 7.32 (1H, m), to 7.84 (1H, d, J=9.8 Hz), 8,18 (1H, s), of 8.27 (1H, d, J=2.4 Hz)

Example 118

Using the same technology as in Example 8, 1-(2-(4-((3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-((3,4-dihydro-2H-(1,4)doxepin(2,3-c)pyridin-8-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it.

1H-NMR (D2O) δ: 1,99-and 2.14 (2H, m), 2,35 (2H, Quint., J=5,9 Hz), 2,50-2,60 (2H, m), 3,20-to 3.34 (2H, m), 3,60 is 3.76 (3H, m), 3.96 points-4,07 (2H, m)4,06 (3H, s), and 4.40 (2H, t, J=5,9 Hz), of 4.44 (2H, s), 4,56 (2H, t, J=5,9 Hz), 4,71-to 4.87 (2H, m), 6.90 to (1H, d, J=9.8 Hz), 7,31 (1H, s), 7,53 (1H, d, J=2.1 Hz), and 8.7 (1H, d, J=9.8 Hz), a 8.34 (1H, s), 8,43 (1H, d, J=2.1 Hz)

Example 119

Using the same technology as in Example 114, (A) 5-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-1-hydroxycyclohexyl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-it is in the form of an oily yellow substance and (B) 5-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-1-hydroxycyclohexyl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-it looks like a solid product is a light yellow color is obtained from 5-(2-(1-hydroxy-4-oxocyclohexyl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-it and 1-(2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)methanamine.

(A)1H-NMR (CDCl3) δ: 1,33-of 1.56 (4H, m), 1.70 to 1,95 (4H, m), 1,99 (2H, t, J=7,3 Hz), 2,62-a 2.71 (1H, m in), 3.75 (2H, s)4,08 (3H, s), 4,25 is 4.35 (4H, m), 4,59 (2H, t, J=7,3 Hz), 6,77 (1H, d, J=9.6 Hz), 6,78 (1H, s), 7,86 (1H, d, J=9.6 Hz), 8,10 (1H, s), 8,13 (1H, s)

(B)1H-NMR (CDCl3) δ: 1,38 is 1.48 (2H, m), 1,50-1,90 (8H, m), 2,42-of 2.54 (1H, m), 3,82 (2H, s)4,08 (3H, s), 4,24 is 4.35 (4H, m), 4,57-to 4.62 (2H, m), 6,77 (1H, d, J=10.0 Hz), 6,83 (1H, s), a 7.85 (1H, d, J=10.0 Hz), 8,10 (1H, s), 8,13 (1H, s)

Example 120

To a suspension of 0.10 g of 1-(2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)-N-(pyrrolidin-3-ylmethyl)methanamine hydrochloride in 5 ml of methanol is added 0.17 g of 28% solution of sodium methoxide/methanol, 66 mg of (7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde, 0.10 g of molecular sieves 3Å, 33 μl of acetic acid and 18 mg cyanoborohydride sodium at room temperature and the mixture is stirred at this same temperature for 2 hours and 30 minutes. To the reaction mixture is added saturated aqueous sodium bicarbonate solution and ethyl acetate, the organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using eluent chloroform:methanol = 30:1 to receive 20 mg of 1-(2-(3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)pyrrolidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it is in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: 1,45-1,55 (1H, m), 1,96-2,07 (1H, m), 2,32-2,47 (2H, m), 2,59-2,88 (7H, m), of 3.77 (2H, s), 4,25-4,37 (6H, m), for 6.81 (1H, s)6,86 (1H, d, J=9.8 Hz), 7,54 (1H, DD, J=10,2, 2,1 Hz), 7,88 (1H, d, J=9.8 Hz), 8,10 (1H, s), to 8.41 (1H, d, J=2.1 Hz)

Example 121

Using the same technology as in Example 55, 7-methoxy-1-(2-(4-(((6-oxido-2,3-dihydro(1,4)like(2,3-c)pyridin-7-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H-she hydrochloride and 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carbaldehyde 6-oxide.

1H-NMR (CDCl3) δ: 1,38 of 1.50 (2H, m), 1.85 to a 1.96 (2H, m), 2,13-of 2.23 (2H, m), 2,44-of 2.54 (1H, m), 2,61 of 2.68 (2H, m), 2,93-to 3.02 (2H, m), 3,93 (2H, s), 3,98 (3H, s), 4,28-,40 (6H, m), 6,74 (1H, d, J=9.8 Hz), 6,94 (1H, s), 7.23 percent (1H, d, J=2.2 Hz), to 7.84 (1H, d, J=9.8 Hz), of 7.97 (1H, s), of 8.28 (1H, d, J=2.2 Hz)

Example 122

To a suspension of 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 2 ml of methanol is added 0.28 g of a 28% solution of sodium methoxide/methanol, 66 mg of 5-ethylpyridine-2-carbaldehyde and 28 μl of acetic acid. Then there was added 61 mg cyanoborohydride sodium and the mixture is stirred at room temperature for 3 hours. It is additionally added 31 mg cyanoborohydride sodium and the mixture is stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of chloroform:methanol = 93:7 to 9:1 to obtain 0.15 g of 1-(2-(4-(((5-ethylpyridine-2-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of an oily material light yellow color.

1H-NMR (CDCl3) δ: 1,24 (3H, t, J=6.6 Hz), 1,40-of 1.52 (2H, m), 1,89-of 1.97 (2H, m), 2,15-of 2.23 (2H, m), 2,50 at 2.59 (1H, m), 2,60-to 2.67 (4H, m), 2.95 and-to 3.02 (2H, m), 3,90 (2H, s), of 3.97 (3H, s), 4,34-4,39 (2H, m), 6,74 (1H, d,J=9.6 Hz), 7,21 (1H, d, J=7.9 Hz), 7,25 (1H, d, J=2.2 Hz), 7,47 (1H, DD, J=7,9, 2.4 Hz), to 7.84 (1H, d, J=9.7 Hz), of 8.27 (1H, d, J=2.4 Hz), 8,39 (1H, d, J=2.2 Hz)

Example 123

Using the same technology as in Example 100, 1-(2-(4-(((5-ethylpyridine-2-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-(((5-ethylpyridine-2-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it.

1H-NMR (D2O) δ: of 1.28 (3H, t, J=7,6 Hz), 2,02-2,17 (2H, m), 2,53-2,62 (2H, m), and 2.83 (2H, t, J=7,6 Hz), 3,22-to 3.35 (2H, m), 3,62-3,82 (3H, m), 3,98-4,10 (2H, m)4,06 (3H, s), br4.61 (2H, s), 4,70 to 4.92 (2H, m), 6,92 (1H, d, J=9.9 Hz), 7,56 (1H, d, J=2.1 Hz), to 7.84 (1H, d, J=8,2 Hz), 8,08 (1H, d, J=9.9 Hz), 8,24 (1H, DD, J=8,2, 1.5 Hz), 8,44 (1H, d, J=2.1 Hz), 8,65 (1H, d, J=1.5 Hz)

Example 124

To a solution of 50 mg of 3-fluoro-4-methylbenzoic acid of 0.64 ml of thionyl chloride are added 50 μl of N,N-dimethylformamide and the mixture is heated under reflux, with stirring, for 1 hour. The solvent is distilled off under reduced pressure, and the mixture is dissolved in 4.0 ml of dichloromethane, there was added while cooling on ice with 0.13 ml of triethylamine and 64 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and the mixture is stirred for 2 hours. To it was added chloroform and water and bring the pH of the mixture to 1 with 6 mol/l hydrochloric acid. The solid product is filtered off to obtain 51 mg of 3-fluoro-N-(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)et the l)piperidine-4-yl)-4-methylbenzamide hydrochloride in the form of a solid white product.

1H-NMR (DMSO-d6) δ: 1,83 is 1.96 (2H, m), 2,00-2,11 (2H, m)to 2.29 (3H, s)3,00-3,50 (4H, m), 3,70-with 3.79 (2H, m), 3,99-4,11 (1H, m), 4,58-of 4.66 (2H, m), 6.90 to (1H, d, J=9.9 Hz), 7,37-7,42 (1H, m), 7,62-to 7.68 (2H, m), 8,02 (1H, d, J=9.9 Hz), 8,27-at 8.36 (1H, m), charged 8.52-to 8.57 (1H, m), 8,61-8,65 (1H, m), 9,95-10,07 (1H, m)

Example 125

To a solution of 50 mg of 2,3-dihydro(1,4)like(2,3-c)pyridine-7-carboxylic acid in 2.0 ml of thionyl chloride are added one drop of N,N-dimethylformamide and the mixture is heated under reflux, with stirring, for 1 hour 30 minutes. The solvent is distilled off under reduced pressure, the mixture is dissolved in 2.0 ml of dichloromethane, and to it was added to 0.14 ml of triethylamine and 53 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and the mixture is stirred for 1 hour. Add chloroform and water, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with aqueous sodium hydroxide solution, and then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue, add a mixed solvent of ethyl acetate:simple diethyl ether to obtain 48 mg of N-(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)-2,3-dihydro(1,4)like(2,3-c)pyridine-7-carboxamide in the form of a solid light-korichnevogo the color.

1H-NMR (CDCl3) δ: 1,50-3,20 (10H, m), 3,94 is 4.13 (1H, m), 4,30-and 4.40 (6H, m)6,86 (1H, d, J=9.9 Hz), of 7.70 (1H, s), to 7.77-of 7.95 (1H, m), to $ 7.91 (1H, d, J=9.9 Hz), 8,07 (1H, s), 8,43 (1H, d, J=2.2 Hz)

Example 126

To a solution of 0.14 g (7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in 12 ml of dichloromethane added to 0.23 g of tert-butyl ((7-oxo-5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)methyl)(piperidine-4-yl)carbamate and 37 μl of acetic acid and the mixture is stirred at room temperature for 30 minutes. Then to the reaction mixture are added 0.17 g of triacetoxyborohydride sodium, and after stirring at room temperature for 30 minutes, the mixture is left overnight and additionally stirred for 5 hours. To the reaction mixture add water, saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using eluent chloroform:methanol = 50:1 with the receipt of 0.23 g of tert-butyl 1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)((7-oxo-5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)methyl)carbamate in the form of the received light yellow color.

