Poly(adp-riboso)polymerase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes poly(ADP-riboso)polymerase inhibitors of formula (Ik) its pharmaceutically acceptable salt wherein R101, R104 and R105 represent H; R102 represents R11 wherein R11 is specified from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl and azepanyl with R102 being substituted by one or two (O) substitutes; R103 represents fluorine, besides, a pharmaceutical composition on the basis of said compounds showing poly(ADP-riboso)polymerase (PARP) inhibitory activity, a method of treating cancer and a method of reducing tumour volume in a mammal.

EFFECT: there are produced and described new compounds which show poly(ADP-riboso)polymerase (PARP) inhibitory activity.

9 cl, 491 ex, 2 tbl

 

RELATED APPLICATIONS

The present invention claims the priority of U.S. patent No. 60/882317, registered on December 28, 2006.

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to inhibitors of poly(ADP-ribose)polymerase, methods for their preparation and methods of treatment using them.

The LEVEL of TECHNOLOGY

Poly(ADP-ribose)polymerase (PARP) is of great importance to facilitate DNA repair, control of RNA transcription, mediating cell death and regulation of the immune response. This activity makes the PARP inhibitors of the target compounds for the treatment of several disorders. PARP inhibitors have shown efficacy in the treatment of diseases such as ischemic and reperfusion injury, inflammatory diseases, retroviral infection, myocardial infarction, stroke, other neural trauma, and organ transplantation, reperfusion of the eye, kidney, gut and skeletal muscle, arthritis, gout, inflammatory bowel disease, inflammatory diseases of the CNS such as multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemorrhagic collapse, pneumosclerosis and uveitis, diabetes, and Parkinson's disease, hepatotoxicity after an overdose of acetaminophen, cardiac and renal toxicity as a result of action of antitumor medicinalfunds, containing doxorubicin and platinum, and skin lesions, secondary to the sulfur mustards. It was also shown that PARP inhibitors enhance the effect of radiation or chemotherapy, increasing necrosis of cancer cells, limiting the growth of cancer cells, reducing metastasis and prolonging the life span of animals, the body has a tumor. In the application for U.S. patent 2002/0183325 A1 describes derivatives of phthalazinone as PARP inhibitors. In the application for U.S. patent 2004/0023968 A1 describes derivatives of phthalazinone as PARP inhibitors. In the application for U.S. patent 2005/0085476 A1 describes condensed derivatives pyridazine as PARP inhibitors. In the application for U.S. patent 2005/0059663 A1 describes derivatives of phthalazinone as PARP inhibitors. In the application for U.S. patent 2006/0063767 A1 describes derivatives of phthalazinone as PARP inhibitors. In the application for U.S. patent 2006/0142293 A1 describes derivatives of phthalazinone as PARP inhibitors. In the application for U.S. patent 2006/0149059 A1 describes derivatives of phthalazinone as PARP inhibitors. In the application for U.S. patent 2007/0093489 A1 describes derivatives of phthalazinone as PARP inhibitors.

Therefore, in therapy, there is a need to PARP inhibitors. Such compounds can be used to treat patients suffering from cancer, and can also optionally RA is spread selection of medicines, available for such patients.

The INVENTION

Thus, one alternative implementation of the present invention refers to compounds that inhibit the activity of poly(ADP-ribose)polymerase, which correspond to the formula I

and their pharmaceutically acceptable salts, where

A1is an R1or R2where A1is unsubstituted or substituted by one or two substituents selected from OH, CN, C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl, cycloalkane, ORAor NRARA;

RArepresents H or alkyl;

R1is cycloalkane or cycloalkene, each of which is unfused or fused with R1A;

R1Arepresents a benzene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen;

R2represents geteroseksualen or geteroseksualen; each of which is unfused or fused with R2A;

R2Arepresents a benzene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen;

A2is a OR4, Other4N(R4)2, SR4, S(O)R4, SO2R4or R5;

where each R4before the hat is C 1-alkyl, C2-alkyl or C3-alkyl, each of which is substituted by an R10;

R5represents a C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl or C5-alkyl, each of which is substituted by an R10and is optionally unsubstituted or optionally substituted one, two or three substituents, independently selected from OR10, Other10N(R10)2, SR10, S(O)R10, SO2R10or CF3;

where each R10is an R10A, R10Bor R10C; each of which must adhere to the carbon atom;

R10Arepresents phenyl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R10Brepresents a

each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, gets what rockleecanon or heterocyclization;

R10Cis cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

where each R10independently is unsubstituted or substituted one, two or three substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2, Other11N(R11)2C(O)R11C(O)OR11C(O)NH2C(O)other11C(O)N(R11)2, NHC(O)R11, NR11C(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NR11C(O)OR11, NHSO2NH2, NHSO2Other11, NHSO2N(R11)2, SO2NH2, SO2Other11, SO2N(R11)2, NHC(O)NH2, NHC(O)other11, NHC(O)N(R11)2, NR11C(O)N(R11)2, NO2, OH, (O), C(O)H, C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I;

where each R11is an R12, R13, R14or R15;

R12represents phenyl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is of condension is or fused with benzene, heteroatom, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R13is heteroaryl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R14is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R15represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)NH2C(O)other16C(O)N(R16)2, NHC(O)R16, NR16C(O)R16, NHC(O)OR16, NR16C(O)OR16, OH, F, Cl, Br or I;

where each R16/sup> is an R17or R17A;

R17represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R18C(O)OH, NH2, Other18or N(R18)2C(O)R18C(O)NH2C(O)other18C(O)N(R18)2, NHC(O)R18, NR18C(O)R18, F, Cl, Br or I;

R17Arepresents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

where each R18represents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

where each of the fragments, represented as R12, R13, R14, R17Aand R18independently is unsubstituted or substituted one, two, three or four substituents, independently selected from R19, OR19, SR19, S(O)R19, SO2R19C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, Other19N(R19)2, NHC(O)R19, NR19C(O)R19NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)other19,NHC(O)N(R 19)2, NR19C(O)other19, NR19C(O)N(R19)2C(O)NH2C(O)other19C(O)N(R19)2C(O)NHOH, C(O)NHOR19C(O)NHSO2R19C(O)NR19SO2R19, SO2NH2, SO2Other19, SO2N(R19)2C(O)H, C(O)OH, C(N)NH2C(N)other19C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

where each R19is an R20, R21, R22or R23;

R20represents phenyl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R21is heteroaryl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R22is cycloalkyl, cycloalkenyl, heteroseksualci Il is geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R23represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R24, OR24, SR24, S(O)2R24C(O)OH, NH2, Other24N(R24)2C(O)R24C(O)NH2C(O)other24C(O)N(R24)2, NHC(O)R24, NR24C(O)R24, NHC(O)OR24, NR24C(O)OR24NHS(O)2R24, NR24S(O)2R24, OH, F, Cl, Br or I;

where each R24is an R24Aor R24B;

R24Arepresents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R24Brepresents alkyl, alkenyl or quinil, each of which is unsubstituted or substituted by one or two substituents, independently selected R 25, OR25, SR25, S(O)2R25C(O)OH, NH2, Other25N(R25)2C(O)R25C(O)NH2C(O)other25C(O)N(R25)2, NHC(O)R25, NR25C(O)R25, NHC(O)OR25, NR25C(O)OR25, OH, F, Cl, Br or I;

where each R25represents alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unsubstituted or substituted NH2, NH(CH3), N(CH3)2, OH or OCH3;

where each of the fragments, represented as R20, R21, R22and R24Aindependently is unsubstituted or substituted by one or two substituents, independently selected from R26, OR26alkenyl, quinil, phenyl, OH, (O), C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; and

R26represents alkyl.

Another variant implementation of the invention includes pharmaceutical compositions comprising a compound of formula I and a filler.

Another variant implementation of the invention includes methods of inhibiting PARP in a mammal, comprising an introduction to the specified mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes methods of treating cancer in a mammal, comprising an introduction to the specified mlekovita the mu therapeutically acceptable amount of the compounds of formula I

or its salts, where

A1is an R1or R2where A1is unsubstituted or substituted by one or two substituents selected from OH, CN, C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl, cycloalkane, ORAor NRARA;

RArepresents H or alkyl;

R1is cycloalkane or cycloalkene, each of which is unfused or fused with R1A;

R1Arepresents a benzene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen;

R2represents geteroseksualen or geteroseksualen; each of which is unfused or fused with R2A;

R2Arepresents a benzene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen;

A2is a OR4, Other4N(R4)2, SR4, S(O)R4, SO2R4or R5;

where each R4represents a C1-alkyl, C2-alkyl or C3-alkyl; each of which is substituted by an R10;

R5represents a C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl or C5-alkyl; each of which is substituted by an R10and it is up to omnitele unsubstituted or optionally substituted with one, two or three substituents, independently selected from OR10, Other10N(R10)2, SR10, S(O)R10, SO2R10or CF3;

where each R10is an R10A, R10Bor R10C; each of which must adhere to the carbon atom;

R10Arepresents phenyl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocloeon.

R10Brepresents a

each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R10Cis cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclic the nom;

where each R10independently is unsubstituted or substituted one, two or three substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2, Other11N(R11)2C(O)R11C(O)OR11C(O)NH2C(O)other11C(O)N(R11)2, NHC(O)R11, NR11C(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NR11C(O)OR11, NHSO2NH2, NHSO2Other11, NHSO2N(R11)2, SO2NH2, SO2Other11, SO2N(R11)2, NHC(O)NH2, NHC(O)other11, NHC(O)N(R11)2, NR11C(O)N(R11)2, NO2, OH, (O), C(O)H, C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I;

where each R11is an R12, R13, R14or R15;

R12represents phenyl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R13is heteroaryl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cyclol the Yong; heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R14is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R15represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)NH2C(O)other16C(O)N(R16)2, NHC(O)R16, NR16C(O)R16, NHC(O)OR16, NR16C(O)OR16, OH, F, Cl, Br or I;

where each R16is an R17or R17A;

R17represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R18C(O)OH, NH2, NH 18or N(R18)2C(O)R18C(O)NH2C(O)other18C(O)N(R18)2, NHC(O)R18, NR18C(O)R18, F, Cl, Br or I;

R17Arepresents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

where each R18represents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

where each of the fragments, represented as R12, R13, R14, R17Aand R18independently is unsubstituted or substituted one, two, three or four substituents, independently selected from R19, OR19, SR19, S(O)R19, SO2R19C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, Other19N(R19)2, NHC(O)R19, NR19C(O)R19NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)other19, NHC(O)N(R19)2, NR19C(O)other19, NR19C(O)N(R19)2C(O)NH2C(O)other19C(O)N(R19)2C(O)NHOH, C(O)NHOR19C(O)NHSO2R19C(O)NR19SO2R19, SO2NH2, SO2Other19, SO2N(R 19)2C(O)H, C(O)OH, C(N)NH2C(N)other19C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

where each R19is an R20, R21, R22or R23;

R20represents phenyl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R21is heteroaryl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R22is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or to hancilova with benzene, heteroatom, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R23represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R24, OR24, SR24, S(O)2R24C(O)OH, NH2, Other24N(R24)2C(O)R24C(O)NH2C(O)other24C(O)N(R24)2, NHC(O)R24, NR24C(O)R24, NHC(O)OR24, NR24C(O)OR24NHS(O)2R24, NR24S(O)2R24, OH, F, Cl, Br or I;

where each R24is an R24Aor R24B;

R24Arepresents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R24Brepresents alkyl, alkenyl or quinil, each of which is unsubstituted or substituted by one or two substituents, independently selected from R25, OR25, SR25, S(O)2R25C(O)OH, NH2, Other25N(R25)2C(O)R25C(O)NH2C(O)other25C(O)N(R25)2, NHC(O)R25, NR25C(O)R25, NHC(O)OR25, NR25C(O)OR25, OH, F, Cl, Br or I;

DG is each R 25represents alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unsubstituted or substituted NH2, NH(CH3), N(CH3)2, OH or OCH3;

where each of the fragments, represented as R20, R21, R22and R24Aindependently is unsubstituted or substituted by one or two substituents, independently selected from R26, OR26alkenyl, quinil, phenyl, OH, (O), C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; and

R26represents alkyl.

Another variant implementation of the invention includes methods of reducing tumor volume in a mammal, comprising an introduction to the specified mammal therapeutically effective amounts of compounds of formula I.

Another variant implementation of the invention includes the use of compounds of formula I to obtain drugs for cancer treatment.

Another variant implementation of the invention includes a method of treating leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast or cervical carcinoma in a mammal, the method comprises the introduction of a given mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of izobreteny which includes the use of compounds of formula I to obtain drugs for the treatment of leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of the breast or cervical carcinoma.

Another variant implementation of the invention includes methods of potentiation of cytotoxic cancer therapy in a mammal, comprising an introduction to the specified mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes methods of potentiation of radiation therapy in a mammal, comprising an introduction to the specified mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes methods of treatment of a mammal ischemic reperfusion injury associated with myocardial infarction, stroke, neural trauma or transplantation of organs, the methods include the introduction of a given mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes methods of treatment of a mammal reperfusion eyes, kidneys, gout and skeletal muscle, the methods include the introduction of a given mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes methods of treatment of a mammal arthritis, gout, inflammatory diseases of the bowels is of cnica, inflammatory diseases of the CNS, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemorrhagic collapse, pneumosclerosis, or uveitis, the methods include the introduction of a given mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes a method of treating in a mammal rheumatoid arthritis or septic shock, the method includes the introduction of the specified mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes methods of treatment in a mammal of diabetes or Parkinson's disease, including the introduction of a given mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes methods of treatment in a mammal of hypoglycemia, including the introduction of a given mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes methods of treatment in mammalian retroviral infection, including the introduction of a given mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes methods of treatment of a mammal, hepatotoxicant is after an overdose of acetaminophen, includes introduction to the specified mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes a method of treating in a mammal cardiac or renal toxicities from anticancer drugs, containing doxorubicin or platinum, the method includes the introduction of the specified mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes methods of treatment of mammalian skin lesions, secondary to the sulfur mustards, the methods include the introduction of a given mammal a therapeutically acceptable amount of the compounds of formula I.

Another variant implementation of the invention includes the following connections:

2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoic acid;

4-(3-amino-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)amino)-4-oxobutanoic acid;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyrrolidin-2,5-dione;

4-(3-(1,4-diazepan-1-ylcarbonyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(aminomethyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((dimethylamino)methyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((cyclohexylamino)methyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-((tetrahydro-2H-Piran-4-ylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-((methyl((1-methylpyrrolidine-3-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-((methyl-(((2R)-1-methylpyrrolidine-2-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(morpholine-4-ylmethyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((cyclohexylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((methylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((ethylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-methylpiperidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(((2-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzyl)-5,6,7,8 - tetrahydropyrazin-1(2H)-he;

4-(3-((cyclohexyl(methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((2-ethylpyrrolidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-((doing what propylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-(morpholine-4-ylmethyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-((cyclohexylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-((methylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-((ethylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-((4-methylpiperidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-(((2-(3-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzyl)-5,6,7,8 - tetrahydropyrazin-1(2H)-he;

4-(4-((cyclohexyl(methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-((2-methylpyrrolidine-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-pyrimidine-2-ylbenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-pyridine-3-ylbenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-pyridine-4-ylbenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N,N-diethyl-2'-fluoro-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-2-carboxamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-piperidine-1-ylpropionic;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)Fe who yl)-3-(4-methylpiperazin-1-yl)propanamide;

2-amino-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide;

3-cyclohexyl-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)piperidine-3-carboxamide;

4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)azetidin-3-carboxamide;

N-(2-(isopropylamino)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-morpholine-4-ylacetamide;

N-(2-morpholine-4-retil)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-pyrrolidin-1-retil)benzamide;

4-(3-((2-methylpyrrolidine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-azepin-1-yl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

4-(3-(piperazine-1-ylcarbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-azetidin-3-yl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-piperidine-3-ylbenzene;

N-(4-(dimethylamino)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(4-methylpiperazin-1-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

4-(3-((4-(isoxazol-5-ilk is bonil)piperazine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-phenylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(piperidine-2-ylmethyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(piperidine-4-ylmethyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-piperidine-1-retil)benzamide;

N-(1-methylisatin-3-yl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

methyl 4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxylate;

N-methyl-4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

4-((2-(methylthio)pyrimidine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((2-(methylsulphonyl)pyrimidine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((2-(methylsulfinyl)pyrimidine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((3-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((6-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((2-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

methyl 6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxylate;

N-ethyl-4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

N-isopropyl-4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

N-cyclohexyl-4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

N-((1-methylpiperid the Jn-2-yl)methyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-((1-methylpiperidin-4-yl)methyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-methyl-6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

N-ethyl-6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

N-isopropyl-6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

N-cyclopropyl-6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

N-cyclohexyl-6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

methyl 3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxylate;

methyl 5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxylate;

4-((5-Bratan-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((3-Bratan-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

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

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

4-(Tien-2-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

methyl 5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)thiophene-2-carboxylate;

N-methyl-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

N-ethyl-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide;

N-ethyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carbox the MFA;

N,N-dimethyl-N'-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)sulphonamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-piperidine-1-ylpropionic;

4-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)butanamide;

4-(3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((2-(2-oxoazetidin-1-yl)pyridine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((2-(2-oxopyrrolidin-1-yl)pyridine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((2-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((6-(2-oxopyrrolidin-1-yl)pyridine-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((6-(2-oxoazetidin-1-yl)pyridine-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-(5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridin-2-yl)benzamide;

N-(5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridin-2-yl)isonicotinamide;

N-(5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridin-2-yl)nicotinamide;

4-((5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-2,2'-bipyridine-5-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-methyl-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)thiophene-2-carboxamide;

N1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)glycinamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)azetidin-2-carboxamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)Aset the Dean-3-carboxamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)methanesulfonamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propane-2-sulfonamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzosulfimide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyridine-3-sulfonamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)furan-2-sulfonamide;

1-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-imidazole-4-sulfonamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)thiophene-2-sulfonamide;

4-cyano-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzosulfimide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)naphthalene-1-sulfonamide;

4-((6-bromopyridin-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-(6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridin-2-yl)benzamide;

4-((3'-((isopropylamino)methyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((3'-((cyclopentylamine)methyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((3'-((2-methylpyrrolidine-1-yl)methyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((3'-((cyclopropylamino)methyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((3'-((cyclobutylamine)met the l)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((2-bromo-1-oxidability-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((1-oxide-2-(2-oxopyrrolidin-1-yl)pyridine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

methyl 5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)thiophene-3-carboxylate;

4-(3-((4-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-1,4-diazepan-1-yl)carbonyl)-4-terbisil)phthalazine-1(2H)-he;

1-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)cyclopropanecarboxamide;

2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)cyclopropanecarboxamide;

3 ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide;

5-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-L-prolinamide;

5-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-D-prolinamide;

N1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)cyclopropane-1,1-dicarboxamide;

2-(benzyloxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-phenylpropanamide;

3-(2,5-acid)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1-phenylcyclopropanecarboxylic;

(2S)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-phenylbutane;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-phenylbutane the MFA;

2-(3-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide;

2-(2-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide;

2-(4-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide;

(2R)-2-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-phenylacetamide;

(2S)-2-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-phenylacetamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-phenoxypropane;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-Tien-2-inputname;

1-acetyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)piperidine-4-carboxamide;

2-(3,5-differenl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide;

N2-acetyl-N1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-L-leucinamide;

N1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-N2N2-dipropyl-L-alaninate;

4-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-phenylbutane;

N-(2-oxo-2-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenylamino)ethyl)benzamide;

3-(3-methoxyphenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide;

3-(4-methoxyphenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide;

2-(3,4-dimethylphenoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide;

(2R)-2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-phenylbutane;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-phenoxybutyric;

4-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-Tien-2-inputname;

2-((4-methylpyrimidin-2-yl)thio)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide;

3-(2-chlorophenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide;

3-(4-chlorophenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide;

3-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-phenylpentane;

2-(4-chloro-2-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-N'-phenylenediamine;

4-(4-methoxyphenyl)-4-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)butanamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2,2-diphenylacetamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-(phenylsulfonyl)propanamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-(3-phenoxyphenyl)ndimethylacetamide;

4-ethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

3-fluoro-2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

5-fluoro-2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)meth is l)phenyl)benzamide;

3-fluoro-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

2,3-debtor-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

2,4-debtor-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

2.5-debtor-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

3,5-debtor-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-propylbenzamide;

4-isopropyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

2 ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

4 isopropoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

4-(diethylamino)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

4 butoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

2-fluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-5-(trifluoromethyl)benzamide;

2-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-5-(trifluoromethyl)benzamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-furamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-furamide;

2,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-furamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)thiophene-2-carbox the MFA;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)thiophene-3-carboxamide;

3-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)thiophene-2-carboxamide;

5-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)thiophene-2-carboxamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-pyrrol-2-carboxamide;

1-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-pyrrol-2-carboxamide;

2,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-pyrrol-3-carboxamide;

1,2,5-trimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-pyrrol-3-carboxamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1,3-thiazol-2-carboxamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1,3-thiazole-4-carboxamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1,3-thiazole-5-carboxamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)isoxazol-5-carboxamide;

3,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)isoxazol-4-carboxamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)nicotinamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)isonicotinamide;

3-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyridine-2-carboxamide;

2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)is enyl)nicotinamide;

6-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)nicotinamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-pyridin-2-ylacetamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-pyridin-3-ylacetamide;

5-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyrazin-2-carboxamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-indol-3-carboxamide;

5-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1-phenyl-1H-pyrazole-4-carboxamide;

6-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2H-chromen-3-carboxamide;

N3N3-dimethyl-N1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-beta-alaninate;

4-(2-(3-bromophenyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(2-(3-bromo-4-forfinal)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(2,2,2-Cryptor-1-phenylethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

2-hydroxy-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

4-acetyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

3-methoxy-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

4 ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

3-fluoro-4-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydrite the Zin-1-yl)methyl)phenyl)-1-naptime;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-naptime;

5-chloro-2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

4-tert-butyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

4-(acetylamino)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-propoxybenzene;

1-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-naptime;

2-chloro-5-(methylthio)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

3,4-diethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

2-benzyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

2-aniline-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

2-benzoyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-(2-phenylethyl)benzamide;

5-bromo-2-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

2-(4-methylbenzoyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

2-iodine-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

3-iodine-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide;

4-iodine-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)Bentham is d;

N-(2'-fluoro-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-3-yl)ndimethylacetamide;

4-((6-fluoro-3'-(methylsulphonyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((6-fluoro-3'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((6-fluoro-4'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

2'-fluoro-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-3-carboxamide;

2'-fluoro-N,N-dimethyl-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-4-carboxamide;

4-(3,3,3-Cryptor-2-phenylpropyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

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

4-(2-(3-bromophenyl)propyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

tert-butyl 2-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)piperazine-1-carboxylate;

4-benzyl 1-tert-butyl 2-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)piperazine-1,4 -, in primary forms;

4-(2-(3-nitrophenyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

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

4-(piperazine-2-ylmethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(2-(3-(2-oxopyrrolidin-1-yl)phenyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenyl)-2-phenoxyacetamide;

4-(2-(6-fluoro-3'-(morpholine-4-ylcarbonyl)-1,1'-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

methyl 3-(2-(4-oxo,4,5,6,7,8-hexahydrophthalate-1-yl)ethyl)benzoate;

methyl 3-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)benzoate;

4-(2-(6-fluoro-4'-(morpholine-4-ylcarbonyl)-1,1'-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(2-(6-fluoro-2'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(2-(6-fluoro-3'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-cyclopropyl-2'-fluoro-5'-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide;

N-(2-(dimethylamino)ethyl)-2'-fluoro-5'-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide;

2'-fluoro-5'-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide;

N-(2'-fluoro-5'-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)methanesulfonamide;

N-(2'-fluoro-5'-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)ndimethylacetamide;

4-(2-(6-fluoro-3'-(morpholine-4-ylcarbonyl)-1,1'-biphenyl-3-yl)propyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(2-(6-fluoro-3'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)propyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-cyclopropyl-2'-fluoro-5'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide;

4-(3-amino-4-Chlorobenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-amino-4-methoxybenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-amino-4-hydroxybenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-amino-4-methylbenzyl)-5,6,7,8-Tetra is hydrophilizing-1(2H)-he;

N-(2-(dimethylamino)ethyl)-3'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide;

3'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide;

N-(3'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)ndimethylacetamide;

3'-(1-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide;

N-(3'-(1-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)ndimethylacetamide;

N-(2-(dimethylamino)ethyl)-3'-(1-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide;

3-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)benzoic acid;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-(4-methoxyphenyl)-4-oxobutanamide;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3,4-dimethyl-1H-pyrrole-2,5-dione;

3-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-azabicyclo(3.1.0)hexane-2,4-dione;

4-((4-(phenoxyacetyl)piperazine-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(2-(3-bromo-4-forfinal)propyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-oxo-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenyl)-4-phenylbutane;

2'-fluoro-5'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide;

N-(2'-fluoro-5'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)ndimethylacetamide;

N-((2'-fluoro-5'-(1-methyl-2-(4-oxo-3,4,5,,7,8-hexahydrophthalate-1-yl)ethyl)-1,1'-biphenyl-3-yl)methyl)methanesulfonamide;

2-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)hexahydro-1H-isoindole-1,3(2H)-dione;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3,3-dimethylpiperidin-2,5-dione;

4-(4-fluoro-3-(2-methyl-5-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxazepan-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)piperidine-2,6-dione;

4-(4-fluoro-3-(2-Oxymetazoline-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(1,1-dioxothiazolidine-2-yl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-(3-furylmethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(Tien-2-ylmethyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(Tien-3-ylmethyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(pyridine-3-ylmethyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(pyridine-4-ylmethyl)benzamide;

N-(2-(dimethylamino)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-(dimethylamino)propyl)-3-((4-oxo-3,4,5,6,7,8-Gex is hydrophilized-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(3-pyrrolidin-1-ylpropyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(3-piperidine-1-ylpropyl)benzamide;

N-(3-morpholine-4-ylpropyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(1H-indol-3-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-1,3-thiazol-2-ylbenzene;

benzyl 2-oxo-2-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenylamino)ethylcarbamate;

4-oxo-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenyl)-4-(4-phenoxyphenyl)butanamide;

benzyl 3-(((3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenyl)amino)carbonyl)piperidine-1-carboxylate;

2-(4-methylphenoxy)-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenyl)ndimethylacetamide;

2-(4-methoxyphenoxy)-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenyl)ndimethylacetamide;

4-(4-fluoro-3-(3-methyl-2-Oxymetazoline-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxotetrahydrothalifendine-1(2H)-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(3-tert-butyl-2-Oxymetazoline-1-yl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-((1S,4R)-3-oxo-2-azabicyclo(2.2.1)hept-2-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-(2-ethylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-ethylphenyl)-3-((4-oxo-3,4,5,6,7,8-Gex is hydrophilized-1-yl)methyl)benzamide;

N-(4-ethylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-propylphenyl)benzamide;

N-(2-isopropylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(4-isopropylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-tert-butylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(4-tert-butylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-1,1'-biphenyl-4-yl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-fluoro-4-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-fluoro-4-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(4-fluoro-2-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(4-fluoro-3-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-chloro-4-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(4-chloro-3-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-bromo-4-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(4-bromo-3-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-fluoro-4-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-methoxy-5-(trifluoromethyl)phenyl)-3-((4-oxo-3,4,5,6,7,8-GE is sagittalis-1-yl)methyl)benzamide;

N-(2-hydroxy-6-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-hydroxy-2-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-hydroxy-4-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-methoxy-5-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-methoxy-4-were)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-hydroxy-4-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-ethoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(4-propoxyphenyl)benzamide;

N-(5-tert-butyl-2-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(5-(acetylamino)-2-methoxyphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-2,3-dihydro-1,4-benzodioxin-6-yl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(5-chloro-2,4-acid)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(3-(methylthio)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(4-(methylthio)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(4-piperidine-1-ylphenyl)benzamide;

N-(4-(morpholine-4-ylphenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-yl)methyl)benzamide;

N-(2-anilinophenol)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(4-((4-methoxyphenyl)amino)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-quinoline-6-ylbenzene;

N-(5-hydroxy-1-naphthyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-1H-indazol-6-yl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

8-(4-terbisil)pyrido(2,3-d)pyridazin-5(6H)-he;

8-(3-chloro-4-terbisil)pyrido(2,3-d)pyridazin-5(6H)-he;

(3aR)-8-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-2,3,3a,4-tetrahydro-1H-pyrrolo(2,1-c)(1,4)benzoxazine-1-it;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-N-methylmethanesulfonamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-hydroxy-2-methylpropanamide;

(3aS)-8-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-2,3,3a,4-tetrahydro-1H-pyrrolo(2,1-c)(1,4)benzoxazine-1-it;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-phenylethyl)benzamide;

N-(2-(2-were)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(3-were)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(4-were)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-pyridin-2-retil)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)shall ethyl)-N-(2-pyridin-3-retil)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-pyridin-4-retil)benzamide;

N-(2-(2-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(3-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(4-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(2-forfinal)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(3-forfinal)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(4-forfinal)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(2-chlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(3-chlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(4-chlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(3-bromophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(4-bromophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(1,1'-biphenyl-4-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-(3-(trifluoromethyl)phenyl)ethyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-(4-(trifluoromethyl)phenyl)ethyl)benzamide;

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-(4-phenoxyphenyl)ethyl)benzamide;

N-(2-(4-dimetilfenil)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(2,4-dimetilfenil)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(2,5-dimetilfenil)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(3-ethoxy-4-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(4-ethoxy-3-methoxyphenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(2,3-acid)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(2,4-acid)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(2,5-acid)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(3,4-acid)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(3,5-acid)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(1,3-benzodioxol-5-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(2,3-dichlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(3,4-dichlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(2,6-dichlorophenyl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

(3aS,4R,7S,7aR)-5-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2,2-dimethylether-4,7-methane(1,3)dioxolo(4,5-c)pyridine-6(3aH)-he;

4-(1-(3-bromo-4-forfinal)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

8-(4-terbisil)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

8-(3-bromo-4-terbisil)pyrido(2,3-d)pyridazin-5(6H)-he;

N-(2-(dimethylamino)ethyl)-N-ethyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-(2-(diethylamino)ethyl)-N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-benzyl-N-ethyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-benzyl-N-isopropyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-benzyl-N-butyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N,N-dibenzyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-benzyl-N-(2-hydroxyethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-pyridin-2-retil)benzamide;

N-(2-(3,4-acid)ethyl)-N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide;

4-(3-((4-hydroxypiperidine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoyl)piperidine-3-carboxamide;

1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoyl)piperidine-4-carboxamide;

4-(3-((4-(2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-methylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-ethylpiperazin-1-yl)shall arbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoyl)piperazine-1-carbaldehyde;

4-(3-((4-acetylpiperidine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-(2-hydroxyethyl)piperazine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-phenylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-pyridine-2-reparation-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-(pyrimidine-2-reparation-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-(2-forfinal)piperazine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-(4-forfinal)piperazine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-(2-chlorophenyl)piperazine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((4-methyl-1,4-diazepan-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(1,1-dioxido-1,2-diazinon-2-yl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

8-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)pyrido(2,3-d)pyridazin-5(6H)-he;

8-(3-chloro-4-terbisil)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

4-(1-(4-fluoro-3-(2-oxoazetidin-1-yl)phenyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyrrolidin-2,5-dione;

N-(2-fluoro-5-((4-OK what about-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-(2-oxopyrrolidin-1-yl)ndimethylacetamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-5-oxohexanoate;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-methoxypropane;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-N'-phenylenediamine;

benzyl 2-(dimethylamino)-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenylcarbamate;

8-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

4-(3-bromo-4-forfinal)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxoazetidin-1-yl)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

2-fluoro-5-((5-oxo-5,6-dihydropyrido(2,3-d)pyridazin-8-yl)methyl)benzamide;

8-(3-amino-4-terbisil)pyrido(2,3-d)pyridazin-5(6H)-he;

8-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

methyl 2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)benzoate;

8-(3-amino-4-terbisil)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)benzoic acid;

N-ethyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)benzamide;

N-cyclobutyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)benzamide;

2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)p is ridazin-8-yl)methyl)-N-(2-pyrrolidin-1-retil)benzamide;

8-(4-fluoro-3-((4-(morpholine-4-ylcarbonyl)piperazine-1-yl)carbonyl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-N'-phenylenediamine;

1-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)pyrrolidin-2,5-dione;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-3-methoxypropane;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-5-oxohexanoate;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-3-phenoxypropane;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-4-oxo-4-phenylbutane;

2-(4-(benzyloxy)phenoxy)-N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)ndimethylacetamide;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-2-(4-methoxyphenoxy)ndimethylacetamide;

N-cyclopropyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)benzamide;

8-(3-((4-(2-ethoxyethyl)piperazine-1-yl)carbonyl)-4-terbisil)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)-N-(2-piperidine-1-retil)benzamide;

2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(3,2-d)pyridazin-8-yl)methyl)-N-(2-oxo-2-(piperidine-1-yl)ethyl)benzamide;

4-(4-fluoro-3-((4-pyrim the DIN-2-reparation-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he; and

4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

and their therapeutically acceptable salts, prodrugs, esters, amides, salts of prodrugs, salts of esters and salts of amides.

DETAILED description of the INVENTION

Changeable parts of the compounds presented in the description by reference (capital letters with upper-numeric and/or alphabetic index) and can be specifically implemented in various embodiments of the invention.

This means that the appropriate valency is stored for all combinations listed in the description, and that monovalent fragments containing more than one atom attached via a free valence, located on the left side.

It is also understood that the particular implementation of the modified fragment may be identical to another particular variant of the implementation of the modified fragment or may be different.

In the descriptions of the schemes and the examples you used the following abbreviations:

BOCdi-tert-BUTYLCARBAMATE
S-18dimethyloctadecyl
DCIdesorption (direct) chemicals the ionization
DME1,2-dimethoxyethan,
DMSOdimethyl sulfoxide,
ESIionization in electrospray

HATUhexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea,
HPLChigh performance liquid chromatography
MSmass spectroscopy
TFUKtriperoxonane acid

In the present description in data1H NMR symbol "δ" refers to the chemical shift in1H NMR spectrum.

In the present description in data1H NMR, the abbreviation "ush." refers to the broadening of1H NMR signal.

In the present data1H NMR, the abbreviation "d" refers to the doublet1H NMR peak.

In the present description in data1H NMR, the abbreviation "DD" refers to the doublet doublet1H NMR peaks.

In the present description in data1H NMR, the abbreviation "m" refers to the multiplet1H NMR peak.

In the present description in data1 H NMR, the abbreviation "square" refers to a Quartet1H NMR peak.

In the present description in data1H NMR, the abbreviation "C" refers to singlet1H NMR peak.

In the present description in data1H NMR, the abbreviation "t" refers to triplet1H NMR peak.

The term "alkenyl", when used in the present description, means monovalent hydrocarbon fragments with a straight or branched chain, containing one or more double carbon-carbon bonds, such as C2alkenyl, C3alkenyl, C4alkenyl, C5alkenyl, C6alkenyl etc.

The term "alkyl", when used in the present description, means monovalent hydrocarbon fragments with a straight or branched chain, such as C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl, C6-alkyl, etc.

The term "quinil", when used in the present description, means monovalent hydrocarbon fragments with a straight or branched chain, containing one or more triple carbon-carbon bonds, such as C2-quinil, C3-quinil, C4-quinil, C5-quinil, C6-quinil etc.

The term "cycloalkane", when used in the present description, means a saturated hydrocarbon cyclic or bicyclic fragments such as C 4-cycloalkyl, C5-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, C8-cycloalkyl, C9-cycloalkyl, C10-cycloalkyl, C11-cycloalkyl, C12-cycloalken etc.

The term "cycloalkyl", when used in the present description, means a monovalent saturated hydrocarbon cyclic and bicyclic fragments, such as C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, C8-cycloalkyl, C9-cycloalkyl, C10-cycloalkyl, C11-cycloalkyl, C12-cycloalkyl etc.

The term "cycloalkene", when used in the present description, means a hydrocarbon cyclic and bicyclic fragments containing one or more double carbon-carbon bonds, such as C5-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, C8-cycloalkyl, C10-cycloalkyl, C10-cycloalkyl, C11-cycloalkyl, C12-cycloalken etc.

The term "cycloalkenyl", when used in the present description, means monovalent hydrocarbon cyclic fragments containing one or more double carbon-carbon bonds, such as C4-cycloalkenyl, C5-cycloalkenyl, C6-cycloalkenyl, C7-cycloalkenyl, C8-cycloalkenyl, C9-cycloalkenyl, C10qi is alkenyl, C11-cycloalkenyl, C12-cycloalkenyl etc.

The term "heteroaryl", when used in the present description, means furan, imidazole, isothiazol, isoxazol, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, oxazole, pyrazin, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1,3,4-thiadiazole, thiophene, triazine and 1,2,3-triazole.

The term "heteroaryl", when used in the present description, means furanyl, imidazolyl, isothiazolin, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl.

The term "geteroseksualen", when used in the present description, means cycloalkane containing one, two or three fragments of CH2replaced by fragments independently selected from O, S, S(O), SO2or NH and one or two fragments of SN, not substituted or substituted by N atom, as well as cycloalkane containing one, two or three fragments of CH2not replaced or replaced by fragments independently selected from O, S, S(O), SO2or NH and one or two fragments of SN, replaced by an atom N.

The term "geteroseksualen", when used in the present description, means cycloalkane containing one, two or three fragm the NTA, replaced by fragments independently selected from O, S, S(O), SO2or NH and one or two fragments of SN, not substituted or substituted by N atom, and cycloalkane containing one, two or three fragments of CH2not replaced or replaced by fragments independently selected from O, S, S(O), SO2or NH and one or two CH fragment is replaced by an atom N.

The term "heteroseksualci", when used in the present description, means cycloalkyl containing one, two or three fragments of CH2replaced by fragments independently selected from O, S, S(O), SO2or NH, or one or two fragments of SN, not substituted or substituted by N atom, and cycloalkyl containing one, two or three fragments of CH2not replaced or replaced by fragments independently selected from O, S, S(O), SO2or NH and one or two CH-fragment replaced by atoms n

The term "geteroseksualen", when used in the present description, means cycloalkenyl containing one, two or three fragments of CH2replaced by fragments independently selected from O, S, S(O), SO2or NH and one or two fragments of SN, not substituted or substituted by N atom, and cycloalkenyl containing one, two or three fragments of CH2not replaced or replaced by fragments independently selected from O, S, S(O), SO2or NH and one or two of the piece is and SN, replaced(e) atom n

The term "cyclic fragment", when used in the present description, means benzene, cycloalkane, cycloalkyl, cycloalkene, cycloalkenyl, heteroaryl, heteroaryl, geteroseksualen, heteroseksualci, geteroseksualen, geteroseksualen and phenyl.

Compounds according to the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration, where the terms "R" or "S" take the values defined in the publication Pure Appl. Chem. (1976) 45, 13-10. Compounds containing an asymmetrically substituted carbon atoms, with equal amounts of R - and S-configurations are racemic in these atoms. Atoms, which have an excess of one configuration over another, define a redundant configuration, preferably with an excess of about 85-90%, more preferably with an excess of about 95-99%, even more preferably with an excess of more than about 99%. Accordingly, it is believed that the present invention includes racemic mixtures, relative and absolute diastereoisomer and their connections.

Compounds according to the present invention may also contain double carbon-carbon links or a double carbon-nitrogen relation in the Z - or E-configuration, where the term "Z" means the presence of more than two substituents on the same side of the carbon-carbon or carbon-nitrogen, Feb the telecommunication, and the term "E" means the presence of more than two substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond. Compounds according to the present invention may also exist as a mixture of Z and E isomers.

Compounds according to the present invention, the group containing NH, C(O)H, C(O)OH, C(O)NH2, OH or SH may contain attached to these groups of fragments, forming a prodrug. Fragments forming prodrugs, are removed as a result of metabolic processesin vivoand release compounds containing free group NH, C(O)H, C(O)OH, C(O)NH2, OH or SH. Prodrugs can be used to regulate such pharmacokinetic properties of compounds as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, permeability in the tissue and the rate of clearance.

Metabolites of compounds of formula I, obtained as a result of metabolic processesin vitroorin vivocan also possess the ability to treat diseases caused or reinforced unregulated or excessive expressed poly(ADP-ribose)polymerase.

Some compounds, which are precursors of the compounds of formula I, can be metabolisedin vitroorin vivowith the formation of compounds of formula I and, thus, can also PR is changing for the treatment of diseases, caused by uncontrolled or enhanced or overly expressed poly(ADP-ribose)polymerase.

The compounds of formula I can exist in the form of an acid additive salts, basic additive salts or zwitterions. Salts of compounds of formula I are formed in the process of allocation, or further treatment. Acid additive salts are salts obtained by the interaction of the compounds of formula I with an acid. Accordingly, it is understood that salts of the compounds of formula I, including acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, bansilalpet (besult), bisulfate, butyrate, comfort, caficultores, digluconate, format, fumarate, glycerol, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonic, methanesulfonate, naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, triptorelin acid, pair-toluensulfonate, undecanoate, are included in the scope of the present invention. Basically additive salts of the compounds are salts resulting from the interaction of the compounds of formula I with bicarbonate, carbonate, hydroxide or phosphate cations such as lithium, sodium, potassium, calcium and magnesium.

the value of the formula I can be introduced, for example, buccal, ophthalmically, orally, osmotically, parenterally (intramuscularly, administered intraperitoneally, intrasternally, intravenously, subcutaneously), rectally, topically, transdermally and vaginally.

Therapeutically effective amounts of compounds of formula I depends on the treatment of the patient, the disease to be treated, and its severity, the composition comprising a compound of formula I, time of administration, route of administration, duration of treatment, efficacy, rate of clearance and whether, if you enter together another medication or not. The amount of the compounds of formula I to obtain a composition intended for daily introduction to the patient in a single dose or in small doses, repeated at intervals of time is from about 0.001 to about 200 mg/kg of body weight. Composition one dose contain the specified quantity or a multiple of number.

The compounds of formula I may be introduced together with the carrier or without it. The fillers include, for example, substances that are used to encapsulate, and other additives, such as absorption accelerators, antioxidants, swaswara substances, buffer additives, chemicals for coatings, paints, thinners, dezintegriruetsja additives, emulsifiers, extenders, fillers, flavorings, humidifiers supplements increasing slip, fragrances, preservatives, dispersants, additives, releasing the active substance, sterilizers, sweeteners, soljubilizatory, wetting agents and mixtures thereof.

The compounds of formula I may be labeled with radioactive isotopes, such as carbon (i.e.13C), hydrogen (i.e.3H), nitrogen (i.e.15N), phosphorus (i.e.32P), sulfur (i.e.35S), iodine (i.e.125I) and other Radioactive isotopes can be introduced into compounds of the formula I by reaction of compounds of formula I with a reagent receiving radioactive compounds or introduction in their synthesis of intermediate compound labeled with a radioactive isotope. The compounds of formula I, radiolabelled, can be used as prognostic and diagnostic applications, as well as forin vivoandin vitrothe visualization.

The compounds of formula I may be incorporated in devices such as, but without limitation, arteriovenous implants, billiary stents, vascular bypass grafts, catheters, shunts the Central nervous system, coronary stents, balloons for delivery of drugs, peripheral stents and ureteral stents, each of which can be used in these areas (but without limitation)as of the vascular network for the introduction of the compounds of formula I in selected tissues or organs of the body naturally. One of the criteria for evaluating the effectiveness of compounds of the formula I is the reduction or removal of blood clots associated with the device, and complications associated with them.

The compounds of formula I can be used as radio sensibilizators that increase the effectiveness of radiation therapy. Examples of radiation therapy include, but without limitation, radiation therapy with external irradiation beams, remote radiation therapy, close-focus radiation therapy or radiation therapy with sealed and unsealed sources of radiation.

