Condensed pyridazine derivatives and drugs having the compounds as active ingredients


FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

 

Description

The present invention relates to condensed derivative pyridazine.

More specifically, the present invention relates to

(1) a derivative of pyridine, represented by the following formula (I)

(where all the symbols have the same meanings as described below), or their pharmaceutically acceptable salts,

(2) the method of obtaining these compounds

(3) medium containing these compounds as the active ingredient.

Poly(ADP-ribose)polymerase (hereinafter abbreviated as PARP), which is a nuclear enzyme, the activity of which increases with the occurrence of DNA breaks, plays a significant role in transfer reactions fragment of ADP-ribose from adenine dinucleotide (abbreviated as NAD+in the future) to various proteins, such as histones, DNA polymerase and DNA topoisomerase etc.

The DNA breaks induced by peroxynitrite (ONOO-) and oxygen radicals, lead to a significant increase in the activity of the polymerase PARP (PARP is activated up to 100 times, when the domain of the polymerase PARP, forming the "Zn-finger, binds to DNA with damage). I believe that excessive activation of PARP causes depletion of NAD+that is an essential link in the system of electronic transport, and subsequent Istomina the Asia-Pacific, leading to lack of energy, ultimately leads to cell death. (The suicide hypothesis of PARP activation:Free It. Biol. Med.,21, 855 (1996);TIPS.,19, 287 (1998)). Therefore, I believe that the inhibitor polymerase PARP can be used for inhibition of cell death.

Because the caspase-3 enzyme, which is one of the enzymes of the family of interleukin-1β-converting enzyme specifically cleaves PARP as the substrate (Cell.,81, 801 (1995))suggest that polymerase PARP is associated with apoptosis.

In the literature it was reported that 3-aminobenzamide and nicotinamide, which are known PARP inhibitors, is used for inhibiting cell death and elimination of diseases in studies on different models of ischemic diseases (cerebral ischemia, myocardial ischemia, ischemia of the intestine, skeletal muscle ischemia or ischemia of the retina and so on), inflammatory diseases (arthritis, inflammatory bowel disease or multiple sclerosis etc), diabetes, stroke, extrapyramidal diseases (TIPS.,19, 287 (1998);Eur. J. Pharmacol.,350, 1 (1998)) and hyperalgesia (Pain,72, 355 (1997))byin vitro,in vivoand mice with deficiency polymerase PARP. In addition, it was indicated that the inhibitor polymerase PARP used as drugs against retroviruses, such as Lek is stenny HIV drug ( Biochem. Biophys. Res.Commum.,180, 504 (1991)), as a sensitizing substances for cancer treatment (Radiat. Res.,126, 367 (1991) ;Br. J. Cancer.,72, 849 (1995)) or as an immunosuppressant (Int. J. Immunopharmac.,17, 265 (1995)).

Inhibitor polymerase PARP is suitable for the prophylaxis and/or treatment of various diseases, such as coronary heart disease (myocardial infarction cerebral, myocardial infarction, injury due to reperfusion and post-operative trauma etc), inflammatory diseases (inflammatory bowel disease, multiple sclerosis, arthritis or lung damage, etc.), neurodegenerative disorders (extrapyramidal disease, Parkinson's disease, Alzheimer's disease, muscular dystrophy, or spinal stenosis of the lumbar spine and so on), glaucoma, diabetes, complications of diabetes, stroke, head injury, spinal cord injury, renal failure, hyperalgesia or delay blood flow, etc. in Addition, the inhibitor is effective as a medicine against retroviruses, such as drug against HIV, sensitizing substances for cancer treatment or immunosuppressant.

As an inhibitor of polymerase PARP, for example, in international publication WO00/44726 described derivatives of 2H-phthalazine-1-she presented formula is (A)

(where R1Arepresents a

(i) C1-4 alkyl, substituted hydroxy or amino, or

(ii),

where A1Ais-NR3AC(O)- and so on, where R3Arepresents hydrogen or C1-4 alkyl, etc., A2Arepresents a C1-8 alkylene etc., A3Ais (i) hydrogen, (ii) -NR17AR18Aor (iii) Cyc2Aand so on, where R17Ais (i) hydrogen, (ii) C1-8 alkyl, etc. and R18Ais (i) hydrogen or (ii) C1-8 alkyl, etc., Cyc2Ais a 3-10-membered mono - or biheterocyclic ring containing 1-4 nitrogen atom, 1-2 oxygen atom and/or one sulfur atom, R2Ais hydrogen or halogen, etc. Necessary parts were extracted from the description of groups), which exhibit inhibitory activity against the polymerase PARP.

In the publication DE3302021 indicated that the compounds represented by formula (I),

(where R1Bis hydrogen or C1-3 alkyl, R2Bis hydrogen, R1Band R2Btaken together, represent a C1-4 alkylene, R3Bis hydrogen or stands, nB is 0-3, R4Bis 1-pyrrolidon. The desired fragments taken from the description of groups), inhibit platelet aggregation.

In the description of international publication WO98/31674 indicates that the connection is to be placed, represented by formula (C)

(where R1Cis a C1-4 alkoxy, etc., R2Cis a C1-8 alkoxy, etc., R3Cand R4Cis hydrogen or R3Cand R4Ctaken together, represent a bond, R5Cis hydrogen, etc.The desired fragments taken from the description of groups), inhibit fosfodiesterazu activity.

The publication presented inJournal of Medicinal Chemistry.,44(16), 2511-2522 and 2523-2535 (2001)described that 4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydropyrazin-1(2H)-(CAS Registry No. 244077-36-9) and 4-(3,4-acid)-5,6,7,8-tetrahydropyrazin-1(2H)-(CAS Registry No. 358368-98-6) inhibit fosfodiesterazu activity.

In the journalTetrahedron.,39(20), 3419-27 (1983)described that 4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazine-1(2H)-(CAS Registry No. 89311-30-8) is a synthetic intermediate connection.

The publication presented inSynthesis., 240-242 (1995)described that the compounds 4-phenyl-5,6,7,8-tetrahydropyrazin-1(2H)-(CAS Registry No. 154810-22-7), 4-(4-were)-5,6,7,8-tetrahydropyrazin-1(2H)-(CAS Registry No. 154810-23-8), 4-(4-forfinal)-5,6,7,8-tetrahydropyrazin-1(2H)-(CAS Registry No. 154810-24-9), 4-(4-chlorophenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-(CAS Registry No. 154810-25-0), and 4-(4-bromophenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-(CAS Registry No. 154810-26-1) is a synthetic intermediate compounds.

In the publication Zhu is Nala Bioorganic andMedicinalChemistry.,6, 349-454 (1998)described that 7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazine-1(2H)-(CAS Registry No. 206126-90-1) and 4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazine-1(2H)-(CAS Registry No. 206126-96-7) are synthetic intermediate compounds.

The publication presented inJournal of Medicinal Chemistry.,43(12), 2310-2323 (2000)described that 4-(pyridine-4-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-(CAS Registry No. 212142-89-7) is a synthetic intermediate connection.

In the publication FR2647676 described that 4-tert-butoxycarbonylmethyl-5,6,7,8-tetrahydropyrazin-1(2H)-(CAS Registry No. 134972-12-6) and 4-ethoxycarbonylmethyl-5,6,7,8-tetrahydropyrazin-1(2H)-(CAS Registry No. 134973-24-3) are synthetic intermediate compounds.

To identify compounds with inhibitory activity against (ADP-ribose)polymerase, conducted extensive research and found that the objective of the invention is achieved derivatives pyridine represented by the formula (I).

The present invention relates to (1) condensed derived pyridazine represented by the formula (I)

where R1represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro, (7) NR2R3, (8) C2-8 acyl, (9) C1-8 alkoxy substituted by phenyl or (10) C2-8 acyl, substituted the first NR 2R3,

R2and R3each independently represents a

(1) hydrogen atom or (2) C1-8 alkyl,

X and Y each independently represents a

(1) C (2) CH or (3) N,

is

(1) single bond or (2) a double bond,

is

(1) partially or fully saturated C3-10 monocarbocyclic the aryl or (2) partially or fully saturated 3 to 10-membered monogatarareba containing from 1 to 4 heteroatoms selected from atoms of oxygen, nitrogen and sulphur,

A is (1) A1, (2) A2, (3) A3, (4) A4or (5) A5,

A1is

A2is,

A3is

A4is

A5is

D1is

(1) -NR6C(O)-, (2) -NR6C(S)-, (3) -NR6SO2-, (4) -CH2-NR6-, (5) -CH2-O-, (6) -OC(O)-, (7) -CH2-NR6C(O)-, (8) -NR6C(O)NR7-, (9) -NR6C(O)O-, (10) -NR6C(S)NR7-, (11) -NR6or (12) -NR6C(=NR7)-,

R6and R7each independently represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) phenyl or (4) C1-8 alkyl substituted by phenyl,

D2represents a

(1) C-8 alkylene, (2) C2-8 albaniles, (3) Cyc2, (4) -(C1-4 alkylene)-O-(C1-4 alkylene)-, (5) -(C1-4 alkylene)-S-(C1-4 alkylene)-, (6) -(C1-4 alkylene)-NR8-(C1-4 alkylene)-, (7) -(Cyc2)-(C1-8 alkylene)-, (8) -(C1-8 alkylene)-(Cyc2)or (9) -(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)-,

R8represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl,

D3represents a

(1) hydrogen atom, (2) -NR9R10, (3) Cyc3, (4) -OR11, (5) COOR12, (6) CONR13R14, (7) cyano, (8) halogen atom, (9) -C(=CR15)NR16R17or (10) -NR18C(=NR19)NR20R21,

R9and R13each independently represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 quinil, (5) Cyc3, (6) C1-8 alkoxy, (7) C2-8 alkenylacyl, (8) C2-8 alkyloxy or (9) C1-8 alkyl, substituted Cyc3, C1-8 alkoxy, C1-8 alkylthio, cyano, hydroxy, or 1 to 3 halogen atoms,

R10and R14each independently represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 quinil, (5) C1-8 alkoxycarbonyl, (6) C2-8 acyl, (7) C3-8 cycloalkyl, (8) C1-8 alkoxycarbonyl, substituted by Cyc4 or 1 to 3 hydrogen atoms, or (9) C1-8 alkyl, substituted C1-8 alkoxy,

R11and R12each independently represents a

(1) hydrogen atom or (2) C1-8 alkyl,

R15, R16, R17, R18, R19, R20and R21each independently represent FDS is th

(1) hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl,

R4represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro, or (7) NR22R23,

R22and R23each independently represents a

(1) hydrogen atom or (2) C1-8 alkyl,

E1is C1-4 alkylene,

E2is

(1) -C(O)NR24-, (2) -NR24C(O)-, (3) -NR24-, (4) -C(O)O -, or (5) -S-,

R24represents a

(1) hydrogen atom, (2) C1-8 alkyl or (3) C1-8 alkyl substituted by phenyl,

E3represents a

(1) a bond or (2) C1-8 alkylene,

E4represents a

(1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 quinil, (4) Cyc5, (5) NR25R26, (6) OR27, (7) SR27, (8) COOR27, (9) C1-8 alkyl, substituted OR two of25, (10) C1-8 alkyl, substituted by 1 to 3 halogen atoms, (11) cyano or (12) C2-8 acyl,

R25represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 quinil, (5) Cyc5 or (6) C1-8 alkyl, substituted Cyc5 or or28,

R26represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl,

R27represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) Cyc5 or (4) C1-8 alkyl, substituted Cyc5,

R28represents a

(1) hydrogen atom or (2 C1-8 alkyl,

G1is C1-8 alkylene,

Cyc1 is a

(1) partially or fully saturated C3-10 mono - or bikebicycle aryl, or (2) partially or fully saturated 3-10 membered mono - or bilateral containing from 1 to 4 heteroatoms selected from atoms of oxygen, nitrogen and sulphur,

G2represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) C2-8 acyl, (5) Cyc6, (6) C1-8 alkyl or

C2-8 alkenyl, substituted by 1 to 2 substituents selected from the Cyc6, hydroxy and C1-8 alkoxy, (7) C1-8 alkoxycarbonyl, substituted Cyc6, (8) -C(O)-Cyc6, (9) nitro, (10) NR41R42,

(11) C1-8 alkoxy; or (12) C1-8 alkyl, substituted NR41R42,

R41and R42each independently represents a

(1) hydrogen atom or (2) C1-8 alkyl,

R5represents a

(1) hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) nitro, (6) NR29R30, (7) C1-8 alkyl, substituted NR29R30, (8) NHSO2OH, (9) amidino, (10) cyano, (11) halogen atom, (12) Cyc8 or (13) C1-8 alkyl, substituted Cyc8,

R29and R30each independently represents a

(1) hydrogen atom or (2) C1-8 alkyl,

Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 each independently represents a

(1) partially or fully saturated C3-10 mono - or bikebicycle aryl, or (2) partially or fully saturated 3-10 membered mono - or bilateral, soda is containing from 1 to 4 heteroatoms, selected from atoms of oxygen, nitrogen and sulphur,

Cyc7 is a

(1) partially or fully saturated C3-mono - or bikebicycle aryl, or (2) partially or fully saturated 3-10 membered mono - or biketrail containing from 1 to 4 heteroatoms selected from atoms of oxygen, nitrogen and sulfur, provided that Cyc7 is not benzene,

Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8, possibly substituted by 1-3 substituents selected from (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C1-8 alkoxy, (4) halogen atom, (5) trihalomethyl, (6) trihalomethane, (7) C1-8 alkoxycarbonyl, (8) oxo, (9) C1-8 alkyl, substituted C1-8 alkoxy or phenyl, (10) hydroxy and (11) NR29R30;

m and n each independently is 1 or 2,

where

(i) when A is A1or A2then

is not

(ii) when A is A4and

is

then

R5is not hydroxy or C1-8 alkoxy,

(iii) when A is A5then

is not

and

(iv) the following compounds (1) to (13) are excluded;

(1) 4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydropyrazin-1(2H)-he,

(2) 4-(3,4-acid)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(3) 4-phenyl-6,7,8,8a-those who rahydropyranyl[1,2-d][1,2,4]triazine-1(2H)-he,

(4) 4-phenyl-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(5) 4-(4-were)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(6) 4-(4-forfinal)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(7) 4-(4-chlorophenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(8) 4-(4-bromophenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(9) 7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazine-1(2H)-he,

(10)4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazine-1(2H)-he,

(11) 4-(pyridine-4-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(12) 4-tert-butoxycarbonylmethyl-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(13) 4-ethoxycarbonylmethyl-5,6,7,8-tetrahydropyrazin-1(2H)-he, or

its pharmaceutically acceptable salt,

(2) the method of obtaining the specified connection, and

(3) the tool comprising such a compound as an active ingredient.

In the description, C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl or their isomers.

In the description, C2-8 alkenyl means ethynyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl or their isomers.

In the description, C2-8 quinil means ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl, heptenyl, octenyl or their isomers.

In the description, C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or their isomers.

In the description, C2-8 alkenylacyl means adenylate, propenyloxy, butenyloxy, pentyloxy, Gex is yloxy heptyloxy, octenoate or their isomers.

In the description, C2-8 alkyloxy means itineracy, propenyloxy, butenyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or their isomers.

In the description, C1-8 alkylthio means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, Reptilia, octylthio or their isomers.

In the description, C1-4 alkylene means methylene, ethylene, trimethylene, tetramethylene or their isomers.

In the description, C1-8 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptameron, octamethylene or their isomers.

In the description, C2-8 albaniles means ethenylene, propylen, butylen, penttinen, hexarelin, heptenyl, hoktanyan or their isomers.

In the description, C1-8 alkoxycarbonyl means methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxybenzoyl, hexyloxymethyl, heptyloxybiphenyl, octyloxybiphenyl or their isomers.

In the description, trihalomethyl is methyl substituted by three halogen atoms.

In the description, trihalomethyl is methoxyl substituted by three halogen atoms.

In the description, C2-8 acyl means ethanoyl (acetyl), propanol (propionyl), butanol (butyryl), pentanol (valeryl), hexanoyl, heptanoyl, octanoyl or their isomers.

In the description, C3-8 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, illogical, cycloheptyl, cyclooctyl.

In the description, halogen means chlorine, bromine, fluorine or iodine.

In the description, partially or fully saturated C3-10 monocarbocyclic the aryl represented by the formula

is cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclonona, cyclodecene, cyclohexadiene, cycloheptadiene, cyclooctadiene etc.

In the description, partially or fully saturated 3 to 10-membered Monogatari containing from 1 to 4 heteroatoms selected from atoms of oxygen, nitrogen and sulfur, represented by the formula

means aziridine, azetidine, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, oxiran, oxetan, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydroacetic, tetrahydroazepine, ambrosia is reoccupy, thiran, tieton, dihydrothiophene, tetrahydrothiophene, dehydration (dihydrothiophene), tetrahydrate (tetrahydrothiopyran), dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazolyl), dihydrooxazolo, tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, dioxolane, dioxane, ditiolan, Titian etc.

In the description, among partially or fully saturated 3-10 membered mono - or bilaterally containing from 1 to 4 heteroatoms selected from atoms of oxygen, nitrogen and sulfur, represented by Cyc1, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6, Cyc7 and Cyc8, 3-10-membered mono - or bilateral containing from 1 to 4 heteroatoms selected from the at the MOU oxygen, nitrogen and sulfur, means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, tiain, tiepin, oxazol, isoxazol, thiazole, isothiazol, furazan, oxadiazole, oxazin, oxadiazon, oxazepine, oxadiazon, thiadiazole, teasin, thiadiazin, diazepin, thiadiazin, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, ditionally, indazole, quinoline, isoquinoline, hemolysin, purine, phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, chrome, benzofurazan, benzothiadiazole, benzotriazole etc.

In addition, partially or fully saturated 3-10 membered mono - or bilateral containing from 1 to 4 heteroatoms selected from atoms of oxygen, nitrogen and sulfur, means aziridine, azetidine, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, oxiran, oxetan, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydroacetic, tetrahydroazepine, perhydroxyl, thiran, tieton, dihydrothiophene, tetrahydrothiophene, dehydration (dihydrothiophene), tetrahydrate (tetrahydrothiopyran), dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazolidine), dihydrooxazolo, tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrothiazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, indolin, isoindoline, dihydrobenzofuran, perhydroanthracene, dihydroisobenzofuran, peligrosamente, dihydrobenzofuran, targetobjecttype, dihydroisobenzofuran, peligrosamente, dihydroindol, peritoneal, dihydroquinoline, Tetra Kohinoor, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, benzocain, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, dioxolane, dioxane, ditiolan, Titian, dioksiinien, benzodioxan, chroman, benzodithiol, benzodithiol etc.

The above heterocyclic ring include N-oxide, which is a compound with oxidized nitrogen.

In the description, partially or fully saturated C3-10 mono - or bikebicycle aryl represented by Cyc1, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6, Cyc7 and Cyc8, is a cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclonona, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, azulene, pergerson, perhydroanthracene, inden, palikonda, is ndan, naphthalene, tetrahydronaphthalene or peritonealis etc.

Unless otherwise noted, all isomersincluded in the present invention. For example, an alkyl group, alkenyl, quinil, alkylene and alkoxy includes straight or branched chain. In addition, isomers on double bond, ring, fused ring (E-, Z -, CIS-, TRANS-isomer), isomers formed in the presence of asymmetric atom(s) C (R-, S-, α-, β-isomer, enantiomer, diastereoisomer), optically active isomers (D-, L-, d-, l-isomer), polar compounds obtained by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, their mixtures with arbitrary relations and racemic mixtures are also included in the present invention.

According to the present invention, unless otherwise indicated, and if it is obvious to experts in this field, the symbolindicates that the link is located on the opposite side of the plane (namely, α-configuration), symbolindicates that the link is located on the front side of the plane (namely, β-configuration), symbolindicates the presence of α-, β-configuration or a mixture thereof, and the symbolindicates the presence of a mixture of α-is configuratie and β configuration.

The connection according to the present invention can be converted into a pharmaceutically acceptable salt by known methods.

Pharmaceutically acceptable salt is preferably water-soluble.

Pharmaceutically acceptable salt means, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium etc), ammonium salt (Tetramethylammonium, tetrabutylammonium etc), salts of organic amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine etc), additive acid salt (inorganic salts (hydrochloride, bromohydrin, loggedout, sulfate, phosphate, nitrate etc), salts of organic acids (acetate, triptorelin, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, aconsultant, bansilalpet, toluensulfonate, isetionate, glucuronate, gluconate, etc. and so on

In addition, a solvate or a solvate of the above alkaline (land) metals, ammonium, organic amines and additive salts of acid compounds according to the present invention included in the definition of pharmaceutically acceptable salts according to the present invention.

Preferably the, MES is non-toxic and water soluble. The corresponding MES means, MES, such as, for example, water, alcohol (ethanol, etc. and so on

In the description,

preferably is partially or fully saturated C3-7 monocarbocyclic-aryl, or partially or fully saturated 3 to 7 membered monogatarareba containing 1-2 heteroatoms selected from atoms of oxygen, nitrogen and sulfur. In addition, partially or fully saturated C3-7 monocarbocyclic aryl or partially or fully saturated 3 to 7 membered Monogatari preferred are the following compounds;

Partially or fully saturated 3 to 7 membered monogatarareba containing 1-2 heteroatoms selected from atoms of oxygen, nitrogen and sulfur, are preferably the following compounds;

In the description, A is preferably A1, A2or A3.

In the description, D1is preferably-NR6C(O)-,

-NR6C(S)-, -NR6SO2- or-CH2-NR6-, and more preferably

-NR6C(O)-.

In the description, D2preferably represents C1-8 alkylene, C2-8 albaniles, -(C1-4 alkylene)-O-(C1-4 alkylene)-, -(C1-4 alkylene)-S-(C1-4 alkylene)-, -(C1-4 alkylene)-NR8-(C1-4 alkyl is n - or -(C1-8 alkylene)-(Cyc2)-, and more preferably C1-8 alkylene.

In the description, D3preferably a is-NR9R10or Cyc3.

In the description, E1preferred is C1-4 alkylene.

In the description, E2preferably is-C(O)NR24-, -NR24C(O)-, -NR24- or-S-.

In the description, E3preferably represents a bond or C1-8 alkylene.

In the description, E4preferably is Cyc5 or NR25R26.

In the description, Cyc1 is preferably partially or fully saturated 3 to 10-membered monogatarareba containing 1-2 heteroatoms selected from atoms of oxygen, nitrogen and sulphur.

In the description, when A is A3or A4at least one of X and Y preferably is N.

In the description, when A is A3or A4,

preferably is

Among the compounds according to the present invention, represented by formula (I), preferred compounds are compounds represented by formula (I-A-1)

(where all the symbols have the same meanings as described above), compounds represented by formula (I-A-2)

(where all the symbols have the same meanings as described above), compounds, predstavleniyami (I-B-1)

(where all the symbols have the same meanings as described above), compounds represented by formula (I-B-2)

(where all the symbols have the same meanings as described above), compounds represented by formula (I-C-1)

(where all the symbols have the same meanings as described above), and compounds represented by formula (I-C-2)

(where all the symbols have the same meanings as described above).

Certain compounds according to the present invention include compounds shown in tables 1 to 90, the compounds described in the examples and their pharmaceutically acceptable salts.

In each table, Me represents methyl group, Et represents an ethyl group, Pr represents a sawn group, i-Pr represents an isopropyl group, Bu represents boutelou group, c-Pr is cyclopropyl group, c-Bu represents cyclobutyl group, c-Pen is cyclopentyloxy group, c-Hex is a tsiklogeksilnogo group, Ph represents a phenyl group, Bn represents a benzyl group, and other symbols have the same meanings as described above.

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

Table 47

Table 48

Table 49

Table 50

Table 51

Table 52

Table 53

Table 54

Table 55

Table 56

Table 57

Table 58

Table 59

Table 60

Table 61

Table 62

Table 63

Table 64

Table 65

Table 66

Table 67

Table 68

Table 69

Table 70

Table 71

Table 72

Table 73

Table 74

Table 75

Table 76

Table 77

Table 78

Table 79

Table 80

Table 81

Table 82

Table 83

Table 84

Table 85

Table 86

Table 87

Table 88

Table 89

Table 90

Methods for obtaining compounds according to the present invention:

The compound represented by formula (I)can be obtained by the following method or a method described in the example.

(1) Among the compounds according to the present invention, represented by formula (I), the compound in whichA represents A1and D1is a-R 6C(O)- or-CH2-NR6C(O)-, i.e. the compound represented by formula (IA-1)

(where D1-1is-NR6C(O)- or-CH2-NR6C(O)-, and other symbols have the same meanings as described above), can be obtained in the following way.

The compound represented by formula (IA-1)can be obtained by amidation of the compounds of the formula (II)

(where R31is-other6or-CH2-Other6and R1-1, R4-1and

are R1, R4and

respectively. Provided that the hydroxyl group or amino group in the group represented by R1-1, hydroxyl group or amino group represented by R4-1and the amino group in the group represented

may be protected, if necessary. Other symbols have the same meanings as defined above, and compounds represented by formula (III)

(where D2-1and D3-1are the D2and D3respectively. Provided that the amino group in the group represented by D2-1and carboxy-, hydroxy-, amino-, amidino or guanidinium in the D3-1may be protected, if necessary)if necessary, the subsequent removal of the protective group from the resulting product.

The method of amidation is known manner. For example, it includes the way

(1) based on the application of acylhalides,

(2) based on the use of a mixed acid anhydride,

(3) based on the use of a condensing reagent.

These methods describe as follows.

(1) the Way in which applied allvalid can be performed, for example, by reacting carboxylic acid with acylhalides (for example, oxalylamino or thionyl chloride etc. in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) or without a solvent at temperatures from -20°With up to a temperature of education phlegmy. And then, formed acylhalides derivative may be subjected to interaction with the amine in an inert organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine and so on) at a temperature of from 0 to 40°C. alternatively, formed acylhalides derivative can react carried out in an organic solvent (dioxane, tetrahydrofuran) using aqueous alkaline solution (for example, sodium bicarbonate, sodium hydroxide) at t is mperature from 0 to 40° C.

(2) the Way in which used mixed acid anhydride may be performed, for example, by reacting carboxylic acid with acylhalides (for example, revalorisation, mozillateam or methylchloride) or acid derivative (ethyl ether harpalinae acid or isobutyl ether harpalinae acid) in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) or without a solvent, in the presence of tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) at a temperature of from 0 to 40°C. And then the obtained mixed acid anhydride may be subjected to interaction with the amine in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) at a temperature of from 0 to 40°C.

(3) the Way in which use of the condensing reagent, may be performed, for example, by reacting carboxylic acid with amine in an organic solvent (e.g. chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent, in the presence or absence of tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine), using a condensing reagent (for example, 1,3-DICYCLOHEXYL is bodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1-carbodiimide (CDI), 2-chloro-1-methylpyridinium or cyclic anhydride 1-papapostolou acid (PPA)), in the presence or absence of 1-hydroxybenzotriazole (HOBt), at temperatures from 0 to 40°C.

The reaction described in paragraphs (1), (2) and (3)may be carried out in an atmosphere of inert gas (e.g. argon, nitrogen) in order to achieve the preferred output.

The removal of the protective group can be carried out by the following method.

The reaction of removing the protective group for carboxyl, hydroxyl, amino, amidino or guanidinium is well known, including, for example, the following:

(1) alkaline hydrolysis,

(2) removal of protection in an acidic environment,

(3) removal of protection by hydrogenolysis,

(4) removing the silyl protection.

These methods describe as follows.

(1) Removal of protection by alkaline hydrolysis can be carried out, for example, in an organic solvent (e.g. methanol, tetrahydrofuran, dioxane) using a hydroxide of an alkali metal (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide), a hydroxide of alkaline earth metal (such as barium hydroxide, calcium hydroxide) or a carbonate (e.g. sodium carbonate, potassium carbonate), or water what's solutions or mixtures thereof, at a temperature of from 0 to 40°C.

(2) Removal of protection in acidic conditions can be realized, for example, in an organic solvent (e.g. dichloromethane, chloroform, dioxane, ethyl acetate, anisole) by organic acids (e.g. acetic acid, triperoxonane acid, methanesulfonate, p-toluenesulfonic acid) or by means of an inorganic acid (e.g. hydrochloric acid, sulfuric acid) or a mixture thereof (hydrogen bromide/acetic acid)at a temperature of from 0 to 100°C.

(3) Removal of protection by hydrogenolysis can be carried out, for example, in a solvent (for example, the type of simple ether (e.g. tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether), the type of alcohol (e.g. methanol, ethanol), type benzene (for example, benzene, toluene), type ketone (e.g. acetone, methylethylketone), type nitrile (e.g. acetonitrile), type amide (e.g. dimethylformamide), water, ethyl acetate, acetic acid, or in a mixed solvent consisting of two or more of these solvents), in the presence of a catalyst (e.g. palladium-on-charcoal, palladium mobiles, palladium hydroxide, platinum oxide, Raney Nickel), at normal pressure or in an atmosphere of high pressure hydrogen or in the presence of moravcikova ammonium, at a temperature of from 0 is about 200° C.

(4) removing the silyl protection can be implemented, for example, mixed with water, an organic solvent (e.g. tetrahydrofuran, acetonitrile) using tetrabutylammonium, at a temperature from 0 to 40°C.

The group protecting the carboxyl group includes, for example, methyl, ethyl, tert-butyl and benzyl.

The group protecting the hydroxyl group includes, for example, methoxymethyl, 2-tetrahydropyranyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl and benzyl.

The group protecting the amino group, amidinopropane and guanidinium includes, for example, benzyloxycarbonyl, tert-butoxycarbonyl, TRIFLUOROACETYL, 9-fluorenylmethoxycarbonyl and trimethylsilyl.

Group protecting the carboxyl group, hydroxyl group, amino group, amidinopropane or guanidinium, can be any other groups other than the above-mentioned groups, can easily and selectively removed, and they are not specifically agreed upon. For example, can be used protective groups described in the publication by T. W. Greene,Protective Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999.

The specified compounds according to the invention can be easily obtained through selective use of the reaction remove the protection, which will not cause much trouble for any specialist who this field.

(2) Among the compounds according to the present invention, represented by formula (I), a compound in which A represents A1and D1represents-NR6SO2-, i.e. the compound represented by formula (IA-2)

(where all the symbols have the same meanings as described above), can be obtained in the following way.

The compound represented by formula (IA-2)can be obtained by sulfonmethane compounds of the formula (II-1)

(where all the symbols have the same meanings as described above) and compounds represented by formula (IV)

(where R32is halogen and the other symbols have the same meanings as described above), if necessary, followed by removal of the protective group from the resulting product.

The reaction sulfonmethane is known. For example, it is carried out at a temperature from 0 to 40°C in an inert organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine).

The removal of the protective group can be carried out as indicated above.

(3) Among the compounds according to the present izopet the tion, represented by formula (I), a compound in which A represents A1and D1represents-OC(O)-, i.e. the compound represented by formula (IA-3)

(where all the symbols have the same meanings as described above), can be obtained in the following way.

The compound represented by formula (IA-3), can be obtained by tarifitsirovannyim compounds of the formula (V)

(where all the symbols have the same meanings as described above) the above compound represented by the formula (III)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group from the resulting product.

Method of esterification is in a known manner. For example, it includes the way

(1) based on the application of acylhalides,

(2) based on the use of a mixed acid anhydride,

(3) based on the use of condensing reagent.

These methods describe as follows.

(1) the Method based on the use of acylhalides, can be carried out, for example, by reacting carboxylic acid with acylhalides (for example, oxalylamino or thionyl chloride, etc. in an inert organic solvent (e.g. chloroform, IU is Langlade, diethyl ether or tetrahydrofuran) or without a solvent at temperatures from -20°C to a temperature of education phlegmy. And then formed acylhalides derivative may be subjected to interaction with alcohol in an inert organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine and so on) at a temperature of from 0 to 40°C.

(2) Method based on the use of a mixed acid anhydride may be carried out, for example, by reacting carboxylic acid with acylhalides (for example, revalorisation, mozillateam or methylchloride) or acid derivative (ethyl ether harpalinae acid or isobutyl ether harpalinae acid) in an inert organic solvent (e.g. chloroform, methylene chloride, diethyl ether, tetrahydrofuran) or without a solvent, in the presence of tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) at a temperature of from 0 to 40°C. And then the obtained mixed acid anhydride may be subjected to interaction with alcohol in an inert organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) at t is mperature from 0 to 40° C.

(3) the Method using condensing reagent can be carried out, for example, by reacting carboxylic acid with an alcohol in an organic solvent (e.g. chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent, in the presence or absence of tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine), using condensing reagent (for example, 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1-carbodiimide (CDI) or 2-chloro-1-methylpyridinium) in the presence or absence of 1-hydroxybenzotriazole (HOBt) at a temperature of from 0 to 40°C.

The reaction described in paragraphs (1), (2) and (3)can be conducted in an atmosphere of inert gas (e.g. argon, nitrogen)to avoid the presence of water and to obtain the preferred result.

The removal of the protective group can be carried out as indicated above.

(4) Among the compounds according to the present invention, represented by formula (I), a compound in which A represents A1and D1represents-CH2-O-, i.e. the compound represented by formula (IA-4)

(where all the symbols have the same meanings as described above), may be is obtained in the following way.

The compound represented by formula (IA-4), can be obtained by esterification of compounds of the formula (VI-1)

(where all the symbols have the same meanings as described above) and compounds of formula (VII-1)

(where R33is a leaving group (halogen atom, mesilate or tosyloxy etc), and other symbols have the same meanings as described above), if necessary, followed by removal of the protective group, esterification of compounds of the formula (VI-2)

(where all the symbols have the same meanings as described above) and compounds of formula (VII-2)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group, or by esterification of the above compounds of formula (VI-1)

(where all the symbols have the same meanings as described above) and compounds of formula (VII-2)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

The reaction of esterification of compounds of formula (VI-1) and the compounds of formula (VII-1), the compounds of formula (VI-2) and the compounds of formula (VII-2) is known. For example, it is carried out when temperature is from 0 to 100° C in an inert organic solvent (e.g. dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide), a hydroxide of alkaline earth metal (such as barium hydroxide, calcium hydroxide) or a carbonate (e.g. sodium carbonate, potassium carbonate), or an aqueous solution, or a mixture thereof.

This reaction is the esterification of the compounds of formula (VI-1) and the compounds of formula (VII-2) is known. For example, the reaction is performed at a temperature from 0 to 60°C by interaction with a corresponding alcohol compound in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc) in the presence of azo compounds (diethylazodicarboxylate, diisopropylcarbodiimide, 1,1'-(azodicarbon)piperidine, 1,1'-azobis(N,N-dimethylformamide), etc) and a phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, etc).

The reaction of removing the protective group can be carried out by the methods described above.

(5) Among the compounds according to the present invention, represented by formula (I), a compound in which A represents A1and D1represents-NR6-i.e. the connection is a group of represented by formula (IA-5)

(where all the symbols have the same meanings as described above), can be obtained in the following way.

The compound represented by formula (IA-5), can be obtained by reacting the above compound of the formula (II-1)

(where all the symbols have the same meanings as described above) with the compound of the formula (VIII-1)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group, or by reacting the compounds of formula (IX)

(where all the symbols have the same meanings as described above) with the compound of the formula (VIII-2)

(where all the symbols have the same meanings as described above), with the subsequent removal of the protective group.

This reaction is the interaction of the compounds of formula (II) with the compound of the formula (VIII-1), and the compounds of formula (IX) with the compound of the formula (VIII-2) is known. For example, the reaction is carried out at a temperature from 0 to 100°C in an inert organic solvent (e.g. dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran or acetonitrile) in the presence or without the s bases (for example, triethylamine, pyridine).

The reaction of removing the protective group can be carried out by the methods described above.

Among the compounds according to the present invention, represented by formula (IA-5), the compound in which D2represents a C1-8 alkylene, C2-8 albaniles, -(C1-4 alkylene)-O-(C1-4 alkylene)-, -(C1-4 alkylene)-S-(C1-4 alkylene)-, -(C1-4 alkylene)-NR8-(C1-4 alkylene)-, -(C1-8 alkylene)-(Cyc2)- or -(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)-, i.e. the compound represented by formula (IA-5-1)

(where D2'represents a C1-8 alkylene, C2-8 albaniles, -(C1-4 alkylene)-O-(C1-4 alkylene)-, -(C1-4 alkylene)-S-(C1-4 alkylene)-, -(C1-4 alkylene)-NR8-(C1-4 alkylene)-, -(C1-8 alkylene)-(Cyc2)- or -(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)-, and other symbols have the same meanings as described above), can be obtained by reductive amination of the above compounds of the formula (II-1)

(where all the symbols have the same meanings as described above), and the compounds of formula (VIII-3)

(where D2"represents a C1-7 alkylene, C2-7 albaniles, -(C1-3 alkylene)-O-(C1-4 alkylene)-, -(C1-3 alkylene)-S-(C1-4 alkylene)-, -(C1-3 alkylene)-NR8-(C1-4 alkylene)-, -(C1-7 alkylene)-(Cyc2)- or -(C1-3 alkylene)-(Cyc2)-(C1-4 alkylene)-, and other symbols have the same meanings as described above), if necessary with subsequent UDA is the group of protective groups.

The reaction of reductive amination is a well known reaction. For example, this reaction can be performed in an organic solvent (e.g. methanol, ethanol) in the presence of a reducing agent (for example, cyanoborohydride sodium, sodium borohydride, triacetoxyborohydride sodium) and, if necessary, in the presence of acid (e.g. acetic acid, hydrogen chloride) at temperatures from -20 to 60°C.

The removal of the protective group may be carried out by the methods described above.

(6) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A1and D1is-CH2-NR6-, i.e. the compound of formula (IA-6)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound represented by formula (IA-6), can be obtained by reacting the compounds of formula (X)

(where all the symbols have the same meanings as described above), with the above-mentioned compound of the formula (VIII-1)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group, or by reductive amination of compounds of formula(XI)

(where all the symbols have the same meanings as described above), the above compound of formula (VIII-2)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

The reaction of interaction of the compounds of formula (X) and the compounds of formula (VIII-1) can be carried out in the same manner as described above, the reaction of interaction of the compounds of formula (IX) with the compound of the formula (VIII-2).

The reaction of interaction of the compounds of formula (XI) with the compound of the formula (VIII-2) can be carried out in the same manner as described above, the reaction of interaction of the compounds of formula (II-1) with the compound of the formula (VIII-3).

The removal of the protective group may be carried out by the methods described above.

(7) Among the compounds represented by formula (I), a compound in which A is A1and D1is-NR6C(O)NR7-, i.e. the compound (IA-7)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound represented by formula (IA-7), can be obtained by reacting the above compound of the formula (II-1)

(where all the symbols have the same meanings, ka is described above), with the compound of the formula (XII)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

This reaction is known. It can be carried out in an organic solvent (e.g. tetrahydrofuran, methylene chloride, diethyl ether) at a temperature of from 0 to 100°C.

The removal of the protective group may be carried out by the methods described above.

(8) Among the compounds represented by formula (I), a compound in which A is A1and D1is-NR6C(S)NR7-, i.e. the compound of formula (IA-8)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound represented by formula (IA-8), can be obtained by reacting the above compound of the formula (II-1)

(where all the symbols have the same meanings as described above) with the compound of the formula (XIII)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

This reaction is known. It can be carried out in an organic solvent (tetrahydrofuran, methylene chloride, diethylamine) at a temperature of from 0 to 100° C.

The removal of the protective group can be performed by methods described above.

(9) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A1and D1is-NR6C(O)O-, i.e. the compound of formula (IA-9)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound represented by formula (IA-9), can be obtained by the interaction of the above compounds of formula (II-1)

(where all the symbols have the same meanings as described above) with the compound of the formula (XIV)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

This reaction is known. It can be carried out in an organic solvent (e.g. tetrahydrofuran, methylene chloride, diethyl ether) at a temperature of from -78 to 40°C.

The removal of the protective group may be carried out by the methods described above.

(10) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A1and D1is-NR6C(S), i.e. the compound of formula (IA-10)

where all symbols have the same meanings, as described above) can be obtained in the following way.

The compound represented by formula (IA-10), can be obtained by thiocarbanilide the compounds of formula (XV)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

This reaction is known. It can be carried out in an organic solvent (e.g. dioxane, benzene, toluene, xylene, tetrahydrofuran) using reagent Lawesson (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide) at a temperature of from 20 to 150°C.

The removal of the protective group may be carried out by the methods described above.

(11) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A1and D1is-NR6C(=NR7)-, i.e. the compound of formula (IA-11)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound of formula (IA-11) can be obtained by the interaction of the above compounds of formula (II-1)

(where all the symbols have the same meanings as described above) with the compound of the formula (XVI)

(where R 34is C1-4 alkyl, and other symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

This reaction is known. For example, it can be carried out in an organic solvent (e.g. methanol, ethanol) at a temperature of from 0 to 50°C.

The removal of the protective group may be carried out by the methods described above.

(12) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A1and D3represents-NR9R10or ring heteroatom, represented

(among Cyc2 ring with a heteroatom is a ring having at least one nitrogen atom, which binds to D2), i.e. the compound of formula (IA-12)

(where D3-2is-NR9R10or ring heteroatom, represented

(among Cyc2 ring with a heteroatom is a ring having at least one nitrogen atom, which binds to D2and other symbols have the same meanings as described above) can be obtained in the following way.

The compound represented by formula (IA-12), can be obtained by the coupling of compounds of formula (XVII)

(where all the symbols have the same meanings as described above) with the compound of the formula (XVIII)

(where all the symbols have the same meanings as described above) or a compound of formula (XIX)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

The interaction of the compounds of formula (XVII) with the compound of the formula (XVIII) or (XIX) may be carried out in the same way, which carried out the above-described interaction of the compounds of formula (IX) with the compound of the formula (VIII-2).

The removal of the protective group may be carried out by the methods described above.

Among the compounds according to the present invention, represented by formula (I), a compound in which A is A1and E2is-C(O)NR24, i.e. the compound of formula (IB-1)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound of the formula (IB-1) can be obtained by amidation of the compounds of formula (XX)

(where all the symbols have the same meanings as described above) and compounds of formula (XXI)

(where E4-1is E4. Provided that the hydroxyl, the Mino or carboxyl in the group, presents E4-1may be protected, if necessary. Other symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

The amidation and the removal of the protective group may be carried out by the methods described above.

(14) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A2and E2is-NR24C(O)-, i.e. the compound of formula (IB-2)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound of the formula (IB-2) can be obtained by amidation reaction of compounds of formula (XXII)

(where all the symbols have the same meanings as described above) and compounds of formula (XXIII)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

The amidation and the removal of the protective group may be carried out by the methods described above.

(15) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A2and E2is-NR24-, i.e. the compound of formula (IB-3)

(where in the e symbols have the same meanings, as described above) can be obtained in the following way.

The compound of the formula (IB-3) can be obtained by reacting the compounds of formula (XXIV)

(where all the symbols have the same meanings as described above) with the above compound of formula (XXI)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

The interaction of the compounds of formula (XXIV) and the compounds of formula (XXI) can be carried out in the same way, which was carried out the above-described interaction of the compounds of formula (IX) and compounds of formula (VIII-2).

The removal of the protective group may be carried out by the methods described above.

(16) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A2and E2is-C(O)O-, i.e. the compound of formula (IB-4)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound of the formula (IB-4) can be obtained by esterification of compounds of formula (XX)

(where all the symbols have the same meanings as described above) of the compound of formula (XXV)

(the de all symbols have the same meanings, as described above, if necessary, followed by removal of the protective group.

The esterification and removal of the protective group can be carried out by the methods described above.

(17) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A2and E2is-S-, i.e. the compound of formula (IB-5)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound of the formula (IB-5) can be obtained by reacting the compounds of formula (XXVI)

(where all the symbols have the same meanings as described above) with the compound of the formula (XXVII)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

This reaction is known. For example, it can be carried out in an inert organic solvent (e.g. dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile) in the presence or absence of a base (e.g. triethylamine, pyridine) at a temperature of from 0 to 100°C.

The removal of the protective group may be carried out by the methods described above.

(18) Among the compounds which s according to the present invention, represented by formula (I), a compound in which A is A2and E4is-NR25R26or ring heteroatom, represented

(a ring is a ring heteroatom containing at least one nitrogen atom (the nitrogen atom binds to E3in Cyc5), i.e. the compound of formula (IB-6)

(where E4-2is-NR25R26or ring heteroatom, represented

(a ring is a ring heteroatom containing at least one nitrogen atom (the nitrogen atom binds to E3in Cyc5), and other symbols have the same meanings as described above), can be obtained in the following way.

The compound of the formula (IB-6) can be obtained by reacting the compounds of formula (XXVIII)

(where all the symbols have the same meanings as described above) with the compound of the formula (XXIX)

(where all the symbols have the same meanings as described above) or a compound of the formula (XXX)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

The interaction of the compounds of formula (XXVIII) with a compound of formula (XXIX) or the (XXX) can be carried out in the same way, which was made of the above described interaction of the compounds of formula (IX) and compounds of formula (VIII-2).

The removal of the protective group may be carried out by the methods described above.

(19) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A3, i.e. the compound of formula (IC-1)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound of formula (IC-1) can be obtained by reacting the compounds of formula (XXXI)

(where G1-1is a bond or C1-7 alkylene, Cyc1' and G2-1are Cyc1 and G2respectively. Provided that the amino group represented by Cyc1, and hydroxy and amino group represented by G2-1may be protected, if necessary. Other symbols have the same meanings as described above) with hydrazine or its salt (for example, hydride, chloride), if necessary, followed by removal of the protective group.

This reaction is known. For example, it can be carried out in an organic solvent (e.g. methanol, ethanol, propanol, isopropanol, butanol, acetic acid, tetrahydrofuran) at a temperature of from 50°C to a temperature of education phlegmy.

In addition, among the compounds according to the present invention, represented by formula (IC-1), a compound in which Cyc1 is a ring heteroatom, represented

(a ring is a ring heteroatom containing at least one nitrogen atom (the nitrogen atom binds to G1in Cyc1), i.e. the compound of formula (IC-1-1)

(where

is a ring heteroatom containing at least one nitrogen atom (the nitrogen atom binds to G1in Cyc1, and other symbols have the same meanings as described above) can be obtained in the following way.

The compound of formula (IC-1-1) can be obtained by reacting the compounds of formula (XXXII)

(where all the symbols have the same meanings as described above) with the compound of the formula (XXXIII)

(where all the symbols have the same meanings as described above), if necessary, followed by removal of the protective group.

The interaction of the compounds of formula (XXXII) and the compounds of formula (XXXIII) can be carried out in the same way, which was held on the above-described interaction of the compounds of formula (IX) and compounds of formula (VIII-2).