1H-NMR (CDCl3) δ: 1,28-1,88 (13H, m), 2,10-of 2.28 (2H, m), 2,58-of 2.72 (4H, m), 2,87-to 3.09 (4H, m), of 3.97 (3H, s), 4,06-to 4.23 (1H, m), 4,27-4,47 (4H, m), of 6.73 (1H, d, J=9.6 Hz), 6,80-6,91 (1H, m), 7,18 (1H, s), 7,42 (1H, d, J=the 7.3 Hz), to 7.84 (1H, d, J=9.6 Hz), 8,21 (1H, s), of 8.28 (1H, d, J=2.2 Hz)

Example 127

Using the same technology as in Example 2, 7-methoxy-1-(2-(4-(((7-oxo-5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl 1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)((7-oxo-5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)methyl)carbamate.

1H-NMR (D2O) δ: 2,01-of 2.21 (2H, m), 2,48-2,63 (2H, m), 2,65 is 2.75 (2H, m), 2,97-of 3.07 (2H, m), 3,19-to 3.41 (2H, m), 3,59-of 3.77 (3H, m), 3,97-4,11 (2H, m), 4.09 to (3H, s), and 4.40 (2H, s), to 4.52-by 5.18 (2H, m), to 6.95 (1H, d, J=9.5 Hz), to 7.15 (1H, d, J=7,4 Hz), 7,66 (1H, s), 7,72 (1H, d, J=7,4 Hz), 8,07 (1H, d, J=9.5 Hz), 8,46 (1H, s)

Example 128

To a solution of 71 mg of 4-methoxy-5-methylpyridin-2-carbaldehyde in 2 ml of methanol added 0.27 g of 28% solution of sodium methoxide/methanol, to 0.19 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and 27 μl of acetic acid. Then there was added 59 mg of cyanoborohydride sodium and the mixture is stirred at room temperature for 4 hours. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and saturated aqueous chlorite is sodium and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of chloroform:methanol = 19:1-86:14 with receipt of 0.13 g of 7-methoxy-1-(2-(4-(((4-methoxy-5-methylpyridin-2-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-it is in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: 1,40-of 1.52 (2H, m), 1,88-of 1.97 (2H, m), and 2.14 (3H, s), 2,14-of 2.23 (2H, m), 2,50-2,60 (1H, m), 2,62 of 2.68 (2H, m), 2,94-3,03 (2H, m), 3,86 (2H, s), 3,88 (3H, s), of 3.97 (3H, s), 4,34-and 4.40 (2H, m), 6,74 (1H, d, J=9.8 Hz), 6,79 (1H, s), 7,25 (1H, d, J=2.4 Hz), to 7.84 (1H, d, J=9.8 Hz), 8,16 (1H, s), of 8.28 (1H, d, J=2.4 Hz)

Example 129

Using the same technology as in Example 8, 7-methoxy-1-(2-(4-(((4-methoxy-5-methylpyridin-2-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 7-methoxy-1-(2-(4-(((4-methoxy-5-methylpyridin-2-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-it.

1H-NMR (D2O) δ: 1,79-of 1.92 (2H, m), 2,22 (3H, s), 2,30-to 2.40 (2H, m), 3,02-3,17 (2H, m), 3,23-to 3.35 (1H, m), 3,42-of 3.53 (2H, m), 3,74-3,86 (2H, m), a 4.03 (3H, s), of 4.05 (3H, s), 4.26 deaths (2H, s), 4,67-4,80 (2H, m), 6.87 in (1H, d, J=9.8 Hz), 7.23 percent-of 7.25 (1H, m), 7,44 (1H, d, J=2.2 Hz), with 8.05 (1H, d, J=9.8 Hz), of 8.25 (1H, s), 8,40 (1H, d, J=2.2 Hz)

Example 130

To a suspension of 0.10 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 2 ml of methanol is added 0.14 g of 28% solution of sodium methoxide/methanol, 40 mg of 5-ethyl-4-methoxypyridine-2-carbaldehyde and 14 ál of kusnoy acid. Then there was added 30 mg of cyanoborohydride sodium and the mixture is stirred at room temperature for 5 hours. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of chloroform:methanol = 9:1-86:14 to obtain 51 mg of 1-(2-(4-(((5-ethyl-4-methoxypyridine-2-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of an oily yellow substance.

1H-NMR (CDCl3) δ: of 1.18 (3H, t, a 7.6 Hz), 1.41 to 1.55V (2H, m), 1,89-to 1.98 (2H, m), 2,12-of 2.24 (2H, m), of 2.51 of 2.68 (5H, m), 2,93-3,03 (2H, m), 3,83-3,90 (5H, m), of 3.97 (3H, s), 4,33-and 4.40 (2H, m), 6,74 (1H, d, J=9.6 Hz), 6,79 (1H, ), 7,24-7,30 (1H, m), to 7.84 (1H, d, J=9.6 Hz), 8,17 (1H, s), of 8.28 (1H, d, J=2.4 Hz)

Example 131

Using the same technology as in Example 8, 1-(2-(4-(((5-ethyl-4-methoxypyridine-2-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-(((5-ethyl-4-methoxypyridine-2-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it.

1H-NMR (D2O) δ: of 1.20 (3H, t, J=7,6 Hz), 1,79-of 1.94 (2H, m), 2,32-to 2.40 (2H, m), 2,68 (2H, square, J=7,6 Hz), 3,12-of 3.32 (3H, m), 3,51 is 3.57 (2H, m), 3,80-,89 (2H, m), Android 4.04 (6H, s), 4.26 deaths (2H, s), 4,70-of 4.90 (2H, m)6,86 (1H, d, J=9.9 Hz), 7,28 (1H, s), 7,42 was 7.45 (1H, m), with 8.05 (1H, d, J=9.9 Hz), compared to 8.26 (1H, s), 8,39 (1H, d, J=2.2 Hz)

Example 132

To a suspension of 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 2 ml of methanol is added 0.28 g of a 28% solution of sodium methoxide/methanol, 73 mg of 5-methoxy-4-methylpyridin-2-carbaldehyde and 28 μl of acetic acid. Then there was added 61 mg cyanoborohydride sodium and the mixture is stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture chloroform, saturated aqueous sodium bicarbonate solution and water. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of chloroform:methanol = 93:7-86:14 to obtain 82 mg of 7-methoxy-1-(2-(4-(((5-methoxy-4-methylpyridin-2-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-it is in the form of solid product is a light yellow color.

1H-NMR (CDCl3) δ: 1,40-of 1.53 (2H, m), 1,89-to 1.98 (2H, m), 2,13-of 2.23 (2H, m), 2,22 (3H, s), 2,50-2,60 (1H, m), 2,62 of 2.68 (2H, m), 2,93-3,03 (2H, m), 3,83 (2H, s), 3,90 (3H, s)of 3.9 (3H, C), 4,34-4,39 (2H, m), 6,74 (1H, d, J=9.8 Hz), was 7.08 (1H, s), 7.24 to 7,28 (1H, m), to 7.84 (1H, d, J=9.8 Hz), 8,08 (1H, s), of 8.27 (1H, d, J=2.2 Hz)

Example 133

Using the same technology as in Example 30, 7-methoxy-1-(2-(4-(((5-(3-thienyl)isoxazol-3-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and 5-(3-thienyl)isoxazol-3-carbaldehyde.

1H-NMR (CDCl3) δ: 1,38 of 1.50 (2H, m), 1,89-of 1.97 (2H, m), 2,15 was 2.25 (2H, m), 2,54 of 2.68 (3H, m), 2.95 and-3,03 (2H, m), 3,93 (2H, s), 3,98 (3H, s), 4,35-4,39 (2H, m), to 6.39 (1H, s), 6,74 (1H, d, J=9.6 Hz), 7.23 percent (1H, d, J=2.2 Hz), 7,38-the 7.43 (2H, m), to 7.77 (1H, DD, J=2,8, and 1.4 Hz), to 7.84 (1H, d, J=9.6 Hz), of 8.28 (1H, d, J=2.2 Hz)

Example 134

To a suspension of 0.14 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 5 ml of methanol is added at room temperature of 0.14 g of a 28% solution of sodium methoxide/methanol, 46 mg of 6-(3-thienyl)pyridine-2-carbaldehyde, 0.10 g of molecular sieves 3Å, 28 μl of acetic acid and 15 mg of cyanoborohydride sodium and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture is added saturated aqueous sodium bicarbonate solution and chloroform, the organic layer is separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified using column chromatography on basic silica gel using eluent chloroform:methanol = 30:1. To a solution of the obtained residue in 2 ml of ethyl acetate is added 2 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 30 minutes. The solid product is filtered off to obtain 97 mg of 7-methoxy-1-(2-(4-(((6-(3-thienyl)pyridine-2-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid yellow color.

1H-NMR (D2O) δ: 2,07-of 2.23 (2H, m), 2,54-of 2.66 (2H, m), 3,20-to 3.36 (2H, m), 3,59-to 3.67 (2H, m), of 3.73-a 3.83 (1H, m), 3,98-4,10 (2H, m), 4,07 (3H, s), 4,54-br4.61 (2H, m), 4,70-of 4.90 (2H, m), 6,92 (1H, d, J=9.8 Hz), 7,41-the 7.65 (3H, m), 7,70-7,80 (1H, m), 7,87-a 7.92 (1H, m), 7,97-8,10 (1H, m), with 8.05 (1H, d, J=9.8 Hz), 8,14 (1H, s), 8,44 (1H, s)

Example 135

To a suspension of 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 2 ml of methanol is added 0.28 g of a 28% solution of sodium methoxide/methanol and 28 μl of acetic acid. To it was added 75 mg of 5-fluoro-6-methoxynicotinate, then to it was added 61 mg cyanoborohydride sodium and the mixture is stirred at room temperature for 1 hour and 20 minutes. It is additionally added 62 mg cyanoborohydride sodium and the mixture is stirred at room temperature for 1 hour and 30 minutes, and then stirred at 30-35°C for 1 hour. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution. The organic layer is separated and the aqueous layer was extragere the chloroform. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of chloroform:methanol = 19:1-9:1, to the resulting pale yellow oily substance add a simple diethyl ether, and the solid product filtered off to obtain 97 mg of 1-(2-(4-(((5-fluoro-6-methoxypyridine-3-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of a solid product slightly yellow.