Fillers to obtain compositions comprising a compound of formula I and intended for oral administration include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butyleneglycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, oil from cotton seeds, cross-povidone, diglycerides, ethanol, ethylcellulose, tillaart, etiloleat, esters of fatty acids, gelatin, oil of wheat germ, glucose, glycerin, oil of groundnuts, hypromellose, isopropanol, isotonic saline the solution, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato to Ajmal, povidone, propylene glycol, ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium lauryl sulphate, sorbitol, sodium, soy oil, stearic acid, fumarate, sucrose, surfactants, talc, tragakant, tetrahydrofurfuryl alcohol, triglycerides, water and their mixtures. Fillers to obtain compositions comprising the compounds of formula I and intended for ophthalmic or oral administration include, for example, 1,3-butyleneglycol, castor oil, corn oil, oil from cotton seeds, ethanol, complex arbitrarily fatty acids, the oil of wheat germ, oil of groundnuts, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Fillers to obtain compositions comprising a compound of formula I and intended for the introduction of osmotically include, for example, chlorofluorocarbons, ethanol, water and mixtures thereof. Fillers to obtain compositions comprising a compound of formula I and intended for parenteral administration include, for example, 1,3-butanediol, castor oil, corn oil, oil from cotton seeds, dextrose, butter, wheat germ, oil of groundnuts, liposomes, oleic acid, olive oil, peanut oil, ringer's solution, CA is lorosae oil, sesame oil, soybean oil, sodium chloride solution Pharmacopoeia of the United States or isotonic sodium chloride solution, water, or mixtures thereof. Fillers to obtain compositions comprising a compound of formula I and designed to be inserted rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.

It is expected that the compounds of formula I can also be used with alkylating agents, inhibitors of the development of blood vessels, antibodies, antimetabolites, antimitoticescoy means, antiproliferative agents, inhibitors of Aurora kinases, inhibitors of Bcr-Abl kinase, biological response modifiers, inhibitors of cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2, inhibitors of receptor viral oncogenic homologue leukemia (ErbB2), inhibitors of growth factor, inhibitors of heat shock proteins (HSP)-90, inhibitors of histone-deacetylase (HDAC), hormonal therapy, immunological medicinal products, intercalating antibiotics, kinase inhibitors, inhibitors target rapamycin mammals, inhibitors mitogen-activated extracellular signal-regulated kinase, non-steroidal anti-inflammatory drugs (NSAID), a chemotherapeutic drug is and means, containing platinum, inhibitors of polo-like kinase, proteasome inhibitors, purine analogues, and pyrimidine analogues, inhibitors of receptor tyrosine kinase, retinoids/deltoids, plant alkaloids, topoisomerase inhibitors, etc.

Alkylating agents include altretamin, AMD-473, AP-5280, apaziquone (apaziquone), bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, Cloretazine(VPN 40101M), cyclophosphamide, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustin (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, treosulfan, trofosfamide etc.

Inhibitors of the development of blood vessels include inhibitors of endothelial cell-specific receptor tyrosinekinase (Tie-2)inhibitors of the receptor for epidermal growth factor-2 (EGFR), a receptor inhibitors of the insulin growth factor-2 (IGFR-2)inhibitors of matrix metalloproteinase-2 (MMP-2)inhibitors of matrix metalloproteinase-9 (MMP-9)inhibitors of receptor platelet-derived growth factor (DERIVED)inhibitors thrombospondin analogues of the receptor tyrosine kinase growth factor vascular endothelial (VEGFR), etc.

Inhibitors euroracing include AZD-1152, MLN-8054, VX-680, etc.

Inhibitors of Bcr-Abl kinase include DASATINIB®(BMS-354825), GLEEVEC® (imatinib), etc.

The CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopiridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and so on

Inhibitors MOR-2 (cyclooxygenase-2) include ABT-963, ARCOXIA®(etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX™ (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX®(deracoxib), JTE-522, 4-methyl-2-(3,4-dimetilfenil)-1-(4-sulfamoyl-1H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX®(rofecoksib), etc.

The EGFR inhibitors include ABX-EGF, anti-EGFr of immunoliposome, EGF-vaccine, EMD-7200, ERBITUX®(cetuximab), HR3, IgA antibodies IRESSA®(gefitinib), TARCEVA®(erlotinib or OSI-774), TP-38, fusion protein EGFR, TYKERB®(lapatinib), etc.

Inhibitors of ErbB2 receptor include CP-724-714, CI-1033 (canertinib), Herceptin®(trastuzumab), TYKERB®(lapatinib), OMNITARG®(2C4, pertuzumab), TAK-165, GW-572016 (inferni), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER2 vaccine), bespecifically antibody to HER/2neu, B7.her2IgG3, AS HER2 trifunctional bespecifically antibodies, mAB AR-209, mAB 2B-1, etc.

Inhibitors of histone-deacetylase include depsipeptide, lunar abyss-824, MS-275, trioxin, suberoylanilide acid (SAHA), TSA, valproate acid, etc.

Inhibitors of HSP-90 include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB®, NCS-683664, PU24FC1, PU-3, radicial, SNX-2112, STA-090 VER49009 etc.

The MEK inhibitors include ARRY-142886, ARRY-438162, PD-325901, PD-98059, etc.

The mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus etc.

Nonsteroidal anti-inflammatory drugs include AMIGESIC®(salsalate), DOLOBID®(diflunisal), MOTRIN®(ibuprofen), ORUDIS®(Ketoprofen), RELAFEN®(nabumetone), FELDENE®(piroxicam) ibuprofen cream ALEVE®and NAPROSYN®(naproxen), VOLTAREN®(diclofenac), INDOCIN®(indomethacin), CLINORIL®(sulindac), TOLECTIN®(tolmetin), LODINE®(etodolac), TORADOL®(Ketorolac), DAYPRO®(oxaprozin), etc.

Inhibitors DERIVED include C-451, CP-673, CP-868596 etc.

Chemotherapeutic drugs, containing platinum, include cisplatin, ELOXATIN®(oxaliplatin) heptaplatin, lobaplatin, nedaplatin, PARAPLATIN®(carboplatin), satraplatin etc.

Inhibitors of polo-like kinases include BI-2536, etc.

Analogues of thrombospondin include ABT-510, ABT-567, ABT-898, TSP-I, etc.

The VEGFR inhibitors include AVASTIN®(bevacizumab), ABT-869, AEE-788, ANGIOZYME™, axitinib (AG-13736), AZD-2171, CP-547632, IM-862, macugen (Macugen) (pegaptanib), NEXAVAR®(sorafenib, BAY43-9006), pazopanib (GW-786034), (PTK-787, ZK-222584), SUTENT®(sunitinib, SU-11248), VEGF trap, vatalanib, ZACTIMA™ (vandetanib, ZD-6474), etc.

Antimetabolites include ALIMTA®(pemetrexed-disodium, LY231514, MTA), 5-saltidin, XELODA®(capecitabine), carmofur, LEUSTAT®(cladribine, Clofarabine, cytarabine, cytarabine-ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR, enocitabine, ethnicities, fludarabine, hydroxyurea, 5-fluorouracil (5-FU) alone or in combination with leucovorin, GEMZAR®(gemcitabine, hydroxyurea, ALKERAN®(melphalan, mercaptopurine, 6-mercaptopurine-ribose, methotrexate, mycophenolate acid, nelarabine, nolatrexed, octocat, political, pentostatin, raltitrexed, ribavirin, triapin, trimetrexate, S-1, tianfuan, tegafur, TS-1, vidarabine, UFT, etc.

Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE®(bleomycin), daunorubicin, CAELYX®or MYOCET®(doxorubicin), elsamitrucin, airboren, parboil, ZAVEDOS®(idarubitsin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimulater, streptozocin, VALSTAR®(valrubicin), zinostatin etc.

The topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, Ekaterin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE®(dexrazoxane), diflomotecan, edotecarin, ELLENCE®or PHARMORUBICIN®(epirubicin, etoposide, exatecan, 10-hydro is scantuary, gimatecan, lurtotecan, mitoxantrone, oracin, parabolin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluprost, topotecan, etc.

Antibodies include AVASTIN®(bevacizumab), CD40-specific antibodies, chTNT-1/B, denosumab, ERBITUX®(cetuximab), HUMAX-CD4®(zanolimumab), IGFlR-specific antibodies, lintuzumab, PANOREX®(edrecolomab), RENCAREX®(WX G250), RITUXAN®(rituximab), ticilimumab, trastuzumab etc.

Hormonal therapeutic drugs include ARIMIDEX®(anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX®(bikalutamid), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN®(trilostane), dexamethasone, DROGENIL®(flutamide), EVISTA®(raloxifene), fadrozole, FARESTON®(toremifene), FASLODEX®(fulvestrant), FEMARA®, (letrozole), formestane, glucocorticoids, HECTOROL®or RENAGEL®(doxercalciferol), lasofoxifene, leuprolide-acetate MEGACE®(megestrol), MIFEPREX®(mifepristone), NILANDRON™ (nilutamide), NOLVADEX®(tamoxifen-citrate), PLENAXIS™ (abarelix), predisone, PROPECIA®(finasteride), elastan, SUPREFACT®(buserelin), TRELSTAR®(growth hormone-releasing factor lutenizing hormone (luteinizing hormone releasing hormone - LHRH)), vantas, VETORYL®(trilostane or morestan), ZOLADEX®(forlin, goserelin), etc.

Deltoids and retinoids include iocality (EB1089, CB1093), lexicality (KH1060), phenetidine, PANRETIN®(alitretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN®(bexarotene), LGD-1550, etc.

Plant alkaloids include, but without limitation, vincristine, vinblastine, vindesine, vinorelbine, etc.

The proteasome inhibitors include VELCADE®(bortezomib), MG132, NPI-0052, PR-171, etc.

Examples of immunological drugs include interferon and other drugs that increase the immunity. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, ACTIMMUNE®(interferon gamma-1b) or interferon gamma-n1, combinations thereof and the like Other medicines include ALFAFERONE®BAM-002, BEROMUN®(tasonermin), BEXXAR®(tositumomab), CamPath®(alemtuzumab), CTLA4 (cytotoxic limfotsity antigen 4), dacarbazin, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha-interferon, imiquimod, MDX-010, melanoma vaccine, mitooma, molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN®(filgrastim), OncoVAC-CL, OvaRex®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE®, sargramostim, sizofiran, azelastin, TheraCys®, ubenimex, VIRULIZIN®, Z-100, WF-10, PROLEUKIN®(aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX®(daclizumab), ZEVALIN®(90Y-Ebrity is omab tiuxetan), etc.

The biological response modifiers are drugs that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells, for the production of antitumor activity and include baptisms, lentinan, sizofiran, picibanil PF-3512676 (CpG 8954), ubenimex etc.

Analogues of pyrimidine include cytarabine (Ara C), cytosine arabinoside, doxifluridine, FLUDARA®(fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR®(gemcitabine), TOMUDEX®(raytraced), TROXATYL™ (triacetyluridine-troxacitabine), etc.

Analogues of purine include LANVIS®(tioguanin) and PURI-NETHOL®(mercaptopurine).

Antimitoticescoe agents include batubulan, epothilone D (KOS-862), N-(2-((4-hydroxyphenyl)amino)pyridine-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE®(docetaxel), PNU100940 (109881), patupilone, XRP-9881, vinflunine, ZK-EPO, etc.

Compounds according to the present invention are intended for use as a radio-sensitizing substance which increases the effectiveness of radiation therapy. Examples of radiation therapy include, but without limitation, radiotherapy with external beam radiation external beam irradiation, short-focus radiation therapy and radiation therapy with hermetization and unsealed radiation source.

In addition, the compounds of formula I may be combined with other chemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (inhibitor farnesyltransferase), ADVEXIN®, ALTOCOR®or MEVACOR®(lovastatin), AMPLIGEN®(poly I:poly C12U, a synthetic RNA), APTOSYN™ (exisulind), AREDIA®(panikanova acid), Arglabin, L-asparaginase, atamestane (1-methyl-3,17-Gianandrea-1,4-diene), AVAGE®(tazarotene), AVE-8062, BEC2 (mitooma), cachectin or cachectin (tumor necrosis factor), canvaxin (vaccine), CeaVac™ (cancer vaccine), CELEUK®(celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX™ vaccine virus palilay person), CHOP®(C: CYTOXAN®(cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: vincristine (ONCOVIN®); P: prednisone), CyPat™, complestatin A4P, DAB(389)EGF or TransMID-107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethylxanthene-4-acetic acid (DMXAA), eniluracil, EVIZON™ (squalamine), DIMERICINE®(T4N5 liposomal lotion), discodermolide, DX-8951f (exatecan-mesilate), enzastaurin, EPO906, GARDASIL®(quadrivalent recombinant vaccine against human papillomavirus (types 6, 11, 16, 18)), Gathrimmon, genasense, GMK (ganglioside conjugate vaccine), GVAX®(a vaccine against prostate cancer), halofuginone, histrelin, hydroxycarbamide, ibandronic KIS the PTA, IGN-101, IL-13-PE38, IL-13-PE38QQR (besudotox cintredekin), IL-13-Pseudomonas exotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide), lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT®(AE-941), NEUTREXIN®(trimetrexate-glucuronate), NIPENT®(pentostatin), ONCONASE®(ribonuclease enzyme), ONCOPHAGE®(vaccine against melanoma), OncoVAX (IL-2 vaccine), ORATHECIN™ (rubitecan), OSIDEM®(the drug on the basis of antibodies acting on the cellular level), OvaRex®MAb (monoclonal antibody mouse), pediacel, PANDIMEX™ (aglionby saponins isolated from a ginseng and including 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF vaccine against cancer undergoing clinical trials), pegaspargase, PEG-interferon A, phenoxodiol, procarbazine, ropemaster, REMOVAB®(catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE®LA (lanreotide), SORIATANE®(acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN®(bexarotene), Taxoprexin®(docosahexanoic acid-paclitaxel), TELCYTA™ (TLK286), timelife, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE®(STn-KLH), thymitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)hinzelin-dihydrochloride), TNFerade™ (adenovector: native DNA, containing the gene for factor-α is crosa tumors), TRACLEER®or ZAVESCA®(bosentan), tretinoin (retin-A), tetrandrine, TRISENOX®(arsenic trioxide), VIRULIZIN®, Ukrain (derivative of alkaloids from the greater celandine is large), vitaxin (antibody to vascular integrin alpha-v/beta-3), XCYTRIN®(motexafin gadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex), YONDELIS™ (trabectedin), ZD-6126, ZINECARD®(dexrazoxane), zometa (zolendronate acid), zorubicin etc.

In one embodiment of the invention the compounds of formula I are used in the method of treating cancer in a mammal, comprising an introduction to the specified mammal a therapeutically acceptable amount of the compounds of formula I in combination with the chemotherapeutic drug is selected from temosolomida, dacarbazine, cyclophosphamide, carmustine, melphalan, lomustina, carboplatin, cisplatin, 5-FU+/- leucovorin, gemcitabine, methotrexate, bleomycin, irinotecan, camptothecin or topotecan.

It is expected that the compounds of formula I also need to inhibit the cell growth of childhood cancer or pediatric neoplasia, such as embryonal rhabdomyosarcoma, childhood acute lymphocytic leukemia, childhood acute myeloid leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic both lymphoma, pediatric anaplastic medulla is asthma, children atypical teratoma/rathena tumor of the Central nervous system, pediatric biphenotypic acute leukemia, pediatric lymphoma Burkitt, baby carcione family of Ewing tumors, including primitive neuroectodermal tumors, children diffuse anaplastic Wilms tumor, children Wilms tumor with favorable histology, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric tumor consisting mainly of plasmic order has been revealed and developed from neuroblastoma, pre-b-cell childhood cancer (such as children's leukemia), baby pseudosarcoma, baby rhabdosarcoma kidney, pediatric rhabdomyosarcoma, and baby T-cell malignancies such as lymphoma and skin cancer, and the like (patent application U.S. ser. No. 10/988388, Cancer Res., 2000, 60, 6101-10), as well as to inhibit an autoimmune disorder, such as acquired immunodeficiency syndrome, autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, thrombocytopenia, etc. (Current Allergy and Asthma Reports 2003, 3:378-384; Br. J. Haematol. 2000 Sep.; 110(3): 584-90; Blood 2000 Feb 15;95(4): 1283-92; New England Journal of Medicine 2004 Sep; 351(14): 1409-1418).

Quantitative determination of inhibition of the enzyme PARP

Nicotinamide[2,5',8-3H]adenindinucleotide and SPA-granules, coated with streptavidin, purchased from Amersham Biosiences. Recombinant poly(ADP-ri is FLA)polymerase (PARP) man, dedicated purification from E.coli and 6-Biotin-17-NAD+purchased from Trevigen. NAD+, histone, aminobenzamide, 3-aminobenzamide and DNA from calf thymus (dc) purchased from Sigma. Oligonucleotide primary closed-loop containing IRU sequence, purchased from Qiagen. The oligonucleotides were dissolved in 1 mm Anneliese buffer (10 mm Tris HCl, pH 7.5, 1 mm EDTA and 50 mm NaCl), the solution was incubated for 5 minutes at 95°C and then anuliruyut at 45°C for 45 minutes. Histone H1 (electrophoretic clean - 95%) was purchased from Roche. Biotinylated histone H1 is obtained by processing protein sulfon-NHS-LC-Biotin was obtained from Pierce. The reaction biotinidase carried out by slowly adding with periodic breaks 3 equivalents 10 mm sulfo-NHS-LC-Biotin to 100 μm histone H1 in phosphate-buffered saline (pH 7.5) at 4°C with careful vortex mixing for 1 min and subsequent incubation at 4°C for 1 hour. The microplate coated with streptavidin (FlashPlate Plus), purchased from Perkin Elmer.

Quantitative determination of inhibition of the enzyme PARP1 carried out in the experimental buffer solution PARP containing 50 mm Tris (pH 8.0), 1 mm DTT, 4 mm MgCl2. In reactions PARP participate 1.5 µm [3H]-NAD+(1,6 MX/mmol), 200 nm biotinylated histone H1, 200 nm sl and 1 nm PARP enzyme. Autoreactive detection when using SPA-pellets is 100-µl volumes in a white 96-well plates. The reaction initiated by adding 50 μl of substrate mixture 2X NAD+to 50 ál of 2X enzyme mixture containing PARP and DNA. These reactions are finished adding 150 ál of 1.5 mm benzamide (~1000-fold concentration relative to its IC50). 170 µl reaction mixtures, which halted interaction, carry on streptavidine flash tablets, incubated them for 1 hour and then read using a TopCount scintillation counter. The values of EC50for typical compounds according to the present invention are presented in table 1.

Quantitative determination of inhibition of cellular PARP:

C41 cells treated with a compound according to the invention for 30 minutes in a 96-well pad. Then activate PARP, damaging DNA by adding 1 mm H2O2, and incubated the mixture for 10 minutes. The cells are then washed once with ice-cold PBS and fixed pre-frozen mixture of methanol:acetone (7:3) at -20°C for 10 minutes. After drying, air tablets again hydratious with PBS and blocked with 5% skim milk powder in a mixture of PBS-TWEEN20® (Sigma, St. Louis, MO) (0,05%) (blocking solution) for 30 minutes at room temperature. Cells incubated with anti-PAR antibody 10H (1:50) in blocking solution at 37°C for 60 minutes, then washed with a mixture of PBS-TWEEN20® 5 times and incubated associated with the antibody goat to mouse fluorescein-5(6)-isothiocyanate (1:50) and 1 µg/ml 4',6-diamidino-2-phenylindole (DAPI) in blocking solution at 37°C for 60 minutes. After washing 5 times with a mixture of PBS-TWEEN20® conducted the analysis using FMAX FLUORESCENCE MICROPLATE READER® (Molecular Devices, Sunnyvalle, CA)set the wavelength of the excitation 490 nm and the wavelength of emission 528 nm fluorescein-5(6)-isothiocyanate (FITC) or wavelength of the excitation 355 nm and the wavelength of emission of 460 nm (DAPI). The activity of PARP (FITC signal) to quantify lead in accordance with the number of cells (DAPI).

This experience determine the formation of cellular poly (ADP-ribose) under the action of PARP inside cells and show that the compounds according to the invention inhibit PARP in intact cells. Due to the possibility of changing conditions for cell analysis in each experiment as a comparator using 2-(1-propylpiperidine-4-yl)-1H-benzimidazole-4-carboxamide, and the data are in the form of the ratio EC50test connection to EC502-(1-propylpiperidine-4-yl)-1H-benzimidazole-4-carboxamide obtained in a particular experience. The average EC502-(1-propylpiperidine-4-yl)-1H-benzimidazole-4-carboxamide for all the conducted experiments is 0,0032 μm (n=270) and is usually in the range from 0.001 to of 0.013 μm (relative EC50= EC50test connection/EC50comparative connections). The values obtained EC50(nm) are presented in table 1.

For the quantitative determination of inhibition of the enzyme PARP and quantitative determination of inhibition of cellular PARP described above, choose some of the compounds of formula I, where A1is an R1where R1represents unsubstituted cyclohexane, which is unfused, and A2is an R5, R5represents a C1-alkyl. Connections that do not match the formula I, in which position a2is the link, also used for the quantitative determination of inhibition of the enzyme PARP and quantitative determination of inhibition of cellular PARP described above. The results of the experiments are presented in table 2 below.

Some compounds of formula I, in which A1is an R1where R1represents unsubstituted cyclohexane, which is unfused, and A2is an R5where R5represents a C1-alkyl, where R5substituted R10where R10represents phenyl, l is Bo substituted in the para-position F, as shown in the formula (Is):

or not containing Deputy F in the para-position can also choose to apply in the experience of the quantitative determination of inhibition of the enzyme PARP and experience the quantitative determination of inhibition of cellular PARP described above.

Compounds according to the present invention as PARP inhibitors have a broad spectrum of therapeutic effects against ischemic reperfusion injury, inflammatory diseases, degenerative diseases, as well as protective effect against adverse effects of cytotoxic compounds and potentiation of cytotoxic cancer therapy. In particular, the compounds according to the present invention patentiert radiation and chemotherapy, increasing necrosis of cancer cells, limiting tumor growth, reducing metastasis and increasing the duration of survival of mammals in the body which has a tumor. The compounds of formula I can be used for the treatment of leukemia, colorectal cancer, glioblastoma, lymphoma, melanomas, carcinomas of the breast and cervical carcinomas.

Other therapeutic applications include the treatment of retroviral infections, arthritis, gout, inflammatory bowel disease, Vespa is sustained fashion CNS diseases, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemorrhagic collapse, pneumosclerosis, uveitis, diabetes, Parkinson's disease, myocardial infarction, stroke, other neural trauma, and organ transplantation, reperfusion of the eye, reperfusion kidney reperfusion of the digestive tract, reperfusion of skeletal muscle, hepatotoxicity after an overdose of acetaminophen, cardiac and renal toxicities as a result of action of anticancer agents on the basis of doxorubicin and platinum and skin lesions, secondary to the sulfur mustards (G. Chen et al., Cancer Chemo. Pharmacol. 22 (1988), 303; C. Thiemermann et al., Proc. Natl. Acad. Sci. USA 94 (1997), 679-683 D. Weltin et al. Int. J. Immunopharmacol. 17 (1995), 265 - 271; H. Kröger et al., Inflammation 20 (1996), 203-215; W. Ehrlich et al., Rheumatol. Int. 15 (1995), 171-172; C. Szabo et al., Proc. Natl. Acad. Sci. USA 95 (1998), 3867-3872; S. Cuzzocrea et al., Eur. J. Pharmacol. 342 (1998), 67-76 (in Russian); V. Burkhart et al., Nature Medicine (1999), 5314-19).

The compounds of formula I

In one embodiment of the invention the compounds of formula I represent a compound of formula

or their salts, where

A1is an R1or R2where A1is unsubstituted or substituted by one or two substituents selected from OH, CN, C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl, cycloalkane, ORAor NRARA;

R Arepresents H or alkyl;

R1is cycloalkane or cycloalkene, each of which is unfused or fused with R1A;

R1Arepresents a benzene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen;

R2represents geteroseksualen or geteroseksualen, each of which is unfused or fused with R2A;

R2Arepresents a benzene, heteroaryl, cycloalkyl, cycloalkene, geteroseksualen or geteroseksualen;

A2is a OR4, Other4N(R4)2, SR4, S(O)R4, SO2R4or R5;

where each R4represents a C1-alkyl, C2-alkyl or C3-alkyl; each of which is substituted by an R10;

R5represents a C1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl or C5-alkyl; each of which is substituted by an R10and is optionally unsubstituted or optionally substituted one, two or three substituents, independently selected from OR10, Other10N(R10)2, SR10, S(O)R10, SO2R10or CF3;

where each R10is an R10A, R10Bor R10C; each of them should join the atom is carbon;

R10Arepresents phenyl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R10Brepresents a

each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R10Cis cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

where each R10independently is unsubstituted or substituted one, two or three substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2, Other11N(R11)2C(O)R11C(O)OR11C(O)NH2C(O)other11 C(O)N(R11)2, NHC(O)R11, NR11C(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NR11C(O)OR11, NHSO2NH2, NHSO2Other11, NHSO2N(R11)2, SO2NH2, SO2Other11, SO2N(R11)2, NHC(O)NH2, NHC(O)other11, NHC(O)N(R11)2, NR11C(O)N(R11)2, NO2, OH, (O), C(O)H, C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I;

where each R11is an R12, R13, R14or R15;

R12represents phenyl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R13is heteroaryl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R14is cycloalkyl, cycloalkenyl, hetero cloacal or geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R15represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)NH2C(O)other16C(O)N(R16)2, NHC(O)R16, NR16C(O)R16, NHC(O)OR16, NR16C(O)OR16, OH, F, Cl, Br or I;

where each R16is an R17or R17A;

R17represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R18C(O)OH, NH2, Other18or N(R18)2C(O)R18C(O)NH2C(O)other18C(O)N(R18)2, NHC(O)R18, NR18C(O)R18, F, Cl, Br or I;

R17Arepresents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is unfused or con is antiroman with benzene, heteroatom, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

where each R18represents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen;

where each of the fragments, represented as R12, R13, R14, R17Aand R18independently is unsubstituted or substituted one, two, three or four substituents, independently selected from R19, OR19, SR19, S(O)R19, SO2R19C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, Other19N(R19)2, NHC(O)R19, NR19C(O)R19NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)other19, NHC(O)N(R19)2, NR19C(O)other19, NR19C(O)N(R19)2C(O)NH2C(O)other19C(O)N(R19)2C(O)NHOH, C(O)NHOR19C(O)NHSO2R19C(O)NR19SO2R19, SO2NH2, SO2Other19, SO2N(R19)2C(O)H, C(O)OH, C(N)NH2C(N)other19C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I;

where each R19is an R20, R21, R22or R23;

R20represents phenyl, which is on Tserovani or fused with benzene, heteroatom, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R21is heteroaryl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R22is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R23represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R24, OR24, SR24, S(O)2R24C(O)OH, NH2, Other24N(R24)2 C(O)R24C(O)NH2C(O)other24C(O)N(R24)2, NHC(O)R24, NR24C(O)R24, NHC(O)OR24, NR24C(O)OR24NHS(O)2R24, NR24S(O)2R24, OH, F, Cl, Br or I;

where each R24is an R24Aor R24B;

R24Arepresents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization;

R24Brepresents alkyl, alkenyl or quinil, each of which is unsubstituted or substituted by one or two substituents, independently selected from R25, OR25, SR25, S(O)2R25C(O)OH, NH2, Other25N(R25)2C(O)R25C(O)NH2C(O)other25C(O)N(R25)2, NHC(O)R25, NR25C(O)R25, NHC(O)OR25, NR25C(O)OR25, OH, F, Cl, Br or I;

where each R25represents alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unsubstituted or substituted NH2, NH(CH3), N(CH3)2, OH or OCH3;

where each of the fragments, represented as R20, R21, R22and R24Aregardless Ki is unsubstituted or substituted by one or two substituents, independently selected from R26, OR26alkenyl, quinil, phenyl, OH, (O), C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; and

R26represents alkyl.

Embodiments of formula I

Selected subgroups of compounds of interest that fall within the scope of compounds of formula I, represented in different ways to the implementation described below, where A1, R1, RA, R1A, R2, R2A, A2, R4, R5, R10, R10A, R10B, R10C, R11, R12, R13, R14, R15, R16, R17, R17A, R18, R19, R20, R21, R22, R23, R24, R24A, R24B, R25and R26can take values that are defined in the description of the compounds of the formula I and in various embodiments of the invention presented in this patent specification.

Embodiments of A1

In one embodiment, formula I-A1is an R1or R2where R1represents the unfused cycloalkane and R2represents an unfused geteroseksualen, where A1is unsubstituted or substituted by one or two substituents selected from OH, CN, C1-alkyl, C2-alkyl, C3-alkyl, C -alkyl, C5-alkyl, cycloalkane, ORAor NRARA; where RArepresents H or alkyl. In another embodiment, formula I-A1is an R1or R2where R1represents cyclohexane and R2is piperidinyl, where A1is unsubstituted or substituted by one or two substituents selected from C1-alkyl, C2-alkyl or C3-alkyl. In another embodiment, formula I-A1is an R1or R2where R1represents unsubstituted cyclohexane and R2represents an unsubstituted piperidinyl. In another embodiment, formula I-A1is an R1and R1represents unsubstituted cyclohexane, which is represented by formula (Ia):

Embodiments of A2

In one embodiment, formula I-A2is a OR4, Other4N(R4)2, SR4, S(O)R4, SO2R4or R5; where each R4represents a C1-alkyl, C2-alkyl or C3-alkyl; each of which is substituted by an R10as presented in the description of formula I; and R5represents a C1-alkyl, C2-alkyl or C3-alkyl, where R is substituted, as represented in the description of formula I. In another embodiment, formula I-A2is an R5and R5represents a C1-alkyl, C2-alkyl or C3-alkyl, where R5is substituted, as represented in the description of formula I. In another embodiment, formula I-A2is an R5where R5represents a C1-alkyl, which is substituted by an R10and is optionally unsubstituted or optionally substituted one, two or three substituents, independently selected from other10N(R10)2, SR10, S(O)R10, SO2R10or CF3where R10takes the values defined in the description of formula I. In another embodiment, formula I-A2is an R5where R5represents a C1-alkyl, substituted R10as presented in the description of formula I, and is optionally unsubstituted, as shown in formula (Ib):

In another embodiment, formula I-A2is an R5where R5represents a C2-alkyl, substituted R10as presented in the description of formula I, and is optionally unsubstituted, as shown in formulas (Ic) and (Id):

the another embodiment, formula I-A 2is an R5where R5represents a C3-alkyl, zameshannyj R10as presented in the description of formula I, and is optionally unsubstituted. In another embodiment, formula I-A2is an R5where R5represents a C1-alkyl or C2-alkyl, each of which is substituted by an R10as presented in the description of formula I, and optionally substituted CF3.

Embodiments of R10

In one embodiment of formula I, R10is an R10A, R10Bor R10Cwhere R10Arepresents phenyl, which is unfused or fused with heterocyclization, which is a condensed geteroseksualen, R10Brepresents a

and R10Cis heteroseksualci, which is unfused, where R10is optionally substituted, as represented in the description of formula I. In another embodiment, formula I R10is an R10A, R10Bor R10Cwhere R10Arepresents phenyl, which is unfused or fused with heterocyclization, which is a condensed geteroseksualen, R10Bpredstavljaet a

and R10Cis heteroseksualci, which is unfused; where R10replaced by F and is optionally unsubstituted or additionally substituted by one or two substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br, where R11takes the values defined in the description of formula I. In another embodiment, formula I R10is an R10A, R10Bor R10Cwhere R10Arepresents phenyl, which is unfused or fused with heterocyclization, which is a condensed geteroseksualen, R10Brepresents a

and R10Cis heteroseksualci, which is unfused; where R10is replaced by F and is optionally unsubstituted or additionally substituted by one or two substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R1111C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; where each R11is an R12, R13, R14or R15; where R12represents phenyl, which is unfused or fused with benzene, heteroarenes, heterocyclization or heterocyclization; R13is heteroaryl, which is unfused; R14is cycloalkyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, cycloalkane, heterocyclization or heterocyclization; each of which is unfused or fused with benzene; and R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I, where R16takes the values defined in the description of formula I. In another embodiment, formula I R10is an R10A, R10Bor R10Cwhere R10Arepresents f the Nile, which is unfused or fused with heterocyclization, which is a condensed geteroseksualen,

R10Brepresentsand R10Cis heteroseksualci, which is unfused; where R10is replaced by F and is optionally unsubstituted or additionally substituted by one or two substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; where each R11is an R12, R13, R14or R15; where R12represents phenyl, which is unfused or fused with benzene, heteroarenes, heterocyclization or heterocyclization; R13is heteroaryl, which is unfused; R14is cycloalkyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, cycloalkane, heterocyclization or heterocyclization; each of which is some what generowanym or fused with benzene; and R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted or substituted R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene or heterocyclization; and R18represents phenyl or heteroseksualci, which is unfused; where fragments represented as R12, R13, R14, R17Aand R18independently are unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I, where R19takes the values defined in the description of formula I. In another embodiment, formula I R10is an R10A, R10B or R10Cwhere R10Arepresents phenyl, which is unfused or fused with heterocyclization, which is a condensed geteroseksualen, R10Brepresents a

and R10Cis heteroseksualci, which is unfused; where R10replaced by F and is optionally unsubstituted or additionally substituted by one or two substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; where each R11is an R12, R13, R14or R15; where R12represents phenyl, which is unfused or fused with benzene, heteroarenes, heterocyclization or heterocyclization; R13is heteroaryl, which is unfused;

R14is cycloalkyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, cycloalkane, heterocyclization or courtesans what cycloalkenes; each of which is unfused or fused with benzene; and R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted or substituted R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene or heterocyclization; R18represents phenyl or heteroseksualci, which is unfused; where fragments represented as R12, R13, R14, R17Aand R18independently are unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23 ; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci; each of which is unfused or fused with benzene; and R23represents alkyl, which is unsubstituted or substituted R24, OR24, Other24N(R24)2NHS(O)2R24or OH, where R24takes the values defined in the description of formula I. In another embodiment, formula I R10is an R10A, R10Bor R10Cwhere R10Arepresents phenyl, which is unfused or fused with heterocyclization, which is a condensed geteroseksualen; R10Brepresents a

and R10Cis heteroseksualci, which is unfused; where R10replaced by F and is optionally unsubstituted or additionally substituted by one or two substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R1111, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; where each R11is an R12, R13, R14or R15; where R12represents phenyl, which is unfused or fused with benzene, heteroarenes, heterocyclization or heterocyclization; R13is heteroaryl, which is unfused;

R14is cycloalkyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, cycloalkane, heterocyclization or heterocyclization; each of which is unfused or fused with benzene; and R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted or substituted R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or the outdoor the IAOD with benzene or heterocyclization; R18represents phenyl or heteroseksualci, which is unfused; where fragments represented as R12, R13, R14, R17Aand R18independently are unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci, each of which is unfused or fused with benzene; and R23represents alkyl, which is unsubstituted or substituted R24, OR24, Other24N(R24)2NHS(O)2R24or OH; where each R24is an R24Aor R24B; R24Arepresents phenyl, cycloalkyl, heteroseksualci or geteroseksualen, which is unfused or fused with heterocyclization; R24Brepresents alkyl, which is is unsubstituted or substituted OR 25, OH, F, Cl, Br or I; R25represents alkyl, which is unsubstituted or substituted NH2; where fragments represented as R20, R21, R22and R24Aindependently are unsubstituted or substituted by one or two substituents, independently selected from R26, OR26(O), F, Cl, Br or I; and R26represents alkyl. In another embodiment, formula I R10is an R10A, R10Bor R10Cwhere R10Arepresentsor, R10Brepresentsorand R10representswhere R10is optionally substituted, as represented in the description of formula I. In another embodiment, formula I R10is an R10Awhere R10Arepresents phenyl, which is unfused, where R10is optionally substituted, as represented in the description of formula I. In another embodiment, formula I R10is an R10Awhere R10Arepresents phenyl, which is unfused, where R10replaced by F and is optionally unsubstituted or additionally substituted by one or two C what Mascitelli, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; where each R11is an R12, R13, R14or R15; where R12represents phenyl, which is unfused or fused with benzene, heteroarenes, heterocyclization or heterocyclization; R13is heteroaryl, which is unfused;

R14is cycloalkyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, cycloalkane, heterocyclization or heterocyclization; each of which is unfused or fused with benzene; and R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17the stand is made by an alkyl, which is unsubstituted or substituted R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene or heterocyclization; R18represents phenyl or heteroseksualci, which is unfused; where fragments represented as R12, R13, R14, R17Aand R18independently are unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci; each of which is unfused or fused with benzene; and R23represents alkyl, which is unsubstituted or substituted R24, OR24, Other24N(R24)2NHS(O)2R24or OH; where each R24is an R 24Aor R24B; R24Arepresents phenyl, cycloalkyl, heteroseksualci or geteroseksualen, which is unfused or fused with heterocyclization; R24Brepresents alkyl, which is unsubstituted or substituted OR25, OH, F, Cl, Br or I; R25represents alkyl, which is unsubstituted or substituted NH2; where fragments represented as R20, R21, R22and R24Aindependently are unsubstituted or substituted by one or two substituents, independently selected from R26, OR26(O), F, Cl, Br or I; and R26represents alkyl. In another embodiment, formula I R10is an R10Awhere R10Arepresents phenyl, which is unfused, where R10replaced by F, and optionally substituted NHC(O)R11where R11is an R15where R16is optionally substituted, as represented in the description of formula I. In another embodiment, formula I R10is an R10Awhere R10Arepresents phenyl, which is unfused, where R10replaced by F, and optionally substituted R11where R11is an R12or R14where R14is heteroseksualci, the which is unsubstituted or substituted one, two, three or four substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I, where R19takes the values defined in the description of formula I. In another embodiment, formula I R10is an R10Awhere R10Arepresents phenyl, which is unfused, where R10replaced by F, and optionally substituted R11where R11represents phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanal, hexahydro-1H-isoindolyl, oxazolidinyl, azepane, piperidinyl, imidazolidinyl, diazolidinyl, triazinyl, azetidine, tetrahydropyrimidines or azabicyclo(2.2.1)hept-2-yl; each of which is independently unsubstituted or substituted with one, two, three or four substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I, where R19takes the values defined in the description of formula I. In another embodiment, formula I R10is a R 10Awhere R10Arepresents phenyl, which is unfused, where R10replaced by F, and optionally substituted R11where R11represents phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanal, hexahydro-1H-isoindolyl, oxazolidinyl, azepane, piperidinyl, imidazolidinyl, diazolidinyl, triazinyl, azetidine, tetrahydropyrimidines or azabicyclo(2.2.1)hept-2-yl; each of which is independently substituted by one or two (O). In another embodiment, formula I R10is an R10Awhere R10Arepresents phenyl, which is unfused, where R10replaced by F, and optionally substituted R11where R11is an R14where R14is heteroseksualci, which is unsubstituted or substituted by one or two (O). In another embodiment, formula I R10is an R10Awhere R10Arepresents phenyl, which is unfused, where R10replaced by F, and optionally substituted R11where R11is an R14, R14is pyrrolidinyl, which is substituted one, two, three or four substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(Rsup> 19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I, where R19takes the values defined in the description of formula I, where R14substituted by at least one (O). In another embodiment, formula I R10is an R10Awhere R10Arepresents phenyl, which is unfused, where R10replaced by F, and optionally substituted R11where R11is an R14where R14is pyrrolidinyl which is substituted by one or two (O).

Embodiments of multiple substituents

Below are additional variants of compounds of formula I. except where otherwise noted, the deputies take the values defined in the description of formula I.

In one embodiment of formula I, R1is cycloalkane, which is unfused; R2represents geteroseksualen, which is unfused, and A2is an R5.

Options for implementation, where A1represents a cyclohexane, A2represents R5

In one embodiment, formula I-A1is an R1where R1is the battle unsubstituted cyclohexane, which is unfused, and A2is an R5that takes the values defined in the description of formula I. In another embodiment, formula I-A1is an R1where R1represents unsubstituted cyclohexane, which is unfused, A2is an R5, R5represents a C1-alkyl, C2-alkyl or C3-alkyl, where R5substituted, as represented in the description of formula I. In another embodiment, formula I-A1is an R1where R1represents unsubstituted cyclohexane, which is unfused, and A2is an R5, R5represents a C1-alkyl, C2-alkyl or C3-alkyl, where R10is an R10Awhere R10Arepresents phenyl, which is unfused and replaced by F, and optionally substituted NHC(O)R11where R11is an R15. In another embodiment, formula I-A1is an R1where R1represents unsubstituted cyclohexane, which is unfused, A2is an R5, R5represents a C1-alkyl, C2-alkyl or C3-alkyl, where R10predstavljaet a R 10Awhere R10Arepresents phenyl, which is unfused, replaced by F, and optionally substituted NHC(O)R11where R11is an R15where R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene or heterocyclization; where each R18represents phenyl or heteroseksualci; where each of the fragments, represented as R17Aand R18independently is unsubstituted or substituted one, two, three or four substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19/sup> )2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci; each of which is unfused or fused with benzene; R23represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R24, OR24, Other24N(R24)2NHS(O)2R24or OH; where each R24is an R24Aor R24B; R24Arepresents unsubstituted phenyl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with heterocyclization; R24Brepresents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from OR25or OH; where each R25represents alkyl, unsubstituted or substituted NH2; where each R20is unsubstituted or substituted by one or two substituents, independently selected from R26, OR26, (O), F, Cl, Br or I; and R26represents alkyl. Even the bottom of the embodiment, formula I-A 1is an R1where R1represents unsubstituted cyclohexane, which is unfused, and A2is an R5, R5represents a C1-alkyl, C2-alkyl or C3-alkyl, where R10replaced by F, and optionally substituted R14where each R10independently is unsubstituted or substituted one, two or three substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2, Other11N(R11)2That is, C(O)R11C(O)OR11C(O)NH2C(O)other11C(O)N(R11)2, NHC(O)R11, NR11C(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NR11C(O)OR11, NHSO2NH2, NHSO2Other11, NHSO2N(R11)2, SO2NH2, SO2Other11, SO2N(R11)2, NHC(O)NH2, NHC(O)other11, NHC(O)N(R11)2, NR11C(O)N(R11)2, NO2, OH, (O), C(O)H, C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; where R14is pyrrolidinyl, azetidine, pyrrolyl, 1,3-oxazolidinyl, azepane, piperidinyl, imidazolidinyl, tetrahydropyrimidin(2H)-yl, azabicyclo(2.2.1)heptyl or 1,6-dihydropyridin; each of which is unfused or fused with benzene, heteroarenes, the cycle is alkanol, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; and where the fragment is represented as R14substituted by one or two substituents (O). In another embodiment, formula I-A1is an R1where R1represents unsubstituted cyclohexane, which is unfused, and A2is an R5, R5represents a C1-alkyl, C2-alkyl or C3-alkyl, where R5substituted R10and is optionally unsubstituted or optionally substituted one, two or three substituents, independently selected from other10N(R10)2, SR10, S(O)R10, SO2R10or CF3where R10takes the values defined in the description of formula I. In another embodiment, formula I-A1is an R1where R1represents unsubstituted cyclohexane, which is unfused, and A2is an R5, R5represents a C1-alkyl, C2-alkyl or C3-alkyl, where R5substituted R10and is optionally unsubstituted or optionally samewe is one CF 3where R10takes the values defined in the description of formula I. In another embodiment, formula I-A1is an R1where R1represents unsubstituted cyclohexane, which is unfused, and A2is an R5selected from the fragments of formulae (Ie), (If), (Ig), (Ih), (Ii) or (Ij):

In one embodiment of formula (Ii) R10is an R10A, R10Bor R10C; each of which is necessary to join the carbon atom; R10Arepresents phenyl, which is unfused or fused with heterocyclization, which is condensed with heterocyclization; R10Brepresentsor;

R10Cis heteroseksualci, which is unfused; where R10substituted C(O)R11C(O)other11C(O)N(R11)2or NHC(O)R11and is optionally unsubstituted or optionally substituted one, two or three substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11N 11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl, Br or I; where each R11is an R12, R13, R14or R15; R12represents phenyl, which is unfused or fused with benzene, heteroarenes, heterocyclization or heterocyclization; R13is heteroaryl, which is unfused; R14is cycloalkyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, cycloalkane, heterocyclization or heterocyclization; each of which is unfused or fused with benzene; R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted or substituted R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is of condension the m or fused with benzene or heterocyclization; R18represents phenyl or heteroseksualci, which is unfused; where fragments represented as R12, R13, R14, R17Aand R18independently are unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci, each of which is unfused or fused with benzene; R23represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R24, OR24, Other24N(R24)2NHS(O)2R24, OH, F, Cl, Br or I; where each R24is an R24Aor R24B; R24Arepresents phenyl, cycloalkyl, heteroseksualci or geteroseksualen; each of which is unfused or condense the Rowan with heterocyclization; R24Brepresents alkyl, which is unsubstituted or substituted OR25, OH, F, Cl, Br or I; R25represents alkyl, each of which is unsubstituted or substituted NH2; where fragments represented as R20, R21, R22and R24Aindependently are unsubstituted or substituted by one or two substituents, independently selected from R26, OR26, (O), F, Cl, Br or I; and R26represents alkyl. In another embodiment, formula I-A1is an R1where R1represents unsubstituted cyclohexane, which is unfused, and A2is an R5, R5represents a C1-alkyl, where R5is replaced by R10and R10takes the values defined in the description of formula I, as shown in formula (Ie)In another embodiment, formula I-A1is an R1where R1represents unsubstituted cyclohexane, which is unfused, A2is an R5, R5is a non-branched C2-alkyl, where R5substituted R10, R10takes the values defined in the description of formula I, as shown in the formula (If).