The removal of the protective group can be the t to be carried out by methods above.

(20) Among the compounds according to the present invention, represented by formula (I), a compound in which A is A4or A5, i.e. the compound of formula (ID-1)

(where A6is A4or A5and other symbols have the same meanings as described above) can be obtained by the following methods a) or b).

a) a Compound of formula (ID-1) can be obtained by reacting the compounds of formula (XXXIV-1)

(where R35is C1-8 alkyl and A6-1is A6. Provided that the hydroxy-group or amino group in the group represented by A6-1may be protected, if necessary. Other symbols have the same meanings as described above) or the compounds of formula (XXXIV-2)

(where all the symbols have the same meanings as described above) with hydrazine or its salt (for example, hydride, chloride), if necessary, followed by removal of the protective group.

This reaction is known. For example, it can be carried out in an organic solvent (e.g. methanol, ethanol, propanol, isopropanol, butanol, acetic acid, tetrahydrofuran) at a temperature of from 50°C to a temperature of education phlegmy.

The removal of the protective group may be the wasp is estreno ways, above.

b) Compound of formula (ID-1) can be obtained by reacting the compounds of formula (XXXV)

(where all the symbols have the same meanings as described above) with hydrazine or its salt (for example, hydride, chloride), if necessary, followed by removal of the protective group.

This reaction is known. For example, it can be carried out in an organic solvent (e.g. methanol, ethanol, propanol, isopropanol, butanol, acetic acid, tetrahydrofuran) at a temperature of from 50°C to a temperature of education phlegmy.

The removal of the protective group may be carried out by the methods described above.

In addition, among the compounds of formula (ID-1), the compound in which X is N,

is a single bond, i.e. a compound of formula (ID-1-1)

(where all the symbols have the same meanings as described above) can be obtained in the following way.

The compound of formula (ID-1-1) can be obtained by reacting the compounds of formula (XXXVI)

(where all the symbols have the same meanings as described above) with the compound of the formula (XXVII)

(where R35has the same meaning as described above), if not bhodemon, with the subsequent removal of the protective group.

The reaction can be carried out, for example, in an organic solvent (e.g. toluene, tetrahydrofuran, chloroform, methylene chloride) in the presence or absence of a catalyst (e.g. p-toluenesulfonic acid, pyridine) at a temperature of from 50°C to a temperature of education phlegmy.

The removal of the protective group may be carried out by the methods described above.

Compounds represented by formulas (II), (II-1), (III), (IV), (V), (VI-1), (VI-2), (VII-1), (VII-2), (VIII-1), (VIII-2), (VIII-3), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV-1), (XXXIV-2), (XXXV), (XXXVI) and (XXXVII)are known compounds or can be obtained in known the methods described in the examples.

For example, the compounds of formula (II), (II-1), (V), (VI-1), (VI-2), (IX), (X), (XI), (XX), (XXII), (XXIV), (XXVI), (XXXI), (XXXIV-1), (XXXIV-2), (XXXV) and (XXXVI) can be obtained, shown in reaction schemes 1, 2, 3 and 4.

In each reaction scheme, R36is-other6, -CH2-Other6, -OH, -CH2-OH, -CH2-R33or a halogen atom. The condition of the reactions is that the hydroxy-group and the amino group in the group represented by R36may be protected, if necessary. R37represents a protective group of amino group, R38is-other6, -CH2-NHRsup> 6, -OH, -CH2-OH, -CH2-R33or a halogen atom, BOP is benzotriazol-1 yloxy-Tris(dimethylamino)fosfodiesterasa, Me is stands, Et is ethyl, E1-1is a bond or C1-3 alkylene, Ph is phenyl, TBAF is tetrabutylammonium, TMSN3is trimethylsilylmethyl, R39is COOH, -other24, a halogen atom or-SCOCH3. The condition of the reaction is that the amino group or carboxypropyl in the group represented by R39may be protected, if necessary. R40is COOH, -other24, a halogen atom or-SCOCH3and other symbols have the same meanings as described above. For any specialist could understand that could be used compounds represented by the formula (XXXIX) and (XXXXXV), where chlorine is replaced by bromine.

Reaction scheme 1

Reaction scheme 2

In the reaction schemes 1, 2, 3 and 4 compounds used as starting materials are known compounds or can be easily obtained by known methods.

When performing each described in the text of the reaction, the reaction product can be purified normal is a means of purification, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or acid magnesium, washing and recrystallization. The treatment can be carried out when carrying out each reaction or after the completion of several reactions.

Pharmacological activity:

The following experimental data confirmed that the compounds according to the present invention of formula (I) exhibit inhibitory activity against the polymerase PARP.

1) Enzymatic analysis of in vitro

Methods

The following procedure was performed in 96-well-plate at room temperature. In the final volume of 80 µl reaction mixture contained each 10 μl of 500 mm Tris/HCl (pH 8.0, WAKO), 100 mm MgCl2, 50 mm dithiothreitol (Sigma), 1 mg/ml activated DNA, and 1 mm NAD (containing3H-NAD). Test the connection in the amount of 10 μl was added to the reaction mixture and the reaction was started by adding 10 µl of 0.1 U/μl of PARP (TREVIGEN). The reaction was stopped after 10 minutes by adding 100 μl of 20% trichloroacetic acid. Poly(ADP-ribose), which is the reaction product was collected on a glass fiber filter (GF/C, PACKARD). Radioactivity was measured by a counter (PACKARD). Inhibitory activity connected what I was expressed as the concentration of inhibitor, producing 50% inhibition, calculated from 100% activity control (distilled water). The results are presented in table 91.

Table 91
Example No.IC50(µm)
6(9)0,61
11(4)0,10
30(4)0,29

2) Model of ischemic-reperfusion injury (brain and heart)

Model of cerebral ischemia and heart due to damage during reperfusion was obtained according to procedures described previously (Jpn. J. Stroke,8, 1 (1986), Stroke,27, 1624-1628 (1996) andEur. J. Pharmacol.,270, 45 (1994)). Compounds according to the present invention proved to be effective against these diseases.

Toxicity:

The toxicity of the compounds according to the present invention, represented by formula (I)is very low (for example, the rats of the compounds according to the present invention, these compounds did not affect the blood circulation, studied in characteristics such as blood pressure, electrocardiogram and heart rate), and therefore, the connection can be considered as safe for pharmaceutical use.

INDUSTRIAL APPLICATION is

Application for the pharmaceutical industry:

Because the connection according to the present invention, represented by formula (I), exhibits inhibitory activity against the polymerase PARP, it is suitable for the prophylaxis and/or treatment of ischemic diseases (cerebral infarction, myocardial infarction, injury due to reperfusion and post-operative trauma etc), inflammatory diseases (inflammatory bowel disease, multiple sclerosis, arthritis or lesions of the lung and so on), neurodegenerative disorders (extrapyramidal disease, Parkinson's disease, Alzheimer's disease, muscular dystrophy, or spinal stenosis of the lumbar spine and so on), glaucoma, diabetes, diabetic complications, stroke, head injury, spinal cord injury, renal failure, or hyperalgesia, etc. in Addition, the connection applicable as a drug against retroviruses, such as drug against HIV, sensitizing substances for cancer treatment or immunosuppressant.

The compound represented by formula (I)or its pharmaceutically acceptable salt may be introduced in combination with other pharmaceutical preparations, in order to achieve the following results:

1) to Supplement or enhance the preventive and/or therapeutic on the op perate connection which combine;

2) to improve the dynamic parameters/suction connection properties, which combine, and reduce the dose of the compound; and/or

to eliminate the side effect of compounds that combine.

The compound represented by formula (I), and other pharmaceutical preparations may be in the form of a composition containing the components included in one medication, or can be entered as separate drugs. When these pharmaceutical preparations are administered as separate preparations, they can be introduced simultaneously or at different times. In the latter case, the compound represented by formula (I)may be introduced prior to the introduction of other pharmaceuticals. Alternatively, other pharmaceutical drugs can be introduced before the introduction of the compounds represented by formula (I). The way of the introduction of these pharmaceutical preparations may be the same or different.

Diseases to which the above-mentioned combination of drugs have a preventive and/or therapeutic effect, is not specifically restricted, but they can be such for which the preventive and/or therapeutic effect of the compound represented by formula (I), supplemented and/or enhanced.

Examples of other pharmaceutical drugs used for the implementing and/or enhancing the preventive and/or therapeutic activity of a compound, represented by formula (I)used for ischemic diseases, include drug, eliminating radicals, astrocyte modulator, antagonist of N-methyl-D-aspartate (NMDA)antagonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), antithrombotic agent, thrombolytic agent, immunosuppressive agent, an inhibitor of adhesion molecules with cells, the inhibitor of nitric oxide synthase (NOS), neurotrophic factor and an inhibitor of interleukin-8 and so on

Examples of other pharmaceutical drugs to complement and/or enhance the preventive and/or therapeutic activity of a compound represented by the formula (I)used in the case of spinal stenosis of the lumbar spine include an inhibitor of nitric oxide synthase (NOS)inhibitor alsoreported (AR), a drug absorber radicals, the antagonist of N-methyl-D-aspartate (NDMA), an antagonist of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), neurotrophic factor and an inhibitor of interleukin-8 and so on

Examples of the drug, eliminating radicals include, for example, edaravone and ebselen (DR-3305), etc.

Examples of the modulator of astrocytes include, for example, ONO-2506, etc.

Examples of antithrombotic agents include, for example, ozagrel sodium, argatroban and aspirin etc.

Examples of thrombolytic cf is DSTV include, for example, plasminogen activator tissue type (t-PA), urokinase and heparin, etc.

Examples of immunosuppressive means include, for example, cyclosporine a, cyclophosphamide and tacrolimus, etc.

Examples of the NOS inhibitor include, for example, L-NMMA and ONO-1714, etc.

Examples of the inhibitor of AR include, for example, epalrestat, zenarestat, fidarestat, zopolrestat and AS-3201, etc.

The weight ratio between the compound represented by formula (I), and other pharmaceutical drugs is not specifically limited.

Arbitrarily in combination can be entered two or more other pharmaceutical products.

Examples of other pharmaceutical drugs used to complement and/or enhance the preventive and/or therapeutic effect of the compound represented by formula (I)include not only those connections that are identified up to the present time, but also such compounds, which are found on the basis of the above mechanism.

Compounds according to the present invention, represented by formula (I)or its pharmaceutically acceptable salts, or compounds represented by formula (I), in combination with other pharmaceutical drugs are usually injected man systemically or topically, orally or parenterally.

Dose that should be entered, determined the t depending for example, the age, body weight, symptom, the desired therapeutic effect, the route of administration and duration of treatment. For an adult dose usually ranges from 1 to 1000 mg, by oral administration, up to several times a day, and from 1 to 100 mg by parenteral administration (preferably intravenous administration), up to several times per day, or continuous introduction from 1 to 24 hours a day through a vein.

As mentioned above, the doses depend on various conditions. Therefore, there are cases in which the use of doses that are below or above the ranges of doses given in the text above.

The compound represented by formula (I)or its pharmaceutically acceptable salt, or a compound represented by the formula (I), combined with pharmaceutical drugs as concomitant drugs may be introduced in the form of, for example, solid compositions, liquid compositions or other compositions intended for oral administration, or injections, drugs for external use or suppositories intended for parenteral administration.

Solid compositions for oral administration include compact tablets, pills, capsules, powders and granules.

Capsules include hard capsules and soft capsules.

In such solid the compositions, one or more active substances may be mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or metasilicates magnesium. The composition may contain, in accordance with a customary method, additives other than the inert diluent, such as lubricating agents, such as magnesium stearate, dezintegriruetsja reagents such as calcium salt glycolate, cellulose, a stabilizer such as lactose, and solubilizers reagent, such as glutamic acid or aspartic acid. Tablets or pills may be coated with a layer of a substance soluble in the stomach or small intestine, such as sucrose, gelatin, hydroxypropylcellulose or phthalate of hydroxypropylmethylcellulose, or two or more layers, if necessary. In addition, capsules, made from a substance that is absorbed into the body, such as gelatin, is included in the scope of the invention.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups and elixirs, etc. Such liquid compositions contain one or more active substances and is generally used inert diluent(s) (for example, purified water or ethanol)dissolving the active substance(s). is oppozitsii can contain, in addition to the inert diluent, adjuvant, such as moisturizers or suspendresume agents, sweeteners, flavorings, aromatizers and antiseptic.

Other compositions for oral administration include liquids for spraying, which contain one or more active substances and are known for this area by the way. The composition may contain, in addition to the inert diluent, a stabilizer such as sodium bisulfite and isotonic buffer such as sodium chloride, sodium citrate or citric acid. A method of manufacturing sprays are described, for example, in U.S. patent No. 2868691 and 3095355.

In the present invention, the injections for parenteral administration include sterile aqueous and/or nonaqueous solutions, suspensions and emulsions. Aqueous solutions or suspensions include, for example, distilled water for injection and physiological saline. Non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohol such as ethanol, and Polysorbate 80 (trade name). In addition, sterile aqueous and non-aqueous solutions, suspensions and emulsions can be used in combination. Such compositions can optionally contain adjuvants, such as antiseptic, HC is arnitel, emulsifier, dispersing agent, a stabilizer (such as lactose) and solubilizers reagent (such as glutamic acid and aspartic acid). They are sterilized by filtration through a filter traps bacteria, using the sterilizer or by irradiation. In addition, after preparation of sterile solid compositions, for example, freeze-dried product can be dissolved in sterilized or sterile distilled water for injection or other sterile solvent prior to use.

Other compositions for parenteral administration include liquids for external use, ointments, percutaneous liniments, suppositories for rectal and pessaries for vaginal use, which contain one or more active substances and can be made by methods known in this field.

The BEST WAY of carrying out the INVENTION

The present invention reveal detail below on the basis of the reference examples and examples, but the present invention is not limited to these examples.

The solvents given in parentheses indicate manifesting or eluting solvents, and the ratio of the used solvent in the chromatographic separation or TLC are given by volume. The solvents given in parentheses in the NMR data indicate the solvent for measurement.

Abbreviations in the NMR data

br - Shire.

q - square

quin. Quain.

sextet - sextet

sex - sec.

Reference example 1

3-(3-AMINOPHENYL)-3-methoxy-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-he

To a solution of anhydride 3,4,5,6-tetrahydrophthalic acid (3.04 from g) in tetrahydrofuran (40,0 ml) was added a solution of 3-(bis(trimethylsilyl)amino)formanilide in tetrahydrofuran (1 M, 20,0 ml) at -78°C. the Mixture was stirred for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was stirred at room temperature for 30 minutes. Anhydrous magnesium sulfate was added to the reaction mixture, which was then filtered. The filtrate was concentrated to obtain an oily product. Thionyl chloride (5,20 ml) was added dropwise to methanol (20,0 ml) at -10°and then the solution was stirred at 0°C for 15 minutes. To the solution was added to the oily product obtained previously, and the solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated. The obtained residue was dissolved in methylene chloride (20 ml) and to the solution was added triethylamine (2,79 ml) at 0°C. To the reaction mixture was added water, then was extracted with methylene chloride. The extract was washed with water, saturated aqueous sodium bicarbonate and saturated saline solution posledovatel is but was dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (ethyl acetate: hexane = 3:7) to obtain specified in the connection header (2,56 g)having the following physical characteristics.

NMR(DMSO-d6):7,03(t, J = 7.8 Hz, 1H), 6,60-6,47(m, 3H), to 5.21(Sirs, 2H), 3,20(s, 3H), 2,17-to 1.60(m, 8H).

Example 1

4-(3-AMINOPHENYL)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Solution connection, the receipt of which is described in reference example 1 (2,56 g), and hydrazine monohydrate (503 mg) in ethanol (30,0 ml) was boiled under reflux for 18 hours. After cooling the mixture to room temperature, the resulting crystals were collected by filtration. They were washed with hexane and dried under reduced pressure. To a suspension of the obtained solid (32,0 mg) in methanol (1,00 ml) was added dropwise 4n. hydrogen chloride in dioxane (0.10 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The obtained crystals were dried under reduced pressure to obtain compound according to the present invention (36.2 mg)having the following physical characteristics. In addition, the compound was converted to the methanesulfonate of the compound in the usual way.

Hydrochloride:

TLC: Rf of 0.27 (ethyl acetate: hexane = 2:1);

NMR(DMSO-d6): to 12.95(s, 1H), 9,40(Sirs, 3H), 7,47(t, J = 8,1 Hz, 1H), 7,32-7,26(m, 3H), 2,43-to 1.59(m, 8H).

Methanesulfonate:

TLC: Rf of 0.55 (methanol: methylene chloride = 1:9);

NMR(DMSO-d6):12,94(s, 1H), 8,31(s, 1H), 7,44(t, J = 7.8 Hz, 1H), 7,26-7,21(m, 2H), 7,18(s, 1H), 2,48-of 2.34(m, 4H), 2,31(s, 3H), 1,71 is 1.60(m, 4H).

Example 2 - example 2(2)

By the same procedure described in reference example 1→example 1, if necessary, the following compounds according to the present invention were obtained by transformation into the corresponding salts in the usual way using anhydride 3,4,5,6-tetrahydrophthalic acid in tetrahydrofuran or an appropriate derivative, and 3-(bis(trimethylsilyl)amino)formanilide or a corresponding derivative.

Example 2

Methanesulfonate of 4-(3-AMINOPHENYL)-4A,5,8,8A-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.50 (a methanol: methylene chloride = 1:9);

NMR(CD3OD):7,66-7,58(m, 2H), 7,51-7,44(m, 2H), of 5.82(m, 1H), 5,73(m, 1H), 3,21(m, 1H), 2,74(s, 3H), 2,72-2,47(m, 3H), and 2.27(m, 1H), 1,92(m, 1H).

Example 2(1)

Methanesulfonate of 4-(3-AMINOPHENYL)-2,5,6,7,8,9-hexahydro-1H-cyclohepta[d]pyridazin-1-it

TLC: Rf of 0.47 (chloroform: methanol = 9:1);

NMR(DMSO-d6):13,01(Sirs, 1H), 7,45(m, 1H), 7,20-to 7.09(m, 3H), 2,86 is 2.80(m, 2H), 2,58-2,52(m, 2H), 2,31(s, 3H), 1,86 to 1.76(m, 2H), 1,58 of 1.46(m, 4H).

Example 2(2)

4-(3-nitro-4-chlorophenyl)-5,6,7,8-tetrahydrophthalic the Jn-1(2H)-he

TLC: Rf is 0.24 (ethyl acetate: hexane = 1:1);

NMR(DMSO-d6):13,07(s, 1H), 8,17(d, J = 1.5 Hz, 1H), 7,86(d, J = 8,4 Hz, 1H), 7,80(DD, J = 8,4, 1.5 Hz, 1H), 2,48-of 2.38(m, 4H), 1,71 is 1.58(m, 4H).

Reference example 2

Ethyl ester of 4-(3-nitrobenzoyl)thiomorpholine-3-carboxylic acid

To a solution of ethyl ester thiomorpholine-3-icarbonell acid (of 5.05 g) in methylene chloride (120 ml) was added dimethylaminopyridine (352 mg), triethylamine (4.9 ml) and 3-nitrobenzanthrone (5,62 g) in a bath with ice and then the mixture was stirred at room temperature overnight. To the reaction mixture was added 2n. hydrochloric acid, the reaction mixture was extracted with methylene chloride. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane: ethyl acetate = 2:1) to obtain specified in the connection header (5,91 g)having the following physical characteristics.

TLC: Rf of 0.23 (hexane: ethyl acetate = 2:1);

NMR(CDCl3):8,32-8,30(m, 2H), 7,79 to 7.62(m, 2H), 5,78 and 4.57(m, 1H), 4,98-4,93 and 3,84-with 3.79(m, 1H), 4,23(sq, J = 7.2 Hz, 2H), 3,71-3,63 and 3,28-3,02 and 2,91-2,70(m, 4H), 2,61-2.57 m and 2.43-2,39(m, 1H), 1,36(t, J = 7.2 Hz, 3H).

Reference example 3

Ethyl ester of 4-((3-nitrophenyl)carbonothioyl)thiomorpholine-3-carboxylic acid

To a solution of the is to be placed, the receipt of which is described in the reference example 2 (5,88 g) in toluene (90 ml) was added a reagent Lawesson (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide) (8,62 g) and the mixture is boiled under reflux for 2 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was purified column chromatography on silica gel (hexane: ethyl acetate = 4:1) to obtain specified in the connection header (6,16 g)having the following physical characteristics.

TLC: Rf of 0.27 (hexane: ethyl acetate = 4:1);

NMR(CDCl3):8,24-8,17(m, 2H), 7,66-of 7.55(m, 2H), of 6.96-6,93 and 4,88-a 4.86(m, 1H), 5,96-5,90 and 4.13-4,06(m, 1H), 4,39-4,32(m, 2H), 3,83-to 3.73 and 3,59-to 3.50(m, 1H), 3,37-3.30, and 3,12-of 3.07(m, 1H), 3,20-3.14, and to 3.02 vs. 2.94(m, 1H), 2,94-2,88 and 2,80-2,71(m, 1H), 2,72-2,64 and 2,49-to 2.41(m, 1H), 1,40 of 1.28(m, 3H).

Example 3

4-(3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazine[4,3-d][1,2,4]triazine-1(2H)-he

To a solution of compounds, which are described in reference example 3, (4,78 g) in ethanol (50 ml) was added hydrazine monohydrate (2.0 ml) and the mixture is boiled under reflux during the night. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration to obtain compound according to the present invention (2.30 g)having the following physical characteristics.

TLC: Rf of 0.45 (chloroform: methanol = 19:1)

NMR(DMSO-d6):10,65(s, 1H), 8,30-of 8.27(m, 2H), 7,89-7,86(m, 1H), 7,76-of 7.70(m, 1H), 4,24(DD, J = 10,8, 2.7 Hz, 1H), 3,49(dt, J = 13,8, 2.7 Hz, 1H), 3,17-is 3.08(m, 1H), 2,97(DD, J = 13,2, and 10.8 Hz, 1H), 2,88-2,82(m, 1H), 2,71(dt, J = of 12.6 and 2.7 Hz, 1H), 2,32-of 2.27(m, 1H).

Example 4 - example 4(32)

By the same procedure described in reference example 2,→reference example 3,→example 3 the following compounds according to the present invention were obtained using ethyl ether thiomorpholine-3-icarbonell acid or a corresponding derivative, and 3-nitrobenzylamine or a corresponding derivative.

Example 4

4-(3-nitrophenyl)-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazine-1(6N)-he

TLC: Rf of 0.50 (chloroform: methanol = 9:1);

NMR(DMSO-d6):10,48(s, 1H), 8,28(d, J = 8,1 Hz, 1H), they were 8.22(s, 1H), 7,86(d, J = 8,1 Hz, 1H), 7,73(t, J= 8,1 Hz, 1H), 3,91(m, 1H), 3,17(m, 1H), 2,87(m, 1H), 2,10(m, 1H), to 1.86(m, 1H), USD 1.43(m, 4H).

Example 4(1)

4-phenyl-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.18 (hexane: ethyl acetate = 2:1);

NMR(DMSO-d6):10,53(s, 1H), 7,50-7,38(m, 5H), to 4.23(DD, J = 9,6, 3.6 Hz, 1H), 3,52(m, 1H), is 3.08(m, 1H), 2,94 is 2.80(m, 2H), 2,68(m, 1H), 2,30(d, J = 10.5 Hz, 1H).

Example 4(2)

(9aR)-4-(3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.18 (hexane: ethyl acetate = 1:1);

NMR(CDCl3):8,32(DD, = 8,1, 1.5 Hz, 1H), of 8.27(s, 1H), 8,14(width, 1H), 7,72(d, J = 8,1 Hz, lH),7,66(t, J = 8,1 Hz, 1H), 4,39(DD, J= 10,8, 2.7 Hz, 1H), and 3.72(dt, J= 14,1, 2.7 Hz, 1H), 3,24(m, 1H), 3,13(m, 1H), 2,99(DD, J = 14,1, and 10.8 Hz, 1H), 2,77(m, 1H), 2,32(m, 1H).

[α]D= -71,9 (s, 0,16, Meon)

Example 4(3)

4-(4-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0.28 in (ethyl acetate: hexane = 1:1);

NMR(DMSO-d6):10,69(s, 1H), 8,28(d, J = 8,4 Hz, 2H), 7,73(d, J = 8,4 Hz, 2H), 4.26 deaths(DD, J = 10,2, 3.0 Hz, 1H), 3,48(d, J = 14.4 Hz, 1H), 3,17-to 2.29(m, 5H).

Example 4(4)

4-(3-methoxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf to 0.17 (hexane: ethyl acetate = 1:1);

NMR(DMSO-d6):of 10.50(s, 1H), 7,33(t, J = 8,1 Hz, 1H), 7,00-6,93(m, 3H), 4,20(DD, J = a 10.5, 3.0 Hz, 1H), 3,76(s, 3H), 3,53(dt, J = 13,8, 3.0 Hz, 1H), 3,10-a 3.01(m, 1H), 2,93-2,78(m, 2H) 2,73-2,63(m, 1H), 2,32-of 2.27(m, 1H).

Example 4(5)

4-(4-methoxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.50 (chloroform: methanol = 8:1);

NMR(DMSO-d6):7,40-7,26(m, 2H),? 7.04 baby mortality-6,92(m, 2H), 4,20(DD, J = 9,3, 4,2 Hz, 1H), of 3.77(s, 3H), of 3.57(dt, J = 14,1, 2.7 Hz, 1H), 3,06(m, 1H), 2,94-2,78(m, 2H), 2,68(m, 1H), 2,30(m, 1H).

Example 4(6)

4-(2-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.50 (methylene chloride: methanol = 10:1);

NMR(CDCl3):8,14(width, 1H), 7,21(DDD, J = 8,4, to 7.5, 2.1 Hz, 1H), to 7.09(t, J = 7.5 Hz, 1H), 6,80(TD, J = 7,5, 1.2 Hz, 1H), 6,74(DD, J = 8,4, 1.2 Hz, 1H), 4,35(DD, J = a 10.5, 3.0 Hz, 1H), and 3.72(dt, = 13,8, 3.0 Hz, 1H), 3,14(m, 1H), is 3.08-2,90(m, 2H), and 2.79(m, 1H), 2,21(DD, J = 13,8, 1,2 Hz, lH).

Example 4(7)

4-(3-nitrophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0,27 (methylene chloride: methanol = 20:1);

NMR(DMSO-d6):11,02(Sirs, 1H), 8,32(d, J = 8,1 Hz, 1H), 8,28(s, 1H), 7,92(d, J = 8,1 Hz, 1H), 7,76(t, J= 8,1 Hz, 1H), 6,28(s, 1H), 3,61(m, 2H), and 3.16(m, 2H).

Example 4(8)

4-phenyl-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0,51 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):10,89(s, 1H), 7,45(m, 5H), 6,24(s, 1H), 3,60(m, 2H), 3,14(m, 2H).

Example 4(9)

4-phenyl-7,8,10,10a-tetrahydro-6H-[1,2,4]triazino[5,4-c][1,4]diazepin-1(2H)-he

TLC: Rf of 0.53 (chloroform: methanol = 9:1);

NMR(DMSO-d6):10,57(Sirs, 1H), 7,50-7,40(m, 5H), the 4.29(DD, J = 6,9, and 4.5 Hz, 1H), 3,44-to 3.36(m, 1H), 3,16-3,00(m, 3H), 2,78-2,70(m, 2H), 1,80-of 1.64(m, 1H), 1,55-of 1.40(m, 1H).

Example 4(10)

4-(3-nitrophenyl)-7,8,10,10a-tetrahydro-6H-[1,2,4]triazino[5,4-c][1,4]diazepin-1(2H)-he

TLC: Rf of 0.60 (chloroform: methanol = 9:1).

Example 4(11)

4-(3-dimethylaminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.50 (chloroform: methanol = 8:1);

NMR(DMSO-d6):7,21(DD, J = 8,1, 7.2 Hz, 1H), 6.75 in(m, 1H), 6,72 return of 6.58(m, 2H), 4,20(DD, J = a 10.5, 3.0 Hz, 1H), to 3.58(dt, J = 13,8, 2.7 Hz, 1H), 3.04 from(m, 1H), 2,98 was 2.76 (m, 2H), 2,90(s, 6H), 2,68(m, 1H), 2,30(m, 1H).

Example 4(12)

(8aR)-4-(3-nitrophenyl)-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazine-1(2H)-he

TLC: R 0,39 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):11,07(s, 1H), 8,33(m, 2H), 8,02(d, J = 7.8 Hz, 1H), 7,76(t, J = 7.8 Hz, 1H), 4.53-in(m, 2H), 4,28(m, 1H), 3.46 in(m, 2H).

Example 4(13)

4-(3-amino-5-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.44 (chloroform: methanol = 8:1);

NMR(DMSO-d6):7,41(DD, J = 2.1 a, 2.1 Hz, 1H), 7,32(DD, J = 2,1, 1.2 Hz, 1H), 6,94(DD, J = 2,1, 1.2 Hz, 1H), 6,52(Sirs, 1H), 6,01(Sirs, 2H), 4,23(DD, J = 7,5, 3.0 Hz, 1H), only 3.57(m, 1H), 3,10(m, 1H), 3.00 and was 2.76(m, 2H), 2,68(m, 1H), of 2.33(m, 1H).

Example 4(14)

(9aS)-4-(3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0,51 (methylene chloride: methanol = 10:1).

Example 4(15)

(7R,8aS)-7-benzyloxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0.26 (hexane: ethyl acetate = 1:1);

NMR(DMSO-d6):10,55(s, 1H), 7,50-of 7.24(m, 10H), a 4.53(d, J = 12.3 Hz, 1H), 4,48(d, J = 12.3 Hz, 1H), 4,16(DD, J = 8,7, 7.2 Hz, 1H), 4.09 to a 4.03(m, 1H), 3,54(DD, J = 10,8, 3.0 Hz, lH), 3,44(DD, J= 10,8, and 4.8 Hz, 1H), 2,39-2,31(m, 1H), 2,24-of 2.15(m, 1H).

Example 4(16A)

(7R,8aS)-7-benzyloxy-4-(3-nitrophenyl)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.10 (hexane: ethyl acetate = 1:1);

NMR(DMSO-d6):of 10.73(s, 1H), 8,31-of 8.27(m, 2H), 7,95(dt, J = 7,5, 1.5 Hz, 1H), 7,75-of 7.69(m, 1H), 7,34-of 7.24(m, 5H), 4,53(d, J = 12.0 Hz, 1H), 4,50(d, J = 12.0 Hz, 1H), 4,24-4,19(m, 1H), 4,11-Android 4.04(m, 1H), only 3.57(DD, J = 10,5, 3,0 Hz, 1H), 3,50(DD, J = 10,5, 5,1 Hz, 1H), 2,41 is 2.33(m, 1H), 2,28-2,19(m, 1H).

Example 4(16b)

(7R, 8aS)-7-benzyloxy-4-(3-aminophen the l)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.51 (chloroform: methanol = 9:1);

NMR(DMSO-d6):10,45(s, 1H), 7,34-of 7.24(m, 5H), 7,03(t, J = 7.8 Hz, 1H), 6,72(t, J = 1.8 Hz, 1H), 6,60(DD, J = 7,8, 1.8 Hz, 1H), 5,19(s, 2H), 4,53(d, J = 12.0 Hz, 1H), 4,48(d, J = 12.0 Hz, 1H), 4,14-4,01(m, 2H), 3,54(DD, J = in 10.8, 2.4 Hz, 1H), 3.46 in(DD, J = 10,8, and 4.8 Hz, 1H), 2,38-of 2.30(m, 1H), 2,22 and 2.13(m, 1H).

Example 4(17)

4-phenyl-9,9a-dihydro-2H-[1,3]thiazino[3,4-d][1,2,4]triazine-1(8H)-he

TLC: Rf of 0.55 (chloroform: methanol = 9:1);

NMR(DMSO-d6):10,55(Sirs, 1H), 7,53-the 7.43(m, 5H), 4,43(d, J = a 13.8 Hz, 1H), 4,20(DD, J = 12,0, 2.4 Hz, 1H), 4,06(DD, J = 13,8, 2.4 Hz, 1H), 3,21(m, 1H), 2,88(m, 1H), 2,07(m, 1H), 1,80(m, 1H).

Example 4(18)

4-(3-nitrophenyl)-9,9a-dihydro-2H-[1,3]thiazino[3,4-d][1,2,4]triazine-1(8H)-he

TLC: Rf of 0.55 (chloroform: methanol = 9:1);

NMR(DMSO-d6):10,70(Sirs, 1H), 8,40(m, 1H), 8,33(m, 1H), of 7.96(m, 1H), to 7.75(m, 1H), 4,48(d, J = 14.1 Hz, 1H), 4,24(DD, J = 12,0, 2.1 Hz, 1H), 4,14(DD, J = 14,1, and 2.1 Hz, 1H), 3,23(m, 1H), 2.91 in(m, 1H), 2,08(m, 1H), 1,86(m, 1H).

Example 4(19)

4-(3-nitro-4-were)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.33 (methylene chloride: methanol = 20:1);

NMR(DMSO-d6):10,97(Sirs, 1H), 8,04(d, J = 1.8 Hz, 1H), of 7.70(DD, J = 7,8, 1.8 Hz, 1H), to 7.59(d, J = 7.8 Hz, 1H), 6,27(s, 1H), 3,61(m, 2H), 3,14(m, 2H), by 2.55(s, 3H).

Example 4(20)

4-(3-cyanophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.20 (hexane: ethyl acetate = 1:1);

NMR(CDCl3):8,10(width, 1H), of 7.75(dt, J = 6,9, 1.8 Hz, 1H), 7,8(m, 1H), 7,62-of 7.55(m, 2H), 4,36(DD, J = 11,1, 2.7 Hz, 1H), 3,69(dt, J = 11,1, 2.7 Hz, 1H), 3,21(DDD, J = 14,1, 12,0, 2.7 Hz, 1H), 3,12(dt, J = 10,8, 2.4 Hz, 1H), 2,96(DD, J = 14,1 and 11.1 Hz, 1H), 2,74(m, 1H), 2,32(DDD, J = 11,1, 4,5 that 2.4 Hz, 1H).

Example 4(21)

4-(3-nitro-4-were)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf is 0.59 (chloroform: methanol = 9:1).

Example 4(22)

4-(3-forfinal)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf to 0.63 (chloroform: methanol = 9:1);

NMR(DMSO-d6):7,56-7,46(m, 1H), was 7.36-7,24(m, 3H), 4,20(DD, J = 10,2, 3.6 Hz, 1H), 3,54-3,44(m, 1H), 3,16-to 3.02(m, 1H), 2,96-2,78(m, 2H), was 2.76-of 2.64(m, 1H), 2,36-of 2.24(m, 1H).

Example 4(23)

4-(3-nitro-5-forfinal)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf to 0.66 (chloroform: methanol = 9:1).

Example 4(24)

4-(2-methyl-5-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf is 0.59 (chloroform: methanol = 9:1).

Example 4(25)

4-(4-nitrophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.54 (chloroform: methanol = 9:1);

NMR(DMSO-d6):11,03(Sirs, 1H), 8,32 is 8.25(m, 2H), to 7.77-of 7.70(m, 2H), 6,29(s, 1H), 3,64-of 3.54(m, 2H), 3,20-of 3.12(m, 2H).

Example 4(26)

4-(2-methyl-3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf is 0.49 (chloroform: methanol = 9:1);

NMR(CDCl3):8,64(s, 1H), to 7.93(DD, J = 7,8, 1.5 Hz, 1H), 7,50-7,40(m, 2H), 4,34(DD, J = 11,1, 2.4 Hz, 1H), 3,41(dt, J = 11,1, 2.7 Hz, 1H), 3,24-3,00(m, 2H), 2.91 in(DD, J = 135, of 11.1 Hz, 1H), 2,70-to 2.40(m, 4H), 2,30-of 2.26(m, 1H).

Example 4(27)

4-(3-methoxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.18 (hexane: ethyl acetate = 2:1);

NMR(DMSO-d6):10,85(s, 1H), 7,37(t, J = 7,6 Hz, 1H), 7,08-of 6.96(m, 3H), 6,23(s, 1H), of 3.77(s, 3H), 3,64 of 3.56(m, 2H), 3,16-is 3.08(m, 2H).

Example 4(28)

4-(3-nitro-4-methoxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.18 (hexane: ethyl acetate = 1:1);

NMR(DMSO-d6):10,92(s, 1H), 7,95(d, J = 2.1 Hz, 1H), 7,73(DD, J = 8,7, and 2.1 Hz, 1H), 7,42(d, J = 8.7 Hz, 1H), and 6.25(s, 1H), 3.96 points(s, 3H), 3,65-of 3.60(m, 2H), 3,20-3,15(m, 2H).

Example 4(29)

4-benzyl-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.37 (methylene chloride: methanol = 10:1);

NMR(CDCl3):8,03(width, 1H), 7,39-of 7.24(m, 5H), 4,17(DD, J = 10,8, 2.7 Hz, 1H), 3,93(dt, J = 14,4, 2.7 Hz, 1H), 3,06(DDD, J = 14,4, 12,0, 2.7 Hz, 1H), 2,89(dt, J = 13,5, 2.7 Hz, 1H), 2,78(DD, J = 13,5, and 10.8 Hz, 1H), of 2.21(DDD, J = 14,4, 12,0, 2.7 Hz, 1H), to 2.06(DCV, J = 14,4, 2.7 Hz, 1H).

Example 4(30)

4-3-nitrobenzyl-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.60 (chloroform: methanol = 9:1);

NMR(CDCl3):8,61(s, 1H), 8,20-8,10(m, 2H), of 7.64-rate of 7.54(m, 2H), to 6.39(s, 1H), 3,82(s, 2H), 3,80-3,74(m, 2H), was 2.76-of 2.72(m, 2H).

Example 4(31)

4-phenyl-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazine-1(6H)-he

TLC: Rf of 0.67 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):10,34(s, 1H), 7,44-7,34(m, 5H), 3,86(DD, J = 1,1, 3.0 Hz, 1H), 3,20(dt, J = 13,2, and 2.1 Hz, 1H), 2,77(TD, J = 13,2, and 2.1 Hz, 1H), 2.06 to(m, 1H), of 1.85(m, 1H), 1,49-of 1.26(m, 4H).

Example 4(32)

5-phenyl-2,3-dihydro-7H-[1,3]thiazolo[3,2-d][1,2,4]triazine-8(8aH)-he

TLC: Rf of 0.30 (ethyl acetate: hexane = 1:1);

NMR(DMCO-d6):10,99(s, 1H), of 7.48(m, 5H), of 5.39(s, 1H), 3,97(DDD, J = 12,0, of 6.3, 1.2 Hz, 1H), 3,35-of 3.25(m, 1H), 2,92(DDD, J = 10,0, of 6.3, 1.2 Hz, 1H), 2,59-2,48(m, 1H).

Example 5

4-(3-nitro-4-hydroxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

The compound obtained in example 4(28), (150 mg) and lithium chloride (59 mg) was dissolved in dimethylformamide (2.0 ml) and the mixture is boiled under reflux for 16 hours. After cooling to room temperature, the reaction mixture was added 1N. hydrochloric acid. The precipitate was collected by filtration. It was dried to obtain compounds according to the present invention (126 mg)having the following physical characteristics.

TLC: Rf to 0.19 (hexane: ethyl acetate = 1:1);

NMR(DMCO-d6):of 11.45(Sirs, 1H), 10,89(s, 1H), 7,92(d, J = 2.4 Hz, 1H), 7,58(DD, J = 9,0, 2.4 Hz, 1H), 7,16(d, J = 9.0 Hz, 1H), 6,24(s, 1H), 3,65-of 3.60(m, 2H), 3,20-3,15(m, 2H).

Example 6

4-(3-AMINOPHENYL)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

To a solution of the compound obtained in example 3 (537 mg) in ethanol (4 ml) was added chloride dihydrate tin (2,07 g) and the mixture is boiled under reflux for 30 minutes. After cooling to room temperature the market, to the reaction mixture were added saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. To a methanol (2 ml) was added to the obtained solid (137 mg) and then to the mixture was added 4n. hydrogen chloride in dioxane (0,26 ml), the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was recrystallized from a mixture solvent (isopropanol: ethanol = 4:1) to give the compounds according to the present invention (144 mg)having the following physical characteristics. In addition, the compound was converted to the methanesulfonate of the compound in the usual way.

Hydrochloride:

TLC: Rf is 0.42 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,90-10,70(width, 1H), 7,51(t, J = 7.8 Hz, 1H), 7,40 and 7.36(m, 3H), 4,25(DD, J = 10,2, 3.0 Hz, 1H), to 3.58-3.49 points(m, 1H), 3,14-of 3.06(m, 1H), 2,96-2,82(m, 2H), 2.77-to to 2.67(m, 1H), 2,34-of 2.30(m, 1H).

Methanesulfonate:

TLC: Rf of 0.36 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,84-10,48 (width, 1H), 7,44 (t, J = 7.8 Hz, 1H), 7,25-to 7.18 (m, 3H), 4,24 (DD, J = 9,9, 3.3 Hz, 1H), 3,56-to 3.49 (m, 1H), 3.15 and was 3.05 (m, 1H), 2.95 and-of 2.81 (m, 2H), 2,75-to 2.65 (m, 1H), 2,33-of 2.30 (m, 4H).

Example 6(1) example 6(19)

By the same procedure as described in example 6, if necessary, the following compounds according infusion is his invention were obtained by transformation into the corresponding salts in the usual way when using compounds obtained in the examples 4, 4(2), 4(3), 4(6), 4(7), 4(10), 4(12), 4(14), 4(13), 4(18), 4(19), 4(21), 4(23)-4(26), 4(28), 4(30) or 5, instead of the compound obtained in example 3.

Example 6(1)

Methanesulfonate of 4-(3-AMINOPHENYL)-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazine-1(6H)-it

TLC: Rf of 0.44 (methanol: methylene chloride = 1:9);

NMR(DMCO-d6):10,65(Sirs, 1H), 7,38(t, J = 7.8 Hz, 1H), 7,13? 7.04 baby mortality(m, 3H), 3,93(m, 1H), 3,26(d, J = 13,2 Hz, 1H), 2,82(m, 1H), 2,31(s, 3H), 2,07(m, 1H), to 1.86(m, 1H), 1,46(m, 4H).

Example 6(2)

(9aR)-4-(3-AMINOPHENYL)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0,27 (methylene chloride: methanol = 10:1);

NMR(DMCO-d6):10,44(s, 1H),? 7.04 baby mortality(t, J = 7.5 Hz, 1H), to 6.57(d, J = 7.5 Hz, 1H), 6,53(s, 1H), 6,47(d, J = 7.5 Hz, 1H), 5,23(s, 2H), 4,19(t, J = 6,6 Hz, 1H), 3,62(m, 1H), 3,03(m, 1H), 2,84 is 2.80(m, 2H), 2,66(m, 1H), 2,31(d, J = 13,2 Hz, 1H).

Example 6(3)

Methanesulfonate of 4-(4-AMINOPHENYL)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf 0.39 to (methanol: methylene chloride = 1:10);

NMR(DMCO-d6):10,87(Sirs, 1H), 7,24(d, J = 8,4 Hz, 2H), 6,86(d, J = 8,4 Hz, 2H), 4.26 deaths(DD, J = 10,6, 3.0 Hz, 1H), 3,66(sird, J = 14.1 Hz, 1H), 3,16 to 2.35(m, 5H), is 2.30(s, 3H).

Example 6(4)

4-(2-AMINOPHENYL)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0,22 (methylene chloride: methanol = 10:1);

NMR(CDCl3):8,24(Sirs, 1H), 7,21(t, J = 7.5 Hz, 1H), to 7.09(d, J = 7.5 Hz, 1H) 6,80(t, J = 7.5 Hz, 1H), 6,74(d, J = 7.5 Hz, 1H), 4,34(DD, J = 11,7, 2.7 Hz, 1H), 3,95(Sirs, 2H) and 3.72(m, 1H), 3,13(m, 1H), is 3.08 of 2.92(m, 2H), 2,80(m, 1H), of 2.21(m, 1H).

Example 6(5)

4-(3-AMINOPHENYL)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

free form:

TLC: Rf 0.31 in (methanol: methylene chloride = 1:10);

NMR(DMCO-d6):10,81(s, 1H), 7,07(t, J = 7.8 Hz, 1H), 6,63(d, J = 7.8 Hz, 1H), 6,56(s, 1H), 6,50(l, J=7,8 Hz, 1H), 6,21(s, 1H), 5,28(s, 2H), 3,62(m, 2H), 3,14(m, 2H).

methanesulfonate:

TLC: Rf of 0.48 (methanol: methylene chloride = 1:9);

NMR(DMCO-d6):of 10.93(s, 1H), 7,44(t, J = 7.8 Hz, 1H), 7,19(m, 3H), of 6.26(s, 1H), 3,60(m, 2H), 3.15 in(m, 2H), 2,33(s, 3H).

Example 6(6)

4-(3-AMINOPHENYL)-7,8,10,10a-tetrahydro-6H-[1,2,4]triazino[5,4-c][1,4]diazepin-1(2H)-he

TLC: Rf of 0.44 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,47(Sirs, 1H),? 7.04 baby mortality(m, 1H), 6,62-of 6.52(m, 3H), to 5.21(Sirs, 2H), 4,25(DD, J = 6,9, and 4.5 Hz, 1H), 3,52-of 3.42(m, 1H), 3,14-2,96(m, 3H), was 2.76-2,60(m, 2H), 1,82-of 1.56(m, 2H).

Example 6(7)

(8aR)-4-(3-AMINOPHENYL)-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0.56 to (methanol: methylene chloride = 1:9);

NMR(DMCO-d6):10,81(s, 1H), 7,07(t, J = 7.8 Hz, 1H), 6,72(s, 1H), 6,63(m, 2H, in), 5.25(s, 2H), 4,50(d, J = 9,3 Hz, 1H), to 4.41(d, J = 9,3 Hz, 1H), 4,16(t, J = 7.2 Hz, 1H), 3,36(m, 2H).

Example 6(8)

(9aS)-4-(3-AMINOPHENYL)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.44 (methylene chloride: methanol = 10:1);

NMR(CDCl3):8,01(width, 1H), 7,20(t, J = 8,1 Hz, 1H), 6,76-6,69(m, 2H), only 6.64(t, J = 1.8 Hz, 1H), 4,33(DD, J = 10,8, 3.0 Hz, 1H) 3,85(dt, J = 10,8, 3.0 Hz, 1H), 3,78(width, 2H), 3,11(m, 1H), 3,05(m, 1H), equal to 2.94(DD, J = 13,5, and 10.8 Hz, 1H), 2,74(m, 1H, in), 2.25(m, 1H).