1H-NMR (CDCl3) δ: 1,35 of 1.46 (2H, m), 1,86-of 1.95 (2H, m), 2,15-of 2.23 (2H, m), 2,47-of 2.58 (1H, m), 2,62 of 2.68 (2H, m), 2,92-to 3.02 (2H, m in), 3.75 (2H, m), 3,98 (3H, s)to 4.01 (3H, s), 4,33-and 4.40 (2H, m), 6,74 (1H, d, J=9.8 Hz), 7.23 percent (1H, d, J=2.3 Hz), 7,38 (1H, DD, J=11,0, 2.0 Hz), 7,82-7,86 (2H, m), of 8.28 (1H, d, J=2.3 Hz)

Example 136

To a suspension of 0.14 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 2 ml of methanol is added 0.20 g of 28% solution of sodium methoxide/methanol, 53 mg of 6-ethyl-5-fioricetonline and 20 μl of acetic acid. Then there was added 43 mg of cyanoborohydride sodium and the mixture is stirred at room temperature for 1 hour and 20 minutes. It is additionally added 43 mg of cyanoborohydride sodium and the mixture re eshivot at room temperature for 1 hour, and then stirred at 30-40°C for 1 hour. To the reaction mixture are added chloroform and saturated aqueous sodium bicarbonate solution. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of chloroform:methanol = 93:7 to 9:1 to obtain 53 mg of 1-(2-(4-(((6-ethyl-5-herperidin-3-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of a light yellow oily material color.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7,6 Hz), of 1.36 to 1.47 (2H, m), 1,87 is 1.96 (2H, m), 2,15-of 2.24 (2H, m), 2,47-to 2.57 (1H, m), 2,62 of 2.68 (2H, m), of 2.86 (2H, DD, J=7,6, 2.0 Hz), 2,95-to 3.02 (2H, m), 3,82 (2H, s), 3,98 (3H, s), 4,33-4,40 (2H, m), of 6.75 (1H, d, J=9.6 Hz), 7,20-7,24 (1H, m), 7,34-7,39 (1H, m), a 7.85 (1H, d, J=9.6 Hz), 8,25-of 8.27 (1H, m), of 8.28 (1H, d, J=2.4 Hz)

Example 137

Using the same technology as in Example 8, 1-(2-(4-(((6-ethyl-5-herperidin-3-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-(((6-ethyl-5-herperidin-3-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it.

1H-NMR (D2O) δ: of 1.30 (3H, t, J=7,7 Hz), 2,0 with 2.14 (2H, m), 2,53-2,61 (2H, m), 2,99 (2H, square, J=7,7 Hz), 3,23-to 3.35 (2H, m), 3,61-of 3.77 (3H, m), 3.96 points-of 4.05 (2H, m), of 4.05 (3H, s), 4,47 (2H, s), with 4.64-of 4.90 (2H, m), 6.90 to (1H, d, J=10.0 Hz), 7,51 (1H, s), 8,02 (1H, d, J=9,2 Hz), 8,07 (1H, d, J=10.0 Hz), to 8.41-8,43 (1H, m), 8,51 (1H, s)

Example 138

Using the same technology as in Example 79, 7-methoxy-1-(2-(4-(((5-methyl-4-oxo-4H-Piran-2-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and 5-methyl-4-oxo-4H-Piran-2-carbaldehyde.

1H-NMR (CDCl3) δ: 1,30-1,50 (2H, m), 1,80-of 1.95 (5H, m), 2,10-of 2.25 (2H, m), 2,45 is 2.55 (1H, m), 2,60-2,70 (2H, m), 2,90 was 3.05 (2H, m), 3,66 (2H, s), 3,98 (3H, s), 4,30-4,45 (2H, m), 6,33 (1H, s), 6,74 (1H, d, J=9.6 Hz), 7,21-to 7.25 (1H, m), 7,66 (1H, s), a 7.85 (1H, d, J=9.6 Hz), of 8.28 (1H, d, J=2.4 Hz)

Example 139

To a suspension of 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 2 ml of methanol is added 0.28 g of a 28% solution of sodium methoxide/methanol, 94 mg of 5-fluoro-6-(pyrrolidin-1-yl)nicotinamide and 28 μl of acetic acid. Then there was added 61 mg cyanoborohydride sodium and the mixture is stirred at room temperature for 2 hours and 20 minutes. To the reaction mixture chloroform, saturated aqueous sodium bicarbonate solution and water. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with water is saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of chloroform:methanol = 95:5-9:1, to it add a simple diethyl ether, and the solid product filtered off to obtain 91 mg of 1-(2-(4-(((5-fluoro-6-(pyrrolidin-1-yl)pyridine-3-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it is in the form of a solid product slightly yellow in color.

1H-NMR (CDCl3) δ: of 1.34 to 1.47 (2H, m), 1.85 to 1,99 (6H, m), 2,12-of 2.23 (2H, m), 2,47 is 2.55 (1H, m), 2,61-to 2.67 (2H, m), 2,92-a 3.01 (2H, m), to 3.58-the 3.65 (4H, m)to 3.67 (2H, s), 3,98 (3H, s), 4,33-and 4.40 (2H, m), 6,74 (1H, d, J=9.6 Hz), to 7.18 (1H, d, J=15.6 Hz), 7,22-of 7.25 (1H, m), 7,81 (1H, s), to 7.84 (1H, d, J=9.6 Hz), of 8.28 (1H, d, J=2.2 Hz)

Example 140

Using the same technology as in Example 30, 1-(2-(4-(((5-(2-furyl)isoxazol-3-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and 5-(2-furyl)isoxazol-3-carbaldehyde.

1H-NMR (CDCl3) δ: 1,36-1,49 (2H, m), 1,87-of 1.97 (2H, m), 2,15 was 2.25 (2H, m), 2,52-2,62 (1H, m)to 2.65 (2H, t, J=7,1 Hz), 2,94-to 3.02 (2H, m), 3,93 (2H, s), of 3.97 (3H, s), 4,36 (2H, t, J=7,1 Hz), 6,44 (1H, s), 6,53 (1H, DD, J=3,4) and 1.7 Hz), 6,74 (1H, d, J=9.6 Hz), 6.89 in (1H, d, J=3,4 Hz), 7,21-7,24 (1H, m), 7,54 (1H, d, J=1.7 Hz), to 7.84 (1H, d, J=9.6 Hz), of 8.28 (1H, d, J=2.0 Hz)

Example 141

Using the same technology as in Example 134, 7-methoxy-1-(2-(4-(((5-(2-thienyl)pyridine-3-yl)methyl)amino)Pipa is one-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and 5-(2-thienyl)nicotinanilide.

1H-NMR (D2O) δ: 2,04-2,19 (2H, m), 2.57 m-to 2.67 (2H, m), 3,24-to 3.38 (2H, m), 3,60-3,70 (2H, m), 3.75 to 3,86 (1H, m), to 4.01-4.09 to (2H, m)4,06 (3H, s), 4,58 with 4.64 (2H, m), 4,71-to 4.87 (2H, m), 6.90 to (1H, d, J=9.6 Hz), 7,29 (1H, DD, J=5.0 and 3.8 Hz), of 7.48-to 7.59 (1H, m), 7,71-7,79 (2H, m), 8,07 (1H, d, J=9.6 Hz), 8,43 (1H, d, J=2.2 Hz), a total of 8.74-to 8.94 (2H, m), 9,10-9,20 (1H, m)

Example 142

Using the same technology as in Example 30, 7-methoxy-1-(2-(4-(((6-(2-thienyl)pyridine-3-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and 6-(2-thienyl)nicotinanilide.

1H-NMR (CDCl3) δ: 1,38 of 1.50 (2H, m), 1,87-of 1.97 (2H, m), 2,14 was 2.25 (2H, m), 2,49-2,70 (3H, m), 2.95 and-3,03 (2H, m), a-3.84 (2H, s), 3,98 (3H, s), 4,35-4,39 (2H, m), 6,74 (1H, d, J=9.6 Hz), 7,09-7,14 (1H, m), 7,20-of 7.25 (1H, m), 7,38 (1H, d, J=5,1 Hz), EUR 7.57 (1H, d, J=3.6 Hz), to 7.61-7,72 (2H, m), to 7.84 (1H, d, J=9.6 Hz), of 8.28 (1H, d, J=1.9 Hz), 8,48-charged 8.52 (1H, m)

Example 143

Using the same technology as in Example 30, 7-fluoro-1-(2-(4-(((5-(2-furyl)isoxazol-3-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and 5-(2-furyl)isoxazol-3-carbaldehyde.

1H-NMR (CDCl3) δ: of 1.35 to 1.47 (2H, m), 1,87 is 1.96 (2H, m), 2,14-of 2.24 (2H, m), 2,53-2,60 (1H, m)to 2.65 (2H, t, J=7.0 Hz), 2,92-to 2.99 (2H, m), 3,93 (2H, s), 4,32 (2H, t, J=7.0 Hz), 6,44 (1H, s), 6,53 (1H, DD, J=3.2, and 2.0 Hz), 6,86 (1H, d, J=9.6 Hz), 6.89 in (1H, d, J=3.2 Hz), 7,50-7,58 (2H, m), 7,88 (1H, d, J=9.6 Hz), 8,42 (1H, d, J=2.0 Hz)

Example 144

To a suspension of 60 mg of 1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride in 2 ml of methanol, add 60 mg of a 28% solution of sodium methoxide/methanol and the mixture is heated under reflux, with stirring, for 4 hours. To it was added water and ethyl acetate, the organic layer is separated and the aqueous layer was saturated with sodium chloride and then extracted with ethyl acetate twice. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue was added 1 ml of ethyl acetate and added dropwise at room temperature 1 ml of 4.0 mol/l solution of hydrochloric acid/ethyl acetate. The solvent is distilled off under reduced pressure, the obtained residue is added ethyl acetate, and the solid product filtered off to obtain 31 mg of 1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid yellow color.