Options is sushestvennee formula (Ie)

In one embodiment of formula (Ie) R10is an R10A, R10Bor R10Cwhere R10Arepresents phenyl, which is unfused or fused with heterocyclization, which is a condensed geteroseksualen, R10Brepresents a

and R10Cis heteroseksualci, which is unfused; where R10substituted, as represented in the description of formula I. In another embodiment of formula of formula (Ie) R10is an R10A, R10Bor R10Cwhere R10Arepresents phenyl, which is unfused or fused with heterocyclization, which is a condensed geteroseksualen, R10Brepresents a

and R10Cis heteroseksualci, which is unfused; where R10substituted by one or two substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl and Br; where R11takes the values defined in the description of formula I. In another embodiment of formula (Ie) R10is an R10A, R10Bor R10Cwhere R10Arepresents phenyl, which is unfused or fused with heterocyclization, which is condensed with heterocyclization, R10Brepresents a

and R10Cis heteroseksualci, which is unfused; where R10replaced by F and is optionally unsubstituted or additionally substituted by one or two substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; R11takes the values defined in the description of formula I. In another embodiment of formula (Ie) R10is an R10A, R10Bor R10Cwhere R10Arepresents phenyl, which is unfused or fused with heterocyclization, which is a condensed geteroseksualen, R10Brepresents and R10Cis heteroseksualci, which is unfused; where R10replaced by F and is optionally unsubstituted or additionally substituted by one or two substituents, independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; R11is an R12, R13, R14or R15; R12represents phenyl, which is unfused or fused with benzene, heteroarenes, heterocyclization or heterocyclization; R13is heteroaryl, which is unfused; R14is cycloalkyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, cycloalkane, heterocyclization or heterocyclization; each of which is unfused or fused with benzene; R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16 C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted or substituted R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene or heterocyclization; R18represents phenyl or heteroseksualci, which is unfused; where fragments represented as R12, R13, R14, R17Aand R18independently are unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci; each of which is of condension the m or fused with benzene; R23represents alkyl which is unsubstituted or substituted R24, OR24, Other24N(R24)2NHS(O)2R24or OH; where each R24is an R24Aor R24B; R24Arepresents phenyl, cycloalkyl, heteroseksualci or geteroseksualen, which is unfused or fused with heterocyclization; R24Brepresents alkyl, which is unsubstituted or substituted OR25, OH, F, Cl, Br or I; R25represents alkyl, which is unsubstituted or substituted NH2; where fragments represented as R20, R21, R22and R24Aindependently are unsubstituted or substituted by one or two substituents, independently selected from R26, OR26(O), F, Cl, Br or I; and R26represents alkyl. In another embodiment of formula (Ie) R10is an R10A, R10Bor R10Cwhere R10Arepresents phenyl, which is unfused,R10Brepresentsand R10Crepresentswhere R10is optionally substituted, as represented in the description of formula I. In another embodiment of formula (Ie) R10depict is to place an R 10A, R10Bor R10cas presented in the description of formula (Ik), (Il), (Im), (In), (Io) or (Ip)

where R101, R102, R103, R104and R105independently selected from R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; R11takes the values defined in the description of formula I.

In another embodiment of formula (Ie) R10is an R10Aor R10Bas presented in the description of formula (Ik), (Il), (Im), (In), (Io) or (Ip). In another embodiment of formula (Ie) R10represents phenyl, as shown in the formula (Ik)

where R101, R102, R103, R104and R105independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; R11takes the values defined in the description of formula I. In yet another variant done by the means of the formula (Ik), at least one of R101, R102, R103, R104and R105represents F and at least one is an R11where R11represents phenyl, pyrrolyl, azabicyclo(3.1.0)hexanal, hexahydro-1H-isoindolyl, 1,3-oxazolidinyl, azepane, piperidinyl, imidazolidinyl, diazolidinyl, triazinyl, azetidine, 1,6-dihydropyridin, tetrahydropyrimidin(2H)-yl or azabicyclo(2.2.1)hept-2-yl; each of which is independently unsubstituted or substituted one, two or three substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci, each of which is unfused or fused with benzene; R23represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R24, OR24, Other24N(R24) 2NHS(O)2R19, OH, F, Cl, Br or I; where each R24is an R24Aor R24B; R24Arepresents phenyl, cycloalkyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with heterocyclization; R24Brepresents alkyl, which is unsubstituted or substituted OR25, OH, F, Cl, Br or I; R25represents alkyl, each of which is unsubstituted or substituted NH2; where fragments represented as R20, R21, R22and R24Aindependently are unsubstituted or substituted by one or two substituents, independently selected from R26, OR26, (O), F, Cl, Br or I; and R26represents alkyl. In another embodiment of formula (Ik) R101, R104and R105are H, and R102is an R11where R11selected from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolinone, piperidinyl and azepane, where R102substituted by one or two substituents (O). In another embodiment of formula (Ik) R101, R104and R105are H, and R102is an R11where R11is pyrrolidinyl.

Additional embodiments of formula (Ik)

In one of variationbetween formula (Ik) R 102represents NHC(O)R11as shown in the formula (Iq):

where R101, R103, R104and R105independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; R11takes the values defined in the description of formula I. In one embodiment of formula (Iq) R11is an R15where R16is optionally substituted, as represented in the description of the formula I, and R101, R103, R104and R105take the values defined in the description of formula (Iq). In another embodiment of formula (Iq) R103represents F, and R101, R104and R105independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; and R11is an R15where R16is optionally substituted, as presented in the Scripture of the formula I. In another embodiment of formula (Iq) is one of R101, R103, R104and R105represents F, R11is an R15where R16is optionally substituted, as represented in the description of formula I. In another embodiment of formula (Iq) R101, R104and R105are F. In another embodiment of formula (Iq) R103represents F. In another embodiment of formula (Iq) is one of R101, R103, R104and R105represents F, R11is an R15where R16represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene or heterocyclization; where each R18pre is is a phenyl or heteroseksualci; where each of the fragments, represented as R17Aand R18independently is unsubstituted or substituted one, two, three or four substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci; each of which is unfused or fused with benzene; R23represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R24, OR24, Other24N(R24)2NHS(O)2R24or OH; where each R24is an R24Aor R24B; R24Arepresents unsubstituted phenyl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with heterocyclization; R24Brepresents alkyl, which is nezamedin the m or substituted by one or two substituents, independently selected from OR25or OH; where each R25represents alkyl, which is unsubstituted or substituted NH2; where each R20is unsubstituted or substituted by one or two substituents, independently selected from R26, OR26, (O), F, Cl, Br or I; and R26represents alkyl. In another embodiment of formula (Iq) R103represents F, and R101, R104and R105each represents H, R11is an R15where R16is optionally substituted, as represented in the description of formula I. In another embodiment of formula (Iq) R11is an R12or R14where R14is heteroseksualci, which is unsubstituted or substituted one, two, three or four substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where R19takes the values defined in the description of formula I. In another embodiment of formula (Iq) R11selected from phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexane, hexahydro-1H-isoindolyl, oxazolidinyl, azepane, Pipa is Iginla, imidazolidinyl, thiazolidine, teinila, azetidine, tetrahydropyrimidine or azabicyclo(2.2.1)hept-2-yl; each of which is independently unsubstituted or substituted with one, two, three or four substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where R19takes the values defined in the description of formula I.

In one embodiment of formula (Ik) R102is an R11where R11is pyrrolidinyl, as shown in the formula (Ir):

where R101, R103, R104and R105independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; R11takes the values defined in the description of formula I, and R201, R202, R203and R204independently represent H, R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19 )2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where R19takes the values defined in the description of formula I. In one embodiment of formula (Ir) R103represents F, and R101, R104and R105represent H, where R201, R202, R203and R204independently represent H, R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where R19takes the values defined in the description of formula I. In another embodiment of formula (Ir) one or two of R201, R202, R203and R204is(are) a (O). In another embodiment of formula (Ir) two of R201, R202, R203and R204represent (O). In another embodiment of formula (Ir) R201and R204represent (O), and R202and R203represent H, as shown in the formula (Ir1):

In one embodiment of formula (Ir1R103represents F, and R101, R104and R105independently selected from H, R11, OR11, SR11, S(O)R11, SOsub> 2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; R11takes the values defined in the description of formula I.

In one embodiment of formula (Ik) R103represents F, as shown in the formula (Is):

where R101, R102, R104and R105independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; R11takes the values defined in the description of formula I. In another embodiment of formula (Is) R101, R102, R104and R105independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; where each R11is an R12, R13 , R14or R15; where R12represents phenyl, which is unfused or fused with benzene, heteroarenes, heterocyclization or heterocyclization; R13is heteroaryl, which is unfused; R14is cycloalkyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, cycloalkane, heterocyclization or heterocyclization; each of which is unfused or fused with benzene; and R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted or substituted R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene or heterocyclization; R18represents phenyl or heteroseksualci, which is decondensation is m; where fragments represented as R12, R13, R14, R17Aand R18independently are unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci; each of which is unfused or fused with benzene; and R23represents alkyl, which is unsubstituted or substituted R24, OR24, Other24N(R24)2NHS(O)2R24or OH; where each R24is an R24Aor R24B; R24Arepresents phenyl, cycloalkyl, heteroseksualci or geteroseksualen, which is unfused or fused with heterocyclization; R24Brepresents alkyl, which is unsubstituted or substituted OR25, OH, F, Cl, Br or I; R25represents alkyl, to the which is unsubstituted or substituted NH 2; where fragments represented as R20, R21, R22and R24Aindependently are unsubstituted or substituted by one or two substituents, independently selected from R26, OR26(O), F, Cl, Br or I; and R26represents alkyl. In another embodiment of formula (Is) R11selected from phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexane, hexahydro-1H-isoindolyl, oxazolidinyl, azepane, piperidinyl, imidazolidinyl, thiazolidine, teinila, azetidine, tetrahydropyrimidine or azabicyclo(2.2.1)hept-2-yl; each of which is independently unsubstituted or substituted with one, two, three or four substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where R19takes the values defined in the description of formula I. In another embodiment of formula (Is) R102is an R11where R11selected from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolinone, piperidinyl, piperazinil and azepane, where R102substituted by one or two substituents (O). In another embodiment of formula (Is) R102represents the FDS is th R 11where R11selected from pyrrolidinyl substituted by one or two substituents (O). In another embodiment of formula (Is) R101, R104and R105are H, and R102selected from R11, OR11, NHC(O)R11or C(O)other11; where R11takes the values defined in the description of formula I. In another embodiment of formula (Is) R101, R104and R105are H, and R102selected from R11, OR11, NHC(O)R11or C(O)other11; where R11represents phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanal, hexahydro-1H-isoindolyl, oxazolidinyl, azepane, piperidinyl, imidazolidinyl, diazolidinyl, triazinyl, azetidine, tetrahydropyrimidines or azabicyclo(2.2.1)hept-2-yl; each of which is independently unsubstituted or substituted with one, two, three or four substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I, where R19takes the values defined in the description of formula I. In another embodiment of formula (Is) R101, R104and R105are H, and R102selected from R11, OR11, NHC(O)R 11or C(O)other11; where R11represents phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanal, hexahydro-1H-isoindolyl, oxazolidinyl, azepane, piperidinyl, imidazolidinyl, diazolidinyl, triazinyl, azetidine, tetrahydropyrimidines or azabicyclo(2.2.1)hept-2-yl; each of which is independently unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I, where R19takes the values defined in the description of formula I. In another embodiment of formula (Is) R101, R104and R105are H, and R102selected from R11, OR11, NHC(O)R11or C(O)other11; where R11is an R15and R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted what does substituted R 18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene or heterocyclization; R18represents phenyl or heteroseksualci, which is unfused; where fragments represented as R12, R13, R14, R17Aand R18independently are unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci, each of which is unfused or fused with benzene; and R23represents alkyl which is unsubstituted or substituted R24, OR24, Other24N(R24)2NHS(O)2R24or OH; where each R24is an R24Aor R24B; R4A represents phenyl, cycloalkyl, heteroseksualci or geteroseksualen, which is unfused or fused with heterocyclization; R24Brepresents alkyl, which is unsubstituted or substituted OR25, OH, F, Cl, Br or I; R25represents alkyl, which is unsubstituted or substituted NH2; where fragments represented as R20, R21, R22and R24Aindependently are unsubstituted or substituted by one or two substituents, independently selected from R26, OR26(O), F, Cl, Br or I; and R26represents alkyl.

In one embodiment of the invention the compound of formula (Is) selected from the following list:

2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoic acid;

4-(3-amino-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)amino)-4-oxobutanoic acid;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyrrolidin-2,5-dione;

4-(3-(1,4-diazepan-1-ylcarbonyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(aminomethyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-((dimethylamino)methyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(cyclohexylamino)methyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-((tetrahydro-2H-Piran-4-ylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-((methyl((1-methylpyrrolidine-3-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-((methyl-(((2R)-1-methylpyrrolidine-2-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-pyrimidine-2-ylbenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-pyridine-3-ylbenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-pyridine-4-ylbenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N,N-diethyl-2'-fluoro-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-2-carboxamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-piperidine-1-ylpropionic;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-(4-methylpiperazin-1-yl)propanamide;

2-amino-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide;

3-cyclohexyl-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)piperidine-3-carboxamide;

4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)azetidin-3-carboxamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-morpholine-4-ylacetamide;

N-(2'-fluoro-5'-((4-oxo-3,4,5,6,7,8-hexahydrophthalic the Jn-1-yl)methyl)-1,1'-biphenyl-3-yl)ndimethylacetamide;

4-((6-fluoro-3'-(methylsulphonyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((6-fluoro-3'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-((6-fluoro-4'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N,N-diethyl-2'-fluoro-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-3-carboxamide;

2'-fluoro-N,N-dimethyl-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-4-carboxamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-(4-methoxyphenyl)-4-oxobutanamide;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3,4-dimethyl-1H-pyrrole-2,5-dione;

3-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-azabicyclo(3.1.0)hexane-2,4-dione;

2-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)hexahydro-1H-isoindole-1,3(2H)-dione;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3,3-dimethylpiperidin-2,5-dione;

4-(4-fluoro-3-(2-methyl-5-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxazepan-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)piperidine-2,6-dione;

4-(4-fluoro-3-(2-Oxymetazoline-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(11-dioxothiazolidine-2-yl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(3-methyl-2-Oxymetazoline-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxotetrahydrothalifendine-1(2H)-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(3-(3-tert-butyl-2-Oxymetazoline-1-yl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-((1S,4R)-3-oxo-2-azabicyclo(2.2.1)hept-2-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-N-methylmethanesulfonamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-hydroxy-2-methylpropanamide;

(3aS,4R,7S,7aR)-5-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2,2-dimethylether-4,7-methane(1,3)dioxolo(4,5-c)pyridine-6(3aH)-he;

4-(3-(1,1-dioxido-1,2-diazinon-2-yl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-(2-oxopyrrolidin-1-yl)ndimethylacetamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-5-oxohexanoate;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-methoxypropane;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-N'-FeNi is pentanedione;

4-(4-fluoro-3-((4-(pyrimidine-2-reparation-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he; or

4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he.

In yet another embodiment of the invention the compound of formula (Is) selected from the following list:

4-((2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)amino)-4-oxobutanoic acid;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyrrolidin-2,5-dione;

4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-(4-methylpiperazin-1-yl)propanamide;

3-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-azabicyclo(3.1.0)hexane-2,4-dione;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3,3-dimethylpiperidin-2,5-dione;

4-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(3-methyl-2-Oxymetazoline-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxazepan-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)piperidine-2,6-dione;

4-(3-(1,1-dioxothiazolidine-2-yl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he;

4-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he; or

4-(4-fluoro-3-((4-(pyrimidine-2-ipaper the Zin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he.

In one embodiment of formula (Ik) R102represents C(O)R11as shown in the formula (It):

where R11takes the values defined in the description of formula I. In one embodiment, formula (It) R101, R103, R104and R105are H. In another embodiment of formula (It) R103represents F, and R101, R104and R105are H. In another embodiment of formula (It) R11is an R15and R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted or substituted R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene or heterocyclization; R18represents phenyl or heteroseksualci, which is unfused; where fragments, not only is installed as R 12, R13, R14, R17Aand R18independently are unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci; each of which is unfused or fused with benzene; and R23represents alkyl, which is unsubstituted or substituted R24, OR24, Other24N(R24)2NHS(O)2R24or OH; where each R24is an R24Aor R24B; R24Arepresents phenyl, cycloalkyl, heteroseksualci or geteroseksualen, which is unfused or fused with heterocyclization; R24Brepresents alkyl, which is unsubstituted or substituted OR25, OH, F, Cl, Br or I; R25represents alkyl, which is unsubstituted or replacement is EN NH 2; where fragments represented as R20, R21, R22and R24Aindependently are unsubstituted or substituted by one or two substituents, independently selected from R26, OR26(O), F, Cl, Br or I; and R26represents alkyl. In another embodiment, formula (It) R11represents phenyl, pyrrolidinyl, azabicyclo(3.1.0)hexanal, hexahydro-1H-isoindolyl, oxazolidinyl, azepane, piperidinyl, imidazolidinyl, diazolidinyl, triazinyl, azetidine, tetrahydropyrimidines or azabicyclo(2.2.1)hept-2-yl; each of which is independently unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I, where R19takes the values defined in the description of formula I.

In one embodiment of formula (Ik) R102represents C(O)other11as shown in the formula (Iu):

where R11takes the values defined in the description of formula I. In one embodiment of formula (Iu) R101, R103, R104and R105are H. In another embodiment fo the formula (Iu) R 103represents F, and R101, R104and R105are H. In another embodiment of formula (Iu) R11is an R15and R15represents alkyl, which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)other16, NHC(O)R16, NHC(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, which is unsubstituted or substituted R18; R17Arepresents phenyl, heteroaryl, cycloalkyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene or heterocyclization; R18represents phenyl or heteroseksualci, which is unfused; where fragments represented as R12, R13, R14, R17Aand R18independently are unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused; R21is heteroaryl, which is unfused; R22is cycloalkyl or heteroseksualci, each of which is unfused or fused with benzene; and R23represents alkyl, which is unsubstituted or substituted R24, OR24, Other24N(R24)2NHS(O)2R24or OH; where each R24is an R24Aor R24B; R24Arepresents phenyl, cycloalkyl, heteroseksualci or geteroseksualen, which is unfused or fused with heterocyclization; R24Brepresents alkyl, which is unsubstituted or substituted OR25, OH, F, Cl, Br or I; R25represents alkyl, which is unsubstituted or substituted NH2; where fragments represented as R20, R21, R22and R24Aindependently are unsubstituted or substituted by one or two substituents, independently selected from R26, OR26(O), F, Cl, Br or I; and R26represents alkyl. In another embodiment of formula (Iu) R11represents phenyl, pyrrolidinyl, sabillo(3.1.0)hexanal, hexahydro-1H-isoindolyl, oxazolidinyl, azepane, piperidinyl, imidazolidinyl, diazolidinyl, triazinyl, azetidine, tetrahydropyrimidines or azabicyclo(2.2.1)hept-2-yl; each of which is independently unsubstituted or substituted by one or two substituents, independently selected from R19, OR19, SR19, SO2R19C(O)R19, CO(O)R19, Other19N(R19)2, NHC(O)R19NHS(O)2R19C(O)NH2C(O)other19C(O)N(R19)2C(O)H, OH, (O), CN, CF3, F, Cl, Br or I, where R19takes the values defined in the description of formula I.

In one embodiment of formula (Ik) R102represents phenyl, which is unsubstituted or substituted by one or two, three or four substituents, independently selected from R19, OR19, SR19, S(O)R19, SO2R19C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, Other19N(R19)2, NHC(O)R19, NR19C(O)R19NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)other19, NHC(O)N(R19)2, NR19C(O)other19, NR19C(O)N(R19)2C(O)NH2C(O)other19C(O)N(R19)2C(O)NHOH, C(O)NHOR19C(O)NHSO2R19C(O)NR19SO2R19, SO2NH2, SO2Other19, SO2 N(R19)2C(O)H, C(O)OH, C(N)NH2C(N)other19C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I; where R19takes the values defined in the description of formula I.

In one embodiment of formula (Ik) R102is heteroseksualci, which is unsubstituted or substituted one, two, three or four substituents, independently selected from R19, OR19, SR19, S(O)R19, SO2R19C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, Other19N(R19)2, NHC(O)R19, NR19C(O)R19NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)other19, NHC(O)N(R19)2, NR19C(O)other19, NR19C(O)N(R19)2C(O)NH2C(O)other19C(O)N(R19)2C(O)NHOH, C(O)NHOR19C(O)NHSO2R19C(O)NR19SO2R19, SO2NH2, SO2Other19, SO2N(R19)2C(O)H, C(O)OH, C(N)NH2C(N)other19C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I; where R19takes the values defined in the description of formula I.

Options for implementation, in which A1before the hat is piperidine, A2represents R5

In one embodiment, formula (I) A1is an R2where R2represents an unsubstituted piperidine, which is unfused, and A2is an R5that takes the values defined in the description of formula I. In another embodiment, formula I-A1is an R2where R2represents an unsubstituted piperidine, which is unfused, and A2is an R5, R5represents a C1-alkyl, C2-alkyl or C3-alkyl, where R5substituted R10and is optionally unsubstituted or optionally substituted one, two or three substituents, independently selected from other10N(R10)2, SR10, S(O)R10, SO2R10or CF3where R10takes the values defined in the description of formula I. In another embodiment, formula I-A1is an R2where R2represents an unsubstituted piperidine, which is unfused, and A2is an R5, R5represents a C1-alkyl, C2-alkyl or C3-alkyl, where R5is replaced by R10and is optionally unsubstituted or is optional substituted with one CF 3where R10takes the values defined in the description of formula I. In another embodiment, formula I-A1is an R2where R2represents an unsubstituted piperidine, which is unfused, A2represents a C1-alkyl and R10represents phenyl, as shown in the formula (Iv):

where R101, R102, R103, R104and R105independently selected from H, R11, OR11, SR11, S(O)R11, SO2R11, NH2N(R11)2C(O)R11C(O)OR11C(O)other11C(O)N(R11)2, NHC(O)R11, NHSO2R11, NR11SO2R11, NHC(O)OR11, NHSO2N(R11)2, NO2, OH, (O), C(O)OH, F, Cl or Br; where each R11is an R12, R13, R14or R15; R12represents phenyl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; R13is heteroaryl, which is unfused or fused with benzene, heteropar the nom, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; R14is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; R15represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R16, OR16, SR16, S(O)2R16C(O)OH, NH2, Other16N(R16)2C(O)R16C(O)NH2C(O)other16C(O)N(R16)2, NHC(O)R16, NR16C(O)R16, NHC(O)OR16, NR16C(O)OR16, OH, F, Cl, Br or I; where each R16is an R17or R17A; R17represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R18C(O)OH, H 2, Other18or N(R18)2C(O)R18C(O)NH2C(O)other18C(O)N(R18)2, NHC(O)R18, NR18C(O)R18, F, Cl, Br or I; R17Arepresents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; where each R18represents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; where each of the fragments, represented as R12, R13, R14, R17Aand R18independently is unsubstituted or substituted one, two, three or four substituents, independently selected from R19, OR19, SR19, S(O)R19, SO2R19C(O)R19, CO(O)R19, OC(O)R19, OC(O)OR19, NH2, Other19N(R19)2, NHC(O)R19, NR19C(O)R19NHS(O)2R19, NR19S(O)2R19, NHC(O)OR19, NR19C(O)OR19, NHC(O)NH2, NHC(O)other19, NHC(O)N(R19)2, NR19C(O)other19, NR19C(O)N(R19)2C(O)NH2C(O)other19C(O)N(R19)2C(O)NHOH, C(O)NHOR19C(O)NHSO2R19C(O)NR19SO2R19, SO2NH2, SO2Other19, SO2N(R1 )2C(O)H, C(O)OH, C(N)NH2C(N)other19C(N)N(R19)2, CNOH, CNOCH3, OH, (O), CN, N3, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br or I; where each R19is an R20, R21, R22or R23; R20represents phenyl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; R21is heteroaryl, which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; R22is cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; each of which is unfused or fused with benzole is, heteroatom, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; R23represents alkyl, alkenyl or quinil; each of which is unsubstituted or substituted by one or two substituents, independently selected from R24, OR24, SR24, S(O)2R24C(O)OH, NH2, Other24N(R24)2C(O)R24C(O)NH2C(O)other24C(O)N(R24)2, NHC(O)R24, NR24C(O)R24, NHC(O)OR24, NR24C(O)OR24NHS(O)2R24, NR24S(O)2R24, OH, F, Cl, Br or I; where each R24is an R24Aor R24B; R24Arepresents phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen, each of which is unfused or fused with benzene, heteroarenes, cycloalkanes, cycloalkenes, heterocyclization or heterocyclization; R24Brepresents alkyl, alkenyl or quinil, each of which is unsubstituted or substituted by one or two substituents, independently selected from R25, OR25, SR25, S(O)2R25C(O)OH, NH2, Other25N(R25)2C(O)R25C(O)NH2C(O)other25C(O)N(R25)2, NHC(O)R25, NR25C(O)R25, NHC(O)OR25, NR25C(O)OR25, OH, F, Cl, Br or I; where each R25before the hat is alkyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heteroseksualci or geteroseksualen; each of which is unsubstituted or substituted NH2, NH(CH3), N(CH3)2, OH or OCH3; where each of the fragments, represented as R20, R21, R22and R24Aindependently is unsubstituted or substituted by one or two substituents, independently selected from R26, OR26alkenyl, quinil, phenyl, OH, (O), C(O)OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; and R26represents alkyl. In yet another embodiment, the compound of formula (Iv) selected from the following compounds:

8-(4-terbisil)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

8-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

8-(3-chloro-4-terbisil)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

8-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

methyl 2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)benzoate;

8-(3-amino-4-terbisil)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)benzoic acid;

N-ethyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)benzamide;

N-cyclobutyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8 and the)methyl)benzamide;

2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)-N-(2-pyrrolidin-1-retil)benzamide;

8-(4-fluoro-3-((4-(morpholine-4-ylcarbonyl)piperazine-1-yl)carbonyl)benzyl)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-N'-phenylenediamine;

1-(2-fluoro-5-((5-oxo-l,2,3,4,5,6-hexahydropyridine(2,3-d)pyridazin-8-yl)methyl)phenyl)pyrrolidin-2,5-dione;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-3-methoxypropane;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-5-oxohexanoate;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-3-phenoxypropane;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-4-oxo-4-phenylbutane;

2-(4-(benzyloxy)phenoxy)-N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)ndimethylacetamide;

N-(2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)phenyl)-2-(4-methoxyphenoxy)ndimethylacetamide;

N-cyclopropyl-2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)benzamide;

8-(3-((4-(2-ethoxyethyl)piperazine-1-yl)carbonyl)-4-terbisil)-2,3,4,6-tetrahydropyrido(2,3-d)pyridazin-5(1H)-he; or

2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo(2,3-d)pyridazin-8-yl)methyl)-N-(2-piperidine-1-retil)benzamide.

Schema

<> Source materials used in this invention are commercially available or can be obtained by conventional methods well known to experts in the field of technology. Compounds according to the present invention can be obtained using the methods presented at the General synthesis schemes and experimental techniques, described in detail below. The General scheme of the synthesis provided for illustration and are not intended to limit the scope of the invention.

Scheme 1

As shown in figure 1, bicyclic anhydride (1can recover from alcohol(2)when using a reducing agent, such as (but without limitation) of sodium borohydride. The reaction is usually conducted in a solvent such as (but not limited to tetrahydrofuran, at a temperature in the range from a temperature below room temperature to the boiling temperature of the solvent. The transformation of(2)in phosphonium salt of(3)can be done by interacting first with trialkylphosphines, such as (but not limited to, tri-n-butylphosphine, in the presence of Hydrobromic acid. The reaction is usually conducted in a solvent such as (but not limited to, acetic acid, boiling under reflux. Reaction(3)with nitrobenzaldehyde b> (4)where R11Ais a Deputy in R10as described in the invention, in the presence of a base, such as (but without limitation) triethylamine, to produce a lactone of the formula(5). The reaction is usually conducted in a solvent such as (but not limited to, dichloromethane, at room temperature. The restoration of the nitro group of compounds of formula(5)using a reducing agent, such as (but without limitation) of iron powder and NH4Cl will lead to the corresponding aniline of the formula(6). The reaction is usually conducted in a solvent such as (but without limitation) ethanol, boiling under reflux. Vzaimodeistvie aniline of the formula(6)with hydrazine to produce tetrahydropalmatine formula(7). The reaction is usually conducted in a solvent such as (but without limitation) ethanol, at elevated temperature. The reaction of the compound of the formula(7)or anhydride of the formula(8)or acid of the formula(11)in standard conditions binding peptide known to specialists in the art and are described in detail in the literature, will lead to the formation of compounds of the formula(9)and(12)respectively. Acid(9)may additionally turn into amide of the formula(10)using standard binding conditions p is putida, including the use of 1,1'-carbonyldiimidazole (CDI) as a binding agent.

Scheme 2

Alternatively, as shown in scheme 2, phosphonium salt of(3)subject to interaction with cyanobenzaldehyde formula(13)to obtain the lactone of the formula(14). The reaction is usually carried out in basic conditions in a solvent such as (but not limited to, dichloromethane, at room temperature. Hydrolysis of the nitrile of the formula(14)to the corresponding acid followed by the addition of hydrazine to produce tetrahydropalmatine formula(15). Stage hydrolysis is usually carried out with an aqueous base, such as (but not limited to, sodium hydroxide, at elevated temperatures. The second stage is carried out in aqueous medium at elevated temperatures. Linking acid formula(15)with an amine of the formula(16)where each R11takes on the values defined in the description of the formula, or represents H or a heterocyclic amine, R14typical binding peptides known to the specialist in the art and are described in detail in the literature, to produce the amide of the formula(17). Alternatively, the compound of the formula(14)subject to transformation in tetrahedrite athinon using hydrazine, as described above, followed by reduction to the primary amine of the formula(18)in terms of recovery in the presence of Raney Nickel. Treatment of compounds of the formula(18)aldehyde R16CHO or a ketone R16C(O)R16in a standard reaction conditions, reductive amination and then optional second aldehyde R16CHO or a ketone R16C(O)R16will result in secondary or tertiary amines of the formula(19)(where each R16can represent N as defined in the description of formula (I)).

Scheme 3

By the way, is similar to scheme 1, phosphonium salt of(3)subject to interaction with a benzaldehyde of the formula(20)where R11Brepresents alkyl, such as (but without limitation) ethyl, and R11Atakes the values defined above in the description of figure 1. The interaction of the compounds of formula(21)with hydrazine, as described in scheme 1, followed by hydrolysis using aqueous acid, such as (but without limitation) sulfuric acid, to produce the compounds of formula(22). The reaction is usually conducted at elevated temperatures in a solvent such as (but without limitation) ethanol. The interaction of the compounds of formula(22)with an amine of the formula(23)the conditions of the reaction, reductive amination, well-known specialists in the art and are described in detail in the literature, will lead to the production of tetrahydropalmatine formula(19).

Scheme 4

As shown in figure 4, phosphonium salt of(3)subject to interaction with bromobenzaldehyde formula(24)obtaining the compounds of formula(25)under the conditions specified in the description of figure 1. The interaction of the compounds of formula(25)with hydrazine, as defined in the description of scheme 1, will lead to the production of tetrahydropalmatine formula(26)that can communicate with stannane formula (27) or borate of the formula(28)obtaining the compounds of formula(29)where R11represents a substituted or unsubstituted phenyl or heteroaryl. Bonding conditions include conditions, well known to specialists in the art and are described in detail in the literature as bonding conditions according to the method of Suzuki and Steele.

Scheme 5

Benzylbromide formula(30)where R11takes on the values described above, can undergo transformation into a Grignard reagent and then added to complex fluids(31)to obtain the keto-ester of the formula(32)as shown in scheme 5. The addition of the Grignard reagent is usually p is Voditsa during cooling and subsequent heating of the reaction mixture to room temperature. The reaction is usually conducted in a solvent such as (but not limited to, tetrahydrofuran, simple ether and the like or mixtures thereof. The Grignard reagent is commercially available or can be obtained from the Mg in the standard conditions described in the literature. Adding hydrazine to the compound of the formula(32)under the conditions specified in the description of figure 1, at room temperature will result in phthalazinone formula(33). The bromide may be subjected to conversion into an ester of the formula(34)under the reaction conditions of carboxylation in the presence of palladium catalyst. For the conversion of the addition of carbon monoxide and methanol usually requires the use of palladium catalyst and a base, such as (but without limitation) triethylamine. Conventional palladium catalysts include [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane and the like, the Reaction is usually conducted at elevated temperatures, and to communicate it may be necessary to use a solvent, such as (but without limitation) N,N-dimethylformamide. Ester of the formula(34)subject to transformation in the primary amide of the formula(35)when using ammonia with subsequent rearrangement of Hoffmann with bromine and aqueous potassium hydroxide to obtain aniline of the formula(36). For the first stage usually requires raising the temperature, and in the second stage to add a reagent necessary low temperature and subsequent heating. The pyridine cycle may be subjected to recovery with the use of a catalyst under such conditions, catalytic reduction, as (but without limitation) gaseous hydrogen and platinum-on-carbon, to obtain compounds of the formula(37). The amide formation using the acid chloride of formula R11C(O)Cl or acid of the formula R11C(O)OH under standard conditions of peptide binding, well-known specialist in the art and are described in detail in the literature, will lead to the formation of compounds of the formula(38). Alternatively, the ester of the formula(34)subject to restoration to the compounds of formula(39)in the conditions described above, followed by hydrolysis and receiving acid formula(40). Conventional hydrolysis conditions include (but without limitation) the use of aqueous base, such as lithium hydroxide, and elevated temperature. The amide formation using primary or secondary amine of the formula NH2R11or NH(R11)2under standard conditions of peptide binding, well-known specialist in the art and are described in detail in the literature, to produce the amide of the formula(41).

Applicants invention believe that Pref is given further examples provide the most practical and understandable description of the methodologies and conceptual aspects of the present invention. The names of typical compounds according to the present invention correspond to the ACD/ChemSketch Version 5.06 (5 June 2001, Advanced Chemistry Development Inc., Toronto, Ontario) except for the compounds of examples 160, 320, 487, matching ChemDraw®Ver. 9.0.5 (CambridgeSoft, Cambrige, MA). Intermediate compounds are named according to standard IUPAC nomenclature.

EXAMPLE 1

2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoic acid

EXAMPLE 1A

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

To a solution of anhydride 1-cyclohexen-1,2-dicarboxylic acid (25,2 g) in tetrahydrofuran (125 ml) at 0°C. add sodium borohydride (1.51 g). The mixture is heated to room temperature and incubated at room temperature for 30 minutes, refluxed for 5 hours, cooled, treated with 1N hydrochloric acid and concentrated. The concentrate is distributed between ethyl acetate and saturated salt solution, the organic layer was washed with a saturated solution of salt and water and concentrate. The concentrate is purified flash chromatography (50% ethyl acetate in hexane).

EXAMPLE 1B

Bromide of tributyl(3-oxo-1,3,4,5,6,7-hexahydro-2-benzofuran-1-yl)phosphonium

A solution of the compound obtained in example 1A (3 g)in acetic acid (10 ml) at room temperature is treated with tri-n-butylphosphine (4,81 ml) and 33% Hydrobromic acid in kusnoy acid (3,34 ml), refluxed for 21 hours, cooled and concentrated. The concentrate is purified flash chromatography on silica gel (10% methanol in dichloromethane).

EXAMPLE 1C

2-fluoro-5-((3-oxo-4,5,6,7-tetrahydrothiopyran-1(3H)-ilidene)methyl)benzonitrile

To a solution of the compound obtained in example 1B (3,05 g), in dichloromethane (30 ml) is added 2-fluoro-5-formylbenzoate (1.08 g) and triethylamine (1,02 ml). The mixture is stirred at room temperature for 16 hours and concentrated. The concentrate is distributed between ethyl acetate and a saturated solution of salt. The organic layer was washed with saturated salt solution and concentrated. The concentrate is purified flash chromatography on silica gel (50% ethyl acetate in hexane).

EXAMPLE 1D

2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoic acid

To a suspension of the compound obtained in example 1C (1,46 g)in water (15 ml) is added 50% sodium hydroxide. The mixture is heated to 90°C and maintained at this temperature for 1 hour. After cooling the mixture to 70°C added hydrazine monohydrate (0.54 ml) and the solution stirred at 70°C for 7 hours. The solution is cooled to room temperature and the pH adjusted to 4 with 6N hydrochloric acid. The precipitate is filtered off, washed with water and dried.1H NMR (DMSO-d6): δ 1,55 was 1.69 (m, 4H), 2,31-to 2.42 (m, 4H), 3,93 (s, 2H), 7,24 (DD, J=10,8, 8.5 Hz, 1H), 7,0-of 7.48 (m, 1H), 7,68 (DD, J=6,9, 2.2 Hz, 1H), was 12.61 (s, 1H), 13,22 (ush. s, 1H).

EXAMPLE 2

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

EXAMPLE 2A

3-(4-fluoro-3-nitrobenzylidene)-4,5,6,7-tetrahydroxybenzophenone-

1(3H)-he

The connection specified in the title of this example is obtained in accordance with the procedure of example 1C, using 4-fluoro-3-nitrobenzaldehyde instead of 2-fluoro-5-formylbenzoate.

EXAMPLE 2B

3-(3-amino-4-formanilide)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

A solution of the compound obtained in example 2A (2.25 g), and ammonium chloride (0,83 g) in ethanol (35 ml) and water (25 ml) at 70°C is treated with powdered iron (4.35 g), stirred for 3 hours and filtered through diatomaceous earth (CELITE®, World Minerals, Santa Barbara, CA) with hot ethanol. The filtrate is concentrated and the resulting concentrate is stirred with water for 30 minutes and filtered. The solid residue washed with water and dried.

EXAMPLE 2C

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

To a solution of the compound obtained in example 2B (1.42 g)in ethanol (10 ml) is added hydrazine monohydrate (0,27 ml). The mixture is refluxed under stirring for 1 hour, cooled to 0°C and filtered. The solid product washed with water and dried.1H NMR (CD3OD): δ 1,63 is 1.75 (m, 4H), 2,36 at 2.45 (m, 2H), 2,46 of $ 2.53 (m, 2H), 3,84 (s, 2H), 6.42 per-of 6.49 (m, 1H), only 6.64 (DD, J=8,6, 2.2 Hz, 1H), 6,86 (DD, J=11,2, 8,1 Hz, 1H).

EXAMPLE 3

4-((2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)amino)-4-oxobutanoic acid

To a solution of the compound obtained in example 2 (872 mg)in acetonitrile added succinic anhydride (370 mg). The mixture is refluxed for 17 hours, cooled and concentrated. The resulting concentrate is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid).1H NMR (DMSO-d6): δ 1,53-of 1.66 (m, 4H), 2,30 is 2.43 (m, 4H), 2,55-to 2.67 (m, 2H), 3,26-of 3.31 (m, 2H), 3,85 (s, 2H), 6,85-6,99 (m, 1H), 7,15 (DD, J=10,8, 8.5 Hz, 1H), 7,74 (d, J=6,4 Hz, 1H), 9,70 (ush. s, 1H), 12,09 (ush. s, 1H), was 12.61 (s, 1H).

EXAMPLE 4

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyrrolidin-2,5-dione

To a mixture of the compound obtained in example 3 (905 mg), dichloromethane (30 ml) and N,N-dimethylformamide (6 ml) is added 1,1'-carbonyldiimidazole (785 mg). The mixture is stirred at room temperature for 3 hours and concentrated. The resulting concentrate is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid).1H NMR (DMSO-d6): δ 1,57 was 1.69 (m, 4H), 2,32-to 2.42 (m, 4H), 2,78-2,89 (m, 4H), 3,93 (s, 2H), 7,09-7,13 (m, 1H), 7,32-7,33 (m, 1H), 7,34 (d, J=1.2 Hz, 1H), br12.62 (s, 1H).

EXAMPLE 5

4-(3-(1,4-diazepan-1-ylcarbonyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 5A

tert-butyl 4-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)shall entail)-1,4-diazepan-1-carboxylate

To the compound obtained in example 1 (294 mg)in a mixture of N,N-dimethylformamide/pyridine (1:1) (6 ml) is added 1,1'-carbonyldiimidazole (166 mg). The mixture is stirred at room temperature for 30 minutes and added tert-butyl 1-homopiperazines (189 μl). The mixture is stirred for 18 hours and concentrated. The concentrate is purified flash chromatography on silica gel (5% methanol in ethyl acetate).

EXAMPLE 5B

4-(3-(1,4-diazepan-1-ylcarbonyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in example 5A (330 mg)in dichloromethane (8 ml) at 0°C. add triperoxonane acid (8 ml). The solution is heated to room temperature and add acetonitrile. The mixture is concentrated. The resulting concentrate is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid). The product is dissolved in methanol/dichloromethane, treated with 1M hydrochloric acid in diethyl ether and filtered to obtain specified in the title compound in the form of cleaners containing hydrochloride salt.1H NMR (CD3OD): δ of 1.70 to 1.76 (m, 4H), 2,02-2,11 (m, 2H), 2,52 (d, J=27.5 Hz, 4H), 3,32-to 3.36 (m, 2H), 3,40-of 3.46 (m, 2H), 3,51 (t, J=6,1 Hz, 2H), 3.95 to 4,01 (m, 2H), 4,06 (s, 2H), 7,19 (t, J=9.0 Hz, 1H), 7,29-7,34 (m, 1H)that was 7.36-7,41 (m, 1H).