Example 6(9)

4-(3,5-diaminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.25 (chloroform: methanol = 8:1);

NMR(DMCO-d6):of 5.82(t, J = 1.8 Hz, 1H), of 5.75(d, J = 1.8 Hz, 2H), 4,86(Sirs, 4H), to 4.15(DD, J = 9,3, 4,2 Hz, 1H), and 3.72(m, 1H), 3,00(m, 1H), 2,84-of 2.50(m, 3H), 2,32(m, 1H).

Example 6(10)

Methanesulfonate of 4-(3-AMINOPHENYL)-9,9a-dihydro-2H-[1,3]thiazino[3,4-d][1,2,4]triazine-1(8H)-it

TLC: Rf of 0.40 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,61(Sirs, 1H), 7,42(m, 1H), 7,29-7,16(m, 3H), of 4.45(d, J = a 13.8 Hz, 1H), 4,21(DD, J = 12,0, 2.4 Hz, 1H), 4,11(DD, J = 13,8, 2.4 Hz, 1H), 3,21(m, 1H), 2,88(m, 1H), 2,32(s, 3H), of 2.08(m, 1H ), 1,78(m, 1H).

Example 6(11)

Methanesulfonate of 4-(3-amino-4-were)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf of 0.38 (methanol: methylene chloride = 1:10);

NMR(DMCO-d6):10,88(s, 1H), 8.30 to(s, 1H), 7,26(d, J = 7.8 Hz, 1H), to 7.09(s, 1H),? 7.04 baby mortality(d, J = 7.8 Hz, 1H), and 6.25(s, 1H), 3,61(m, 2H), and 3.16(m, 2H), 2,32(s, 3H), 2,24(s, 3H).

Example 6(12)

Methanesulfonate of 4-(3-amino-4-were)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf is 0.42 (chloroform: methanol = 9:1);

NMR(DMCO-d6):7,40-7,35(m, 1H), 7,30-7,25(m, 2H), 4,25(DD, J = 10,2, 3.6 Hz, 1H), 3,60-to 3.50(m, 1H), 3,20 was 3.05(m, 1H), 2.95 and is 2.80(m, 2H), 2,80-to 2.65(m, 1H), 2,40 was 2.25(m, 7H).

Example 6(13)

Methanesulfonate of 4-(3-amino-5-forfinal)-6,7,9,9a-Tetra the draw[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf of 0.37 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,65(Sirs, 1H), 6,55-6,40(m, 3H), 4,21(DD, J = 10,2, 3.3 Hz, 1H), 3,64-of 3.54(m, 1H), 3,14-to 3.02(m, 1H), 2,94-2,78(m, 2H), was 2.76-of 2.64(m, 1H), 2.40 a-2,30(m, 4H).

Example 6(14)

4-(2-methyl-5-AMINOPHENYL)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.40 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,43(s, 1H), to 6.88(d, J = 8,1 Hz, 1H), 6,51(DD, J = 8,1, 2.4 Hz, 1H), 6,45(Sirs, 1H), 4,20-4,12(m, 1H), 3,40-3,26(m, 1H), 3,06-to 2.94(m, 1H), 2,90-2,70(m, 2H), 2,58 is 2.46(m, 1 H), 2,34-2,22(m, 1H), 2,02(s, 3H).

Example 6(15)

Methanesulfonate of 4-(4-AMINOPHENYL)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf to 0.39 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,85(Sirs, 1H), 7,40-to 7.32(d, J = 8,4 Hz, 2H), 7,12-7,05(d, J = 8,4 Hz, 2H), 6,24(s, 1H), 3,64-to 3.58(m, 2H), 3,20-of 3.12(m, 2H), 2,34(s, 3H).

Example 6(16)

Methanesulfonate of 4-(2-methyl-3-AMINOPHENYL)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf of 0.41 (chloroform: methanol = 9:1);

NMR(DMCO-d6):7,35-7,27(m, 2H), 7,20(Sirs, 1H), 4,34-is 4.21(m, 1H), 3,26-and 3.16(m, 1H), 3,10-2,98(m, 1H), 2,96-2,78(m, 2H), 2,58-2,48(m, 1H), 2,34(s, 3H), 2,32-2,22(m, lH),2,17(s, 3H).

Example 6(17)

Methanesulfonate of 4-(3-amino-4-methoxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf of 0.53 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,86(s, 1H), 7.24 to 7,10(m, 3H), and 6.25(s, 1H), 3,90(s, 3H), 3,65-to 3.58(m, 2H), 3,20-3,13(m, 2H), 2,32(s, 3H).

p> Example 6(18)

4-(3-amino-4-hydroxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0.14 (chloroform: methanol = 9:1);

NMR(DMCO-d6):of 10.72(s, 1H), 9,45(Sirs, 1H), 6,66(d, J = 7.5 Hz, 1H), 6,60(d, J = 2.1 Hz, 1H), 6.42 per(DD, J = 7,5, and 2.1 Hz, 1H), to 6.19(s, 1H), 4,70(Sirs, 2H), 3,70-of 3.60(m, 2H), 3,20-3,10(m, 2H).

Example 6(19)

4-3-aminobenzyl-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.29 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,69(s, 1H), 6,95(dt, J = 1,2, 7.2 Hz, 1H), 6,44-6,32(m, 3H), the 6.06(s, 1H), to 5.08(s, 2H), 3.72 points-to 3.64(m, 2H), to 3.58(s, 2H), was 2.76-of 2.66(m, 2H).

Example 7

(7R,8aS)-7-hydroxy-4-(3-nitrophenyl)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazine-1(2H)-he

To a solution of the compound obtained in example 4(16a), (76 mg) in methylene chloride (0.5 ml) was added trichromacy Bor (2 ml; 1.0 M in methylene chloride) at -40°C and the mixture was stirred for 1.5 hours. To the reaction mixture were added sodium bicarbonate (approximately 1 g). The reaction mixture was left to slowly warm to room temperature and then the reaction mixture was added a saturated salt solution, the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (chloroform: methanol = 19:1→9:1) to give the compounds according to the present invention (57 mg)having the following the physical characteristics.

TLC: Rf of 0.37 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,69(s, 1H), 8,30-of 8.27(m, 2H), 7,99-of 7.96(m, 1H), 7,76-7,71(m, 1H), total of 5.21(d, J = 3.6 Hz, 1H), 4,22-4,13(m, 2H), 3,40(d, J = 3,6 Hz, 2H), 2,17-2,12(m, 2H).

Example 8

Methanesulfonate (7R,8aS)-7-hydroxy-4-(3-AMINOPHENYL)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazine-1(2H)-it

To a solution of the compound obtained in example 4(16b), (188 mg) in methylene chloride (2 ml) was added aluminum trichloride (153 mg) and the mixture was stirred at room temperature overnight. In addition, aluminum trichloride (151 mg) was added to the reaction mixture, which was stirred at room temperature for 7 hours. To the reaction mixture was sequentially added sodium bicarbonate (approximately 1 g), a small amount of water and methanol, and the mixture was stirred for 30 minutes. The reaction mixture was filtered through celite. The filtrate was concentrated. The residue was purified column chromatography on silica gel (chloroform: methanol = 19:1→9:1→4:1). To a methanol (1 ml) was added to the obtained solid substance, and this solution was added to methansulfonate (42 mg) in methanol (1 ml). The mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to obtain compound according to the present invention (147 mg)having the following physical characteristics.

TLC: Rf to 0.17 (chloroform: methane is = 9:1);

NMR(DMCO-d6):10,90-to 10.62(width, 1H), 7,44(t, J = 7.8 Hz, 1H), 7,34-7,21(m, 3H), 4,24-4,16(m, 2H), 3,44(DD, J = 10,5, 2.4 Hz, 1H), 3,39(DD, J = 10,5, 4.8 Hz, 1H), 2,32(s,3H),2,16-2,12(m, 2H).

Example 9

Methanesulfonate of 4-(3-aminomethylphenol)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

To a solution of ethyl ester of 4-((3-chloromethylene)carbonothioyl)thiomorpholine-3-carboxylic acid (131 mg; compound was obtained by the same procedure as described in reference example 2,→reference example 3, using 3-chlorodibenzofuran instead of 3 nitrobenzotrifluoride) in dimethylformamide (1.5 ml) was added sodium salt of phthalimide (70 mg) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, the mixture was extracted with mixed solvent (hexane: ethyl acetate = 1:1). The extract was sequentially washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated. To a solution of the obtained solid in ethanol (2 ml) was added hydrazine monohydrate (92 μl) and the mixture is boiled under reflux for 1 hour. After cooling the reaction mixture to room temperature, the precipitation was separated by filtration and the filtrate was concentrated. The precipitate and the residue was purified column chromatography on silica gel (chloroform: methanol: water = 8:2:0,2), respectively. To the obtained solid substance was added to the solution of methanesulfonate in methanol (1M, 0.11 ml) and the mixture was concentrated. To the obtained residue was added ethyl acetate, and the precipitate was separated by filtration. The precipitate was dried under reduced pressure to obtain compound according to the present invention (40 mg)having the following physical characteristics.

TLC: Rf 0,11 (methylene chloride: methanol = 10:1);

NMR(DMCO-d6):10,59(s, 1H), 8,14(width, 3H), 7,60-7,40(m, 4H), 4,25(t, J = 6,6 Hz, 1H), 4,12-was 4.02(m, 2H), 3,52(m, 1H), 3,12(m, 1H), 2,88-and 2.83(m, 2H), 2,72(m, 1H), 2,30(m, 1H), 2,28(s, 3H).

Example 10

4-(3-amino-4-forfinal)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

By the same procedure described in reference example 2,→example 6→reference example 3,→example 3, using ethyl ester of 3,4-dihydro-2H-1,4-thiazin-5-carboxylic acid instead of the ethyl ester thiomorpholine-3-icarbonell acid, and 3-nitro-4-tormentilla instead of 3 nitrobenzotrifluoride, was the compound obtained according to the present invention having the following physical characteristics.

TLC: Rf 0,41 (methanol: methylene chloride = 1:10);

NMR(DMCO-d6):10,81(s, 1H),? 7.04 baby mortality(DD, J = 11,4, and 7.8 Hz, 1H), 6,79(d, J = 7.8 Hz, 1H), 6,55(m, 1H), from 6.22(s, 1H), of 5.34(s, 2H), 3,61(m, 2H), 3,12(m, 2H).

Example 11

8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

In almost the re hydrogen, a mixture of 8-phenylpyrimido[2,3-d]pyridazin-5(6H)-it (100 mg; compound was obtained by the same procedure described in reference example 1→example 1, using furo[3,4-b]pyridine-5,7-dione instead of 4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and magnicharters instead of 3-(bis(trimethylsilyl)amino)magnicharters), platinum oxide(IV) (10 mg), 1H. hydrochloric acid (0.5 ml) and dimethylformamide (5 ml) was stirred at room temperature for 6 hours. The reaction mixture was filtered through celite. The filtrate was concentrated. The residue was diluted with ethyl acetate. The diluted solution was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethanol to obtain compounds according to the present invention (42 mg)having the following physical characteristics. In addition, the compound was converted into its corresponding salt in the usual way.

Free form:

TLC: Rf of 0.43 (chloroform: methanol = 9:1);

NMR(DMCO-d6):12,11(Sirs, 1H), 7,52-7,40(m, 5H), 5,72(Sirs, 1H), 3,13(m, 2H), 2,39(t, J = 6.6 Hz, 2H), 1,72(m, 2H).

Hydrochloride:

TLC: Rf of 0.40 (chloroform: methanol = 8:1);

NMR(DMCO-d6):12,41(Sirs, 1H), 7,52-7,40(m, 5H), 5,88(Sirs, 2H), and 3.16(t, J = 5.4 Hz, 2H), 2,43(t, J = 6.3 Hz, 2), 1,73(TT, J = 6.3, in a 5.4 Hz, 2H).

Methanesulfonate:

TLC: Rf to 0.39 (chloroform: methanol = 8:1);

NMR(DMCO-d6):12,37(s, 1H), 7,54-7,40(m, 5H), 4,53(Sirs, 2H), 3,22-is 3.08(m, 2H), 2,42(t, J = 6.0 Hz, 2H), 2,35(s, 3H), 1,82-of 1.64(m, 2H).

Example 11(1) example 11(4)

By the same procedure described in example 11, if necessary, the following compounds according to the present invention were obtained by transformation into the corresponding salts in the usual way using a corresponding derivative instead of 8-phenylpyrimido[2,3-d]pyridazin-5(6H)-it.

Example 11(1)

Methanesulfonate of 4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-it

TLC: Rf of 0.30 (chloroform: methanol = 9:1);

NMR(DMCO-d6):13,30(s, 1H), 8,94(Sirs, 2H), 7,55-the 7.43(m, 5H), of 4.00(s, 2H), 3,37(t, J = 6.0 Hz, 2H), 2,74(t, J = 6.0 Hz, 2H), 2,30(s, 3H).

Example 11(2)

1-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-4(3H)-he

TLC: Rf of 0.29 (chloroform: methanol = 9:1);

NMR(DMCO-d6):12,93(Sirs, 1H), 7,52-7,40(m, 5H), 3,61(width-s, 2H), and 2.79(t, J =5.7 Hz, 2H), 2,32(m, 2H).

Example 11(3)

5-phenyl-1,3,4,7-tetrahydropyrido[2,3-d]pyridazin-8(2H)-he

TLC: Rf is 0.49 (chloroform: methanol = 9:1);

NMR(DMCO-d6):12,51(Sirs, 1H), 7,50 was 7.36(m, 5H), 6,69(Sirs, 1H), 3.27 to(m, 2H), 2,39(t, J = 5.7 Hz, 2H), 1,67(m, 2H).

Example 11(4)

8-(3-AMINOPHENYL)-2,3,4,6-tetrahydropyrido[2,3-d]peridas the h-5(1H)-he

Hydrochloride:

TLC: Rf of 0.40 (methylene chloride: methanol = 9:1);

NMR(DMCO-d6):of 1.73(m, 2H), 2,41(t, J = 6,04 Hz, 2H), 3,14(m, 2H), of 5.92(Sirs, 1H), 7,37(m, 3H), 7,52(m, 1H), 12,23(Sirs, 1H).

The dihydrochloride:

TLC: Rf of 0.33 (chloroform: methanol = 8:1);

NMR(DMCO-d6):12,60(Sirs, 1H), of 7.64-7,42(m, 4H), 6,07(width, 4H), 3,24-is 3.08(m, 2H), 2,44(t, J = 6.0 Hz, 2H), 1,84-of 1.64(m, 2H).

Reference example 4

6-methoxymethyl-8 fenspiride[2,3-d]pyridazin-5(6H)-he

After washing of sodium hydride (103 mg; 62.6 % in oil) hexane, and the mixture is suspended in dimethylformamide (1.5 ml). A solution of 8-phenylpyrimido[2,3-d]pyridazin-5(6H)-she (200 mg; compound was obtained by the same procedure described in reference example 1→example 1, using furo[3,4-b]pyridine-5,7-dione instead of 4,5,6,7-tetrahydro-2-benzofuran-1,3-dione and magnicharters instead of 3-(bis(trimethylsilyl)amino)magnicharters) in dimethylformamide (5.7 ml) was added dropwise to the suspension at 0°C. the Mixture was stirred at room temperature for 40 minutes. Methoxymethane (0.27 ml) was added dropwise to the reaction mixture, which was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was diluted with a mixed solvent consisting of water and ethyl acetate. The mixture was poured into saturated aqueous sodium bicarbonate solution and the ex who was regionali with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the title compound (269 mg)having the following physical characteristics. The compound obtained was used in the next reaction without purification.

TLC: Rf to 0.78 (chloroform: methanol = 8:1).

Reference example 5

6-methoxymethyl-8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

In an argon atmosphere to platinum oxide (70 mg) was added dimethylformamide (1.0 ml). A solution of the compound obtained in reference example 4, (269 mg) in dimethylformamide (8.0 ml) was added dropwise to the reaction mixture and this was added 1N. hydrochloric acid (0.9 ml). In an atmosphere of hydrogen the mixture was stirred at room temperature for 4 hours. In argon atmosphere, the reaction mixture was filtered through celite. The filtrate was concentrated. The residue was purified column chromatography on silica gel (methylene chloride: methanol = 40:1→30:1) to obtain the compound indicated in heading (224 mg)having the following physical characteristics.

TLC: Rf of 0.16 (hexane: ethyl acetate = 1:1);

NMR(DMCO-d6):7,56-7,40(m, 5H), of 5.92(Sirs, 1H), 5,23(s, 2H), 3,29(s, 3H), 3,20-of 3.06(m, 2H), 2,43(t, J = 6.0 Hz, 2H), 1,84-of 1.64(m, 2H).

Reference example 6

6-methoxymethyl-1-methyl-8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

After PR is mevania of sodium hydride (141 mg; 62.6 % in oil) hexane, and the mixture is suspended in dimethylformamide (1.0 ml). A solution of the compound obtained in reference example 5 (200 mg) in dimethylformamide (6.4 ml) was added dropwise to the suspension at 0°C and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added dropwise methyliodide (0,37 ml), the mixture was stirred at room temperature overnight. After adding water to the reaction mixture, the mixture was poured into ice water and was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (methylene chloride: methanol = 100:1→50:1) to obtain the specified title compound (116 mg)having the following physical characteristics.

TLC: Rf of 0.23 (hexane: ethyl acetate = 1:1).

Example 12

1-methyl-8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

To a solution of the compound obtained in reference example 6, (110 mg) in methanol (1.2 ml) was added dropwise 6N. hydrochloric acid (2.4 ml), the mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise 6N. hydrochloric acid (2.4 ml), the mixture was stirred at 110°C during the night. After cooling the reaction mixture to room temperature, it was poured into cold water. After the neitralizatsii 5h. a solution of sodium hydroxide, the solution was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ethyl acetate to obtain compound according to the present invention (39 mg)having the following physical characteristics.

TLC: Rf of 0.44 (chloroform: methanol = 4:1);

NMR(DMCO-d6):12,50(s, 1H), 7,58-7,34(m, 5H), 3,12-3,00(m, 2H), 2,41(t, J = 6.0 Hz, 2H), and 2.27(s, 3H), 1,84-of 1.66(m, 2H).

Reference example 7

N-methyl-N-methoxy-1-tert-butoxycarbonylamino-2-carboxamide

To a solution of 1-tert-butoxycarbonylamino-2-carboxylic acid (2.29 g) in methylene chloride (30 ml) was added the hydrochloride of N,O-dimethylhydroxylamine (1,17 g), benzotriazol-1 yloxy-Tris(dimethylamino)phosphodiesterase (4,87 g, BOP reagent) and triethylamine (4,88 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was diluted with ethyl acetate. The diluted solution was washed successively with water, 1N. hydrochloric acid, water, saturated aqueous sodium bicarbonate and nasystem saline solution, dried over anhydrous sodium sulfate and concentrated to obtain specified in the connection header (2,59 g)having the following physical characteristics.

TLC: Rf of 0.54 (hexane: ethyl acetate = 3:1);

NMR(CDCl3):5,30-a 4.86(m, 1H), 4,06-a-3.84(m, 1H), of 3.77(Sirs, 3H), 3,56-to 3.36(m, 1H), 3,19(s, 3H), 2,04 is 1.96(m, 1H), 1,76-1,32(m, 14H).

Reference example 8

Tert-butyl ester 2-benzoylpiperidine-1-carboxylic acid

The solution finelite in a mixture of cyclohexane-ether (1,06 M, 6,23 ml) was added dropwise to a solution of the compound obtained in reference example 7, (1.63 g) in tetrahydrofuran (30 ml) at -25°C and the mixture was stirred at -25°C for 3 hours. The reaction mixture was poured into a 1M solution of dinatriumfosfaatti and were extracted with ethyl acetate. The extract was washed successively with water and nasystem saline solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane: ethyl acetate = 9:1) to obtain the specified title compound (850 mg)having the following physical characteristics.

TLC: Rf of 0.56 (hexane: ethyl acetate = 4:1);

NMR(CDCl3):of 7.96-to 7.84(m, 2H), 7,66-7,40(m, 3H), 5,70-5,44(m, 1H), 4.04 the-3,86(m, 1H), 3,30-is 3.08(m, 1H), 2,20-to 1.98(m, 1H), 1,92 to 1.76(m, 1H), 1,74 is 1.20(m, 13H).

Reference example 9

Hydrochloride of 2-benzoylpiperidine

To the compound obtained in reference example 8, (270 mg) was added 4n. a solution of hydrogen chloride in ethyl acetate (4 ml) and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated with a receipt which m is specified in the title compound (211 mg), having the following physical characteristics.

TLC: Rf of 0.48 (chloroform: methanol: acetic acid= 40:10:1);

NMR(DMCO-d6):9,02(Sirs, 2H), with 8.05(m, 2H), to 7.75(m, 1H), to 7.61(m, 2H), 5,09(DD, J = 12,0, 3.0 Hz, 1H), 2,97(m, 1H), 2,09(m, 1H), 1,82 is 1.58(m, 4H), of 1.44(m, 1H).

Example 13

1-phenyl-3,6,7,8,9,9a-hexahydro-4H-pyrido[1,2-d][1,2,4]triazine-4-one (compound a) and 1-phenyl-3,6,7,8-tetrahydro-4H-pyrido[1,2-d][1,2,4]triazine-4-one (compound b)

The compound obtained in reference example (199 mg) was separated with ethyl acetate and saturated aqueous sodium bicarbonate solution and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The obtained powder was dissolved in toluene (10 ml). To the solution was added ethyl ether gidratirovannoi acid (184 mg) and the monohydrate of p-toluenesulfonic acid (8,4 mg) and the mixture is boiled under reflux during the night. After cooling the reaction mixture to room temperature, it was diluted with ethyl acetate. The diluted solution was washed sequentially 1H. hydrochloric acid, water and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane: ethyl acetate = 2:1→1:1). The fraction from the column with greater polarity is recrystallized from ethyl acetate to obtain compound (16,3 mg), having the following physical characteristics. The fraction from the column with lower polarity recrystallized from a mixed solution of ethyl acetate and hexane (1:1) to obtain compound b (13,6 mg)having the following physical characteristics.

Connection a:

TLC: Rf of 0.30 (hexane: ethyl acetate = 1:1);

NMR(DMCO-d6):10,14(s, 1H), 7,76-7,66(m, 2H), 7,46-7,34(m, 3H), of 4.77(DD, J = 11,7, 2.7 Hz, 1H), 4,18(m, 1H), 2,72(m, 1H), 1,88 is 1.34(m, 6H).

Connection b:

TLC: Rf and 0.46 (hexane: ethyl acetate = 1:1);

NMR(DMCO-d6):a 10.74(s, 1H), 7,56-7,34(m, 5H), 4,82(t, J = 4.5 Hz, 1H), to 3.64(m, 2H), 2,10(m, 2H), 1,71(m, 2H).

Example 14

1-phenyl-3,8,9,9a-tetrahydro-4H-[1,3]thiazino[3,4-d][1,2,4]triazine-4-one

By the same procedure described in reference example 7→reference example 8→reference example 9→example 13, using 3-tert-butoxycarbonyl-1,3-diazinon-4-carboxylic acid instead of 1-tert-butoxycarbonylamino-2-carboxylic acid, there was obtained the compound according to the present invention having the following physical characteristics.

TLC: Rf of 0.48 (hexane: ethyl acetate = 1:1);

NMR(DMCO-d6):10,42(s, 1H), 7,75-of 7.70(m, 2H), 7,46-7,38(m, 3H), 5,10(DD, J = 11,4, 2.7 Hz, 1H), 4,90(DD, J = 13,2, 2.7 Hz, 1H), 4,34(d, J = 13,2 Hz, 1H), 3,36(m, 1H), 2,75(m, 1H), 1,88-of 1.62(m, 2H).

Reference example 10

Methyl ester ((E)-3-oxo-4,5,6,7-tetrahydro-2-be is zofran-1(3H)-ilidene)acetic acid

A solution of anhydride 3,4,5,6-tetrahydrophthalic acid (3.04 from g) and methyl ester (triphenylphosphorane)acetic acid (6,69 g) in chloroform (50,0 ml) was boiled under reflux for 3 hours. After cooling the reaction mixture to room temperature, it was concentrated. The residue was purified column chromatography on silica gel (ethyl acetate: hexane = 1:9→3:7) to obtain specified in the connection header (1,93 g)having the following physical characteristics.

TLC: Rf of 0.71 (ethyl acetate: hexane = 1:1);

NMR(CDCl3): δ of 5.92(s, 1H), 3,76(s, 3H), of 2.81(m, 2H), of 2.38(m, 2H), 1,76(m, 4H).

Example 15

4-methoxycarbonylmethyl-5,6,7,8-tetrahydropyrazin-1(2H)-he

A solution of the compound obtained in reference example 10, (1.04 g) and hydrazine monohydrate (250 mg) in ethanol (10.0 ml) was boiled under reflux for 18 hours. After cooling the reaction mixture to room temperature, it was concentrated. The resulting crystals were washed with ethanol and ethyl acetate and dried under reduced pressure to obtain compound according to the present invention (672 mg)having the following physical characteristics.

TLC: Rf 0.45 in (methanol: methylene chloride = 1:9);

NMR(DMSO-d6): δ 12,66 (Sirs, 1H), the 3.65(s, 2H), 3,63(s, 3H), of 2.38(m, 4H), of 1.64(m, 4H).

Example 16

4-(1-ethoxycarbonylethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

By Taco the same procedure that described in reference example 10→example 15, using the ethyl ester of 2-(triphenylphosphonio)propanoic acid instead of methyl ester (triphenylphosphonio)acetic acid, there was obtained the compound according to the present invention having the following physical characteristics.

TLC: Rf 0.56 to (methanol: methylene chloride = 1:10);

NMR(DMCO-d6):12,67(Sirs, 1H), 4,07(sq, J = 6,9 Hz, 2H), 3,91(sq, J = 6,9 Hz, 1H), 2,48 is 2.33(m, 4H), of 1.65(m, 4H), of 1.33(d, J = 6.9 Hz, 3H), of 1.13(t, J = 6.9 Hz, 3H).

Reference example 11

4-carboxymethyl-5,6,7,8-tetrahydropyrazin-1(2H)-he

A solution of 5h. sodium hydroxide (1,72 ml) was added dropwise to a suspension of the compound obtained in example 15, (635 mg) in methanol (10.0 ml) in an ice bath and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. To the residue was added 2n. hydrochloric acid, the pH was brought to pH 2. The resulting crystals were collected by filtration. They were washed with hexane and dried under reduced pressure to obtain specified in the title compound (478 mg)having the following physical characteristics.

TLC: Rf 0,62 (methanol: methylene chloride: acetic acid= 2:8:0,1);

NMR(DMCO-d6):br12.62(Sirs, 2H), 3,54(s, 2H), 2,39(m, 4H), of 1.64(m, 4H).

Reference example 11(1)

4-(1-carboxyethyl)-5,6,7,8-tetrahydrofolic is n-1(2H)-he

By the same procedure described in reference example 11 using the compound obtained in example 16, instead of the compound obtained in example 15 was obtained is listed in the title compound having the following physical characteristics.

TLC: Rf 0.28 in (methanol: methylene chloride = 1:4);

NMR(DMCO-d6):12,64(s, 1H), 12,48(Sirs, 1H), 3,81(sq, J = 7.5 Hz, 1H), 2,48-is 2.37(m, 4H), 1,65(Sirs, 4H), 1,32(d, J = 7.5 Hz, 3H).

Example 17 and example 17(1)

By the same procedure described in reference example 10→example 15→example 11, if necessary, were obtained the following compounds according to the present invention by transformation into the corresponding salts in the usual way using the corresponding derivative instead of 4,5,6,7-tetrahydro-2-benzofuran-1,3-dione and ethyl ether (triphenylphosphorane)acetic acid instead of methyl ester (triphenylphosphorane)acetic acid.

Example 17

8-ethoxycarbonylmethyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf and 0.46 (chloroform: methanol = 9:1);

NMR(DMCO-d6):11,88(Sirs, 1H), 6,32(Sirs, 1H), 4,07(sq, J = 7.2 Hz, 2H), 3,54(s, 2H), 3.15 in(m, 2H), 2,33(t, J = 6.3 Hz, 2H), 1.69 in(m, 2H), of 1.18(t, J = 7.2 Hz, 3H).

Example 17(1)

Hydrochloride 5-ethoxycarbonylmethyl-1,3,4,7-tetrahydropyrido[2,3-d]pyridazin-8(2H)-it

T is X: Rf of 0.48 (chloroform: methanol = 9:1);

NMR(DMCO-d6):12,60(Sirs, 1H), 4,10(sq, J = 7.2 Hz, 2H), 3,75(Sirs, 2H), or 3.28(m, 2H), 2,45(m, 2H), 1.77 in(m, 2H), of 1.18(t, J = 7.2 Hz, 3H).

Reference example 12

4-(2-hydroxyethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The compound obtained in example 15, (350 mg) was dissolved in tetrahydrofuran (8.0 ml). In an argon atmosphere to the resulting solution was added borohydride sodium (239 mg) at 0°C and the mixture is boiled under reflux for 13 hours. After cooling to 0°C, the reaction mixture was added 1N. hydrochloric acid, the pH of the mixture was brought to pH 5. Precipitated precipitated solid substance was collected by filtration. The filtrate was concentrated and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated to obtain specified in the title compound having the following physical characteristics.

TLC: Rf of 0.32 (chloroform: methanol = 9:1);

NMR(CDCl3):a 3.87(t, J = 6.6 Hz, 2H), 2,80(t, J = 6.6 Hz, 2H), 2,64-of 2.58(m, 2H), 2,54-2,48(m, 2H), 1,88 is 1.70(m, 4H).

Reference example 13

4-(2-chloroethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in reference example 12, (2,47 g) and pyridine (201 mg) in methylene chloride (60 ml) was added thionyl chloride (2.25 g) and the mixture was stirred at room temperature for 20 hours. To the reaction mixture were added chloroform and saturated wagnerstr sodium bicarbonate, the mixture was separated. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the title compound (2.58 g)having the following physical characteristics.

TLC: Rf value of 0.52 (chloroform: methanol = 9:1);

NMR(CDCl3):3,88(t, J = 7.2 Hz, 2H), 3,05(t, J = 7.2 Hz, 2H), 2,60-of 2.50(m, 4H), 1.85 to to 1.70(m,4H).

Reference example 14

4-(2-azidoethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

A solution of the compound obtained in reference example 13, (106 mg), trimethylsilane (86,4 mg) and tetrabutylammonium (237 mg) in tetrahydrofuran (2.00 ml) was boiled under reflux for 24 hours. The reaction mixture was concentrated. The residue was purified column chromatography on silica gel (ethyl acetate: hexane = 1:1) to obtain specified in the connection header (85,0 mg)having the following physical characteristics.

TLC: Rf value of 0.52 (ethyl acetate: hexane = 4:1);

NMR(DMCO-d6):br12.62(Sirs, 1H), 3,63(t, J = 6.9 Hz, 2H), and 2.79(t, J = 6.9 Hz, 2H), 2,48-is 2.37(m, 4H), to 1.67(m, 4H).

Reference example 15

The hydrochloride of 4-(2-amino-ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

A suspension of the compound obtained in reference example 14, (50.0 mg) and 5% palladium on calcium carbonate (20.0 mg) in ethanol (3.0 m is) was stirred in hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered through celite. The filtrate was concentrated. To a solution of the obtained solid substance (to 44.0 mg) in methanol (3.0 ml) was added dropwise 4n. a solution of hydrogen chloride in ethyl acetate and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was recrystallized from a solvent mixture of methanol and ethyl acetate to obtain specified in the connection header (45,9 mg)having the following physical characteristics.

TLC: Rf 0.39 to (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,1);

NMR(DMCO-d6):12,65(s, 1H), 8,07(Sirs, 3H), of 3.07(m, 2H), and 2.83(t, J = 7.2 Hz, 2H), 2,44(m, 2H), of 2.38(m, 2H), of 1.66(m, 4H).

Reference example 16

4-(2-cyanoethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a suspension of the compound obtained in reference example 13, (500 mg) in tetrahydrofuran (12 ml) was added trimethylsilylacetamide (0,94 ml) and tetrabutylammonium (1.84 g) and the mixture was stirred at 80°C during the night. After cooling to room temperature, the reaction mixture was poured into cold saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (methylene chloride: methanol= 20:1). The obtained solid is washed with tert-butylmethylamine ether to obtain specified in the title compound (249 mg)having the following physical characteristics.

TLC: Rf value of 0.52 (chloroform: methanol = 8:1);

NMR(DMCO-d6):12,66(s, 1H), 2,94-of 2.72(m, 4H), 2,60-of 2.26(m, 4H), 1,78-and 1.54(m, 4H).

Reference example 17

4-(2-carboxyethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a suspension of the compound obtained in reference example 16, (130 mg) in ethanol (3.2 ml) was added 5N. a solution of sodium hydroxide (0,64 ml) and the mixture was stirred at 90°C for 1 day. After cooling to 0°C, the reaction mixture was poured into cold water and washed with ethyl acetate. The aqueous layer was neutralized 2n. hydrochloric acid and concentrated. The residue was washed with water. The solid is washed with water and ether to obtain specified in the title compound (131 mg)having the following physical characteristics.

TLC: Rf of 0.36 (chloroform: methanol = 4:1);

NMR(DMCO-d6):12,51(s, 1H), 12,08(Sirs, 1H), 2,71(t, J = 6.9 Hz, 2H), has 2.56(t, J = 6.9 Hz, 2H), 2,54-of 2.26(m, 4H), 1,78-and 1.54(m, 4H).

Example 18

The pyridine salt of 3-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)phenylalaninol acid

To a suspension of the compound obtained in example 1 (100 mg) in methylene chloride (1.5 ml) and dimethylformamide (1.5 ml) was added to the complex of sulfur trioxide and pyridine (mg) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The residue was washed with ethyl acetate to obtain compound according to the present invention (160 mg)having the following physical characteristics.

TLC: Rf to 0.17 (chloroform: methanol = 4:1);

NMR(CDCl3):8,90-8,78(m, 2H), 8,59(dddd, J = 7,8, 7,8, 1.5 and 1.5 Hz, 1H), 8,12-7,98(m, 2H), of 7.48-7,14(m, 3H), 6.89 in(m, 1H), 2,66-2,52(m, 2H), 2,52-of 2.38(m, 2H), 1,90-to 1.60(m,4H).

Example 19

Methanesulfonate of 4-(3-amidinophenoxy)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

To a solution of the compound obtained in example 4(20), (127 mg) in dimethylformamide (3 ml) was added sulfuric acid sodium (215 mg) and uranyl magnesium chloride (474 mg) and the mixture was stirred at room temperature for 3 hours in argon atmosphere. To the reaction mixture were added ethyl acetate and the precipitate was separated by filtration. The filtrate was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. To a solution of the obtained solid (277 mg) in acetone (2 ml) was added methyliodide (0.15 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. To the residue was added methanol (2 ml) and ammonium acetate (43 mg) and the mixture is boiled under reflux for 2 hours. The reaction mixture was concentrated. The residue was purified column is cromatografia on silica gel (chloroform: methanol: water = 9:1:0.1 to→ 8:2:0,2). The obtained solid substance was washed with a mixture solvent of methanol, ethyl acetate and hexane and turned into the methanesulfonate of the compound in the usual way of obtaining the compounds according to the present invention (149 mg)having the following physical characteristics.

TLC: Rf 0,22 (methylene chloride: methanol = 10:1);

NMR(DMCO-d6):for 10.68(s, 1H), 9,36(s, 2H), 9,02(s, 2H), 7,86(d, J = 7.8 Hz, 1H), 7,84-to 7.77(m, 2H), 7,69(t, J = 7.8 Hz, 1H), 4.26 deaths(DD, J = 8,7, 4.8 Hz, 1H), 3,50(m, 1H), and 3.16(m, 1H), 2.95 and-2,84(m, 2H), 2,71(m, 1H), 2,366 and 2,362(s, 3H), 2,30(d, J = 13,8gts, lH).

Example 20

4-(3-hydroxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

To a solution of the compound obtained in example 4(4), (175 mg) in methylene chloride (1.3 ml) was added trichromacy boron (1.3 ml; and 1.0 M in methylene chloride) in an ice bath and the mixture was stirred at room temperature for 5 hours. To the reaction mixture were added trichromacy boron (1.3 ml; and 1.0 M in methylene chloride) and the mixture was stirred at room temperature overnight. To the reaction mixture was added methanol, and the mixture was concentrated. The residue was washed with methylene chloride. To the residue was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile to obtain compounds according to astasia invention (73 mg), having the following physical characteristics.

TLC: Rf of 0.43 (chloroform: methanol = 9:1);

NMR(DMCO-d6):of 10.47(s, 1H), 9,67(bc, 1H), 7,20(t, J = 7.8 Hz, 1H), for 6.81-6.73 x(m, 3H), 4,19(DD, J = 9,3, 3,9 Hz, 1H), of 3.56(dt, J = 14,1, 3.0 Hz, 1H), 3,09-2,99(m, 1H), 2,90-and 2.79(m, 2H) 2,69-2,60(m, 1H), 2,33-of 2.28(m, 1H).

Example 20(1) and example 20(2)

By the same procedure described in example 20, using the compound obtained in example 4(5) or 4(27)instead of the compound obtained in example 4(4), the following compounds according to the present invention were obtained.

Example 20(1)

4-(4-hydroxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.32 (chloroform: methanol = 8:1);

NMR(DMCO-d6):9,74(Sirs, 1H), 7.24 to 7,14(m, 2H), 6,84-6,74(m, 2H), 4,18(DD, J = 8,1, 5,1 Hz, 1H), 3,60(dt, J = 14,1, 2.7 Hz, 1H), 3,05(m, 1H), 2,92-2,78(m, 2H), 2,68(m, 1H),2,31(m, 1H).

Example 20(2)

4-(3-hydroxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.40 (chloroform: methanol = 9:1);

NMR(DMCO-d6):10,83(s, 1H), to 9.70(s, 1H), 7,24(t, J = 7.8 Hz, 1H), 6,88 to 6.75(m, 3H), from 6.22(s, 1H), 3,66 of 3.56(m, 2H), 3,16-of 3.06(m, 2H).

Example 21

Bromohydrin N-(3-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)phenyl)ethanamide

To a suspension of the compound obtained in example 1 (60 mg) in ethanol (2.5 ml) was added 2-naphthylethylenediamine (74 mg) and the mixture was stirred at room temperature is f within 4 hours. To the reaction mixture were added methanol (1.5 ml) and 2-naphthylethylenediamine (222 mg), the mixture was stirred at 75°C during the night. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified column chromatography on silica gel (methylene chloride: methanol = 20:1→6:1) to give the compounds according to the present invention (84 mg)having the following physical characteristics.

TLC: Rf is 0.24 (chloroform: methanol = 4:1);

NMR(DMCO-d6):12,97(s, 1H), to 7.59(DD, J = 8,1, 8,1 Hz, 1H), 7,50(m, 1H), 7,44-7,34(m, 2H), 2,54 of-2.32(m, 4H), of 2.34(s, 3H), 1,80 of 1.50(m, 4H).

Example 21(1) of example 21(3)

By the same procedure described in example 21, using the compound synthesized in example 6, 6(5) or 11(4), instead of the compound obtained in example 1 was synthesized following compounds according to the present invention.

Example 21(1)

Bromohydrin N-(3-(1-oxo-1,2,6,7,9,9a-hexahydro[1,4]thiazino[4,3-d][1,2,4]triazine-4-yl)phenyl)ethanamide

TLC: Rf of 0.25 (chloroform: methanol: water= 8:2:0,2);

NMR(DMCO-d6):11,13(width, 1H), or 10.60(s, 1H), 9,43(width, 1H), 8,56(width, 1H), to 7.59(t, J = 7.8 Hz, 1H), 7,47(d, J = 7.8 Hz, 1H), 7,38(d, J = 7.8 Hz, 1H), was 7.36(s, 1H), 4,24(DD, J = 9,6, 3,9 Hz, 1H), 3,63(d, J = a 13.8 Hz, 1H), 3,10(d, J = 12.0 Hz, 1H), 2,96-2,82(m, 2H), 2,72(m, 1H), 2,32(s, 3H), to 2.29(m, 1H).

Example 21(2)

Bromohydrin N-(3-(1-oxo-1,2,6,7-tetrahydro[1,4]thiazino[4,3d][1,2,4]triazine-4-yl)phenyl)ethanamide

TLC: Rf is 0.24 (chloroform: methanol: water= 8:2:0,2);

NMR(DMCO-d6):10,95(s, 1H), of 9.30(width, 1H), 8,87(width, 1H), 8,35(width, 1H), 7,60(m, 1H), of 7.48(m, 1H), 7,42 and 7.36(m, 2H), 6,28(s, 1H), 3.72 points-to 3.64(m, 2H), 3,20-of 3.12(m, 2H), 2,30(Sirs, 3H).

Example 21(3)

N-(3-(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)phenyl)ethanamine

TLC: Rf 0.14 (chloroform: methanol = 4:1).

Example 22

4-(3-methylaminophenol)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

To a suspension of the compound obtained in example 6(5), (100 mg) in methanol (1.1 ml) was added a solution of sodium methylate in methanol (0.5 ml; 28% solution) and paraformaldehyde (32 mg) and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added methanol (1.1 ml) and sodium borohydride (22 mg), the mixture was stirred at 75°C for 1 hour. After cooling to room temperature, the reaction mixture was added water, the mixture was poured into cold water. The solution was concentrated. The residue was washed with a mixture solvent of methanol and methylene chloride and filtered through celite. The filtrate was concentrated. The residue was purified column chromatography on silica gel (methylene chloride: methanol = 15:1) to give the compounds according to the present invention (15 mg)having the following physical characteristics.

TLC: Rf of 0.44 (chloroform: methanol = 8:1);

NMR(DMCO-d6):10,80(s, H), to 7.15(DD, J = 7,5, 7.5 Hz, 1H), 6,66-6,46(m, 3H), 6,21(s, 1H), 5,86(sq, J = 4,8 Hz, 1H), 3,68 of 3.56(m, 2H), 3,20-of 3.06(m, 2H), to 2.67(d, J = 4,8 Hz, 3H).

Example 23

4-(N-(2-(N'-tert-butoxycarbonylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

A mixture of the compound obtained in reference example 11, (183 mg), triethylamine (178 mg), tert-butyl ester N-(2-amino-ethyl)carbamino acid (160 mg), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (338 mg), 1-hydroxybenzotriazole (238 mg) and dimethylformamide (3,00 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated. To the residue was added water and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate and dried under reduced pressure to obtain compound according to the present invention (189 mg)having the following physical characteristics.

TLC: Rf of 0.50 (methylene chloride: methanol = 9:1);

NMR(DMCO-d6):12,56(s, 1H), 8,01(Sirs, 1H), 6,77(Sirs, 1H), 3,39(s, 2H), is 3.08-2.95 and(m, 4H), of 2.38(m, 4H), of 2.25(m, 4H), to 1.37(s, 9H).

Example 23(1) example 23(37)

By the same procedure described in example 23, if necessary, were synthesized the following compounds according to the present invention by transformation into the corresponding salts in the usual way using the compound obtained in example 11, or the appropriate proizvodnog the carboxylic acid, and tert-butyl ether N-(2-amino-ethyl)carbamino acid or a corresponding derivative.

Example 23(1)

4-(N-(2-(morpholine-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.37 (methanol: methylene chloride = 1:9);

NMR(DMCO-d6):12,60(Sirs, 1H), 11,06(Sirs, 1H), 8,45(t, J = 5.7 Hz, 1H), 3.95 to of 3.77(m, 4H), 3,47(s, 2H), 3.43 points(m, 4H), 3,18-to 3.02(m, 4H), is 2.37(m, 4H), 1,64(Sirs, 4H).

Example 23(2)

4-(N-(2-(N',N'-dimethylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf 0,60 (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,1);

NMR(DMCO-d6):12,56(Sirs, 1H), 7,94(shirt, J = 6.2 Hz, 1H), 3,40(s, 2H), 3,13(TD, J = 6,2, 6.2 Hz, 2H), 2,43(Sirs, 2H), 2,36(Sirs, 2H), and 2.26(t, J = 6.2 Hz, 2H), 2,12(s, 6H), 1,63(Sirs, 4H).

Hydrochloride:

TLC: Rf 0,69 (methanol: methylene chloride: saturated aqueous ammonia= 2:8:0,1);

NMR(DMCO-d6):12,60(s, 1H), 10,22(Sirs, 1H), 8,39(t, J = 5.7 Hz, 1H), 3,41 are 2.98(m, 4H), 2,24(m, 8H), 2,48-of 2.36(m, 4H), 1,64(Sirs, 4H).

Example 23(3)

4-(N-(3-(N'-tert-butoxycarbonylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

NMR(DMCO-d6):12,56(s, 1H), 7,97(t, J = 5,1 Hz, 1H), 6.75 in(m, 1H), 3,39(s, 2H), 3,02(sq, J = 6,6 Hz, 2H), 2,90(sq, J = 6,6 Hz, 2H), 2,46 is 2.33(m, 4H), 1,68 is 1.58(m, 4H), 1,55-of 1.44(m, 2H), of 1.36(s, 9H).

Example 23(4)

4-(N-(2-(N'-tert-butoxycarbonyl-N'-methylamino)ethyl)carb is oilmeal)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf is 0.59 (chloroform: methanol: water= 8:2:0,2);

NMR(CDCl3):10,69(width, 1H), 6,88(width, 1H), 3,49(s, 2H), 3.45 points-of 3.32(m, 4H), of 2.86(s, 3H), 2,60-2,48(m, 4H), 1,90 and 1.80(m, 4H), 1,45(s, 9H).

Example 23(5)

The hydrochloride of 4-(N-(2-(pyrrolidin-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf is 0.24 (ethyl acetate: acetic acid: water= 3:3:1);

NMR(DMSO-d6):12,60(s, 1H), 10,46(width, 1H), 8,39(m, 1H), 3,61-to 3.50(m, 2H), 3,47(s, 2H), 3,40(kV, J = 6.0 Hz, 2H), 3,17(kV, J = 6.0 Hz, 2H), 3.04 from-2,90(m, 2H), 2,50-of 2.34(m, 4H), 2,04-1,90(m, 2H), 1,90 and 1.80(m, 2H), 1.70 to to 1.60(m, 4H).

Example 23(6)

4-(2-hydroxyethoxymethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.60 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,66(s, 1H), 4,80(t, J = 5,1 Hz, 1H), 4,07(t, J = 5,1 Hz, 2H), 3,66(s, 2H), 3,55(kV, J = 5,1 Hz, 2H), 2,45-of 2.34(m, 4H), 1.70 to to 1.60(m, 4H).