1H-NMR (D2O) δ: 2,00-2,12 (4H, m), 2,50-2,60 (2H, m), of 2.92 (2H, t, J=6.2 Hz), 3,20-to 3.34 (2H, m), 3,60-3,74 (3H, m), 3,98-4,07 (2H, m), of 4.05 (3H, s), 4,34 (2H, t, J=5,2 Hz), 4,43 (2H, s), 4,70-of 4.90 (2H, m), 6.89 in (1H, d, J=9.9 Hz), of 7.48-7,52 (2H, m), 8,07 (1H, d, J=9.9 Hz), 8,18 (1H, s), 8,42 (1H, d, J=1.7 Hz)

Example 145

Using the same technology as in Example 1, the pet-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl) - (piperidine-4-yl)carbamate is obtained from (7-fluoro-4-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,30-1,70 (13H, m), 2,07 was 2.25 (2H, m), 2,53 (3H, d, J=1.0 Hz), at 2.59 (2H, t, J=7,1 Hz), 2,94-to 3.02 (2H, m), 4.04 the-4,18 (1H, m), 4,20-4,48 (8H, m), 6,70-6,76 (2H, m), 7,41-of 7.48 (1H, m), with 8.05 (1H, s), to 8.41 (1H, d, J=2.2 Hz)

Example 146

Using the same technology as in Example 4, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-4-methyl-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 2,01-of 2.16 (2H, m), 2,53-2,62 (2H, m), of 2.56 (3H, s), 3,22-to 3.36 (2H, m), 3,60-to 3.67 (2H, m), 3.72 points-is 3.82 (1H, m), 3,97-4,08 (2H, m), 4,48-a 4.53 (2H, m), of 4.57 (2H, s), br4.61-of 4.66 (2H, m), 4,70-4,78 (2H, m), 6.89 in (1H, s), 7,53 (1H, s), to 7.93 (1H, DD, J=10,4, 2.2 Hz), to 8.41 (1H, s), 8,55 (1H, d, J=2.2 Hz)

Example 147

Using the same technology as in Example 30, 1-(2-(4-(((5-(2-furyl)pyridine-3-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride and 5-(2-furyl)nicotinanilide.

1H-NMR (CDCl3) δ: 1,38-and 1.54 (2H, m), 1,89 is 2.00 (2H, m), 2,14-of 2.28 (2H, m), 2,52-2,62 (1H, m)to 2.66 (2H, t, J=7,3 Hz), 2,97 was 3.05 (2H, m), a 3.87 (2H, s), 3,98 (3H, s), to 4.38 (2H, t, J=7,3 Hz), of 6.52 (1H, DD, J=3.3, which is 1.8 Hz), 6.73 x-6,77 (2H, m), 7.23 percent-7,27 (1H, m), 7,53 (1H, d, J=1.4 Hz), the 7.85 (1H, d, J=9.8 Hz), 7,92-of 7.96 (1H, s), of 8.28 (1H, d, J=2.2 Hz), 8,44 (1H, d, J=2.0 Hz), 8,82 (1H, d, J=2.0 Hz)

Example 148

To a solution of 72 mg of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 2.5 ml of methanol is added at room temperature and 77 mg of a 28% solution of sodium methoxide/methanol and the mixture is heated under reflux, with stirring, for 2 hours. After cooling to room temperature, to the reaction mixture are added water and chloroform, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using the eluent of chloroform to obtain 82 mg of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-4-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate as a pale brown oily material color.

1H-NMR (CDCl3) δ: 1.32 to 1,72 (13H, m), 2,07 was 2.25 (2H, m), of 2.51 (3H, d, J=1.0 Hz), 2,56-2,62 (2H, m), 2,96 was 3.05 (2H, m), of 3.95 (3H, s), 4,05-4,17 (1H, m), 4,25 is 4.45 (8H, m), 6,62 (1H, d, J=1.0 Hz), of 6.71-6,76 (1H, m), 7,16 (1H, d, J=2.4 Hz), with 8.05 (1H, s), of 8.28 (1H, d, J=2.4 Hz)

Example 149

Using the same technology as in Example 4, 1-(2-(4-((2,3-dihydro(1,)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-4-methyl-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-methoxy-4-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 1,98-and 2.14 (2H, m), 2,50-2,61 (2H, m), of 2.54 (3H, s), 3,20-to 3.35 (2H, m), to 3.58-3,66 (2H, m), 3,68-with 3.79 (1H, m), 3.95 to 4.09 to (2H, m), of 4.05 (3H, s), 4,45-4,50 (2H, m), 4,51 (2H, s), 4,56-to 4.62 (2H, m), 4,71-4,89 (2H, m), 6,77-to 6.80 (1H, m), the 7.43 (1H, s), 7,46 (1H, d, J=2.3 Hz), 8,35 (1H, s), scored 8.38 (1H, d, J=2.3 Hz)

Example 150

Using the same technology as in Example 1, tert-butyl (1-(2-(7-(deformedarse)-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate is obtained from (7-(deformedarse)-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,30-1,70 (13H, m), 2,08-of 2.26 (2H, m), 2,58-to 2.65 (2H, m), 2,92-a 3.01 (2H, m), 4,00-4,18 (1H, m), 4,22-4,48 (8H, m)6,70 (1H, t, J=72,1 Hz), was 6.73 (1H, s)6,86 (1H, d, J=9.9 Hz), 7,58 (1H, d, J=2.1 Hz), 7,88 (1H, d, J=9.8 Hz), with 8.05 (1H, s), to 8.41 (1H, d, J=2.1 Hz)

Example 151

Using the same technology as in Example 4 7-(deformedarse)-1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (1-(2-(7-(deformedarse)-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate.

1H-NMR (D2O) δ: 1,99-and 2.14 (2H, m), 2,50-2,60 (2H, m), 3,22-to 3.34 (2H, m), 3,59-of 3.78 (3H, m), 3.96 points-4,06 (2H, m), of 4.44-4,50 (2H, m), 4,48 (2H, s), 4,54-4,60 (2H, m), 4,70-4,88 (2H, m), 7,01 (1H, d, J=9.8 Hz), 7,06 (1H, t, J=72,2 Hz), 7,39 (1H, s), 7,87 (1H, d, J=2.1 Hz), ,10 (1H, d, J=9.8 Hz), with 8.33 (1H, s), to 8.57 (1H, d, J=2.1 Hz)

Example 152

To a suspension of 86 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride in 4 ml of methanol added 33 mg of 1,5-naphthiridine-3-carbaldehyde, 0.12 g of 28% solution of sodium methoxide/methanol and 12 μl of acetic acid. Then there was added 26 mg of cyanoborohydride sodium and the mixture is stirred at room temperature for 4 hours. To the reaction mixture chloroform, saturated aqueous sodium bicarbonate solution and water. The organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on basic silica gel using a gradient elution of chloroform:methanol = 87:13-85:15 to 11 mg of 7-methoxy-1-(2-(4-((1,5-naphthiridine-3-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-it is in the form of an oily material light yellow color.

1H-NMR (CDCl3) δ: 1,42-of 1.53 (2H, m), 1.93 and is 2.00 (2H, m), 2,14-of 2.26 (2H, m), 2,56-2,69 (3H, m), 2,96 is 3.40 (2H, m), 3,98 (3H, s), 4,10 (2H, s), 4,35-4,39 (2H, m), 6,74 (1H, d, J=9.8 Hz), 7,21-of 7.25 (1H, m), a 7.62 (1H, DD, J=8,5, a 4.3 Hz), to 7.84 (1H, d, J=9.8 Hz), of 8.28 (1H, d, J=2.4 Hz), 8,31-to 8.34 (1H, m), scored 8.38-8,42 (1H, m), 8,97 (1H, d is, J=4,3, and 1.6 Hz), 8,99 (1H, d, J=2.0 Hz)

Example 153

Using the same technology as in Example 103, 1-(2-(4-(((6-(2-furyl)pyrazin-2-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and 6-(2-furyl)pyrazin-2-carbaldehyde.

1H-NMR (CD3OD) δ: 2.06 to of 2.20 (2H, m), 2,46 at 2.59 (2H, m), 3.04 from-3,70 (5H, m), 3,85-4,01 (2H, m), 4,08 (3H, s), 4,59 (2H, s), 4,70-5,08 (2H, m), 6,70 (1H, DD, J=3,6, 1.8 Hz), to 6.80 (1H, d, J=9.6 Hz), 7,40 (1H, d, J=3.6 Hz), 7,53-to 7.59 (1H, m), 7,79-of 7.82 (1H, m), to 7.99 (1H, d, J=9.6 Hz), a 8.34 (1H, d, J=2.2 Hz), 8,58 (1H, s), of 9.02 (1H, s)

Example 154

To a solution of 0.10 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate in 2 ml of dioxane is added 90 mg of 2-tributylstannyl and 17 mg of bis(tri-tert-butylphosphine)palladium(0) under nitrogen atmosphere and the mixture heated under reflux, with stirring, in 6 hours 30 minutes. The resulting residue is purified using column flash chromatography on silica gel using a gradient elution of chloroform:methanol = 98:2-95:5 to obtain 87 mg of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-(1,3-oxazol-2-yl)-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in the form of an oily yellow substance.

1H-NMR (CDCl3 ) δ: 1,30-1,86 (13H, m), 2,12 was 2.25 (2H, m)to 2.67 (2H, t, J=6,7 Hz), 2,97-of 3.06 (2H, m), 4,00 was 4.42 (9H, m), of 6.71 (1H, s), to 6.95 (1H, d, J=9.8 Hz), 7,34 (1H, s), 7,86 (1H, s), to 7.93 (1H, d, J=9.8 Hz), with 8.05 (1H, C)8,44 (1H, s), 9,18 (1H, d, J=1.5 Hz)

Example 155

Using the same technology as in Example 2, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-piperidine-1-yl)ethyl)-7-(1,3-oxazol-2-yl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-(1,3-oxazol-2-yl)-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 2,00-of 2.15 (2H, m), 2,50-2,60 (2H, m), 3,24-to 3.36 (2H, m), 3,63 is 3.76 (3H, m), 3.95 to to 4.15 (2H, m), 4,42-4,58 (6H, m), 4,70-of 4.95 (2H, m), 7,10 (1H, d, J=9.8 Hz), 7,35 (1H, s), 7,45 (1H, s), 8,10 (1H, s), to 8.14 (1H, d, J=9.8 Hz), 8,31 (1H, s), 8,56 (1H, s), 9,19 (1H, d, J=1.5 Hz)

Example 156

Using the same technology as in Example 154, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(2-oxo-7-(1,3-thiazol-2-yl)-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate obtained from tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)-like(2,3-c)pyridine-7-ylmethyl)carbamate.