EXAMPLE 6

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

EXAMPLE 6A

The compound of this example get in soo is according to the method of example 2C, using the compound obtained in example 1C, instead of the compound obtained in example 2B.

EXAMPLE 6B

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

To a solution of compound of example 6A (1.5 g) in 20% solution of ammonia in methanol (150 ml) is added Raney Nickel (15 g). The mixture is shaken in an atmosphere of hydrogen (60 psi) at ambient temperature for 2 hours, filtered and concentrated. The resulting concentrate is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid) to produce specified in the title compound in the form triperoxonane salt.1H NMR (CD3OD): δ 1,55-1,65 (m, 4H), 2,33-to 2.41 (m, 4H), 3,90 (s, 2H), Android 4.04 (s, 2H), 7,21-7,25 (m, 1H), 7,27-7,29 (m, 1H), 7,31 (d, J=7,0 Hz, 1H), 8,20-8,27 (ush, s, 2H).

EXAMPLE 7

4-(3-((dimethylamino)methyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of compound of example 6 (75 mg) in methanol (8 ml) was added 37% (wt.) a solution of formaldehyde in water (39 ml) and triethylamine (36 μl). The solution was stirred at ambient temperature for 1 hour. To the solution add cyanoborohydride sodium (49 mg) and zinc chloride (35 mg), the reaction mixture is stirred for 60 hours and concentrated. The obtained concentrate was dissolved in a mixture triperoxonane acid/methanol and purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/in the and from 0.1% triperoxonane acid). The product is dissolved in methanol/dichloromethane and treated with 1M hydrochloric acid in diethyl ether, obtaining mentioned in the title compound in the form of cleaners containing hydrochloride salt.1H NMR (CD3OD): δ 1,68 and 1.80 (m, 4H), 2,50-2,60 (m, 4H), 2,88 (s, 6H), 4,10 (s, 2H), 4,39 (s, 2H), 7,22-7,27 (m, 1H), 7,40-7,44 (m, 1H), 7,46 (DD, J=6,9, 2.0 Hz, 1H).

EXAMPLE 8

4-(4-fluoro-3-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 7, using acetone instead of formaldehyde.1H NMR (CD3OD): δ of 1.39 (d, J=6,7 Hz, 6H), 1,68-to 1.77 (m, 4H), 2,43 at 2.59 (m, 4H), 3,41-to 3.50 (m, 1H), of 4.05 (s, 2H), 4,24 (s, 2H), 7.18 in-7,24 (m, 1H), 7,35-7,38 (m, 1H), 7,38-7,42 (m, 1H).

EXAMPLE 9

4-(3-((cyclohexylamino)methyl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title, get in the form of cleaners containing hydrochloride salt according to the method of example 7, using cyclohexanone in place of formaldehyde.1H NMR (CD3OD): δ 1.32 to a 1.46 (m, 4H), 1,68-of 1.81 (m, 6H), 1,84-of 1.94 (m, 2H), 2,13-2,22 (m, 2H), 2,43-2,61 (m, 4H), is 3.08-3,18 (m, 1H), 4,07 (s, 2H), 4.26 deaths (s, 2H), 7.18 in-of 7.23 (m, 1H), 7,35-7,39 (m, 1H), 7,40-the 7.43 (m, 1H).

EXAMPLE 10

4-(4-fluoro-3-((tetrahydro-2H-Piran-4-ylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title, get in the form of cleaners containing hydrochloride salt according to the method of example 7, using tetrahydro-4H-Piran-on instead of formaldehyde. 1H NMR (CD3OD): δ of 1.66 to 1.76 (m, 6H), 2,04 with 2.14 (m, 2H), 2.40 a-to 2.57 (m, 4H), 3,40-3,51 (m, 3H), a 4.03 (s, 2H), 4,05 (d, J=4,6 Hz, 2H), 4,29 (s, 2H), 7.18 in-7,25 (m, 1H), was 7.36-7,39 (m, 1H), 7,40 (d, J=1.8 Hz, 1H).

EXAMPLE 11

4-(4-fluoro-3-((methyl((1-methylpyrrolidine-3-yl)methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in example 6 (75 mg)in methanol (8 ml) is added tert-butyl ether 3-formylpyridine-1-carboxylic acid (104 mg) and triethylamine (36 μl). The mixture was stirred at ambient temperature for 1 hour. To the mixture add cyanoborohydride sodium (49 mg) and zinc chloride (35 mg). The mixture is stirred for 60 hours, add triperoxonane acid, again stirred for one hour and concentrated. The obtained concentrate was dissolved in a mixture of water/acetonitrile and purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid). The residue is treated as described above, 37% (wt.) a solution of formaldehyde in water (39 ml), then 1M hydrochloric acid in diethyl ether, obtaining mentioned in the title compound in the form of the HCl salt.1H NMR (CD3OD): δ 1,69-of 1.74 (m, 6H), 1,80-of 1.88 (m, 3H), 2,10-of 2.20 (m, 2H), 2,44-of 2.58 (m, 6H), 3,10 (DD, J=11,4, 7.5 Hz, 2H), 3,22-3,26 (m, 1H), 3,34-to 3.38 (m, 2H), 3,52 of 3.56 (m, 1H), a 4.03 (s, 2H), or 4.31 (s, 2H), 7.18 in-of 7.23 (m, 1H), 7,35-7,39 (m, 1H), 7,49 (DD, J=6,9, 2.0 Hz, 1H).

EXAMPLE 12

4-(4-fluoro-3-((methyl(((2R)-1-methylpyrrolidine-2-yl)methyl)amino)methyl)benzyl)-5,6,7,-tetrahydropyrazin-1(2H)-he

The connection specified in the title, get in the form of cleaners containing hydrochloride salt according to the method of example 11, using N-(tert-butoxycarbonyl)-D-prolinal instead of tert-butyl methyl ether 3-formylpyridine-1-carboxylic acid.1H NMR (CD3OD): δ 1,74 of-1.83 (m, 4H), 1,95-2,07 (m, 1H), 2,10-of 2.28 (m, 2H), 2,52-2,70 (m, 5H), 2.91 in (s, 3H), 3.04 from (s, 3H), 3,21-3,29 (m, 1H), 3,63 at 3.69 (m, 1H), of 3.73-3,81 (m, 1H), 3,90-4,00 (m, 1H), 4,05 is 4.13 (m, 1H), 4,20 (s, 2H), 4,50-to 4.62 (m, 2H), 7,27 (t, J=9.1 Hz, 1H), 7,44-7,49 (m, 1H), to 7.64 (d, J=5,2 Hz, 1H).

EXAMPLE 13

4-(3-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 13A

3-(3-(diethoxylate)benzylidene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

The connection specified in the title of this example is obtained in accordance with the procedure of example 1C, using 3-(diethoxylate)benzaldehyde instead of 2-fluoro-5-formylbenzoate.

EXAMPLE 13B

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

The connection specified in the title of this example is obtained in accordance with the procedure of example 2C, using the compound obtained in example 13A, instead of the compound obtained in example 2B.

EXAMPLE 13C

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzaldehyde

To a solution of the compound obtained in example 13B (681 mg)in a mixture of ethanol/water (1:1, 20 ml) is added concentrated sulfuric acid (0.4 ml). The mixture is refluxed for 16 hours the century The mixture is cooled and concentrated, the resulting concentrate is triturated with a saturated solution of sodium bicarbonate. The solid product is filtered off, washed with water and dried.

EXAMPLE 13D

4-(3-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

A solution of the compound obtained in example 13C (80 mg), and cyclopropylamine (51 mg) in methanol (8 ml) was stirred at room temperature for 1 hour. To the mixture add cyanoborohydride sodium (57 mg) and the resulting solution stirred for 18 hours and concentrated. The obtained concentrate was dissolved in methanol/triperoxonane acid and purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid). The product is dissolved in methanol/dichloromethane, treated with 1M hydrochloric acid in diethyl ether and concentrated to obtain specified in the title compound in the form of cleaners containing hydrochloride salt.1H NMR (CD3OD): δ of 0.82 to 0.92 (m, 4H), of 1.65-1.77 in (m, 4H), 2,41-2,60 (m, 4H), 2,69-and 2.79 (m, 1H), 4,11 (s, 2H), 4,28 (s, 2H), 7,31 (d, J=6,7 Hz, 1H), 7,34-7,40 (m, 2H), 7,41 was 7.45 (m, 1H).

EXAMPLE 14

4-(3-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13, using Isopropylamine instead of cyclopropylamine.1H NMR (CD OD): δ to 1.38 (d, J=6,7 Hz, 6H), 1,68-to 1.79 (m, 4H), 2,41-to 2.65 (m, 4H), 3,38-of 3.48 (m, 1H), 4,12 (s, 2H), 4,17 (s, 2H), 7,31 (d, J=7,1 Hz, 1H), 7,35-7,38 (m, 1H), 7,38-7,41 (m, 1H), 7,41-7,46 (m, 1H).

EXAMPLE 15

4-(3-(morpholine-4-ylmethyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13, using morpholine instead of cyclopropylamine.1H NMR (CD3OD): δ 1,67-of 1.78 (m, 4H), 2,39-to 2.57 (m, 4H), 3,13-3,24 (m, 2H), 3,32-3,39 (m, 2H), 3,71-of 3.80 (m, 2H), a 4.03 (DD, J=13.3-inch, 3.2 Hz, 2H), 4,08 (s, 2H), 4,34 (s, 2H), 7,37 (d, J=6,7 Hz, 1H), 7,39-7,42 (m, 1H), 7,41-7,44 (m, 1H), 7,44-of 7.48 (m, 1H).

EXAMPLE 16

4-(3-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13, using pyrrolidine instead of cyclopropylamine.1H NMR (CD3OD): δ 1,67-to 1.79 (m, 4H), 1,95-2,07 (m, 2H), 2,11-of 2.24 (m, 2H), 2,44-to 2.65 (m, 4H), 3,09-3,26 (m, 2H), 3,41-of 3.54 (m, 2H), 4,15 (s, 2H), 4,35 (s, 2H), 7,32-7,37 (m, 1H), 7,39-7,47 (m, 3H).

EXAMPLE 17

4-(3-((cyclohexylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13, using cyclohexylamine instead of cyclopropylamine,1H NMR (CD3OD): δ 1,20-of 1.27 (m, 1H), 1,31-of 1.45 (m, 4H), 1,66-of 1.78 (m, 5H), 1.85 to of 1.93 (m, 2H), 2,12-of 2.20 (m, 2H), 2,45-2,60 (m, 4H), is 3.08 (DD, J=14,6, 7,6 Hz, 1H), 4,11 (s, 2H), 4,19 (s, H), to 7.32 (d, J=7,0 Hz, 1H), 7,34-7,38 (m, 1H), 7,38-7,42 (m, 1H), 7,41 was 7.45 (m, 1H).

EXAMPLE 18

4-(3-((methylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13, using a 2M solution of methylamine in methanol instead of cyclopropylamine.1H NMR (CD3OD): δ 1,69-of 1.78 (m, 4H), 2,45 at 2.59 (m, 4H), 2,70 (s, 3H), of 4.13 (s, 2H), 4.16 the (s, 2H), 7,30-7,33 (m, 1H), 7,33-7,37 (m, 1H), 7,37-7,40 (m, 1H), 7,43 (t, J=7,4 Hz, 1H).

EXAMPLE 19

4-(3-((ethylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13, using a 2M solution of ethylamine in methanol instead of cyclopropylamine.1H NMR (CD3OD): δ of 1.33 (t, J=7.2 Hz, 3H), 1,66 and 1.80 (m, 4H), 2,42-2,62 (m, 4H), 3,10 (sq, J=7,4 Hz, 2H), 4,13 (s, 2H), 4.16 the (s, 2H), 7,31 (d, J=7,1 Hz, 1H), 7,34-7,37 (m, 1H), 7,38-7,40 (m, 1H), 7,41 was 7.45 (m, 1H).

EXAMPLE 20

4-(3-((4-methylpiperidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13 using 4-methylpiperidin instead of cyclopropylamine.1H NMR (CD3OD): δ 0,99 (d, J=6.4 Hz, 3H), 1,39-and 1.54 (m, 2H), 1,67 to 1.76 (m, 5H), 1,83-of 1.95 (m, 2H), 2,44 2.63 in (m, 4H), 2,92 totaling 3.04 (m, 2H), 3,35-of 3.46 (m, 2H), 4,15 (s, 2H), 4.26 deaths (s, 2H), 7,34-7,37 (m, 1H), 7,40-7,44 (m, 2H,), 7,44-7,47 (m, 1H).

EXAMPLE 21

4-(3-(((2-(4-(t is iformity)phenyl)ethyl)amino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13, using 3-(trifluoromethyl)phenethylamine instead of cyclopropylamine.1H NMR (CD3OD): δ 1,64-1,72 (m, 4H), 2.40 a-to 2.57 (m, 4H), 3,06-3,14 (m, 2H), 3.27 to be 3.29 (m, 2H), 4,07 (s, 2H), 4,22 (s, 2H), 7,33 (d, J=7,3 Hz, 1H), 7,35-7,38 (m, 1H), 7,38-7,42 (m, 1H), 7,44 (t, J=7.5 Hz, 1H), 7,55 (d, J=0.9 Hz, 1H), 7,55-7,58 (m, 1H), to 7.59 (d, J=5,2 Hz, 1H), 7,60 to 7.62 (m, 1H).

EXAMPLE 22

4-(3-((cyclohexyl(methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13 using N-methylcyclohexylamine instead of cyclopropylamine.1H NMR (CD3OD): δ 1,23-of 1.40 (m, 3H), 1,53-of 1.65 (m, 2H), 1,67-to 1.79 (m, 5H), 1,90-2,00 (m, 2H), 2,02-to 2.18 (m, 2H), 2.40 a-2,49 (m, 2H), 2,49-of 2.58 (m, 2H), 2,71 (s, 3H), 3,16 of 3.28 (m, 1H), 4,07 (s, 2H), 4,17 (d, J=12.9 Hz, 1H), of 4.45 (d, J=13,2 Hz, 1H), 7,34 and 7.36 (m, 1H), 7,37-7,39 (m, 1H), 7,41 (s, 1H), 7,43-7,49 (m, 1H).

EXAMPLE 23

4-(3-((2-ethylpyrrolidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13 using 2-ethylpyrrolidin instead of cyclopropylamine.1H NMR (CD3OD): δ were 0.94 (t, J=7.5 Hz, 3H), 1,52-to 1.63 (m, 1H), 1,69-to 1.77 (m, 4H), 1,78-to 1.87 (m, 2H), 1.91 a-2,04 (m, 1H), 2,05-2,17 (m, 1H), 2,31 is 2.44 (m, 1H), 2,45-of 2.64 (m, 4H), 3,19 of 3.28 (m, 1H), 3,34-3,47 (m, 2H), 4,15 (, 2H), 4,21 (d, J=12.9 Hz, 1H), 4,50 (d, J=13,2 Hz, 1H), and 7.3-7,38 (m, 1H), 7,40-7,44 (m, 2H), 7,44-of 7.48 (m, 1H).

EXAMPLE 24

4-(4-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 24A

3-(4-(diethoxylate)benzylidene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

The connection specified in the title of this example is obtained in accordance with the procedure of example 1C, using 4- (diethoxylate)benzaldehyde instead of 2-fluoro-5-formylbenzoate.

EXAMPLE 24B

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

The connection specified in the title of this example is obtained in accordance with the procedure of example 2C, using the compound obtained in example 24A, instead of the compound obtained in example 2B.

EXAMPLE 24C

4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzaldehyde

The connection specified in the title of this example is obtained in accordance with the procedure of example 13C, using the compound obtained in example 24B, instead of the compound obtained in example 13B.

EXAMPLE 24D

4-(4-((cyclopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C.1H NMR (CD3OD): δ 0,82-0,88 (m, 2H), 0,89-0,94 (m, 2H), 1,62-to 1.77 (m, 4H), 2,35 is 2.44 (m, 2H), 2,45 is 2.55 (m, 2H), 2,70-2,82 (m, 1H), was 4.02 (s, 2H) 4,27 (s, 2H), 7,30 (d, J=8,3 Hz, 2H), 7,43 (d, J=8.0 Hz, 2H).

EXAMPLE 25

4-(4-((isopropylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and 2-Propylamine instead of cyclopropylamine.1H NMR (CD3OD): δ to 1.38 (d, J=6.4 Hz, 6H), 1,65-1,72 (m, 4H), 2,37 at 2.45 (m, 2H), 2,46-2,52 (m, 2H), 3,39-to 3.50 (m, 1H), 4,01 (s, 2H), 4,17 (s, 2H), 7,31 (d, J=8,3 Hz, 2H), 7,44 (d, J=8.0 Hz, 2H).

EXAMPLE 26

4-(4-(morpholine-4-ylmethyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and morpholine instead of cyclopropylamine.1H NMR (CD3OD): δ of 1.65 to 1.76 (m, 4H), 2,43-2,48 (m, 2H), 2,49-of 2.58 (m, 2H), 3,13-3,24 (m, 2H), 3.33 and-3,37 (m, 2H), 3,36-to 3.41 (m, 1H), 3,70-of 3.80 (m, 2H), 3,99-a 4.03 (m, 1H), 4,06 (s, 2H), 4,34 (s, 2H), 7,35 (d, J=8.0 Hz, 2H,), 7,49 (d, J=8.0 Hz, 2H).

EXAMPLE 27

4-(4-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and pyrrole is in instead of cyclopropylamine. 1H NMR (CD3OD): δ of 1.63 to 1.76 (m, 4H), 1,94-to 2.06 (m, 2H), 2,10-of 2.24 (m, 2H), 2,37 is 2.46 (m, 2H), 2,46 is 2.55 (m, 2H), 3,11-of 3.23 (m, 2H), 3,38-to 3.58 (m, 2H), was 4.02 (s, 2H), 4,34 (s, 2H), 7,33 (d, J=7.7 Hz, 2H), 7,46 (d, J=8,0 Hz, 2H).

EXAMPLE 28

4-(4-((cyclohexylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and cyclohexylamine instead of cyclopropylamine.1H NMR (CD3OD): δ 1,21-of 1.29 (m, 1H), 1,33 was 1.43 (m, 4H), 1,64 is 1.75 (m, 5H), 1,86-of 1.93 (m, 2H), 2,13-of 2.21 (m, 2H), 2,37 is 2.44 (m, 2H), 2.49 USD (t, J=4.9 Hz, 2H), 3,05-and 3.16 (m, 1H), 4,01 (s, 2H), 4,18 (s, 2H), 7,30 (d, J=8,0 Hz, 2H), 7,43 (d, J=8.0 Hz, 2H).

EXAMPLE 29

4-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and 4-phenylpiperidine instead of cyclopropylamine.1H NMR (CD3OD): δ 1,64 to 1.76 (m, 4H), 1.93 and-2,03 (m, 2H), 2.05 is-of 2.15 (m, 2H), 2.40 a-2,49 (m, 2H), 2,48 is 2.55 (m, 2H), 2,81-to 2.94 (m, 1H), 3,10-of 3.23 (m, 2H), 3,54-to 3.64 (m, 2H), Android 4.04 (s, 2H), 4,33 (s, 2H), 7,19-7,22 (m, 1H), 7.24 to (d, J=7,1 Hz, 2H), 7,28-7,33 (m, 2H), was 7.36 (d, J=8.0 Hz, 2H), 7,51 (d, J=7.7 Hz, 2H).

EXAMPLE 30

4-(4-((methylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified saglasie this example, receive in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and a 2M solution of methylamine in methanol instead of cyclopropylamine.1H NMR (CD3OD): δ 1,64-of 1.73 (m, 4H), 2,38 is 2.44 (m, 2H), 2,47-of 2.54 (m, 2H), 2,71 (s, 3H), was 4.02 (s, 2H), 4,15 (s, 2H), 7,31 (d, J=8,3 Hz, 2H), 7,43 (d, J=8.0 Hz, 2H).

EXAMPLE 31

4-(4-((ethylamino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and a 2M solution of ethylamine in methanol instead of cyclopropylamine.1H NMR (CD3OD): δ of 1.32 (t, J=7.4 Hz, 3H), 1,64-1,72 (m, 4H), 2,37 is 2.44 (m, 2H), 2,45-2,52 (m, 2H), 3,10 (kV, J=7,4 Hz, 2H), 4,01 (s, 2H), 4,15 (s, 2H), 7,30 (d, J=8,3 Hz, 2H), 7,43 (d, J=8.0 Hz, 2H).

EXAMPLE 32

4-(4-((4-methylpiperidin-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and 4 methylpiperidin instead of cyclopropylamine.1H NMR (CD3OD): δ 0,99 (d, J=6.4 Hz, 3H), of 1.33 to 1.48 (m, 2H), of 1.66 and 1.75 (m, 5H), 1.85 to 1,95 (m, 2H), 2.40 a-2,48 (m, 2H), 2,48-to 2.57 (m, 2H), 2,90 was 3.05 (m, 2H), 3,44 (d, J=12.3 Hz, 2H), Android 4.04 (s, 2H),4,25 (s, 2H), 7,33 (d, J=8.0 Hz, 2H), 7,46 (d, J=8.0 Hz, 2H).

EXAMPLE 33

4-(4-(((2-(3-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzyl-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and 3-(trifluoromethyl)phenethylamine instead of cyclopropylamine.1H NMR (CD3OD): δ 1,62-1,72 (m, 4H), 2,38 is 2.44 (m, 2H), 2,46-2,52 (m, 2H), 3,06-3,14 (m, 2H), 3.27 to the 3.35 (m, 2H), was 4.02 (s, 2H), 4,22 (s, 2H), 7,31 (d, J=8,3 Hz, 2H), 7,45 (d, J=8,3 Hz, 2H), 7,53-EUR 7.57 (m, 2H), EUR 7.57-7,62 (m, 2H).

EXAMPLE 34

4-(4-((cyclohexyl(methyl)amino)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and N-methylcyclohexylamine instead of cyclopropylamine.1H NMR (CD3OD): δ of 1.20 to 1.31 (m, 1H), 1.32 to the 1.44 (m, 2H), 1,54-to 1.63 (m, 2H), 1,65 is 1.75 (m, 5H), 1,91 is 2.01 (m, 2H), 2.05 is-to 2.18 (m, 2H), 2,39 is 2.46 (m, 2H), 2,47 of $ 2.53 (m, 2H), 2,71 (s, 3H), 3,23-3,29 (m, 1H), a 4.03 (s, 2H), 4,13 (d, J=13,2 Hz, 1H), 4,47 (d, J=13,2 Hz, 1H), 7,34 (d, J=8,3 Hz, 2H), 7,43-7,46 (m, 2H).

EXAMPLE 35

4-(4-((2-methylpyrrolidine-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt in accordance with the tvii to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and 2-methylpyrrolidine instead of cyclopropylamine.1H NMR (CD3OD): δ of 1.39 (d, J=6,7 Hz, 3H), 1,66-of 1.78 (m, 5H), 1.93 and-2,02 (m, 1H), 2,03 and 2.13 (m, 1H), 2,29-of 2.38 (m, 1H), 2,39 at 2.45 (m, 2H), 2,47 of $ 2.53 (m, 2H), 3,15-of 3.27 (m, 1H), 3,34 is 3.40 (m, 1H), 3,51-3,62 (m, 1H), was 4.02 (, 2H), 4.09 to to 4.17 (m, 1H), 4,43-4,55 (m, 1H), 7,33 (d, J=8.0 Hz, 2H), 7,46 (d, J=8,3 Hz, 2H).

EXAMPLE 36

4-(4-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using the compound obtained in example 24C, instead of the compound obtained in example 13C, and 1-methylhomopiperazine instead of cyclopropylamine.1H NMR (CD3OD): δ 1,68-to 1.79 (m, 4H), 2,29-to 2.42 (m, 2H), 2,46 of $ 2.53 (m, 2H), 2,53-2,62 (m, 2H), 2,97 (s, 3H), 3,35-3,44 (m, 1H), 3,47-the 3.65 (m, 2H), 3,67-of 3.96 (m, 5H), 4,11 (s, 2H), 4,46 (s, 2H), 7,35 (d, J=8.0 Hz, 2H), to 7.59 (d, J=8.0 Hz, 2H).

EXAMPLE 37

4-(3-((4-methyl-1,4-diazepan-1-yl)methyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 13D, using 1-methylhomopiperazine instead of cyclopropylamine.1H NMR (CD3OD): δ 1,68-of 1.81 (m, 4H), 2,29-to 2.41 (m, 2H), 2,44 of $ 2.53 (m, 2H), 2,55-of 2.64 (m, 2H), 2,98 (s, 3H), 3.33 and is 3.40 (m, 1H), 3,40 of 3.56 (m, 2H), to 3.58-and 3.72 (m, 1H), of 3.73-of 3.97 (m, 4H), to 4.15 (s, 2H), 4,46 (s, 2H), 7,37 (d, J=7.7 Hz, 1H), 7,46 (t, J=7.8 Hz, 1H), 7,51 (d, J=6,1 Hz, 2H).

38

4-(4-fluoro-3-pyrimidine-2-ylbenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 38A

3-(3-bromo-4-formanilide)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

The connection specified in the title of this example is obtained in accordance with the procedure of example 1C, using 3-bromo-4-forbindelse instead of 2-fluoro-5-formylbenzoate.

EXAMPLE 38B

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

The connection specified in the title of this example is obtained in accordance with the method of example 2D, using the compound obtained in example 38A, instead of the compound obtained in example 2B.

EXAMPLE 38C

4-(4-fluoro-3-pyrimidine-2-ylbenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To the compound obtained in example 38B (75 mg)in N,N-dimethylformamide (8 ml) is added 2-tributyltinchloride (81 mg), Tris(dibenzylideneacetone)dipalladium(0) (20 mg), tri-o-tolylphosphino (20 mg) and triethylamine (92 μl). The mixture was stirred at 70°C for 17 hours. After cooling, the mixture is filtered and the filtrate concentrated. The resulting concentrate is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid). The product is dissolved in methanol/dichloromethane, treated with 1M hydrochloric acid in diethyl ether and concentrated to obtain specified in the title compound in the form of cleaners containing hydrochloride salt.1H the Mr (CD 3OD): δ 1,69-of 1.78 (m, 4H), 2,48-2,60 (m, 4H), 4,11 (s, 2H), 7,27 (DD, J=10,8, 8.5 Hz, 1H), 7,43-to 7.50 (m, 1H), to 7.61 (t, J=5,1 Hz, 1H), 7,87 (DD, J=7,1, 2.4 Hz, 1H), 9,01 (d, J=5,1 Hz, 2H).

EXAMPLE 39

4-(4-fluoro-3-pyridine-3-ylbenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To the compound obtained in example 38B (75 mg), 3-pyridineboronic acid (54 mg) and dichlorobis(triphenylphosphine)palladium(II) (28 mg) in a mixture of 1,2-dimethoxyethane/water/ethanol (7:3:2, 3 ml) is added 2M sodium carbonate solution (0,22 ml). The mixture is stirred in a microwave reactor CEM Explorer® (Matthews, NC) for 10 minutes at 150°C. After cooling, the mixture is filtered and the filtrate concentrated. The resulting concentrate is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid). The product is dissolved in methanol/dichloromethane, treated with 1M hydrochloric acid in diethyl ether and concentrated to obtain specified in the title compound in the form of cleaners containing hydrochloride salt.1H NMR (CD3OD): δ 1,70-1,80 (m, 4H), 2,50-2,62 (m, 4H), 4,17 (s, 2H), 7,33 (DD, J=10,7, 8.5 Hz, 1H), 7,40-of 7.48 (m, 1H), 7,60 (DD, J=7,3, 1.8 Hz, 1H), they were 8.22 (DD, J=8,2, 5.8 Hz, 1H), 8,87 (d, J=8,2 Hz, 1H), 8,90 (d, J=5,5 Hz, 1H), 9,12 (s, 1H).

EXAMPLE 40

4-(4-fluoro-3-pyridine-4-ylbenzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 39, using 4-pyridineboronic acid instead of 3-pyridin ronojoy acid. 1H NMR (CD3OD): δ 1,68-of 1.84 (m, 4H), 2,46-of 2.64 (m, 4H), to 4.15 (s, 2H), 7,35 (DD, J=11,0, 8.5 Hz, 1H), of 7.48-7,53 (m, 1H), 7,69 (DD, J=7,2, 2.0 Hz, 1H), 8,32 (d, J=5.8 Hz, 2H), 8,91 (d, J=6,7 Hz, 2H).

EXAMPLE 41

N,N-diethyl-2'-fluoro-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-2-carboxamide

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 39, using (2-(N,N-diethylaminomethyl)phenyl)baronova acid instead of 3-pyridineboronic acid.1H NMR (CD3OD): δ 0,83 (t, J=7.2 Hz, 3H), of 0.93 (t, J=7.2 Hz, 3H), 1,72 of-1.83 (m, 4H), of 2.51-of 2.66 (m, 4H), 2,73-a 3.01 (m, 2H), 3,02-of 3.25 (m, 2H), 4,11 (s, 2H), 7,13-7,17 (m, 1H), 7,17-7,19 (m, 1H), 7,26-7,31 (m, 1H), 7,38-7,41 (m, 2H), 7,47-to 7.50 (m, 1H), 7,51-rate of 7.54 (m, 1H).

EXAMPLE 42

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-piperidine-1-ylpropionic

To 3-(1-piperidinyl)propionic acid (28 mg) in dichloromethane (3 ml) add oxalicacid (24 μl) and a drop of N,N-dimethylformamide. The mixture is stirred at room temperature for 1 hour and concentrated. The obtained concentrate was dissolved in dichloromethane (3 ml) and added to a solution of the compound obtained in example 2C (50 mg)in tetrahydrofuran (3 ml). Add the triethylamine (31 μl). The mixture is stirred at room temperature for 16 hours and concentrated. The resulting concentrate is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water is from 0.1% triperoxonane acid). The product is dissolved in methanol/dichloromethane, treated with 1M hydrochloric acid in diethyl ether and concentrated, obtaining mentioned in the title compound in the form of cleaners containing hydrochloride salt.1H NMR (CD3OD): δ 1,50-to 1.59 (m, 1H), 1,68 is 1.75 (m, 4H), 1,76-to 1.87 (m, 3H), 1,92 is 2.01 (m, 2H), 2,41-to 2.57 (m, 4H), 2,94 are 2.98 (m, 2H), 2,98-3,03 (m, 2H), 3.45 points (t, J=6.9 Hz, 2H), 3,57 (d, J=12,2 Hz, 2H), 3,99 (s, 2H), 6,99-7,05 (m, 1H), 7,11 (DD, J=10,4, 8.5 Hz, 1H), 7,81 (DD, J=7,3, 1.8 Hz, 1H).

EXAMPLE 43

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-(4-methylpiperazin-1-yl)propanamide

The connection specified in the title of this example are in the form of cleaners containing hydrochloride salt according to the method of example 42, using 3-(4-methylpiperazin-1-yl)propionic acid instead of 3-(1-piperidinyl)propionic acid.1H NMR (CD3OD): δ 1,65-to 1.79 (m, 4H), 2,38-of 2.58 (m, 4H), 3,03 (s, 3H), of 3.07 (t, J=6,7 Hz, 2H), 3,60-the 3.65 (m, 2H), 3,65-3,68 (m, 3H), 3,70-to 3.89 (m, 4H), 3,97-4,06 (m, 1H), 4.00 points (s, 2H), 6,99? 7.04 baby mortality (m, 1H), 7,12 (DD, J=10,7 that 8.5 Hz, 1H), 7,83 (DD, J=7,3, 1.8 Hz, 1H).

EXAMPLE 44

2-amino-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide

A solution of the compound obtained in example 2 (50 mg)and Boc-L-glycine-N-hydroxysuccinimide ester (54 mg) in tetrahydrofuran (4 ml) was stirred at ambient temperature for 16 hours and concentrated. To the resulting solid residue in dichloromethane (2 ml) is added triperoxonane acid (1 ml), a mixture of AC who're asked at ambient temperature for 1 hour and concentrated. The resulting concentrate is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid), getting mentioned in the title compound in the form triptoreline salt.1H NMR (CD3OD): δ 1,65-of 1.74 (m, 4H), 2,38 is 2.55 (m, 4H), to 3.89 (s, 2H), 3.96 points (s, 2H), 7,00-7,06 (m, 1H), 7,09-7,16 (m, 1H), 7,87 (DD, J=7,4, and 2.1 Hz, 1H).

EXAMPLE 45

3-cyclohexyl-N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide

The connection specified in the title of this example is obtained in accordance with the method of example 42, using cyclohexylpropionic acid instead of 3-(1-piperidinyl)propionic acid.1H NMR (CD3OD): δ 0,90-1,00 (m, 2H), 1,16-of 1.33 (m, 4H), 1,53-to 1.61 (m, 2H), 1,63 by 1.68 (m, 1H), 1.70 to around 1.74 (m, 5H), 1,74-to 1.82 (m, 3H), 2,39 is 2.46 (m, 4H), 2,48 is 2.51 (m, 2H), 3,94 (s, 2H), of 6.96-7,01 (m, 1H), 7,07 (DD, J=10,7, 8.5 Hz, 1H), 7,69 (DD, J=7,2, 1.7 Hz, 1H).

EXAMPLE 46

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)piperidine-3-carboxamide

The connection specified in the title of this example, are in the form triptoreline salt according to the method of example 42, using 1-(tert-butoxycarbonyl)-3-piperidinylcarbonyl acid instead of 3-(1-piperidinyl)propionic acid.1H NMR (CD3OD): δ of 1.66 to 1.76 (m, 4H), 1,79-to 1.87 (m, 1H), 1,89-2,03 (m, 2H), 2,12 (DD, J=9,3, a 4.9 Hz, 1H), 2,38-of 2.56 (m, 4H), 2,96 totaling 3.04 (m, 1H), is 3.08-3.15 in (m, 1H), 3,17-of 3.25 (m, 2H), 3.33 and-to 3.35 (m, 1H), 3,95 (s, 2H), 6,99-7,06 (m, 1H), 7,07-to 7.15 (m, 1H), 7,71 (DD, J=7,5, 2.0 Hz, 1H).

EXAMPLE 47

p> 4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in example 2 (200 mg), in dichloromethane (5 ml) is added 4-chlorbutanol (103 mg) and triethylamine (0,12 ml). The solution was stirred at ambient temperature for 16 hours and concentrated. The obtained concentrate was dissolved in ethanol (2 ml) and add 21% (wt.) to a solution of ethoxide sodium in ethanol (0,47 ml). The mixture was stirred at ambient temperature for 16 hours, treated with 2M hydrochloric acid (1 ml) and concentrated. The resulting concentrate is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid).1H NMR (CD3OD): δ of 1.66-1.77 in (m, 4H), 2,15-of 2.27 (m, 2H), 2.40 a is 2.51 (m, 4H), of 2.51-of 2.58 (m, 2H), 3,78-3,86 (m, 2H), of 3.97 (s, 2H), 7,11-to 7.15 (m, 1H), 7,16-7,19 (m, 1H), 7,22-7,27 (m, 1H).

EXAMPLE 48

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)azetidin-3-carboxamide

The connection specified in the title of this example, are in the form triptoreline salt according to the method of example 42, using 1-(tert-butoxycarbonyl)-3-azetidinone acid instead of 3-(1-piperidinyl)propionic acid.1H NMR (CD3OD): δ 1,64-of 1.78 (m, 4H), 2.40 a-2,49 (m, 2H), 2,47 is 2.55 (m, 2H), 3,81-3,93 (m, 1H), 3.96 points (s, 2H), 4,20-to 4.33 (m, 4H), 6,99-7,06 (m, 1H), 7,07 - to 7.15 (m, 1H), 7,87 (DD, J=7,3, 2.2 Hz, 1H).

EXAMPLE 49

N-(2-(isopropylamino)is Teal)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

EXAMPLE 49A

Methyl 3-((3-oxo-4,5,6,7-tetrahydrothiopyran-1(3H)-ilidene)methyl)benzoate

The connection specified in the title of this example is obtained in accordance with the procedure of example 1C, using methyl-3-formylbenzoate instead of 2-fluoro-5-formylbenzoate.

EXAMPLE 49B

3-((3-oxo-4,5,6,7-tetrahydrothiopyran-1(3H)-ilidene)methyl)benzoic acid

The compound obtained in example 49A (6,09 g)in a mixture of tetrahydrofuran/water (1:1, 60 ml) at ambient temperature is treated with the hydrochloride monohydrate of lithium (1.8 g) and stirred for 16 hours. The mixture is acidified with 2N hydrochloric acid and distributed between ethyl acetate and a saturated solution of salt. The organic layer is washed with water and concentrated and the concentrate purified flash chromatography on silica gel (ethyl acetate).

EXAMPLE 49C

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoic acid

The connection specified in the title of this example is obtained in accordance with the procedure of example 2C, using the compound obtained in example 49B, instead of the compound obtained in example 2B.

EXAMPLE 49D

N-(2-(isopropylamino)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

To a solution of the compound obtained in example 49C (75 mg)in N,N-dimethylformamide (3 ml) is added N-isopropylacetanilide (27 mg), 1-(3-dimethylaminopropyl)-3-ticarbodine hydrochloride (50 mg), 1-hydroxybenzotriazole hydrate (35 mg) and triethylamine (0,11 ml). The mixture was stirred at ambient temperature for 16 hours and partitioned between a saturated solution of salt and water. The organic phase is washed with saturated salt solution and concentrated. The resulting concentrate is purified by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-100% acetonitrile/water with 0.1% triperoxonane acid), getting mentioned in the title compound in the form triptoreline salt.1H NMR (CD3OD): δ of 1.34 (d, J=6,7 Hz, 6H), 1,65-of 1.74 (m, 4H), 2,37 is 2.44 (m, 2H), 2,47-of 2.54 (m, 2H), 3,23 (t, J=5,9 Hz, 2H), 3,39-3,47 (m, 1H), to 3.67 (t, J=5,9 Hz, 2H), of 4.05 (s, 2H), 7,41-7,44 (m, 2H), 7,71-7,74 (m, 2H).

EXAMPLE 50

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-morpholine-4-ylacetamide

The connection specified in the title of this example, are in the form triptoreline salt according to the method of example 41, using morpholine-4-luksusowe acid instead of 3-(1-piperidinyl)propionic acid.1H NMR (CD3OD): δ 1,65-of 1.73 (m, 4H), 2,38 is 2.46 (m, 2H), 2,46-2,52 (m, 2H), 3,34-to 3.52 (m, 4H), 3,90-a 4.03 (m, 6H), 4,19 (s, 2H), 7.03 is-to 7.09 (m, 1H), 7,10-7,17 (m, 1H), a 7.85 (DD, J=7,3, 2.1 Hz, 1H).

EXAMPLE 51

N-(2-morpholine-4-retil)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

EXAMPLE 51A

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoic acid

Specified in the title compound get in line with me is odili of example 1, using 3-formylbenzoate instead of 2-fluoro-5-formylbenzoate in the method of example 1C. MS (DCI/NH3) m/z 285 (M+H)+.

EXAMPLE 51B

N-(2-morpholine-4-retil)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

To a solution of the compound obtained in example 51A (75 mg, 0.26 mmol)in anhydrous dichloromethane (5 ml) is added 4-(2-amino-ethyl)morpholine (68 mg, 0.52 mmol), hexaflurophosphate benzotriazol-1-electroparadise (271 mg, 0.52 mmol) and N,N'-diisopropylethylamine (0.18 mmol, 1.04 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours and evaporated. The remainder is shared by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 397 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,64 is 1.75 (m, 4H), 2,37 at 2.45 (m, 2H), 2,45 is 2.55 (m, 2H), 3,15-of 3.27 (m, 2H), 3,40 (t, J=5,80 Hz, 2H), 3,63-3,71 (m, 2H), 3,74-3,81 (m, 4H), was 4.02 is 4.13 (m, 4H), 7,42-7,46 (m, 2H), 7,71 to 7.75 (m, 2H).

EXAMPLE 52

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-pyrrolidin-1-retil)benzamid

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 51, using 1-(2-amino-ethyl)pyrrolidin instead of 4-(2-amino-ethyl)research. MS (DCI/NH3) m/z 381 (M+H)+;1H NMR (500 MHz, CD3OD): δ ,65-1,74 (m, 4H), 1,97-of 2.08 (m, 2H), 2,13-2,22 (m, 2H), 2,39 at 2.45 (m, 2H), 2,46-of 2.54 (m, 2H), of 3.10-3.20 (m, 2H), 3,42 (t, J=5,80 Hz, 2H), of 3.73 (t, J=5,95 Hz, 2H), 3.75 to 3,82 (m, 2H), of 4.05 (s, 2H), 7,42-7,46 (m, 2H), 7,70-7,74 (m, 2H).

EXAMPLE 53

4-(3-((2-methylpyrrolidine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 51 using 2-methylpyrrolidine instead of 4-(2-amino-ethyl)research. MS (DCI/NH3)m/z 352 (M+H)+;1H NMR (500 MHz, CD3OD): δ 0,86 (d, J=6,41 Hz, 1H), 1,33 (d, J=6,41 Hz, 2H), 1.60-to a rate of 1.67 (m, 2H), 1,70 (d, J=2,75 Hz, 3H), 1,73 and 1.80 (m, 1H), 1,90 of 1.99 (m, 1H), 2,11-2,22 (m, 1H), 2,39-2,47 (m, 2H), 2,46-of 2.56 (m, 2H), 3,43-3,51 (m, 1H), 3,57-to 3.67 (m, 1H), was 4.02 (s, 2H), 4,21-to 4.28 (m, 1H), 7.24 to 7,33 (m, 2H), 7,33 and 7.36 (m, 1H), 7,37-7,42 (m, 1H).

EXAMPLE 54

N-azepin-1-yl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 51, using 1-aminoguanidine instead of 4-(2-amino-ethyl)research. MS (DCI/NH3) m/z 381 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,68-of 1.74 (m, 4H), 1,73-of 1.81 (m, 4H), 1,92 is 2.01 (m, 4H), 2,41 is 2.46 (m, 2H), 2,48-of 2.54 (m, 2H), 3,53-of 3.60 (m, 4H), 4,06 (s, 2H), 7,45 is 7.50 (m, 2H), 7,70-7,73 (m, 2H).

EXAMPLE 55

4-(3-(piperazine-1-ylcarbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 55A

tert-Butyl 4-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoyl)piperazine-1-carboxylate

Specified in zaglav and connection receive in accordance with the method of example 51, using tert-butyl 1-piperidinecarboxylate instead of 4-(2-amino-ethyl)research. MS (DCI/NH3) m/z 453 (M+H)+.

EXAMPLE 55B

4-(3-(piperazine-1-ylcarbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in example 55A (480 mg, of 1.76 mmol)in methylene chloride (10 ml) add triperoxonane acid (5 ml). The solution was stirred at room temperature for 1 hour and concentrated. The residue is purified by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 353 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,68-of 1.74 (m, 4H), 2,43-2,48 (m, 2H), 2,48-of 2.54 (m, 2H), 3,19-3,29 (m, 3H), 3,67-of 3.97 (m, 5H), Android 4.04 (s, 2H), 7,30-7,33 (m, 1H), 7,33 and 7.36 (m, 1H), was 7.36-7,39 (m, 1H), 7,44 (t, J=of 7.48 Hz, 1H).

EXAMPLE 56

N-azetidin-3-yl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 55, using 3-amino-1-N-Boc-azetidin instead of tert-butyl-1-piperidinecarboxylate. MS (DCI/NH3) m/z 339 (M+H)+;1H NMR (500 MHz, CD3OD): δ of 1.63 to 1.76 (m, 4H), 2,37 at 2.45 (m, 2H), 2,46 is 2.55 (m, 2H), of 4.05 (s, 2H), 4,28-4,37 (m, 4H), 4,76-4,82 (m, 1H), 7,41 was 7.45 (m, 2H), 7,69-7,74 (m, 2H).