Example 23(7)

The hydrochloride of 4-(N-(3-(N',N'-dimethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,12 (chloroform: methanol: water= 7:3:0,3);

NMR(DMSO-d6):12,60(s, 1H), 10,43(width, 1H), 8,28(m, 1H), 3,42(s, 2H), 3,11(kV, J = 6.0 Hz, 2H), 3.04 from-2,96(m, 2H), 2,71(s, 3H), 2,69(s, 3H), 2,46-of 2.34(m, 4H), 1,84-of 1.74(m, 2H), 1,68 is 1.48(m, 4H).

Example 23(8)

The hydrochloride of 4-(N-(3-(imidazol-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,82 (chloroform: methanol: water= 7:3:0,3);

NMR(DMSO-d6):14,64(width, 1H), 1260(s, 1H), 9,17(m, 1H), 8,39(m, 1H), 7,81(d, J = 1.5 Hz, 1H), 7,68(d, J = 1.5 Hz, 1H), 4,22(t, J = 6.6 Hz, 2H), 3,44(s, 2H), 3,03(kV, J = 6,6 Hz, 2H), 2,46 of-2.32(m, 4H), 1.93 and(Quain, J = 6,6 Hz, 2H), 1,68 of 1.46(m, 4H).

Example 23(9)

4-(1-(N-(2-(N'-tert-butoxycarbonylamino)ethyl)carbarnoyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.44 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,60(s, 1H), to 7.93(t, J = 5,1 Hz, 1H),6,74(Sirs, 1H), 3,66(kV, J = 7.2 Hz, 1H), 3,05(m, 2H), 2,96(m, 2H), 2,48-of 2.30(m, 4H), and 1.63(m, 4H), of 1.36(s, 9H), of 1.30(d, J-7,2 Hz, 3H).

Example 23(10)

The hydrochloride of 4-(N-(1-ethylpyrrolidin-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,59 (methanol: methylene chloride: saturated aqueous ammonia= 2:8:0,1);

NMR(DMSO-d6):was 12.61(s, 1H), 10,42(Sirs, 1H), 8,56(m, 1H), to 3.58-2,96(m, 9H), 2,42-of 2.36(m, 4H), 2,08-of 1.64(m, 8H), 1,24(t, J = 6.9 Hz, 3H).

Example 23(11)

4-(N-(3-(morpholine-4-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.48 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,57(s, 1H), 8,00(shirt, 1H), 3,64-of 3.48(m, 4H), 3.46 in-3,18(m, 6H), 3,14-2,96(m, 2H), 2,50 with 2.14(m, 6H), 1,74-of 1.44(m, 6H).

Example 23(12)

The hydrochloride of 4-(N-(3-(pyrrolidin-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.25 (chloroform: methanol: water= 7:3:0,3);

NMR(DMSO-d6):12,59(s, 1H), 10,59(width, 1H), 8,25(width, 1H), 3,52-to 3.38(m, 4H), 3,17-3,00(m, 4H), 2,98-2,84(m, 2H), 2,46 of-2.32(m, 4H), 2.00 in a 1.75(m, 6H), 1,69 is 1.58(m, 4H).

Example 23(13)

The hydrochloride of 4-(N-(pyridin-3-yl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.47 (methanol: methylene chloride = 1:9);

NMR(DMSO-d6):12,67(s, 1H), 11,31(s, 1H), 9,12(d, J = 2.1 Hz, 1H), 8,55(d, J = 4,8 Hz, 1H), 8,43(d, J = 8.7 Hz, 1H), 7,86(DD, J = 8,7, 4.8 Hz, 1H), 3,78(s,2H), 2,48-2,39(m,4H), 1,65(Sirs, 4H).

Example 23(14)

The hydrochloride of 4-(N-(2-(piperidine-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.53 (chloroform: methanol: water= 7:3:0,3);

NMR(DMSO-d6):12,60(s, 1H), 10.30 a.m. (lat., 1H), 8,44(width, 1H), 3,50-to 3.34(m, 2H), and 3.31(s, 2H), 3,10-2,96(width, 2H), 2,90-2,72(width, 2H), 2,48 of-2.32(m, 4H), 1,80-1,68(width, 4H), 1,68-1,56(width, 6H), 1,50-1,40(width, 2H).

Example 23(15)

The hydrochloride of 4-(N-(2-(N',N'-dimethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.26 (chloroform: methanol: water= 7:3:0,3);

NMR(DMSO-d6):12,60(s, 1H), the 10.40(width, 1H), 8,32(width, 1H), 3,48(s, 2H), 3,42-of 3.12(m, MN), 2,58(s, 6H), 2,46 of-2.32(m, 4H), 1,68 is 1.58(m, 4H), of 1.12(d, J = 6.0 Hz, 3H).

Example 23(16)

4-(N-(4-(N'-tert-butoxycarbonylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

NMR(DMSO-d6):8,12(width, 1H), 6,59(width, 1H), 3,54(s, 2H), 3,23 is 3.15(m, 2H), is 3.08 are 2.98(m, 2H), 2,56-2,47(m, 4H), 1,82-of 1.74(m, 4H), 1.56 to a 1.46(m, 4H), of 1.42(s, 9H).

Example 23(17)

The hydrochloride of 4-(N-(pyridin-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,51 (methanol: Meiling orid = 1:10);

NMR(DMSO-d6):12,64(s, 1H), 11,08(s, 1H),8,33(m, 1H), of 7.97(d, J = 8,4 Hz, 1H), 7,87(m, 1H), 7,18(m, 1H), of 3.77(s, 2H), 2,45-of 2.38(m, 4H), 1,65(Sirs, 4H).

Example 23(18)

4-(2-(N',N'-dimethylamino)ethoxycarbonylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf 0,51 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,66(s, 1H), 4,13(t, J = 5.7 Hz, 2H), to 3.64(s, 2H), 2,44(t, J = 5.7 Hz, 2H), 2,44 to 2.35(m, 4H), 2,12(s, 6H), 1,72 is 1.58(m, 4H).

Hydrochloride:

TLC: Rf of 0.51 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,70(s, 1H), of 10.72(width, 1H), of 4.44 is 4.36(m, 2H), 3,74(s, 2H), 3,40-of 3.32(m, 2H), 2,75(s, 6H), 2,46 of-2.32(m, 4H), 1,72 is 1.60(m, 4H).

Example 23(19)

4-(N-(2-(pyrrol-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.60 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,57(s, 1H), 8,11(m, 1H), 6,69(d, J = 1.2 Hz, 2H), 5,96(d, J = 1.2 Hz, 2H), 3,92(t, J = 6.0 Hz, 2H), 3,38(s, 2H), 3,35(t, J = 6.0 Hz, 2H), 2.40 a-2,24(m, 4H), 1,68 is 1.58(m, 4H).

Example 23(20)

The hydrochloride of 4-(N-(2-(imidazol-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.56 (chloroform: methanol: water= 7:3:0,3);

NMR(DMSO-d6):12,56(s, 1H), 8,10(m, 1H), 7,73(width, 1H), 6,86(s,1H), 3,39(s,2H), 3,34 is 3.23(m, 2H),2,74-2,62(m, 2H), 2.40 a-2,30(m, 4H), 1,66-of 1.56(m, 4H).

Example 23(21)

4-(1-(N-(4-(N'-tert-butoxycarbonylamino)butyl)carbarnoyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

T is X: Rf of 0.38 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,59(s, 1H), to 7.93(t, J = 5.7 Hz, 1H), 6,77(m, 1H), 3,66(kV, J = 7,0 Hz, 1H), 3,01(m, 2H), 2,88(m, 2H), 2,48-of 2.26(m, 4H), 1,63(Sirs, 4H), 1,42 of 1.28(m, 16H).

Example 23(22)

4-(N-(pyridine-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,85 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,60(s, 1H), 8,62(t, J = 6.0 Hz, 1H), 8,49(m, 1H), of 7.75(dt, J = 7,5, 1.8 Hz, 1H), 7,29(m, 1H), 7,25(m, 1H), 4,35(d, J = 6.0 Hz, 2H), 3,51(s, 2H), 2,48-of 2.34(m, 4H), 1.70 to was 1.58(m, 4H).

Example 23(23)

4-(N-(2-bromacil)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.64 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,59(s, 1H), 8,32(m, 1H) 3,52-3,44(m, 2H), 3.43 points(s, 2H), 3,42-to 3.33(m, 2H), 2,48 is 2.33(m, 4H), 2.70 height is 1.60(m, 4H).

Example 23(24)

4-(N-(3-nonproper)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,60 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):to 12.58(s, 1H), 8,10(t, J = 6.0 Hz, 1H), 3,51(t, J = 6.0 Hz, 2H), 3,40(s, 2H), 3.15 in(kV, J = 6.0 Hz, 2H), 2,45 is 2.33(m, 4H), 1.93 and(Quain, J = 6.0 Hz, 2H), 1,68-to 1.59(m, 4H).

Example 23(25)

4-(N-(5-(N'-tert-butoxycarbonylamino)pentyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

NMR(DMSO-d6):12,56(s, 1H), 7,99(t, J = 6.0 Hz, 1H), 6.75 in(t, J = 6.0 Hz, 1H), 3,38(s, 2H), 3,10(kV, J = 6.0 Hz, 2H), 2,86(kV, J = 6.0 Hz, 2H), 2,45 is 2.33(m, 4H), 1,69-of 1.62(m, 4H), 1,44-of 1.29(m, 4H), of 1.36(s, 9H), 1,28-1,18(m, 2H).

Example 23(26)

4-(N-(5-methylthiazole-2-yl)carbama lmutil)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.57 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,65(Sirs, 1H), 12,12(Sirs, 1H), 7,12(s, 1H), of 3.73(s, 2H), 2,39(m,4H), 2,32(s, 3H), 1,65(Sirs, 4H).

Example 23(27)

The hydrochloride of 4-(N-(3-(N',N'-dimethylamino)propyl)-N-methylcarbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,11 (methylene chloride: methanol: water= 7:3:0,3);

NMR(DMSO-d6):12,59(s, 1H), 10,92 and 10,51(width, 1H), 3.68 and 3,66(s, 2H), 3.43 points and to 3.36(t, J = 6.6 Hz, 2H), 3,80-2,90(m, 2H), 3,01 and 2.82(s, 3H), 2,73, and a 2.71 and 2,69(s, 6H), 2,42 of-2.32(m, 4H), 2,02-to 1.82(m, 2H), 1,67 is 1.58(m, 4H).

Example 23(28)

The hydrochloride of 4-(N-(2-(N',N'-dimethylamino)ethyl)-N-methylcarbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.21 in (methylene chloride: methanol: water= 7:3:0,3);

NMR(DMSO-d6):12,59(s, 1H), 10,69 and to 9.93(width, 1H), 3.75 to and 3,68(s, 2H), to 3.64(t, J = 6.0 Hz, 2H), 3,20(kV, J = 6.0 Hz, 2H), 3.04 from and 2,84(s, 3H), 2,79 and 2.77 and was 2.76(s, 6H), 2,42 is 2.33(m, 4H), 1,68-1,6 0(m, 4H).

Example 23(29)

4-(N-(4-bromobutyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.65 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,56(s, 1H),8,02(t, J = 6.3 Hz, 1H), 3,52(t, J = 6.3 Hz, 2H), 3,39(s, 2H), 3,06(kV, J = 6.3 Hz, 2H), 2,45 is 2.33(m, 4H), 1,82-of 1.73(m, 2H), 1,67 is 1.58(m, 4H), 1,58 is 1.48(m, 2H).

Example 23(30)

4-(2-(N-tert-butoxycarbonylamino)ethoxycarbonylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

NMR(CD3OD):to 4.15(t, J = 5.7 Hz, 1H), 3,71(m, 2H), 3,54(t, J = 5.7 G is, 2H), 3,29(t, J = 5.7 Hz, 1H), 3,14(t, J = 5.7 Hz, 1H), 2,56-2,47(m, 4H), 1,91-of 1.84(m, 4H), USD 1.43(s, 9H).

Example 23(31)

4-(N-(4-oxo-4,5-dihydro-1,3-thiazol-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

NMR(DMSO-d6):of 12.73(Sirs, 1H), 12,67(s, 1H), 3,88(s, 2H), 3,80(s, 2H), 2,38(Sirs, 4H), 1,65(Sirs, 4H).

Example 23(32)

4-(N-(1-methyl-4-oxo-1,5-dihydro-4H-imidazol-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,49 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):to 12.52(Sirs, 1H), 11,03(Sirs, 1H), 4.00 points(s, 2H), to 3.58(s, 2H), 2,90(s, 3H), 2,41(m, 4H), 1,63(Sirs, 4H).

Example 23(33)

4-(2-(N-(2-(N'-tert-butoxycarbonylamino)ethyl)carbarnoyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf to 0.66 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,50(s, 1H), 7,87(shirt, 1H), 6,78(shirt, 1H), 3,12-2,84(m, 4H), 2,78-2,62(m, 2H), 2,56-of 2.26(m, 6H), 1,76-and 1.54(m, 4H), of 1.36(s, 9H).

Example 23(34)

4-(N-(2-cyanoethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,79 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,59(s, 1H), 8,39(t, J = 5.7 Hz, 1H), 3.43 points(s, 2H), 3,32 is 3.23(m, 2H), 2,64(t, J = 6.3 Hz, 2H), 2,45 is 2.33(m, 4H), 1,68 is 1.60(m, 4H).

Example 23(35)

4-(N-(4-(imidazol-1-yl)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.75 (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6): 12,57(1H), 8,03(m, 1H), 7,60(s, 1H), 7,13(s, 1H), 6.87 in(s, 1H), 3,94(t, J = 6.6 Hz, 2H), 3,38(s, 2H), 3,05(kV, J = 6,6 Hz, 2H), 2,46 is 2.33(m, 4H), 1,74 is 1.60(m, 6H), 1,31(Quain, J = 6,6 Hz, 2H).

Example 23(36)

4-(N-(2-methoxycarbonylethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.83 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,57(1H), 8,13(m, 1H), to 3.58(s, 3H), 3,38(s, 2H), 3,32-3,24(m, 2H), 2,50 is 2.43(m, 2H), 2,42 of-2.32(m, 4H), 1,68 is 1.60(m, 4H).

Example 23(37)

4-(N-methyl-N-(3-chlorpropyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,81 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,56(s, 1H), 3.68 and of 3.60(m, 2H), 3,63, and of 3.31(s, 2H), 3.45 points and to 3.41(t, J = 6.3 Hz, 2H), 3,02 and of 2.81(s, 3H), 2,41 is 2.33(m, 4H), 2,01 and 1,90(m, 2H), 1.70 to to 1.60(m,4H).

Example 24

4-(N-(2-hydroxyethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The mixture of compounds obtained in example 15, (222 mg) and 2-aminoethanol (305 mg) was stirred at 100°C for 1 hour. After cooling the reaction mixture to room temperature, the formed crystals were washed with ethyl acetate. The obtained crystals are recrystallized from a solvent mixture of methanol and ethyl acetate to obtain compound according to the present invention (190 mg)having the following physical characteristics.

TLC: Rf of 0.23 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,55(Sirs, 1H), 8,03(t, J = 54 Hz, 1H), 4,66(t, J = 5.4 Hz, 1H), 3,41(s, 2H), 3,38(m, 2H), 3,11(m, 2H), 2,42(Sirs, 2H), 2,36(Sirs, 2H), 1,63(Sirs, 4H).

Example 24(1) of example 24(48)

By the same procedure described in example 24, if necessary, the following compounds according to the present invention were synthesized by transformation into the corresponding salts in the usual way using the compound obtained in example 15, or the corresponding ether derivative, and the corresponding derivative instead of 2-aminoethanol.

Example 24(1)

The dihydrochloride 8-(N-(2-amino-ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf of 0.36 (chloroform: methanol: 28% ammonia water= 15:5:1);

NMR(DMSO-d6):12,32(Sirs, 1H), to 8.41(t, J = 5.4 Hz, 1H), 8,06(Sirs, 3H), 3,49(s, 2H), 3,30(m, 2H), 3,20(m, 2H), 2,86(m, 2H), of 2.38(t, J = 6.0 Hz, 2H), 1.70 to(m, 2H).

Example 24(2)

4-(N-(2-methoxyethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.53 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,56(Sirs, 1H), 8,11(t, J = 5.4 Hz, 1H), 3,41(s, 2H), 3,32(m, 2H), 3,23(s, 3H), 3,19(m, 2H), 2,41-of 2.36(m, 4H), 1,63(Sirs, 4H).

Example 24(3)

4-(N-(2-(N',N'-diethylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.35 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,57(s, 1H), 7,85(t, J = 5.4 Hz, 1H), 3,39(s, 2H), 3,09(kV, J = 6,6 Hz, 2H), 2,48 of-2.32(m, 10H), 1,67 is 1.58(m, 4H),of 0.91(t, J = 7.2 Hz, 6H).

Example 24(4)

4-(N-propylgallate)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.60 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,56(s, 1H), 8,00(t, J = 6,9 Hz, 1H), 3,39(s, 2H), 2,99(kV, J =6,9 Hz, 2H), 2,46 of-2.32(m, 4H), 1,68 is 1.58(m, 4H), of 1.39(sextet, J = 6,9 Hz, 2H), or 0.83(t, J = 6.9 Hz, 3H).

Example 24(5)

4-(N-(4-hydroxybutyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,68 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):12,54(Sirs, 1H), 8,00(t, J = 5.6 Hz, 1H), 4,37(t, J = 5,1 Hz, 1H), 3,38(s, 2H), 3,36(m, 2H), to 3.02(m, 2H), 2,42-of 2.36(m, 4H), 1,63(Sirs, 4H),to 1.38(m, 4H).

Example 24(6)

4-(N-(furan-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.37 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,58(Sirs, 1H),8,51(t, J = 5.4 Hz, 1H), 7,56(m, 1H), 6,38(m, 1H), from 6.22(m, 1H), 4,25(d, J = 5.4 Hz, 2H), 3,44(s, 2H), is 2.37(m, 4H), 1,62(Sirs, 4H).

Example 24(7)

The hydrochloride of 4-(N-(piperidine-4-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.21 in (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,2);

NMR(DMSO-d6):12,59(s, 1H), 8,92(m, 1H), 8,63(m, 1H), 8,19(t, J = 5.4 Hz, 1H), 3,42(s, 2H), 3,21(m, 2H), 2,97-of 2.72(m, 4H), of 2.38(m, 4H), 1,76-of 1.26(m, 9H).

Example 24(8)

4-(N-(2,3,4,5-tetrahydrofuran-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.45 in (methanol: methylene chloride = 110);

NMR(DMSO-d6):12,56(Sirs, 1H), 8,10(t, J = 5.7 Hz, 1H), 3,85 of 3.56(m, 3H), 3,42(s, 2H), 3,18 totaling 3.04(m, 2H), 2,41-of 2.36(m, 4H), 1,90-of 1.42(m, 8H).

Example 24(9)

4-(1-(N-(2-(piperidine-1-yl)ethyl)carbarnoyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,20 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):12,60(Sirs, 1H), 7,80(t, J = 5.7 Hz, 1H), 3,69(kV, J = 6,9 Hz, 1H), 3,20 was 3.05(m, 2H), 2,48 was 2.25(m, 10H), 1,65 is 1.34(m, 10H), of 1.30(d, J = 6.9 Hz, 3H).

Example 24(10)

4-(N-(2-(pyridin-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.37 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,53(Sirs, 1H), 8,44(d, J = 6.3 Hz, 2H), 8,10(t, J = 5.7 Hz, 1H), 7,22(d, J = 6.3 Hz, 2H), 3,35(m, 4H), 2,84 2.63 in(m, 2H), 2,34-of 2.27(m, 4H), 1,59(Sirs, 4H).

Example 24(11)

4-(N-(2-(pyridin-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.36 and (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,57(s, 1H), 8,48(d, J = 3,9 Hz, 1H), 8,09(t, J = 5.4 Hz, 1H), of 7.70(m, 1H), 7.23 percent(m, 2H), 3.42 points(TD, J = 6,9, a 5.4 Hz, 2H), 3,36(s, 2H), 2,87(t, J = 6.9 Hz, 2H), 2,33(m, 4H), 1,60(Sirs, 4H).

Example 24(12)

4-(N-(2,2-dimethyl-3-(N',N'-dimethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,24 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):was 12.61(s, 1H), 7,89(t, J = 6.0 Hz, 1H), 3,44(s, 2H), 2,95(d, J = 6.0 Hz, 2H), 2,43(m, 2H), a 2.36(m, 2H), 2,15(s, 6H), was 2.05(s, 2H), 1,63(Sirs, 4H), to 0.78(s, 6H).

Example 24(13)

4-(N-(2-(N'-isopropylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.27 (ethyl acetate: acetic acid: water= 3:1:1);

NMR(DMSO-d6):12,57(width, 1H), of 7.96(m, 1H), 3,40(s, 2H), 3,09(kV, J = 6.0 Hz, 2H), 2,66(m, 1H), 2,58-2,48(m, 2H), 2,45 of-2.32(m, 4H), 1,68-to 1.59(m, 4H), of 0.93(d,J = 6.0 Hz, 6H).

Example 24(14)

4-(N-(2-(N'-ethylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf is 0.22 (ethyl acetate: acetic acid: water= 3:1:1);

NMR(DMSO-d6):12,53(width, 1H), of 7.96(m, 1H), 3,40(s, 2H), 3,10(kV, J = 6.0 Hz, 2H), 2.57 m at 2.45(m, 4H), 2,45-of 2.34(m, 4H), 1,68 is 1.58(m, 4H), of 0.97(t, J = 6.9 Hz, 3H).

Example 24(15)

4-(N-(3-(N'-methylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.20 (ethyl acetate: acetic acid: water= 3:1:1);

NMR(DMSO-d6):8,01(t, J = 6,9 Hz, 1H), 3,38(s, 2H), 3,07(kV, J = 6,9 Hz, 2H), 2,41(t, J = 6.9 Hz, 2H), 2,45 is 2.33(m, 4H), of 2.21(s, 3H), 1.70 to to 1.60(m, 4H), 1,52(Quain, J = 6,9 Hz, 2H).

Example 24(16)

4-(N-(2-(pyridin-3-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.47 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,56(Sirs, 1H), 8,40(m, 2H), 8,10(t, J = 5.7 Hz, 1H), to 7.61(m, 1H), 7,30(m, 1H), 3,36(s, 2H), and 3.31(m, 2H), by 2.73(t, J = 6.9 Hz, 2H), 2,31(m, 4H), 1,60(Sirs, 4H).

Example 24(17)

4-(N-(1-benzylpiperidine-4-yl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf of 0.38 (methanol: methylene chloride = 1:10);/p>

NMR(CD3OD):of 7.36(m, 5H), 3,76(m, 1H), 3,69(s, 2H)and 3.59(s, 2H), 3,01(m, 2H), 2,56(Sirs, 4H), 2,33(m, 2H), 1,97-to 1.61(m, 8H).

Hydrochloride:

TLC: Rf 0,49 (methanol: methylene chloride: saturated aqueous ammonia= 1:9:0,1);

NMR(DMSO-d6):to 12.58(s, 1H), 10,63(Sirs,1H), with 8.33(d, J = 7.2 Hz, 1H), 7,58(m, 2H), 7,44(m, 3H), 4,29 of 2.92(m, 9H), of 2.38(m, 4H), 1,94 is 1.70(m, 4H), 1,62(Sirs, 4H).

Example 24(18)

4-(N-(2-(N'-phenylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf of 0.47 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,58(Sirs, 1H), 8,12(t, J = 5.7 Hz, 1H), 7,05(DD, J = 8,4, 7.2 Hz, 2H), of 6.52(m, 3H), of 5.55(t, J = 5.7 Hz, 1H), 3,42(s, 2H), up 3.22(m, 2H), 3,06(m, 2H), of 2.38(m,4H), 1,60(Sirs, 4H).

Hydrochloride:

TLC: Rf of 0.57 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,60(s, 1H), 8,31(m, 1H), 7,35? 7.04 baby mortality(m, 5H), 3,44(s, 2H), 3.33 and is 3.23(m, 4H), of 2.38(m,4H), 1,62(Sirs, 4H).

Example 24(19)

4-(N-(2-(1-methylpyrrole-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.47 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,57(Sirs, 1H), 8,13(t, J = 5.7 Hz, 1H), return of 6.58(t, J = 2.4 Hz, 1H), of 5.84(t, J = 2.4 Hz, 1H), 5,76(Sirs, 1H), 3,49(s, 3H), 3,39(s, 2H), 3,24(m, 2H), 2,64(t, J = 7.2 Hz, 2H), is 2.37(m, 4H), 1,63(Sirs, 4H).

Example 24(20)

4-(N-(5-hydroxyphenyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.29 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6 ):12,56(Sirs, 1H), 7,99(t, J = 5.4 Hz, 1H), 4,33(t, J = 5.4 Hz, 1H), 3,38(s, 2H), 3,35(m, 2H), to 3.02(TD, J = 6.3, in a 5.4 Hz,2H), 2,39(m, 4H), 1,63(Sirs, 4H), 1.41 to to 1.22(m, 6H).

Example 24(21)

4-(N-(2-(N'-benzylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.15 (methanol: methylene chloride = 1:9);

NMR(DMSO-d6):12,55(Sirs, 1H), 7,97(t, J = 6.0 Hz, 1H), 7,30-7,17(m, 5H), to 3.67(s, 2H), 3,40(s, 2H), 3.15 in(kV, J = 6.0 Hz, 2H), 2,56 to 2.35(m, 6H), 1,61(Sirs, 4H).

Example 24(22)

4-(N-(2-(furan-2-immedilty)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.38 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,57(Sirs, 1H),8,16(t, J = 5.7 Hz, 1H), 7,56(t, J = 1.5 Hz, 1H), 6,37(DD, J = 3,0, 1.5 Hz, 1H), of 6.26(d, J = 3.0 Hz, 1H), of 3.77(s, 2H), 3,40(s, 2H), up 3.22(m, 2H), 2,53-of 2.36(m, 6H), 1,63(Sirs, 4H).

Example 24(23)

4-(N-(3-(2-methylpiperidin-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.43 (methanol: methylene chloride: saturated aqueous ammonia= 2:8:0,1);

NMR(DMSO-d6):12,57(Sirs, 1H), 8,00(t, J = 5.7 Hz, 1H), 3,38(s, 2H), 3,03(m, 2H), 2,73 is 1.96(m, 11H), 1,63 is 1.13(m, 10H), were 0.94(d, J = 6.3 Hz, 3H).

Example 24(24)

4-(N-(3-(N'-cyclohexylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,41 (methanol: methylene chloride: saturated aqueous ammonia= 2:8:0,1);

NMR(DMSO-d6):12,58(Sirs, 1H), 8,01(t, J = 5,1 Hz, 1H), 3,38(s, 2H), 308(m, 2H), of 2.51 was 2.25(m, 7H), 1,77 to 0.92(m, 16H).

Example 24(25)

4-(N-(2-(N'-butylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,66 (methanol: methylene chloride: saturated aqueous ammonia= 2:8:0,1);

NMR(DMSO-d6):12,58(Sirs, 1H), 7,95(t, J = 5.4 Hz, 1H), 3,40(s, 2H), 3,11(m, 2H), 2,55-of 2.36(m, 8H), 1,63(Sirs, 4H), to 1.31(m, 4H), of 0.85(t, J = 6.9 Hz, 3H).

Example 24(26)

4-(N-(2-(N'-(2-hydroxypropyl)amino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,51 (methanol: methylene chloride: saturated aqueous ammonia= 1:10:0,1);

NMR(DMSO-d6):to 7.99(t, J = 5,1 Hz, 1H), of 4.44(Sirs, 1H), 3,62(m, 1H), 3,40(s, 2H), 3,11(m, 2H), 2.57 m-is 2.37(m, 8H), 1,63(Sirs, 4H), 1,01(d, J = 6.3 Hz, 3H).

Example 24(27)

4-(N-(3-(N'-methyl-N'-phenylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,58 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,58(Sirs, 1H), 8,07(t, J = 5.4 Hz, 1H), 7,14(t, J = 7.5 Hz, 2H), is 6.61(m, 3H), 3,41(s, 2H), 3,29(m, 2H), is 3.08(m, 2H), and 2.83(s, 3H), 2,39(m, 4H), of 1.62(m, 6H).

Example 24(28)

4-(N-(3-hydroxypropyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.26 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,54(Sirs, 1H), 7,99(t, J = 5.4 Hz, 1H), to 4.41(t, J = 5.4 Hz, 1H), 3,40(m, 2H), 3,39(s, 2H), to 3.09(m, 2H), 2,39(m, 4H), 1,63(Sirs, 4H), 1,58-1,49(m, 2H).

Example 24(29)

4-(N-(2-(thiophene-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahedrite Azin-1(2H)-he

TLC: Rf of 0.48 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,57(Sirs,1H), 8,16(t, J = 5.7 Hz, 1H), 7,32(d, J = 5,1 Hz, 1H), 6,94(DD, J = 5,1, 3.3 Hz, 1H), to 6.67(d, J = 3.3 Hz, 1H), 3,39(s, 2H), 3,30(m, 2H), 2,92 (t, J = 6.9 Hz, 2H), 2,35(Sirs, 4H), 1,62(Sirs, 4H).

Example 24(30)

4-(N-(2-(1-methylpyrrolidine-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.30 (methanol: methylene chloride: saturated aqueous ammonia= 2:8:0,1);

NMR(DMSO-d6):12,58(Sirs, 1H), 8,01(t, J = 5.4 Hz, 1H), 3,38(s, 2H), of 3.07(m, 2H), 2,88(m, 1H), of 2.38(m, 4H), of 2.15(s, 3H), 2,03-of 1.24(m, 12H).

Example 24(31)

4-(N-(2-(1-benzylpiperidine-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf of 0.44 (methanol: methylene chloride: saturated aqueous ammonia= 2:8:0,1);

NMR(DMSO-d6):12,56(Sirs, 1H), of 7.96(t, J = 5.4 Hz, 1H), 7,32-7,19(m, 5H), 3,40(s, 2H), 3,37(s, 2H), 3,06(m, 2H), 2,75(m, 2H), 2,31(m, 4H), 1,87-of 1.03(m, 13H).

Hydrochloride:

TLC: Rf of 0.48 (methanol: methylene chloride: saturated aqueous ammonia= 1:9:0,1);

NMR(DMSO-d6):to 12.58(s, 1H), of 10.21(Sirs, 1H), 8,05(t, J = 5.4 Hz, 1H), 7,56(m, 2H), 7,45(m, 3H), 4,24(m, 2H), 3,38-2,78(m, 8H), is 2.37(m, 4H), 1,83 to 1.31(m, 11H).

Example 24(32)

4-(N-(2-(N'-(2-hydroxyethyl)amino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.18 (ethyl acetate: acetic acid: water= 3:1:1);

NMR(DMSO-d6): 12,55(width, 1H), 7,99(t, J = 6.0 Hz, 1H), 4,43(m, 1H), 3,44-3,37(m, 2H), 3,40(s, 2H), 3,11(kV, J = 6.0 Hz, 2H), 2,59-2,52(m, 4H), 2,45 is 2.33(m, 4H), 1,68 is 1.60(m, 4H).

Example 24(33)

4-(N-(3-metaltipped)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,60 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,57(Sirs, 1H), 8,05(t, J = 5.4 Hz, 1H), 3,39(s, 2H), 3,11(m, 2H), 2,44-of 2.36(m, 6H), 2,02(s, 3H), of 1.66(m, 6H).

Example 24(34)

4-(N-(2-(N'-ethyl-N'-(3-were)amino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,63 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,59(Sirs, 1H), 8,12(t, J = 5.4 Hz, 1H), 7,00(DD, J = 7,2, 7.2 Hz, 1H), 6,50(m, 2H), 6,37(d, J = 7.2 Hz, 1H), 3,40(s, 2H), 3.33 and-3,18(m, 6H), of 2.38(m, 4H), of 2.20(s, 3H), 1,62(Sirs, 4H), was 1.04(t, J = 6.9 Hz, 3H).

Example 24(35)

4-(N-(4,4-dimethoxymethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.34 in (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,56(Sirs, 1H), 8,01(t, J = 5.4 Hz, 1H), or 4.31(t, J = 5.4 Hz, 1H), 3,39(s, 2H), 3,19(s, 6H), 3,01(m, 2H), 2,39(m, 4H), 1,63(Sirs, 4H), 1,52 is 1.34(m, 4H).

Example 24(36)

4-(N-(3-(N',N'-diethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.34 in (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):12,57(s, 1H), 7,99(t, J = 5.7 Hz, 1H), 3,38(s, 2H), 3,05(kV, J =5.7 Hz, 2H), 2,44-to 2.29(m, 10 H), 1,66-to 1.59(m, 4H), 1,49(Quain, J = 5.7 Hz, 2H), of 0.91(t, J = 6.9 Hz, 6H).

P the emer 24(37)

4-(N-(3-(N'-isopropylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,18 (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):to 12.52(width, 1H), 8,00(m, 1H), 3,38(s, 2H),is 3.08(q, J = 6.0 Hz, 2H), 2,62(s, J = 6.0 Hz, 1H), 2,48 of-2.32(m, 6H), 1,68 is 1.60(m,4H), 1,49(Quain, J = 6.0 Hz, 2H), 0,92(d, J = 6.0 Hz, 6H).

Example 24(38)

4-(N-(2-(1,3-dioxolane-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,41 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,57(Sirs, 1H), 8,01(t, J = 5.7 Hz, 1H), 4,79(t, J = 4,8 Hz, 1H), 3,89-3,71(m, 4H), to 3.38(s, 2H), 3,13(m, 2H), of 2.38(m, 4H), to 1.70(m, 2H), 1,63(Sirs, 4H).

Example 24(39)

4-(N-(3-(N'-propylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.14 (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):12,60(width, 1H), 8,00(m, 1H), 3,38(s, 2H), is 3.08(q, J = 6.6 Hz, 2H), 2,47-of 2.34(m, 8H), 1.70 to to 1.60(m, 4H), 1,50(Quain, J = 6,6 Hz, 2H), 1,38(s, J = 6,6 Hz, 2H), or 0.83(t, J = 6.6 Hz, 3H).

Example 24(40)

4-(N-(2-(N'-propylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.31 in (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):12,59(width, 1H), of 7.96(m, 1H), 3,40(s, 2H), 3,11(kV, J = 6.3 Hz, 2H), 2.57 m-2,47(m, 2H), 2,45 is 2.33(m,6H), 1.70 to to 1.60(m, 4H), to 1.37(s, J = 7.2 Hz, 2H), from 0.84(t, J = 7.2 Hz, 3H).

Example 24(41)

-(N-(2-(4-methoxyphenyl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.47 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,56(Sirs, 1H), 8,04(t, J = 5.7 Hz, 1H), 7,10(d, J = 8.7 Hz, 2H), 6,83(d, J = 8.7 Hz, 2H), 3,70(s, 3H), 3,36(s, 2H), 3,24(m, 2H), 2.63 in(t, J = 7.2 Hz, 2H), 2,33(m, 4H), 1,60(Sirs, 4H).

Example 24(42)

The hydrochloride of 4-(N-(2-(4-AMINOPHENYL)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.39 to (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,58(Sirs, 1H), 10,38(Sirs, 3H), 8,19(t, J = 5.4 Hz, 1H), 7,31(m, 4H), 3,37(s, 2H), 3,29(kV, J = 6,9 Hz, 2H), by 2.73(t, J = 6.9 Hz, 2H), 2,35(Sirs, 4H), 1,61 (Sirs, 4H).

Example 24(43)

The dihydrochloride 8-(N-(2-(N'-phenylamino)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.40 in (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,27(Sirs, 1H), at 8.36(m, 1H), 7,31(t, J = 7.8 Hz, 2H), 7,10-6,00(m, 7H), of 3.46(s, 2H), 3,24(m, 6H), of 2.38(t, J = 6.3 Hz, 2H), 1.70 to(m, 2H).

Example 24(44)

Methanesulfonate 8-(N-(2-(1-benzylpiperidine-4-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.36 and (methanol: methylene chloride: saturated aqueous ammonia= 1:10:0,1);

NMR(DMSO-d6):11.87 per(s, 1H), 9,20(Sirs, 1H), 8,05(t, J = 5,1 Hz, 1H), of 7.48(m, 5H), 6,38(Sirs, 1H), 4,27(m, 2H), 3.33 and-a 3.06(m, 8H), and 2.83(m, 2H), 2,33(m, 2H), 2,30(s, 3H), 1,87-1,22(m, 9H).

Example 24(45)

8-(N-(3-(morpholine-4-yl)propyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf 0.31 in (methanol: telengard = 1:4);

NMR(DMSO-d6):11,85(s, 1H), 8,05(t, J = 5.4 Hz, 1H), 6,41(s, 1H), 3,54(m, 4H), 3,29(m, 2H), 3,17(Sirs, 2H), 3,06(kV, J = 6,6 Hz, 2H), 2,28(m, 8H), 1.69 in(m, 2H), 1,53(m, 2H).

Example 24(46)

Methanesulfonate 8-(N-(2-(piperidine-1-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.14 (methanol: methylene chloride: acetic acid= 1:4:0,2);

NMR(DMSO-d6):11,91(s, 1H), 8,94(Sirs, 1H), 8,29(t, J = 5.4 Hz, 1H), 6.30-in(Sirs, 1H), 3,50-to 3.38(m, 6H), of 3.12(m, 4H), 2,90(m, 2H), 2,35(m, 2H), 2,32(s, 3H), 1,98-of 1.33(m, 8H).

Example 24(47)

8-(N-(2-(morpholine-4-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf of 0.29 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):11,85(s, 1H), 7,99(t, J = 5.4 Hz, 1H), 6,40(s, 1H), 3,53(m, 4H), to 3.34(s, 2H), and 3.16(m, 4H), of 2.30(m, 8H), to 1.70(m, 2H).

Example 24(48)

8-(N-(3-(N'-tert-butoxycarbonylamino)propyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf 0.35 in (methanol: methylene chloride = 1:9);

NMR(DMSO-d6):11,84(s, 1H), 8,02(t, J = 5.4 Hz, 1H), 6,76(t, J = 5.4 Hz, 1H), 6,38(s, 1H), and 3.31(m, 2H), 3,18(Sirs, 2H), 2,98(TD, J = 6,6, a 5.4 Hz, 2H), 2,90(TD, J = 6,6, a 5.4 Hz, 2H), 2,32(t, J = 6.3 Hz, 2H), 1.69 in(m, 2H), 1,47(m, 2H), of 1.36(s, 9H).

Example 25

4-(3-(N-(5-Charpentier)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a mixed solution of the compound obtained in example 1 (241 mg) and potassium carbonate (89,8 mg) in tetrahydrofuran (3.00 m is) and water (1,00 ml) in an ice bath was added dropwise 5-chlorphentermine (171 mg) and the mixture was stirred for 30 minutes. In addition, to the reaction mixture were added potassium carbonate (45.0 mg) and 5-chlorphentermine (85.5 mg), the mixture was stirred for 30 minutes. To the reaction mixture were added 1N. hydrochloric acid, the pH of the mixture was brought to pH 2. To the reaction mixture were added water and the resulting crystals were collected by filtration. The crystals were washed successively with water and hexane and dried under reduced pressure to obtain compound according to the present invention (347 mg)having the following physical characteristics.

NMR(DMSO-d6):12,88(s, 1H), 10,00(s, 1H), 7,69(s, 1H), to 7.59(d, J = 7.8 Hz, 1H), 7,35(t, J = 7.8 Hz, 1H), was 7.08(d, J = 7.8 Hz, 1H), 3,65(t, J = 6.0 Hz, 2H), 2,56 of-2.32(m, 6H), 1,75-to 1.59(m, 8H).

Example 25(1) - example 25(13)

By the same procedure described in example 25 were synthesized the following compounds according to the present invention using a corresponding derivative instead of the compound obtained in example 1, and a corresponding derivative instead of 5-chlorphentermine.

Example 25(1)

4-(3-(N-(5-bromopentane)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.28 in (methanol: methylene chloride = 1:20);

NMR(DMSO-d6):12,88(s, 1H), 10,00(s,1H), 7,69(t, J = 1.2 Hz, 1H), to 7.59(DD, J = 7,8, 1.2 Hz, 1H), 7,35(t, J = 7.8 Hz, 1H), to 7.09(DD, J = 7,8, 1.2 Hz, 1H), 3,55(t, J = 6.6 Hz, 2H), 2,48 of-2.32(m, 6H), 1,86-to 1.59(m, 8H).

Example 25(2)

4-(3-(N-(4-shall albuterol)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.50 (chloroform: methanol = 9:1);

NMR(CDCl3):of 8.47-8,28(width, 1H), 7,69(Sirs, 1H), 7.62mm(Sirs, 1H), 7,53(d, J = 7.8 Hz, 1H), 7,37(t, J = 7.8 Hz, 1H), to 7.09(d, J = 7.8 Hz, 1H), 4,35(DD, J = 10,5, 2.7 Hz, 1H), 3,85(dt, J = 13,5, 2.7 Hz, 1H), to 3.67(t, J = 6.3 Hz, 2H), 3,21-3,11(m, 1H), is 3.08-to 3.02(m, 1H), equal to 2.94(DD, J = 13,5, 10.5 Hz, 1H),2,86 was 2.76(m, 1H), has 2.56(t, J = 7.2 Hz, 2H), 2,32-of 2.16(m, 3H).

Example 25(3)

4-(3-(N-acetylamino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.40 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):10,52(s, 1H), of 10.05(s, 1H), to 7.67(s, 1H), 7,56(d, J = 8,1 Hz, 1H), 7,34(t, J = 8,1 Hz, 1H), 7,06(d, J = 8,1 Hz, 1H), 4,23(DD, J = 8,7, 4.8 Hz, 1H), of 3.56(m, 1H), is 3.08(m, 1H), 2,89-and 2.83(m, 2H), 2,70(m, 1H), 2,32(m,1H), 2,04(s, 3H).

Example 25(4)

4-(3-(N-acetylamino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0,51 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):10,88(s, 1H), 10,08(s, 1H), of 7.70(s, 1H), to 7.61(d, J= 7.8 Hz, 1H), 7,38(t, J = 7.8 Hz, 1H), to 7.09(d, J = 7.8 Hz, 1H), of 6.26(s, 1H), 3,61(m, 2H), 3.15 in(m, 2H), 2.05 is(s, 3H).

Example 25(5)

4-(3-(N-acetylamino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.45 in (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,87(s, 1H), 10,02(s, 1H), to 7.67(s, 1H), 7,58(d, J = 7.8 Hz, 1H), 7,35(t, J = 7.8 Hz, 1H), was 7.08(d, J = 7.8 Hz, 1H), 2,39(m, 4H), 2,04(s, 3H), of 1.64(m, 4H).

Example 25(6)

4-(3-(N-(4-chlorobutanol)amino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

NMR(DMSO-d6): 10,89(s, 1H), 10,12(s, 1H), 7,71(t, J = 1.5 Hz, 1H), 7.62mm(m, 1H), 7,38(t, J = 7.8 Hz, 1H), 7,10(dt, J = 7,8, 1.5 Hz, 1H), of 6.26(s, 1H), 3,70(t, J = 6.9 Hz, 2H), 3,64-to 3.58(m,2H), 3,18-3,13(m, 2H), 2,35(t, J = 6,9 Hz, 2H), 2,03(Quain, J = 6,9 Hz, 2H).

Example 25(7)

4-(3-(N-(2-chloroacetyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,27 (methanol: methylene chloride = 1:20);

NMR(DMSO-d6):12,90(s, 1H), the 10.40(s, 1H), 7,68(s, 1H), 7,60(d, J = 7.8 Hz, 1H), 7,40(t, J = 7.8 Hz, 1H), 7,15(d, J = 7.8 Hz, 1H), 4,25(s, 2H), 2,39(m, 4H), by 1.68(m, 2H), 1,59(m, 2H).

Example 25(8)

4-(3-(N-(3-bromopropyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,20 (methanol: methylene chloride = 1:20);

NMR(DMSO-d6):12,88(s, 1H), 10,15(s, 1H), of 7.70(s, 1H), 7,60(d, J = 7.8 Hz, 1H), 7,37(t, J = 7.8 Hz, 1H), 7,12(d, J = 7.8 Hz, 1H), and 3.72(t, J = 6.3 Hz, 2H), 2.95 points(t, J = 6.3 Hz, 2H), 2,48-of 2.34(m, 4H), to 1.70(m, 2H), 1,60 m, 2H).

Example 25(9)

8-(3-(N-acetylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

Free form:

TLC: Rf 0.31 in (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,11(s, 1H), 10,06(s, 1H), of 7.70(m, 1H), to 7.61(m, 1H), 7,37(DD, J = 7,8, and 7.8 Hz, 1H), to 7.09(m, 1H), lower than the 5.37(s, 1H), 3,20-of 3.06(m, 2H), 2,39(t, J = 6.3 Hz, 2H), 2,04(s, 3H), 1,82 is 1.60(m, 2H).

Methanesulfonate:

TLC: Rf 0.31 in (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):12,31(s, 1H), 10,06(s, 1H), of 7.70(m, 1H), 7.62mm(m, 1H), 7,38(t, J = 7.9 Hz, 1H), to 7.09(m, 1H), 3,14(m, 2H), 2,41(t, J = 6.2 Hz, 2H), 2,33(s, 3H), 2,04(s, 3H), at 1.73(m, 2H).

Example 25(10)

4-(3-(N-methylamino)phenyl)-5,6,7,8-those who rehydratation-1(2H)-he

TLC: Rf 0.56 to (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,89(s, 1H), 9,86(Sirs, 1H), 7,39(t, J = 7.8 Hz, 1H), 7,25(d, J =7,8 Hz, 1H), 7.23 percent(s, 1H), 7,16(d, J = 7.8 Hz, 1H), 3.00 and(s, 3H), 2,48-of 2.34(m, 4H), 1.69 in(m, 2H), 1,59(m, 2H).

Example 25(11)

8-(3-(N-(4-chlorobutanol)amino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf of 0.41 (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,11(s, 1H), to 10.09(s, 1H), 7,72(m, 1H), 7,63(s, 1H), 7,38(DD, J = 7,8, and 7.8 Hz, 1H), to 7.09(m, 1H), 5,74(s, 1H), 3,69(t, J = 6.3 Hz, 2H), 3,22 totaling 3.04(m, 2H), 2,60 of-2.32(m, 4H), 2,12-of 1.94(m, 2H), 1,82-1,64(m, 2H).

Example 25(12)

4-(2-(N-(2-bromoacetyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.68 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,56(s, 1H), 8,33(shirt, J = 5,1 Hz, 1H), 3,82(s, 2H), 3,44-3,26(m, 2H), 2,64(t, J = 6.9 Hz, 2H), 2,54-of 2.28(m, 4H), 1,78-of 1.52(m, 4H).