1H-NMR (CDCl3) δ: 1,12-1,90 (13H, m), 2,10-of 2.23 (2H, m), 2,62 is 2.75 (2H, m), 2,98-is 3.08 (2H, m), 4,20-4,48 (9H, m)6,70 (1H, s)6,94 (1H, d, J=9.8 Hz), 7,46-7,52 (1H, m), 7,92 (1H, d, J=9.8 Hz), 7.95 is-to 7.99 (1H, m), of 8.04 (1H with), 8,42 (1H, s), 9,05 (1H, s)

Example 157

Using the same technology as the Example 2, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-piperidine-1-yl)ethyl)-7-(1,3-thiazol-2-yl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(2-oxo-7-(1,3-thiazol-2-yl)-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate.

1H-NMR (D2O) δ: 2,03-to 2.18 (2H, m), 2,53-of 2.64 (2H, m), 3,24-3,39 (2H, m), 3,62-a-3.84 (3H, m), 3,99-4,10 (2H, m), 4,48 with 4.64 (6H, m), 4,70-of 4.90 (2H, m), to 7.09 (1H, d, J=9.9 Hz), 7,54 (1H, s), to 7.84 (1H, d, J=3.2 Hz), 8,05 (1H, d, J=3.2 Hz), to 8.12 (1H, d, J=9.9 Hz), to 8.41 (1H, s), 8,48 (1H, s), the remaining 9.08 (1H, d, J=1.5 Hz)

Example 158

Using the same technology as in Example 103, 7-fluoro-1-(2-(4-((5,6,7,8-tetrahydroquinoxalin-2-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and 5,6,7,8-tetrahydroquinoxalin-2-carbaldehyde.

1H-NMR (D2O) δ: 1,89-of 1.97 (4H, m), 2,04-of 2.15 (2H, m), 2,52-2,62 (2H, m), 2,94-a 3.01 (4H, m), 3,20-to 3.36 (2H, m), 3,63 (2H, t, J=6.0 Hz), 3,68-of 3.78 (1H, m), 3,97-4,07 (2H, m), of 4.49 (2H, s), 4.75 V-5,00 (2H, m), 7,00 (1H, d, J=9.8 Hz), of 7.96 (1H, d, J=10.5 Hz), 8,10 (1H, d, J=9.8 Hz), 8,40 (1H, s), to 8.57 (1H, s)

Example 159

Using the same technology as in Example 134, 7-fluoro-1-(2-(4-(((5-(2-furyl)-1,3-oxazol-2-yl)methyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and 5-(2-furyl)-1,3-oxazol-2-karbalaei the A.

1H-NMR (D2O) δ: 2,00-and 2.14 (2H, m), 2,50-2,60 (2H, m), 3,20-to 3.34 (2H, m), 3,63 (2H, t, J=6,1 Hz), 3,68-of 3.80 (1H, m), 3,98-4,06 (2H, m), to 4.62 (2H, s), 4,70-4,88 (2H, m), 6,60-6,70 (1H, m), 6,85 (1H, d, J=3,4 Hz), 6,99 (1H, d, J=9.8 Hz), 7,40 (1H, s), the 7.65 (1H, s), 7,95 (1H, d, J=9.8 Hz), 8,10 (1H, d, J=9.8 Hz), 8,56 (1H, s)

Example 160

Using the same technology as in Example 117, 1-(2-(3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he obtained from 1-(2-(3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride.

1H-NMR (CDCl3) δ: 0.90 or was 1.04 (1H, m), 1,48-to 2.18 (6H, m), 2,47-of 2.54 (2H, m), 2,60 of 2.68 (2H, m), 2,89 are 2.98 (1H,m), 3,01-to 3.09 (1H, m), 3,74 (2H, s), of 3.97 (3H, s), 4,24-4,43 (6H, m), 6,74 (1H, d, J=9.8 Hz), for 6.81 (1H, s), 7,27-7,28 (1H, m), to 7.84 (1H, d, J=9.8 Hz), 8,10 (1H, s), of 8.27 (1H, d, J=2.4 Hz)

Example 161

Using the same technology as in Example 8, 1-(2-(3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)-methyl)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(3-(((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)methyl)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it.

1H-NMR (D2O) δ: 1.33 full of 1.50 (1H, m), 1,76-of 1.94 (1H, m), 1,99-2,17 (2H, m), 2,32-2,47 (1H, m), 2,88-3,13 (2H, m), 3,16-and 3.31 (2H, m), 3,54-3,68 (2H, m), 3.75 to of 3.85 (1H, m), 3.95 to Android 4.04 (1H, m)4,06 (3H, s), of 4.44-4,65 (6H, m), 4,70-of 4.90 (2H, m)6,91 (1H, d, J=9.8 Hz), 7,51 (1H, s), 7,55 (1H, d, J=2.3 Hz), 8,07 (1H, d, J=9.8 Hz), scored 8.38 (1H, s), 8,43 (1H, d, J=2.3 Hz)

Example 162

Using the same technology as in Example 103, 1-(2-(4-((3,4-dihydro-2H-pyrano(3,2-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride and 3,4-dihydro-2H-pyrano(3,2-c)pyridine-7-carbaldehyde.

1H-NMR (D2O) δ: 2,00-of 2.15 (4H, m), 2,50-of 2.64 (2H, m), of 2.92 (2H, t, J=6.4 Hz), 3,24-to 3.36 (2H, m)to 3.64 (2H, t, J=5,9 Hz), 3,68-of 3.80 (1H, m), 3.96 points-4,07 (2H, m), 4,51-4,59 (4H, m), 4,70-of 4.90 (2H, m), 7,00 (1H, d, J=9,8 Hz), 7,38 (1H, s), of 7.96 (1H, DD, J=10,4, 2.2 Hz), 8,11 (1H, d, J=9.8 Hz), 8,44 (1H, s), to 8.57 (1H, d, J=2.2 Hz)

Example 163

Using the same technology as in Example 144, 1-(2-(4-((3,4-dihydro-2H-pyrano(3,2-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from 1-(2-(4-((3,4-dihydro-2H-pyrano(3,2-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it.

1H-NMR (D2O) δ: 2,00-of 2.15 (4H, m), 2,50-2,61 (2H, m), of 2.92 (2H, t, J=6.2 Hz), 3,21-to 3.36 (2H, m)to 3.64 (2H, t, J=5,9 Hz), 3,68-with 3.79 (1H, m), 3,98-4,08 (2H, m), of 4.05 (3H, s), 4,51-4,58 (2H, m), 4,56 (2H, s), 4,77-4,90 (2H, m), to 6.88 (1H, d, J=9.6 Hz), 7,37 (1H, s)of 7.48 (1H, s), of 8.06 (1H, d, J=9.6 Hz), to 8.41 (1H, s), 8,44 (1H, s)

Example 164

Using the same technology as in Example 1, tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(2-oxo-7-(trifluoromethyl)-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate p is obtain from (2-oxo-7-(trifluoromethyl)-1,5-naphthiridine-1(2H)-yl)acetaldehyde and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,33-1,71 (13H, m), 2,10-of 2.26 (2H, m), 2.63 in (2H, t, J=6.6 Hz), 2,93-a 3.01 (2H, m), 4,07-4,18 (1H, m), 4,25-4,37 (8H, m), of 6.71 (1H, s), 7,02 (1H, d, J=9.8 Hz), 7,95 (1H, d, J=9.8 Hz), 8,02 (1H, s), 8,05 (1H, s), is 8.75 (1H, s)

Example 165

To a solution of 80 mg of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(2-oxo-7-(trifluoromethyl)-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 1.4 ml of isopropyl alcohol added 57 μl of concentrated hydrochloric acid and the mixture is heated under reflux, with stirring, for 1 hour 30 minutes. The reaction mixture is cooled to room temperature and the solid product filtered off to obtain 70 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-(trifluoromethyl)-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid light brown color.

1H-NMR (D2O) δ: 1,94-2,07 (2H, m), 2,44-2,52 (2H, m), of 3.10-3.20 (2H, m), 3,50-3,63 (3H, m), a 3.87-of 3.94 (2H, m), the 4.29 (2H, s), 4,36-to 4.46 (4H, m), 4.75 V-4,85 (2H, m), to 7.09 (1H, s), 7,17 (1H, d, J=10.0 Hz), 8,14-8,19 (2H, m,), 8,39 (1H, s), 8,93 (1H, s)

Example 166

Using the same technology as in Example 3 tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-6-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate is obtained from (7-fluoro-6-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde and tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ilma is Il)(piperidine-4-yl)carbamate.

1H-NMR (CDCl3) δ: 1,25-1,70 (13H, m), 2.05 is was 2.25 (2H, m), 2,50-2,61 (2H, m), 2,58 (3H, d, J=2,9 Hz), 2.95 and 3.00 for (2H, m), 4,01-4,20 (1H, m), 4,23-and 4.40 (8H, m), 6,72 (1H, s), for 6.81 (1H, d, J=9.8 Hz), 7,41 (1H, d, J=10,7 Hz), 7,81 (1H, d, J=9.8 Hz), with 8.05 (1H, s)

Example 167

To a solution of 0.48 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-6-methyl-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 4.7 ml of isopropyl alcohol added to 0.44 ml of concentrated hydrochloric acid, the temperature was raised to 60°C and the mixture is stirred for 3 hours. The reaction mixture is cooled to room temperature, and the solid product filtered off to obtain 0.33 g of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-6-methyl-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid white product.

1H-NMR (D2O) δ: 1,99-and 2.14 (2H, m), 2,49-2,61 (2H, m), 2,59 (3H, d, J=2.4 Hz), 3,19-to 3.34 (2H, m), 3,56-3,74 (3H, m), 3,94-Android 4.04 (2H, m), 4,39 (2H, s), 4,39-of 4.54 (4H, m), to 4.73 (2H, t, J=6.0 Hz), of 6.96 (1H, d, J=9.9 Hz), of 7.23 (1H, s), 7,88 (1H, d, J=10.5 Hz), 8,02 (1H, d, J=9.9 Hz), 8,23 (1H, s)

Example 168

To 0.16 g of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-6-methyl-1,5-naphthiridine-2(1H)-she hydrochloride add chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the ex is ract unite, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the residue add to 2.6 ml of methanol and 0.15 ml of 28% solution of sodium methoxide/methanol and the mixture is heated under reflux, with stirring, for 2 hours. The reaction mixture is cooled to room temperature, there was added chloroform and saturated aqueous sodium bicarbonate solution, the organic layer is separated and the aqueous layer was extracted with chloroform. The organic layer and the extract combine, the resulting solution was dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. To the obtained residue is added to 1.4 ml of isopropyl alcohol and 93 μl of concentrated hydrochloric acid and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is cooled on ice, and the solid product filtered off to obtain 0.15 g of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-6-methyl-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid white product.