EXAMPLE 57

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-piperidine-3-ylbenzene

p> Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 55, using (+/-)-3-amino-1-N-Boc-piperidine instead of tert-butyl 1-piperidinecarboxylate. MS (DCI/NH3) m/z 367 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,68-1,72 (m, 4H), 1,72-to 1.77 (m, 1H), 1,80-1,89 (m, 1H), 2,02-of 2.15 (m, 2H), 2,37 is 2.46 (m, 2H), 2,47-of 2.54 (m, 2H), 2,85-3,00 (m, 2H), 3.33 and-3,39 (m, 1H), 3,52 (DD, J=12,21, 4,27 Hz, 1H), Android 4.04 (s, 2H), 4,18-4.26 deaths (m, 1H), 7,40-the 7.43 (m, 2H), 7,66-7,71 (m, 2H).

EXAMPLE 58

N-(4-(dimethylamino)phenyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 51, using N,N-dimethyl-1,4-phenylenediamine instead of 4-(2 - amino-ethyl)research. MS (DCI/NH3) m/z 403 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,67-of 1.73 (m, 4H), 2,42-2,48 (m, 2H), 2,47 is 2.55 (m, 2H), or 3.28 (s, 6H), 4,08 (s, 2H), 7,43 was 7.45 (m, 1H), 7,45-7,49 (m, 1H), 7,55 (d, J=cent to 8.85 Hz, 2H), to 7.77-7,80 (m, 1H), 7,79-of 7.82 (m, 1H), 7,89-to 7.93 (m, 2H,).

EXAMPLE 59

N-(2-(4-methylpiperazin-1-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 51 using 2-(4-methylpiperazin-1-yl)ethylamine instead of 4-(2-amino-ethyl)research. MS (DCI/NH3) m/z 410 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,67-of 1.73 (m, 4H), 2,41 is 2.46 (m, 2H), 2,48-of 2.54 (m, 2H), 2,82 (t, J=6,41 Hz, 2H), 2,87 (s, 3H), 2,89-to 3.09 (m, H), 3,17-3,26 (m, 2H), 3.33 and-to 3.41 (m, 1H), only 3.57 (t, J=6,26 Hz, 2H), Android 4.04 (s, 2H), 4,72 of 4.83 (m, 2H), 7,39-7,44 (m, 2H), 7,63-7,66 (m, 1H), 7,66-of 7.69 (m, 1H).

EXAMPLE 60

4-(3-((4-(isoxazol-5-ylcarbonyl)piperazine-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

The solution isoxazol-5-carboxylic acid (32 mg, 0.28 mmol) in a mixture of anhydrous N,N-dimethylformamide (2 ml) and pyridine (2 ml) is treated with 1,1'-carbonyl diimidazol (48 mg, 0.30 mmol) at 40°C for 2 hours. Add the compound obtained in example 55 (50 mg, 0.14 mmol), the reaction mixture is heated to 60°C and maintained at this temperature for 3 hours. After cooling, the reaction mixture is evaporated on a rotary evaporator and the residue purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 448 (M+H)+;1H NMR (500 MHz, CD3OD): δ of 1.65 to 1.76 (m, 4H), 2,41-2,47 (m, 2H), 2,48-of 2.56 (m, 2H), 3,51-3,66 (m, 3H), 3,66-with 3.79 (m, 3H), 3,79-of 3.94 (m, 2H), Android 4.04 (s, 2H), 7,27-7,30 (m, 1H), 7,32-7,35 (m, 1H), was 7.36-7,39 (m, 1H), 7,43 (t, J=of 7.48 Hz, 1H), to 7.61-7,66 (m, 1H), 7,86-to $ 7.91 (m, 1H).

EXAMPLE 61

4-(3-((4-phenylpiperazin-1-yl)carbonyl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 51, using 4-phenylpiperidine instead of 4-(2-amino-ethyl)research. MC (DCI/NH3) m/z 428 (M+H) +;1H NMR (500 MHz, CD3OD): δ 1,54-of 1.65 (m, 1H), 1,64-1,71 (m, 4H), 1,72-to 1.82 (m, 2H), 1,91 of 1.99 (m, 1H), 2.40 a at 2.45 (m, 2H), 2.49 USD is 2.51 (m, 2H), 2,80-2,89 (m, 1H), 2,89 are 2.98 (m, 1H), 3,15-3,26 (m, 1H), 3,71-3,82 (m, 1H), Android 4.04 (s, 2H), 4,72-to 4.81 (m, 1H), 7,16-7,20 (m, 1H), 7,22-7,26 (m, 3H), 7,27-7,30 (m, 2H), 7,30-7,32 (m, 1H), 7,34 (d, J=to 7.93 Hz, 1H), 7,42 (t, J=7,63 Hz, 1H).

EXAMPLE 62

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(piperidine-2-ylmethyl)benzamide

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 55, using tert-butyl 2-(aminomethyl)piperidine-1-carboxylate instead of tert-butyl 1-piperidinecarboxylate. MS (DCI/NH3) m/z 381 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,46-of 1.56 (m, 2H), 1.60-to of 1.78 (m, 6H), 1,79-of 1.93 (m, 2H), 2,38-2,47 (m, 2H), 2,47 is 2.55 (m, 2H), 3,14 (DD, J=of 13.27, was 4.42 Hz, 2H), 3.46 in-to 3.52 (m, 1H), 3,55-to 3.64 (m, 1H), Android 4.04 (s, 2H), 4,91-of 5.05 (m, 1H), 7,27-7,32 (m, 1H), 7,35-7,40 (m, 2H), 7,43 (t, J=of 7.48 Hz, 1H).

EXAMPLE 63

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(piperidine-4-ylmethyl)benzamide

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 55, using tert-butyl ether 4-aminomethylpyridine-1-carboxylic acid instead of tert-butyl 1-piperidinecarboxylate. MS (DCI/NH3) m/z 381 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,40-of 1.52 (m, 2H), 1,64 -1,74 (m, 4H), 1.91 a-2,03 (m, 3H), 2,37-2,47 (m, 2H), 2,47 is 2.55 (m, 2H), 2,93-to 3.02 (m, 2H), 3,32-to 3.36 (m, 2H), 3,37-3,44 (m, 2H), Android 4.04 (s, 2H), 7,38-the 7.43 (m, 2H), 7,65-of 7.69 (m, 2H).

EXAMPLE 64

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(2-piperidine-1-retil)benzamid

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 51 using 2-(piperidine-1-yl)ethanamine instead of 4-(2-amino-ethyl)research. MS (DCI/NH3) m/z 395 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,50 is 1.58 (m, 1H), 1,67-of 1.73 (m, 4H), 1,76-of 1.88 (m, 3H), of 1.97 (d, J=14,34 Hz, 2H), 2,38-2,47 (m, 2H), 2,46-of 2.54 (m, 2H), 2,93 totaling 3.04 (m, 2H), 3,32-3,37 (m, 2H), 3,68 (d, J=12,21 Hz, 2H), 3,74 (t, J=6,10 Hz, 2H), of 4.05 (s, 2H), 7,42 was 7.45 (m, 2H), 7,70-7,74 (m, 2H).

EXAMPLE 65

N-(1-methylisatin-3-yl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

To a solution of the compound obtained in example 56 (25 mg, 0.07 mmol), in methanol (2 ml) was added formaldehyde (37% solution in water, 16 μl, 0.21 mmol) and triethylamine (10 μl, 0.07 mmol). The mixture is stirred at room temperature for 2 hours, then add cyanoborohydride sodium (13 mg, 0.21 mmol) and zinc chloride (10 mg). The reaction mixture was stirred at room temperature for 16 hours and concentrated. The residue is dissolved in a mixture of acetonitrile and water (1:1) and purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 353 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,63-of 1.74 (m, 4H), 2,36 at 2.45 (m, H), 2,46 of $ 2.53 (m, 2H), 3,01 (d, J=17,70 Hz, 3H), 4,06 (d, J=is 10.68 Hz, 2H), 4,21-to 4.28 (m, 1H), or 4.31 (DD, J=11,44, to 8.70 Hz, 1H), 4,56-of 4.66 (m, 2H), 5,51 (s, 1H), 7,41-7,44 (m, 1H), 7,44-of 7.48 (m, 1H), 7,70 for 7.78 (m, 2H).

EXAMPLE 66

Methyl 4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxylate

EXAMPLE 66A

3-((2-bromopyridin-4-yl)methylene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the procedure of example 1C, using 2-bromopyridin-4-carbaldehyde instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 307 (M+H)+.

EXAMPLE 66B

4-((2-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 66A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 321 (M+H)+.

EXAMPLE 66C

Methyl 4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxylate

The mixture of compounds obtained in example 66B (800 mg, 2.5 mmol), dichloromethane dichloro(1,1'-ferrocenes(diphenylphosphine))palladium(II) 125 mg, 0.15 mmol) and triethylamine(1 ml) in a mixture of methanol (40 ml) and N,N-dimethylformamide (16 ml) was heated to 110°C in an atmosphere of carbon monoxide in the reactor with a pressure of 30 psi for 16 hours. After cooling, the solid product is filtered off and the filtrate evaporated. The solid residue is washed with methanol and is dried, getting listed in the title compound. MS (DCI/NH3) m/z 300 (M+H)+.

EXAMPLE 67

N-methyl-4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

A solution of the compound obtained in example 66 (100 mg, 0.33 mmol), in methanol (5 ml) is treated with methylamine (2,0 N in methanol, 2 ml) at 50°C for 24 hours and concentrated. The residue is washed with methanol and dried, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 299 (M+H)+.

EXAMPLE 68

4-((2-(methylthio)pyrimidine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 68A

3-((2-(methylthio)pyrimidine-4-yl)methylene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the procedure of example 1C, using 2-methylthio-4-pyrimidinecarboxylic instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 275 (M+H)+.

EXAMPLE 68B

4-((2-(methylthio)pyrimidine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 68A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 289 (M+H)+.

EXAMPLE 69

4-((2-(methylsulphonyl)pyrimidine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a suspension of the compound obtained in example 68 (280 mg, 1 mmol)in methylene chloride (5 ml) add Aut m-chloroperoxybenzoic acid (256 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 4 hours and evaporated. The obtained solid residue is shared by flash chromatography on silica gel (80% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 321 (M+H)+;1H NMR (300 MHz, CD3OD): δ 1,61-1,89 (m, 4H), 2,37-a 2.71 (m, 4H), of 3.32 (s, 3H), 4,29 (s, 2H), 7,65 (d, J=5,09 Hz, 1H), 8,88 (d, J=5.43 Hz, 1H).

EXAMPLE 70

4-((2-(methylsulfinyl)pyrimidine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound produce as a by-product in example 69. MS (ESI) m/z 305 (M+H)+.

EXAMPLE 71

4-((3-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 71A

3-((3-bromopyridin-4-yl)methylene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the procedure of example 1C, using 3-bromosalicylaldehyde instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 306 (M+H)+.

EXAMPLE 71B

4-((3-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 71A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 321 (M+H)+.

EXAMPLE 72

4-((6-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 72 A

3-((6-bromopyridin-3-yl)methylene)-4,5,6,7-tetrahydroxybenzophenone--1(3H)-he

Specified in the title compound receive in accordance with the procedure of example 1C, using 6-bromonicotinate instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 306 (M+H)+.

EXAMPLE 72B

4-((6-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 72A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 321 (M+H)+.

EXAMPLE 73

4-((2-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 73A

3-((2-bromopyridin-3-yl)methylene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the procedure of example 1C, using 2-bromonicotinate instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 306 (M+H)+.

EXAMPLE 73B

4-((2-bromopyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 72A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 321 (M+H)+.

EXAMPLE 74

Methyl 6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxylate

EXAMPLE 74A

3-((6-bromopyridin-2-yl)stands is)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the procedure of example 1C, using 6-bromopyridin-2-carbaldehyde instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 300 (M+H)+.

EXAMPLE 74B

4-((6-bromopyridin-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 74A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 321 (M+H)+.

EXAMPLE 74C

Methyl 6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)picolinate

Specified in the title compound receive in accordance with the method of example 66C, using the compound obtained in example 74B, instead of the compound obtained in example 66B. MS (DCI/NH3) m/z 300 (M+H)+.

EXAMPLE 75

N-ethyl-4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using ethylamine instead of methylamine. MS (ESI) m/z 313 (M+H)+.

EXAMPLE 76

N-isopropyl-4-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using Isopropylamine instead of methylamine. MS (ESI) m/z 327 (M+H)+.

EXAMPLE 77

N-cyclohexyl-4-((4-oxo-3,4,5,6,7,8-gexa drahtlosen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using cyclohexanamine instead of methylamine. MS (ESI) m/z 367 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,23-of 1.45 (m, 6N), 1,60-of 1.64 (m, 4H), 1,65 is 1.86 (m, 5H), 2,30-to 2.40 (m, 4H), a 4.03 (s, 2H), 7,41 (DD, J=4,92, to 1.86 Hz, 1H), 7,86 (s, 1H), to 8.41 (d, J=8,82 Hz, 1H), 8,53 (d, J=5,09 Hz, 1H), 12,64 (s, 1H).

EXAMPLE 78

N-methyl-N-((1-methylpiperidin-2-yl)methyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 65, using the compound obtained in example 62, instead of the compound obtained in example 56. MS (DCI/NH3) m/z 409 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,47-of 1.57 (m, 1H), 1,58-to 1.67 (m, 1H), 1,67-to 1.77 (m, 6H), 1.77 in-to 1.87 (m, 1H), 1.85 to 1,95 (m, 1H), 2,43 is 2.51 (m, 2H), 2,53-2,63 (m, 2H), 2,99 (s, 3H), is 3.08 (s, 3H), 3,26 (DD, J=13,73, 3,36 Hz, 2H), 3,51-3,61 (m, 1H), 3,95 (DD, J=of 13.27, 11.44 Hz, 1H), 4,13 (s, 2H), 5,11-5,24 (m, 1H), 7,35-7,40 (m, 2H), 7,41-7,47 (m, 2H).

EXAMPLE 79

N-((1-methylpiperidin-4-yl)methyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 65, using the compound obtained in example 63, instead of the compound obtained in example 56. MS (DCI/NH3) m/z 395 (M+H)+;1H NMR (500 MHz, CD3OD): δ 1,49-to 1.61 (m, 2H), 1,69-of 1.78 (m, 4H), 1,90-,98 (m, 1H), 1,97-of 2.08 (m, 2H), 2,43 of $ 2.53 (m, 2H), 2,54-to 2.65 (m, 2H), 2,85 (s, 3H), 2.95 and totaling 3.04 (m, 2H), 3,32-to 3.38 (m, 2H), 3,53 (DD, J=10,53, to 1.98 Hz, 2H), 4,15 (s, 2H), 7,39-7,41 (m, 1H), 7,43 (t, J=7,63 Hz, 1H), 7,68 (, 1H), 7,70-7,73 (m, 1H).

EXAMPLE 80

N-methyl-6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using the compound obtained in example 74, instead of the compound obtained in example 66. MS (ESI) m/z 299 (M+H)+;1H NMR (300 MHz, CD3OD): δ 1,61-of 1.81 (m, 4H), 2,38-2,61 (m, 4H), 2.95 and (s, 3H), 4,22 (s, 2H), 7,41 (DD, J=7,46, of 1.36 Hz, 1H), 7,88 (t, J=7,63 Hz, 1H), to $ 7.91-7,98 (m, 1H).

EXAMPLE 81

N-ethyl-6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using the compound obtained in example 74, instead of the compound obtained in example 66, and ethylamine instead of methylamine. MS (ESI) m/z 313 (M+H)+.

EXAMPLE 82

N-isopropyl-6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using the compound obtained in example 74, instead of the compound obtained in example 66, and Isopropylamine instead of methylamine. MS (ESI) m/z 327 (M+H)+.

EXAMPLE 83

N-cyclopropyl-6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

is shown in the title compound receive in accordance with the method of example 67, using the compound obtained in example 74, instead of the compound obtained in example 66, and cyclopropylamine instead of methylamine. MS (ESI) m/z 325 (M+H)+.

EXAMPLE 84

N-cyclohexyl-6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using the compound obtained in example 74, instead of the compound obtained in example 66, and cyclohexylamine instead of methylamine. MS (ESI) m/z 367 (M+H)+.

EXAMPLE 85

Methyl 3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxylate

Specified in the title compound receive in accordance with the method of example 66C, using the compound obtained in example 73B, instead of the compound obtained in example 66B. MS (DCI/NH3) m/z 300 (M+H)+.

EXAMPLE 86

Methyl 5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxylate

Specified in the title compound receive in accordance with the method of example 66C, using the compound obtained in example 72B, instead of the compound obtained in example 66B. MS (DCI/NH3) m/z 300 (M+H)+.

EXAMPLE 87

4-((5-bromothiophene-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 87A

3-((5-bromothiophene-2-yl)methylene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound get matched with the accordance with the procedure of example 1C, using a 5-bromothiophene-2-carbaldehyde instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 312 (M+H)+.

EXAMPLE 87B

4-((5-bromothiophene-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 87A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 326 (M+H)+.

EXAMPLE 88

4-((3-bromothiophene-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 88A

3-((3-bromothiophene-2-yl)methylene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the procedure of example 1C, using 3-bromothiophene-2-carbaldehyde instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 312 (M+H)+.

EXAMPLE 88B

4-((3-bromothiophene-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 88A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 326 (M+H)+.

EXAMPLE 89

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

Specified in the title compound receive in accordance with the method of example 2, using 3-nitrobenzaldehyde instead of 4-fluoro-3-nitrobenzaldehyde in the method of obtaining compounds of example 2A. MS (DCI/NH3) m/z 256 (M+H)+; 1H NMR (300 MHz, CD3OD): δ of 1.62 and 1.75 (m, 4H), 2,37 is 2.44 (m, 2H), 2,46-of 2.54 (m, 2H), 3,86 (s, 2H), 6,46-is 6.54 (m, 2H), to 6.57 (DD, J=7,93, to 1.98 Hz, 1H), 7,01 (t, J=7,73 Hz, 1H).

EXAMPLE 90

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

Specified in the title compound receive in accordance with the procedure of example 2C, using 3-bromobenzaldehyde instead of 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 256 (M+H)+;1H NMR (300 MHz, CD3OD): δ 1,64-to 1.77 (m, 4H), 2,37 is 2.46 (m, 2H), 2,47 is 2.55 (m, 2H), 3.96 points (s, 2H), 7,13-to 7.18 (m, 1H), 7.18 in-7,24 (m, 1H), 7,35-7,40 (m, 2H).

EXAMPLE 91

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

The mixture of compounds obtained in example 87 (100 mg, 0.31 mmol), and ndimethylacetamide (1 g) was stirred at 180°C during the night. After cooling, the mixture is dissolved in methanol and separated using HPLC (sorbent Bond® C-8 [Agilent Technologies, Santa Clara, CA] 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound. MS (DCI/NH3) m/z 247 (M+H)+.

EXAMPLE 92

Methyl-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)thiophene-2-carboxylate

Specified in the title compound receive in accordance with the method of example 66C, using the compound obtained in example 87, instead of the compound obtained in example 66B. MS (DCI/NH3) m/z 305 (M+H)+.

EXAMPLE 93

N-methyl-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title with the unity gain in accordance with the method of example 67, using the compound obtained in example 86, instead of the compound obtained in example 66. MS (ESI) m/z 299 (M+H)+,1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,51-of 1.73 (m, 4H), 2.40 a (d, J=14,92 Hz, 4H), of 2.81 (d, J=5,09 Hz, 3H), was 4.02 (s, 2H), of 7.75 (DD, J=7,97, 2.20 Hz, 1H), of 7.96 (d, J=8,14 Hz, 1H), 8,49 (d, J=1.70 Hz, 1H), to 8.70 (d, J=4,75 Hz, 1H), 12,60 (s, 1H).

EXAMPLE 94

N-ethyl-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using the compound obtained in example 86, instead of the compound obtained in example 66, and ethylamine instead of methylamine. MS (ESI) m/z 313 (M+H)+.

EXAMPLE 95

N-methyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using the compound obtained in example 85, instead of the compound obtained in example 66. MS (ESI) m/z 299 (M+H)+,1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,53-to 1.79 (m, 4H), 2,29 is 2.44 (m, 4H), 2,73 (d, J=5,16 Hz, 3H), 4,35 (s, 2H), 7,50 (DD, J=7,73, 4,56 Hz, 1H), 7,66 (DD, J=7,93, of 1.59 Hz, 1H), 8,49 (DD, J=4,36, of 1.59 Hz, 1H), 8,65 (d, J=5,16 Hz, 1H), 12,35 (s, 1H).

EXAMPLE 96

N-ethyl-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridine-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using the compound obtained in which the Rimera 85, instead of the compound obtained in example 66, and ethylamine instead of methylamine. MS (ESI) m/z 313 (M+H)+.

EXAMPLE 97

N,N-dimethyl-N'-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)sulphonamide

To a solution of the compound obtained in example 89 (50 mg, 02 mmol), in dichloromethane (4 ml) add dimethylsulphamoyl (31 mg, 0.22 mmol) and pyridine (17 ml, 0.22 mol). The solution was stirred at room temperature for 16 hours and evaporated. The resulting residue is separated by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 363 (M+H)+;1H NMR (400 MHz, CD3OD): δ 1,64 to 1.76 (m, 4H), 2,37 is 2.46 (m, 2H), 2,47-of 2.54 (m, 2H), 2,72 (s, 6H), of 3.95 (s, 2H), 6,91-of 6.96 (m, 1H), 7,02-7,06 (m, 2H), 7,19-7,24 (m, 1H).

EXAMPLE 98

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-piperidine-1-ylpropionic

To a solution of 3-(piperidine-1-yl)propanoic acid (31 mg) in anhydrous dichloromethane (2 ml) add oxalicacid (25,7 μl) and a drop of N,N-dimethylformamide. The solution is stirred for 1 hour and concentrated. The residue is again dissolved in anhydrous dichloromethane (2 ml) and quickly added to a solution of compound of example 89 (50 mg) in anhydrous tetrahydrofuran (2 ml). To the mixture add triethylamine (32,8 μl) and the reaction mixture was premesis the Ute at room temperature over night. The mixture is evaporated. The residue is distributed between ethyl acetate and a saturated solution of salt. The organic phase is washed with saturated salt solution and evaporated. The solid residue separated by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 395 (M+H)+;1H NMR (400 MHz, CD3OD): δ 1,48 is 1.60 (m, 1H), 1,65-1,71 (m, 4H), 1,73-to 1.87 (m, 3H), 1,92 is 2.01 (m, 2H), 2,38 at 2.45 (m, 2H), 2,46 of $ 2.53 (m, 2H), 2,87 (t, J=6,60 Hz, 2H), 2,93-3,03 (m, 2H), 3,44 (t, J=6.75 Hz, 2H), 3,57 (d, J=12,58 Hz, 2H), of 3.97 (s, 2H), 6,95-7,00 (m, 1H), 7,26 (t, J=7,83 Hz, 1H), was 7.36-7,39 (m, 1H), 7,41-of 7.48 (m, 1H).

EXAMPLE 99

4-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)butanamide

A solution of the compound obtained in example 89 (150 mg, 0.59 mmol)and 4-chlorobutyronitrile (83 mg, 0.59 mmol) in dichloromethane (5 ml) was stirred at room temperature for 16 hours and evaporated. The residue is distributed between ethyl acetate and a saturated solution of salt. The organic phase is washed with saturated salt solution, getting mentioned in the title compound. MS (DCI/NH3) m/z 360 (M+H)+;1H NMR (400 MHz, CD3OD): δ 1,66-of 1.73 (m, 4H), 2,07-of 2.15 (m, 2H), 2.40 a is 2.46 (m, 2H), 2,48 is 2.51 (m, 2H), 2,50-of 2.56 (m, 2H), 3,63 (t, J=6,44 Hz, 2H), 3.96 points (s, 2H), 6,93 (d, J=to 7.67 Hz, 1H), 7,21-7,26 (m, 1H), was 7.36 (s, 1H), 7,38-7,46 (m, 1H).

EXAMPLE 100

4-(3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-Tetra is hydrophilizing-1(2H)-he

A suspension of the compound obtained in example 90 (150 mg, 0.47 mmol), pyrrolidin-2-she (80 mg, of 0.94 mmol), Tris(dibenzylideneacetone)diplegia(0) (43 mg, 0.05 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (41 mg, 0.07 mmol) and cesium carbonate (214 mg, 0.66 mmol) in anhydrous dioxane (2 ml) incubated in a microwave reactor CEM Explorer® (Matthews, NC) at 200°C for 30 minutes. After cooling, the reaction mixture is evaporated. The residue is separated by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 324 (M+H)+;1H NMR (400 MHz, CD3OD): δ of 1.65 and 1.75 (m, 4H), 2,11-of 2.23 (m, 2H), 2,41-2,47 (m, 2H), 2,48 of $ 2.53 (m, 2H), 2.57 m (t, J=7,98 Hz, 2H), 3,83-to 3.92 (m, 2H), 3,99 (s, 2H), 7,01 (d, J=to 7.67 Hz, 1H), 7,31 (t, J=7,98 Hz, 1H), 7,38-7,42 (m, 1H), 7,51 (t, J=1,69 Hz, 1H).

EXAMPLE 101

4-((2-(2-oxoazetidin-1-yl)pyridine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

In a tubular microwave reactor load Tris(dibenzylideneacetone)dipalladium(0) (5.4 mg, 0,006 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (5.4 mg, 0.01 mmol), the compound of example 103 (50 mg, 0.16 mmol), azetidin-2-he (53 mg, of 0.62 mmol) and Cs2CO3(70 mg, 0.21 mmol). Add anhydrous dioxane, and the resulting suspension is incubated in a microwave reactor CEM Explorer® (Matthews, NC) at 200°C for 30 minutes. The mixture is evaporated and the resulting residue is distributed between ethyl acetate and a saturated solution of salt. The organic phase is evaporated. The obtained solid residue is shared by flash chromatography on silica gel (100% ethyl acetate), obtaining mentioned in the title compound. MS (DCI/NH3) m/z 311 (M+H)+.

EXAMPLE 102

4-((2-(2-oxopyrrolidin-1-yl)pyridine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 101, using pyrrolin-2-he instead of azetidin-2-it. MS (ESI) m/z 339 (M+H)+.

EXAMPLE 103

4-((2-bromopyridin-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 66B. MS (DCI/NH3) m/z 321 (M+H)+.

EXAMPLE 104

4-((6-(2-oxopyrrolidin-1-yl)pyridine-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 101, using the compound obtained in example 72, instead of the compound obtained in example 103, and pyrrolin-2-he instead of azetidin-2-it. MS (ESI) m/z 325 (M+H)+.

EXAMPLE 105

4-((6-(2-oxoazetidin-1-yl)pyridine-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 101, using the compound obtained in example 72, instead of the compound obtained in example 103. MS (ESI) m/z 311 (M+H)+.

EXAMPLE 106

N-(5-((4-oxo-3,4,5,6,7,8-hexahydrophthalic the Jn-1-yl)methyl)pyridin-2-yl)benzamid

Specified in the title compound receive in accordance with the method of example 101, using the compound obtained in example 72, instead of the compound obtained in example 103, and benzamide instead of azetidin-2-it. MS (ESI) m/z 361 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,48 is 1.70 (m, 4H), to 2.41 (d, J=17,29 Hz, 4H), to 3.92 (s, 2H), 7,86 (t, J=1,86 Hz, 3H), 7,86-of 7.90 (m, 2H), 7,99-of 8.06 (m, 1H), 8,12 (d, J=8,48 Hz, 1H), 8,24 (d, J=2.37 Hz, 1H), of 10.72 (s, 1H), 12,60 (s, 1H).

EXAMPLE 107

N-(5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridin-2-yl)isonicotinamide

Specified in the title compound receive in accordance with the method of example 101, using the compound obtained in example 72, instead of the compound obtained in example 103, and isonicotinamide instead of azetidin-2-it. MS (ESI) m/z 362 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ of 1.65 (d, J=5,09 Hz, 4H), to 2.41 (d, J=16.28 per Hz, 4H), 3,93 (s, 2H), 7,68 (DD, J=8,48, 2.37 Hz, 1H), of 7.90-of 8.00 (m, 2H), 8,11 (d, J=8,48 Hz, 1H), 8,27 (d, J=2,03 Hz, 1H), 8,76-8,82 (m, 2H), 11,12 (s, 1H), 12,60 (, 1H).

EXAMPLE 108

N-(5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridin-2-yl)nicotinamide

Specified in the title compound receive in accordance with the method of example 101, using the compound obtained in example 72, instead of the compound obtained in example 103, and nicotinamide instead of azetidin-2-it. MS (ESI) m/z 362 (M+H)+.

EXAMPLE 109

4-((5'-((4-oxo-3,4,5,6,7,8-hexahydrophthalic the Jn-1-yl)methyl)-2,2'-bipyridine-5-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound as a by-product in example 108. MS (ESI) m/z 481 (M+H)+.

EXAMPLE 110

N-methyl-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)thiophene-2-carboxamide

Specified in the title compound receive in accordance with the method of example 67, using the compound obtained in example 92, instead of the compound obtained in example 66. MS (ESI) m/z 304 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,63 (d, J=3,05 Hz, 4H), 2,29 is 2.46 (m, 4H), of 2.72 (d, J=to 4.41 Hz, 3H), 4.09 to (s, 2H), to 6.88 (d, J=to 3.73 Hz, 1H), 7,51 (d, J=to 3.73 Hz, 1H), 8,31 (d, J=to 4.41 Hz, 1H), 12,66 (s, 1H).

EXAMPLE 111

N1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)glycinamide

A solution of the compound obtained in example 89 (50 mg, 0.2 mmol), and 2,5-dioxopiperidin-1-yl-2-(tert-butoxycarbonylamino)acetate (59 mg, 0.22 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature for 16 hours and evaporated. The obtained solid residue was dissolved in dichloromethane (4 ml) and treated triperoxonane acid (2 ml) at room temperature for 1 hour. The reaction mixture was concentrated and the residue is shared by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 313 (M+H)+; H NMR (300 MHz, CD3OD): δ 1,64 is 1.75 (m, 4H), 2,36 at 2.45 (m, 2H), 2,46-of 2.54 (m, 2H), 3,80 (s, 2H), 3,98 (s, 2H), 7,00 (d, J=7,80 Hz, 1H), 7,28 (t, J=7,97 Hz, 1H), 7,37-7,40 (m, 1H), 7,42-7,47 (m, 1H).

EXAMPLE 112

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)azetidin-2-carboxamide

EXAMPLE 112A

tert-butyl 2-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenylcarbamoyl)azetidine-1-carboxylate

Specified in the title compound receive in accordance with the method of example 98, using 1-(tert-butoxycarbonyl)azetidin-2-carboxylic acid instead of 3-(piperidine-1-yl)propanoic acid. MS (DCI/NH3) m/z 439 (M+H)+.

EXAMPLE 112B

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)azetidin-2-carboxamide

A solution of the compound obtained in example 112A (64 mg), in dichloromethane (4 ml) is treated triperoxonane acid (2 ml) at room temperature for 1 hour. The reaction mixture is evaporated and the residue purified by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 339 (M+H)+;1H NMR (300 MHz, CD3OD): δ 1,64-of 1.73 (m, 4H), 2,36 is 2.44 (m, 2H), 2,46 of $ 2.53 (m, 2H), 2.57 m-2,69 (m, 1H), 2,81-of 2.93 (m, 1H), 3,94-Android 4.04 (m, 1H), 3,98 (s, 2H), 4,08-4,20 (m, 1H), 5,07 (DD, J=9,49, 7,80 Hz, 1H), 7,03 (d, J=8,14 Hz, 1H), 7,30 (t, J=7,80 Hz, 1H), 7,41 (t, J=1.70 Hz, 1H), 7,49 (DD, J=7,97, of 1.53 Hz, 1H).

EXAMPLE 113

N-(3((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)azetidin-3-carboxamide

Specified in the title compound receive in accordance with the method of example 112, using 1-(tert-butoxycarbonyl)azetidin-3-carboxylic acid instead of 1-(tert-butoxycarbonyl)azetidin-2-carboxylic acid. MS (DCI/NH3) m/z 339 (M+H)+;1H NMR (300 MHz, CD3OD): δ of 1.62 and 1.75 (m, 4H), 2,36 is 2.44 (m, 2H), 2,46-of 2.54 (m, 2H), 3,69-a 3.83 (m, 1H), 3,97 (s, 2H), 4,17-to 4.33 (m, 4H), 7,00 (DD, J=7,14, 1,19 Hz, 1H), 7,27 (t, J=to 7.93 Hz, 1H), 7,40 (t, J=1,59 Hz, 1H), 7,45-7,51 (m, 1H).

EXAMPLE 114

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

Specified in the title compound receive in accordance with the method of example 97 using methanesulfonamide instead of dimethylsulfoxide. MS (DCI/NH3) m/z 334 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,53-to 1.67 (m, 4H), 2,29-to 2.42 (m, 4H), 2.95 and (s, 3H), 3,88 (s, 2H), 6,92 (d, J=7,63 Hz, 1H), 7,00 (s, 1H), 7,06 (DD, J=7,93, 1,22 Hz, 1H), 7,26 (t, J=7,78 Hz, 1H), 9,68 (ush. s, 1H), 12,63 (ush. s, 1H).

EXAMPLE 115

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propane-2-sulfonamide

Specified in the title compound receive in accordance with the method of example 97 using propane-2-sulphonylchloride instead of dimethylsulfoxide. MS (DCI/NH3) m/z 362 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,19 (d, J=7,02 Hz, 6H), 1,53-of 1.66 (m, 4H), 2,25 is 2.33 (m, 2H), 2,34-to 2.41 (m, 2H), is 3.08-up 3.22 (m, 1H), a 3.87 (s, 2H), 6,88-6,91 (m, 1H), 7,01 (s, 1H), was 7.08 (DD, J=8,24, 1,22 Hz, 1H), 7.23 percent (t, J=7,78 Hz, 1H), 9,68 (ush. s, 1H) 12,64 (ush. s, 1H).

EXAMPLE 116

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

Specified in the title compound receive in accordance with the method of example 97 using benzosulphochloride instead of dimethylsulfoxide. MS (DCI/NH3) m/z 396 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,48 is 1.60 (m, 4H), 2,10-of 2.21 (m, 2H), 2,29-2,39 (m, 2H), of 3.78 (s, 2H), 6,83-6,87 (m, 2H), 6,92 (DD, J=8,09, to 1.37 Hz, 1H), 7,15 (t, J=7,78 Hz, 1H), of 7.48 (t, J=7,78 Hz, 2H), 7,58 (t, J=of 7.48 Hz, 1H), of 7.64-7,69 (m, 2H), 10,24 (ush. s, 1H), 12,64 (ush. s, 1H).

EXAMPLE 117

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyridine-3-sulfonamide

Specified in the title compound receive in accordance with the method of example 97 using pyridine-3-sulphonylchloride hydrochloride instead of dimethylsulfoxide. MS (DCI/NH3) m/z 397 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,50-to 1.61 (m, 4H), 2,12-of 2.21 (m, 2H), 2,33-to 2.40 (m, 2H), 3,80 (s, 2H), 6,85 (s, 1H), 6,92 (d, J=7,63 Hz, 1H), of 6.96 (DD, J=7,93, 1,22 Hz, 1H), 7,19 (t, J=7,78 Hz, 1H), 7,55 (DD, J=8,09, to 4.73 Hz, 1H), 8,02-8,06 (m, 1H), up 8.75 (DD, J=4,88, of 1.53 Hz, 1H), 8,77 (d, J=1,83 Hz, 1H), 10,43 (ush. s, 1H), 12,63 (ush. s, 1H).

EXAMPLE 118

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)furan-2-sulfonamide

Specified in the title compound receive in accordance with the method of example 97 using furan-2-sulphonylchloride instead of dimethylsulfoxide. MS (DCI/NH3) m/z 386 (M+H)+;1 H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,52-to 1.63 (m, 4H), 2,19-of 2.28 (m, 2H), 2,32-to 2.40 (m, 2H), 3,82 (s, 2H), to 6.57 (DD, J=3,66 and 1.83 Hz, 1H), 6.89 in (d, J=1,53 Hz, 1H), 6,91 (d, J=7,63 Hz, 1H), 6,95-6,99 (m, 1H),? 7.04 baby mortality (d, J=3,36 Hz, 1H), 7,20 (m, J=7,78 Hz, 1H), of 7.90 (DD, J=1,83, to 0.92 Hz, 1H), or 10.60 (ush. s, 1H), 12,65 (ush. s, 1H).

EXAMPLE 119

1-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-imidazole-4-sulfonamide

Specified in the title compound receive in accordance with the method of example 97 using 1-methyl-1H-imidazol-4-sulphonylchloride instead of dimethylsulfoxide. MS (DCI/NH3) m/z 400 (M+H)+.1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,55-to 1.61 (m, 4H), 2,24 of-2.32 (m, 2H), 2,32-to 2.40 (m, 2H), 3,63 (s, 3H), 3,80 (s, 2H), 6,80 (d, J=to 7.93 Hz, 1H), 6,92 (s, 1H), 6,99 (DD, J=8,09, to 1.37 Hz, 1H), 7,13 (t, J=7,78 Hz, 1H), of 7.70 (d, J=1,22 Hz, 1H), 7,73 (d, J=1,22 Hz, 1H), 10,15 (ush. s, 1H), 12,64 (ush. s, 1H).

EXAMPLE 120

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)thiophene-2-sulfonamide

Specified in the title compound receive in accordance with the method of example 97 using thiophene-2-sulphonylchloride instead of dimethylsulfoxide. MS (DCI/NH3) m/z 402 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.41 to of 1.64 (m, 4H), 2,18-of 2.24 (m, 2H), 2,34-to 2.40 (m, 2H), 3,82 (s, 2H), 6.90 to-6,94 (m, 2H), 6,97 (d, J=to 7.93 Hz, 1H), 7,06 (DD, J=5,03, 3,81 Hz, 1H), 7,17-7,24 (m, 1H), 7,45 (DD, J=3,81, to 1.37 Hz, 1H), a 7.85 (DD, J=5,03, to 1.37 Hz, 1H), 10,36 (ush. s, 1H), 12,65 (ush. s, 1H).

EXAMPLE 121

4-cyano-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)m is Teal)phenyl)benzosulfimide

Specified in the title compound receive in accordance with the method of example 97 using 4-cyanobenzoyl-1-sulphonylchloride instead of dimethylsulfoxide. MS (DCI/NH3) m/z 421 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,49-of 1.62 (m, 4H), 2,14-of 2.20 (m, 2H), 2,31-2,39 (m, 2H), 3,80 (s, 2H), at 6.84 (s, 1H), make 6.90 (d, J=7,63 Hz, 1H), 6,94 (DD, J=7,93, 1,22 Hz, 1H), 7,19 (t, J=to 7.93 Hz, 1H), 7,83 (d, J=cent to 8.85 Hz, 2H), 8,00 (d, J=8,54 Hz, 2H), 10,52 (ush. s, 1H), 12,65 (ush. s, 1H).

EXAMPLE 122

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)naphthalene-1-sulfonamide

Specified in the title compound receive in accordance with the method of example 97 using naphthalene-1-sulphonylchloride instead of dimethylsulfoxide. MS (DCI/NH3) m/z 421 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.41 to about 1.47 (m, 2H), 1,47-of 1.56 (m, 2H), 2,00-2,10 (m, 2H), 2,30-2,39 (m, 2H), 3,71 (s, 2H), 6.75 in-to 6.80 (m, 2H), 6,83-6,89 (m, 1H), 7,07 (t, J=7,78 Hz, 1H), 7,50-7,56 (m, 1H), to 7.64 (t, J=7,02 Hz, 1H), to 7.67-7,72 (m, 1H), 8,04 (d, J=7,63 Hz, 1H), 8,06-8,10 (m, 1H), 8,18 (d, J=8,24 Hz, 1H), 8,67 (d, J=8.54 in Hz, 1H), 10,65 (ush. s, 1H), 12,64 (ush. s, 1H).

EXAMPLE 123

4-((6-bromopyridin-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 74B. MS (DCI/NH3) m/z 321 (M+H)+.

EXAMPLE 125

4-((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of the coy example 101, using the compound obtained in example 123, instead of the compound obtained in example 103, and pyrrolin-2-he instead of azetidin-2-it. MS (ESI) m/z 325 (M+H)+.

EXAMPLE 126

N-(6-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)pyridin-2-yl)benzamid

Specified in the title compound receive in accordance with the method of example 101, using the compound obtained in example 123, instead of the compound obtained in example 103, and benzylamine instead of azetidin-2-it. MS (ESI) m/z 361 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,63 (m, 4H), 2.40 a (m, 4H), was 4.02 (s, 2H), 6,95 (d, J=7,46 Hz, 1H), 7,38-rate of 7.54 (m, 2H), 7,50 to 7.62 (m, 1H), to 7.67-to 7.84 (m, 1H), of 7.90-to 8.12 (m, 3H), 10,69 (s, 1H), was 12.61 (s, 1H).

EXAMPLE 127

4-((3'-((isopropylamino)methyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin - 1(2H)-he

EXAMPLE 127 A

3'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)biphenyl-3-carbaldehyde

A suspension of the compound obtained in example 90 (500 mg, 1.57 mmol), 3-formylphenylboronic acid (352 mg, 2,35 mmol), dichloro-bis(triphenylphosphine)palladium(II) (112 mg, 0.16 mmol) and sodium carbonate (2M solution of 3.13 mmol, 1.6 ml) in a mixture of 1,2-dimethoxyethane/water/ethanol (7/3/3, 23 ml), rinsed with nitrogen, heated to 70°C and maintained at this temperature for 16 hours. After cooling to room temperature the reaction mixture was concentrated on a rotary evaporator. The crude solid product based on separate treatment of the t using HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound. MS (DCI/NH3) m/z 345 (M+H)+.

EXAMPLE 127B

4-((3'-((isopropylamino)methyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 65, using the compound obtained in example 127A, instead of formaldehyde, and propane-2-amine instead of the compound obtained in example 56. MS (DCI/NH3) m/z 388 (M+H)+;1H NMR (500 MHz, CD3OD): δ of 1.41 (d, J=of 6.71 Hz, 6H), 1,64 to 1.76 (m, 4H), 2,43-2,48 (m, 2H), 2,48 of $ 2.53 (m, 2H), 3,42-to 3.52 (m, 1H), 4,06 (s, 2H), 4,27 (s, 2H), 7,22 (d, J=to 7.93 Hz, 1H), 7,41 (t, J=7,63 Hz, 1H), 7,45 is 7.50 (m, 2H), 7,51-7,56 (m, 2H), of 7.64-of 7.69 (m, 1H), 7,71-7,74 (m, 1H).

EXAMPLE 128

4-((3'-((cyclopentylamine)methyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 65, using the compound obtained in example 127A, instead of formaldehyde and Cyclopentanone instead of the compound obtained in example 56. MS (DCI/NH3) m/z 414 (M+H)+.

EXAMPLE 129

4-((3'-((2-methylpyrrolidine-1-yl)methyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound is obtained in the form of salt triperoxonane acid in accordance with the methodology applied is as 65, using the compound obtained in example 127A, instead of formaldehyde and 2-methylpyrrolidine instead of the compound obtained in example 56. MS (DCI/NH3) m/z 414 (M+H)+.

EXAMPLE 130

4-((3'-((cyclopropylamino)methyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 65, using the compound obtained in example 127A, instead of formaldehyde, and cyclopropylamine instead of the compound obtained in example 56. MS (DCI/NH3) m/z 386 (M+H)+.