Example 25(13)

4-(2-(N-(3-bromopropyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,71 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,55(Sirs, 1H), 8,07(shirt, J = 6.0 Hz, 1H), 3,61(t, J = 6.0 Hz, 2H), 3,44-3,24(m, 2H), 2,72-of 2.28(m, 8H), 1,78-and 1.54(m, 4H).

Example 26

4-(3-(N-(5-(N'-methyl-N'-tert-butoxycarbonylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The mixture of compounds obtained in example 1 (277 mg), triethylamine (223 mg), (N-methyl-N-tert-butoxycarbonylamino)pentanol acid (277 mg), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl the Il)carbodiimide (230 mg), 1-hydroxybenzotriazole (184 mg) and dimethylformamide (3,00 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated. To the residue was added water, the residue was extracted with ethyl acetate. The extract was washed successively 1H. hydrochloric acid, water, saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from a solvent mixture of ethyl acetate and hexane to obtain compound according to the present invention (298 mg)having the following physical data.

TLC: Rf 0,49 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):12,88(s, 1H), becomes 9.97(s, 1H), 7,69(s, 1H), 7,58(d, J = 8,1 Hz, 1H), 7,35(t, J = 8,1 Hz, 1H), was 7.08(d, J = 8,1 Hz, 1H), 3.15 in(t, J = 6,8 Hz, 2H), 2,74(s, 3H), 2,48-of 2.30(m, 6H), 1.70 to 1,50(m, 8H), of 1.36(s, 9H).

Example 26(1) - example 26(19)

By the same procedure described in example 26, if necessary, were synthesized the following compounds according to the present invention by transformation into the corresponding salts in the usual way using the compound obtained in example 1 or the corresponding derivative and (N-methyl-N-tert-butoxycarbonylamino)pentanol acid or a corresponding derivative.

Example 26(1)

4-(3-(N-(5-(N'-methyl-N'-benzyloxycarbonylamino)pins shall anoil)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.29 (methanol: methylene chloride = 1:20);

NMR(DMSO-d6):12,88(s, 1H), 9,98(s, 1H), of 7.70(s, 1H), 7,58(d, J = 7.8 Hz, 1H), 7,32(m, 6H), was 7.08(d, J = 7.8 Hz, 1H), 5,04(s, 2H), 3,28 is 2.33(m, 11H), 1,69-is 1.51(m, 8H).

Example 26(2)

4-(3-(N-(4-chlorobutanol)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.48 (methanol: methylene chloride = 1:20);

NMR(DMSO-d6):12,88(s, 1H), 10,07(s, 1H), 7,69(s, 1H), to 7.59(d, J = 7.8 Hz, 1H), 7,35(t, J = 7.8 Hz, 1H), to 7.09(d, J = 7.8 Hz, 1H), 3,69(t, J = 6.3 Hz, 2H), 2,46-to 1.59(m, 12H).

Example 26(3)

Methanesulfonate of 4-(3-(N-(5-(N',N'-dimethylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.30 (methanol: methylene chloride: saturated aqueous ammonia= 2:8:0,1);

NMR(CD3OD): δ of 7.75(t, J = 1.8 Hz, 1H), 7,63(sird, J = 8,1 Hz, 1H), 7,45(t, J = 8,1 Hz, 1H), 7,20(sird, J = 8,1 Hz, 1H), and 3.16(m, 2H), 2,89(s, 6H), is 2.74(s, 3H), 2,66-of 2.50(m, 6H), is 1.81(m, 8H).

Example 26(4)

4-(3-(N-(5-(N'-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,79 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):12,88(s, 1H), becomes 9.97(s, 1H), 7,69(s, 1H), to 7.59(d, J = 7.8 Hz, 1H), 7,37-7,26(m, 6H), was 7.08(d, J = 7.8 Hz, 1H), 4,99(s, 2H), 3,00(m, 2H), 2,48-of 2.28(m, 6H), 1,69-of 1.42(m, 8H).

Example 26(5)

4-(3-(N-(2-(2-chloroethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,41 (methanol: methylene chloride = 1:20);

NMR(DMSO-d6):12,89(s, 1H), 9,81(s, 1H), 7,73(s, 1H), to 7.67(d, J = 7.8 for the C, 1H), 7,38(t,J = 7.8 Hz, 1H), 7,13(d, J = 7.8 Hz, 1H), 4,14(s, 2H), 3,81(s, 4H), 2,48-of 2.34(m,4H), 1.70 to to 1.59(m, 4H).

Example 26(6)

4-(3-(N-(5-(N'-methyl-N'-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazine-1(6H)-he

TLC: Rf 0.28 in (methanol: methylene chloride = 1:20);

NMR(DMSO-d6):10,34(s, 1H), 9,98(s,1H), 7,68(s, 1H), 7,56(d, J = 9.0 Hz, 1H), 7,33(m, 6H), 7,01(d, J = 7.8 Hz, 1H), 5,04(s, 2H), 3,86(m, 1H), 3.25 to to 1.42(m, 19H).

Example 26(7)

4-(3-(5-(N'-methyl-N'-benzyloxycarbonylamino)pentanoyl)AMINOPHENYL)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0,24 (methanol: chloroform = 1:10);

NMR(DMSO-d6):10,53(s, 1H), 10,01(s, 1H), to 7.67(t, J = 1.5 Hz, 1H), 7,58(m, 1H), 7,34(m, 6H), 7,06(m, 1H), 5,04(s, 2H), 4,23(DD, J = 8,6, and 4.8 Hz, 1H), 3,57(sird, J = a 13.8 Hz, 1H), or 3.28(m, 3H), of 3.07(t, J = 12.0 Hz, 1H), 2,88-to 2.65(m, 5H), 2,33(m, 3H), of 1.52(m, 4H).

Example 26(8)

4-(3-(N-(5-(N'-methyl-N'-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-2,5,6,7,8,9-hexahydro-1H-cyclohepta[d]pyridazin-1-he

TLC: Rf of 0.54 (chloroform: methanol = 9:1);

NMR(CDCl3):of 10.58(Sirs, 1H), 8,21(Sirs, 1H), 7,69(Sirs, 1H),7,60(m, 1H), 7,40-7,28(m, 6H),? 7.04 baby mortality(m, 1H), 5,13(s, 2H), 3,42 of 3.28(m, 2H), 3.00 and-of 2.86(m, 5H), 2,70-of 2.64(m, 2H), 2,46-of 2.30(m, 2H), 1,94-of 1.84(m, 2H), 1,80-1,60(m, 8H).

Example 26(9)

4-(3-(N-(4-(N'-methyl-N'-tert-butoxycarbonylamino)butanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0.35 in (methylene chloride: methanol = 10:1).

Example 26(10)

4(3-(N-(6-(N'-methyl-N'-tert-butoxycarbonylamino)hexanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0.35 (methylene chloride: methanol = 10:1).

Example 26(11)

4-(3-(N-(5-(N'-(3-methyl-2-butenyl)-N'-tert-butoxycarbonylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.31 in (hexane: ethyl acetate = 1:3);

NMR(DMSO-d6):12,87(s, 1H), 9,95(s, 1H), 7,68(m, 1H), 7,58(m, 1H), 7,34(DD, J = 7,8, and 7.8 Hz, 1H), 7,07(m, 1H), 5,10(m, 1H), and 3.72(d, J = 6.6 Hz, 2H), 3,16-3,00(m, 2H), 2,62-to 2.40(m, 2H), 2.40 a-2,22(m, 4H), 1,78-of 1.30(m, 8H), of 1.64(s, 3H), 1,60(s, 3H), of 1.36(s, 9H).

Example 26(12)

4-(3-(N-(5-(N'-methyl-N'-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf to 0.63 (chloroform: methanol: water= 8:2:0,2);

NMR(CD3OD):7,74(s, 1H), EUR 7.57(d, J = 7.8 Hz, 1H), 7,41(t, J = 7.8 Hz, 1H), 7,35-7,20(m, 5H), 7,14(d, J = 7.8 Hz, 1H), to 6.39(s, 1H), to 5.08(s, 2H), of 3.73-3,68(m, 2H), 3,38 of 3.28(m, 2H), 3,16-3,10(m, 2H), 2.91 in(Sirs, 3H), 2,44 was 2.25(m, 2H), 1,78 of 1.50(m, 4H).

Example 26(13)

The hydrochloride of 4-(3-(N-(2-(N',N'-dimethylamino)acetyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.27 (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,92(s, 1H), 10,97(s, 1H), 9,96(Sirs, 1H), 7,72(m, 1H), 7,65(m, 1H), 7,43(DD, J = 7,8, and 7.8 Hz, 1H), 7,20(m, 1H), 4.16 the(s, 2H), 2,87(s, 6H), 2,60-of 2.24(m, 4H), 1,80 of 1.50(m, 4H).

Example 26(14)

4-(3-(N-(1-tert-butoxycarbonylamino-3-ylcarbonyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.27 (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,88(s, 1H), 10,13(s, 1H), 7,71(m, 1H), 7,60(m, 1H), 7,37(DD, J = 7,5, 7.5 Hz, 1H), 7,12(m, 1H), 4,08-a-3.84(m, 4H), 3.46 in(m, 1H), 2,54-of 2.28(m, 4H), 1,78-of 1.52(m, 4H), l,38(s, 9H).

Example 26(15)

4-(3-(N-(1-tert-butoxycarbonylamino-2-ylcarbonyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

NMR(DMSO-d6):12,88(s, 1H), 10,07(s, 1H), 7,71(s, 1H), 7.62mm(d, J = 7.8 Hz, 1H), 7,37(t, J = 7.8 Hz, 1H), 7,10(d, J = 7.8 Hz, 1H), 4,17(m, 1H), 3,38-of 2.34(m, 8H), 1,98 is 1.60(m, 6H), to 1.38(s, 9H x 1/3), of 1.26(s, 9H x 2/3).

Example 26(16)

4-(2-(N-(2-(N'-tert-butoxycarbonylamino)acetyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.31 in (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,54(s, 1H), 7,82(shirt, 1H), 6,91(shirt, 1H), 3,47(d, J = 6.3 Hz, 2H), 3,40-3,26(m, 2H), 2,61(t, J = 7.2 Hz, 2H), 2,56-of 2.30(m, 4H), 1,76-and 1.54(m, 4H), of 1.36(s, 9H).

Example 26(17)

4-(2-(N-(3-(N'-tert-butoxycarbonylamino)propanol)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.44 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,54(s, 1H), 7,92(t, J = 6.0 Hz, 1H), 6,72(shirt, 1H), 3,42-3,18(m, 2H), 3,16-to 3.02(m, 2H), 2,68-of 2.28(m, 6H), to 2.18(t, J = 7.2 Hz, 2H), 1,78-of 1.52(m, 4H), of 1.36(s, 9H).

Example 26(18)

4-(2-(N-(2-(N',N'-dimethylamino)acetyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf and 0.62 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,54(Sirs, 1H), 7,80(t, J = 5.7 Hz, 1H), 3,44-3,24(m, 2H), 2,80(s, 2H), 2,64(t, J = 7.2 Hz, 2H), 2,54-of 2.26(m, 4H), of 2.16(s, 6H), 1,76-of 1.52(m, 4H).

Example 26(19)

4-(2-(N-(4-(N'-tert-butoxycarbonylamino)butanoyl)amino)this is l)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.67 (chloroform: methanol = 4:1);

NMR(DMSO-d6):of 12.53(s, 1H), 7,85(t,J = 5.4 Hz, 1H), 6,78(t, J = 5.7 Hz, 1H), 3,40-3,20(m, 2H), 2,94 is 2.80(m, 2H), 2,60(t, J = 7.2 Hz, 2H), 2,56-of 2.28(m, 4H), for 2.01(t, J = 7.2 Hz, 2H), 1,78 of 1.46(m, 6H), of 1.36(s, 9H).

Example 27

4-(2-(N-benzylamino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The compound obtained in reference example 13, (40 mg), sodium iodide (8,4 mg) and benzylamine (0,21 ml) was stirred at room temperature for 10 hours. To the reaction mixture were added methylene chloride and saturated aqueous sodium bicarbonate solution, the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (chloroform: methanol = 50:1) to give the compounds according to the present invention (18 mg)having the following physical characteristics.

TLC: Rf of 0.29 (chloroform: methanol = 9:1);

NMR(DMSO-d6):12,46(s, 1H), 7,40-to 7.15(m, 5H), of 3.69(s, 2H), 2,80-2,60(m, 4H), 2,50-of 2.30(m, 4H), 1,63(Sirs, 4H).

Example 27(1) - example 27(80)

By the same procedure described in example 27, if necessary, were synthesized the following compounds according to the present invention by transformation into the corresponding salts in the usual way using the compound obtained in reference example 13, or the corresponding derivative and soo the relevant derivative instead of benzylamine.

Example 27(1)

4-(2-(morpholine-4-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf of 0.38 (chloroform: methanol: acetic acid= 90:10:1);

NMR(CD3OD):3,74-3,66(m, 4H), 2,84-2,77(m, 2H), 2,75-of 2.66(m, 2H), 2,64-2,48(m, 8H), 1,88-1,72(m, 4H).

Hydrochloride:

TLC: Rf is 0.24 (chloroform: methanol = 9:1);

NMR(DMSO-d6):12,68(s, 1H), 10,85(Sirs, 1H), was 4.02-to 3.92(m, 2H), 3,82-3,70(m, 2H), 3,54-3,44(m, 2H), 3,44-of 3.32(m, 2H), 3.15 and was 3.05(m,2H), 3,05-2,96(m, 2H), 2,53 is 2.33(m, 4H), 1,76 is 1.58(m, 4H).

Example 27(2)

The hydrochloride of 4-(2-(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,12 (chloroform: methanol = 9:1);

NMR(CD3OD):3,78-3,66(m, 2H), 3,63(t, J = 8,1 Hz, 2H), 3,26-3,10(m, 2H), 3,06(t, J = 8,1 Hz, 2H), 2,62-2,48(m, 4H), 2.26 and is 1.96(m,4H), 1,90-1,72(m, 4H).

Example 27(3)

The dihydrochloride of 4-(2-(4-methylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.32 (chloroform: methanol = 9:1);

NMR(DMSO-d6):12,68(s, 1H), 11,80(Sirs, 2H), 4,00-3,20(m, 10H), 3,10-2,95(m, 2H), 2,80(s, 3H), 2,50-of 2.30(m, 4H), 1,75-of 1.55(m, 4H).

Example27(4)

The hydrochloride of 4-(2-(piperidine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.34 (chloroform: methanol = 9:1);

NMR(DMSO-d6):12,66(s, 1H), 10,45(Sirs, 1H), 3,52-of 3.42(m, 2H), 3,34-up 3.22(m, 2H), 3,06-2,96(m, 2H), 2,96 is 2.80(m, 2H), 2,54 of-2.32(m, 4H), 1,84-of 1.56(m, 9H), 1,46-of 1.26(m, 1H).

Example 27(5)

The hydrochloride of 4-(2-(N-cyclohexyl what Mino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.34 (chloroform: methanol = 9:1);

NMR(DMSO-d6):12,65(s, 1H), cent to 8.85(Sirs, 2H), 3,26-3,10(m, 2H), 3,10-2,96(m, 1H), 2,90(t, J = 7.2 Hz, 2H), 2,50-of 2.36(m, 4H), 2.06 to to 1.98(m, 2H), 1,80-and 1.54(m, 7H), of 1.40 to 1.00(m, 5H).

Example 27(6)

The hydrochloride of 4-(2-(azepin-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.28 in (chloroform: methanol = 9:1);

NMR(DMSO-d6):12,66(s, 1H), 10,55(s, 1H), 3.46 in of 3.28(m, 4H), 3,20-of 3.06(m, 2H), 3,06 are 2.98(m, 2H), 2,56 is 2.46(m, 2H), 2,44-of 2.34(m, 2H), 1,90 of 1.50(m, 12H).

Example 27(7)

4-(2-(4-tert-butoxycarbonylmethyl-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.29 (chloroform: methanol = 9:1);

NMR(DMSO-d6):12,51(s, 1H), 3,32-3,24(m, 6H), 2,70-2,60(m,2H), 2,60-of 2.50(m, 2H), 2.40 a-2,30(m, 6H), 1,72-of 1.56(m, 4H), to 1.37(s, 9H).

Example 27(8)

The hydrochloride of 4-(2-(thiomorpholine-4-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.40 (chloroform: methanol = 9:1);

NMR(DMSO-d6):12,67(s, 1H), 10,90(Sirs, 1H), 3,84-3,70(m, 2H), 3,44-3,30(m, 2H), 3,24-3,10(m, 4H), is 3.08 are 2.98(m, 2H), 2,90 was 2.76(m, 2H), 2,52 is 2.44(m, 2H), 2,42-of 2.34(m, 2H), 1,76 is 1.58(m, 4H).

Example 27(9)

The hydrochloride of 4-(2-(N-(2-PROPYNYL)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.28 in (chloroform: methanol = 9:1);

NMR(DMSO-d6):12,66(s, 1H), 9,70-to 9.45(m, 2H), 3,98-3,88(m, 2H), 3,70(t, J = 2.4 Hz, 1H), 3,30-3,18(m, 2H), only 2.91(t, J = 7.8 Hz, 2H), 2,48 of-2.32(m, 4H), 1,76 is 1.58(m, 4H).

Example 27(10)

4-(2-(4-ethylpiperazin-1-yl)ethyl)-5,6,7,8-tetr hydrophilizing-1(2H)-he

TLC: Rf to 0.19 (chloroform: methanol = 5:1);

NMR(CD3OD):2,84 was 2.76(m, 2H), 2,75-to 2.67(m, 2H), 2,67-2,47(m, 12H), 2,44(kV, J = 7,5 H, 2H), 1,79(m, 4H), 1,10(t, J = 7.5 Hz, 3H).

Example 27(11)

The hydrochloride of 4-(2-(N-cyclohexylethylamine)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf is 0.49 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,66(s, 1H), 8,86(Sirs, 2H), 3,26-is 3.08(m, 2H), 3,02-is 2.88(m, 2H), 2,86-2,70(m, 2H), 2,58-of 2.30(m, 4H), 1,88 of 1.50(m, 10H), 1,32-of 0.82(m, 5H).

Example 27(12)

4-(2-(asokan-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.41 (chloroform: methanol = 5:1);

NMR(CD3OD):3,61(t, J = 6.6 Hz, 2H), to 3.58-3,30(m, 4H), is 3.08(t, J = 6.6 Hz, 2H), 2,62-of 2.50(m, 4H), 2,12-to 1.60(m, 14H).

Example 27(13)

4-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.29 (chloroform: methanol: saturated aqueous ammonia= 5:1:0,1);

NMR(CD3OD):3,26(m, 4H), is 3.08-a 3.01(m, 4H), 2,96(t, J = 6.0 Hz, 2H), 2,84(m, 2H), of 2.81(s, 3H), 2,60(m, 2H), 2,52(m,2H), 2,03(m, 2H), 1,80(m, 4H).

Example 27(14)

4-(2-(N-(2-(N'-tert-butoxycarbonylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.47 (chloroform: methanol = 8:1);

NMR(DMSO-d6):to 12.52(Sirs, 1H), 6.73 x(shirt, 1H), 3,34(width, 1H), 3,06-to 2.94(m, 2H), 2,80(t, J = 7.2 Hz, 2H), 2,70-of 2.54(m, 4H), 2,54-of 2.28(m, 4H), 1,76-and 1.54(m, 4H), of 1.36(s, 9H).

Example 27(15)

4-(2-(4-phenylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-12H)-he

TLC: Rf of 0.50 (chloroform: methanol = 9:1);

NMR(CD3OD):of 7.23(DD, J = 7,5, 7.5 Hz, 2H), 6,97(d, J = 7.5 Hz, 2H), 6,83(DD, J = 7,5, 7.5 Hz, 1H), 3,20(m, 4H), 2,90-2,70(m, 8H), 2,62(m, 2H), 2,52(m, 2H), 1,80(m, 4H).

Example 27(16)

4-(2-(4-(2-chlorophenyl)piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.44 (chloroform: methanol = 9:1);

NMR(CDCl3):10,61(s, 1H), was 7.36(d, J = 7.8 Hz, 1H), 7,22(DD, J = 7,8, and 7.8 Hz, 1H), 7,05(d, J = 7.8 Hz,1H), 6,98(DD, J = 7,8, and 7.8 Hz, 1H), 3,11(m, 4H), 2,78(s,4H), to 2.74(m, 4H), 2,59(m, 2H), 2,53(m,2H), 1,78(m, 4H).

Example 27(17)

4-(2-(4-benzylpiperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.43 (chloroform: methanol = 9:1);

NMR(CD3OD):of 7.36-7,22(m, 5H), of 3.54(s, 2H), 2,84-of 2.64(m, 4H), 2,64 at 2.45(m, 12H), 1,86-1,72(m, 4H).

Example 27(18)

4-(2-(N-(4-trifloromethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.33 (chloroform: methanol = 9:1);

NMR(CD3OD):7,63(d, J = 8,4 Hz, 2H), 7,54(d, J = 8,4 Hz, 2H), 3,90(s, 2H), 2,96(t, J = 6.9 Hz, 2H), 2,80(t, J = 6.9 Hz, 2H), 2,52(m, 4H), 1.77 in(m, 4H).

Example 27(19)

4-(2-(N-methyl-N-benzylamino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf of 0.32 (chloroform: methanol = 9:1);

NMR(CD3OD):7,28(m, 5H), of 3.56(s, 2H), 2,83-to 2.65(m, 4H), 2.49 USD(m, 4H), 2,31(s, 3H), at 1.73(m, 4H).

Methanesulfonate:

TLC: Rf of 0.44 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6): 12,69(s, 1H), 9,42(m, 1H), 7,49(m, 5H), 4,48(m, 1H), or 4.31(m, 1H), 3,50-of 3.25(m, 2H), 2,98(m, 2H), 2,75(m, ZN), of 2.38(m, 4H), to 2.29(s, MN), by 1.68(m, 4H).

Example 27(20)

4-(2-(N-(2-phenylethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,41 (methanol: methylene chloride = 1:10);

NMR(CD3OD):7,37(m, 5H), 3,52(t, J = 6,8 Hz, 2H), 3,38(m, 2H), of 3.07(m, 4H), 2,60(m, 4H), of 1.85(m, 4H).

Example 27(21)

4-(2-(N-(4-cryptomaterial)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.37 (chloroform: methanol = 9:1);

NMR(CD3OD):7,44(d, J = 7.5 Hz, 2H), 7.23 percent(d, J = 7.5 Hz, 2H), 3,82(s, 2H), 2,93(t, J = 6.9 Hz, 2H), and 2.79(t, J = 6.9 Hz, 2H), 2,59-2,49(m, 4H), 1.77 in(m, 4H).

Example 27(22)

4-(2-(4-(pyridin-2-yl)piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.55 (chloroform: methanol = 9:1);

NMR(CD3OD):8,08(m, 1H), 7,56(m, 1H), PC 6.82(d, J = 8,4 Hz, 1H), of 6.68(DD, J = 6,3, 4.8 Hz, 1H), 3,54(t, J = 5.1 Hz, 4H), 2,90-to 2.74(m, 4H), 2,68(t, J = 5.1 Hz, 4H), 2,62(m, 2H), 2,52(m, 2H), 1,79(m, 4H).

Example 27(23)

4-(2-(N-(2-(N'-phenylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.26 (chloroform: methanol = 9:1);

NMR(CD3OD):7,18-was 7.08(m, 2H), 6,74-only 6.64(m, 3H), 3,48-to 3.36(m, 4H), up 3.22(t, J = 6.0 Hz, 2H), 2.95 points(t, J = 6.6 Hz, 2H), of 2.51(m, 4H), of 1.78(m, 4H).

Example 27(24)

4-(2-(4-acetylpiperidine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.21 in (chloroform: methanol = 9:1);

NMR(CD3OD):3,623,52(m, 4H), 2,85-2,70(m, 4H), 2,64-2,48(m, 8H), is 2.09(s, 3H), 1,79(m, 4H).

Example 27(25)

4-(2-(N-(naphthalen-1-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.45 in (methanol: methylene chloride = 1:9);

NMR(DMSO-d6):12,49(Sirs, 1H), 8,15(m, 1H), 7,89(m, 1H), 7,79(d, J = 7.2 Hz, 1H), 7,53-7,40(m, 4H), to 4.15(s, 2H), 2,87(t, J = 7.2 Hz, 2H), 2,69(t, J = 7.2 Hz, 2H), 2,35(m, 4H), 1,62(Sirs, 4H).

Example 27(26)

4-(2-(N-ethyl-N-benzylamino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.41 (chloroform: methanol = 9:1);

NMR(CD3OD):7,30-7,20(m, 5H), of 3.60(s, 2H), 2,72(s, 4H), 2,62(kV, J = 7.2 Hz, 2H), 2,48(m, 2H), 2.40 a(m, 2H), 1.70 to(m, 4H), 1,10(t, J = 7.2 Hz, 3H).

Example 27(27)

4-(2-(N-(1-benzylpiperidine-4-yl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,17 (methylene chloride: methanol: water= 9:1:0,1);

NMR(CD3OD):7,43-of 7.23(m, 5H), of 3.60(s, 2H), 3,41(t, J = 6.6 Hz, 2H), 3,14(m, 1H), 3,06 are 2.98(m, 2H), 2.95 points(t, J = 6.6 Hz, 2H), 2,60-of 2.50(m, 4H), 2,22-to 2.06(m, 4H), 1,86 is 1.60(m, 6H).

Example 27(28)

4-(2-(N-(2-hydroxyethyl)-N-benzylamino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.44 (methylene chloride: methanol = 9: 1);

NMR(CD3OD):7,19(m, 5H), the 3.65(t, J = 8.7 Hz, 2H), 3,61(s, 2H), 2,78-to 2.67(m, 6H), 2,43(m, 2H), 2,30(m, 2H), 1,64(m, 4H).

Example 27(29)

4-(2-(4-cyclohexylpiperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.55 (methylene chloride: methanol = 9:1);

NMR(CD3OD):3,30-2,70(m, 13), at 2.59(m, 2H), of 2.51(m, 2H), 2.05 is(m, 2H), 1.91 a(m, 2H), 1,86-of 1.65(m, 6H), 1,44 is 1.20(m, 4H).

Example 27(30)

4-(2-(N-(4-terbisil)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf of 0.50 (methylene chloride: methanol = 4:1);

NMR(CD3OD):7,41(m, 2H), 7,10(DD, J= 8,7, to 8.7 Hz, 2H), 3,94(s, 2H), 3,10(t, J= 6.9 Hz, 2H), 2,85(t, J = 6.9 Hz, 2H), 2,52(m, 4H), of 1.78(m, 4H).

Hydrochloride:

TLC: Rf of 0.43 (methylene chloride: methanol = 4:1);

NMR(DMSO-d6):12,68(s, 1H), 9,00(s, 2H), EUR 7.57(m, 2H), 7,29(m, 2H), 4,20(m, 2H), 3,21(m, 2H), 2,90(m, 2H), 2,58-of 2.38(m, 4H), to 1.67(m, 4H).

Example 27(31)

4-(2-(N-(4-methoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.39 to (methylene chloride: methanol: saturated aqueous ammonia= 4:1:0,3);

NMR(CD3OD):7,40(d, J = 8.7 Hz, 2H), 6,99(d, J = 8.7 Hz, 2H), 4,15(s, 2H), 3,81(s, 3H), 3,37(t, J = 6.9 Hz, 2H), 2.95 points(t, J = 6.9 Hz, 2H), 2,53(m, 4H), of 1.78(m, 4H).

Example 27(32)

4-(2-(N-(1-phenylethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.38 (methylene chloride: methanol = 9:1);

NMR(CD3OD):to 7.50(m, 5H), 4,48(kV, J = 6,9 Hz, 1H), 3,29(m, 2H), 2,92(t, J = 6.6 Hz, 2H), of 2.51(m, 4H), of 1.78(m, 4H), to 1.70(d, J = 6.9 Hz, 3H).

Example 27(33)

4-(2-(N-(3-terbisil)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.39 to (methylene chloride: methanol = 9:1);

NMR(CD3OD):of 7.48-7,06(m, 4H), 4,06(s, 2H), 3,20(t, J = 6.9 Hz, 2H), 2,90(t, J = 6.9 Hz, 2H), 2,53(m, 4H), 1.77 in(m, 4H).

4-(2-(4-diphenylbutylpiperidine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.48 (methylene chloride: methanol = 9:1);

NMR(CD3OD):of 7.48-7,40(m, 4H), 7,32-7,13(m, 6H), 4,25(s, 1H), and 3.16(t, J = 5,1 Hz, 2H), 2,81-to 2.40(m, 14H), of 1.78(m, 4H).

Example 27(35)

4-(2-(N-(3-methoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.44 (methylene chloride: methanol = 9:1);

NMR(CD3OD):to 7.32(DD, J = 8,1, 8,1 Hz, 1H), 7,02-of 6.90(m, 3H), of 4.05(s, 2H), 3,81(s, 3H), 3,24(t, J = 6.9 Hz, 2H), 2,90(t, J = 6.9 Hz, 2H), of 2.51(m, 4H), 1.77 in(m, 4H).

Example 27(36)

Hydrochloride 8-(2-(piperidine-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.26 (chloroform: methanol = 4:1);

NMR(DMSO-d6):11,94(s, 1H), 9,31(Sirs, 1H), 6,39(Sirs, 1H), 3,60-3,10(m,6H), 3,06-to 2.74(m, 4H), of 2.34(t, J = 6.6 Hz, 2H), 1,94 of 1.50(m, 7H), to 1.38(m, 1H).

Example 27(37)

4-(2-(N-(2-phenoxyethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,62 (methylene chloride: methanol: water= 4:1:0,2);

NMR(CD3OD):7,26(DD, J = 8,1, 8,1 Hz, 2H), 6,98-to 6.88(m, 3H), 4,11(t, J = 5,1 Hz, 2H), 3,14 was 3.05(m, 4H), 2,84(t, J = 6.6 Hz, 2H), 2,60-of 2.50(m, 4H), of 1.78(m, 4H).

Example 27(38)

4-(2-(4-benzyloxycarbonyl-1,4-diazepan-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf of 0.67 (methylene chloride: methanol: saturated aqueous ammonia= 4:1:0,3);

NMR(CD3OD):7,34(m,5H), 5,11(s, 2H), 3,54(m,4H), 2,82-2,70(m,8H), 2,60(m, 2H), 2,52(m, 2H), 1,90-1,72(m, 6H).

Methanesulfonate:

TLC: Rf of 0.64 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):a 12.7(s, 1H), 9,35(s, 1H), 7,40-7,30(m, 5H), 5,11(s, 2H), with 3.89(m, 1H), 3.72 points is 3.40(m, 7H), 3,35-and 3.16(m, 2H), 2.95 points(t, J = 7.2 Hz, 2H), 2,65-of 2.50(m, 4H), of 2.30(s, 3H), of 1.85(m, 2H), 1,67(m, 4H).

Example 27(39)

The dihydrochloride of 4-(2-(4-cyclopentylpropionyl-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.14 (methylene chloride: methanol = 9:1);

NMR(CD3OD):4,00 is 3.40(m, 11H), of 3.12(t, J = 7.5 Hz, 2H), 2,62-of 2.50(m, 4H), 2,22-of 2.15(m, 2H), 1,92 by 1.68(m, 10H).

Example 27(40)

The dihydrochloride of 4-(2-(4-butylpiperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.16 (methylene chloride: methanol = 9:1);

NMR(CD3OD):4,10 is-3.45(m, 8H), 3,74(t, J = 7.2 Hz, 2H), 3,30(m, 2H), and 3.16(t, J = 7.2 Hz, 2H), 2,60(m, 2H), 2,53(m, 2H), 1,90 is 1.75(m, 6H), of 1.45(m, 2H), 1,01(t, J = 7.2 Hz, 3H).

Example 27(41)

Trihydrochloride 8-(2-(4-cyclohexylpiperazine-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf of 0.36 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,17(s, 1H), 11,85(Sirs, 1H), 5,09(width, 3H), 3,98-is 3.08(m, 11H), 2,96(m, 2H), a 2.36(t, J = 6.0 Hz, 2H), 2,10(m, 2H), 1,94-and 0.98(m, 12H).

Example 27(42)

The hydrochloride of 4-(2-(N-(4-Chlorobenzyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.75 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):12,66(s, 1H), 9,39(Sirs, 2H), to 7.59(d, J = 8.4 and the C, 2H), 7,51(d, J =an 8.4 Hz, 2H), 4,19(m, 2H), 3,18(m, 2H), equal to 2.94(t, J = 7.5 Hz, 2H), 2.40 a(m, 4H), of 1.66(m, 4H).

Example 27(43)

The dihydrochloride of 4-(2-(4-hexylpyridine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,68 (methylene chloride: methanol = 4:1);

NMR(CD3OD):Android 4.04 is-3.45(m, 8H), 3,71(t, J = 7.2 Hz, 2H), 3,26(m, 2H), 3.15 in(t, J = 7.2 Hz, 2H), 2,59(m, 2H), 2,53(m, 2H), 1,80(m, 6H), of 1.39(m, 6H), of 0.93(t, J = 6.9 Hz, 3H).

Example 27(44)

The dihydrochloride of 4-(2-(4-isopropylpiperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.25 in (methylene chloride: methanol = 4:1);

NMR(CD3OD):4,12-to 3.58(m, 11H), 3,18(t, J = 6.9 Hz, 2H), 2,60(m, 2H), 2,53(m, 2H), 1,80(m, 4H), of 1.44(d, J = 6.9 Hz, 6H).

Example 27(45)

The hydrochloride of 4-(2-(N-(2-terbisil)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.65 (methylene chloride: methanol = 4:1);

NMR(CD3OD):to 7.61-to 7.50(m, 2H), 7,32-7,20(m, 2H), 4,39(s, 2H), 3,51(t, J = 6.9 Hz, 2H), to 3.02(t, J = 6.9 Hz, 2H), 2,52(m, 4H), to 1.79(m, 4H).

Example 27(46)

The hydrochloride of 4-(2-(N-(3-methoxypropyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,42 (methylene chloride: methanol = 4:1);

NMR(CD3OD):3,55(t, J = 6.6 Hz, 2H), 3.45 points(t, J = 6.9 Hz, 2H), 3,35(s, 3H), 3,21(t, J = 6.9 Hz, 2H), 2,99(t, J = 6.6 Hz, 2H), 2,54(m, 4H), of 1.97(m, 2H), 1,79(m, 4H).

Example 27(47)

The dihydrochloride 8-(2-(N-(4-terbisil)amino)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf of 0.30 (chloroform: methanol = 4:1)

NMR(DMSO-d6):12,41(Sirs, 1H), 9,60(Sirs, 2H), 7,65(DD, J = 8,4, 5.7 Hz, 2H), 7,27(DD, J = 8,4, and 8.4 Hz, 2H), 6,00(Sirs, 2H), 4.16 the(m, 2H), 3,34-of 3.06(m, 4H), 2.95 points(t, J = 7.2 Hz, 2H), 2,39(t, J = 6.0 Hz, 2H), 1,71(m, 2H).

Example 27(48)

The hydrochloride of 4-(2-(N-(furan-2-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.32 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,66(s, 1H), was 9.33(Sirs, 2H), 7,78(d, J = 1.5 Hz, 1H), 6,65(d, J = 3.3 Hz, 1H), 6,53(DD, J = 3.3V, 1.5 Hz, 1H), 4,27(m, 2H), 3,18(m, 2H), 2,90(t, J = 7,6 Hz, 2H), 2.40 a(m, 4H), of 1.66(m, 4H).

Example 27(49)

The hydrochloride of 4-(2-(N-(4-methylbenzyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.16 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,66(s, 1H), 9,23(Sirs, 2H), 7,43(d, J = 7.8 Hz, 2H), 7,24(d, J = 7.8 Hz, 2H), 4,13(m, 2H), and 3.16(m, 2H), 2,92(t, J = 7.2 Hz, 2H), 2.40 a(m, 4H), 2,31(s, 3H), of 1.66(m, 4H).

Example 27(50)

The hydrochloride of 4-(2-(N-(2-methoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.34 in (methylene chloride: methanol = 4:1);

NMR(CD3OD):7,50-7,42(m, 2H), 7,15-7,00(m, 2H), 4,29(s, 2H), 3,92(s, 3H), of 3.48(t, J = 6.6 Hz, 2H), 3,00(t, J = 6.6 Hz, 2H), 2,53(m, 4H), of 1.78(m, 4H).

Example 27(51)

The hydrochloride of 4-(2-(N-(3-metaltipped)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,069 (methylene chloride: methanol = 4:1);

NMR(CD3OD):3,47(t, J = 6.6 Hz, 2H), 3,20(t, J = 7.2 Hz, 2H), 3,00(t, J = 6.6 Hz, 2H), 2,62(t, J = 7.2 Hz, 2H), 2,6-of 2.50(m, 4H), 2,12(s, 3H), a 2.01(m, 2H), 1,90 is 1.75(m, 4H).

Example 27(52)

4-(2-(N-(pyridine-4-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.39 to (methylene chloride: methanol = 4:1);

NMR(CD3OD):8,53(d, J = 6.0 Hz, 2H), of 7.48(d, J = 6.0 Hz, 2H), 4,06(s, 2H), 3.15 in(t, J=6,9 Hz, 2H), 2,89(t, J = 6.9 Hz, 2H), 2,60 at 2.45(m, 4H), 1,88-1,72(m, 4H).

Example 27(53)

Trihydrochloride 8-(2-(4-ethylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.26 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,24(s, 1H), 11,73(Sirs, 1H), 5,59(width, 3H), 4,00-of 3.06(m, 14H), of 2.97(t, J = 8,1 Hz, 2H), 2,37(t, J = 6.0 Hz, 2H), 1,73(m, 2H), 1.26 in(t, J = 6.9 Hz, 3H).

Example 27(54)

The dihydrochloride of 4-(2-(4-(4-forfinal)piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,60 (methylene chloride: methanol = 9:1);

NMR(CD3OD):7,10-7,00(m, 4H), 3,82-and 3.72(m, 4H), to 3.67(t, J = 7.2 Hz, 2H), 3,42-3,30(m, 4H), 3.15 in(t, J = 7.2 Hz, 2H), 2,65-of 2.50(m, 4H), equal to 1.82(m, 4H).

Example 27(55)

Trihydrochloride 4-(2-(4-(pyridin-4-yl)piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.14 (methylene chloride: methanol = 4:1);

NMR(CD3OD):of 8.28(d, J = 8.1 Hz, 2H), 7,33(d, J = 8.1 Hz, 2H), 4,50(m, 2H), 3.95 to 3,30(m, 6H), 3,71(t, J = 6.9 Hz, 2H), 3,18(t, J = 6.9 Hz, 2H), 2,62(m, 2H), 2,53(m, 2H), is 1.81(m, 4H).

Example 27(56)

Trihydrochloride 8-(2-(4-cyclopentylpropionyl-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.45 in (choroform: methanol = 4:1);

NMR(DMSO-d6):12,23(s, 1H), 12,22(Sirs, 1H), 4,66(width, 3H), 4,00-3,30(m, 11H), 3,23(m, 2H), 2,98(m, 2H), 2,37(t, J = 6.0 Hz, 2H), 2,00(m, 2H), 1,92-of 1.40(m, 8H).

Example 27(57)

Trihydrochloride 8-(2-(4-isopropylpiperazine-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.26 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,18(s, 1H), up 11,86(Sirs, 1H), 4,55(width, 3H), 3,98-3,30(m, 11H), up 3.22(m, 2H), 2,97(m, 2H), 2,37(t, J = 6.3 Hz, 2H), 1,72(m, 2H), 1,30(d, J = 6.3 Hz, 6H).

Example 27(58)

The hydrochloride of 4-(2-(N-(thiophene-2-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.32 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,65(s, 1H), 9,59(Sirs, 2H), 7.62mm(d, J = 5,1 Hz, 1H), 7,37(d, J = 2.7 Hz, 1H), to 7.09(DD, J = 5,1, 2.7 Hz, 1H), to 4.41(s, 2H), 3,18(m, 2H), 2,96(t, J = 7.8 Hz, 2H), 2.40 a(m, 4H), of 1.66(m, 4H).

Example 27(59)

The dihydrochloride of 4-(2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,72 (methylene chloride: methanol = 9:1);

NMR(CD3OD):7,15-of 6.90(m, 4H), a 3.87(s, 3H), 3,82 was 3.05(m, 8H), to 3.67(t, J = 6.9 Hz, 2H), 3,13(t, J = 6.9 Hz, 2H), 2,62-of 2.50(m, 4H), of 1.80(m, 4H).

Example 27(60)

4-(2-(N-methyl-N-(2-(N',N'-dimethylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,13 (methylene chloride: methanol: saturated aqueous ammonia= 4:1:0,5);

NMR(CD3OD):and 3.16(t, J = 6.3 Hz, 2H), 3,00(t, J = 6.9 Hz, 2H), 2,94-and 2.83(m, 4H), 2,78(s, 6H) 2,61(m,2H), 2,52(m, 2H), 2,48(s, 3H), of 1.80(m, 4H).

Example 27(61)

The dihydrochloride of 4-(2-(4-(3-methoxyphenyl)piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,54 (methylene chloride: methanol = 9:1);

NMR(CD3OD):then 7.20(DD, J = 8,4, and 8.4 Hz, 1H), 6,66-of 6.52(m, 3H), 3,90-is 3.08(m, 8H), of 3.77(s, 3H), to 3.67(t, J = 7.2 Hz, 2H), 3,14(t, J = 7.2 Hz, 2H), 2,61(m, 2H), 2,54(m, 2H), is 1.81(m, 4H).

Example 27(62)

The dihydrochloride of 4-(2-(4-((2E)-3-phenyl-2-propenyl)piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.53 (methylene chloride: methanol = 9:1);

NMR(CD3OD):7,52(m, 2H), 7,42-to 7.32(m, 3H), of 6.96(d, J = 16.2 Hz, 1H), 6,36(dt, J = 16,2, 7.2 Hz, 1H), Android 4.04(d, J = 7.2 Hz, 2H), 3,90 is-3.45(m, 10H), of 3.13(t, J = 7.2 Hz, 2H), 2,59(m, 2H), 2,53(m, 2H), 1,79(m, 4H).

Example 27(63)

The dihydrochloride of 4-(2-(4-(1-methylpropyl " piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,13 (methylene chloride: methanol = 9:1);

NMR(CD3OD):4,15 is 3.40(m, 11N)and 3.15(t, J = 6.9 Hz, 2H), 2,60(m, 2H), 2,53(m, 2H), 2,02 is 1.58(m, 6H), of 1.41(d, J = 6,6 Hz, MN), was 1.06(t, J = 7.5 Hz, 3H).

Example 27(64)

The hydrochloride of 4-(2-(4-(furan-2-ylcarbonyl)piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,42 (methylene chloride: methanol = 9:1);

NMR(CD3OD):7,73(DD, J = 1,8, 0.9 Hz, 1H), 7,17(DD, J = 2,4, and 0.9 Hz, 1H), 6,63(DD, J = 2.4, 1.8 and Hz, 1H), 4.80 to the 4.65(m, 2H), 3,90 is 3.25(m, 6H), 3,66(t, J = 7.2 Hz, 2H), 3,13(t, J = 7.2 Hz, 2H), 2,60(m, 2H), 2,53(m, 2H), 1,80(m, 4H).

Example 27(65)

Methanesulfonate of 4-(-(N-(3-Chlorobenzyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.38 (methylene chloride: methanol = 9:1);

NMR(CD3OD):of 7.60(s, 1H), 7,47(s, MN), or 4.31(s, 2H), 3,49(t, J = 6.9 Hz, 2H), to 3.02(t, J = 6.9 Hz, 2H), 2,72(s, ZN), of 2.54(m, 4H), to 1.79(m, 4H).

Example 27(66)

8-(2-(N-benzylamino)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf 0,42 (methylene chloride: methanol = 4:1);

NMR(CD3OD):7,58 was 7.45(m, 5H), 4,28(s, 2H), 3,47(t, J = 6.6 Hz, 2H), 3,34(m, 2H), 2,89(t, J = 6.6 Hz, 2H), 2,52(t, J = 6.6 Hz, 2H), to 1.86(m, 2H).

Example 27(67)

8-(2-(N-(2-(N'-phenylamino)ethyl)amino)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf of 0.23 (methylene chloride: methanol = 4:1);

NMR(CD3OD):to 7.15(m, 2H), 6,69(m, 3H), 3,50(m, 4H), of 3.32(m, 4H), 2,89(t, J = 6.6 Hz, 2H), of 2.51(t, J = 6.6 Hz, 2H), of 1.84(m, 2H).

Example 27(68)

Trihydrochloride 8-(2-(4-hexylpyridine-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,51 (methylene chloride: methanol = 4:1);

NMR(CD3OD):4,10-3,55(m, 10H), 3,47(t, J = 5.7 Hz, 2H), 3,30(m, 2H), 3,18(t, J = 7.2 Hz, 2H), 2.63 in(t, J = 6.3 Hz, 2H), 1,92(m, 2H), is 1.81(m, 2H), 1.39 in(m, 6H), of 0.93(m, 3H).

Example 27(69)

4-(2-(N-(2,4-diferensial)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.15 (methanol: methylene chloride = 1:10).

Example 27(70)

The dihydrochloride of 4-(2-(4-(2-methylpropyl " piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,63 (methylene chloride: methanol = 4:1);

NMR(CD3OD): 4,05-to 3.50(m, 8H), of 3.78(t, J = 7.2 Hz, 2H), 3,24 is 3.15(m, 4H), 2,60(m, 2H), 2,53(m, 2H), measuring 2.20(m, 1H), 1,80(m, 4H), 1,10(d, J = 6.6 Hz, 6H).

Example 27(71)

Trihydrochloride 8-(2-(4-(4-forfinal)piperazine-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,69 (methylene chloride: methanol = 9:1);

NMR(CD3OD):7,12-7,00(m, 4H), 3,85-3,70(m, 6H), 3,51(t, J = 5.7 Hz, 2H), 3,50-3,18(m, 6H), to 2.67(t, J = 6.3 Hz, 2H), 1,95(m, 2H).

Example 27(72)

Methanesulfonate 8-(2-(4-(pyridin-4-yl)piperazine-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,12 (methylene chloride: methanol = 4:1);

NMR(CD3OD):of 8.15(d, J = 7.8 Hz, 2H), 7,20(d, J = 7.8 Hz, 2H), 3,90 of 3.75(m, 4H), to 3.35(m, 2H), 3,05-2,78(m, 8H), 2,69(s, 3H), 2,52(t, J = 6.3 Hz, 2H), to 1.86(m, 2H).