1H-NMR (D2O) δ: 1,95-2,15 (2H, m), 2,50-2,60 (2H, m), 2,59 (3H, s), 3,30-to 3.35 (2H, m), 3,60 of 3.75 (3H, m), 3.95 to-4,10 (2H, m), 4.09 to (3H, s), to 4.38-4,55 (6H, m), 4.75 V-4,85 (2H, m)6,91 (1H, d, J=9.8 Hz), 7,27 (1H, s), 7,49 (1H, s), of 8.04 (1H, d, J=9.8 Hz), compared to 8.26 (1H, s)

Example 169

Using the same technology as in Example 78, which requires the-butyl (5-(((1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)pyrazin-2-yl)carbamate obtained from 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-she hydrochloride and tert-butyl (5-formylpyridine-2-yl)carbamate.

1H-NMR (CDCl3) δ: 1,40-1,60 (11H, m), 1,87-of 1.97 (2H, m), 2.13 and was 2.25 (2H, m), 2,49-of 2.58 (1H, m), 2,61-2,70 (2H, m), 2.95 and was 3.05 (2H, m), 3,91 (2H, s), 3,98 (3H, s), 4,33 was 4.42 (2H, m), 6,74 (1H, d, J=9.6 Hz), 7,15-7,19 (1H, m), to 7.84 (1H, d, J=9.6 Hz), to 8.20 (1H, s), of 8.28 (1H, d, J=2.4 Hz), 9,19 (1H, s)

Example 170

Using the same technology as in Example 167, 1-(2-(4-(((5-aminopyridin-2-yl)methyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-he hydrochloride is obtained from tert-butyl (5-(((1-(2-(7-methoxy-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)amino)methyl)pyrazin-2-yl)carbamate.

1H-NMR (D2O) δ: 1,97-to 2.13 (2H, m), 2,49-2,60 (2H, m), 3,19-to 3.34 (2H, m), 3,57-3,74 (3H, m), 3.96 points-4,07 (2H, m), Android 4.04 (3H, s), 4,30-to 4.38 (2H, m), 4,78-4,80 (2H, m), 6,85-6,91 (1H, m), 7,43-7,52 (1H, m), 7,98-8,32 (2H, m), of 8.06 (1H, d, J=9.8 Hz), 8,40 (1H, d, J=2.2 Hz)

Example 171

To a solution of 211 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she and 120 mg of 2,3-dihydro(1,4)like(2,3-b)pyridine-7-carbaldehyde in 22 ml of chloroform added 88 mg of acetic acid and the mixture is stirred at room temperature for 14 hours. To the reaction mixture 232 mg triacetoxyborohydride sodium and the mixture is stirred for 2 hours. To it was added a saturated aqueous solution of sodium bicarbonate and the organic layer separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent banished is under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Silica Gel 60N production KANTO CHEMICAL CO., INC. and eluent chloroform:methanol = 10:1 to obtain 185 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-b)pyridin-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it is in the form of solid product is a light yellow color.

To a solution of 185 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-b)pyridin-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she's in 4 ml of ethyl acetate is added 2 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 1 hour. The solid product is filtered off with getting 244 mg of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-b)pyridin-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid white product.

1H-NMR (DMSO-d6) δ: 2,01-2,12 (2H, m), 2,34-to 2.41 (2H, m), 3,17 (2H, s), 3,24-to 3.35 (3H, m), 3.75 to 3,82 (2H, m), 4,11-4,17 (2H, m), 4,25-4,30 (2H, m), to 4.41 is 4.45 (2H, m), 4,59 with 4.65 (2H, m), 6.89 in (1H, d, J=9.6 Hz), to 7.61-to 7.67 (1H, m), of 7.90-of 7.95 (1H, m), 8,01 (1H, d, J=9.6 Hz), 8,32-8,39 (1H, m), 8,60-8,65 (1H, m), being 9.61-9,76 (3H, m), 10,79-11,02 (1H, m)

Example 172

To 7,00 g (7-bromo-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde add a solution 10,07 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate in 140 ml of chloroform and 1.57 g of acetic acid and the mixture was stirred at the room for the Noah temperature for 19 hours then add 8,77 g triacetoxyborohydride sodium and the mixture is stirred for 2 hours. To the reaction mixture add 140 ml of a saturated aqueous solution of sodium bicarbonate, the organic layer is separated, then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel using silica gel: Chromatorex-NH production Fuji Silysia Chemical Ltd. and gradient elution with hexane:ethyl acetate = 50:50-5:95, and then recrystallized in 24 ml of ethanol with the receipt of 11.26 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate in the form of a solid white product.

1H-NMR (CDCl3) δ: 1.32 to 1.55V (9H, m), 1.69 in (4H, m), of 2.20 (2H, m), 2,62 (2H, t, J=6.6 Hz), 2,97 (2H, d, J=11.5 Hz), 4,12 (1H, s), 4,27 (4H, m), 4,32 (4H, m), 6,72 (1H, s), make 6.90 (1H, d, J=9.6 Hz), the 7.85 (1H, d, J=9.6 Hz), 8,01 (1H, s), of 8.06 (1H, s), 8,54 (1H, d, J=1.4 Hz)

Example 173

To 0.51 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate add 18 ml of 2 mol/l solution of hydrochloric acid/ethanol at room temperature, the mixture is stirred at room temperature for 59 hours and at 50°C for 9 hours, and then the scientists the solid product is filtered off. Then the solid product is suspended in 3 ml of chloroform, add to it 5 ml triperoxonane acid, the mixture is stirred at room temperature for 100 minutes and then the solvent is distilled off under reduced pressure. The remainder of the load 10 ml of chloroform and 3 ml of water and pH adjusted to 10 with 2 mol/l aqueous solution of sodium hydroxide, and then the organic layer separated. The aqueous layer was twice extracted with chloroform and combined with the organic layer, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 2 ml ethyl acetate and 3 ml of ethanol and to it add 10 ml of 2 mol/l solution of hydrochloric acid/ethanol, the mixture is stirred for 15 minutes and the solvent is distilled off under reduced pressure. To the residue add 4 ml of ethyl acetate and suspended and the solid product is filtered off with getting 0,41 g of 7-bromo-1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid product is slightly yellow in color.

1H-NMR (D2O) δ: 2,03-of 2.15 (2H, m), 2,59 (2H, d, J=13.3 Hz), 3,30 (2H, s)to 3.64 (2H, t, J=5.7 Hz), with 3.79 (1H, TT, J=11,9, 4,1 Hz), Android 4.04 (2H, s), 4,51 (2H, DD), 4,59 (2H, s)and 4.65 (2H, m), and 4.75 (2H, t, J=6.2 Hz),? 7.04 baby mortality (1H, d, J=9.6 Hz), 7,56 (1H, s), with 8.05 (1H, d, J=9.6 Hz), of 8.37 (1H, d, J=0.9 Hz), 8,42 (1H, s), to 8.70 (1H, d, J=1,8 Hz)

When the EP 174

To a solution of 0.85 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate in 5 ml of 1,4-dioxane is added 0.20 g of tert-butyl carbamate, 0,69 g of cesium carbonate and 13 mg of Tris(benzylideneacetone)diplodia and 24 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and the mixture was stirred at 90°C for 38 hours in a nitrogen atmosphere. After cooling to room temperature nerastvorimaya substance separated by filtration and the filtered solution is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using silica gel: Silica Gel 60 manufactured KANTO CHEMICAL CO., INC. and eluent hexane:ethyl acetate = 33:67-5:95 to obtain 0.68 g of tert-butyl (1-(2-(7-((tert-butoxycarbonyl)amino)-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate in the form of a solid white product.

1H-NMR (CDCl3) δ: 1,33-is 1.51 (9H, m)of 1.53 (9H, s), 1,55-1,65 (2H, m), of 1.78 (2H, s), 2,11-of 2.26 (2H, m)to 2.66 (2H, t, J=7,1 Hz), 3,01 (2H, d, J=10.5 Hz), 4,06-to 4.15 (1H, m), 4,24-the 4.29 (2H, m), 4,29-4,37 (5H, m), 4,37-of 4.44 (1H, m), 6,72 (1H, s)6,76 (1H, d, J=9.6 Hz), 7,09-7,24 (1H, m), 7,80 (1H, d, J=9.6 Hz), of 8.04 (1H, s), of 8.25 (1H, d, J=1.4 Hz), 8,32 (1H, s)

Example 175

To a solution of 0.66 g of tert-butyl (1-(2-(7-((tert-butoxycarbonyl)amino)-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-the l)(2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate in 8 ml of methanol is added at room temperature, 8 ml of 4 mol/l solution of hydrochloric acid/ethyl acetate, the mixture is stirred for 18 hours and then the solid product is filtered off. Then the solid product is suspended in 3 ml of chloroform, is added at room temperature, 6 ml triperoxonane acid, the mixture is stirred for 2 hours and then the solvent is distilled off under reduced pressure. The remainder of the load chloroform and water and the pH adjusted to 9 with 2 mol/l aqueous sodium hydroxide solution and the organic layer separated. The aqueous layer was extracted with chloroform three times and combined with the organic layer, the resulting solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain 0.31 g of 7-amino-1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-it is in the form of a white foam.

1H-NMR (CDCl3) δ: 1,44-of 1.52 (2H, m), of 1.94 (2H, d, J=12,4 Hz), measuring 2.20 (2H, t, J=11.0 in Hz)of 2.51-2.57 m (1H, m), 2,60-to 2.65 (2H, m), 2,98-3,03 (2H, m), 3,80 (2H, s), 4,20 (2H, s), 4.26 deaths-4,30 (2H, m), 4,30 is 4.35 (4H, m), 6,63 (1H, d, J=9.6 Hz), PC 6.82 (1H, s), 7,00 (1H, d, J=1,8 Hz), 7,76 (1H, d, J=9.6 Hz), 8,03 (1H, d, J=1,8 Hz), 8,11 (1H, s)

Example 176

To a solution 0,095 g of 7-amino-1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-it's in 3 ml of ethanol and 2 ml of ethyl acetate added at room temperature, 4 ml of 2 mol/l of salt solution to the slot/ethanol and the mixture is stirred at room temperature for 20 minutes and the solvent is distilled off under reduced pressure. To the residue add 8 ml simple diethyl ether, the residue is suspended in it and the solid product is filtered off with getting 0,41 g of 7-amino-1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-she hydrochloride in the form of a solid yellow color.