EXAMPLE 131

4-((3'-((cyclobutylamine)methyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound is obtained in the form of salt triperoxonane acid according to the method of example 65, using the compound obtained in example 127A, instead of formaldehyde and cyclobutanone instead of the compound obtained in example 56. MS (DCI/NH3) m/z 400 (M+H)+.

EXAMPLE 132

4-((2-bromo-1-oxidability-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

A solution of the compound obtained in example 103 (100 mg, 0.31 mmol), in dichloromethane (15 ml) was treated with meta-chloroperoxybenzoic acid (100 mg, of 0.58 mmol) at room temperature overnight and the reaction mixture is evaporated. The residue is dissolved in methanol and separated using HPLC (with the bent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 336 (M+H)+.

EXAMPLE 133

4-((1-oxido-2-(2-oxopyrrolidin-1-yl)pyridine-4-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 132 using the compound obtained in example 102, instead of the compound obtained in example 103. MS (ESI) m/z 341 (M+H)+.

EXAMPLE 134

Methyl 5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)thiophene-3-carboxylate

EXAMPLE 134A

3-((4-bromothiophene-2-yl)methylene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the procedure of example 1C, using 5-bromothiophene-2-carbaldehyde instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 312 (M+H)+.

EXAMPLE 134B

4-((4-bromothiophene-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 134A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 326 (M+H)+.

EXAMPLE 134C

Methyl 5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)thiophene-3-carboxylate

Specified in the title compound receive in accordance with the method of example 66, ISOE is isua connection, obtained in example 134B, instead of the compound obtained in example 66B. MS (DCI/NH3) m/z 305 (M+H)+.

EXAMPLE 135

4-(3-((4-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-1,4-diazepan-1-yl)carbonyl)-4-terbisil)phthalazine-1(2H)-he

EXAMPLE 135

tert-Butyl 2-(2-(2-(4-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoyl)-1,4-diazepan-1-yl)ethoxy)ethoxy)ethylcarbamate

To a solution of 2-(2-(tert-Boc-aminoethoxy)ethoxy)ethylbromide (Toronto, 137 mg, 0.44 mmol) in N,N-dimethylformamide (4 ml) is added the compound obtained in example 5 (84 mg, 0.22 mmol), and potassium carbonate (91 mg, 0.66 mmol). The reaction mixture is heated to 35°C and maintained at this temperature overnight, then distributed between ethyl acetate and a saturated solution of salt. The organic phase is washed with saturated salt solution and concentrated. The residue is separated by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 250×of 2.54 column, mobile phase A: 0.1% of triperoxonane acid in H2O; B: 0.1% of triperoxonane acid in CH3CN; gradient 0-100%), getting mentioned in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 612 (M+H)+.

EXAMPLE 135B

4-(3-((4-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-1,4-diazepan-1-yl)carbonyl)-4-terbisil)phthalazine-1(2H)-he

To a suspension of the compound obtained in example 135A (43 mg, 0.06 mmol), in dichloromethane (5 ml) is added tripto the acetic acid (1 ml) at room temperature. The solution is incubated at room temperature for 1 hour and evaporated. The residue is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], column 250×2,54, mobile phase A: 0.1% of triperoxonane acid in H2O; B: 0.1% of triperoxonane acid in CH3CN; gradient 0-100%), getting mentioned in the title compound in the form of a salt triperoxonane acid. Salt triperoxonane acid dissolved in a mixture of methylene chloride and methanol and treated with 1M HCl solution in ether. Removal of volatile solvents results specified in the title compound in the form of an HCl salt. MS (DCI/NH3) m/z 338 (M+H)+.

EXAMPLE 136

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

A solution of the compound obtained in example 89 (20 mg, 0.08 mmol), 1-methylcyclopropene acid (10 mg, 0,096 mmol), HATU (2-(1H-7-asobancaria-1-yl)-1,1,3,3-tetramethylene hexaphosphate of methanamine) (38 mg, 0.1 mmol) and triethylamine (20 mg, 0.2 mmol) in dimethylacetamide (2.5 ml) was stirred at room temperature for 18 hours and then evaporated. The residue is dissolved in a mixture of dimethylsulfoxide/methanol (1:1) and separated by HPLC (analytical column Waters Sunfire® C-8 [Milford, MA], 0,1% triperoxonane acid/water/CH3CN), getting mentioned in the title compound. MS (DCI/NH3) m/z 338 (M+H)+;1H NMR (500 MHz, D2/sub> O/dimethylsulfoxide-d6): δ 0,57-0.69 (m, 2H), 1,02-1,10 (m, 2H), 1,38 (s, 3H), 1,57-of 1.65 (m, 4H), 2,29 is 2.44 (m, 4H), a 3.87 (s, 2H), 6.89 in (d, J=7,63 Hz, 1H), 7.23 percent (t, J=to 7.93 Hz, 1H), 7,42 (s, 1H), 7,46 (d, J=8,24 Hz, 1H).

EXAMPLE 137

2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)cyclopropanecarboxamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2-methylcyclopropane acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 338 (M+H)+.

EXAMPLE 138

3 ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide

Specified in the title compound receive in accordance with the procedure of example 136 using 3-ethoxypropanol acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 356 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ1H NMR (500 MHz, solvent): δ 1,08 (t, J=7,02 Hz, 3H), 1,54-of 1.64 (m, 4H), 2,32-to 2.42 (m, 4H), of 2.51 (t, J=6,26 Hz, 2H), 3.43 points (kV, J=7,02 Hz, 2H), to 3.64 (t, J=6,26 Hz, 2H), 3,88 (s, 2H), make 6.90 (d, J=7,63 Hz, 1H), 7,24 (t, J=7,78 Hz, 1H), was 7.36 (s, 1H), of 7.48 (d, J=to 7.93 Hz, 1H).

EXAMPLE 139

5-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-L-prolinamide

Specified in the title compound receive in accordance with the procedure of example 136 and using (S)-5-oxopyrrolidin-2-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 367 (M+H)+/sup> ;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56 to of 1.66 (m, 4H), 1.93 and-2,03 (m, 1H), 2,14-of 2.27 (m, 2H), 2,32 is 2.43 (m, 5H), of 3.96 (s, 2H), 4,19 (DD, J=8,70, was 4.42 Hz, 1H), 6,94 (d, J=7,63 Hz, 1H), 7,27 (t, J=to 7.93 Hz, 1H), 7,40 (s, 1H), 7,49 (d, J=7,93 Hz, 1H).

EXAMPLE 140

5-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-D-prolinamide

Specified in the title compound receive in accordance with the procedure of example 136 and using (R)-5-oxopyrrolidin-2-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 367 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56 to of 1.66 (m, 4H), 1.93 and-2,02 (m, 1H), 2,13 was 2.25 (m, 2H), 2,32-to 2.42 (m, 5H), to 3.89 (s, 2H), 4,18 (DD, J=8,70, was 4.42 Hz, 1H), 6,94 (d, J=7,63 Hz, 1H), 7,27 (t, J=to 7.93 Hz, 1H), 7,39 (s, 1H), 7,49 (d, J=8,24 Hz, 1H).

EXAMPLE 141

N1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)cyclopropane-1,1-dicarboxamide

Specified in the title compound receive in accordance with the procedure of example 136 using 1-carbamoylaspartate acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 367 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,35-of 1.44 (m, 4H), 1,55-to 1.67 (m, 4H), 2,31 is 2.44 (m, 4H), 3,88 (s, 2H), 6,91 (d, J=7,63 Hz, 1H), 7,26 (t, J=7,78 Hz, 1H), 7,40 (s, 1H), 7,43 (d, J=to 7.93 Hz, 1H).

EXAMPLE 142

2-(benzyloxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide

Specified in the title compounds is their gain in accordance with the procedure of example 136, using 2-(benzyloxy)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 404 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56 to of 1.64 (m, 4H), 2,32-to 2.42 (m, 4H), to 3.89 (s, 2H), 4,06 (s, 2H), 4,60 (s, 2H), 6,93 (d, J=7,63 Hz, 1H), 7,26 (t, J=7,78 Hz, 1H), 7,31-7,34 (m, 1H), was 7.36-7,42 (m, 5H), 7,50 (d, J=to 7.93 Hz, 1H).

EXAMPLE 143

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

Specified in the title compound receive in accordance with the procedure of example 136 using 3-phenylpropane acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 388 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,55-1,65 (m, 4H), 2,32-to 2.42 (m, 4H), 2,60 (t, J=7,63 Hz, 2H), 2,89 (t, J=7,63 Hz, 2H), a 3.87 (s, 2H), 6.89 in (d, J=7,63 Hz, 1H), 7,18 (t, J=7,17 Hz, 1H), 7,21-7,26 (m, 3H), 7,28 (t, J=of 7.48 Hz, 2H), 7,32 (, 1H), 7,45 (d, J=8,24 Hz, 1H).

EXAMPLE 144

3-(2,5-acid)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide

Specified in the title compound receive in accordance with the procedure of example 136, using 3-(2,5-acid)propanoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 448 (M+H)+.

EXAMPLE 145

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

Specified in the title compound receive in accordance with the procedure of example 136, use the I 1-phenylcyclopropanecarboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 400 (M+H)+.

EXAMPLE 146

(2S)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-phenylbutane

Specified in the title compound receive in accordance with the procedure of example 136 and using (S)-2-phenylbutanoate acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 402 (M+H)+.

EXAMPLE 147

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

Specified in the title compound receive in accordance with the procedure of example 136 using 4-phenylbutanoate acid 1-methylcyclopropene acid. MS (DCI/NH3) m/z 402 (M+H)+.

EXAMPLE 148

2-(3-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(m-tolyloxy)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 404 (M+H)+.

EXAMPLE 149

2-(2-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(o-tolyloxy)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 404 (M+H)+.

EXAMPLE 150

2-(4-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)Hairdryer is l)ndimethylacetamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(p-tolyloxy)acetic acid instead of 1-methylcyclopropane acid. MC (DCI/NH3) m/z 404 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56 to of 1.65 (m, 4H), of 2.23 (s, 3H), 2,33 is 2.44 (m, 4H), to 3.89 (s, 2H), br4.61 (s, 2H), to 6.88 (d, J=8.54 in Hz, 2H), 6,94 (d, J=7,63 Hz, 1H), 7,11 (d, J=8,24 Hz, 2H), 7,27 (t, J=7,78 Hz, 1H), 7,41 (s, 1H), 7,50 (d, J=8,24 Hz, 1H).

EXAMPLE 151

(2R)-2-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-phenylacetamide

Specified in the title compound receive in accordance with the procedure of example 136 and using (R)-2-methoxy-2-phenylacetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 404 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,53-of 1.66 (m, 4H), 2,29 is 2.44 (m, 4H), to 3.35 (s, 3H), a 3.87 (s, 2H), to 4.81 (s, 1H), 6,91 (d, J=7,63 Hz, 1H), 7,25 (t, J=to 7.93 Hz, 1H), 7,33 and 7.36 (m, 1H), 7,39 (t, J=7,17 Hz, 2H), 7,45-7,49 (m, 3H), 7,52 (d, J=8,24 Hz, 1H).

EXAMPLE 152

(2S)-2-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-phenylacetamide

Specified in the title compound receive in accordance with the procedure of example 136 and using (S)-2-methoxy-2-phenylacetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 404 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,53-of 1.66 (m, 4H), 2,30-to 2.42 (m, 4H), to 3.34 (s, 3H), with a 3.87, 2H), to 4.81 (s, 1H), 6,91 (d, J=7,63 Hz, 1H), 7,25 (t, J=to 7.93 Hz, 1H), 7,32 and 7.36 (m, 1H), 7,39 (t, J=7,17 Hz, 2H), 7,44-7,49 (m, 3H), 7,51 (d, J=8,24 Hz, 1H).

EXAMPLE 153

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

Specified in the title compound receive in accordance with the procedure of example 136 using 3-phenoxypropanol acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 404 (M+H)+.

EXAMPLE 154

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-Tien-2-albuminemia

Specified in the title compound receive in accordance with the procedure of example 136, using 4-(thiophene-2-yl)butane acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 408 (M+H)+.

EXAMPLE 155

1-acetyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)piperidine-4-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136 using 1-acetylpiperidine-4-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 409 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,36 of 1.46 (m, 1H), 1,52-to 1.67 (m, 5H), to 1.79 (t, J=14,19 Hz, 2H), 2,02 (s, 3H), 2,30 is 2.43 (m, 4H), of 2.56 2.63 in (m, 1H), 3,06 (t, J=12,97 Hz, 1H), 3,85-3,90 (m, 2H), of 3.97 (s, 2H), 4,39 (d, J=13,43 Hz, 1H), 6.89 in (d, J=7,63 Hz, 1H), 7,24 (t, J=7,78 Hz, 1H), 7,38 (s, 1H), of 7.48 (d, J=8,24 Hz, 1H).

EXAMPLE 156

2-(3,5-differenl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydric Latin-1-yl)methyl)phenyl)ndimethylacetamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(3,5-differenl)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 410 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,53-to 1.67 (m, 4H), 2,31-to 2.42 (m, 4H), to 3.67 (s, 2H), 3,88 (s, 2H), 6,91 (d, J=7,63 Hz, 1H),? 7.04 baby mortality (d, J=6,41 Hz, 1H), 7,07-7,13 (m, 1H), 7,25 (t, J=to 7.93 Hz, 1H), was 7.36 (s, 1H), 7,46 (d, J=8,24 Hz, 1H).

EXAMPLE 157

N2-acetyl-N1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-L-leucinamide

Specified in the title compound receive in accordance with the procedure of example 136 and using (S)-2-acetamido-4-methylpentanol acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 411 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 0,88 (d, J= of 6.71 Hz, 3H), of 0.90 (d, J= of 6.71 Hz, 3H), 1,43-of 1.53 (m, 2H), 1.56 to of 1.66 (m, 5H), to 1.87 (s, 3H), 2,29 is 2.43 (m, 4H), 3,88 (s, 2H), 4,39 (DD, J=being 9.61, of 5.34 Hz, 1H), 6,91 (d, J=7,63 Hz, 1H), 7,25 (t, J=for 7.78 Hz, 1H), 7,38 (s, 1H), 7,49 (d, J=8,24 Hz, 1H).

EXAMPLE 158

N1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-N2N2-dipropyl-L-alaninate

Specified in the title compound receive in accordance with the procedure of example 136 and using (S)-2-(dipropylamino)propanoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 411 (M+H)+.

EXAMPLE 159

4-the CSR-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-phenylbutyramide

Specified in the title compound receive in accordance with the procedure of example 136, using 4-oxo-4-phenylbutanoate acid instead of 1-methylcyclopropane acid. MC (DCI/NH3) m/z 411 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,55-of 1.66 (m, 4H), 2,31-to 2.42 (m, 4H), 2,70 (t, J=6,26 Hz, 2H), 3,32 (t, J=6,26 Hz, 2H), a 3.87 (s, 2H), to 6.88 (d, J=7,63 Hz, 1H), 7.23 percent (t, J=to 7.93 Hz, 1H), 7,37 (s, 1H), 7,45 (d, J=8,24 Hz, 1H), 7,55 (t, J=7,63 Hz, 2H), 7,66 (t, J=7,32 Hz, 1H), 7,99 (t, J=6,41 Hz, 2H).

EXAMPLE 160

N-(2-oxo-2-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenylamino)ethyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2-benzamidoxime acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 417 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,55-of 1.66 (m, 4H), 2,31-to 2.40 (m, 4H), to 3.89 (s, 2H), Android 4.04 (s, 2H), 6,92 (d, J=to 7.93 Hz, 1H), 7,26 (t, J=to 7.93 Hz, 1H), 7,38 (s, 1H), 7,47 (d, J=8,24 Hz, 1H), 7,49-rate of 7.54 (m, 2H), 7,58 (t, J=7,32 Hz, 1H), 7,85-of 7.90 (m, 2H).

EXAMPLE 161

3-(3-methoxyphenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide

Specified in the title compound receive in accordance with the procedure of example 136, using 3-(3-methoxyphenyl)propanoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 418 (M+H)+.

EXAMPLE 162

3-(4-methoxyphenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-the l)methyl)phenyl)propanamide

Specified in the title compound receive in accordance with the procedure of example 136, using 3-(4-methoxyphenyl)propanoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 418 (M+H)+.

EXAMPLE 163

2-(3,4-dimethylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(3,4-dimethylphenoxy)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 418 (M+H)+.

EXAMPLE 164

(2R)-2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-phenylbutyramide

Specified in the title compound receive in accordance with the procedure of example 136 and using (R)-2-hydroxy-4-phenylbutanoate acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 418 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,55-1,65 (m, 4H), 1,80-1,90 (m, 1H), 1,95-2,03 (m, 1H), 2,31 is 2.44 (m, 4H), 2,69 (t, J=to 7.93 Hz, 2H), 3,88 (s, 2H), 3.96 points (s, 1H), 4,01 (DD, J=8,09, 4,12 Hz, 1H), 6,91 (d, J=7,63 Hz, 1H), 7,17-of 7.23 (m, 3H), of 7.25 (t, J=7,78 Hz, 1H), 7,29 (t, J=of 7.48 Hz, 2H), 7,49 (s, 1H), 7,53 (d, J=to 7.93 Hz, 1H).

EXAMPLE 165

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

Specified in the title compound receive in accordance with the procedure of example 136 using 4-phenoxybutyl acid instead of 1-metals klonopinklonopin acid. MS (DCI/NH3) m/z 418 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,55-to 1.67 (m, 4H), 1,96-to 2.06 (m, 2H), 2,31-to 2.42 (m, 4H), 2,47 (t, J=of 7.48 Hz, 2H), 3,88 (s, 2H), 3,99 (t, J=6,26 Hz, 2H), 6.87 in-6,91 (m, 2H), 6,91-of 6.96 (m, 2H), 7,24 (t, J=7,78 Hz, 1H), 7,26-7,30 (m, 2H), of 7.36 (s, 1H), of 7.48 (d, J=8,24 Hz, 1H).

EXAMPLE 166

4-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-Tien-2-albuminemia

Specified in the title compound receive in accordance with the procedure of example 136, using 4-oxo-4-(thiophene-2-yl)butane acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 422 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,55-1,65 (m, 4H), 2,32-to 2.42 (m, 4H), 2,69 (t, J=6,41 Hz, 2H), 3,26 (t, J=6,41 Hz, 2H), a 3.87 (s, 2H), to 6.88 (d, J=7,63 Hz, 1H), 7.23 percent (t, J=to 7.93 Hz, 1H), 7,25-7,29 (m, 1H), 7,37 (s, 1H), 7,44 (d, J=8,24 Hz, 1H), of 7.97 (d, J=4,88 Hz, 1H), to 7.99 (d, J=2,75 Hz, 1H).

EXAMPLE 167

2-((4-methylpyrimidin-2-yl)thio)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(4-methylpyrimidin-2-ylthio)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 422 (M+H)+.

EXAMPLE 168

3-(2-chlorophenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide

Specified in the title compound receive in accordance with the procedure of example 136, using 3-(2-chlorophenyl)disappear to the OIC acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 422 (M+H)+.

EXAMPLE 169

3-(4-chlorophenyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)propanamide

Specified in the title compound receive in accordance with the procedure of example 136, using 3-(4-chlorophenyl)propanoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 422 (M+H)+.

EXAMPLE 170

3-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-phenylpentane

Specified in the title compound receive in accordance with the procedure of example 136, using 3-methyl-2-phenylpentane acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 430 (M+H)+.

EXAMPLE 171

2-(4-chloro-2-methylphenoxy)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)ndimethylacetamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(4-chloro-2-methylphenoxy)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 438 (M+H)+.

EXAMPLE 172

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-N'-phenylenediamine

Specified in the title compound receive in accordance with the procedure of example 136 using 5-oxo-5-(phenylamino)pentane acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 445 (M+H)+;1H NMR (500 MHz, D2O/dimetilan the oxide- d6): δ 1,55-1,65 (m, 4H), 1,84-of 1.94 (m, 2H), 2,31-to 2.42 (m, 8H), a 3.87 (s, 2H), 6.89 in (d, J=7,63 Hz, 1H), 7,05 (t, J=7,32 Hz, 1H), 7,24 (t, J=to 7.93 Hz, 1H), 7,30 (t, J=8,09 Hz, 2H), was 7.36 (s, 1H), of 7.48 (d, J=8,24 Hz, 1H), EUR 7.57 (d, J=7,63 Hz, 2H).

EXAMPLE 173

4-(4-methoxyphenyl)-4-oxo-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)butanamide

Specified in the title compound receive in accordance with the procedure of example 136, using 4-(4-methoxyphenyl)-4-oxobutanoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 446 (M+H)+.

EXAMPLE 174

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2,2-diphenylacetamide

Specified in the title compound receive in accordance with the procedure of example 136, 2,2-diphenyloxazole acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 450 (M+H)+.

EXAMPLE 175

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-(phenylsulfonyl)propanamide

Specified in the title compound receive in accordance with the procedure of example 136, using 3-(phenylsulfonyl)propanoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 452 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,52 is 1.70 (m, 4H), 2,29-to 2.42 (m, 4H), to 2.66 (t, J=to 7.32 Hz, 2H)and 3.59 (t, J=to 7.32 Hz, 2H), a 3.87 (s, 2H), make 6.90 (d, J=7,32 Hz, 1H), 7,20-7,26 (m, 2H), 7,37 (d, J=8.54 in Hz, 1H), 7,66 (t, J=7,63 Hz, 2H), 7,74 (t, J=of 7.48 Hz, 1H), to $ 7.91 (d, J=to 7.32 Hz, 2H).

EXAMPLE 176/p>

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-(3-phenoxyphenyl)ndimethylacetamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(3-phenoxyphenyl)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 466 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,54-of 1.65 (m, 4H), 2,29-to 2.42 (m, 4H), of 3.60 (s, 2H), a 3.87 (s, 2H), 6,86-6,92 (m, 2H), 6,98-7,03 (m, 3H), 7,10 (d, J=to 7.93 Hz, 1H), 7,16 (t, J=of 7.48 Hz, 1H), 7,24 (t, J=7,78 Hz, 1H), 7,32-7,37 (m, 2H), 7,38-7,42 (m, 2H), 7,46 (d, J=8,24 Hz, 1H).

EXAMPLE 177

4-ethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 4-ethylbenzoyl acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 388 (M+H)+.

EXAMPLE 178

3-fluoro-2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136, using 3-fluoro-2-methylbenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 392 (M+H)+.

EXAMPLE 179

5-fluoro-2-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136, using 5-fluoro-2-methylbenzoic acid is 1-methylcyclopropene acid. MS (DCI/NH3) m/z 392 (M+H)+.

EXAMPLE 180

3-fluoro-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136, using 3-fluoro-4-methylbenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 392 (M+H)+.

EXAMPLE 181

2,3-debtor-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2,3-differentyou acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 396 (M+H)+.

EXAMPLE 182

2,4-debtor-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2,4-differentyou acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 396 (M+H)+.

EXAMPLE 183

2.5-debtor-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2.5-differentyou acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 396 (M+H)+.

EXAMPLE 184

3,5-debtor-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

is shown in the title compound receive in accordance with the procedure of example 136, using 3,5-differentyou acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 396 (M+H)+.

EXAMPLE 185

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

Specified in the title compound receive in accordance with the procedure of example 136 using 4-propylbenzoyl acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 402 (M+H)+.

EXAMPLE 186

4-isopropyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 4-isopropylbenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 402 (M+H)+.

EXAMPLE 187

2 ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 4-ethoxybenzoyl acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 404 (M+H)+.

EXAMPLE 188

4 isopropoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 4-isopropoxybenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 418 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ of 1.30 (d, J=6,10 Hz, 6H), 1,53-to 1.67 (m, 4H), 2,33 is 2.46 (m, 4H), 3,91 (s, 2H), 4,67-4,80 (m, 1H), 6,94 (d, J=7,63 Hz, 1H), 7,02 (d, J=cent to 8.85 Hz, 2H), 7,29 (t, J=7,78 Hz, 1H), 7,55 (s, 1H), 7.62mm (d, J=8,24 Hz, 1H), 7,89 (d, J=cent to 8.85 Hz, 2H).

EXAMPLE 189

4-(diethylamino)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136, using 4-(diethylamino)benzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 431 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,11 (t, J=7,02 Hz, 6H), 1,57-of 1.66 (m, 4H), 2,34 is 2.44 (m, 4H), 3.45 points (kV, J=7,02 Hz, 4H), 3,91 (s, 2H), 6.87 in (d, J=cent to 8.85 Hz, 2H), 6,91 (d, J=7,63 Hz, 1H), 7,27 (t, J=to 7.93 Hz, 1H), 7,55 (s, 1H), 7.62mm (d, J=8,24 Hz, 1H), a 7.85 (d, J=cent to 8.85 Hz, 2H).

EXAMPLE 190

4 butoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 4-butoxybenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 432 (M+H)+.

EXAMPLE 191

2-fluoro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-5-(trifluoromethyl)benzamid

Specified in the title compound receive in accordance with the procedure of example 136, using 2-fluoro-5-(trifluoromethyl)benzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 446 (M+H)+

EXAMPLE 192

2-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-5-(trifluoromethyl)benzamid

Specified in the title compound receive in accordance with the procedure of example 136, using 2-chloro-5-(trifluoromethyl)benzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 461 (M+H)+.

EXAMPLE 193

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-furamide

Specified in the title compound receive in accordance with the procedure of example 136 using furan-2-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 350 (M+H)+.

EXAMPLE 194

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

Specified in the title compound receive in accordance with the procedure of example 136 using furan-3-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 350 (M+H)+.

EXAMPLE 195

2,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-furamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2.5-dimethylfuran-3-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 378 (M+H)+.

EXAMPLE 196

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)thiophene-2-carboxamide

Specified in the title is Obedinenie receive in accordance with the procedure of example 136, using thiophene-2-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 366 (M+H)+.

EXAMPLE 197

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)thiophene-3-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136 using thiophene-3-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 366 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,54-of 1.66 (m, 4H), 2,32 is 2.44 (m, 4H), to 3.92 (s, 2H), of 6.96 (d, J=7,63 Hz, 1H), 7,30 (t, J=to 7.93 Hz, 1H), 7,53 (s, 1H), to 7.59-the 7.65 (m, 3H), 8,31 (DD, J=2,75, of 1.53 Hz, 1H).

EXAMPLE 198

3-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)thiophene-2-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136 using 3-methylthiophene-2-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 380 (M+H)+.

EXAMPLE 199

5-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)thiophene-2-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136, using a 5-methylthiophene-2-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 380 (M+H)+.

EXAMPLE 200

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-pyrrol-2-carboxamide

Specified in C is glavie connection receive in accordance with the procedure of example 136, using pyrrole-3-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 349 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56 to of 1.66 (m, 4H), 2,33 is 2.44 (m, 4H), 3,91 (s, 2H), 6,18 (DD, J=3,51, to 2.29 Hz, 1H), 6,92 (d, J=7,63 Hz, 1H), 6,98 (d, J=1,53 Hz, 1H), 7.03 is-7,07 (m, 1H), 7,27 (t, J=to 7.93 Hz, 1H), 7,53 (s, 1H), 7,60 (d, J=to 7.93 Hz, 1H).

EXAMPLE 201

1-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-pyrrol-2-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136, using 1-methyl-1H-pyrrole-2-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 363 (M+H)+.

EXAMPLE 202

2,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-pyrrol-3-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2,5-dimethyl-1H-pyrrole-3-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 377 (M+H)+.

EXAMPLE 203

1,2,5-trimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-pyrrol-3-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136, using 1-methyl-1H-pyrrole-3-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 363 (M+H)+.

EXAMPLE 204

N-(3-((4-oxo-3,4,5,6,7,8-hexage ritalin-1-yl)methyl)phenyl)-1,3-thiazol-2-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136 using thiazole-2-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 367 (M+H)+.

EXAMPLE 205

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1,3-thiazole-4-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136 using thiazole-4-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 367 (M+H)+.

EXAMPLE 206

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1,3-thiazole-5-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136 using thiazole-5-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 367 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,54-to 1.67 (m, 2H), 2,32 is 2.44 (m, 2H), 3,92 (s, 2H), 7,00 (d, J=7,63 Hz, 1H), 7,32 (t, J=to 7.93 Hz, 1H), 7,49 (s, 1H), to 7.59 (d, J=8,24 Hz, 1H), 8,66 (s, 1H), 9,27 (s, 1H).

EXAMPLE 208

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)isoxazol-5-carboxamid

Specified in the title compound receive in accordance with the procedure of example 136 using isoxazol-5-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 351 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxid the- d6): δ 1,54 by 1.68 (m, 4H), 2,33 at 2.45 (m, 4H), 3,93 (s, 2H), 7,03 (d, J=7,63 Hz, 1H), 7,22 (d, J=2,14 Hz, 1H), 7,34 (t, J=to 7.93 Hz, 1H), 7,54 (s, 1H), 7,63 (d, J=to 7.93 Hz, 1H), 8,77 (d, J=1,83 Hz, 1H).

EXAMPLE 209

3,5-dimethyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)isoxazol-4-carboxamid

Specified in the title compound receive in accordance with the procedure of example 136 using 3,5-dimethylisoxazol-4-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 379 (M+H)+.

EXAMPLE 210

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

Specified in the title compound receive in accordance with the procedure of example 136 using nicotinic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 361 (M+H)+.

EXAMPLE 211

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

Specified in the title compound receive in accordance with the procedure of example 136 using isonicotinoyl acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 361 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.57 in by 1.68 (m, 4H), 2,33 at 2.45 (m, 4H), of 3.94 (s, 2H),? 7.04 baby mortality (d, J=7,63 Hz, 1H), was 7.36 (t, J=7,78 Hz, 1H), 7,56 (s, 1H), 7,66 (d, J=8,24 Hz, 1H), 8,10 (d, J=6,41 Hz, 2H), of 8.90 (d, J=6,10 Hz, 2H).

EXAMPLE 212

3-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyridine-2-carboxamide

is shown in the title compound receive in accordance with the procedure of example 136, using 3-gidroksipropilovu acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 377 (M+H)+.

EXAMPLE 213

2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)nicotinamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2-hydroxynicotinic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 377 (M+H)+.

EXAMPLE 214

6-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)nicotinamide

Specified in the title compound receive in accordance with the procedure of example 136, using 6-hydroxynicotinic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 377 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,53-of 1.65 (m, 4H), 2,32 is 2.43 (m, 4H), 3,91 (s, 2H), 6,45 (d, J=10,07 Hz, 1H), 6,95 (d, J=7,63 Hz, 1H), 7,29 (t, J=to 7.93 Hz, 1H), 7,46 (s, 1H), EUR 7.57 (d, J=8,24 Hz, 1H), 7,98 (DD, J=9,76, a 2.75 Hz, 1H), 8,16 (d, J=2,14 Hz, 1H).

EXAMPLE 215

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-pyridin-2-ylacetamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(pyridin-2-yl)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 375 (M+H)+.

EXAMPLE 216

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-pyridin-3-ilocate the ID

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(pyridin-3-yl)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 375 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,54-of 1.66 (m, 4H), 2,30-to 2.42 (m, 4H), 3,88 (s, 2H), 3,98 (s, 2H), 6,94 (d, J=7,32 Hz, 1H), 7,27 (t, J=to 7.93 Hz, 1H), 7,38 (s, 1H), 7,46 (d, J=cent to 8.85 Hz, 1H), 8,04 (DD, J=7,93, 5,80 Hz, 1H), charged 8.52 (d, J=8,24 Hz, 1H), 8,81 (d, J=5,49 Hz, 1H), cent to 8.85 (s, 1H).

EXAMPLE 217

5-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyrazin-2-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136, using a 5-methylpyrazine-2-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 376 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,54 was 1.69 (m, 4H), 2,34 is 2.46 (m, 4H), 2.63 in (s, 3H), 3,93 (s, 2H), 7,00 (d, J=7,63 Hz, 1H), 7,33 (t, J=8,09 Hz, 1H), 7.68 per-7,74 (m, 2H), 8,68 (s, 1H), 9,13 (d, J=1,22 Hz, 1H).

EXAMPLE 218

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1H-indol-3-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136, using 1H-indole-3-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 399 (M+H)+.

EXAMPLE 219

5-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-1-phenyl-1H-pyrazole-4-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136, using 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 440 (M+H)+.

EXAMPLE 220

6-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2H-chromen-3-carboxamide

Specified in the title compound receive in accordance with the procedure of example 136, using 6-chloro-2H-chromen-3-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 448 (M+H)+.

EXAMPLE 221

N3N3-dimethyl-N1-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-beta-alaninemia

Specified in the title compound receive in accordance with the procedure of example 136, using 3-(dimethylamino)propanoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 355 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,55-of 1.66 (m, 4H), 2,30 is 2.43 (m, 4H), 2.77-to of 2.93 (m, 10H), 3,93 (s, 2H), 6,74 (s, 1H), 6.90 to (DD, J=8,09, to 1.37 Hz, 1H), 7,06 (d, J=7,63 Hz, 1H), 7,37 (t, J=7,78 Hz, 1H).

EXAMPLE 222

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

EXAMPLE 222A

2-(3-bromophenyl)-N-methoxy-N-methylacetamide

To a solution of 2-(3-bromophenyl)acetic acid (4.4 g, 20,56 mmol) in N,N-dimethylformamide (125 ml) was successively added N,O-dimetilgidrazina is in (4.5 g, 46,26 mmol), triethylamine (10 ml), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (8,9 g, 46,26 mmol) and 1-hydroxybenzotriazole (6,24 g, 46,26 mmol). The reaction mixture was stirred at room temperature overnight and distributed between ethyl acetate and a saturated solution of salt. The organic phase is washed with saturated salt solution and concentrated. The residue is purified flash chromatography on silica gel (50% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 258 (M+H)+.

EXAMPLE 222B

2-(3-bromophenyl)acetaldehyde

A solution of the compound obtained in example 222A (2.5 g, 9.7 mmol) in anhydrous tetrahydrofuran (50 ml) is treated with LiAlH4(0,37 g, 9.7 mmol) at 0°C for 10 minutes and quenched with water. The mixture is distributed between ethyl acetate and a saturated solution of ammonium chloride. The organic phase is washed with water and concentrated. The residue is purified flash chromatography on silica gel (20% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 199 (M+H)+.

EXAMPLE 222C

3-(2-(3-bromophenyl)ethylidene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the method of example 1C using the compound obtained in example 222B, instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 319 (M+H)+.

EXAMPLE 222D

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

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 222C, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 333 (M+H)+.

EXAMPLE 223

4-(2-(3-bromo-4-forfinal)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 223A

2-(3-bromo-4-forfinal)acetaldehyde

Specified in the title compound receive in accordance with the method of example 222, using 2-(3-bromo-4-forfinal)acetic acid instead of 2-(3-bromophenyl)acetic acid in example 223B. MS (DCI/NH3) m/z 216 (M+H)+.

EXAMPLE 223B

4-(2-(3-bromo-4-forfinal)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 1C using the compound obtained in example 223A, instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 351 (M+H)+.

EXAMPLE 224

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

EXAMPLE 224A

3-(2,2,2-Cryptor-1-fenretinide)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the procedure of example 1C, using 2,2,2-Cryptor-1-phenylethanol instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 295 (M+H)+.

EXAMPLE 224B

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

Specified in the title compound floor is up in accordance with the procedure of example 2C, using the compound obtained in example 224A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 309 (M+H)+.

EXAMPLE 225

2-hydroxy-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2-hydroxy-4-methylbenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 390 (M+H)+.

EXAMPLE 226

4-acetyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 4-acetylbenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 402 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,54 was 1.69 (m, 4H), 2,34 is 2.46 (m, 4H), of 2.64 (s, 3H), 3,93 (s, 2H), 6,99 (d, J=7,63 Hz, 1H), 7,32 (t, J=to 7.93 Hz, 1H), EUR 7.57 (s, 1H), 7,65 (d, J=to 7.93 Hz, 1H), 8,01-with 8.05 (m, 2H), 8,05-8,10 (m, 2H).

EXAMPLE 227

3-methoxy-4-methyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136, using 3-methoxy-4-methylbenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 404 (M+H)+.

EXAMPLE 228

4 ethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

The decree of the TES in the title compound receive in accordance with the procedure of example 136, using 4-ethoxybenzoyl acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 404 (M+H)+.

EXAMPLE 229

3-fluoro-4-methoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136, using 3-fluoro-4-methoxybenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 408 (M+H)+.

EXAMPLE 230

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

Specified in the title compound receive in accordance with the procedure of example 136 using 1-naphthoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 410 (M+H)+.

EXAMPLE 231

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-naptime

Specified in the title compound receive in accordance with the procedure of example 136 using 2-naphthoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 410 (M+H)+.

EXAMPLE 232

5-chloro-2-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2-hydroxy-5-methylbenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 390 (M+H)+.

EXAMPLE 233

4-tert-b is Teal-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136, using 4-tert-butylbenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 416 (M+H)+.

EXAMPLE 234

4-(acetylamino)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 4-acetamidobenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 417 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,53 by 1.68 (m, 4H), 2,10 (s, 3H), 2,33 is 2.44 (m, 4H), to 3.92 (s, 2H), 6,95 (d, J=to 7.93 Hz, 1H), 7,30 (t, J=to 7.93 Hz, 1H), 7,56 (s, 1H), 7,63 (d, J=7,63 Hz, 1H), of 7.70 (d, J=cent to 8.85 Hz, 2H), of 7.90 (d, J=cent to 8.85 Hz, 2H,).

EXAMPLE 235

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

Specified in the title compound receive in accordance with the procedure of example 136 using 4-propoxybenzene acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 418 (M+H)+.

EXAMPLE 236

1-hydroxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-naptime

Specified in the title compound receive in accordance with the procedure of example 136 using 1-hydroxy-2-naphthoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 426 (M+H)+.

EXAMPLE 237

2-chlor-(methylthio)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-chloro-5-(methylthio)benzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 440 (M+H)+.

EXAMPLE 238

3,4-diethoxy-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 3,4-diethoxybenzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 448 (M+H)+.

EXAMPLE 239

2-benzyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2-benzoylbenzene acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 450 (M+H)+.

EXAMPLE 240

2-aniline-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound is obtained in the form of salt triperoxonane acid in accordance with the procedure of example 136, using 2-(phenylamino)benzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 451 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,55 by 1.68 (m, 4H), 2,31 at 2.45 (m, 4H), 3,91 (s, 2H), 6,91-of 6.99 (m, 3H), 7,13 (d, J=7,63 Hz, 2H), 7,27-7,34 (m, 4H), 7,38-7,42 (m, 1H), 7,49 (s, 1H), 7,58 (d, J=cent to 8.85 Hz, 1H), 7,71 to 7.75 (m, 1H).

p> EXAMPLE 241

2-benzoyl-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2-benzoylbenzene acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 464 (M+H)+.

EXAMPLE 242

N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-2-(2-phenylethyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 2-phenetylamine acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 464 (M+H)+.

EXAMPLE 243

5-bromo-2-chloro-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136, using 5-bromo-2-chlorbenzoyl acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 472 (M+H)+.

EXAMPLE 244

2-(4-methylbenzoyl)-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136, using 2-(4-methylbenzoyl)benzoic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 478 (M+H)+.

EXAMPLE 245

2-iodine-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title with the unity gain in accordance with the procedure of example 136, using 2-identify acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 486 (M+H)+.

EXAMPLE 246

3-iodine-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 3-identify acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 486 (M+H)+.

EXAMPLE 247

4-iodine-N-(3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)benzamide

Specified in the title compound receive in accordance with the procedure of example 136 using 4-identify acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 486 (M+H)+.

EXAMPLE 248

N-(2'-fluoro-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-3-yl)ndimethylacetamide

Specified in the title compound is obtained in the form of the free base in accordance with the method of example 39 using 3-acetaminophenydrocodone acid instead of 3-pyridineboronic acid, but excluding the last stage of obtaining the HCl salt. MS (DCI/NH3) m/z 392 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,58-to 1.67 (m, 4H), of 2.05 (s, 3H), 2,33-2,39 (m, 2H), 2.40 a is 2.46 (m, 2H), 3,95 (s, 2H), 7,16 (d, J=7,02 Hz, 1H), 7.18 in-7,21 (m, 1H), 7,22-7,27 (m, 1H), 7,30 (DD, J=7,63, and 2.14 Hz, 1H), 7,38 (t, J=to 7.93 Hz, 1H), to 7.59 (d, J=7,32 Hz, 1H), 7,76 (s, 1H), 10,04 (ush. s, 1H), 12,61 (ush. s, 1H).

EXAMPLE 249

4-((6-fluoro-3'-(meth sulfonyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound is obtained in the form of the free base in accordance with the method of example 39 using 3-(methylsulphonyl)phenylboronic acid instead of 3-pyridineboronic acid, but excluding the last stage of obtaining the HCl salt. MS (DCI/NH3) m/z 413 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,57-of 1.73 (m, 4H), 2,34-to 2.41 (m, 2H), 2,41-2,48 (m, 2H), or 3.28 (s, 3H), 3,98 (s, 2H), 7.24 to 7,28 (m, 1H), 7,28-7,33 (m, 1H), 7,47 (DD, J=7,63, and 2.14 Hz, 1H), to 7.77 (t, J=7,78 Hz, 1H), of 7.90 (d, J=to 7.93 Hz, 1H), of 7.96-of 8.00 (m, 1H), 8,04 (s, 1H), 12,61 (ush. s, 1H).

EXAMPLE 250

4-((6-fluoro-3'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound is obtained in the form of the free base in accordance with the method of example 39 using 3-(pyrrolidin-1-carbonyl)phenylboronic acid instead of 3-pyridineboronic acid, but excluding the last stage of obtaining the HCl salt. MS (DCI/NH3) m/z 432 (M+H)+.

EXAMPLE 251

4-((6-fluoro-4'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound is obtained in the form of the free base in accordance with the method of example 39, using 4-(pyrrolidin-1-carbonyl)phenylboronic acid instead of 3-pyridineboronic acid, but excluding the last stage of obtaining the HCl salt. MS (DCI/NH3) m/z 432 (M+H)+;1H NMR (500 MHz, dimethylsulfone the led-d 6): δ 1.57 in by 1.68 (m, 4H), 1,78-of 1.93 (m, 4H), 2,32-2,39 (m, 2H), 2.40 a-2,47 (m, 2H), 3,39-of 3.53 (m, 4H), of 3.95 (s, 2H), 7,21-7,24 (m, 1H), 7.24 to 7,31 (m, 1H), 7,39 (DD, J=7,63, to 1.86 Hz, 1H), 7,55-to 7.59 (m, 2H), 7,60-to 7.64 (m, 2H), 12,60 (ush. s, 1H).

EXAMPLE 252

2'-fluoro-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-3-carboxamide

Specified in the title compound is obtained in the form of the free base in accordance with the method of example 39 using 3-carbamoilirovaniem acid instead of 3-pyridineboronic acid, but excluding the last stage of obtaining the HCl salt. MS (DCI/NH3) m/z 378 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,55-1,72 (m, 4H), 2,33-to 2.41 (m, 2H), 2,41-2,47 (m, 2H), of 3.97 (s, 2H), 7,19-7,24 (m, 1H), 7.24 to 7,30 (m, 1H), 7,42 (DD, J=7,63, and 2.14 Hz, 1H), 7,44 (s, 1H), 7,56 (t, J=7,78 Hz, 1H), 7,68 (d, J=7,63 Hz, 1H), 7,88-a 7.92 (m, 1H), 8,02 (s, 1H), 8,07 (s, 1H), was 12.61 (s, 1H).