Example 27(73)

Methanesulfonate 8-(2-(4-(4-methoxyphenyl)piperazine

-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf of 0.65 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):to 12.0(s, 1H), at 9.53(Sirs, 1H), 6,97(d, J = 9.0 Hz, 2H), 6,85(d, J = 9.0 Hz, 2H), 6.42 per(s, 1H), 3,80-of 3.60(m, 4H), of 3.69(s, 3H), 3,50(m, 2H), 3,30-3,18(m, 4H), 2,98 is 2.80(m, 4H), to 2.35(m, 2H), 2,32(s, 3H), of 1.73(m, 2H).

Example 27(74)

4-(2-(N-methyl-N-(3-(N',N'-dimethylamino)propyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,10 (methylene chloride: methanol: saturated aqueous ammonia= 4:1:0,5%);

NMR(CD3OD):2,77(m, 4H), 2,64 at 2.45(m, 6H), a 2.36(m, 2H), 2,33(s, 3H), and 2.26(s, 6H), 1.85 to of 1.65(m, 6H).

Example 7(75)

4-(2-(N-(2-(N',N'-diethylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,13 (methylene chloride: methanol: saturated aqueous ammonia= 4:1:0,5%);

NMR(CD3OD):to 3.38(t, J = 6,6 H, 2H), 3,24(m, 2H), 3,10(m, 2H), 3,05 of 2.92(m, 6H), 2,62-2,48(m, 4H), of 1.80(m, 4H), to 1.21(t, J = 7,2 H, 6H).

Example 27(76)

8-(2-(morpholine-4-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

Free form:

TLC: Rf 0,60 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):11,73(s, 1H), return of 6.58(s, 1H), to 3.58-3,55(m, 4H), 3,17(m, 2H), 2,58(m, 4H), to 2.41(m, 4H), 2,32(t, J = 6.0 Hz, 2H), 1,71-to 1.67(m, 2H).

Methanesulfonate:

TLC: Rf value of 0.52 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):11,96(s, 1H), 9,65(Sirs, 1H), 6,36(s, 1H), 4,01(m, 2H), 3,65(t, J = 11.7 Hz, 2H), of 3.45(m, 4H), and 3.16(m, 4H), and 2.83(t, J = 7.8 Hz, 2H), 2,35(m, 2H), 2,31(s, 3H), 1,72(m, 2H).

Example 27(77)

Methanesulfonate 8-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,41 (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,1);

NMR(DMSO-d6):11,85(s,1H), 10,28(Sirs, 1H), 6,41(s, 1H), 3,32-2,78(m, 16H), 2,42-of 2.20(m, 6H), 2,12(m, 2H), 1,71(m, 2H).

Example 27(78)

The dihydrochloride of 4-(2-(4-cyclohexylpiperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf value of 0.52 (methylene chloride: methanol = 4:1);

NMR(CD3OD):4,10-to 3.50(m, 8H), 3,76(t, J = 6,9 H, 2H), 3,20-of 3.12(m, 4), 2,65-2,48(m, 4H), 1,98-of 1.65(m, 12H), 1,48 of 1.00(m, 3H).

Example 27(79)

Trihydrochloride 8-(2-(4-butylpiperazine-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.28 in (methylene chloride: methanol = 4:1);

NMR(CD3OD):4,15-of 3.60(m, 8H), 3,80(t, J = 7.2 Hz, 2H), 3,48(t, J = 5.7 Hz, 2H), or 3.28(m, 2H), 3,19(t, J = 7.2 Hz, 2H), 2,65(t, J = 6.6 Hz, 2H), was 1.94(m, 2H), 1,80(m, 2H), 1,45(m, 2H), 1,01(t, J = 7.2 Hz, 3H).

Example 27(80)

4-(5-(morpholine-4-yl)pentyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.43 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,48(s, 1H), 3,54(t, J = 7.5 Hz, 4H), 2,54 is 2.43(m, 4H), 2.40 a-2,28(m, 6H), 2,22(t, J = 7.5 Hz, 2H), 1,74 is 1.60(m, 4H), 1,64 is 1.48(m, 2H), 1,50 to 1.37(m, 2H), 1,40-of 1.26(m, 2H).

Example 28

Methanesulfonate of 4-(3-(N-(5-(morpholine-4-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

A mixture of the compound obtained in example 25(1), (115 mg) and research (0.5 ml) was boiled under reflux for 3 hours. The reaction mixture was concentrated. To the residue was added water, the residue was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from a solvent mixture of isopropanol and hexane. A solution of the obtained solid (56,2 mg) and methanesulfonate (13.2 mg) in methanol (3.0 ml) PE is amasyali at room temperature for 1 hour. The reaction mixture was concentrated to obtain compound according to the present invention (67,9 mg)having the following physical characteristics.

TLC: Rf 0,41 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):12,90(s, 1H), 10,04(s, 1H), 9,42(Sirs, 1H), of 7.70(s, 1H), 7,60(d, J = 8,1 Hz, 1H), was 7.36(t, J = 8,1 Hz, 1H), 7,10(d, J = 8,1 Hz, 1H), 3.96 points(m, 2H), 3,61(t, J = 11,4 Hz, 2H), 3.43 points-of 2.30(m, 12H), to 2.29(s, 3H), 1,63(m, 8H).

Example 28(1) - example 28(42)

By the same procedure described in example 28, if necessary, were synthesized the following compounds according to the present invention by transformation into the corresponding salts in the usual way using the compound obtained in example 25(1), or compounds obtained in example 23(23), 23(24), 23(29), 23(37), 25, 25(2), 25(6) - 25(8), 25(11) - 25(13), 26(2) or 26(5), and the research or the corresponding derivative.

Example 28(1)

Methanesulfonate of 4-(3-(N-(4-(morpholine-4-yl)butanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,22 (methanol: methylene chloride = 1:9);

NMR(DMSO-d6):12,90(s,1H), 10,12(s, 1H), 9,54(Sirs, 1H), of 7.70(s, 1H), to 7.59(d, J = 7.8 Hz, 1H), 7,37(t, J = 7.8 Hz, 1H), 7,11(d, J = 7.8 Hz, 1H), 3,98(m, 2H), 3,63(t, J = 11,6 Hz, 2H), 3.43 points of-2.32(m, 12H), is 2.30(s, 3H), 1,95(m, 2H), 1,64(m, 4H).

Example 28(2)

Methanesulfonate of 4-(3-(N-(5-(4-methoxypiperidine-1-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.29 (methanol: methylene is lorid = 2:3);

NMR(DMSO-d6):12,89(s, 1H), 10,04(s, 1H), 8,95(Sirs, 1H), of 7.70(s, 1H), to 7.59(d, J = 7.8 Hz, 1H), was 7.36(t, J = 7.8 Hz, 1H), 7,10(d, J = 7.8 Hz, 1H), 3,52 is 2.33(m, 13H), 3,24(s, 3H), to 2.29(s, 3H), 2,15-of 1.46(m, 12H).

Example28(3)

Methanesulfonate of 4-(3-(N-(2-(2-(morpholine-4-yl)ethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.50 (a methanol: methylene chloride = 1:9);

NMR(DMSO-d6):12,91(s, 1H), 10,00(s, 1H), 9,78(Sirs, 1H), of 7.70(s, 1H), to 7.64(d, J = 7.8 Hz, 1H), 7,40(t, J = 7.8 Hz, 1H), 7,15(d, J = 7.8 Hz, 1H), 4,20(s, 2H), 4,05 is 3.40(m, 10H), and 3.16(m, 2H), 2,56 is 2.33(m, 4H), 2,31(s, 3H), 1.70 to to 1.59(m, 4H).

Example 28(4)

Methanesulfonate of 4-(3-(N-(4-(morpholine-4-yl)butanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf of 0.16 (chloroform: methanol = 9:1);

NMR(DMSO-d6):10,53(s, 1H), 10,15(s, 1H), 9,59(bc, 1H), of 7.70(s, 1H), 7,58-of 7.55(m, 1H), 7,35(t, J = 7.8 Hz, 1H), 7,07(d, J = 7.8 Hz, 1H), 4,28-4,18(m, 1H), 3,99-of 3.94(m, 2H), 3,68-of 3.42(m, 5H), 3,17-3,00(m, 5H), 2,90-2,80(m, 2H), 2,74-of 2.64(m, 1H), 2,43(t, J = 6.9 Hz, 2H), 2,33-of 2.26(m, 4H), 2.00 in 1,90(m, 2H).

Example 28(5)

Methanesulfonate of 4-(3-(N-(5-(N'-(2-PROPYNYL)amino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.30 (methanol: methylene chloride = 1:9);

NMR(DMSO-d6):12,88(s, 1H), there is a 10.03(s, 1H), 8,93(Sirs, 2H), of 7.70(s, 1H), 7,60(d, J = 7.8 Hz, 1H), was 7.36(t, J = 7.8 Hz, 1H), to 7.09(d, J = 7.8 Hz, 1H), 3,92(m, 2H), and 3.72(t, J = 2.4 Hz, 1H), 2,96(m, 2H), 2,48 of-2.32(m, 6H), 2,31(s, 3H), of 1.65(m, 8H).

Example 28(6)

Methanesulfonate of 4-(3-(N-(5-(N'-(2-m is Teal-2-propenyl)amino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.36 and (methanol: methylene chloride: saturated aqueous ammonia= 1:9:0,1);

NMR(DMSO-d6):12,88(Sirs, 1H), 10,07(s, 1H), 8,54(Sirs, 2H), 7,71(s, 1H), to 7.61(d, J = 7.8 Hz, 1H), 7,35(t, J = 7.8 Hz, 1H), to 7.09(d, J = 7.8 Hz, 1H), 5,08(s, 1H), 5,07(s,1H), 3,51(t, J = 6.0 Hz, 2H), 2,89(m, 2H), 2,48-2,34(m, 9H), 1.77 in(s, 3H), 1,69-to 1.59(m, 8H).

Example 28(7)

Methanesulfonate of 4-(3-(N-(5-(1,2,3,6-tetrahydropyridine-1-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.48 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,88(s, 1H), of 10.05(s, 1H), 9,43(Sirs, 1H), of 7.70(s, 1H), 7,60(m, 1H), was 7.36(DD, J = 7,8, and 7.8 Hz, 1H), to 7.09(d, J = 7.8 Hz, 1H), 5,90(m, 1H), 5,70(m, 1H), 3,80(m, 1H), 3,54(m, 1H), 3,22 are 2.98(m, 4H), 2,60-to 2.18(m, 8H), of 2.50(s, 3H), 1,82 of 1.50(m, 8H).

Example 28(8)

Methanesulfonate of 4-(3-(N-(5-(N'-cyclopropylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.35 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,88(s, 1H), 10,06(s, 1H), 8,56(Sirs, 2H), of 7.70(s, 1H), 7,60(m, 1H), was 7.36(DD, J = 7,8, and 7.8 Hz, 1H), to 7.09(m, 1H), is 3.08-2,90(m, 2H), 2,69(m, 1H), 2,56-of 2.20(m, 6H), was 2.34(s, 3H), 1,80 of 1.46(m, 8H), 0,84-0,64(m, 4H).

Example 28(9)

Methanesulfonate of 4-(3-(N-(4-(morpholine-4-yl)butanoyl)amino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf 0,69 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):10,89(s, 1H), 10,16(s, 1H), 9,52(width, 1H), 7,74(s, 1H), to 7.61(d, J = 7.8 Hz, 1H), 7,40(t, J = 7.8 Hz, 1H), 7,12(d, J = 7.8 Hz, 1H), 6,27(s, 1H), was 4.02-of 3.94(m, 2H), 3,6-to 3.58(m, 4H), 3,50-of 3.42(m, 2H), 3,20-a 3.01(m, 6H), 2,48-to 2.42(m, 2H), 2,02-of 1.92(m, 2H).

Example 28(10)

The hydrochloride of 4-(3-(N-(2-(2-(piperidine-1-yl)ethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.30 (methanol: methylene chloride = 1:9);

NMR(DMSO-d6):12,89(s, 1H), 10,19(s, 2H), 7,83(s, 1H), 7,79(d, J = 8,1 Hz, 1H), 7,38(t, J = 8,1 Hz, 1H), 7,13(d, J = 8,1 Hz, 1H), 4.16 the(s, 2H), 3,85(t, J = 5,1 Hz, 2H), or 3.28(m, 2H), 2,58(m, 2H), 2,48 to 2.35(m, 6H), 1,82-to 1.59(m, 10H).

Example 28(11)

The hydrochloride of 4-(3-(N-(2-(2-(pyrrolidin-1-yl)ethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.55 (methanol: methylene chloride: saturated aqueous ammonia= 1:9:0,1);

NMR(DMSO-d6):12,88(s, 1H), 10,66(Sirs, 1H), 10,17(s,1H), 7,86(s, 1H), 7,83(d, J = 7.8 Hz, 1H), 7,37(t,J = 7.8 Hz, 1H), 7,12(d, J = 7.8 Hz, 1H), 4.16 the(s,2H),3,82 -3,55(m,4H), to 3.38(m, 2H), 3,03(m, 2H), 2,48-of 2.36(m,4H), 1,99-to 1.59(m, 8H).

Example 28(12)

The hydrochloride of 4-(3-(N-(5-(3-methoxypiperidine-1-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.45 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,88(s, 1H), 10,51(Sirs, 1/2H), 10,24(s, 1/2H), and 10.20(s,1/2H), 9,11(Sirs,1/2H), 7,73(s, 1H), to 7.64(m, 1H), 7,35(DD, J = 7,8, and 7.8 Hz, 1H), to 7.09(m, 1H), 3,74-3,20(m, 8H), 3,14-to 2.94(m, 2H), 2,80-2,24(m, 8H), 2,16-1,10(m, 10H).

Example 28(13)

The hydrochloride of 4-(3-(N-(2-(morpholine-4-yl)acetyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.44 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6): 12,92(s, 1H), 10,92(Sirs, 1H), 10,52(Sirs, 1H), 7,71(s, 1H), to 7.64(d, J = 7.8 Hz, 1H), 7,43(t, J = 7.8 Hz, 1H), 7,20(d, J = 7.8 Hz, 1H), 4,20-of 2.27(m, 14H), was 1.69(m, 2H), 1,60(m, 2H).

Example 28(14)

The hydrochloride of 4-(3-(N-(2-(N'-(2-PROPYNYL)amino)acetyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.43 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,92(s, 1H), 10,88(s,1H), for 9.64(Sirs, 2H), 7,69(s, 1H),7.62mm(d, J = 7.8 Hz,1H), 7,43(t, J = 7.8 Hz, 1H), 7,18(d, J = 7.8 Hz, 1H), was 4.02(s, 2H), of 3.97(s, 2H), 3,76(t, J = 2.1 Hz, 1H), 2,48 to 2.35(m, 4H), 1.69 in(m, 2H), 1,60(m, 2H).

Example 28(15)

The hydrochloride of 4-(3-(N-(2-(N'-cyclobutylamine)acetyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.40 in (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,92(s, 1H), 10,81(s, 1H), 9,29(m, 2H), 7,69(s, 1H), 7,63(d, J = 7.8 Hz, 1H), 7,43(t, J = 7.8 Hz, 1H), 7,18(d, J = 7.8 Hz, 1H), 3,85-3,71(m, 3H), 2,45 and 2.13(m, 8H), 1,80-to 1.61(m, 6H).

Example 28(16)

The hydrochloride of 4-(3-(N-(3-(morpholine-4-yl)propanol)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,41 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,89(s, 1H), 10,57(Sirs, 1H), 10,42(s, 1H), of 7.70(s, 1H), to 7.61(d, J = 7.8 Hz, 1H), 7,38(t, J = 7.8 Hz, 1H), 7,12(d, J = 7.8 Hz, 1H), 3.96 points(m, 2H), 3,74(t, J = 11.5 Hz, 2H), 3,42-to 3.33(m, 4H), to 3.09(m, 2H), 2,92(t, J = 7.5 Hz, 2H), 2,48-of 2.34(m, 4H), 1.69 in(m, 2H), 1,60(m, 2H).

Example 28(17)

The hydrochloride of 4-(3-(N-(3-(N'-(2-PROPYNYL)amino)propanol)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.40 in (methanol: methylene chloride = 1:10);

NMR(DMSO-d ):12,89(s, 1H), 10,43(s, 1H), 9,37(Sirs, 2H), 7,72(s, 1H), to 7.61(d, J = 7.8 Hz, 1H), 7,38(t, J = 7.8 Hz, 1H), 7,12(d, J = 7.8 Hz, 1H), 3,93-3,71(m, 3H), of 3.25(m, 2H), and 2.83(t, J = 6.9 Hz, 2H), 2,48-of 2.34(m, 4H)that was 1.69(m, 2H), 1,59(m, 2H).

Example 28(18)

The hydrochloride of 4-(3-(N-(4-(N'-(2-PROPYNYL)amino)butanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.25 in (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,89(s, 1H), 10,24(s, 1H), 9,35(Sirs, 2H), of 7.70(s, 1H), 7.62mm(d, J = 8,1 Hz, 1H), was 7.36(t, J = 8,1 Hz, 1H), 7,10(d, J = 8,1 Hz, 1H), 3,91(d, J = 2.7 Hz, 2H), 3,70(t, J = 2.7 Hz, 1H), 3,00(m, 2H), 2,44(m, 4H), was 2.34(m, 2H), 1,92(m, 2H), 1.69 in(m, 2H),1,60(m, 2H).

Example 28(19)

The dihydrochloride 8-(3-(N-(4-(morpholine-4-yl)butanoyl)amino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf of 0.54 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,34(Sirs, 1H), 11,04(Sirs, 1H), 10,31(s, 1H), 7,78-to 7.64(m, 2H), 7,39(DD, J = 7,8, and 7.8 Hz, 1H), 7,11(m, 1H), was 4.02-3,70(m, 4H), 3,50-of 3.32(m, 2H), 3,24-2,90(m, 6H), 2,60-of 2.34(m, 4H), 2,12-1,90(m, 2H), 1,82-1,62(m, 2H).

Example 28(20)

4-(2-(N-(2-(pyrrolidin-1-yl)acetyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.43 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,56(s, 1H), to 7.77(t, J = 5.7 Hz, 1H), 3,42-3,26(m, 2H), 2,97(s, 2H), 2.63 in(t, J = 6.9 Hz, 2H), 2,54-of 2.28(m, 8H), 1,76-of 1.52(m, 8H).

Example 28(21)

4-(N-(2-(N'-cyclobutylamine)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.21 in (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6): 12,57(width, 1H), 7,97(t, J = 6.0 Hz, 1H), 3,40(s, 2H), 3,18-3,03(m, 3H), 2,52 at 2.45(m, 2H), 2,44 of-2.32(m, 4H), 2,12-2,02(m, 2H), 1,78-of 1.56(m, 8H).

Example 28(22)

4-(N-(2-(azepin-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf of 0.29 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,58(width, 1H), 7,82(t, J = 6.0 Hz, 1H), 3,39(s, 2H), 3,10(kV, J = 6.0 Hz, 2H), 2,60-2,52(m, 4H), 2,52 at 2.45(m, 2H), 2,44 is 2.33(m, 4H), 1,68 is 1.60(m, 4H), 1,58 of 1.46(m, 8H).

Hydrochloride:

TLC: Rf 0.34 in (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):was 12.61(s, 1H), 10,44(width, 1H), 8,49(m, 1H), 3,51-of 3.42(m,2H), 3,47(s, 2H), 3,42-of 3.31(m, 2H), 3,18-3,03(m, 4H), 2,46-of 2.34(m, 4H), 1,88 to 1.76(m, 4H), 1,72 of 1.50(m, 8H).

Example 28(23)

4-(2-(N-(3-(N'-cyclobutylamine)propanol)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf to 0.17 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,55(Sirs, 1H), 7,99(t, J = 5.4 Hz, 1H), 4,08(width, 1H), 3.46 in-3,20(m, 2H), to 3.09(m, 1H), 2,68-of 2.28(m, 8H), 2,13(t, J = 6.9 Hz, 2H), 2,04(m, 2H), 1,80-of 1.40(m, 8H).

Example 28(24)

4-(2-(N-(3-(piperidine-1-yl)propanol)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.26 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,55(s, 1H), 8,05(t, J = 5.4 Hz, 1H), 3,42-3,24(m, 4H), 2,60(t, J = 7.2 Hz, 2H), 2,56-2,22(m, 8H), to 2.18(t, J = 7.2 Hz, 2H), 1,76-and 1.54(m, 4H), 1,52-of 1.24(m, 6H).

Example 28(25)

4-(N-(2-(N'-methyl-N'-isopropylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0.25 in (chlorop the RM: methanol: water = 8:2:0,2);

NMR(DMSO-d6):12,57(s, 1H), to 7.84(m, 1H), 3,39(s, 2H), 3,09(kV, J = 6.0 Hz, 2H), 2,72(m, 1H), 2,46-of 2.30(m, 6H), 2,10(s, 3H), 1,66-to 1.60(m, 4H), to 0.89(d, J = 6.6 Hz, 6H).

Example 28(26)

4-(N-(2-(N'-cyclopropylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.43 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,56(s, 1H), to 7.93(m, 1H), 3,40(s, 2H), 3,12(kV, J = 6.0 Hz, 2H), 2,61(t, J = 6.0 Hz, 2H), 2,44 of-2.32(m, 2H), 2,04(m, 1H), 1,68 is 1.60(m, 4H), from 0.37 to 0.30(m,2H), of 0.20 to 0.14(m, 2H).

Example 28(27)

4-(N-(3-(piperidine-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.20 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,70(s, 1H), 8,00(m, 1H), 3,38(s, 2H), 3.04 from(kV, J = 6.3 Hz, 2H), 2,46 is 2.33(m, 4H), 2,32-of 2.16(m, 6H), 1,68 is 1.60(m, 4H), 1,59-of 1.42(m, 6H), 1.41 to of 1.30(m, 2H).

Example 28(28)

Bromohydrin 4-(N-(2-(N'-cyclopentylamine)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.35 (ethyl acetate: acetic acid: water= 3:1:1);

NMR(DMSO-d6):br12.62(s, 1H), 8,44(m, 2H), 8,21(t, J = 6.0 Hz, 1H), 3.46 in(m, 1H), 3.46 in(s, 2H), 3,38-3,26(m, 2H), 3.00 and of 2.92(m, 2H), 2,45-of 2.34(m, 4H), 2.00 in to 1.86(m, 2H), 1,74 is 1.60(m, 6H), 1,60 is 1.48(m, 4H).

Example 28(29)

Bromohydrin 4-(N-(3-(N'-cyclobutylamine)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.30 (ethyl acetate: acetic acid: water= 3:1:1);

NMR(DMSO-d6):was 12.61(s, 1H), 8,53(m, 2H), 8,19(t, J = 6.0 Hz, 1H), 3,65(Quai is, J = 7.8 Hz, 1H), 3,42(s, 2H), 3,12(kV, J = 6.0 Hz, 2H), 2,80-2,70(m, 2H), 2,45-of 2.36(m, 4H), 2,20-2,00(m, 4H), 1,84 is 1.60(m, 8H).

Example 28(30)

Bromohydrin 4-(N-(4-(N'-cyclobutylamine)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.26 (ethyl acetate: acetic acid: water= 3:1:1);

NMR(DMSO-d6):to 12.58(s, 1H), 8,53(width, 2H), 8,09(t, J = 6.0 Hz, 1H), 3,64(Quain, J = 6.0 Hz, 1H), 3,40(s, 2H), 3,06(q,J = 6.0 Hz, 2H), 2,82-2,70(m, 2H), 2,46 is 2.33(m, 4H), 2,22-2,02(m, 4H), 1,84-1,72(m, 2H), 1.70 to to 1.60(m, 4H), 1.60-to to 1.38(m, 4H).

Example 28(31)

Bromohydrin 4-(N-(2-(N'-cyclohexylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.18 (ethyl acetate: acetic acid: water= 3:1:1);

NMR(DMSO-d6):br12.62(width, 1H), 8,40-to 8.20(m, 2H), by 8.22(m, 1H), 3.45 points(s, 2H), 3,30(m, 1H), 3,03-2,90(m, 2H), 2,43 of-2.32(m, 4H), 2.00 in 1,90(m, 2H), 1,78-and 1.54(m, 8H), 1,28 of 1.00(m, 6H).

Example 28(32)

Bromohydrin 4-(N-(4-(N'-methylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,063 (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):12,58(Sirs, 1H), 8,28-8,00(width, 2H), 8,10(m, 1H), 3,40(s, 2H), 3,05(kV, J = 6.0 Hz, 2H), 2,86(t, J = 7.2 Hz, 2H), 2,52(s, 3H), 2,48 of-2.32(m, 4H), 1.70 to to 1.60(m, 4H), 1.60-to of 1.36(m, 4H).

Example 28(33)

Bromohydrin 4-(N-(4-(N'-cyclopentylamine)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.28 in (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6: to 12.58(s, 1H), of 8.37(width, 2H), 8,11(m, 1H), 3.43 points(m, 1H), 3,41(s, 2H), 3,07(kV, J = 6.0 Hz, 2H), 2,92-and 2.83(m, 2H), 2,46 is 2.33(m, 4H), 2.00 in a 1.88(m, 2H), 1,74-of 1.40(m, 14H).

Example 28(34)

Bromohydrin 4-(N-(3-(N'-cyclopentylamine)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.56 to (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):was 12.61(1H), 8.30 to-8,00(width, 2H), by 8.22(m, 1H), 3.43 points(s, 2H), 3.43 points(m, 1H), 3,14(kV, J = 6,6 Hz, 2H), 2,86(t, J = 7.5 Hz, 2H), 2,46-of 2.34(m, 4H), 1,96-of 1.84(m, 2H), 1,80 of 1.46(m, 12H).

Example 28(35)

Bromohydrin 4-(N-(4-(N'-cyclohexylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.56 to (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):to 12.58(1H), 8,24(width, 2H), 8,10(m, 1H), 3,40(s, 2H), 3,07(kV, J = 6.3 Hz, 2H) 3,00-2,84(m, 3H), 2,46-of 2.34(m, 4H), 2,04-of 1.95(m, 2H), 1,80-of 1.40(m, 11H), 1,28-1,10(m, 5H).

Example 28(36)

4-(N-(3-(N'-cyclopropylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.44 (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):12,59(1H), 8,09(t, J = 6.0 Hz, 1H), 3,40(s, 2H), 3,09(kV, J = 6.0 Hz, 2H), 2,74(t, J = 5,2 Hz, 2H), 2,46 was 2.25(m, 5H), 1.70 to 1.55V(m, 6H), 0,58-0,50(m, 2H), from 0.50 to 0.40(m, 2H).

Example 28(37)

4-(N-(4-(N'-cyclopropylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.44 (methylene chloride: methanol: saturated aqueous solution Ammi is ka = 8:2:0,2);

NMR(DMSO-d6):12,56(Sirs, 1H), 8,01(t, J = 6.0 Hz, 1H), 3,38(s, 2H), 3,18 are 2.98(m, 2H), 2,60-2,52(m, 2H), 2,46 of-2.32(m, 4H), to 2.06(m, 1H), 1.70 to to 1.60(m, 4H), of 1.44 and 1.35(m, 4H), 0,40-0,34(m, 2H), 0,26-0,18(m, 2H).

Example 28(38)

The hydrochloride of 4-(N-methyl-N-(3-(N'-cyclohexylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.20 methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):12,60(s, 1H), 8,62 and 8,42(width, 2H), 3,68(s, 2H), 3.43 points-to 3.34(m, 2H), 3,02 and 2.82(s, 3H), 3.00 and-2,78(m, 3H), 2,42 of-2.32(m, 4H), 2,02-and 1.54(m, 12H), 1.32 to-1,17(m, 4H).

Example 28(39)

The hydrochloride of 4-(N-methyl-N-(3-(N'-cyclopentylamine)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,20 (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):12,60(s, 1H), 8,73 and 8,49(width, 2H), 3.68 and to 3.67(s, 2H), 3.46 in-to 3.36(m, 3H), 3,01 and 2.82(s, 3H), 2,98-2,78(m, 2H), 2,42-of 2.34(m, 4H), 1,98 to 1.76(m, 4H), 1.70 to the 1.44(m, 10H).

Example 28(40)

The hydrochloride of 4-(N-methyl-N-(3-(N'-cyclobutylamine)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,24 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,59(s, 1H), 8,63(width, 2H), 3,67 and the 3.65(s, 2H), 3,62(m, 1H), 3,44-3,30(m, 2H), 3.00 and of 2.81(s, 3H), 2,82-to 2.67(m, 2H), 2,41 of-2.32(m, 4H), 2,20-2,04(m, 4H), 1,90 is 1.70(m, 4H), 1.70 to to 1.60(m, 4H).

Example 28(41)

The hydrochloride of 4-(N-methyl-N-(3-(N'-cyclopropylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydro Alain-1(2H)-it

TLC: Rf 0,24 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,59 and 12,57(s, 1H), 8,57(width, 2H), to 3.67(s, 2H), 3.46 in-3,30(m, 2H), 3,01 and of 2.81(s, 3H), 2.95 and-2,82(m, 2H), 2.57 m(m, 1H), 2,41 is 2.33(m, 4H), 1,95 is 1.75(m, 2H), 1.70 to was 1.58(m, 4H), 0,81-to 0.72(m, 2H), 0,72-of 0.64(m, 2H).

Example 28(42)

4-(N-(4-(morpholine-4-yl)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf of 0.38 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):12,57(s, 1H), 8,00(t, J = 5.4 Hz, 1H), 3,55(m, 4H), 3,39(s, 2H), 3,29-of 2.20(m, 12H), 1,63(Sirs, 4H), 1,40(Sirs, 4H).

Hydrochloride:

TLC: Rf of 0.37 (methanol: methylene chloride: saturated aqueous ammonia= 1:9:0,1);

NMR(DMSO-d6):12,59(s, 1H), 10,34(Sirs, 1H), 8,13(t, J = 5.4 Hz, 1H), 3,94(m, 2H), and 3.72(t, J = 11,4 Hz, 2H), 3,41(s, 2H), 3,38(m, 2H), of 3.07(m, 6H), 2,39(m, 4H), 1,63-of 1.40(m, 8H).

Methanesulfonate:

TLC: Rf 0.34 in (methanol: methylene chloride: 28% ammonia water= 1:9:0,1);

NMR(DMSO-d6):to 12.58(s, 1H), 9,54(Sirs, 1H), 8,10(t, J = 5.4 Hz, 1H), 4,00-of 3.94(m, 2H), 3,69-3,61(m, 2H), 3,41(s, 2H), 3,36(m, 2H), 3,11-of 2.97(m, 6H), 2,42 is 2.33(m, 4H), of 2.34(s, 3H), and 1.63(m, 6H), 1,48-to 1.38(m, 2H).

Example 29

Methanesulfonate of 4-(3-(N-(5-aminopentyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

A mixture of the compound obtained in example 26(4), (430 mg) and 10% palladium-on the corner (86,0 mg) in methanol (5.0 ml) was stirred in hydrogen atmosphere at room temperature for 10 hours. The reaction mixture was filter and through celite. The filtrate was concentrated. The resulting powder was recrystallized from ethyl acetate to obtain the free form specified in the title compound (268 mg). The suspension obtained free form (264 mg) and methanesulfonate (74,6 mg) in methanol (3.0 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain compound according to the present invention (307 mg)having the following physical characteristics.

TLC: Rf 0.28 in (methanol: methylene chloride: saturated aqueous ammonia= 4:8:0,1);

NMR(CD3OD):7,80(s, 1H), 7,66(m, 1H), 7,47(t, J = 7.8 Hz, 1H), 7,22(m, 1H), 3,01(t, J = 6,8 Hz, 2H), 2,75(s, 3H), 2,68(shirt, J = 6.0 Hz, 2H), 2,53(m, 4H), 1,90-of 1.74(m, 8H).

Example 29(1) - example 29(6)

By the same procedure described in example 29, if necessary, the following compounds according to the present invention were synthesized by transformation into the corresponding salts in the usual way using the compounds obtained in examples 26(6) - 26(8), 26(12), 24(31) or 27(38)instead of the compound obtained in example 26(4).

Example 29(1)

Methanesulfonate of 4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazine-1(6H)-it

TLC: Rf 0.34 in (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,2);

NMR(CD3OD):10,02(width is, 1H), 7,78(s, 1H), 7,65(d, J = 7.8 Hz, 1H), 7,45(t, J = 7.8 Hz, 1H), 7,17(d, J = 7.8 Hz, 1H), 4,07(m, 1H), 3,47(m, 1H), of 3.07(t, J = 6.9 Hz, 2H), 2.91 in(m, 1H), 2,75(s, 6H), of 2.53(t, J = 6.6 Hz, 2H), 2,29-of 1.52(m, 10H).

Example 29(2)

Methanesulfonate of 4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf 0.26 (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,2);

NMR(CD3OD):to 8.14(t, J = 1.8 Hz, 1H), 7,78(m, 1H), to 7.64(t, J = 7.8 Hz, 1H), 7,39(m, 1H), and 4.68(DD, J = 11,1, 2.4 Hz, 1H), 4,00(dt, J = 14,1, 3.0 Hz, 1H), 3,53-to 3.34(m, 2H), 3,10(m, 4H), was 2.76(s, 6H), 2.57 m(m, 3H), of 1.84(m, 4H).

Example 29(3)

Methanesulfonate of 4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-2,5,6,7,8,9-hexahydro-1H-cyclohepta[d]pyridazin-1-it

TLC: Rf of 0.29 (chloroform: methanol: 28% ammonia water= 40:10:1);

NMR(DMSO-d6):12,96(Sirs, 1H), of 10.05(s, 1H), they were 8.22(Sirs, 2H), 7,69(m, 1H), EUR 7.57(m, 1H), 7,37(m, 1H), 7,00(m, 1H), 2,92-2,78(m, 4H), 2,58-2,52(m, 5H), 2,40 of-2.32(m, 2H), 2,30(s, 3H), 1,86 to 1.76(m, 2H), 1,66 of 1.46(m, 8H).

Example 29(4)

The hydrochloride of 4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf of 0.34 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):10,89(s, 1H), 10,37(width, 1H), 8,83(width, 2H), 7,76(s, 1H), 7,68(d, J = 7.8 Hz, 1H), 7,38(t, J = 7.8 Hz, 1H), was 7.08(d, J = 7.8 Hz, 1H), of 6.26(s, 1H), 3,64-to 3.58(m, 2H), 3,20-3,14(m, 2H), 2,94-2,84(m, 2H), 2,54-of 2.30(m, 5H), 1.70 to to 1.60(m, 4H).

Example 29(5)

4-(N-(2-(piperidine-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-then it is carbonated who ritalin-1(2H)-he

Free form:

TLC: Rf 0.14 (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,1);

NMR(DMSO-d6):12,54(Sirs, 1H), 8,44(s, 1H), 8,01(t, J = 5.4 Hz, 1H), 3,38(s, 2H), is 3.08-of 2.26(m, 12H), 1,63(Sirs, 4H), 1,34 of 1.00(m, 5H).

Methanesulfonate:

TLC: Rf of 0.43 (methylene chloride: methanol: 28% ammonia water= 6:3:1);

NMR(DMSO-d6):12,58(Sirs, 1H), 8,18(Sirs, 2H), 8,02(t, J = 5.4 Hz, 1H), 3,38(s, 2H), up 3.22(m, 2H), is 3.08(m, 2H), was 2.76(m, 2H), 2,46-of 2.34(m, 4H), of 2.30(s, 3H), 1.77 in(m-2H), and 1.63(m, 4H), 1,50(m, 1H), 1,40-1,24(m, 4H).

Example 29(6)

4-(2-(1,4-diazepan-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,083 (methylene chloride: methanol = 4:1);

NMR(DMSO-d6):12,5(Sirs, 1H), 2,80-to 2.55(m, 12H), 2.49 USD(m, 2H), 2,35(m, 2H), 1,75 by 1.68(m, 6H).

Example 30

Methanesulfonate of 4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

To a solution of the compound obtained in example 26, (290 mg) in methanol (3.0 ml) was added dropwise 4n. hydrogen chloride in dioxane (2,50 ml) in an ice bath, the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was purified column chromatography on silica gel (methanol: methylene chloride = 1:9→ methanol: methylene chloride: saturated aqueous ammonia = 2:8:0,1). To a suspension of the obtained solid (134 mg) in methanol (1.0 ml) was added dropwise 1N. rastvoryaetsya sodium and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added saturated aqueous solution of ammonium chloride, the mixture was extracted with methylene chloride. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. A solution of the obtained solid (64,8 mg) and methanesulfonate (17.6 mg) in methanol (3.0 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to obtain compound according to the present invention (and 82.4 mg)having the following physical characteristics.

TLC: Rf 0,27 (methanol: methylene chloride: saturated aqueous ammonia= 2:8:0,5);

NMR(CD3OD):10,00(Sirs, 1H), of 7.75(d, J = 1.2 Hz, 1H), 7,63(DD, J = 8,1, 1.2 Hz, 1H), 7,45(t, J = 8,1 Hz, 1H), 7,21(d, J = 8,1 Hz, 1H), 3,07(shirt, J = 7.2 Hz, 2H), 2,74(s, 6H), 2,65(shirt, J = 6.3 Hz, 2H), 2,52(m, 4H), equal to 1.82(m, 8H).

Example 30(1) 30(19)

By the same procedure described in example 30, if necessary, the following compounds according to the present invention were synthesized by transformation into the corresponding salts in the usual way using the compound obtained in example 26(9), 26(10), 26(11), 23, 26(14), 26(15), 23(3), 23(4), 23(9), 23(16), 26(16), 27(7), 23(21), 26(17), 27(14), 26(19), 23(25), 23(33) or 24(48)instead of the compound obtained in example 26.

Example 30(1)

Methanesulfonate of 4-(3-(N-(4-(N'-methylamino)butanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]t is the Zino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf of 0.20 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):10,56(s, 1H), 10,17(s, 1H), 8,45(width, 2H), 7,71(s, 1H), 7,58(d, J = 7.8 Hz, 1H), was 7.36(t, J = 7.8 Hz, 1H), was 7.08(d, J = 7.8 Hz, 1H), 4,24(DD, J = 8,4, and 4.5 Hz, 1H), of 3.56(m, 1H), 3,09(m, 1H), 2,98-2,90(m, 2H), 2,88-2,84(m, 2H), 2,71(m, 1H), 2,56(t, J = 6.0 Hz, 3H), 2,44(t, J = 6.0 Hz, 2H), 2,31(s, 3H), 2,31(m, 1H), 1,94 is 1.86(m, 2H).

Example 30(2)

Methanesulfonate of 4-(3-(N-(6-(N'-methylamino)hexanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-it

TLC: Rf to 0.17 (chloroform: methanol: water= 8:2:0,2);

NMR(DMSO-d6):10,54(s, 1H), of 10.05(s, 3H), at 8.36(width, 2H), 7,71(s, 1H), 7,58(d, J = 7.5 Hz, 1H), 7,35(t, J = 7.5 Hz, 1H), 7,06(d, J = 7.5 Hz, 1H), 4,24(m, 1H)and 3.59(m, 1H), is 3.08(m, 1H), 2,92-2,82(m, 2H), 2,71(m, 1H), 2,60-to 2.40(m, 3H), 2,31(m, 1H), 2,293(s, 3H), 2,289(s, 3H), 1,68-of 1.55(m, 4H), 1,40-of 1.30(m, 2H).

Example 30(3)

The hydrochloride of 4-(3-(N-(5-(N'-(3-methyl-2-butenyl)amino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.34 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,88(s, 1H), 10,24(s, 1H), 8,84(s, 2H), 7,73(s, 1H), to 7.64(m, 1H), 7,35(DD, J = 7,8, and 7.8 Hz, 1H), was 7.08(m, 1H), 5.25 in(t, J = 7.2 Hz, 1H), 3,56 is 3.40(m, 2H), 2,98-of 2.72(m, 2H), 2,60-of 2.24(m, 6H), 1,80-1,50(m, 14H).

Example 30(4)

4-(N-(2-amino-ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf 0,19 (methylenechloride: methanol: ammonia water= 8:2:0,2);

NMR(DMSO-d6):7,98(m, 1H), 3,41(s, 2H), 3,03(kV, J = 6,6 Hz, 2H), by 2.55(t, J = 6.6 Hz, 2H), 2,46 is 2.33(m, 4H), 1.70 to to 1.60(m, H).

Hydrochloride:

TLC: Rf of 0.44 (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,2);

NMR(DMSO-d6):12,60(Sirs, 1H), 8,42(t, J = 6.0 Hz, 1H), 8,11(Sirs, 3H), 3.46 in(s, 2H), and 3.31(q, J = 6.0 Hz, 2H), 2,84(kV, J = 6.0 Hz, 2H), 2,39(m, 4H), and 1.63(m, 4H).

Example 30(5)

The hydrochloride of 4-(3-(N-(azetidin-3-ylcarbonyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.18 (chloroform: methanol = 4:1);

NMR(DMSO-d6):10,43(s, 1H), 9,10(Sirs, 1H), 8,82(Sirs, 1H), 7,73(m, 1H), to 7.64(m, 1H), 7,39(DD, J = 7,8, and 7.8 Hz, 1H), 7,14(m, 1H), 4,20-to 3.92(m, 4H), 3,79(m, 1H), 2,62-of 2.20(m, 4H), 1,78 of 1.50(m, 4H).

Example 30(6)

The hydrochloride of 4-(3-(N-(pyrrolidin-2-ylcarbonyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.53 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):12,91(s, 1H), 10,86(s, 1H), 9,65(Sirs, 1H), 8,67(Sirs, 1H), 7,71(s, 1H), to 7.64(d, J = 7.8 Hz, 1H), 7,43(t, J = 7.8 Hz, 1H), 7,19(d, J = 7.8 Hz, 1H), 4,37(m, 1H), 3.27 to and 2.26(m, 6H), was 1.94(m, 4H), 1.70 to to 1.59(m, 4H).

Example 30(7)

The hydrochloride of 4-(N-(3-aminopropyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,41 (ethyl acetate: acetic acid: water= 3:3:1);

NMR(DMSO-d6):12,59(s, 1H), 8,23(width, 1H), 7,88(width, 3H), 3,42(s, 2H), 3,11(kV, J = 6,6 Hz, 2H), was 2.76(q, J = 6.6 Hz, 2H), 2,50 of-2.32(m, 4H), 1,76 is 1.60(m, 6H).

Example 30(8)

The hydrochloride of 4-(N-(2-(N'-methylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.29 (ethyl acetate: uksu the Naya acid: water = 3:3:1);

NMR(DMSO-d6):12,60(Sirs, 1H), 8,86(width, 2H), scored 8.38(width, 1H), 3,47(s, 2H), 3,35(kV, J = 6.0 Hz, 2H), 2,94(Quain, J = 6.0 Hz, 2H), 2,53(t, J = 5.4 Hz, 3H), 2,50-of 2.34(m, 4H), 1.70 to to 1.60(m, 4H).

Example 30(9)

The hydrochloride of 4-(1-(N-(2-amino-ethyl)carbarnoyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,62 (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,2);

NMR(DMSO-d6):br12.62(s, 1H), 8,25(t, J = 5.4 Hz, 1H), 8,00(Sirs, 3H), of 3.73(q, J = 6,9 Hz, 1H), 3,26(m, 2H), and 2.83(m, 2H), 2,48-of 2.30(m, 4H), of 1.64(m, 4H), to 1.31(d, J = 6.9 Hz, 3H).

Example 30(10)

The hydrochloride of 4-(N-(4-aminobutyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.15 (ethyl acetate: acetic acid: water= 3:1:1);

NMR(DMSO-d6):to 12.58(s, 1H), 8,17(t, J = 6.3 Hz, 1H), 7,95(width, 3H), 3,41(s, 2H), 3,05(kV, J = 6.3 Hz, 2H), 2,75(m, 2H), 2,46 is 2.33(m, 4H), 1,68 is 1.60(m, 4H), 1.60-to of 1.40(m, 4H).

Example 30(11)

The hydrochloride of 4-(2-(N-(2-aminoacetyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,11 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,58(Sirs, 1H), 8,59(t, J = 5.7 Hz, 1H), 8,19(Sirs, 3H), 3,56 of 3.28(m, 4H), to 2.65(t, J = 7.2 Hz, 2H), 2,54-of 2.28(m, 4H), 1,76-and 1.54(m, 4H).

Example 30(12)

The dihydrochloride of 4-(2-(piperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.15 (chloroform: methanol = 9:1);

NMR(CD3OD):3,80-3,50(m, 10H), 3,14(t, J = 7.5 Hz, 2H), 2,64-of 2.50(m, 4H), 1,90-of 1.74(m, 4H).

Example 30(13

The hydrochloride of 4-(1-(N-(4-aminobutyl)carbarnoyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,19 (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,1);

NMR(DMSO-d6):12,60(s, 1H), 8,04(t, J = 5.4 Hz, 1H), 7,83(Sirs, 3H), of 3.69(q, J = 7.2 Hz, 1H), 3,09(m, 2H), 2,74(m, 2H), 2,48 was 2.25(m, 4H), 1,64-of 1.42(m, 8H), is 1.31(d, J = 7.2 Hz, 3H).

Example 30(14)

The hydrochloride of 4-(2-(N-(3-aminopropanol)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,11 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,56(Sirs, 1H), 8,24(t, J = 5.7 Hz, 1H), 7,94(Sirs, 3H), 3,42-3,24(m, 2H), 3.04 from-2,84(m, 2H), 2.63 in(t, J = 7.2 Hz, 2H), 2,56-of 2.28(m, 6H), 1,76-of 1.52(m, 4H).

Example 30(15)

The dihydrochloride of 4-(2-(N-(2-amino-ethyl)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,10 (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,1);

NMR(DMSO-d6):12,69(s, 1H), 9,63(Sirs, 2H), to 8.41(Sirs, 3H), 3,78-of 3.06(m, 6H), to 2.94(t, J = 7.5 Hz, 2H), 2,58-of 2.30(m, 4H), 1,78-and 1.54(m, 4H).

Example 30(16)

The hydrochloride of 4-(2-(N-(4-aminobutanol)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.10 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,56(Sirs, 1H), 8,09(m, 4H), 3,36-3,20(m, 2H), 2,82-of 2.66(m, 2H), 2,61(t, J = 7.2 Hz, 2H), 2,54-of 2.28(m, 4H), of 2.15(t, J = 7.2 Hz, 2H), 1,84-of 1.52(m, 6H).

Example 30(17)

The hydrochloride of 4-(N-(5-aminopentyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.34 in (chlorofor is: methanol: water = 8:2:0,2);

NMR(DMSO-d6):12,57(width, 1H), 8,09(m, 1H), 7,87(width, 2H), 3,40(s, 2H), 3,03(kV, J = 6.0 Hz, 2H), 2,80-of 2.66(m, 2H), 2,46 is 2.33(m, 4H), 1.70 to to 1.60(m, 4H), 1.60-to for 1.49(m, 2H), 1,48-of 1.36(m, 2H), 1,36-of 1.26(m, 2H).