1H-NMR (CDCl3) δ: 2,02-2,12 (2H, m), of 2.56 (2H, d, J=13.3 Hz), or 3.28 (2H, t, J=10.5 Hz), 3,62 (2H, t, J=6.0 Hz), 3,69 is 3.76 (1H, m), 3,98-of 4.05 (2H, m), of 4.44 figure-4.49 (4H, m), 4,54-4,58 (2H, m), 4,71 (2H, t, J=6.0 Hz), 6,83 (1H, d, J=9.6 Hz), 7,37 (1H, s)of 7.48 (1H, d, J=2.3 Hz), to 7.99 (1H, d, J=9.6 Hz), 8,18 (1H, d, J=2.3 Hz), 8,31 (1H, s)

Industrial application

The present heterocyclic compound or its salt has a high antimicrobial activity and high safety and for this reason is suitable for use as an excellent antimicrobial agent.

1. The connection represented by the General formula:
[Formula 1]

[where R1denotes optionally substituted C2-C12alkyl, aryl or heterocyclic group, which is mono - or bicyclic 5-11-membered radical, where the heteroatoms may be nitrogen, oxygen or sulfur; X1represents C2-C4alkylenes group; X2denotes a bond; X3refers to a group represented by the General formula NR3or CR4R5NR3where R 3denotes a hydrogen atom, optionally substituted lower alkyl group or imino-protective group; and R4and R5are the same or different and each represents a hydrogen atom or a lower alkyl group) or a bond; X4indicates the lowest alkylenes, or lower alkynylamino or lower alkynylamino group which may be substituted by one or more oxo groups or bond; X5denotes a sulfur atom or a bond; Y1denotes optionally substituted divalent 4-, 5 - or 6-membered alicyclic hydrocarbon residue or an optionally substituted divalent 5 - or 6-membered alicyclic amine residue, where the heteroatoms may be nitrogen or oxygen; Z1, Z2, Z3, Z4, Z5and Z6are the same or different, and each of them represents a nitrogen atom or a group represented by the General formula CR7where R7denotes a hydrogen atom, halogen atom, hydroxyl group, cyano group, optionally protected amino group, or amino group substituted by one or more C1-6alkyl group, a lower alkyl group, cycloalkyl, a lower alkoxy group or a monocyclic 5-membered heterocyclic group which may be substituted by one or a number of the mi halogen atoms, where as the heteroatom can be nitrogen, oxygen or sulfur, or a group represented by the General formula Q1CO2R10(where R10denotes carboxyl-protective group, and Q1indicates the lowest alkenylamine group), provided that at least one of the Z3, Z4, Z5and Z6represents a nitrogen atom], or its salt, where the substituents for R1that represents a C2-C12alkyl, aryl and heterocyclic group, represent one or more groups selected from halogen atom, optionally protected carboxyl group, alkyl groups, alkoxy groups, protected amino groups, amino groups, monocyclic 5-membered heterocyclic group and oxo group;
the substituents for the lower alkyl group, R3represent one or more groups selected from optionally protected carboxyl groups and2-C6alkenylphenol group, which is substituted by one or more aryl groups; and
substitutes for divalent 4-, 5 - or 6-membered alicyclic hydrocarbon residue or an optionally substituted divalent 5 - or 6-membered alicyclic amine residue Y1represent one or more groups selected from a halogen atom, a hydroxyl group, a long is correctly protected carboxyl group and alkyl group and alkenylphenol group, which may be substituted acyl group.

2. The compound or its salt according to claim 1, where Z1represents CH.

3. The compound or its salt according to any one of claims 1 or 2, where X1represents an ethylene group.

4. The compound or its salt according to any one of claims 1 or 2, where X3represents NH, CH2NH or a bond, and X4represents the lowest alkylenes group.

5. The compound or its salt according to any one of claims 1 or 2, where R1represents optionally substituted aryl or heterocyclic group, which is mono - or bicyclic 5-11-membered radical, where the heteroatoms may be nitrogen, oxygen or sulfur; where the substituents for aryl and heterocyclic groups are one or more groups selected from halogen atom, optionally protected carboxyl group, alkyl groups, alkoxy groups, protected amino groups, amino groups, monocyclic 5-membered heterocyclic group and oxo group.

6. The compound or its salt according to any one of claims 1 or 2, where Y1represents an optionally substituted cyclohexylamine, piperazinyl or piperidinyl group, where the substituents are one or more groups selected from hydroxyl group, optionally protected carboxyl gr is PPI and alkyl groups.

7. The compound or its salt according to any one of claims 1 or 2, where Z5represents a group represented by the General formula CR7b(where R7brepresents a hydrogen atom, a halogen atom or a lower alkyl or lower alkoxy group which may be substituted by one or more halogen atoms).

8. The compound or its salt according to any one of claims 1 or 2, where Z1, Z2and Z4each represents CH; Z3represents a nitrogen atom; Z5represents a group represented by the General formula CR7d(where R7drepresents a halogen atom or a lower alkyl or lower alkoxy group which may be substituted by one or more halogen atoms); and Z6represents a nitrogen atom or CH.

9. The compound or its salt according to any one of claims 1 or 2, where Z5represents a group represented by the General formula CR7e(where R7erepresents a halogen atom, a lower alkyl group or alkoxy group).

10. The compound or its salt according to any one of claims 1 or 2, where X1represents an ethylene group; X5is a bond; X3represents NH; and X4represents a methylene group.

11. The compound or its salt according to any one of claims 1 or 2, where Y1is a piperidine-1,4-dialnow GRU is PU (the nitrogen atom in the 1-position is bound to X 2).

12. The compound or its salt according to any one of claims 1 or 2, where R1
represents a 2,3-dihydro(1,4)like(2,3-C)pyridine-7-ilen group.

13. The compound or its salt according to claim 1, where the compound is selected from 7-chloro-1-(2-(4-((2,3-dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-it,
1-(2-(4-((2,3-dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it,
1-(2-(4-((2,3-dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-it
5-(2-(4-((2,3-dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-it.

14. 7-Chloro-1-(2-(4-((2,3-dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl) amino)piperidine-1-yl)ethyl)-1,5-naphthiridine-2(1H)-one or its salt.

15. 1-(2-(4-((2,3-Dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-one or its salt.

16. 1-(2-(4-((2,3-Dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-methoxy-1,5-naphthiridine-2(1H)-one or its salt.

17. 5-(2-(4-((2,3-Dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-3-methoxypyridine(2,3-b)pyrazin-6(5H)-one or its salt.

18. The connection represented by the General formula:
[Formula 2]

[where X1Arepresents C1-C3alkylenes group; Y2oboznacheniyalari protected carbonyl group; Z1, Z2, Z3, Z4, Z5and Z6are the same or different, and each of them represents a nitrogen atom or a group represented by the General formula CR7(where R7denotes a hydrogen atom, halogen atom, hydroxyl group, cyano group, optionally protected amino group, amino group, which is substituted by one or more C1-6alkyl group, a lower alkyl group, cycloalkyl group, lower alkoxy group or a monocyclic 5-membered heterocyclic group which may be substituted by one or more halogen atoms, which heteroatoms can be nitrogen, oxygen or sulfur, or a group represented by the General formula Q1CO2R10(where R10denotes carboxyl-protective group, and Q1indicates the lowest alkenylamine group), provided that at least one of the Z3, Z4, Z5and Z6represents a nitrogen atom], or its salt.

19. Connection p, where Z1represents CH.

20. The compound according to any one of p or 19, where X1arepresents a methylene group and Y2represents a carbonyl group.

21. The compound according to any one of p or 19, where Z1, Z2and Z4each represent CH; Z3represents a nitrogen atom; Z5represents a group represented by the General formula CR7d(where R7drepresents a halogen atom or a lower alkyl or lower alkoxy group which may be substituted by one or more halogen atoms); and Z6represents a nitrogen atom or CH.

22. The compound according to any one of p or 19, where Z5represents a group represented by the General formula CR7e(where R7erepresents a halogen atom, a lower alkyl group or alkoxy group).

23. The connection represented by the General formula:
[Formula 3]

[where R7cdenotes a halogen atom, hydroxyl group, cyano group, optionally protected amino group, amino group which may be optionally substituted by one or more1-6alkyl group, a lower alkyl group, cycloalkyl group, lower alkoxy group or a monocyclic 5-membered heterocyclic group which may be substituted by one or more halogen atoms, which heteroatoms can be nitrogen, oxygen or sulfur, or a group represented by the General formula Q1CO2R10(where R10denotes carboxyl-protective group, and Q1indicates the lowest alkenylamine group), Z2aand Z6aare the same or the difference is significant, or a group represented by the General formula CR7(where R7denotes a hydrogen atom or lower alkyl), provided that 3-amino-8-methylpurine(2,3b)pyrazin-6(5H)-it is excluded.

24. Connection item 23, where R7crepresents a halogen atom or a lower alkyl or lower alkoxy group which may be substituted by one or more halogen atoms; Z2arepresents CH and Z6arepresents a nitrogen atom or CH.

25. An antimicrobial agent containing the compound or salt of the compound according to any one of claims 1 to 17.



 

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SUBSTANCE: present invention refers to compounds (la) of formula applied as tyrosine kinase c-Met inhibitors. , where: LA is selected from ,

or ; RA is selected from:

or each RA2 and RA6 represents hydrogen; RA3 represents RAr; or RA3, RA4 and carbon atoms whereto attached form 6-members aryl, optionally substituted, in the amount up to 4 by independent groups RAr, or a 5-6-members heterocyclyl or heteroaryl ring containing at least one O, N or S atom; R represents -OH; RA5 represents hydrogen or RAr; LB represents a covalent bond or -N(R*)-; RB represents halogen, NH2 or C1-8aliphatic group, optionally substituted by R; a 6-10-members aryl ring; a 3-7-members carbocyclyl ring, a 5-10-members heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, where each said aryl or heteroaryl ring is optionally substituted, in the amount up to five by independent groups RAr; R represents halogen, -R°, -SR°, Ph, optionally substituted R° or -C(O)OR°; each RAr is independently selected from halogen, -R°, -OR°, -SR°, Ph, optionally substituted in the amount up to five by independent groups -R°, -CN, -N(R°)2 or -C(O)OR°; or two adjacent groups RAr taken together, represent 1,2-methylenedixy or 1,2-ethylenedixy; each R* represents hydrogen; and each R° represents independently hydrogen, an optionally substituted C1-6aliphatic radical or an unsubstituted 5-6-members heteroaryl or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms.