EXAMPLE 253

2'-fluoro-N,N-dimethyl-5'-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-1,1'-biphenyl-4-carboxamid

Specified in the title compound is obtained in the form of the free base in accordance with the method of example 39, using 4-(dimethylcarbamoyl)phenylboronic acid instead of 3-pyridineboronic acid, but excluding the last stage of obtaining the HCl salt. MS (DCI/NH3) m/z 406 (M+H)+.1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.56 to 1.69 in (m, 4H), 2,31-to 2.40 (m, 2H), 2.40 a-2,47 (m, 2H), 2.95 and (s, 3H), of 3.00 (s, 3H), of 3.96 (s, 2H), 7,20-7,24 (m, 1H), 7.24 to 7,30 (m, 1H), 7,40 (DD, J=of 7.48, to 1.98 Hz, 1H), 7,49-7,52 (m, 1H), 7,56-to 7.59 (m, 2H), 7,60-the 7.65 (m, 1H), 12,61 (ush. the, 1H).

EXAMPLE 254

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

EXAMPLE 254A

3-(1,1,1-Cryptor-3-phenylpropane-2-ilidene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the method of example 1C using 1,1,1-Cryptor-3-phenylpropane-2-he instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 309 (M+H)+.

EXAMPLE 254B

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

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 254A, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 323 (M+H)+.

EXAMPLE 255

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

Specified in the title compound is obtained as a side product in accordance with the method of example 101, using the compound obtained in example 222, instead of the compound obtained in example 103. MS (DCI/NH3) m/z 255 (M+H)+.

EXAMPLE 256

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

EXAMPLE 256A

2-(3-bromophenyl)-N-methoxy-N-methylpropanamide

A solution of the compound obtained in example 222A (3.5 g, 13.56 mmol)in anhydrous tetrahydrofuran (50 ml) is treated with 1N solution of dicyanamide sodium in tetrahydrofuran (16 ml, 16,27 mmol) at -78°C for 1 hour. To with whom thou syringe add logmean (3,85 g, 27,1 mmol) and the mixture allow to warm to room temperature for 2 hours. The mixture is evaporated and the residue distributed between ethyl acetate and a saturated solution of salt. The organic phase is evaporated, the residue is purified flash chromatography (30% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 273 (M+H)+.

EXAMPLE 256B

2-(3-bromophenyl)propanol

Specified in the title compound receive in accordance with the method of example 222B using the compound obtained in example 256A, instead of the compound obtained in example 222A. MS (DCI/NH3) m/z 214 (M+H)+.

EXAMPLE 256C

3-(2-(3-bromophenyl)propylidene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the method of example 1C using the compound obtained in example 256B, instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 334 (M+H)+.

EXAMPLE 256D

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

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 256C, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 348 (M+H)+.

EXAMPLE 257

tert-Butyl 2-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)piperazine-1-carboxylate

EXAMPLE 257A

4-benzyl-1-tert-butyl-2-(IU is hydroxy(methyl)carbarnoyl)piperazine-1,4 -, in primary forms

Specified in the title compound receive in accordance with the method of example 222A, using 4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid instead of 2-(3-bromophenyl)acetic acid. MS (DCI/NH3) m/z 408 (M+H)+.

EXAMPLE 257B

4-benzyl 1-tert-butyl 2-formylpiperazine-1,4, in primary forms

Specified in the title compound receive in accordance with the method of example 222B using the compound obtained in example 257A, instead of the compound obtained in example 222A. MS (DCI/NH3) m/z 349 (M+H)+.

EXAMPLE 257C

4-benzyl-1-tert-butyl 2-((3-oxo-4,5,6,7-tetrahydrothiopyran-1(3H)-ilidene)methyl)piperazine-1,4 -, in primary forms

Specified in the title compound receive in accordance with the method of example 1C using the compound obtained in example 257B, instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 469 (M+H)+.

EXAMPLE 257D

4-benzyl-1-tert-butyl 2-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)piperazine-1,4 -, in primary forms

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 257C, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 483 (M+H)+.

EXAMPLE 257E

tert-butyl 2-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)piperazine-1-carboxylate

Solution connection polucen the th in the example 257D (0,77 g, 1.6 mmol)in tetrahydrofuran (100 ml) is treated with 10% palladium-on-carbon (85 mg, 0.8 mmol) at room temperature in an atmosphere of hydrogen (balloon) overnight. The catalyst was removed by filtration and the filtrate evaporated. The residue is purified flash chromatography (methanol in CH2Cl2the elution gradient: 0-15%), getting mentioned in the title compound. MS (DCI/NH3) m/z 349 (M+H)+.

EXAMPLE 258

4-benzyl 1-tert-butyl 2-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)piperazine-1,4 -, in primary forms

Specified in the title compound receive in accordance with the method of example 257D. MS (DCI/NH3) m/z 483 (M+H)+.

EXAMPLE 259

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

EXAMPLE 259A

N-methoxy-N-methyl-2-(3-nitrophenyl)ndimethylacetamide

Specified in the title compound receive in accordance with the method of example 222A, using 3-nitrobenzoic acid instead of 2-(3-bromophenyl)acetic acid. MS (DCI/NH3) m/z 225 (M+H)+.

EXAMPLE 259B

2-(3-nitrophenyl)acetaldehyde

Specified in the title compound receive in accordance with the method of example 222B using the compound obtained in example 259A, instead of the compound obtained in example 222A.

EXAMPLE 259C

3-(2-(3-nitrophenyl)ethylidene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound get back in the availa able scientific C to the method of example 1C, using the compound obtained in example 259B, instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 286 (M+H)+.

EXAMPLE 259D

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

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 259C, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 300 (M+H)+.

EXAMPLE 260

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

A suspension of the compound obtained in example 259 (110 mg, 0,17 mmol), in methanol (20 ml) is treated with Raney Nickel (20 mg) at room temperature in an atmosphere of hydrogen (balloon) overnight. The solid product is filtered off and the filtrate is concentrated and receiving specified in the title compound. MS (DCI/NH3) m/z 270 (M+H)+.

EXAMPLE 261

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

A solution of the compound obtained in example 258 (35 mg, 0.1 mmol), triperoxonane acid (5 ml) was stirred at room temperature for 1 hour and evaporated. The residue is purified by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 249 (M+H)+.

EXAMPLE 262

4-(2-(3-(2-oxopyrrolidin-1-yl)Fe who yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in example 260 (100 mg, of 0.37 mmol)in methylene chloride (5 ml) is added 4-chlorobutyrate (52,3 mg of 0.37 mmol) and triethylamine (0,12 ml, 0.45 mmol). The mixture is stirred at room temperature overnight and then evaporated. The residue is dissolved in absolute ethanol (5 ml) and treated with ethoxide sodium (0.2 ml, 21% (wt.) in ethanol) at room temperature for 16 hours. Add 1 ml of 2N HCl and the mixture is again evaporated. The residue is separated by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 338 (M+H)+.

EXAMPLE 263

N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenyl)-2-phenoxyacetamide

A solution of 2-phenoxyalkanoic acid (28 mg, 0,186 mmol) in anhydrous dichloromethane (3 ml) is treated with oxalylamino (35,3 mg, 0,186 mmol) with the addition of drops of N,N-dimethylformamide at room temperature for 1 hour and concentrated. The residue is again dissolved in anhydrous dichloromethane (5 ml). To the resulting solution was added a suspension of compound of example 260 (50 mg, 0,186 mmol) in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred at room temperature overnight and then evaporated. The residue is purified by HPLC (sorbent Bond® C-18 OD [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 404 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,60-1,70 (m, 4H), 2,35-2,39 (m, 2H), 2,42-of 2.50 (m, 2H), 2,66-of 2.93 (m, 4H), and 4.68 (s, 2H), 6,82-to 7.09 (m, 4H), of 7.23 (t, J=7,80 Hz, 1H), 7.24 to 7,38 (m, 2H), 7,40-of 7.60 (m, 2H), 10,01 (s, 1H), 12,54 (s, 1H).

EXAMPLE 264

4-(2-(6-fluoro-3'-(morpholine-4-ylcarbonyl)-1,1'-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

In a container for microwave processing load connection example 223 (50 mg, 0.14 mmol), dichloro-bis(triphenylphosphine)palladium(II) (10 mg, 0.014 mmol), 3-(morpholine-4-carbonyl)phenylboronic acid (40 mg, 0,17 mmol), a mixture of DME/water/ethanol (7:3:2, 3 ml) and a solution of sodium carbonate (2M, 0.1 ml), the mixture was incubated in a microwave reactor CEM Explorer® (Matthews, NC) at 150°C in within 15 minutes. After cooling, the reaction mixture was diluted with methanol (20 ml) and filtered. The filtrate is evaporated and the residue is shared by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound. MS (DCI/NH3) m/z 462 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.60-to a rate of 1.67 (m, 4H), 2,35-2,39 (m, 2H), of 2.44-2.50 (m, 2H), 2,75-a 3.01 (m, 4H), 3,44-to 3.73 (m, 8H), 7,17-7,28 (m, 1H), 7,27-7,34 (m, 1H), 7,38-7,47 (m, 1H), 7,50-to 7.67 (m, 4H), 12,55 (s, 1H).

EXAMPLE 265

Methyl 3-(2-(4-oxo-,4,5,6,7,8-hexahydrophthalate-1-yl)ethyl)benzoate

Specified in the title compound receive in accordance with the method of example 66, using the compound obtained in example 222, instead of the compound obtained in example 66B. MS (DCI/NH3) m/z 313 (M+H)+.

EXAMPLE 266

Methyl 3-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)benzoate

Specified in the title compound receive in accordance with the method of example 66, using the compound obtained in example 256, instead of the compound obtained in example 66B. MS (DCI/NH3) m/z 237 (M+H)+.

EXAMPLE 267

4-(2-(6-fluoro-4'-(morpholine-4-ylcarbonyl)-1,1'-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 264, by using 4-(morpholine-4-carbonyl)phenylboronic acid instead of 3-(morpholine-4 - carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 462 (M+H)+.

EXAMPLE 268

4-(2-(6-fluoro-2'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 264, by using 2-(pyrrolidin-1-carbonyl)phenylboronic acid instead of 3-(morpholine-4 - carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 446 (M+H)+.

EXAMPLE 269

4-(2-(6-fluoro-3'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title with the Association receive in accordance with the method of example 264, using 3-(pyrrolidin-1-carbonyl)phenylboronic acid instead of 3-(morpholine-4 - carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 446 (M+H)+;1H NMR (300 MHz, CDCl3): δ 1,64-of 1.81 (m, 4H), 1,83-2,03 (m, 4H), 2,43-2,47 (m, 2H), 2,56 at 2.59 (m, 2H), was 2.76-is 2.88 (m, 2H), 2.93 which is a 3.06 (m, 2H), 3,48 (t, J=6,54 Hz, 2H), to 3.67 (t, J=6,74 Hz, 2H), 7,01-7,11 (m, 1H), 7,11-7,21 (m, 1H), 7.29 trend (DD, J=7,54, 2.38 Hz, 1H), 7,39-rate of 7.54 (m, 2H), 7,55 to 7.62 (m, 1H), 7,69 (s, 1H), 10,10 (s, 1H).

EXAMPLE 270

N-cyclopropyl-2'-fluoro-5'-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide

Specified in the title compound receive in accordance with the method of example 264, by using 3-(cyclopropanecarbonyl)phenylboronic acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 432 (M+H)+.

EXAMPLE 271

N-(2-(dimethylamino)ethyl)-2'-fluoro-5'-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide

Specified in the title compound receive in accordance with the method of example 264, by using 3-(2-(dimethylamino)ethylcarbamate)phenylboronic acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 463 (M+H)+;1H NMR (300 MHz, CDCl3): δ 2,28-2,39 (m, 2H), 2,35 (m, 3H), of 2.45 (s, 6N), 2,60-2,69 (m, 2H), 2,73-2,82 (m, 2H), 2,87 (t, J=7,14 Hz, 2H), 3,01 (t, J=7,14 Hz, 2H), 3,54-to 3.64 (m, 1H), 3,69 (kV, J=of 5.29 Hz, 2H), 6,95-7,10 (m, 1H), 7,10-7,20 (m, 1H), 7,35-7,53 (m, 2H), 7,65-7,80 (m, 2H), 7,79-7,88 (m, 1H).

EXAMPLE 272

2'-fluoro-5'-(2-(4-oxo-3,4,5,6,7,8-hexage ritalin-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide

Specified in the title compound receive in accordance with the method of example 264, by using 3-carbamoilirovaniem acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 392 (M+H)+;1H NMR (500 MHz, pyridine-d5): δ 1,54 (s, 4H), and 2.27 (s, 2H), 2,70 (s, 2H), was 2.76-2.95 and (m, 2H), 2,98-is 3.21 (m, 2H), 7,19-7,27 (m, 2H), 7,31 (s, 1H), 7,49 (d, J=7,02 Hz, 1H), 7,82 (d, J=7,32 Hz, 1H), 8,42 (d, J=7,63 Hz, 1H), of 8.47 (s, 1H), 8,68 (s, 1H), of 9.02 (s, 1H), 14,05 (s, 1H).

EXAMPLE 273

N-(2'-fluoro-5'-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)methanesulfonamide

Specified in the title compound receive in accordance with the method of example 264, by using 3-(methylsulfonylamino)phenylboronic acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 442 (M+H)+;1H NMR (300 MHz, CDCl3): δ 2,31-2,48 (m, 4H), at 2.59 (m, 4H), 2.77-to 2,96 (m, 4H), to 3.02 (t, J=7,80 Hz, 3H), 6,92-7,03 (m, 1H), 7,02 for 7.12 (m, 1H), 7,10-7,22 (m, 2H), 7,27-7,33 (m, 1H), 7,32-7,47 (m, 2H), 10,96 (s, 1H).

EXAMPLE 274

N-(2'-fluoro-5'-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)ndimethylacetamide

Specified in the title compound receive in accordance with the method of example 264, by using 3-acetaminophenydrocodone acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 406 (M+H)+;1H NMR (300 MHz, CDCl3): δ 2.06 to of 2.21 (m, 4H), of 2.25 (s, 3H), of 2.34 (m, 2H), 2,58 (m, 2H), 2,80-to 2.94 (m, 2H), 2,92-of 3.06 (m, 2H), 6,93-7,10 (m, 2H) 7,10-7,19 (m, 1H), 7.23 percent (d, J=4,36 Hz, 1H), 7,27-7,33 (m, 1H), 7,38 (t, J=7,73 Hz, 1H), to 7.67-7,76 (m, 1H), 11,25 (s, 1H).

EXAMPLE 275

4-(2-(6-fluoro-3'-(morpholine-4-ylcarbonyl)-1,1'-biphenyl-3-yl)propyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 293, instead of the compound obtained in example 223. MS (DCI/NH3) m/z 476 (M+H)+.

EXAMPLE 276

4-(2-(6-fluoro-3'-(pyrrolidin-1-ylcarbonyl)-1,1'-biphenyl-3-yl)propyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 293, instead of the compound obtained in example 223, and 3-(pyrrolidin-1-carbonyl)phenylboronic acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 460 (M+H)+;1H NMR (300 MHz, CDCl3): δ of 1.36 (d, J=6,74 Hz, 3H), 1,61-of 1.78 (m, 4H), 1,76-to 2.06 (m, 4H), 2.26 and at 2.45 (m, 2H), 2,49-to 2.67 (m, 2H), 2,84 (m, 2H), 3,21-to 3.36 (m, 1H), 3,40 is 3.57 (m, 2H), 3,59-a 3.83 (m, 2H), 7,13-of 7.23 (m, 1H), was 7.36 (t, J=to 7.93 Hz, 1H), 7,40-7,51 (m, 3H), 7,55-to 7.64 (m, 1H), 7,73 (s, 1H), 9,98 (s, 1H).

EXAMPLE 277

N-cyclopropyl-2'-fluoro-5'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 293, instead of the compound obtained in example 223, and 3(C is cloprostenol)phenylboronic acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 446 (M+H)+.

EXAMPLE 278

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

Specified in the title compound receive in accordance with the method of example 2 using 4-chloro-3-nitrobenzaldehyde instead of 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 290 (M+H)+.

EXAMPLE 279

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

Specified in the title compound receive in accordance with the method of example 2, using 4-methoxy-3-nitrobenzaldehyde instead of 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 286 (M+H)+.

EXAMPLE 280

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

Specified in the title compound receive in accordance with the method of example 2 using 4-hydroxy-3-nitrobenzaldehyde instead of 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 272 (M+H)+.

EXAMPLE 281

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

Specified in the title compound receive in accordance with the method of example 2, using 4-methyl-3-nitrobenzaldehyde instead of 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 270 (M+H)+.

EXAMPLE 282

N-(2-(dimethylamino)ethyl)-3'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide

Specified in the title compound receive in accordance with the method of example 264, use the Zuya connection, obtained in example 256, instead of the compound obtained in example 223, and 3-(2-(dimethylamino)ethylcarbamate)phenylboronic acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 459 (M+H)+.

EXAMPLE 283

3'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 256, instead of the compound obtained in example 223, and 3-carbamoilirovaniem acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 388 (M+H)+;1H NMR (300 MHz, CD3OD): δ of 1.40 (d, J=7,14 Hz, 3H), 1,53-of 1.81 (m, 4H), 2,25 at 2.59 (m, 4H), 2.91 in (d, J=7,14 Hz, 2H), 3,31-to 3.41 (m, 1H), 7.23 percent (d, J=rate of 7.54 Hz, 1H), was 7.36 (t, J=to 7.93 Hz, 1H), 7,42-7,51 (m, 2H), 7,50-to 7.59 (m, 1H), 7,73 (d, J=to 7.93 Hz, 1H), 7,79-to $ 7.91 (m, 1H), of 8.09 (s, 1H).

EXAMPLE 284

N-(3'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)ndimethylacetamide

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 256, instead of the compound obtained in example 223, and 3-acetaminophenydrocodone acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 402 (M+H)+;1H NMR (300 MHz, CD3OD): δ of 1.40 (d, J=7,12 Hz, 3H), 1,50-of 1.78 (m, 4H), of 2.16 (s, 3H), 2,36 of $ 2.53 (m, 4H), and 2.83 (m, 1H), 2,88 (d, J=7,46 Hz, 2H), 7,16-of 7.23 (m, 1H), 7,227,29 (m, 1H), 7.29 trend was 7.36 (m, 2H), of 7.36 was 7.45 (m, 2H), 7,47-to 7.67 (m, 1H), 7,72 (t, J=1,86 Hz, 1H).

EXAMPLE 285

3'-(1-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide

EXAMPLE 285A

1-bromo-3-(1-bromacil)benzene

A solution of 3-brahmativartate (2 g, 11 mmol), N-bromosuccinimide (91,9 g, 11 mmol) and azo-bis-isobutyronitrile (10 mg, 0.06 mmol) in chloroform (30 ml) was stirred at 65°C. in a nitrogen atmosphere for 18 hours. After cooling, the reaction mixture is evaporated and the residue distributed between ethyl acetate and a saturated solution of salt. The organic layer was washed with saturated salt solution and evaporated. The remainder is shared by flash chromatography on silica gel (10% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 262 (M+H)+.

EXAMPLE 285B

Bromide (1-(3-bromophenyl)ethyl)triphenylphosphane

A solution of the compound obtained in example 285A (1.0 g, 3.8 mmol), and triphenylphosphine (1.1 g, 4.2 mmol) in toluene (15 ml) is heated under nitrogen atmosphere to 120°C. and maintained under these conditions for three days. After cooling to room temperature the solid product is collected by filtration, washed with toluene and dried, obtaining mentioned in the title compound.

EXAMPLE 285C

3-(1-(3-bromophenyl)ethylidene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

A suspension of the compound obtained in example 285B (1.88 g, 3.4 mmol)in tetrahydrofuran the e (100 ml) is treated with tert-piperonyl potassium (1N solution in tetrahydrofuran, 3.4 ml, 3.4 mmol) at -78°C for 1 hour and then enable the mixture to warm to 0°C for 30 minutes. Then add a solution of 4,5,6,7-tetrahydroxybenzophenone-1,3-dione (0.54 g, 3.4 mmol) in tetrahydrofuran (10 ml). The reaction mixture is heated to room temperature and stirred at room temperature for an additional 4 hours. The mixture is quenched with water and distributed between ethyl acetate and a saturated solution of salt. The organic phase is washed with saturated salt solution and evaporated. The remainder is shared by flash chromatography (20% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 320 (M+H)+.

EXAMPLE 285D

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

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 285C, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 334 (M+H)+.

EXAMPLE 285E

3'-(1-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 285D, instead of the compound obtained in example 223, and 3-carbamoilirovaniem acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 374 (M+H)+;1N I Is R (300 MHz, CD3OD): δ equal to 1.59 (d, J=7,12 Hz, 3H), 1,61-of 1.81 (m, 4H), 2,10-2,22 (m, 1H), 2,39 is 2.55 (m, 2H), 2,61-by 2.73 (m, 1H), 4,32 (kV, J=is 6.78 Hz, 1H), 7,08-7,21 (m, 1H), 7,35-the 7.43 (m, 1H), of 7.48-to 7.59 (m, 3H), of 7.75 (d, J=7,80 Hz, 1H), 7,80-7,87 (m, 1H), 8,06-8,11 (m, 1H).

EXAMPLE 286

N-(3'-(1-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)ndimethylacetamide

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 285D, instead of the compound obtained in example 223, and 3-acetaminophenydrocodone acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 388 (M+H)+;1H NMR (300 MHz, CD3OD): δ was 1.58 (d, J=7,12 Hz, 3H), 1.60-to is 1.82 (m, 4H), and 2.14 (s, 3H), 2,10-of 2.23 (m, 1H), 2,47 is 2.55 (m, 2H), 2,60-by 2.73 (m, 1H), 4,30 (kV, J=is 6.78 Hz, 1H), 7,15 (d, J=7,46 Hz, 1H), 7.23 percent-7,30 (m, 1H), 7,31-7,40 (m, 2H), 7,41-7,47 (m, 1H), 7,47-7,56 (m, 1H), 7,56-of 7.69 (m, 1H), to 7.77 (t, J=1,86 Hz, 1H).

EXAMPLE 287

N-(2-(dimethylamino)ethyl)-3'-(1-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 285D, instead of the compound obtained in example 223, and 3-(2-(dimethylamino)ethylcarbamate)phenylboronic acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 445 (M+H)+.

EXAMPLE 288

3-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)benzoic acid

The joint solution is, obtained in example 266 (50 mg, 0.16 mmol)in tetrahydrofuran (10 ml) is treated with a solution of LiOH·H2O (100 mg, 4 mmol) in water (4 ml) at 50°C during the night. The mixture is evaporated and the residue purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound. MS (DCI/NH3) m/z 313 (M+H)+.

EXAMPLE 289

N-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-4-(4-methoxyphenyl)-4-oxobutanamide

To a solution of 4-(4-methoxyphenyl)-4-oxobutanoic acid (29 mg, 0.14 mmol) in dioxane (1.5 ml) is added 2-(1H-7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate methanamine (HATU) (42 mg) and N,N'-diisopropylethylamine (32 μl). The mixture is stirred at room temperature for 15 minutes, then add the compound of example 2 (25 mg, 0,091 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated. The crude product is shared by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 464 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1,53-of 1.66 (m, 4H), 2,29-to 2.40 (m, 4H), to 2.74 (t, J=6,41 Hz, 2H), 3,25 (t, J=6,56 Hz, 2H), 3,84 (s, 2H), 3,85 (s, 3H), 6,88-of 6.96 (m, 1H), 7,05 (d, J=cent to 8.85 Hz, 2H), 7,12-7,20 (m, 1H), 7,74 (d, J=6,41 Hz, 1H), of 7.97 (d, J=9.15, With G the, 2H), 9,75 (ush. s, 1H), 12,60 (ush. s, 1H).

EXAMPLE 290

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3,4-dimethyl-1H-pyrrole-2,5-dione

To a solution of the compound obtained in example 2 (100 mg, of 0.37 mmol)in acetic acid (8 ml) is added 3,4-dimethylfuran-2,5-dione (46 mg, of 0.37 mmol). The reaction mixture is heated to 80°C and maintained at this temperature for 16 hours, then evaporated. The remainder is shared by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 382 (M+H)+;1H NMR (500 MHz, dimethylsulfoxide-d6): δ 1.56 to its 1.68 (m, 4H), to 1.98 (s, 6H), 2,30 is 2.43 (m, 4H), 3,93 (s, 2H), 7,18 (DD, J=7,02, of 1.53 Hz, 1H), 7,31-7,35 (m, 2H), 12,63 (ush. s, 1H).

EXAMPLE 291

3-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3-azabicyclo(3.1.0)hexane-2,4-dione

To a suspension of the compound obtained in example 2 (210 mg, 0.77 mmol)in acetonitrile (8 ml) is added 3-oxabicyclo(3.1.0)hexane-2,4-dione (95 mg, 0.85 mmol) and the resulting mixture was stirred at 80°C for 16 hours. The reaction mixture is cooled and evaporated on a rotary evaporator. The obtained solid residue was dissolved in dioxane (4 ml) and treated with hexaphosphate O-(benzotriazol-1-yl-N,N,N',N'-tetramethylurea (380 mg, 0,99 mmol) and N,N'-diisopropylethylamine (0.3 ml, was 1.69 mmol) in anatoy temperature for an additional 16 hours. The reaction mixture was concentrated and share HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of a salt triperoxonane acid. MS (DCI/NH3) m/z 368 (M+H)+;1H NMR (400 MHz, dimethylsulfoxide-d6): δ 1,57-of 1.64 (m, 4H), 1,66-1,72 (m, 2H), 2,32-to 2.41 (m, 4H), to 2.75 (DD, J=7,82, 3,22 Hz, 2H), 3,91 (s, 1H), 7,16 (d, J=of 7.36 Hz, 1H), 7,27-7,29 (m, 1H), 7,29-7,32 (m, 1H), 12,61 (ush. s, 1H).

EXAMPLE 292

4-((4-(phenoxyacetyl)piperazine-2-yl)methyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

A solution of the compound obtained in example 258 (138 mg, 0.29 mmol)in methylene chloride (10 ml) is treated triperoxonane acid (2 ml) at 40°C for 2 hours, then evaporated. The residue is purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title compound in the form of TFU salt. MS (DCI/NH3) m/z 383 (M+H)+.

EXAMPLE 293

4-(2-(3-bromo-4-forfinal)propyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 293A

2-(3-bromo-4-forfinal)-N-methoxy-N-methylacetamide

Specified in the title compound receive in accordance with the method of example 222A, using 2-(3-bromo-4-forfinal)acetic acid instead of 2-(3-bromophenyl)acetic acid. MS (DCI/NH3) m/z 276 (M+H)+.

EXAMPLE 293B

2-(3-bromo-4-forfinal)-N-methoxy-N-methylpropanamide

The criminal code is mentioned in the title compound receive in accordance with the method of example 256A, using the compound obtained in example 293A, instead of the compound obtained in example 222A. MS (DCI/NH3) m/z 291 (M+H)+.

EXAMPLE 293C

2-(3-bromo-4-forfinal)propanal

Specified in the title compound receive in accordance with the method of example 256B, using the compound obtained in example 293B, instead of the compound obtained in example 256A. MS (DCI/NH3) m/z 232 (M+H)+.

EXAMPLE 293D

3-(2-(3-bromo-4-forfinal)propylidene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the method of example 1C using 293C instead of 2-fluoro-5-formylbenzoate. MS (DCI/NH3) m/z 352 (M+H)+.

EXAMPLE 293E

4-(2-(3-bromo-4-forfinal)propyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 293D, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 366 (M+H)+.

EXAMPLE 294

4-oxo-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenyl)-4-phenylbutyramide

A mixture of 4-oxo-4-phenylbutanoate acid (50 mg, 0.28 mmol), hexaflurophosphate 2-(3H-(1,2,3)triazolo(4,5-b)pyridine-3-yl)-1,1,3,3-tetramethyldisilazane(V) (106 mg, 0.28 mmol) and substrate Janiga (120 mg, 0.9 mmol) in anhydrous N,N-dimethylformamide (0.5 ml) was stirred at room temperature for 10 minutes, the eat one portion add the compound of example 260 (50 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for additional 1 hour, then diluted with 5 ml of methanol. The solid product is collected by filtration, washed with methanol and dried, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 430 (M+H)+.1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,54-to 1.77 (m, 4H), 2,30-to 2.42 (m, 2H), 2,42-2,49 (m, 2H), 2,65-and 2.79 (m, 4H), 2,79-2,89 (m, 2H), 3,30-to 3.38 (m, 2H), make 6.90 (d, J=7,80 Hz, 1H), 7,19 (t, J=7,80 Hz, 1H), 7,38-7,49 (m, 2H), 7,54 (t, J=7,46 Hz, 2H), to 7.61-of 7.69 (m, 1H), 7,99 (t, J=6,61 Hz, 2H), 9,96 (s, 1H), to 12.52 (s, 1H).

EXAMPLE 295

2'-fluoro-5'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-carboxamide

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 293, instead of the compound obtained in example 223, and 3-carbamoilirovaniem acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 406 (M+H)+.

EXAMPLE 296

N-(2'-fluoro-5'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)ndimethylacetamide

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 293, instead of the compound obtained in example 223, and 3-acetaminophenydrocodone acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 420 (M+H)+ .

EXAMPLE 297

N-((2'-fluoro-5'-(1-methyl-2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)-1,1'-biphenyl-3-yl)methyl)methanesulfonamide

Specified in the title compound receive in accordance with the method of example 264, by using the compound obtained in example 293, instead of the compound obtained in example 223, and 3-(methylsulfonylmethyl)phenylboronic acid instead of 3-(morpholine-4-carbonyl)phenylboronic acid. MS (DCI/NH3) m/z 470 (M+H)+.

EXAMPLE 298

2-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)hexahydro-1H-isoindole-1,3(2H)-dione

Specified in the title compound receive in accordance with the procedure of example 291 using hexahydrobenzene-1,3-dione instead of oxabicyclo(3.1.0)hexane-2,4-dione. MS (DCI/NH3) m/z 410 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,31-of 1.53 (m, 5H), 1,57 by 1.68 (m, 4H), 1,66-of 1.78 (m, 3H), 1,76-of 1.92 (m, 2H), 2,29 is 2.43 (m, 4H), 3,93 (s, 2H), 7,12-7,17 (m, 1H), 7,28-7,33 (m, 1H), 7,33-7,37 (m, 1H), 12,63 (ush. s, 1H).

EXAMPLE 299

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-3,3-dimethylpiperidin-2,5-dione

Specified in the title compound receive in accordance with the procedure of example 291 using 3,3-dimethyltetrahydrofuran-2,5-dione instead oxabicyclo(3.1.0)hexane-2,4-dione. MS (DCI/NH3) m/z 384 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ is 1.31 (s, 6H), 1,54 is 1.70 (m, 4H), 2,30 is 2.44 (m, 4H), 2,78 (s, 2H), 3,94 (who, 2H), 7,19 (d, J=7,46 Hz, 1H), 7,30-7,33 (m, 1H), 7,35 (s, 1H), br12.62 (ush. s, 1H).

EXAMPLE 300

4-(4-fluoro-3-(2-methyl-5-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 300A

4-fluoro-3-(2-methyl-5-oxopyrrolidin-1-yl)benzaldehyde

In a round bottom flask of 100 ml load 3-bromo-4-forbindelse (1.0 g, is 4.93 mmol), Tris(dibenzylideneacetone)dipalladium(0) (450 mg, 0,493 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (428 mg, 0,739 mmol) and cesium carbonate (2.4 g, 7,39 mmol). The mixture is blown with nitrogen and add anhydrous dioxane (15 ml) and 5-methylpyrrolidine (0,586 g, 5,91 mmol). The reaction mixture is again rinsed with nitrogen, heated to 100°C and maintained at this temperature for 20 hours. After cooling to room temperature the reaction mixture is distributed between ethyl acetate and a saturated solution of salt. The organic phase is dried over MgSO4, filtered and evaporated. The remainder is shared by flash chromatography (50% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 222 (M+H)+.

EXAMPLE 300B

4-(4-fluoro-3-(2-methyl-5-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

A solution of the compound obtained in example 1B (486 mg, of 1.16 mmol), example 300A (265 mg) and triethylamine (0.16 ml) in dichloromethane (8 ml) was stirred at room temperature for 16 hours and evaporated. The residue is dissolved in e is anole (5 ml) and treated with hydrazinoacetate (0,11 ml) at 80°C for 2 hours. The mixture allow to cool, then the solid precipitate is filtered and dried, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 356 (M+H)+;1H NMR (400 MHz, dimethylsulfoxide-d6): δ of 1.02 (d, J=6,14 Hz, 3H), 1,57-to 1.63 (m, 4H), 1,64-1,72 (m, 1H), 2,27-of 2.34 (m, 1H), 2,34-to 2.40 (m, 4H), 2,41 is 2.46 (m, 2H), 3,90 (s, 2H), 4,08 (sq, J=6,44 Hz, 1H), 7,10-7,14 (m, 1H), 7,14-to 7.18 (m, 1H), 7,20-7,27 (m, 1H), was 12.61 (s, 1H).

EXAMPLE 301

4-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 301A

4-fluoro-3-(2-oxoacridine-3-yl)benzaldehyde

Specified in the title compound receive in accordance with the method of example 300A, using oxazolidin-2-he instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 210 (M+H)+.

EXAMPLE 301B

4-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 301A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 344 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,55-1,75 (m, 4H), 2,30 at 2.45 (m, 4H), 3,90 (s, 2H), 3,98 (t, J=to 7.93 Hz, 2H), 4,45 (DD, J=8,72, 7,14 Hz, 2H), 7,11-7,17 (m, 1H), 7,25 (DD, J=10,91, 8.53 Hz, 1H), was 7.36 (DD, J=7,54, 2.38 Hz, 1H), 12,61 (ush. s, 1H).

EXAMPLE 302

4-(4-fluoro-3-(2-oxazepan-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 302A

4-fluoro-3-(2-oxazepan-1-yl)benzamides is d

Specified in the title compound receive in accordance with the method of example 300A, using azepin-2-he instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 236 (M+H)+.

EXAMPLE 302B

4-(4-fluoro-3-(2-oxazepan-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 302A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 370 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,54-of 1.65 (m, 4H), of 1.65 and 1.80 (m, 6H), 2,32 at 2.45 (m, 4H), of 2.54 2.63 in (m, 2H), 3,57-and 3.72 (m, 2H), 3,88 (s, 2H),? 7.04 baby mortality for 7.12 (m, 2H), 7,13-7,22 (m, 1H), 12,61 (ush. s, 1H).

EXAMPLE 303

1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)piperidine-2,6-dione

Specified in the title compound receive in accordance with the procedure of example 291 using dihydro-2H-Piran-2,6(3H)-dione instead of oxabicyclo(3.1.0)hexane-2,4-dione. MS (DCI/NH3) m/z 370 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,53 was 1.69 (m, 4H), 1,84-of 1.97 (m, 1H), 1,98-2,11 (m, 1H), 2,29-to 2.42 (m, 4H), to 2.75 (t, J=6,44 Hz, 4H), 3,90 (s, 2H),? 7.04 baby mortality (d, J=7,80 Hz, 1H), 7,24 (s, 1H), 7,26 (d, J=1,36 Hz, 1H), 12,63 (s, 1H).

EXAMPLE 304

4-(4-fluoro-3-(2-Oxymetazoline-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 304A

4-fluoro-3-(2-Oxymetazoline-1-yl)benzaldehyde

Specified in the title compound receive in accordance with the methodology PR is a measure 300A, using imidazolidin-2-he instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 209 (M+H)+.

EXAMPLE 304B

4-(4-fluoro-3-(2-Oxymetazoline-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 304A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 343 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,55 was 1.69 (m, 4H), 2,31 is 2.44 (m, 4H), 3,39 (t, J=7,97 Hz, 2H), 3.75 to a 3.83 (m, 2H), 3,86 (s, 2H), 6,86 (ush. s, 1H), 6,94-7,03 (m, 1H), 7,16 (DD, J=11,19, 8,48 Hz, 1H), 7,31 (DD, J=7,63, 2.20 Hz, 1H), 12,61 (ush. s, 1H).

EXAMPLE 305

4-(3-(1,1-dioxothiazolidine-2-yl)-4-terbisil)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in example 2 (150 mg, 0.55 mmol), in dichloromethane (5 ml) is added 3-chloropropane-1-sulphonylchloride (97 mg, 0.55 mmol) and the resulting mixture is stirred for 16 hours. The reaction mixture is evaporated and the resulting solid residue is dissolved in dioxane (3 ml). To the resulting solution add ethoxide sodium (0,14 ml, 21% (wt.) in ethyl alcohol), solution is heated to 80°C and maintained at this temperature for 16 hours. After cooling, the reaction mixture is evaporated. The remainder is shared by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0,1% triperoxonane acid/CH3CN/H2O)receiving specified in the title with the Association in the form of a free base. MS (DCI/NH3) m/z 378 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.56 to to 1.70 (m, 4H), 2,33-2,47 (m, 6H), 3,40 (t, J=7.29 trend Hz, 2H), and 3.72 (t, J=6,44 Hz, 2H), 3,90 (s, 2H), 7,09-7,16 (m, 1H), 7.23 percent (d, J=8,48 Hz, 1H), 7,25-7,28 (m, 1H), 12,61 (ush. s, 1H).

EXAMPLE 306

4-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 306A

4-fluoro-3-(2-oxoazetidin-1-yl)benzaldehyde

Specified in the title compound receive in accordance with the method of example 300A, using azetidin-2-he instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 194 (M+H)+.

EXAMPLE 306B

4-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 306A, instead of the compound of example 300A. MS (DCI/NH3) m/z 328 (M+H)+.1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,55 by 1.68 (m, 4H), 2,31 is 2.43 (m, 4H), 3,11 (t, J=4,58 Hz, 2H), 3,82 (kV, J=to 4.41 Hz, 2H), 3,86 (s, 2H), 6,86-6,94 (m, 1H), 7,18 (DD, J=11.87 per, 8,48 Hz, 1H), 7,74 (DD, J=7,63, 2.20 Hz, 1H), 12,60 (ush. s, 1H).

EXAMPLE 307

4-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 307A

4-fluoro-3-(2-oxopiperidin-1-yl)benzaldehyde

Specified in the title compound receive in accordance with the method of example 300A, using piperidine-2-he instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 222 (M+H)+.

P the EMER 307B

4-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 307A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 356 (M+H)+;1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1,54-to 1.67 (m, 4H), 1.77 in-of 1.93 (m, 4H), 2,31 is 2.44 (m, 6H), 3,44-of 3.53 (m, 2H), 3,88 (s, 2H), 7,10-7,14 (m, 1H), 7,15 (d, J=6,35 Hz, 1H), 7,17-of 7.23 (m, 1H), br12.62 (s, 1H).

EXAMPLE 308

N-(3-furylmethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

EXAMPLE 308A

Methyl 3-((3-oxo-4,5,6,7-tetrahydrothiopyran-1(3H)-ilidene)methyl)benzoate

A solution of the compound obtained in example 1B (25,8 g, is 61.5 mmol), methyl-3-formylbenzoate (of 10.01 g, 61,0 mmol), and triethylamine (8.7 ml of 62.4 mmol) in dichloromethane (125 ml) was stirred at room temperature for 16 hours and evaporated. The residue is mixed with a mixture of ethyl acetate and water. The solid precipitate is filtered off, washed with water and dried, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 285 (M+H)+.

EXAMPLE 308B

3-((3-oxo-4,5,6,7-tetrahydrothiopyran-1(3H)-ilidene)methyl)benzoic acid

A solution of the compound obtained in example 308A (9,9 g, 35 mmol)in a mixture of tetrahydrofuran/water (1:1, 100 ml) is treated with a monohydrate of lithium hydroxide (2,93 g, 70 mmol) at room temperature in the tip is of 16 hours. To the mixture are added ethyl acetate (100 ml) and 2M HCl (100 ml). The combined organic fractions evaporated and dried in vacuum, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 271 (M+H)+.

EXAMPLE 308C

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoic acid

A solution of the compound obtained in example 308B (9.0 g, 33,33 mmol)in absolute ethanol (120 ml) is heated with hydrazinoacetate (3,3 ml, 66,66 mmol) up to 80°C and maintained at this temperature for 16 hours. After cooling to room temperature, the solid precipitate is filtered and dried, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 285 (M+H)+.

EXAMPLE 308D

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzoyl chloride

A solution of the compound obtained in example 308C (2,73 g, 9.6 mmol)in anhydrous tetrahydrofuran (30 ml) is treated with oxalylamino (1.3 ml, 14.4 mmol) and two drops of N,N-dimethylformamide at room temperature for 10 minutes and at 50°C for 1 hour. The reaction mixture was concentrated and dried, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 303 (M+H)+.

EXAMPLE 308E

N-(3-furylmethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

A solution of the compound obtained in example 308D (19 mg, 0.06 mmol), furan-3-ylmethanone (0.07 mmol) and triethylamine (14.6 mg, 0.14 mmol) in t is traditionale (1.0 ml) was stirred at room temperature for 16 hours. The reaction mixture is evaporated. The residue is dissolved in a mixture of dimethylsulfoxide/methanol (1:1) and purified HPLC (analytical column Waters Sunfire® C-8 [Milford, MA]/0,1% triperoxonane acid/water/100% CH3CN), getting mentioned in the title compound. MS (DCI/NH3) m/z 363 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,54 was 1.69 (m, 4H), 2,32 at 2.45 (m, 4H), of 3.96 (s, 2H), 4,29 (s, 2H), 6,41-of 6.49 (m, 1H), 7,32-7,37 (m, 1H), 7,41 (t, J=7,63 Hz, 1H), 7,52-of 7.60 (m, 2H), of 7.64-7,72 (m, 2H).

EXAMPLE 309

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(Tien-2-ylmethyl)benzamide

Specified in the title compound receive in accordance with the method of example 308, using thiophene-2-ylmethanone instead furan-3-ylmethanone. MS (DCI/NH3) m/z 380 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56 to to 1.70 (m, 4H), 2,32 is 2.43 (m, 4H), of 3.97 (s, 2H), br4.61 (s, 2H), 6,97 (DD, J=5,03, 3,51 Hz, 1H), 7,02 (d, J=2,44 Hz, 1H), 7,34-7,39 (m, 2H), 7,42 (t, J=7,63 Hz, 1H), to 7.67 (s, 1H), of 7.70 (d, J=to 7.93 Hz, 1H).

EXAMPLE 310

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(Tien-3-ylmethyl)benzamide

Specified in the title compound receive in accordance with the method of example 308, using thiophene-3-ylmethanone instead furan-3-ylmethanone. MS (DCI/NH3) m/z 380 (M+H)+.

EXAMPLE 311

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(pyridine-3-ylmethyl)benzamide

Specified in the title compound receive in accordance with what logikoi example 308, using pyridine-3-ylmethanone instead furan-3-ylmethanone. MS (DCI/NH3) m/z 375 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,53 is 1.70 (m, 4H), 2,31 at 2.45 (m, 4H), 3,98 (s, 2H), br4.61 (s, 2H), 7,37-7,41 (m, 1H), 7,45 (t, J=7,63 Hz, 1H), 7,69 (s, 1H), 7,74 (d, J=7,63 Hz, 1H), to $ 7.91 (DD, J=7,93, 5,49 Hz, 1H), of 8.37 (d, J=to 7.93 Hz, 1H), 8,72 (d, J=5,19 Hz, 1H), 8,78 (s, 1H).

EXAMPLE 312

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(pyridine-4-ylmethyl)benzamide

Specified in the title compound receive in accordance with the method of example 308, using pyridine-4-ylmethanone instead furan-3-ylmethanone. MS (DCI/NH3) m/z 375 (M+H)+.