Example 30(18)

The hydrochloride of 4-(2-(N-(2-amino-ethyl)carbarnoyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.18 (chloroform: methanol = 4:1);

NMR(DMSO-d6):to 12.52(s, 1H), 8,20(t, J = 5.4 Hz, 1H), 8,02(Sirs, 3H), 3,36-3,20(m, 2H), 2,92 was 2.76(m, 2H), by 2.73(t, J = 7.5 Hz, 2H), 2,54-of 2.28(m, 6H), 1,76-and 1.54(m, 4H).

Example 30(19)

The dihydrochloride 8-(N-(3-aminopropyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.25 in (methanol: acetic acid = 5:1);

NMR(DMSO-d6):12,24(s, 1H), to 8.41(t, J = 5.4 Hz, 1H), 7,94(Sirs, 5H), 3,42(s, 2H), 3,20(t, J = 5.4 Hz, 2H), 3,12(m, 2H), 2,78(m, 2H), 2,37(t, J = 6.0 Hz, 2H), 1.69 in(m, 4H).

Example 31

4-(2-acetylethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in reference example 13, (650 mg) in dimethylformamide (15 ml) was added thioacetic potassium (698 mg) and potassium carbonate (422 mg) and the mixture was stirred at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain compound according to the present invention (688 mg), having the following physical characteristics.

TLC: Rf of 0.40 (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,60(s, 1H), 3,11(t, J = 7.2 Hz, 2H), 2,75(t, J = 7.2 Hz, 2H), 2,56-of 2.28(m, 4H), 2,31(s, 3H), 1,76-and 1.54(m, 4H).

Example 31(1)

8-(2-acetylethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

By the same procedure described in example 31, using a corresponding derivative instead of the compound obtained in reference example 13 was synthesized compound according to the present invention having the following physical characteristics.

TLC: Rf of 0.43 (chloroform: methanol = 8:1);

NMR(DMSO-d6):11,82(s, 1H), 6,32(s, 1H), and 3.16(m, 2H), to 3.09(t, J = 7.2 Hz, 2H), 2,66(t, J = 7.2 Hz, 2H), 2,32(t, J = 6.3 Hz, 2H), 2,31(s, 3H), 1.69 in(m, 2H).

Example 32

4-(2-benzyldimethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a suspension of the compound obtained in example 31, (100 mg) in methanol (4.0 ml) was added benzylbromide (0.06 ml) and potassium carbonate (82 mg) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into cold 0,5h. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (methylene chloride: methanol = 70:1→30:1) to obtain from the organisations according to the present invention (47 mg), having the following physical characteristics.

TLC: Rf is 0.42 (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,54(s, 1H), 7,38-7,16(m, 5H), of 3.77(s, 2H), 2,80-of 2.58(m, 4H), 2,50-of 2.26(m, 4H), 1,76-of 1.52(m, 4H).

Example 32(1) and example 32(2)

By the same procedure described in example 32, if necessary, the following compounds according to the present invention were obtained by transformation into the corresponding salts in the usual way using a corresponding derivative instead of benzylbromide.

Example 32(1)

4-(2-(3-(piperidine-1-yl)propylthio)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.57 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,56(s, 1H), 2,78-2,70(m, 4H), 2,58-of 2.20(m, 12H), 1,76-of 1.56(m, 6H), 1,54-of 1.26(m, 6H).

Example 32(2)

4-(2-(2-(piperidine-1-yl)ethylthio)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf 0.28 in (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,56(s, 1H), 2,82-2,70(m, 4H), 2,68-of 2.56(m, 2H), 2,54-2,22(m, 10H), 1,76-of 1.55(m, 4H), 1,54-of 1.26(m, 6H).

Hydrochloride:

TLC: Rf 0.28 in (chloroform: methanol = 8:1);

NMR(DMSO-d6):was 12.61(s, 1H), 10,22(Sirs, 1H), 3,44(m, 2H), 3,19(m, 2H), 3.04 from of 2.68(m, 8H), 2,62-of 2.28(m, 4H), 1,90-and 1.54(m, 9H), of 1.35(m, 1H).

Example 33

4-(2-(2-hydroxyethylthio)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of 4-(2-(2-tert-butyldimethylsilyloxy)this is)-5,6,7,8-tetrahydropyrazin-1(2H)-she (300 mg; the compound was obtained by the same procedure described in example 32, using 1-tert-butyldimethylsilyloxy-2-iodata instead of benzylbromide) in tetrahydrofuran (4.0 ml) was added tetrabutylammonium (638 mg) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into cold saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated. The residue was washed tert-butylmethylamine ether to obtain compound (191 g) according to the present invention having the following physical characteristics.

TLC: Rf of 0.36 (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,56(s, 1H), 4,77(t, J = 5.4 Hz, 1H), 3,53(dt, J = 5,4, and 6.6 Hz, 2H), 2,84-of 2.72(m, 4H), at 2.59(t, J = 6.6 Hz, 2H), 2,56-of 2.28(m, 4H), 1,76-and 1.54(m, 4H).

Example 33(1) - example 33(3)

By the same procedure described in example 33, using 4-(2-(3-tert-butyldimethylsilyloxy)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it, 8-(2-(2-tert-butyldimethylsilyloxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-or 8-(2-(3-tert-butyldimethylsilyloxy)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it instead 4-(2-(2-tert-butyldimethylsilyloxy)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it, SL is blowing compounds according to the present invention were obtained.

Example 33(1)

4-(2-(3-hydroxypropylamino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TCX: Rf of 0.37 (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,56(s, 1H), 4,46(t, J = 5,1 Hz, 1H), 3,44(dt, J = 5,1, 6,9 Hz, 2H), 2,80 of 2.68(m, 4H), of 2.56(t, J = 7.2 Hz, 2H), 2,54-of 2.30(m, 4H), 1,76-and 1.54(m, 6H).

Example 33(2)

8-(2-(2-hydroxyethylthio)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf 0.31 in (chloroform: methanol = 8:1);

NMR(DMSO-d6):11,78(s, 1H), 6,33(s, 1H), 4,78(t, J = 5.4 Hz, 1H), 3,53(dt, J = 5,4, and 6.6 Hz, 2H), 3,17(m, 2H), 2,84-2,60(m, 4H), at 2.59(t, J = 6.6 Hz, 2H), 2,32(t, J = 6.3 Hz, 2H), 1.69 in(m, 2H).

Example 33(3)

8-(2-(3-hydroxypropylamino)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf of 0.32 (chloroform: methanol = 8:1);

NMR(DMSO-d6):11,77(s, 1H), 6,33(s, 1H), 4,46(t, J = 5,1 Hz, 1H), 3,44(dt, J = 5,1, 5.7 Hz, 2H), and 3.16(m, 2H), 2,80-2,60(m, 4H), to 2.55(t, J = 7.2 Hz, 2H), 2,32(t, J = 6.3 Hz, 2H), 1,78 of 1.50(m, 4H).

Example 34

4-(2-(2-brometalia)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in example 33, (160 mg) in chloroform (5.0 ml) was added triphenylphosphine (248 mg) and tetrabromomethane (313 mg) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added dropwise methanol (1.0 ml), the mixture was stirred for 5 minutes and concentrated. The residue was purified column chromatography on silica gel (methylene chloride: methanol = 80:1→501) to obtain the crude compound according to the present invention (598 mg), having the following physical characteristics. The compound obtained was used in the next reaction without purification.

TLC: Rf is 0.49 (chloroform: methanol = 8:1);

NMR(CD3OD):3,55(t, J = 6.3 Hz, 2H), 2,96-2,82(m, 4H), of 2.72(t, J = 6.3 Hz, 2H), 2,64 is 2.44(m, 4H), 1,86 is 1.70(m, 4H).

Example 35

4-(2-(3-chlorpropyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a suspension of the compound obtained in example 33(1), (110 mg) in methylene chloride (2.1 ml) was added thionyl chloride (0,08 ml) and pyridine (0.01 ml) and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into cold water and extracted with methylene chloride. The extract was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and concentrated to obtain compound according to the present invention (109 mg)having the following physical characteristics.

TLC: Rf is 0.49 (chloroform: methanol = 8:1);

NMR(DMSO-d6):12,57(s, 1H), 3,70(t, J = 6.3 Hz, 2H), 2,82-of 2.72(m, 4H), of 2.64(t, J = 6.9 Hz, 2H), 2,54-of 2.30(m, 4H), 1,95(TT, J = 6,9, and 6.3 Hz, 2H), 1,76-and 1.54(m, 4H).

Example 36 and example 36(1)

By the same procedure described in example 28, if necessary, were synthesized the following compounds according to the present invention by transformation into the corresponding salt as the major method using the connection, obtained in example 34 or 35, instead of the compound obtained in example 25(1), and cyclopentylamine instead of research.

Example 36

4-(2-(2-(N-cyclopentylamine)ethylthio)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.36 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,56(Sirs, 1H), 3.00 and(quintet, J = 6.3 Hz, 1H), 2,82-of 2.72(m, 4H), 2.71 to 2,28(m, 8H), 1,80-of 1.16(m, 12H).

Example 36(1)

The hydrochloride of 4-(2-(3-(N-cyclopentylamine)propylthio)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.38 (chloroform: methanol = 4:1);

NMR(DMSO-d6):12,59(s, 1H), 8,99(Sirs, 2H), 3,41(m, 1H), 2,92(m, 2H), 2,84-2,70(m, 4H), 2.63 in(t, J = 7.2 Hz, 2H), 2,58-of 2.28(m, 4H), 2.06 to to 1.38(m, 14H).

Example 37

Methanesulfonate 8-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

By the same procedure described in reference example 1→example 1→example 26→example 29, using furo[3,4-d]pyrazin-5,7-dione instead of 4,5,6,7-tetrahydro-2-benzofuran-1,3-dione was synthesized compound according to the present invention having the following physical characteristics.

TLC: Rf 0,17 (methanol: methylene chloride: saturated aqueous ammonia= 1:4:0,2);

NMR(CD3OD):7,81(s, 1H), 7,69(d, J = 7.8 Hz, 1H), 7,49(t, J = 7.8 Hz, 1H), 7,32(d, J = 7.8 Hz, 1H), 3,50(m, 2H), 3,39(m, 2H), is 3.08(m, 2H), 2,75(s, 3H), 2,74(s, 3H), of 2.53(m, 2H), is 1.81(m, 4H).

Example 38

4-(N-(2-(1H-tetrazol-5-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

A mixture of the compound obtained in example 23(34), (180 mg), azide trimethylurea (285 mg) and toluene (1.5 ml) was boiled under reflux overnight. The reaction mixture was concentrated. The residue was washed successively with ethyl acetate and hot methanol to obtain compound according to the present invention (113 mg)having the following physical characteristics.

TLC: Rf 0.14 (methylene chloride: methanol: saturated aqueous ammonia= 8:2:0,2);

NMR(DMSO-d6):12,57(s, 1H), 8,19(t, J = 6.0 Hz, 1H), 3,44(kV, J = 6.0 Hz, 2H), 3,37(s, 2H), to 3.02(t, J = 6.0 Hz, 2H), 2.40 a-2,24(m, 4H), 1,67 is 1.58(m, 4H).

Example 39

6-acetyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-he

To a suspension of the compound obtained in example 11(1), (150 mg) in tetrahydrofuran (2.9 ml) was added an aqueous solution (1.1 ml), potassium carbonate (157 mg) and then to the mixture was added acetylchloride (0.05 ml) at 00C, the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and was added 1N. a solution of hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ether to obtain compounds according to the present image is ateneu (131 mg), having the following physical characteristics.

TLC: Rf of 0.36 (chloroform: methanol = 8:1);

NMR(DMSO-d6):13,08(s, 1H), 7,60-7,40(m, 5H), 4,28(s, 2H), 3,66(t, J = 5.7 Hz, 2H), 2.63 in(t, J = 5.7 Hz, 2H), 2,04(s, 3H).

Example 39(1)

The hydrochloride of 6-(2-(N,N-dimethylamino)acetyl)-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-it

By the same procedure described in example 39, and then by transformation into the corresponding salt in the usual way using 2-dimethylaminoacetonitrile instead of acetylchloride received the connection according to the present invention having the following physical characteristics.

TLC: Rf of 0.57 (chloroform: methanol = 4:1);

NMR(DMSO-d6):13,17(s, 1H), 9,75(Sirs, 1H), of 7.64 and 7.36(m, 5H), 4,48-4,30(m, 3H), is 4.21(m, 1H), 3.96 points-to 3.52(m, 8H), 2,86-of 2.64(m, 2H).

Example 40

4-(N-(2-carboxyethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

By the same procedure described in reference example 11 using the compound obtained in example 23(36)instead of the compound obtained in example 15 was synthesized compound according to the present invention having the following physical characteristics.

TLC: Rf 0.26 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,57(s, 1H), 8,15(m, 1H), 4,11(m, 1H), 3,39(s, 2H), 3,23(kV, J = 6.0 Hz, 2H), 2,58 to 2.35(m, 2H), 2,42 of-2.32(m, 4H), of 1.66 is 1.58(m, 4H).

Example 41

4-(N-(2-(4-hydroxyphenyl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

By the same procedure described in example 20, using the compound obtained in example 24(41), instead of the compound obtained in example 4(4), was synthesized compound having the following physical characteristics.

TLC: Rf 0.35 in (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,57(s, 1H), 9.15, with(s, 1H), 8,04(t, J = 5.7 Hz, 1H), of 6.96(d, J = 8,4 Hz, 2H), 6,65(d, J = 8,4 Hz, 2H), 3,36(s, 2H), up 3.22(m, 2H), 2,58(t, J = 7.5 Hz, 2H), 2,33(m, 4H), 1,61(Sirs, 4H).

Reference example 18

3-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-he

To a solution of anhydride 3,4,5,6-tetrahydrophthalic acid (10.0 g) in tetrahydrofuran (50,0 ml) was added borohydride sodium (600 mg) in an ice bath. The mixture was stirred at room temperature for 30 minutes and boiled under reflux for 5 hours. After cooling to room temperature, the reaction mixture was added 1N. a solution of hydrochloric acid (10.0 ml), the mixture was concentrated. Water was added to the residue, which was then extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (ethyl acetate: hexane = 1:4) with the teachings specified in the connection header (of 5.40 g), having the following physical characteristics.

TLC: Rf of 0.64 (ethyl acetate: hexane = 1:1);

NMR(CDCl3):5,98(Sirs, 1H), 4,90 ñ 4.50(m, 1H), 2,52-to 2.40(m, 1H), 2,32-of 2.16(m, 3H), 1,86 is 1.60(m, 4H).

Reference example 19

Tributyl(3-oxo-1,3,4,5,6,7-hexahydro-2-benzofuran-1-yl)phospholipase

A mixed solution of the compound obtained in reference example 18, (1.54 g), tri-n-butylphosphine (2,02 g) and acetic acid solution of HBR (47%, 1.20 ml) in acetic acid (0,700 ml) was boiled under reflux for 21 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified column chromatography on silica gel (methylene chloride: methanol = 20:1) to obtain the specified title compound (3.56 g)having the following physical characteristics.

TLC: Rf 0,51 (methanol: methylene chloride = 1:10).

Reference example 20

3 benzyliden-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-he

To a solution of the compound obtained in reference example 19, (419 mg) and benzaldehyde (106 mg) in methylene chloride (4,00 ml) was added triethylamine (0,130 ml) and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and the end of what was tarawali. The residue was purified column chromatography on silica gel (ethyl acetate: hexane = 1:8) to obtain the specified title compound (206 mg)having the following physical characteristics.

TLC: Rf 0,83 (hexane: ethyl acetate = 2:1).

Example 42

4-benzyl-5,6,7,8-tetrahydropyrazin-1(2H)-he

A solution of the compound obtained in reference example 20, (206 mg) and hydrazine monohydrate (49,0 μl) in ethanol (4,00 ml) was boiled under reflux for 1 hour. To the reaction mixture was added hydrazine monohydrate (49,0 μl), the mixture was boiled under reflux for 1 hour. After cooling the reaction mixture to room temperature, the resulting crystals were collected by filtration. The crystals were washed with ethanol and hexane and dried under reduced pressure to obtain compound according to the present invention (152 mg)having the following physical characteristics.

TLC: Rf 0,63 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):was 12.61(s, 1H), 7,32-7,24(m, 2H), 7.23 percent-7,13(m, 3H), 3,88(s, 2H), 2,44 was 2.25(m, 4H), 1,65-and 1.54(m, 4H).

Example 43 example 43(6)

By the same procedure described in reference example 20→example 42, using a corresponding derivative instead of benzaldehyde were synthesized the following compounds according to the present invention.

Example 43

4-(2-FeNi is ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,51 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,54(s, 1H), 7,35-to 7.15(m, 5H), 2,90-2,82(m, 2H), 2,81-of 2.72(m, 2H), 2,52-to 2.42(m, 2H), 2,41 of-2.32(m, 2H), 1.70 to was 1.58(m, 4H).

Example 43(1)

4-(pyridine-3-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,42 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,59(s, 1H), 8,45-8,39(m, 2H), 7,56(m, 1H), 7,31(DD, J = 7,5, and 4.8 Hz, 1H), 3,92(s, 2H), 2,46 is 2.33(m, 4H), 1,72-of 1.56(m, 4H).

Example 43(2)

4-(pyridine-2-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,59 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):to 12.58(s, 1H), 8,45(d, J = 4.5 Hz, 1H), 7,71(t, J = 7.8 Hz, 1H), 7,28-to 7.18(m, 2H), Android 4.04(s, 2H), 2,44 of-2.32(m, 4H), 1,68-of 1.56(m, 4H).

Example 43(3)

4-(5-methylfuran-2-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,68 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,60(s, 1H), 5,95(m, 2H), 3,84(s, 2H), 2,50 to 2.35(m, 4H), to 2.18(s, 3H), 1.70 to was 1.58(m, 4H).

Example 43(4)

4-(2-nitrobenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,59 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,40(s, 1H), 8,03(DD, J = 7,8, 1.2 Hz, 1H), 7,68(dt, J = 1,2, 7,8 Hz, 1H), 7,53(m, 1H), 7,46(d, J = 7.8 Hz, 1H), 4,24(s, 2H), 2,56 is 2.46(m, 2H), 2,44 to 2.35(m, 2H), 1,78-of 1.62(m, 4H).

Example 43(5)

4-(3-nitrobenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

NMR(DMSO-d6):was 12.61(s, 1H), 8,15-of 8.06(m, 2H), 7.68 per-EUR 7.57(m, 2H), 4,06(s, 2H), 2,47-of 2.34(m, 4H), 1.70 to 156(m, 4H).

Example 43(6)

4-(4-nitrobenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,60 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,65(s, 1H), 8,16(dt, J = 6,9, 1.8 Hz, 2H), 7,46(dt, J = 6,9, 1.8 Hz, 2H), of 4.05(s, 2H), 2,42 is 2.33(m, 4H), 1.70 to 1.55V(m, 4H).

Example 44

4-(2-aminobenzoyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The mixture solution of the compound obtained in example 43(4), (145 mg) and 10% palladium-on the corner (30.0 mg) in methanol (15.0 ml) was stirred in hydrogen atmosphere at room temperature for 30 minutes. The reaction mixture was filtered through celite. The filtrate was concentrated to obtain compound according to the present invention (129 mg)having the following physical characteristics.

TLC: Rf 0,42 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,57(s, 1H), 6,91(dt, J = 1,2, 7,8 Hz, 1H), 6,72(DD, J = 7,8, 1.2 Hz, 1H), is 6.61(DD, J = 7,8, 1.2 Hz, 1H), 6,46(dt, J = 1,2, 7,8 Hz, 1H), equal to 4.97(s, 2H), 3,66(s, 2H), 2,50-of 2.30(m, 4H), 1.70 to of 1.57(m, 4H).

Example 44(1) and example 44(2)

By the same procedure described in example 44, using the compound obtained in example 43(5) or 43(6), instead of the compound obtained in example 43(4), were synthesized the following compounds according to the present invention.

Example 44(1)

4-(3-aminobenzoyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Free form:

TLC: Rf of 0.38 (methylene chloride: methanol = 10:1);

6):12,60(s, 1H), 6,91(t, J = 8,1 Hz, 1H), 6,37(d, J = 8,1 Hz, 1H), of 6.31(s, 1H), 6,29(d, J = 8,1 Hz, 1H), 5,00(s, 2H), 3,71(s, 2H), 2,45-of 2.30(m, 4H), 1.70 to 1,50(m, 4H).

Methanesulfonate:

TLC: Rf of 0.53(methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,67(s, 1H), 9,60(width, 3H), 7,41(t, J = 7.8 Hz, 1H), 7,22(d, J = 7.8 Hz, 1H), 7,16(d, J = 7.8 Hz, 1H), 7,06(s, 1H), 3,93(s, 2H), 2,43-of 2.28(m, 4H), of 2.33(s,3H), 1,67-and 1.54(m, 4H).

Example 44(2)

4-(4-aminobenzoyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TCXC: Rf of 0.44 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,55(s, 1H), 6,78(d, J = 8.1 Hz, 2H), 6,47(d, J = 8.1 Hz, 2H), 4,90(s, 2H), 3,68(s, 2H), 2,42 was 2.25(m, 4H), 1.70 to 1,50(m, 4H).

Example 45

4-phenyl-2,5,6,7-tetrahydro-1H-cyclopent[d]pyridazin-1-he

A solution of (4aS,7aR)-4-phenyl-2,4a,5,6,7,7a-hexahydro-1H-cyclopent[d]pyridazin-1-she (210 mg; compound was obtained by the same procedure described in example 1 using (1R,2S)-2-benzoylisothiocyanate acid instead of the compound obtained in reference example 1), and thionyl chloride (0,500 ml) in benzene (3,00 ml) was boiled under reflux for 18 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was recrystallized from ethyl acetate to obtain compound according to the present invention (154 mg)having the following physical characteristics.

TLC: Rf 0.21 in (methanol: metranil the IAR = 1:20);

NMR(DMSO-d6):13,02(s, 1H), 7,62-7,58(m, 2H), 7,50-7,42(m, 3H), 2,99(t, J = 7.5 Hz, 2H), was 2.76(t, J = 7.5 Hz, 2H), 2.06 to a 1.96(m, 2H).

Reference example 21

6-phenyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

To a solution of anhydride 2,3-pyridineboronic acid (19,4 g) in tetrahydrofuran (260 ml) was added aniline (11.8 ml) and the mixture is boiled under reflux for 2 hours. The reaction mixture was concentrated. To the reaction mixture was added acetic anhydride (65 ml), the mixture was boiled under reflux for 1.5 hours. After cooling in an ice bath, the reaction mixture was poured into ice water (200 ml) and was stirred for 1 hour. The precipitate was collected by filtration. The precipitate was washed with water and then washed with ethanol under heating to obtain specified in the connection header (20,9 g)having the following physical characteristics.

TLC: Rf 0.31 in (hexane: ethyl acetate = 1:1);

NMR(CDCl3):of 7.48(m, 5 H) of 7.70(DD, J = 7,69, 4,94 Hz, 1H) 8,28(DD, J = 7,69, 1.65 Hz, 1H) 9,06(DD, J = 4,94, 1.65 Hz, 1H).

Reference example 22

7-(3-AMINOPHENYL)-7-hydroxy-6-phenyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-he

A solution of 3-(bis(trimethylsilyl)amino)formanilide in tetrahydrofuran (5.50 ml, 1,0M) was added dropwise to a suspension of the compound obtained in reference example 21, (1.12 g) in tetrahydrofuran (20 ml) in an ice bath ismes was stirred for 1 hour. To the reaction mixture was added dropwise 1N. a solution of hydrochloric acid (10 ml), the mixture was stirred for 30 minutes. To the reaction mixture were added saturated aqueous sodium bicarbonate solution (10 ml), the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was washed with ethyl acetate under heating to obtain specified in the title compound (1.35 g)having the following physical characteristics.

TLC: Rf value of 0.52 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):5,02(s, 2 H) 6,36(m, 1H) 6,47(m, 1H) 6,62(t, J = 1,92 Hz, 1H) 6,86(t, J = 7,83 Hz, 1H) 7,14(m, 1H) 7,28(m, 2 H) rate of 7.54(m, 4 H) to 8.20(DD, J = 7,69, 1.65 Hz, 1H) 8,70(DD, J = 4,94, 1.65 Hz, 1H).

Reference example 23

2-(3-aminobenzoyl)nicotinic acid

To the compound obtained in reference example 22, (3,17 g) was added 6N. a solution of hydrochloric acid (20 ml) and the mixture is boiled under reflux during the night. The reaction mixture was cooled in an ice bath, the pH of the mixture was brought to pH 5 by 5h. of sodium hydroxide solution (24 ml) and concentrated. The residue was distilled in the form azeotropic mixtures with ethanol and suspended in ethanol (50 ml) by boiling under reflux. Unneeded sodium chloride was separated by filtration. The filtrate was concentrated. The residue was washed with isopropanol (15 ml) under load, the processes of obtaining specified in the connection header (2,13 g), having the following physical characteristics.

TLC: Rf 0,49 (methylene chloride: methanol: acetic acid= 8:1:1);

NMR(DMSO-d6):6,74(m, 2 H) 6,85(t, J = 2.00 Hz, 1H) to 7.09(t, J = 7.87 in Hz, 1H) 7,63(DD, J = 7,97, was 4.76 Hz, 1H) 8,33(DD, J = 7,97, of 1.55 Hz, 1H) 8,77(DD, J = 4,76, of 1.55 Hz, 1H).

Reference example 24

8-(3-AMINOPHENYL)pyrido[2,3-d]pyridazin-5(6H)-he

To a suspension of the compound obtained in reference example 23, (1,94 g) in ethanol (40 ml) was added hydrazine monohydrate (400 mg) and the mixture is boiled under reflux during the night. After cooling the reaction mixture to room temperature, the precipitate was collected by filtration. The precipitate was washed with ethanol to obtain specified in the title compound (1.70 g)having the following physical characteristics.

TLC: Rf 0,54 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):5,14(s, 2H), only 6.64(m, 1H), 6,94(m, 1H), 6,99(m, 1H), to 7.09(t, J = of 7.69 Hz, 1H), to 7.84(DD, J = 8,06, 4,39 Hz, 1H), 8,63(DD, J = 8,06 and 1.83 Hz, 1H), 9,12(DD, J = 4,39 and 1.83 Hz, 1H), 13,00(s, 1H).

Example 46

8-(3-AMINOPHENYL)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

To a suspension of the compound obtained in reference example 24 (1,67 g) and platinum oxide (83 mg) in dimethylformamide (35 ml) was added 6N. a solution of hydrochloric acid (2.5 ml) and the mixture was stirred for 8 hours in an atmosphere of hydrogen. The reaction mixture was filtered through celite. The filtrate conc who was narrowly. To the residue was added saturated aqueous sodium bicarbonate solution, the residue was extracted with tetrahydrofuran (THF three times. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in methanol (35 ml) under heating. To the mixture was added activated carbon (340 mg), the mixture was stirred for 15 minutes. Activated charcoal was removed by filtration through celite. The filtrate was concentrated. The residue was washed with isopropanol by heating to obtain compounds according to the present invention (1,25 g; free form)having the following physical characteristics. The obtained compound (242 mg) suspended in methanol (4 ml). The solution methansulfonate (96 mg) in methanol (1 ml) was added to the mixture and stirred. The resulting crystals were collected by filtration. The crystals were washed with methanol to obtain compound according to the present invention (258 mg; methanesulfonate)having the following physical characteristics.

Free form:

TLC: Rf of 0.40 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):12,00(s, 1H), 7,07(m, 1H), 6,64-6,60(m, 2H), 6,53(d, J = 7,3 Hz, 1H), ceiling of 5.60(s, 1H), total of 5.21(s, 2H), 3.15 in(m, 2H), of 2.38(t, J = 6.2 Hz, 2H), 1,71(m, 2H).

Methanesulfonate:

TLC: Rf of 0.40 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6): to 12.28(s, 1H), 7,53(m, 1H), 7,40-7,30(m,

3 (H) of 3.13(m, 2 H), 2.40 a(t, J = 6.0 Hz, 2 H), to 2.35(s, 3 H), of 1.73(m, 2 H).

Example 47 example 47(13)

By the same procedure described in reference example 21→reference example 22→reference example 23→reference example 24→example 46, if necessary, were obtained the following compounds according to the present invention by transformation into the corresponding salts in the usual way using furo[3,4-b]pyridine-5,7-dione or a corresponding derivative and a corresponding derivative instead of 3-(bis(trimethylsilyl)amino)formanilide.

Example 47

Methanesulfonate 8-(3-(N,N-dimethylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.56 to (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):12,29(s, 1H), 7,39(t, J = 8,1 Hz, 1H), 7,22-of 6.78(m, 3H), 3.15 in(m, 2H), 3,01(s, 6H), is 2.41(t, J = 6.0 Hz, 2H), 2,33(s, 3H), at 1.73(m, 2H).

Example 47(1)

Methanesulfonate 8-benzyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,51 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,13(s, 1H), 7,31-7,16(m, 5H), 6.22 per(Sirs, 2H), 3,83(s, 2H), 3,19(t, J = 6.0 Hz, 2H), a 2.36(t, J = 6.0 Hz, 2H), 2,32(s, 3H), 1,73-of 1.65(m, 2H).

Example 47(2)

Methanesulfonate 8-(3-methoxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.50 (a methanol: methylene chloride = 1:10);

NMR(DMSO-d6):/img> 12,27(s, 1H), 7,38(t, J = 7.8 Hz, 1H), 7.03 is-of 6.96(m, 3H), 6,21(m, 2H), of 3.78(s, 3H), 3,16-3,13(m, 2H), 2,41(t, J = 6.0 Hz, 2H), 2,32(s, 3H), 1,76-1,71(m, 2H).

Example 47(3)

Methanesulfonate 8-(4-AMINOPHENYL)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0.25 in (methylene chloride: methanol = 19:1);

NMR(DMSO-d6):12,2(Sirs, 1H), 7,42(d, J = 8.1 Hz, 2H), 7,16(d, J = 8.1 Hz, 2H), 3,14(m, 2H), 2.40 a(t, J = 6.3 Hz, 2H), 2,33(s, 3H), at 1.73(m, 2H).

Example 47(4)

Methanesulfonate 8-(3-(morpholine-4-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,49 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):12,21(s, 1H), 9,79(Sirs, 1H), 7,80-7,37(m, 4H), of 5.83(s, 1H), and 4.40(d, J = 4.0 Hz, 2H), 3.96 points(d, J = 12.1 Hz, 2H), 3,62(t, J = 11.7 Hz, 2H), 3,30(d, J = 12.1 Hz, 2H), 3,20-of 3.06(m, 4H), 2.40 a(t, J = 6.0 Hz, 2H), 2,30(s, 3H), at 1.73(m, 2H).

Example 47(5)

Methanesulfonate 8-(4-(N,N-dimethylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf of 0.50 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):12,38(s, 1H), 7,34(d, J = 8.1 Hz, 2H), 6,95(m, 2H), 3.15 in(m, 2H), 2,99(s, 6H), 2,42(m, 2H), 2,34(s, 3H), at 1.73(m, 2H).

Example 47(6)

Dimethanesulfonate 8-(4-(morpholine-4-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,51 (methylene chloride: methanol = 10:1);

NMR(CD3OD):7,72(d, J = 8.1 Hz, 2H), 7,66(d, J = 8.1 Hz, 2H), 4,46(s, 2H), 4,11-was 4.02(m, 2H), 3,80(t, J = 12,6 Hz, 2H), 3,42(d, J = 12,6 Hz, 2H), 3,40-3,18(m, 4H), 2,69(s, 6H), 2,72-of 2.64(m, 2H), 2.00 in 1,89(m, 2H).

Por the measures 47(7)

Methanesulfonate 8-(2-(morpholine-4-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,54 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,32(s, 1H), 9,45(width, 1H), 7,76(m, 1H), of 7.64-7,53(m, 2H), 7,43(m, 1H), 5,64(width, 1H), 4,25(s, 2H), a 3.87(d, J = 12.0 Hz, 2H), to 3.67(t, J = 12.0 Hz, 2H), 3,25(d, J = 12.0 Hz, 2H), 3,16-3,00(m, 4H), 2,42(t, J = 6.0 Hz, 2H), 2,33(s, 3H), 1,79-of 1.66(m, 2H).

Example 47(8)

Trihydrochloride 8-(3-(4-ethylpiperazin-1-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,42 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,40(width, 1H), 11,99(width, 1H), to 7.77-of 7.69(m, 2H), 7,62-of 7.48(m, 2H), 6.30-in-5,30(width, 3H), of 4.45(s, 2H), 3,80-to 3.50(m, 4H), 3,70 is 3.40(m, 4H), 3,30-3,00(m, 4H), 2,42(t, J = 6.3 Hz, 2H), 1,80-of 1.66(m, 2H), 1,24(t, J = 7.2 Hz, 3H).

Example 47(9)

Methanesulfonate 8-(3-(N,N-dimethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,27 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,21(s, 1H), 9,59(width, 1H), 7,62-7,52(m, 4H), of 5.82(s, 1H), 4,35-or 4.31(m, 2H), 3,20-of 3.12(m, 2H), was 2.76(s, 3H), of 2.75(s, 3H), 2,41(t, J = 6.3 Hz, 2H), 2,30(s,3H), 1,81 by 1.68(m, 2H).

Example 47(10)

Methanesulfonate 8-(4-(N,N-dimethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf 0,82 (methylene chloride: methanol: ammonia water= 8:2:0,2);

NMR(DMSO-d6):12,19(s, 1H), 9,68(width, 1H), EUR 7.57(d, J = 8,4 Hz, 2H), 7,53(d, J = 8,4 Hz, 2H), USD 5.76(s, 1H), 4,34(s, 2H), 3,18-3,10(m, 2H), and 2.7(s, 6H), 2.40 a(t, J = 6.0 Hz, 2H), 2,3 l(s, 3H), 1,80 by 1.68(m, 2H).

Example 47(11)

Methanesulfonate 8-(4-(N,N-diethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf of 0.38 (methylene chloride: methanol: ammonia water= 8:2:0,2);

NMR(DMSO-d6):12,20(s, 1H), 9,34(width, 1H), 7,60(d, J = 8,4 Hz, 2H), 7,54(d, J = 8,4 Hz, 2H), 5,77(s, 1H), 4,36(d, J = 4,8 Hz, 2H), 3,12-to 3.02(m, 6H), 2.40 a(t, J = 6.0 Hz, 2H), 2,30(s, 3H), 1,80 by 1.68(m, 2H), 1,24(t, J = 7.2 Hz, 6H).

Example 47(12)

Methanesulfonate of 4-(4-(N,N-dimethylaminomethyl)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,49 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):to 12.95(s, 1H), for 9.64(width, 1H), 7,60-7,52(m, 4H), to 4.33(s, 2H), was 2.76(s, 6H), 2,50-to 2.40(m, 2H), 2,40 of-2.32(m, 2H), 2,30(s, 3H), 1,76-of 1.66(m, 2H), 1,66-of 1.55(m, 2H).

Example 47(13)

Methanesulfonate 8-(4-(2-(N,N-dimethylamino)ethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf of 0.50 (methylene chloride: methanol: ammonia water= 8:2:0,2);

NMR(DMSO-d6):of 12.12(s, 1H), 9,41(width, 1H), 7,42(d, J = 8.1 Hz, 2H), 7,37(d, J = 8.1 Hz, 2H), 5,70(s, 1H), 3,35-of 3.25(m, 2H), 3,18-to 3.09(m, 2H), 3,05-2,96(m, 2H), and 2.83(s, 6H), 2,39(t, J = 6.3 Hz, 2H), 2,30(s, 3H), 1,80 by 1.68(m, 2H).

Reference example 25

Methyl ester 2-(3-aminobenzoyl)nicotinic acid

After cooling, methanol (5 ml) to -15°C were added dropwise thionyl chloride (1.3 ml) and the solution was stirred for 15 minutes. To the solution was added the compound obtained in ssy is face-to-face example 23 (1,21 g). The solution was left to warm to room temperature and then boiled under reflux during the night. The reaction mixture was concentrated. To the residue was added saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from isopropanol (5 ml) to obtain the specified title compound (815 mg)having the following physical characteristics.

TLC: Rf of 0.37 (hexane: ethyl acetate = 1:3);

NMR(DMSO-d6):of 3.69(s, 3H) are 5.36(s, 2H) 6,79(m, 2H) 6.89 in(m, 1H) 7,12(t, J = 7,83 Hz, 1H) of 7.70(DD, J = 8,04, to 4.81 Hz, 1H) 8,39(DD, J = 8,04, 1.65 Hz, 1H) 8,83(DD,J =4,74, 1.65 Hz, lH).

Reference example 26

Methyl ester of 2-(3-(TRIFLUOROACETYL)aminobenzoyl)nicotinic acid

To a solution of the compound obtained in reference example 25, (800 mg) in methylene chloride (15 ml) was added sequentially pyridine (505 μl) and the anhydride triperoxonane acid (529 ml) in an ice bath and the mixture was stirred for 30 minutes. The reaction mixture was diluted with methylene chloride and washed successively 1H. solution of hydrochloric acid and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane: ethyl acetate = 1:1) to obtain what is shown in the title compound (1.10 g), having the following physical characteristics.

TLC: Rf of 0.48 (hexane: ethyl acetate = 1:1);

NMR(CDCl3):3,79(s, 3 H) 7,49(t, J = 7,97 Hz, 1H) 7,56(DD, J = 8,11, to 4.81 Hz, 1H) 7,63(m, 1H) 7,99(m, 2 H) 8,28(s, 1H) 8,39(DD, J = 8,11, 1.65 Hz, 1H) 8,82(DD, J =4,81, 1.65 Hz, 1H).

Reference example 27

Methyl ester of 2-(3-(N-methyl-N-(TRIFLUOROACETYL)amino)benzoyl)nicotinic acid

To a solution of the compound obtained in reference example 26, (1.06 g) in dimethylformamide (12 ml) was added sodium hydride (127 mg) in an ice bath and the mixture was stirred for 30 minutes. Methyliodide (224 μl) was added to the reaction mixture, which was stirred at 0°C for 1 hour and then at room temperature for 6 hours. The reaction mixture was poured into ice water and was extracted with a mixture of solvents (ethyl acetate: hexane = 1:1) twice. The combined organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from a mixture solvent (isopropanol: hexane = 1:1) to obtain specified in the connection header (892 mg)having the following physical characteristics.

TLC: Rf 0.31 in (hexane: ethyl acetate = 1:1);

NMR(CDCl3):3,37(s, 3H) 3,76(s, 3H) at 7.55(m, 3H) 7,71(s, 1H) 7,87(d, J = of 7.69 Hz, 1H) 8,40(DD, J = 7,97, 1.65 Hz, 1H) 8,83(DD, J = 4,94, 1.65 Hz, 1H).

Saloon the second example 28

8-(3-(N-methylamino)phenyl)pyrido[2,3-d]pyridazin-5(6H)-he

To a solution of the compound obtained in reference example 27, (880 mg) in ethanol (12 ml) solution was added hydrazine monohydrate (240 mg) in ethanol (3 ml) and the mixture is boiled under reflux during the night. To the reaction mixture were added 1N. the sodium hydroxide solution (5 ml), the mixture was boiled under reflux for 1 hour. The reaction mixture was cooled in an ice bath and to the mixture was added 1N. a solution of hydrochloric acid (5 ml). The precipitation was collected by filtration. The precipitate was washed with water and then washed with ethanol under heating to obtain specified in the title compound (581 mg)having the following physical characteristics.

TLC: Rf 0.39 to (methylene chloride: methanol = 19:1);

NMR(DMSO-d6):2,69(d, J = 5,13 Hz, 3H), 5,73(kV, J = 5,13 Hz, 1H), 6,62(m, 1H), 6,97(m, 2H), 7,18(t, J = of 7.69 Hz, 1H), a 7.85(DD, J = 8,06, 4,39 Hz, 1H) 8,64(DD, J = 8,06 and 1.83 Hz, 1H), 9,13(DD, J = 4,39 and 1.83 Hz, 1H), 13,02(s, 1H).

Example 48

Methanesulfonate 8-(3-(N-methylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

By the same procedure described in example 46, using the compound obtained in reference example 28 and, instead of the compound obtained in reference example 24, were synthesized compounds according to the present invention having the following physical characteristics.

TLC: Rf 0,49 (methylene chloride: methanol = 9:1);

NMR(DMSO-d6):12,31(s, 1H), was 7.36(t, J = 7.9 Hz, 1H), 7.18 in-6,85(m, 3H), and 3.16(m, 2H), and 2.83(s, 3H), 2,41(t, J = 6.0 Hz, 2H), 2,34(s, 3H), at 1.73(m, 2H).

Example 49

Methanesulfonate 8-(4-(N-methylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

By the same procedure described in reference example 25→reference example 26→reference example 27→reference example 28→example 46, using a corresponding derivative instead of the compound obtained in reference example 23, were synthesized compounds according to the present invention having the following physical characteristics.

TLC: Rf 0.39 to (methanol: methylene chloride = 1:9);

NMR(DMSO-d6):of 12.26(Sirs, 1H), 7,27(d, J = 7.8 Hz, 2H), 6,79(d, J = 7.8 Hz, 2H), 5,96(Sirs, 3H), and 3.16(m, 2H), was 2.76(s, 3H), 2,41(m, 2H), 2,32(s, 3H), 1,72(m, 2H).

Example 50 example 50(4)

By the same procedure described in reference example 20→example 42, using a corresponding derivative instead of benzaldehyde were synthesized compounds according to the present invention having the following physical characteristics.

Example 50

4-(2-phenoxyethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,41 (methylene chloride: methanol = 19:1);

NMR(DMSO-d6):of 12.6(s, 1H), 7,30-722(m, 2H), 6,95-of 6.90(m, 3H), 4.26 deaths(t, J = 6.9 Hz, 2H), 2,97(t, J = 6.9 Hz, 2H), 2,60 to 2.35(m, 4H), of 1.66(m, 4H).

Example 50(1)

4-(3-phenoxypropan)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.40 (methylene chloride: methanol = 19:1);

NMR(DMSO-d6):to 12.52(s, 1H), 7,26(m, 2H), 6.90 to(m, 3H), 4,01(t, J = 6.3 Hz, 2H), 2,65(t, J = 7.5 Hz, 2H), 2,55-of 2.30(m, 4H), for 2.01(m, 2H), 1,64(m, 4H).

Example 50(2)

The hydrochloride of 4-(4-(3-(N,N-dimethylamino)propoxy)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.37(methylene chloride: methanol: ammonia water= 8:2:0,2);

NMR(DMSO-d6):12,60(s, 1H), to 9.32(Sirs, 1H), was 7.08(d, J = 8,4 Hz, 2H), 6,86(d, J = 8,4 Hz, 2H), 3,99(t, J = 6.0 Hz, 2H), 3,81(s, 2H), 3,24-and 3.16(m, 2H), and 2.79(s, 6H), 2.40 a-2,28(m, 4H), 2,14-2,02(m, 2H), 1,64-and 1.54(m, 4H).

Example 50(3)

4-(2-benzyloxyethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf 0,54 (methylene chloride: methanol = 19:1);

NMR(DMSO-d6):of 12.5(s, 1H), 7,35-7,22(m, 5H), 4,47(s, 2H), 3,69(t, J = 7.2 Hz, 2H), 2,78(t, J = 7.2 Hz, 2H), 2,50-of 2.36(m, 4H), and 1.63(m, 4H).

Example 50(4)

4-(quinoline-3-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.53(methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,60(s, 1H), 8,79(d, J = 1.8 Hz, 1H), 8,08(d, J = 1.8 Hz, 1H), 7,98(d, J = 8,1 Hz, 1H), 7,92(DD, J = 8,1, 1.5 Hz, 1H), of 7.70(DDD, J = 8,1, to 6.9, 1.5 Hz, 1H), EUR 7.57(DDD, J = 8,1, to 6.9, 1.5 Hz, 1H), 4,12(s, 2H), 2,54-2,40(m, 2H), 2,46-of 2.30(m, 2H), 1.70 to 1.55V(m, 4H).

Example 51 example 51(3)

By the same procedure described in example 27, if neo is absolutely essential, were synthesized the following compounds by transformation into the corresponding salts in the usual way using a corresponding derivative instead of the compound obtained in reference example 13, and a corresponding derivative instead of benzylamine.

Example 51

The hydrochloride of 4-(5-(piperidine-1-yl)pentyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.83(methylene chloride: methanol: ammonia water= 8:2:0,2);

NMR(DMSO-d6):12,51(s, 1H), 9,96(width, 1H), 3.46 in of 3.28(m, 2H), 3,02-2,84(m, 2H), 2.95 and-to 2.65(m, 2H), 2,54 is 2.44(m, 2H), 2,42 of-2.32(m, 2H), 1,84-and 1.54(m, 14H), 1,44-of 1.26(m, 4H).

Example 51(1)

8-(2-(4-(2-(morpholine-4-yl)ethyl)piperazine-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3,-d]pyridazin-5(1H)-he

TLC: Rf of 0.15 (methylene chloride: methanol: saturated aqueous ammonia= 4:1:0,5%);

NMR(CD3OD):δ of 3.69(m, 4H), to 3.33(m, 2H), 2,78-to 2.42(m, 22H), of 1.85(m, 2H).

Example 51(2)

Methanesulfonate 8-(2-(4-benzyloxycarbonyl-1,4-diazepan-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3,-d]pyridazin-5(1H)-it

TLC: Rf 0,19 (methylene chloride: methanol = 19:1);

NMR(DMSO-d6):of $ 11.97(s, 1H), 9,39(s, 1H), 7,41-7,30(m, 5H), 6,38(Sirs, 1H), 5,11(s, 2H), 4,32(Sirs, 2H), a 3.87(m, 1H), 3,70 is 3.40(m, 7H), 3,30-3,15(m, 2H), 2,84(t, J = 7.5 Hz, 2H), 2,35(t, J = 6.3 Hz, 2H), 2,31(s, 3H), 2,07(m, 2H), 1,72(m, 2H).

Example 51(3)

4-(4-(morpholine-4-yl)butyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Hydrochloride:

TLC: Rf of 0.29 (methylene chloride: methanol = 10:1);

NMR(300 MG IS, CD3OD) 3,10-3,00(m, 4H), 2,37-of 2.26(m, 4H), 2,25-of 2.16(m, 2H), 1,85(t, J = 6.9 Hz, 2H), 1,83 is 1.75(m, 2H), 1,75-to 1.67(m, 2H), 1,08-0,88(m, 8H).