EFFECT: invention refers to pharmaceutically acceptable compositions containing the compounds under the invention, and methods of application of the compositions in treatment of various proliferative disorders.

10 cl, 4 tbl, 548 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula IB , where radicals R1-R5 have values, given in invention formula. In range of claimed invention also described are pharmaceutical compositions, which include compounds of IB formula, and methods of application of such compounds and compositions for treatment of different malfunctions, mainly selected from immune response reactions.

EFFECT: compounds by claimed invention have inhibiting action with respect to proteinkinases and, in particular with respect to JAK-3, ROCK or Aurora kinases.

55 cl, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of general formula , where R is an optional ortho- or meta-substitute selected from halogen and (C1-4)alkyloxy; R1 is halogen or CF3; R2 is H, (C1-4)alkyloxy or halogen; R3 is H or (CH2)n-NR5R6; R4 is H or (C1-6)alkyl, optionally substituted COOR7 or NR8R9; R5 and R6 independently denote H, (C3-8)cycloalkyl, quinuclidin-3-yl, (C2-6)alkenyl or (C1-6)alkyl, optionally substituted mono-substituted with CF3, (C3-8)cycloalkyl, (C6)aryl, a 5- or 6-member heteroaryl group, OH, (C1-6)alkyloxy, (C6-10)aryloxy, CONR11R12, NR13R14 or NR13SO2(C1-4)alkyl; or R5 and R6 together with a nitrogen atom to which they are bonded form a 4-8-member saturated heterocyclic ring which also contains 1 heteroatom selected from O, SO2 and NR15, where the ring is optionally mono-substituted or di-substituted with oxo, (C1-4)alkyl, (C3-8)cycloalkyl, NR16R17 or CONR18R19; R7 is H or (C1-4)alkyl; R8 and R9 independently denote H, (C1-4)alkyl (optionally substituted di(C1-4)alkylamino) or (C3-8)cycloalkyl; or R8 and R9 together with a nitrogen atom with which they are bonded form a 4-8-member saturated heterocyclic ring which also contains one heteroatom which is O; R11 and R12 independently denote H or (C1-4)alkyl; R13 and R14 independently denote H or (C1-4)alkyl; R15 is H, (C1-4)alkyl (optionally mono-substituted OH, (C1-4)alkyloxy or di(C1-4)alkylamino), phenyl, pyridyl or COR20; R16 and R17 denote (C1-4)alkyl; or R16 and R17 together with a nitrogen atom with which they are bonded from a 4-8-member saturated heterocyclic ring; R18 and R19 denote H; R20 is (C1-4)alkyl, (C3-8)cycloalkyl or furyl; and n equals 0 or 1; or its pharmaceutically acceptable salt. The invention also relates to use of formula I compounds to prepare a medicinal agent and to a pharmaceutical composition based on formula I compound.

EFFECT: novel derivatives have catepsin S and K inhibitory activity.

9 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of photoactivation of a photocatalyst by irradiating a composition containing the said catalyst. The method of using a photolatent catalyst (a) in which a composition containing said catalyst is irradiated before subsequent treatment is characterised by that, the photolatent catalyst is: (a1) a compound selected from a group consisting of a photolatent acid, an aromatic iodonium salt or oxime-based photolatent acid; (a2) a photolatent base compound. Also described is a substrate on which a coating made from the composition is deposited in accordance with the above described method. Also described is a method of using photolatent catalyst (a), in which a composition containing said catalyst is irradiated before subsequent treatment, characterised by that subsequent treatment is preparation of foam material and the composition contains polyol and isocyanate components and photolatent base (a2) as photolatent catalyst.

EFFECT: provision for solidification of the system.

13 cl, 10 tbl, 16 ex

FIELD: pharmacology.

SUBSTANCE: present invention refers to compounds of formula (I) , to its N-oxides, salts, stereoisomer forms where n is equal 1, 2 or 3; R1 means cyano group; X means bivalent radical NR2 or O; R2 means hydrogen or C1-10alkyl, each Q1 independently stands for direct coupling, -CH2- or -CH2-CH2-; each R4 independently means hydrogen or C1-4alkyl; each R5a, R5b, R5c independently means hydrogen, C1-4alkyl or arylC1-4alkyl; each R5e, R5f independently means hydrogen, C1-4alkyl or arylC1-4alkyl, or R5e and R5f together can form bivalent alkandiyl radical of formula -CH2-CH2- or -CH2-CH2-CH2-; R11 means aryl, arylC1-4alkyl, C1-4alkylcarbonyl, arylcarbonyl, arylC1-4alkylcarbonyl, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, R5aR5bN-carbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, arylC1-4alkyloxyC1-4alkyl, aryloxyC1-4alkyl, pyridyl; -a1=a2-a3=a4- means a bivalent radical of formula -CH=CH-CH=CH- (c-1); where one or two hydrogen atoms in (c-1) are substituted by radical C1-6alkyl, C1-4alkoxy, halogen, hydroxy group, (R5g)(R5h)N-(C1-4alkandiyl)-O-trifluoromethyl, cyano group, radical -COOR4, (R5a)(R5b)N-sulphonyl, pyrrolidinyl-sulphonyl, piperidinyl sulphonyl, radical N(R5a)(R5b), radical (a-1), (a-7), morpholinyl, (R5g)(R5h)N-(C1-4alkandiyl)-N(R5c)-, C1-6alkylcarbonylamino, C1-6alkyloxycarbonylamino, C1-6alkylsulphonylamino, (R5a)(R5b)N-C1-4alkyl; R20 means hydrogen, spiro (C2-4alkylenedioxy), spiro (diC1-4alkyoxy) or -NR5gR5h; each R5g or R5h independently means either hydrogen, or C1-4alkyl, or R5g and R5h together with nitrogen atom whereto attached form pyrrolidinyl, piperidinyl or morpholinyl; R3 means nitro group, cyano group, amino group, halogen, hydroxy group or C1-4alkoxy; aryl means phenyl optionally substituted with one or more substitutes chosen from the group consisting of C1-6alkyl, C1-4alkoxy, halogen, hydroxy, amino and trifluoromethyl. Besides it relates to the pharmaceutical composition with antiviral activity, and method for making said compounds.

EFFECT: there are prepared and described new compounds with antiviral activity.

9 cl, 15 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to RSV replication inhibitors of formula (I) or salts thereof or stereochemically isomeric forms, where R is a radical of formula (a) or (b) . Q is hydrogen or C1-6alkyl substituted with a heterocycle selected from oxazolidine, morpholinyl and hexahydrooxazepine. Alk denotes C1-6alkanediyl. X is O; -a1=a2-a3=a4 - is -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH- or -CH=CH-CH=N-; R1 is selected from optionally substituted pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrrolyl. R2 is C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, Ar-C1-6alkyloxyC1-6alkyl, C3-7cycloalkyl, Ar-C1-6alkyl. R3 is cyano. Ar is phenyl o substituted phenyl. The invention also relates to pharmaceutical compositions containing compounds (I) and a method of producing compounds (I).

EFFECT: high efficiency of the compositions.

9 cl, 20 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel bicyclic derivatives of general formula (I)

(values of radicals are given in the description) and a pharmaceutical composition containing said derivatives, as well as use of said novel compounds to treat or inhibit symptomatic diseases where CEPT is involved, and a method of treating said diseases.

EFFECT: high efficiency of using compounds when treating diseases.

14 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in free form or in form of a pharmaceutically acceptable salt, where A is independently selected from CH and at least one nitrogen atom; D denotes CR3; R1 and R2 denote H, R3 denotes C1-C8-alkyl, R5 denotes , R5j and R5k are independently selected from H, C1-C8-alkyl and C3-C15-carbocyclic group, or R5j and R5k together with the nitrogen atom to which they are bonded form an optionally substituted 4-14-member heterocyclic group; R6 denotes H; W denotes a C6-C15-aromatic carbocyclic group; X denotes -CH2-; n assumes values from 0 to 3, a pharmaceutical composition based on said compounds and having CRTh2 receptor modulating activity, as well as a method for synthesis of compounds of formula I.

EFFECT: novel compounds which can be used as anti-inflammatory agents are obtained and described.

9 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: in general formula I R1 denotes hydrogen atom, a halogen atom, hydroxy, lower alkyl, benzyloxy or -O-(CH2)-(CO)-(5-member heteroaryl with 2 heteroatoms selected from N, O), substituted with phenyl or lower alkyl; R2 denotes a hydrogen atom, a halogen atom, lower alkyl, lower alkynyl, amino, -NHC(O)Ra or -(CO)-Ra; R3 denotes a hydrogen atom, a halogen atom, cyano, lower alkyl, lower alkynyl, amino, -NHC(O)-Ra, -(CO)-Ra, 4- or 5-member heterocycloalkyl substituted with a =O group or a 5-member heteroaryl with 1-2 heteroatoms selected from N; R4 denotes a hydrogen atom or a 5-member heteroaryl with 2 heteroatoms selected from N; R5 denotes lower alkyl or C3-C7cycloalkyl; Ra denotes lower alkoxy, -(CH2)n-(6-member heteroaryl with 1 heteroatom selected from N), phenyl C3-C7-cycloalkyl or NR'R", where each of R' and R" independently denotes a hydrogen atom, lower alkyl, substituted hydroxy, lower alkynyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-member heterocycloalkyl with 1-2 heteroatoms selected from O, N) or -(CH2)n-(5- or 6-member heteroaryl with 1 heteroatom selected from N, O); n assumes values from 0 to 3. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare the medicinal agent.

EFFECT: high activity and selectivity towards GABA A receptor subunit α5.

18 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of medicine and deals with vaccines, which contain C.perfringens alpha toxoids. Claimed vaccine contains supernatant of C.perfringens alpha toxoid except C.perfringens of C type, which was concentrated by ultrafiltration and has two or more units of Total Combining Power (NCP).

EFFECT: vaccine can be used for protection of animals against clostridial diseases caused by Cperfringens, except Cperfringens of C type.

12 cl, 23 tbl, 6 ex

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