Methanesulfonate:

TLC: Rf 0.25 in (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,55(s, 1H), 9,52(width, 1H), 4,01-to 3.92(m, 2H), to 3.64(t, J = 11,4 Hz, 2H), 3.45 points-to 3.36(m, 2H), 3,17-2,95(m, 4H), 2,58 is 2.43(m, 4H), 2,43-of 2.34(m, 2H), 2,31(s, 3H), 1.77 in-and 1.54(m, 8H).

Example 52 example 52(3)

By the same procedure described in example 24, if necessary, were synthesized the following compounds according to the present invention by transformation into the corresponding salts in the usual way using the corresponding ether derivative instead of the compound obtained in example 15, and a corresponding derivative instead of 2-aminoethanol.

Example 52

8-(N-(4-hydroxybutyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3,-d]pyridazin-5(1H)-he

TLC: Rf 0,54 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):11,84(s, 1H), of 8.06(t, J = 5.7 Hz, 1H), 6.42 per(s, 1H), 4,37(t, J = 4,8 Hz, 1H), 3,35(m, 4H), 3,18(m, 2H), 3,03(TD, J = 6,6, 5.7 Hz, 2H), 2,32(t, J = 6.3 Hz, 2H), 1.69 in(m, 2H), 1,41(m, 4H).

Example 52(1)

8-(N-(4-(morpholine-4-yl)butyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3,-d]pyridazin-5(1H)-he

TLC: Rf 0,22 (methanol: methylene chloride = 1:4);

NMR(DMSO-d6):11,84(s, 1H), of 8.06(t, J = 5.4 Hz, 1H), gold 6.43(s, 1H), 3,55-to 3.52(m, 4H), 3,32-of 3.31(m, 2H), 3,18(Sirs, 2H), 3.04 from(m, 2H), 2,34-2,19(m, 8H), 1,71 by 1.68(m, 2H), 1,40-1,36(who, 4H).

Example 52(2)

Methanesulfonate 8-(N-(2-(azepin-1-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3,-d]pyridazin-5(1H)-it

TLC: Rf 0.39 to (methanol: methylene chloride: saturated aqueous ammonia= 2:8:0,1);

NMR(DMSO-d6):11,90(s, 1H), 9,13(Sirs, 1H), 8,30(t, J = 5.4 Hz, 1H), 6.30-in(Sirs,( 1H), 3,45-to 3.35(m, 6H), 3,19-is 3.08(m, 6H), 2.40 a-to 2.29(m, 2H), 2,33(s, 3H), 1,80-of 1.52(m, 10H).

Example 52(3)

4-(N-(6-hydroxyhexyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.23 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,56(s, 1H), 7,99(t, J = 5.7 Hz, 1H), 4,32(t, J = 5,1 Hz, 1H), 3,38(s, 2H), 3,37-to 3.33(m, 2H), 3,05-to 2.99(m, 2H), 2,41-of 2.36(m, 4H), and 1.63(m, 4H), 1,40-of 1.23(m, 8H).

Example 53 and example 53(1)

By the same procedure described in example 34 were synthesized the following compounds according to the present invention when using a corresponding derivative instead of the compound obtained in example 33.

Example 53

4-(N-(5-bromopentyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.53(methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,57(s, 1H), 8,02(t, J = 5,1 Hz, 1H), 3,51(t, J = 6.3 Hz, 2H), 3,39(s, 2H), 3.04 from(kV, J = 6.3 Hz, 2H), 2,46 is 2.33(m, 4H), 1,78(Quain, J = 6.3 Hz, 2H), 1.70 to was 1.58(m, 4H), 1,48-of 1.30(m, 4H).

Example 53(1)

4-(N-(6-bromohexyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.37 (methanol: methylene chloride = 1:10)

NMR(DMSO-d6):12,57(s, 1H), 7,99(t, J = 5.4 Hz, 1H), 3,51(t, J = 6.6 Hz, 2H), 3,38(s, 2H), 3,06-3,00(m, 2H), 2,41-of 2.36(m, 4H), 1,82 is 1.75(m, 2H), 1,64(m, 4H), 1.41 to to 1.16(m, 6H).

Example 54 example 54(2)

By the same procedure described in example 28, if necessary, were synthesized the following compounds according to the present invention by transformation into the corresponding salts in the usual way using the compound obtained in example 53, 23(23) or 53(1), instead of the compound obtained in example 25(1).

Example 54

4-(N-(5-(morpholine-4-yl)pentyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

TLC: Rf of 0.57 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,57(s, 1H), 7,99(t, J = 5.7 Hz, 1H), 3,54(t, J = 4.8 Hz, 4H), to 3.38(s, 2H), 3,02(kV, J = 6,9 Hz, 2H), 2,46 is 2.33(m, 4H), 2,33 was 2.25(m, 4H), of 2.21(t, J = 6.9 Hz, 2H), 1,68 is 1.58(m, 4H), 1.39 in(Quain, J = 6,9 Hz, 4H), 1,31-1,19(m, 2H).

Example 54(1)

Methanesulfonate of 4-(N-(2-(asokan-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.67 (methanol: methylene chloride: 28% ammonia water= 2:8:0,1);

NMR(DMSO-d6):12,63(s, 1H), 9,37(Sirs, 1H), at 8.36(t, J = 5.7 Hz, 1H), 3.46 in(s, 2H), 3.43 points-to 3.34(m, 4H), 3,16-of 3.12(m, 4H), 2,42-is 2.37(m, 4H), to 2.29(s, 3H), 1,84-1,49(m, 14H).

Example 54(2)

Methanesulfonate of 4-(N-(6-(morpholine-4-yl)hexyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,22 (methanol: methylene chloride = 1:9);

NMR(MSO-d 6):to 12.58(s, 1H), 9,48(Sirs, 1H), 8,03(t, J = 5.4 Hz, 1H), 3,98-of 3.94(m, 2H), 3,67-3,39(m, 6H), 3,07-a 3.01(m, 6H), 2,48-of 2.36(m, 7H), 1,63-of 1.27(m, 12H).

Example 55 example 55(2)

By the same procedure described in reference example 22→reference example 24→example 20→example 46, if necessary, were synthesized the following compounds according to the present invention by transformation into the corresponding salts in the usual way using a corresponding derivative instead of 4-(bis(trimethylsilyl)amino)phenylmagnesium.

Example 55

8-(3,4-dihydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf 0,59 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):11,94(s, 1H), 9,14(width, 2H), 6,80(s, 1H), 6,79(d, J = 7.8 Hz, 1H), of 6.68(m, 1H), 5,65(s, 1H), 3,16-is 3.08(m, 2H), 2,37(t, J = 6.0 Hz, 2H), 1.77 in-of 1.65(m, 2H).

Example 55(1)

Methanesulfonate 8-(4-hydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

TLC: Rf of 0.29 (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):12,40(Sirs, 1H), 9,20(Sirs, 1H), 7,26(d, J = 8.7 Hz, 2H), at 6.84(d, J = 8.7 Hz, 2H), and 3.16(t, J = 5,1 Hz, 2H), 2,42(t, J = 6.0 Hz, 2H), 2,34(s, 3H), 1,71(m, 2H).

Example 55(2)

8-(2-hydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf of 0.4 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,58(width, 1H), 9,58(width, 1H), 7,29(t, J 7.5 Hz, 1H), 7,12(d, J = 7.5 Hz, 1H), 6,93(d, J = 7.5 Hz, 1H), to 6.88(t, J = 7.5 Hz, 1H), 5,96(width, 1H), 3,23-of 3.12(m, 2H), 2,54-2,4(m, 2H), 1,82-of 1.64(m, 2H).

Example 56 example 56(6)

By the same procedure described in example 46, if necessary, were synthesized the following compounds according to the present invention by transformation into the corresponding salts in the usual way using the compound obtained in example 43(1), example 43(2), 23(17), 23(22), 24(11) or 24(16), or when using 4-(pyridine-4-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it instead of the compound obtained in reference example 24.

Example 56

Acetate 4-(piperidine-3-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.21 in (methylene chloride: methanol: ammonia water= 8:2:0,2);

NMR(DMSO-d6):12,49(width, 1H), 2,97-2,84(m, 2H), 2,53-to 2.42(m, 5H), 2,41-2,31(m, 4H), and 2.26(m, 1H), of 1.84(m, 1H), equal to 1.82(s, 3H), 1.77 in-1,53(m, 6H), of 1.40(m, 1H), 1,09(m, 1H).

Example 56(1)

Acetate 4-(piperidine-4-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.16 (methylene chloride: methanol: ammonia water= 8:2:0,2);

NMR(DMSO-d6):12,51(width, 1H), 2,90(m, 1H), 2,78(m, 1H), 2,58-to 2.40(m, 7H), 2,40 of-2.32(m, 2H), 1,86(s, 3H), 1,74-of 1.45(m, 7H), 1,38 is 1.20(m, 2H), 1,10(m, 1H).

Example 56(2)

Acetate 4-(piperidine-2-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,58 (methylene chloride: methanol: ammonia water= 8:2:0,2);

NMR(DMSO-d6):12,SR., 1H), 3,01-only 2.91(m, 2H), 2,56-to 2.42(m, 6H), 2,41 of-2.32(m, 4H), of 1.81(s, 3H), of 1.80(m, 1H), 1.70 to 1.55V(m, 6H), 1,22-of 1.07(m, 2H).

Example 56(3)

Methanesulfonate of 4-(N-(piperidine-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0,27 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,64(s, 1H), which 9.22(d, J = 7.5 Hz, 1H), 8,77(width, 2H), a 4.83(m, 1H), 3,55(s, 2H), 3,10(m, 1H), 2,97(m, 1H), 2,55 to 2.35(m, 4H), of 2.34(s, 3H), 1,94 of 1.50(m, 10H).

Example 56(4)

Methanesulfonate of 4-(N-(piperidine-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.55 (methylene chloride: methanol: 28% ammonia water= 15:5:1);

NMR(DMSO-d6):br12.62(s, 1H), and 8.50(m, 1H), 8,30-8,10(m, 2H), 3,48(s, 2H), 3,40-3,00(m, 4H), 2,84(m, 1H), 2,46-of 2.34(m, 4H), 2,32(s, 3H), 1,82-of 1.20(m, 10H).

Example 56(5)

Methanesulfonate of 4-(N-(2-(piperidine-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf of 0.40 (methylene chloride: methanol: 28% ammonia water= 15:5:1);

NMR(DMSO-d6):was 12.61(s, 1H), to 8.41(m, 1H), 8.30 to-8,16(m, 2H), 3,42(s, 2H), 3,30-2,70(m, 5H), 2,46 of-2.32(m, 4H), 2,31(s, 3H), 1,92 is 1.20(m, 12H).

Example 56(6)

Methanesulfonate of 4-(N-(2-(piperidine-3-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

TLC: Rf 0.28 in (methylene chloride: methanol: 28% ammonia water= 15:5:1);

NMR(DMSO-d6):12,57(Sirs, 1H), compared to 8.26(Sirs, 2H), of 8.06(t, J = 5.5 Hz, 1H), 3,39(s, 2H), 3,24-to 3.02(m, 4H), 2,73(m, 1H), 2,46 of-2.32(m, 4H), of 2.30(s, 3H), 1,80 of-1.04(m, 12H).

Example 57

8-(3-what hydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

By the same procedure described in example 20, if necessary, by transformation into the corresponding salts in the usual way using the compound obtained in example 47(2), instead of the compound obtained in example 4(4), were synthesized compounds according to the present invention, having the following characteristics :

Free form:

TLC: Rf of 0.33 (methanol: methylene chloride = 1:20);

NMR(DMSO-d6):12,06(s, 1H), 9,60(s, 1H), 7,25(t, J = 8,1 Hz, 1H), for 6.81(m, 3H), 5,71(s, 1H), 3,13(m, 2H), a 2.36(m, 2H), 1,71(m, 2H).

Sodium salt:

TLC: Rf of 0.43 (methanol: methylene chloride = 1:9);

NMR(DMSO-d6):11,85(Sirs, 1H), 6,92(t, J = 7.8 Hz, 1H), 6,36(Sirs, 2H), 6,17(Sirs, 1H), of 5.40(s, 1H), 3,13(m, 2H), a 2.36(m, 2H), by 1.68(m, 2H).

Example 58

8-(N-(2-(piperidine-4-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

A mixed solution of the compound obtained in example 24(44), (307 mg), 10% palladium-on the corner (307 mg) and moravcikova ammonium (236 mg) in methanol (3,00 ml) was boiled under reflux for 30 minutes. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated. The residue is washed with a mixed solution of methanol and ethyl acetate and dried under reduced pressure to obtain compound according to the present invention (187 mg), with follow what their physical characteristics.

TLC: Rf 0,13 (methanol: methylene chloride: acetic acid= 1:4:1);

NMR(DMSO-d6):11,83(Sirs, 1H), of 8.06(t, J = 5,1 Hz, 1H), 6,44(s, 1H), 3,18-of 2.09(m, 13H), was 1.69(m, 2H), of 1.52(m, 2H), 1,29(m, 3H), were 0.94(m, 2H).

Example 59

8-(pyridin-2-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he (compound A) and 8-(piperidine-2-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he (compound B)

In the atmosphere of argon, 8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-ONU (118 mg; this compound was obtained by the same procedure described in reference example 22→reference example 23→reference example 24) when using bromide and pyridine-2-elminia instead of 3-(bis(trimethylsilyl)amino)formanilide) were added sequentially methanol (6 ml), methanesulfonate (51 mg) and platinum oxide (12 mg). The reaction mixture was stirred in hydrogen atmosphere at room temperature for 5.5 hours. The reaction mixture was filtered through celite. The filtrate was concentrated. The residue was purified column chromatography on silica gel (methylene chloride: methanol = 20:1→methylene chloride: methanol: water = 8:2:0,2) to obtain the free form of compound (14 mg) and methanesulfonate compound (77 mg)having the following physical characteristics. The compounds a and b were converted into the corresponding salts or the free form of compounds in the usual way with what rucenim compounds according to the invention, having the following physical characteristics.

Free connection form:

TLC: Rf 0,51 (methylene chloride: methanol = 10:1).

NMR(DMSO-d6):KZT 12.39(width, 1H), 8,88(width, 1H), 8,59(m, 1H), 8,04(d, J = 8,4 Hz, 1H), to 7.93(m, 1H), 7,44(m, 1H), 3,40-of 3.25(m, 2H), 2,43(t, J = 6.3 Hz, 2H), 1.85 to around 1.74(m, 2H).

Methanesulfonate connection:

TLC: Rf of 0.15 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):12,36(s, 1H), 8,76(width, 2H), 6,63(s, 1H), 4,21(d, J = 9.9 Hz, 1H), 3,30(m, 1H), 3,28-and 3.16(m, 2H), 2,89(m, 1H), a 2.36(t, J = 6.0 Hz, 2H), to 2.29(s, 3H), 2,03(d, J = 12.3 Hz, 1H), 1,84 is 1.60(m, 6H), USD 1.43(m, 1H).

Freeform connection:

TLC: Rf 0.14 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):11,74(s, 1H), was 7.36(s, 1H), 3,54(DD, J = 9,6, 3,9 Hz, 1H), 3,26-and 3.16(m, 2H), 2,94(d, J = 12.0 Hz, 1H), 2,65-of 2.50(m, 1H), 2,32(t, J = 6.3 Hz, 2H), 1,79(m, 1H), 1,76-of 1.26(m, 7H).

Methanesulfonate connection:

TLC: Rf of 0.50 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,63(width, 1H), 9,45(width, 2H), at 8.60(d, J = 4.5 Hz, 1H), of 8.06(d, J =and 8.4 Hz, 1H), 7,97(t, J = 8,4 Hz, 1H), of 7.48(m, 1H), 3,40-to 3.33(m, 2H), 2,52-to 2.42(m, 2H), a 2.36(s, 3H), 1,84-of 1.73(m, 2H).

Dimethanesulfonate connection:

TLC: Rf 0,66 (methylene chloride: methanol: ammonia water= 8:2:0,2);

NMR(DMSO-d6):of 1.45(m, 1H) 1,72(m, 6 H) 2,04(d, J = 12,82 Hz, 1H) 2,37(m, 8 H) to 2.94(s, 1H) 3,25(m, 3 H) 4.26 deaths(t, J = 10,44 Hz, 1H) 7,21(m, 1H) 8,71(m, 1H) 8,89(m, 1H) 12,48(s, 1H).

Example 59(1) example 59(3)

Through this W the procedures that described in example 59, if you were synthesized the following compounds according to the present invention by transformation into the corresponding salts in the usual way when using 8-(pyridin-3-yl)pyrido[2,3-d]pyridazin-5(6H)-it, 8-(pyridin-4-yl)pyrido[2,3-d]pyridazin-5(6H)-or 8-(1-benzylpiperidine-4-yl)pyrido[2,3-d]pyridazin-5(6H)-it instead of 8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-it.

Example 59(1)

Methanesulfonate 8-(pyridin-3-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-she (compound A) and acetate 8-(piperidine-3-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-she (compound B)

Connection:

TLC: Rf 0,66 (methylene chloride: methanol = 4:1);

NMR(DMSO-d6):12,46(s, 1H), of 8.92(s, 1H), 8,86(d, J = 5,1 Hz, 1H), of 8.37(d, J = 7.5 Hz, 1H), to $ 7.91(DD, J = 7,5, 5,1 Hz, 1H), 6,20(Sirs, 1H), 3,13(m, 2H), 2,41(m, 2H), 2,31(s,3H), of 1.75(m, 2H).

Connection:

TLC: Rf 0,12 (methylene chloride: methanol: acetic acid= 4:1:2%);

NMR(DMSO-d6):of 11.75(s, 1H), 6.48 in(s, 1H), 3,18(m, 2H), 2,98(m, 2H), 2,71(m, 1H), 2,44(m, 2H), 2,32(m, 2H), 1,86(s, 3H)and 1.83(m, 1H), 1,74 was 1.43(m, 5H).

Example 59(2)

Methanesulfonate 8-(pyridin-4-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-she (compound A) and 8-(piperidine-4-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he (compound B)

Connection A:

TLC: Rf 0.28 in(methylene chloride: methanol = 10:1);

NMR(DMSO-d6):12,63(width, 1H), 8,90(who, J = 6.0 Hz, 2H), 8,00(d, J = 6.0 Hz, 2H), 6,23(width, 1H), 3,18-3,10(m, 2H), 2,42(t, J = 6.0 Hz, 2H), 2,31(s, 3H), 1,82 is 1.70(m, 2H).

The free form of compounds B:

TLC: Rf 0,053 (methylene chloride: methanol: acetic acid= 4:1:2%);

NMR(DMSO-d6):11,71(s, 1H), 6,33(s, 1H), and 3.16(m, 2H), equal to 2.94(m, 2H), 2,74-of 2.38(m, 3H), 2,32(m, 2H), 1,75-of 1.32(m, 6H).

Dimethanesulfonate connection B:

TLC: Rf 0,86 (methylene chloride: methanol: water= 8:2:0,2);

NMR(DMSO-d6):to 11.79(width, 1H), 8,13(width, 3H), 6,40(s, 1H), 3,23 is 3.15(m, 2H), 3.15 and totaling 3.04(m, 2H), 2,81-of 2.64(m, 3H), 2,33(t, J = 6.3 Hz, 2H), equal to 1.82(s, 6H), 1,80-of 1.65(m, 4H), 1,64 of 1.46(m, 2H).

Example 59(3)

8-(1-cyclohexylpiperidine-4-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

TLC: Rf 0,41 (methylene chloride: methanol: acetic acid= 4:1:2%).

Example 60 example 60(7)

By the same procedure described in reference example 2,→reference example 3,→example 3, were synthesized the following compounds according to the present invention using ethyl ether thiomorpholine-3-icarbonell acid or corresponding derivative and a corresponding derivative instead of 3 nitrobenzotrifluoride.

Example 60

4-cyclohexenyl-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.18 (hexane: ethyl acetate = 2:1);

NMR(DMSO-d6):10,27(s, 1H), 5,79(m, 1H), a 4.03(DD, J = 10,3, 3.0 Hz, 1H), 3,82(dt, J = 13,8, 3.0 Hz, 1H), 3,06(DDD, J = 1,8, 11,7, 2.1 Hz, 1H), 2,77(m, 1H), 2,74-of 2.58(m, 2H), 2,42(m, 1H), 2,10-2,00(m, 4H), 1,68 of 1.50(m, 4H).

Example 60(1)

4-(furan-2-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.37 (hexane: ethyl acetate = 1:1);

NMR(DMSO-d6):10,66(s, 1H) 7,80(m, 1H), 6,72(d, J = 3.3 Hz, 1H), return of 6.58(m, 1H), 4,22(DD, J = 10,2, 3.0 Hz, 1H), of 3.73(dt, J = 14,1, 3.0 Hz, 1H), up 3.22(m, 1H), 2,94-of 2.72(m, 3H), 2.49 USD(m, 1H).

Example 60(2)

4-(thiophene-2-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.37 (hexane: ethyl acetate = 1:1);

NMR(DMSO-d6):to 10.62(s, 1H), 7,65(DD, J = 5,1, 1.2 Hz, 1H), 7,30(DD, J = 3,6, 1.2 Hz, 1H), 7,11(DD, J = 5,1, 3.6 Hz, 1H), 4,24(DD, J = 8,1, 3.3 Hz, 1H), 3.96 points(dt, J = 13,8, 3.3 Hz, 1H), 3,20(m, 1H), 2,92-2,7 6(m, 3H), 2.49 USD(m, 1H).

Example 60(3)

4-(thiazol-2-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.53 (hexane: ethyl acetate = 1:1);

NMR(CDCl3):8,24(width, 1H), a 7.85(d, J = 3.3 Hz, 1H), 7,42(d, J = 3.3 Hz, 1H), 5,15(m, 1H), 4,20(DD, J = 11,1, 3.0 Hz, 1H), 3,36-3,20(m, 2H), 3,03-and 2.83(m, 2H), 2,41(m, 1H).

Example 60(4)

4-(pyridin-3-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.32 (methylene chloride: methanol = 10:1);

NMR(CDCl3):to 8.70(DD, J = 4,8, 1.8 Hz, 1H), 8,66(d, J = 1.8 Hz, 1H), 8,13(width, 1H), 7,71(dt,J = 8,1, 1.8 Hz, 1H), 7,39(DD, J = 8,1, 4.8 Hz, 1H), to 4.38(DD, J = 11,1,2,7 Hz, 1H, in), 3.75(dt,J =14, 1,2, 7 Hz, 1H), 3,21(DDD, J = 14,1, 12,0, 2.7 Hz, 1H), 3,11(m, 1H), 2,98(DD, J = 14,1, and 10.8 Hz, 1H), was 2.76(m, 1H), 2,31(m, 1H).

Example 60(5)

4-(1,3-dioksiinien-5-the l)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf of 0.30 (chloroform: methanol = 9:1);

NMR(CD3OD):8,10-8,00(Sirs, 1H), 6,85-6,83(m, 2H), 6,82-to 6.80(m, 1H), 6,01(s, 2H), 4,33(DD, J = 10,8, 2.4 Hz, 1H), 3,83(dt, J = 13,5, 2.7 Hz, 1H), 3,20-to 3.02(m, 2H), 3.00 and-is 2.88(m, 1H), 2,80 of 2.68(m, 1H), 2,32-2,22(m, 1H).

Example 60(6)

4-(pyridin-3-yl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0.36 and (methanol: methylene chloride = 1:10);

NMR(DMSO-d6):10,99(s, 1H), 8,66(m, 2H), of 7.90(dt, J = 7,8, and 2.1 Hz, 1H), 7,50(DD, J = 7,8, and 4.8 Hz, 1H), 6,27(s, 1H), 3,62(m, 2H), and 3.16(m, 2H).

Example 60(7)

4-(naphthalene-2-yl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-1(2H)-he

TLC: Rf 0,54 (methylene chloride: methanol = 10:1);

NMR(DMSO-d6):10,96(s, 1H), 8,04-to 7.95(m, 4H), 7,62-7,53(m, 3H), 6,28(s, 1H), 3,69-to 3.64(m, 2H), 3,24-and 3.16(m, 2H).

Example 61

The hydrochloride of 4-(piperazine-1-yl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

To a suspension of 4-chloro-5,6,7,8-tetrahydropyrazin-1(2H)-she (150 mg; CAS Registry No. 89981-21-5; the compounds described in the publication ofYakugaku Zassi.,82, 302-303 (1962)) in ethylene glycol (1.6 ml) was added piperazine (420 mg) and the mixture was stirred at 200°C for 7 hours. After cooling to room temperature, the reaction mixture was poured into cold saturated aqueous sodium bicarbonate solution and was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified column of HRO what ecografia on silica gel (methylene chloride: methanol = 20:1→ 10:1) to obtain the free form specified in the title compound (64 mg). To a solution of the obtained free form of the compound in methanol (2.0 ml) was added 4n. a solution of hydrogen chloride-ethyl acetate (1 ml). The mixture was stirred at room temperature and concentrated. The residue was recrystallized from a solvent mixture of methanol and ethyl acetate to obtain compound according to the present invention (21 mg)having the following physical characteristics.

TLC: Rf 0,46 (methylene chloride: methanol: acetic acid= 20:5:2);

NMR(DMSO-d6):12,31(s, 1H), 8,98(Sirs, 2H), 3,24-to 3.02(m, 8H), 2,58-of 2.30(m, 4H), 1,78 of 1.50(m, 4H).

Example 62

8-(piperazine-1-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

By the same procedure described in example 60→example 59, using 8-chloropyrid[2,3-d]pyridazin-5(6H)-she (the compound described in the publication ofChem. Pharm. Bull., 13(5), 586-593 (1965)) instead of 4-chloro-5,6,7,8-tetrahydropyrazin-1(2H)-she was the compound obtained according to the present invention having the following physical characteristics.

TLC: Rf 0,18 (methylene chloride: methanol: acetic acid= 20:5:2);

NMR(DMSO-d6):11,51(s, 1H), 6,12(s, 1H), 3,26 totaling 3.04(m, 8H), 3,02-is 2.88(m, 3H), 2,31(t, J = 6.0 Hz, 2H), 1,71(m, 2H).

Composition example 1

The following components were mixed in the usual way and tablet is ovali with getting 100 tablets, containing each 50 mg of the active ingredient.

· 4-(N-(2-amino-ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he5.0 g
· carboxymethylcellulose calcium (disintegrity agent)0.2 g
· magnesium stearate (lubricating agent)0.1 g
· microcrystalline cellulose4.7 grams

Composition example 2

After mixing the following components in the usual way, the resulting solution was sterilized in a standard way and in portions of 5 ml of filled ampoules, respectively, liofilizirovanny the usual way to obtain 100 ampoules for injection, each containing 20 mg of active ingredient.

· 4-(N-(2-amino-ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he2.0 g
· mannitol20 g
· distilled water1000 ml

1. Condensed derived pyridazine represented by the formula (I)

where R1represents a

(1) hydrogen atom, (2)1-8alkyl, (3) hydroxy, (5) halogen atom, (3)2-8acyl, 4) C1-8ALCO is si, substituted by phenyl, or (5)2-8acyl, substituted NR2R3;

R2and R3each independently represents a

(1) hydrogen atom or (2)1-8alkyl,

X and Y each independently represents a

(1), (2) SN or (3) N

is

(1) single bond or (2) a double bond,

is

(1) 5-7-membered carbocyclic group selected from the

5-7-membered partially or fully saturated heterocyclic group selected from the

And is (1) And1, (2) And2, (3) And3 , (4) And4or (5) And5,

And1is

And2is

And3is

And4is

And5is

D1is

(1) -NR6C(O)-, (2) -NR6SO2or (3) -NR6C(=NR7)-,

R6and R7each independently represents a

(1) hydrogen atom or (2) C1-8alkyl,

D2represents a

(1) C1-8alkylene, (2) azetidine or pyrrolidinyl, (3) -(C1-4alkylene)-O-(C1-4alkylene)-, (4) -(C1-4alkylene)-NR8-(C1-4alkylen)or (5) -(C1-8alkylen)-(piperidinyl optionally substituted by a methoxy group)-,

R8represents a

(1) hydrogen atom or (2) C1-8alkoxycarbonyl,

D3represents a

(1) hydrogen atom, (2) -NR9R10, (3) heterocyclyl selected from morpholinyl, piperidinyl, tetrahydropyridine and pyrrolidinyl, (4) COOR12or (5) a halogen atom,

R9represents a

(1) hydrogen atom, (2) C1-8alkyl, (3)2-8alkenyl, (4)

With2-8quinil or (5)3-8cycloalkyl,

10represents a

(1) hydrogen atom, (2)1-8alkyl, (3) C1-8alkoxycarbonyl or (4) C1-8alkoxycarbonyl, substituted phenyl,

R12represents a

(1) C1-8alkyl,

R4represents a

(1) hydrogen atom, (2) C1-8alkyl, (3) C1-8alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro, or (7) NR22R23,

R22and R23each independently represents (1) hydrogen atom,

E1is1-4alkylen,

E2is

(1) -C(O)NR24-, (2) -NR24C(O)-, (3) -NR24-, (4) -C(O)O -, or (5) -S-,

R24represents a

(1) hydrogen atom, (2)1-8alkyl or (3) C1-8alkyl, substituted phenyl,

E3represents a

(1) a bond or (2)1-8alkylen,

E4represents a

(1) C1-8alkyl, (2)2-8alkenyl, (3) C2-8quinil, (4) As, (5) NR25R26, (6) OR27, (7) SR27, (8) COOR27, (9) C1-8alkyl, substituted OR two of25, (10) C1-8alkyl substituted by 1-3 halogen atoms, (11) cyano or (12) C2-8acyl,

R25represents a

(1) hydrogen atom, (2)1-8alkyl, (3)3-8cycloalkyl or phenyl substituted With1-8the alkyl or (4)1-8alkyl, W is displaced by phenyl or or 28,

R26represents a

(1) hydrogen atom, (2)1-8alkyl, (3)1-8alkoxycarbonyl, (4) phenyl or (5)1-8alkyl, substituted phenyl,

R27represents a

(1) hydrogen atom, (2)1-8alkyl, (3) phenyl or (4)1-8alkyl, substituted furyl,

R28represents a

(1) hydrogen atom or (2)1-8alkyl,

G1is1-8alkylene,

Cyc1 is a

(1) phenyl, or (2) optionally partially or fully saturated 5-to 10-membered mono - or bilateral containing from 1 to 4 heteroatoms selected from atoms of oxygen, nitrogen and sulphur,

G2represents a

(1) hydrogen atom, (2)1-8alkyl, (3)1-8alkoxycarbonyl, (4)2-8acyl, (5) phenyl, which may be substituted with halogen, C1-8alkoxygroup and amino group, (6) With3-8cycloalkyl or pyridyl, (7)1-8alkyl or C2-8alkenyl, substituted by 1-2 substituents selected from phenyl, cyclohexyl, morpholino, (8) -C1-8alkoxycarbonyl, substituted phenyl, (9) -C(O)-furanyl (10) nitro or (11) NR41R42,

R41and R42each independently represents a

(1) hydrogen atom or (2)1-8alkyl,

R5represents a

(1) atom in Dorada, (2)1-8lcil, (3)1-8alkoxy, (4) hydroxy, (5) nitro, (6) NR29R30, (7)1-8alkyl, substituted NR29R30, (8) NHSO2OH, (9) amidino, (10) cyano, (11) halogen atom, (12)1-8alkyl, substituted cyclohexyl, morpholino or M-(C1-8alkyl)piperazinone,

R29and R30each independently represents a

(1) hydrogen atom or (2)1-8alkyl,

As is (1) C6-10mono - or bicyclic carbocycle or (2) 5-8 membered carbocycles containing 1 or 4 heteroatoms selected from nitrogen, oxygen or sulphur,

SUS represents a cyclic group selected from naphthyl, pyridinyl, thiophenyl, furil, cyclohexyl and benzodioxole, piperidinyl and thiazolyl,

As optionally substituted by 1-3 substituents selected from (1) With the1-8of alkyl, (2) C2-8alkenyl, (3)1-8alkoxy, (4) halogen atom, (5) trihalomethyl, (6) trihalomethane, (7) C1-8alkoxycarbonyl, (8) oxo, (9)1-8of alkyl, substituted C1-8alkoxy or phenyl, (10) hydroxy and (11) NR29R30;

m and n each independently is 1 or 2,

where

(i) when a is A4and

is

then R5is not hydroxy or1-8 alkoxy,

(ii) the following compounds (1) to (13) are excluded;

(1) 4-(3-chloro-4-methoxyphenyl)-4A,5,8,8A-tetrahydropyrazin-1(2H)-he,

(2) 4-(3,4-acid)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(3) 4-phenyl-6,7,8,8A-tetrahydropyrrolo[1,2-d][1,2,4]triazine-1(2H)-he,

(4) 4-phenyl-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(5) 4-(4-were)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(6) 4-(4-forfinal)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(7) 4-(4-chlorophenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(8) 4-(4-bromophenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(9) 7-hydroxy-4-phenyl-6,7,8,8A-tetrahydropyrrolo[1,2-d] [1,2,4]triazine-1(2H)-he,

(10) 4-phenyl-8,8A-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazine-1(2H)-he,

(11) 4-(pyridine-4-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(12) 4-tert-butoxycarbonylmethyl-5,6,7,8-tetrahydropyrazin-1(2H)-he,

(13) 4-ethoxycarbonylmethyl-5,6,7,8-tetrahydropyrazin-1(2H)-he, or its pharmaceutically acceptable salt.

2. The compound represented by formula (I)according to claim 1, where

is a 5-7-membered carbocyclic group selected from the

and As is And1or its pharmaceutically acceptable with the l.

3. The compound represented by formula (I)according to claim 1, where

is a 5-7-membered carbocyclic group selected from the

and As is And2or its pharmaceutically acceptable salt.

4. The compound represented by formula (I)according to claim 1, where

is a 5-7-membered carbocyclic group selected from the

and As is And3or its pharmaceutically acceptable salt.

5. The compound represented by formula (I)according to claim 1, where

is a 5-7-membered carbocyclic group selected from the

and As is And4or And5or its pharmaceutically acceptable salt.

6. The compound represented by formula (I)according to claim 1, where

is a 5-7-membered partially or fully saturated heterocyclic the treatment group, selected from the

and As is And1or its pharmaceutically acceptable salt.

7. The compound represented by formula (I)according to claim 1, where

is a 5-7-membered partially or fully saturated heterocyclic group selected from the

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and As is And2or its pharmaceutically acceptable salt.

8. The compound represented by formula (I)according to claim 1, where

is a 5-7-membered partially or fully saturated heterocyclic group selected from the

and As is And3or its pharmaceutically acceptable salt.

9. The compound represented by formula (I)according to claim 1, where

is a 5-7-membered partially or fully saturated heterocyclic group selected from the

and As is And4or And5or its pharmaceutically acceptable salt.

10. The compound represented by formula (I)according to claim 1, where

is

or its pharmaceutically acceptable group.

11. Inhibitor of poly(ADP-ribose)polymerase, comprising as active ingredient a compound represented by the formula (I)according to claim 1, or its pharmaceutically acceptable salt.

12. Preventive and/or medicinal product intended for the treatment of ischemic diseases, inflammatory diseases, neurodegenerative disorders, glaucoma, diabetes, complications of diabetes, stroke, head injury, spinal cord injury, renal failure, or hyperalgesia, which contains as active ingredient a compound represented by the formula (I)according to claim 1, or its pharmaceutically acceptable salt.

13. Antiretroviral medicinal products containing as active is ngredient connection, represented by formula (I)according to claim 1, or its pharmaceutically acceptable salt.

14. Sensitizing tool designed for anti-cancer therapy comprising as active ingredient a compound represented by the formula (I)according to claim 1, or its pharmaceutically acceptable salt.

15. An immunosuppressive agent containing as an active ingredient the compound represented by formula (I)according to claim 1, or its pharmaceutically acceptable salt.

16. The remedy for the prevention and/or treatment indicated in paragraph 12, where coronary artery disease is a heart attack brain.

17. The compound according to claim 1, selected from

4-(3-AMINOPHENYL)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazine-11(2H)-it

4-(N-(3-(morpholine-4-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

8-(3-(N-acetylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

4-(3-(N-(5-(N, N'-dimethylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

4-(2-(morpholine-4-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

4-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

4-(2-(N-(4-terbisil)amino)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

8-(2-(4-cyclohexylpiperazine-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

4-(2-(4-isopropylpiperazine-1-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

8-(2-(4-ethylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

8-(2-(4-cyclopentylpropionyl-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

8-(2-(4-(pyridin-4-yl)piperazine-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

4-(3-(N-(5-(morpholine-4-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

4-(N-(2-(azepin-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

4-(3-(N-(5-(N'-cyclopropylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

4-(N-(4-(N'-cyclohexylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

4-(N-(4-(morpholine-4-yl)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

4-(3-(N-(5-(N'-methylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

4-(N-(2-amino-ethyl)carbamoylmethyl)-5,6,7,8-tetrahydro-phthalazine-1(2H)-it

8-(3-AMINOPHENYL)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

8-(4-AMINOPHENYL)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

8-(4-(N,N-dimethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

8-(4-(N,N-diethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

8-(4-(2-(N,N-dimethylamino)ethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

8-(3-(N-methylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

8-(4-(N-methylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

4-(5-(piperidine-1-yl)pentyl)-5,6,7,8-tetrahydropyrazin-1(2H)-it

4-(N-(5-(morpholine-4-yl)pentyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

8-(piperidine-2-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

8-(piperidine-3-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-it

or their pharmaceutically acceptable salts.

18. The compound according to claim 1, which represents 4-(N-(4-(morpholine-4-yl)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he.

19. The compound according to claim 1, which represents 4-(N-(4-(morpholine-4-yl)butyl)carbamoylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-one or its pharmaceutically acceptable salt.

Priority items:

19.02.2002 - 1, except for the definition And5;

09.07.2002 - p.1 definition And5;

18.02.2003 - claim 2-19.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydroxytiazolo[5,4-b]indole of formula useful in liver protection from poisoning with carbon tetrachloride. Said compound has boiling point of 174-175°C (decomposition) and LD50 of 1950±180 mg/kg. Method for production of claimed compound also is disclosed.

EFFECT: new compound for liver protection from poisoning with carbon tetrachloride.

2 ex, 1 tbl

FIELD: organic chemistry, medicine, pulmonology.

SUBSTANCE: invention relates to a new chemical compound, namely, 7-bromo-4-acetylthiazolo[5,4-b]indol-2-succinimide of the formula: that is able to protect body against hypoxia and possesses the curative effect in lung toxic edema. The melting point of this compound is 267-269°.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, medicine, pulmonology.

SUBSTANCE: invention relates to a new chemical substance, namely, 4-acetylthiazolo[5,4-b]indol-2-succinimide of the formula: that is able to protect body against hypoxia and possesses the prophylactic effect in lung toxic edema. The melting point of this substance is 264-265°C.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydrothiazolo[5,4-b]indole hydrobromide of the formula (1) that is able to protect body against hypoxia and liver against poisoning with carbon tetrachloride. The melting point of this compound is 266-267°C (with decomposition). The compound is synthesized from 1-acetyl-5-bromo-3-indolinone and elemental bromine in dioxane medium followed by addition of thiourea in isopropyl alcohol.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

EFFECT: improved preparing method, valuable biological and medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 6 ex

FIELD: medicine, pharmacology, organic chemistry.

SUBSTANCE: invention relates to using 2-amino-4-acetyl-8b-hydroxy-3a,8b-dihydrothiazole[5,4-d]indole as a substance protecting body against hypoxia effect. Invention provides enhanced effectiveness of the protection effect.

EFFECT: enhanced effectiveness of effect of agent.

1 tbl, 1 ex

FIELD: medicine, pharmacology, organic chemistry.

SUBSTANCE: invention relates to using 2-amino-4-acetylthiazolo[5,4-d]indole for protection of body against effect of hemic and hypercapnic hypoxia. Invention proves high effectiveness of the protection effect.

EFFECT: enhanced effectiveness of agent.

2 tbl

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and its pharmaceutically acceptable salts possessing properties of tumor necrosis factor (TNF-α) and to pharmaceutical composition based on thereof wherein R1 means substituted or unsubstituted phenyl wherein substitutes are chosen from halogen atoms or halide-(C1-C6)-alkyl; R4b is substituted or unsubstituted with 1-3 aryl substituted chosen from phenyl, naphthyl wherein substitutes are chosen from halogen atoms, (C1-C6)-alkyl, halide-(C1-C6)-alkyl, (C1-C6)-alkoxyl, cyano-, amino-, (C1-C6)-acylamino-group, (C1-C6)-alkanesulfonyl, or two adjacent substitutes in benzene ring form dioxol group, or unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with 1-3 nitrogen atoms in ring wherein substitutes are chosen from halogen atoms.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 9 sch, 10 tbl, 15 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel pyrimidotriazines of the general formula (I):

wherein each R1 and R2 is chosen from the group comprising hydrogen atom, or R1 and R2 form in common chemical bond, -CH2-Ar and Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono- or disubstituted with (lower)-alkoxy-group and naphthyl mono- or disubstituted with (lower)-alkyl, or their pharmaceutically acceptable salts. Also, invention relates to a method for synthesis of these compounds, pharmaceutical composition based on thereof and to using novel pyrimidotriazines for prophylaxis and/or treatment of diabetes mellitus as these compounds possess the strong expressed inhibitory effect on activity of protein tyrosine phosphatase PTP1B.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: chemical industry; method of production of the fluorine-containing compounds.

SUBSTANCE: the invention is pertaining to the chemical industry, in particular, to the improved method of production of fluorine-containing compounds from the halogen-containing, compounds, preferably, from chlorine-containing compounds due to an exchange of halogen for fluorine at presence of the HF-additional compound of the mono- or bicyclic amine with at least two atoms of nitrogen. At that at least one atom of nitrogen is built in the cyclic system as the fluorating agent; or at presence of anhydrous hydrogen fluoride - as the fluorating agent and the indicated HF-additional compound of the mono- or bicyclic amine as the catalyst. At usage of the applicable solvents the reaction mixtures can be divided into two phases and thus to simplify the reprocessing of the products. The invention also is pertaining to the HF-additional compounds of 1.5-diazabicyclo[4.3.0]non-5-en and N,N-dialkylaminopiridin, where alkyl represents C1-C4alkyl and where the molar ratio of HF to amine makes 1:1, and to HF- additional compounds 1.8- diazabicyclo[5.4.0]undecyl-7-ene, where the molar ratio of HF to amine compounds more than 1:1.

EFFECT: the invention ensures at usage of the applicable solvents to divide the reaction mixture into two phases and thus to simplify reprocessing of the products.

17 cl, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel derivative of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole, namely its hydrobromide, eliciting properties of antagonist of serotonin 5-HT3-receptors that can be used in therapy of cytotoxic nausea and vomiting. New salt is low toxic and exceeds bemesetron by anti-serotonin activity that is a selective 5-HT3- antagonist.

EFFECT: improved and valuable medicinal properties of derivative.

2 cl, 2 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

EFFECT: improved preparing method, valuable biological and medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to new compounds of the formula (I) wherein R1 and R2 can be similar or different and represent independently (C1-C6)-alkyl that are selective inhibitors of enzyme phosphodiesterase, and to their pharmaceutically acceptable salts or stereoisomers. Also, invention involves a method for preparing the preferable compound, i. e. 5-[[2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulfonyl)phenyl]]-1-methyl-3-n-propyl-7,6-dihydro-1H-pyrazolo[4,3-d]pyrimidine-7-one. Also, invention proposes new intermediate compounds used in method for synthesis of this compound. Compounds of the formula (I) show very high effectiveness in treatment of diseases associated with impotence, such as the male erectile sterility but they exhibit such features as prolonged therapeutic effectiveness and lower toxicity. Also, invention relates to a pharmaceutical composition used in treatment of impotence and using compound of the formula (I) in preparing the medicinal preparation designated for treatment of diseases associated with impotence.

EFFECT: valuable medicinal properties of compound.

8 cl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound and to all its enantiomeric and diastereomeric forms and pharmaceutically acceptable salts that are able to prevent extracellular release of inflammatory cytokines. Proposed compounds have the formula (I): wherein R represents: (a) -OR3 or (b) -NR4aR4b; R3 represents unsubstituted or substituted phenyl wherein substitutes are: (i) halogen atom; (ii) (C1-C6)-alkyl; (iii) trifluoromethyl; (iv) trichloromethyl; (v) tribromomethyl; (vi) cyano-group, and (vii) (C1-C6)-alkoxy-group; each R4a and Rb represents independently: (a) hydrogen atom or (b) -[C(R5aR5b)]xR6 wherein index x = 0-5; each R5a and R5b represents independently hydrogen atom, linear or branched (C1-C4)-alkyl, (C3-C7)-cyclic alkyl; R6 represents -OR7 or (C1-C4)-alkyl; R7 represents hydrogen atom or (C1-C4)-alkyl; R1 represents halogen-substituted phenyl; each among links R2a and R2b is chosen independently from the groups consisting of: (a) hydrogen atom; (b) -O(CH2)jR8; (c) -(CH2)jCO2R10; (d) -(CH2)jCON(R10)2; (e) a double bond when R2a and one R2b are chosen with formation of a double bond; (f) a ring when one R2a and one R2b are chosen with formation a ring and indicated ring is chosen from the group consisting of: (i) benzene and (ii) dioxalane; each R8 and R10 represents independently hydrogen atom or (C1-C4)-alkyl; j represents index from 0 to 5; m represents index from 1 to 3; n represents index from 1 to 3, and m + n = 4. Also, invention relates to a pharmaceutical composition based on abovementioned compounds that inhibits extracellular release of inflammatory cytokines, and a method for regulation of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds.

10 cl, 9 tbl, 11 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes a herbicide against weeds resistant to sulfonylurea-base herbicide and comprising compound of the formula (I):

wherein Q represents condensed heterocyclic group of the formula (Q1), (Q3), (Q4) given in the invention description; X represents lower alkyl or lower alkoxyl group; Y represents lower alkoxyl group. Invention describes compound of the formula (II):

wherein R1 represents halogen atom or optionally halogenated lower alkyl group; R2 represents hydrogen atom; R3 represents (C2-C4)-alkyl group or lower cycloalkyl group; X represents lower alkyl group or lower alkoxyl group; Y represents lower alkoxyl group. Also, invention describes herbicides comprising compounds of the formula (II) and a method for control of weeds resistant to sulfonylurea-base herbicide. Method involves applying herbicide comprising compound of the formula (I) or compound of the formula (II). Herbicide is used for control of weeds resistant to sulfonylurea-base herbicide in rice-paddy fields.

EFFECT: valuable properties of herbicides.

10 cl, 8 tbl, 69 ex

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