EXAMPLE 313

N-(2-(dimethylamino)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

Specified in the title compound receive in accordance with the method of example 308, using the N1N1-dimethylated-1,2-diamine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 355 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56 to of 1.66 (m, 4H), 2,33 is 2.44 (m, 4H), 2,84 (s, 6H), 3,26 (t, J=5,95 Hz, 2H), 3,60 (t, J=5,95 Hz, 2H), 3,98 (s, 2H), 7,38-7,41 (m, 1H), 7,45 (t, J=7,63 Hz, 1H), to 7.67 (s, 1H), 7,71 (d, J=to 7.93 Hz, 1H).

EXAMPLE 314

N-(3-(dimethylamino)propyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

Specified in the title compound receive in accordance with the method of example 308, using the N1N1-DIMETHYLPROPANE-1,3-diamine instead of furan-3-Ilmatar is mine. MS (DCI/NH3) m/z 369 (M+H)+.

EXAMPLE 315

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(3-pyrrolidin-1-ylpropyl)benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-(pyrrolidin-1-yl)propan-1-amine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 395 (M+H)+.

EXAMPLE 316

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-(3-piperidine-1-ylpropyl)benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-(piperidine-1-yl)propan-1-amine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 409 (M+H)+.

EXAMPLE 317

N-(3-morpholine-4-ylpropyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-morpholinopropan-1-amine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 411 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1.56 to its 1.68 (m, 4H), 1,87-of 1.97 (m, 2H), 2,31 at 2.45 (m, 4H), is 3.08 (t, J=12,05 Hz, 2H), 3,11-3,17 (m, 2H), 3.33 and (t, J=of 6.71 Hz, 2H), 3,42 (d, J=12,51 Hz, 2H), 3,65 (t, J=12,05 Hz, 2H), 3.96 points-was 4.02 (m, 2H), 3,97 (s, 2H), 7,35-7,39 (m, 1H), 7,43 (t, J=7,63 Hz, 1H), 7,65 (s, 1H), 7,69 (d, J=to 7.93 Hz, 1H).

EXAMPLE 318

N-(2-(1H-indol-3-yl)ethyl)-3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)benzamide

Specified in the title compound receive in accordance with the method of example 308, use the I 2-(1H-indol-3-yl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 427 (M+H)+.

EXAMPLE 319

3-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)-N-1,3-thiazol-2-ylbenzene

Specified in the title compound receive in accordance with the method of example 308, using thiazole-2-amine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 367 (M+H)+;1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 1,59 by 1.68 (m, 4H), 2,35 is 2.46 (m, 4H), to 4.01 (s, 2H), 7,28 (d, J=3,66 Hz, 1H), 7,45-of 7.48 (m, 1H), 7,50 (t, J=of 7.48 Hz, 1H), 7,56 (d, J=3,66 Hz, 1H), 7,87 (s, 1H), to 7.93 (d, J=7,63 Hz, 1H).

EXAMPLE 320

Benzyl 2-oxo-2-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenylamino)ethylcarbamate

Specified in the title compound receive in accordance with the method of example 294, using 2-(benzyloxycarbonylamino)acetic acid instead of 4-oxo-4-phenylbutanoate acid. MS (DCI/NH3) m/z 461 (M+H)+.

EXAMPLE 321

4-oxo-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenyl)-4-(4-phenoxyphenyl)butanamide

Specified in the title compound receive in accordance with the method of example 294, using 4-oxo-4-(4-phenoxyphenyl)butane acid instead of 4-oxo-4-phenylbutanoate acid. MS (DCI/NH3) m/z 522 (M+H)+.

EXAMPLE 322

Benzyl 3-[({3-[2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl]phenyl}amino)carbonyl]piperidine-1-carboxylate

Specified in the title compound receive in accordance with the method of example 294, use the UYa 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid instead of 4-oxo-4-phenylbutanoate acid. MS (DCI/NH3) m/z 515 (M+H)+.

EXAMPLE 323

2-(4-methylphenoxy)-N-{3-[2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl]phenyl}ndimethylacetamide

Specified in the title compound receive in accordance with the method of example 294, using 2-(p-tolyloxy)acetic acid instead of 4-oxo-4-phenylbutanoate acid. MS (DCI/NH3) m/z 418 (M+H)+.

EXAMPLE 324

2-(4-methoxyphenoxy)-N-(3-(2-(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)ethyl)phenyl)ndimethylacetamide

Specified in the title compound receive in accordance with the method of example 294, using 2-(4-methoxyphenoxy)acetic acid instead of 4-oxo-4-phenylbutanoate acid. MS (DCI/NH3) m/z 434 (M+H)+.

EXAMPLE 325

4-[4-fluoro-3-(3-methyl-2-Oxymetazoline-1-yl)benzyl]-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 325A

4-fluoro-3-(3-methyl-2-Oxymetazoline-1-yl)benzaldehyde

Specified in the title compound receive in accordance with the method of example 300A, using 1-methylimidazolidine-2-he instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 223 (M+H)+.

EXAMPLE 325b choose close

4-[4-fluoro-3-(3-methyl-2-Oxymetazoline-1-yl)benzyl]-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 325A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 357 (M+H)+;1H NMR(300 MHz, DMSO-d6): δ 1,54 was 1.69 (m, 4H), 2,32 is 2.43 (m, 4H), to 2.74 (s, 3H), 3,39-3,44 (m, 2H), 3,67 is 3.76 (m, 2H), 3,86 (s, 2H), 6,97-7,05 (m, 1H), 7,17 (DD, J=11,19, 8,48 Hz, 1H), 7,31 (DD, J=7,63, 2.20 Hz, 1H), 12,60 (s, 1H).

EXAMPLE 326

4-[4-fluoro-3-(2-oxotetrahydrothalifendine-1(2H)-yl)benzyl]-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 326A

4-fluoro-3-(2-oxotetrahydrothalifendine-1(2H)-yl)benzaldehyde

Specified in the title compound receive in accordance with the method of example 300A, using tetrahydropyrimidin-2(1H)-he instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 223 (M+H)+.

EXAMPLE 326B

4-[4-fluoro-3-(2-oxotetrahydrothalifendine-1(2H)-yl)benzyl]-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 326A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 357 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1.57 in by 1.68 (m, 4H), 1,87 is 2.00 (m, 2H), 2,33 is 2.43 (m, 4H), 3,23 (t, J=USD 5.76 Hz, 2H), 3,44-to 3.52 (m, 2H), 3,86 (s, 2H), 6,60 (s, 1H), 7,00-7,07 (m, 1H), 7,09-to 7.18 (m, 2H), was 12.61 (s, 1H).

EXAMPLE 327

4-[3-(3-tert-butyl-2-Oxymetazoline-1-yl)-4-terbisil]-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 327A

3-(3-tert-butyl-2-Oxymetazoline-1-yl)-4-forbindelse

Specified in the title compound receive in accordance with the method of example 300A, using 1-tert-butylimidazole-2-he instead of 5-methylpyrrolidinone. MS (DCI/NH 3) m/z 265 (M+H)+.

EXAMPLE 327B

4-[3-(3-tert-butyl-2-Oxymetazoline-1-yl)-4-terbisil]-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 327A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 399 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,3 (s, 9H), 1,53 by 1.68 (m, 4H), 2,31 at 2.45 (m, 4H), 3.43 points-of 3.48 (m, 2H), to 3.58 at 3.69 (m, 2H), 3,86 (s, 2H), 6,95-7,02 (m, 1H), 7,15 (DD, J=11,36, 8,31 Hz, 1H), 7,28 (DD, J=7,46, 2,03 Hz, 1H), 12,59 (s, 1H).

EXAMPLE 328

4-{4-fluoro-3-[(1,4R)-3-oxo-2-azabicyclo[2.2.1]hept-2-yl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 328A

4-fluoro-3-((1S,4R)-3-oxo-2-azabicyclo[2.2.1]heptane-2-yl)benzaldehyde

Specified in the title compound receive in accordance with the method of example 300A, using (1S,4R)-2-azabicyclo[2.2.1]heptane-3-one instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 234 (M+H)+.

EXAMPLE 328B

4-{4-fluoro-3-[(1S,4R)-3-oxo-2-azabicyclo[2.2.1]hept-2-yl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 328A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 368 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,49-of 1.56 (m, 2H), 1,57-of 1.65 (m, 4H), 1,69 to 1.76 (m, 1H), 1,79 is 1.86 (m, 1H), 1,89 is 1.96 (m, 1H), 1,97-2,03 (m, 1H), 2,32 at 2.45 (m, 4H), 2,74-2,82 (m, 1H, a 3.87 (s, 2H), 4,25 (s, 1H), 7,01-was 7.08 (m, 1H), 7,16-of 7.23 (m, 1H), 7.23 percent-7,28 (m, 1H), 12,59 (ush. s, 1H).

EXAMPLE 329

N-(2-ethylphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-ethylaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 388 (M+H)+.

EXAMPLE 330

N-(3-ethylphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-ethylaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 388 (M+H)+.

EXAMPLE 331

N-(4-ethylphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 4-ethylaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 388 (M+H)+.

EXAMPLE 332

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-(2-propylphenyl)benzamid

Specified in the title compound receive in accordance with the method of example 308, using 2-propylaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 402 (M+H)+.

EXAMPLE 333

N-(2-isopropylphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-isopropylaniline WHI is about furan-3-ylmethanone. MS (DCI/NH3) m/z 402 (M+H)+.

EXAMPLE 334

N-(4-isopropylphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 4-isopropylaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 402 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ of 1.20 (d, J=7,02 Hz, 6H), 1,55-1,72 (m, 4H), 2,34-2,47 (m, 4H), 2,82-2,96 (m, 1H), 4,01 (s, 2H), 7.23 percent (d, J=8,24 Hz, 2H), 7,39 (d, J=7,63 Hz, 1H), 7,47 (t, J=7,63 Hz, 1H), 7,63 (d, J=8.54 in Hz, 2H), 7,74 (, 1H), 7,80 (d, J=to 7.93 Hz, 1H).

EXAMPLE 335

N-(3-tert-butylphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-tert-butylaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 416 (M+H)+.

EXAMPLE 336

N-(4-tert-butylphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 4-tert-butylaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 416 (M+H)+.

EXAMPLE 337

N-1,1'-biphenyl-4-yl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using biphenyl-4-amine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 436 (M+H)+;1H NMR (500 MHz, 2O/DMSO-d6): δ 1,57 is 1.70 (m, 4H), 2,34-2,48 (m, 4H), was 4.02 (s, 2H), was 7.36 (t, J=7,32 Hz, 1H), 7,42 (d, J=to 7.93 Hz, 1H), 7,45-of 7.48 (m, 2H), 7,49-7,52 (m, 1H), 7,66-7,71 (m, 4H), 7,78 (s, 1H), 7,81-7,87 (m, 3H).

EXAMPLE 338

N-(2-fluoro-4-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-fluoro-4-methylaniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 392 (M+H)+.

EXAMPLE 339

N-(3-fluoro-4-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-fluoro-4-methylaniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 392 (M+H)+.

EXAMPLE 340

N-(4-fluoro-2-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 4-fluoro-2-methylaniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 392 (M+H)+.

EXAMPLE 341

N-(4-fluoro-3-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 4-fluoro-3-methylaniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 392 (M+H)+.

EXAMPLE 342

N-(3-chloro-4-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)meth is l]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-chloro-4-methylaniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 408 (M+H)+.

EXAMPLE 343

N-(4-chloro-3-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 4-chloro-3-methylaniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 408 (M+H)+.

EXAMPLE 344

N-(3-bromo-4-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-bromo-4-methylaniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 452 (M+H)+.

EXAMPLE 345

N-(4-bromo-3-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 4-bromo-3-methylaniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 452 (M+H)+.

EXAMPLE 346

N-(3-fluoro-4-methoxyphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-fluoro-4-methoxyaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 408 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6 ): δ 1,55 was 1.69 (m, 4H), 2,33-2,49 (m, 4H), 3,83 (s, 3H), 4,01 (s, 2H), 7,16 (t, J=9,31 Hz, 1H), 7,40 (d, J=to 7.93 Hz, 1H), 7,44 is 7.50 (m, 2H), 7,69 (DD, J=of 13.58, at 2.59 Hz, 1H), 7,73 (s, 1H), 7,79 (d, J=to 7.93 Hz, 1H).

EXAMPLE 347

N-[3-methoxy-5-(trifluoromethyl)phenyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-methoxy-5-(trifluoromethyl)aniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 458 (M+H)+.

EXAMPLE 348

N-(2-hydroxy-6-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-amino-3-METHYLPHENOL instead furan-3-ylmethanone. MS (DCI/NH3) m/z 390 (M+H)+.

EXAMPLE 349

N-(3-hydroxy-2-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-amino-2-METHYLPHENOL instead furan-3-ylmethanone. MS (DCI/NH3) m/z 390 (M+H)+.

EXAMPLE 350

N-(3-hydroxy-4-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-amino-5-METHYLPHENOL instead furan-3-ylmethanone. MC (DCI/NH3) m/z 390 (M+H)+.

EXAMPLE 351

N-(2-methoxy-5-were)-3-[(4-oxo-3,4,5,6,7,8-g is calidrisalpina-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-methoxy-5-methylaniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 404 (M+H)+.

EXAMPLE 352

N-(3-methoxy-4-were)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 5-methoxy-2-methylaniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 404 (M+H)+.

EXAMPLE 353

N-(3-hydroxy-4-methoxyphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 5-amino-2-methoxyphenol instead furan-3-ylmethanone. MS (DCI/NH3) m/z 406 (M+H)+.

EXAMPLE 354

N-(2-ethoxyphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-ethoxyaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 404 (M+H)+.

EXAMPLE 355

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-(4-propoxyphenyl)benzamid

Specified in the title compound receive in accordance with the method of example 308, using 4-propociacion instead furan-3-ylmethanone. MS (DCI/NH3) m/z 418 (M+H)+.

EXAMPLE 356

N-(5-tert-butyl-2-methoxide who yl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 5-tert-butyl-2-methoxyaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 446 (M+H)+.

EXAMPLE 357

N-[5-(acetylamino)-2-methoxyphenyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using N-(3-amino-4-methoxyphenyl)ndimethylacetamide instead furan-3-ylmethanone. MS (DCI/NH3) m/z 447 (M+H)+.

EXAMPLE 358

N-2,3-dihydro-1,4-benzodioxin-6-yl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2,3-dihydrobenzo[b][1,4]dioxin-6-amine instead of furan-3-ylmethanone. MC (DCI/NH3) m/z 418 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ 1.56 to its 1.68 (m, 4H), 2,34-2,48 (m, 4H), of 4.00 (s, 2H), 4,15-4,32 (m, 4H), at 6.84 (d, J=cent to 8.85 Hz, 1H), 7,16 (DD, J=cent to 8.85, of 2.44 Hz, 1H), 7,34 (d, J=2,44 Hz, 1H), 7,38 (d, J=to 7.93 Hz, 1H), 7,46 (t, J=7,63 Hz, 1H), 7,72 (s, 1H), to 7.77 (d, J=7,63 Hz, 1H).

EXAMPLE 359

N-(5-chloro-2,4-acid)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 5-chloro-2,4-dimethoxyaniline instead furan-3-ylmethanone. MS (DCI/NH3) m/z 454 (M+H)+.

EXAMPLE 360

N-[3-(methylthio)phenyl]-3-[(4-oxo-3,4,5,6,7,8-Gex is hydrophilized-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-(methylthio)aniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 406 (M+H)+.

EXAMPLE 361

N-[4-(methylthio)phenyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 4-(methylthio)aniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 406 (M+H)+.

EXAMPLE 362

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-(4-piperidine-1-ylphenyl)benzamid

Specified in the title compound receive in accordance with the method of example 308, using 4-(piperidine-1-yl)aniline instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 443 (M+H)+.

EXAMPLE 363

N-(4-(morpholine-4-ylphenyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 4-morpholinyl instead furan-3-ylmethanone. MS (DCI/NH3) m/z 445 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ 1.57 in by 1.68 (m, 4H), 2,34 is 2.46 (m, 4H), 3.15 and is 3.23 (m, 4H), 3,79-3,82 (m, 4H), to 4.01 (s, 2H), 7,10 (d, J=9.15, with Hz, 2H), 7,39 (d, J=7,63 Hz, 1H), 7,45 is 7.50 (m, 1H), 7,66 (d, J=9.15, with Hz, 2H), 7,72-to 7.77 (m, 1H), 7,80 (d, J=to 7.93 Hz, 1H).

EXAMPLE 364

N-(2-anilinophenol)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound floor is up in accordance with the method of example 308, using the N1-phenylbenzo-1,2-diamine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 451 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ 1,54 was 1.69 (m, 4H), 2,31 is 2.44 (m, 4H), of 3.95 (s, 2H), 6,78 (t, J=7,32 Hz, 1H), 6,86 (d, J=7,63 Hz, 2H), 7,02-to 7.09 (m, 1H), 7,15-of 7.23 (m, 3H), 7,28-7,32 (m, 1H), 7,35-7,39 (m, 1H), 7,42 (t, J=7,63 Hz, 1H), to 7.59 (d, J=7,32 Hz, 1H), 7,63 (s, 1H), 7,69 (d, J=7,63 Hz, 1H).

EXAMPLE 365

N-{4-[(4-methoxyphenyl)amino]phenyl}-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using the N1-(4-methoxyphenyl)benzene-1,2-diamine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 481 (M+H)+.

EXAMPLE 366

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-quinoline-6-ylbenzene

Specified in the title compound receive in accordance with the method of example 308, using quinoline-7-amine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 411 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ 1.57 in-1,72 (m, 4H), a 2.36-2.49 USD (m, 4H), Android 4.04 (s, 2H), 7,44 is 7.50 (m, 1H), 7,54 (t, J=7,63 Hz, 1H), 7,82 (s, 1H), 7,88 (DD, J=8,24, 5,19 Hz, 2H), 8,19 (d, J=9.15, with Hz, 1H), 8,27 (DD, J=9.15, with, and 2.14 Hz, 1H), total of 8.74 (d, J=2,44 Hz, 1H), 8,88 (d, J=to 7.93 Hz, 1H), 9,04 (d, J=4,88 Hz, 1H).

EXAMPLE 367

N-(5-hydroxy-1-naphthyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using a 5-aminonaphthalene-1-ol instead of furan--eletania. MS (DCI/NH3) m/z 426 (M+H)+.

EXAMPLE 368

N-1H-indazol-6-yl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 1H-indazol-6-amine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 400 (M+H)+.

EXAMPLE 369

8-(4-terbisil)pyrido[3,2-d]pyridazin-5(6H)-he

EXAMPLE 369A

Methyl 2-(2-(4-forfinal)acetyl)nicotinate

To a solution of dimethylpyridin-2,3-in primary forms (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) is added via syringe chloride (4-terbisil)magnesium (0.25 M in tetrahydrofuran, 20 ml, 5.1 mmol) at -78°C. the Reaction mixture was stirred at the same temperature for 30 minutes and then quenched by addition of water. The reaction mixture allow to warm to room temperature and distributed between ethyl acetate and a saturated solution of salt. The organic phase is washed with saturated salt solution and evaporated. The residue is purified flash chromatography (15% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 274 (M+H)+.

EXAMPLE 369B

8-(4-terbisil)pyrido[3,2-d]pyridazin-5(6H)-he

A solution of the compound obtained in example 369A (0,46 g, by 1.68 mmol), in ethanol (20 ml) is treated with hydrazine (108 mg, 3,37 mmol) at room temperature for 5 hours. The reaction mixture con is intronaut to about 5 ml. The solid precipitate is collected by filtration, washed with ethanol and dried, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 256 (M+H)+.

EXAMPLE 370

8-(3-chloro-4-terbisil)pyrido[3,2-d]pyridazin-5(6H)-he

EXAMPLE 370A

Methyl 2-(2-(3-chloro-4-forfinal)acetyl)nicotinate

Specified in the title compound receive in accordance with the method of example 369A, using chloride (2-chloro-4-terbisil)magnesium instead chloride (4-terbisil)magnesium. MS (DCI/NH3) m/z 308 (M+H)+.

EXAMPLE 370B

8-(3-chloro-4-terbisil)pyrido[3,2-d]pyridazin-5(6H)-he

Specified in the title compound receive in accordance with the method of example 369B, using the compound obtained in example 370A, instead of the compound obtained in example 369A. MS (DCI/NH3) m/z 290 (M+H)+.

EXAMPLE 371

(3aR)-8-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazin-1-he

EXAMPLE A

(R)-1-oxo-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-8-carbaldehyde

Specified in the title compound receive in accordance with the method of example 300A, using (R)-5-(hydroxymethyl)pyrrolidin-2-he instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 232 (M+H)+.

EXAMPLE 371B

(3aR)-8-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazin-1-he

Specified in the title compounds is their gain in accordance with the method of example 300B, using the compound obtained in example 371A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 352 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,54-to 1.63 (m, 4H), 1,64-1,72 (m, 1H), 2,13-2,22 (m, 1H), 2,23-2,31 (m, 1H), 2,33 is 2.44 (m, 4H), 2,54-of 2.64 (m, 1H), and 3.72 (t, J=10,17 Hz, 1H), 3,78-a-3.84 (m, 2H), 3,91-of 4.05 (m, 1H), 4,48 (DD, J=10,51, of 3.05 Hz, 1H), 6,77-PC 6.82 (m, 1H), 6,84-6,89 (m, 1H), compared to 8.26 (d, J=2,03 Hz, 1H), 12,58 (ush. s, 1H).

EXAMPLE 372

N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-N-methylmethanesulfonamide

EXAMPLE 372A

N-(2-fluoro-5-formylphenyl)-N-methylmethanesulfonamide

Specified in the title compound receive in accordance with the method of example 300A, using N-methylmethanesulfonamide instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 232 (M+H)+.

EXAMPLE 372B

N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-N-methylmethanesulfonamide

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 372A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 366 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1.57 in-1,71 (m, 4H), 2,34-2,47 (m, 4H), of 3.13 (s, 6H), 3,93 (s, 2H), 7,25 (DD, J=8,33, to 1.98 Hz, 1H), 7,51 (d, J=to 7.93 Hz, 1H), 7,58 (d, J=1,98 Hz, 1H), br12.62 (ush. s, 1H).

EXAMPLE 373

N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-2-hydroxy-2-methylpropanamide

EXAMPLE 373A

N-(2-fluoro-5-formylphenyl)-2-hydrox the-2-methylpropanamide

Specified in the title compound receive in accordance with the method of example 300A, using 5,5-dimethyloxazolidine-2,4-dione instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 226 (M+H)+.

EXAMPLE 373B

N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-2-hydroxy-2-methylpropanamide

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 373A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 360 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ of 1.34 (s, 6H), 1,53 is 1.70 (m, 4H), 2,29 at 2.45 (m, 4H), a 3.87 (s, 2H), 6,85-7,02 (m, 1H), 7,20 (DD, J=10,91, 8.53 Hz, 1H), to $ 7.91 (DD, J=7,54, to 1.98 Hz, 1H), 9,24 (s, 1H), br12.62 (s, 1H).

EXAMPLE 374

(3aS)-8-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazin-1-he

EXAMPLE 374A

(S)-1-oxo-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-8-carbaldehyde

Specified in the title compound receive in accordance with the method of example 300A, using (S)-5-(hydroxymethyl)pyrrolidin-2-he instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 232 (M+H)+.

EXAMPLE 374B

(3aS)-8-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazin-1-he

Specified in the title compound receive in accordance with the method of example 300A, using the compound obtained in example 374A, the seat connection obtained in example 300B. MS (DCI/NH3) m/z 352 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,54-of 1.62 (m, 4H), and 1.63 to 1.76 (m, 1H), 2,13-2,22 (m, 1H), 2,23-2,31 (m, 2H), 2,32-to 2.40 (m, 4H), and 3.72 (t, J=10,31 Hz, 1H), 3,81 (s, 2H), 3,90-Android 4.04 (m, 1H), 4,48 (DD, J=10,71, 3,17 Hz, 1H), 6,77-6,83 (m, 1H), 6,84-6,91 (m, 1H), compared to 8.26 (d, J=1,98 Hz, 1H), 12,58 (ush. s, 1H).

EXAMPLE 375

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-(2-phenylethyl)benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-fenilatilamin instead furan-3-ylmethanone. MS (DCI/NH3) m/z 388 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ 1.56 to 1.69 in (m, 4H), 2,33 at 2.45 (m, 4H), 2,84 (t, J=of 7.48 Hz, 2H), 3,43-3,51 (m, 2H), 3.96 points (s, 2H), 7,21 (t, J=7,17 Hz, 1H), 7.23 percent-7,26 (m, 2H), 7,27-to 7.32 (m, 2H), to 7.32 and 7.36 (m, 1H), 7,40 (t, J=7,63 Hz, 1H), of 7.60 (s, 1H), to 7.64 (d, J=to 7.93 Hz, 1H).

EXAMPLE 376

N-[2-(2-were)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-o-trilateration instead furan-3-ylmethanone. MS (DCI/NH3) m/z 402 (M+H)+.

EXAMPLE 377

N-[2-(3-were)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-m-trilateration instead furan-3-ylmethanone. MS (DCI/NH3) m/z 402 (M+H)+.

EXAMPLE 378

N-[2-(4-were)ethyl]-3-[(4-oxo-3,4,5,6,7,8-Huck who hydrophilizing-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-p-trilateration instead furan-3-ylmethanone. MS (DCI/NH3) m/z 402 (M+H)+.

EXAMPLE 379

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-(2-pyridin-2-retil)benzamid

Specified in the title compound receive in accordance with the method of example 308, using 2-(pyridin-2-yl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 389 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ 1.57 in by 1.68 (m, 4H), 2,31 is 2.43 (m, 4H), 3,24 (t, J=6,56 Hz, 2H), 3,69 (t, J=6,41 Hz, 2H), 3,95 (s, 2H), 7,33-7,37 (m, 1H), 7,40 (t, J=7,63 Hz, 1H), 7,53 (s, 1H), EUR 7.57 (d, J=7,63 Hz, 1H), 7,86-7,89 (m, 1H), of 7.90-7,94 (m, 1H), 8,40-8,49 (m, 1H), up 8.75 (d, J=4,88 Hz, 1H).

EXAMPLE 380

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-(2-pyridin-3-retil)benzamid

Specified in the title compound receive in accordance with the method of example 308, using 3-(pyridin-2-yl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 389 (M+H)+.

EXAMPLE 381

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-(2-pyridin-4-retil)benzamid

Specified in the title compound receive in accordance with the method of example 308, using 4-(pyridin-2-yl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 389 (M+H)+.

EXAMPLE 382

N-[2-(2-methoxyphenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

The criminal code is mentioned in the title compound receive in accordance with the method of example 308, using 2-(2-methoxyphenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 418 (M+H)+.

EXAMPLE 383

N-[2-(3-methoxyphenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 3-(2-methoxyphenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 418 (M+H)+.

EXAMPLE 384

N-[2-(4-methoxyphenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 4-(2-methoxyphenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 418 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ 1,55 by 1.68 (m, 4H), 2,32 at 2.45 (m, 4H), 2,77 (t, J=of 7.48 Hz, 2H), 3,37-3,47 (m, 2H), 3,71 (s, 3H), of 3.96 (s, 2H), 6,83-to 6.88 (m, 2H), 7,14-7,20 (m, 2H), to 7.32 and 7.36 (m, 1H), 7,40 (t, J=7,63 Hz, 1H), to 7.61 (s, 1H), to 7.64 (d, J=7,63 Hz, 1H).

EXAMPLE 385

N-[2-(2-forfinal)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(2-forfinal)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 406 (M+H)+.

EXAMPLE 386

N-[2-(3-forfinal)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-3-forfinal)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 406 (M+H)+.

EXAMPLE 387

N-[2-(4-forfinal)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(4-forfinal)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 406 (M+H)+.

EXAMPLE 388

N-[2-(2-chlorophenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(2-chlorophenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 422 (M+H)+.

EXAMPLE 389

N-[2-(3-chlorophenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(3-chlorophenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 422 (M+H)+.

EXAMPLE 390

N-[2-(4-chlorophenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(4-chlorophenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 422 (M+H)+.

EXAMPLE 391

N-[2-(3-bromophenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, and the but using 2-(3-bromophenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 467 (M+H)+.

EXAMPLE 392

N-[2-(4-bromophenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(4-bromophenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 467 (M+H)+.

EXAMPLE 393

N-[2-(1,1'-biphenyl-4-yl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(biphenyl-4-yl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 464 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ 1,54-to 1.67 (m, 4H), 2,30 is 2.44 (m, 4H), 2,89 (t, J=of 7.48 Hz, 2H), 3,52 (t, J=to 7.32 Hz, 2H), 3.96 points (s, 2H), 7,33-7,37 (m, 4H), 7,41 (t, J=7,63 Hz, 1H), 7,44 is 7.50 (m, 2H), to 7.59 (d, J=8,24 Hz, 2H), to 7.64 (d, J=8,24 Hz, 2H), of 7.64-to 7.68 (m, 2H).

EXAMPLE 394

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-{2-[3-(trifluoromethyl)phenyl]ethyl}benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(3-(trifluoromethyl)phenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 456 (M+H)+.

EXAMPLE 395

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-{2-[4-(trifluoromethyl)phenyl]ethyl}benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(4-(trifluoromethyl)phenyl)ethanamine instead of fu is an-3-ylmethanone. MS (DCI/NH3) m/z 456 (M+H)+.

EXAMPLE 396

3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-[2-(4 - phenoxyphenyl)ethyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(4-phenoxyphenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 480 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ 1,55-of 1.66 (m, 4H), 2,32 is 2.43 (m, 4H), and 2.83 (t, J=to 7.32 Hz, 2H), 3,48 (t, J=to 7.32 Hz, 2H), 3.96 points (s, 2H), 6,91-6,94 (m, 2H), of 6.96 (d, J=7,63 Hz, 2H), 7,12 (t, J=of 7.48 Hz, 1H), 7,26 (d, J=8.54 in Hz, 2H), 7,32-7,35 (m, 1H), 7,35-7,38 (m, 2H), 7,38-the 7.43 (m, 1H), 7.62mm (s, 1H), to 7.64 (d, J=7,63 Hz, 1H).

EXAMPLE 397

N-[2-(3,4-dimetilfenil)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(3,4-dimetilfenil)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 416 (M+H)+.

EXAMPLE 398

N-[2-(2,4-dimetilfenil)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(2,4-dimetilfenil)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 416 (M+H)+.

EXAMPLE 399

N-[2-(2,5-dimetilfenil)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(2,5-dimetyl the Nile)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 416 (M+H)+.

EXAMPLE 400

N-[2-(3-ethoxy-4-methoxyphenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(3-ethoxy-4-methoxyphenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 462 (M+H)+.

EXAMPLE 401

N-[2-(4-ethoxy-3-methoxyphenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(4-ethoxy-3-methoxyphenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 462 (M+H)+.

EXAMPLE 402

N-[2-(2,3-acid)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(2,3-acid), ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 448 (M+H)+.

EXAMPLE 403

N-[2-(2,4-acid)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(2,4-acid), ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 448 (M+H)+.

EXAMPLE 404

N-[2-(2,5-acid)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

The criminal code is mentioned in the title compound receive in accordance with the method of example 308, using 2-(2,5-acid), ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 448 (M+H)+.

EXAMPLE 405

N-[2-(3,4-acid)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(3,4-acid), ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 448 (M+H)+.

EXAMPLE 406

N-[2-(3,5-acid)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(3,5-acid), ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 448 (M+H)+.

EXAMPLE 407

N-[2-(1,3-benzodioxol-5-yl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(benzo[d][1,3]dioxol-5-yl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 432 (M+H)+;1H NMR (500 MHz, D2O/DMSO-d6): δ 1,54-1,72 (m, 4H), 2,32 is 2.44 (m, 4H), to 2.75 (t, J=to 7.32 Hz, 2H), 3.43 points (t, J=to 7.32 Hz, 2H), 3.96 points (s, 2H), 5,94 (s, 2H), 6,70 (DD, J=7,93, of 1.53 Hz, 1H), 6,80 (s, 1H), for 6.81-6,83 (m, 1H), 7,32 and 7.36 (m, 1H), 7,40 (t, J=7,63 Hz, 1H), to 7.61 (s, 1H), to 7.64 (d, J=to 7.93 Hz, 1H).

EXAMPLE 408

N-[2-(2,3-dichlorophenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title soedineniya in accordance with the method of example 308, using 2-(2,3-dichlorophenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 457 (M+H)+.

EXAMPLE 409

N-[2-(3,4-dichlorophenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(3,4-dichlorophenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 457 (M+H)+.

EXAMPLE 410

N-[2-(2,6-dichlorophenyl)ethyl]-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(2,6-dichlorophenyl)ethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 457 (M+H)+.

EXAMPLE 411

(3aS,4R,7S,7aR)-5-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-2,2-dimethylether-4,7-methane[1,3]dioxolo[4,5-c]pyridine-6(3aH)-he

EXAMPLE 411A

3-[(3aS,4R,7S,7aR)-2,2-dimethyl-6-exoterica-4,7-methane[1,3]dioxolo[4,5-c]pyridine-5(4H)-yl]-4-forbindelse

Specified in the title compound receive in accordance with the method of example 300A, using (1S,2R,6S,7R)-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.0(2,6)]decane-9-he instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 306 (M+H)+.

EXAMPLE 411B

(3aS,4R,7S,7aR)-5-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-2,2-dimethylether-4,7-methane[1,3]dioxolo[4,5-c]pyridine-6(3aH)-he

Specified in the-Lavie connection receive in accordance with the method of example 300B, using the compound obtained in example 411A, instead of the compound obtained in example 300B. MS (DCI/NH3) m/z 440 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ of 1.29 to 1.34 (m, 3H), of 1.42 (s, 3H), 1,55-to 1.67 (m, 4H), 2,01-2,11 (m, 1H), 2,12-of 2.21 (m, 1H), 2,32 at 2.45 (m, 4H), 2.77-to 2,84 (m, 1H), 3,88 (s, 2H), 4,16-4,24 (m, 1H), 4,58 with 4.64 (m, 1H), with 4.64-4,69 (m, 1H), 7,02-to 7.09 (m, 1H), 7,22 (DD, J=11,19, 8,48 Hz, 1H), 7,31 (DD, J=7,46, 2,03 Hz, 1H), 12,59 (s, 1H).

EXAMPLE 412

4-(1-(3-bromo-4-forfinal)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

EXAMPLE 412A

1-(3-bromo-4-forfinal)ethanol

A solution of 1-(3-bromo-4-forfinal)ethanone (15.0 g, 69 mmol) in tetrahydrofuran (200 ml) is treated with sodium borohydride (5,3 g, 138 mmol) at 0°C. After addition of the components in the ice bath removed, and the mixture is stirred at room temperature for 30 minutes and refluxed over night. After cooling the mixture slowly add 1N HCl (10 ml) and the reaction mixture is evaporated. The residue is distributed between ethyl acetate and a saturated solution of salt. The organic phase is washed with water and evaporated. The residue is purified flash chromatography (30% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 220 (M+H)+.

EXAMPLE 412B

2-bromo-4-(1-bromacil)-1-torbenson

To a solution of the compound obtained in example 412A (1.5 g, 6.8 mmol), and triphenylphosphine (1.9 g, 7.2 mmol) in dimethylformamide (20 ml) is added via syringe to the rum (1.1 g, 6.8 mmol). After the addition the reaction mixture was stirred at room temperature for an additional 15 minutes and partitioned between water (100 ml) and ethyl acetate (200 ml). The organic phase is washed with saturated salt solution and evaporated. The residue is purified flash chromatography (2.6% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 282 (M+H)+.

EXAMPLE 412B

Bromide (1-(3-bromo-4-forfinal)ethyl)triphenylphosphane

Specified in the title compound receive in accordance with the method of example 285B, by using the compound obtained in example 412A, instead of the compound obtained in example 285A.

EXAMPLE 412C

3-(1-(3-bromo-4-forfinal)ethylidene)-4,5,6,7-tetrahydrothiopyran-1(3H)-he

Specified in the title compound receive in accordance with the method of example 285C, using the compound obtained in example 412B, instead of the compound obtained in example 285B. MS (DCI/NH3) m/z 338 (M+H)+.

EXAMPLE 412D

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

Specified in the title compound receive in accordance with the procedure of example 2C, using the compound obtained in example 412C, instead of the compound obtained in example 2B. MS (DCI/NH3) m/z 352 (M+H)+.

EXAMPLE 413

4-(1-(4-fluoro-3-(2-oxopyrrolidin-1-yl)phenyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

At asanee in the title compound receive in accordance with the method of example 101, using the compound obtained in example 412, instead of the compound obtained in example 103, and pyrrolin-2-he instead of azetidin-2-it. MS (ESI) m/z 356 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ of 1.42 (d, J=6,74 Hz, 3H), 1,46 is 1.70 (m, 4H), 1.93 and-of 2.16 (m, 4H), 2,29-to 2.67 (m, 6N), 4,25 (kV, J=6,74 Hz, 1H), 7,07-to 7.15 (m, 1H), 7,18 (s, 1H), 7,19-7,29 (m, 1H), 12,70 (s, 1H).

EXAMPLE 414

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

A mixture of compound of example 369 (150 mg, 0.6 mmol), 5% platinum on carbon (30 mg), concentrated HCl (50 μl) and dimethylformamide (5 ml) was stirred at room temperature in hydrogen atmosphere with a pressure of 50 psig for 16 hours. The mixture is filtered and the filtrate evaporated. The obtained solid residue purified HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0.1% TFWC/CH3CN/H2O)receiving specified in the title compound in the form of TFU salt. MS (ESI) m/z 260 (M+H)+.

EXAMPLE 415

8-(3-bromo-4-terbisil)pyrido[3,2-d]pyridazin-5(6H)-he

EXAMPLE 415A

Methyl 2-(2-(3-bromo-4-forfinal)acetyl)nicotinate

A mixture of magnesium turnings (880 mg, 37 mmol) and 2-bromo-4-(methyl bromide)-1-fervently (1.0 g, 3.7 mmol) in anhydrous diethyl ether (15 ml) is treated with solid iodine. The mixture is then gently heated to the boiling point of the solvent and refluxed until the disappearance of the color mixture, then heating is continued even in those who tell the hour. The suspension is cooled to room temperature and transfer it via cannula into a solution of dimethyl pyridine-2,3-in primary forms (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) at -78°C. the Reaction mixture is maintained at a specified temperature for 30 minutes and quenched by addition of water. The mixture allow to warm to room temperature, and then distributed between ethyl acetate and a saturated solution of salt. The organic phase is washed with saturated Rasbora salt and concentrate. The residue is purified flash chromatography (15% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 353 (M+H)+.

EXAMPLE 415B

8-(3-bromo-4-terbisil)pyrido[3,2-d]pyridazin-5(6H)-he

Specified in the title compound receive in accordance with the method of example 369B, using the compound obtained in example 415A, instead of the compound obtained in example 369A. MS (DCI/NH3) m/z 335 (M+H)+.

EXAMPLE 418

N-[2-(dimethylamino)ethyl]-N-ethyl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using the N1-ethyl-N2N2-dimethylated-1,2-diamine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 383 (M+H)+.

EXAMPLE 419

N-[2-(diethylamino)ethyl]-N-methyl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

The decree of the TES in the title compound receive in accordance with the method of example 308, using the N1N1-diethyl-N2-mutilate-1,2-diamine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 397 (M+H)+.

EXAMPLE 420

N-benzyl-N-ethyl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using N-benzylideneamino instead furan-3-ylmethanone. MS (DCI/NH3) m/z 402 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 0,97-1,11 (m, 3H), 1,36-of 1.57 (m, 4H), 2,22-of 2.30 (m, 2H), 2,50-of 2.66 (m, 2H), 3.27 to is-3.45 (m, 2H), 3,98 (s, 2H), br4.61-4,74 (m, 2H), 7,26-7,31 (m, 1H), 7,32-7,40 (m, 6H), 7,42-7,47 (m, 1H), 7,52 (s, 1H).

EXAMPLE 421

N-benzyl-N-isopropyl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using N-benzylparaben-2-amine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 416 (M+H)+.

EXAMPLE 422

N-benzyl-N-butyl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using N-benzylbutyl-1-amine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 430 (M+H)+.

EXAMPLE 423

N,N-dibenzyl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using dibenzylamine instead furan-3-Ilmatar is mine. MS (DCI/NH3) m/z 464 (M+H)+.

EXAMPLE 424

N-benzyl-N-(2-hydroxyethyl)-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(benzylamino)ethanol instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 418 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1,40-and 1.54 (m, 4H), 2.21 are of 2.33 (m, 2H), 2,50-2,61 (m, 2H), 3,62-of 3.78 (m, 2H), 3,89-was 4.02 (m, 2H), 3.96 points (s, 2H), 4,82-equal to 4.97 (m, 2H), 7,25-7,29 (m, 1H), 7,30 and 7.36 (m, 5H), was 7.36-the 7.43 (m, 1H), 7,43-7,47 (m, 1H), to 7.50 (d, J=7,32 Hz, 1H).

EXAMPLE 426

N-methyl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]-N-(2-pyridin-2-retil)benzamid

Specified in the title compound receive in accordance with the method of example 308, using N-methyl-2-(pyridin-2-yl)ethanamine instead furan-3-ylmethanone. MC (DCI/NH3) m/z 403 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1,42-of 1.52 (m, 4H), 2,24-of 2.34 (m, 2H), of 2.51-2,62 (m, 2H), 2,97 (s, 3H), of 3.07 3.21-in (m, 2H), 3,83-of 3.94 (m, 2H), 3,99 (s, 2H), 7,12 (DD, J=7,32, 5,49 Hz, 1H), 7,14-7,20 (m, 1H), 7,28-to 7.32 (m, 2H), 7,32-7,37 (m, 1H), 7,37 was 7.45 (m, 1H), EUR 7.57 (t, J=7,63 Hz, 1H), 8,55 (d, J=3,66 Hz, 1H).

EXAMPLE 427

N-[2-(3,4-acid)ethyl]-N-methyl-3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzamide

Specified in the title compound receive in accordance with the method of example 308, using 2-(3,4-acid)-N-methylethanamine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 462 (M+H)+.

NOTE THE R 428

4-{3-[(4-hydroxypiperidine-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using piperidine-4-ol instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 368 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1,42-of 1.52 (m, 4H), 1,63 is 1.75 (m, 2H), 1,87-to 1.98 (m, 2H), and 2.27 to 2.35 (m, 2H), 2,54-2,62 (m, 2H), 3.25 to 3.40 in (m, 2H), 4,01 (s, 2H), 4,01-Android 4.04 (m, 2H), 4,05-4,07 (m, 1H), 7,35 (t, J=7,17 Hz, 1H), 7,37-7,40 (m, 1H), 7,40-7,44 (m, 1H), 7,51 (s, 1H).

EXAMPLE 429

1-{3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzoyl}piperidine-3-carboxamide

Specified in the title compound receive in accordance with the method of example 308, using piperidine-3-carboxamide instead furan-3-ylmethanone. MS (DCI/NH3) m/z 395 (M+H)+.

EXAMPLE 430

1-{3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzoyl}piperidine-4-carboxamide

Specified in the title compound receive in accordance with the method of example 308, using piperidine-4-carboxamide instead furan-3-ylmethanone. MS (DCI/NH3) m/z 395 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1.41 to 1.55V (m, 4H), 1,82-of 1.97 (m, 4H), 2,27-is 2.37 (m, 2H), 2,54-2,61 (m, 2H), 2,63-by 2.73 (m, 1H), 2,94-of 3.06 (m, 2H), 4.00 points (s, 2H), 4,16-4,32 (m, 2H), to 7.32 and 7.36 (m, 1H), was 7.36-7,40 (m, 2H), of 7.48-7,51 (m, 1H).

EXAMPLE 434

4-(3-{[4-(2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Pointed to by the e in the title compound receive in accordance with the method of example 308, using 1-(piperidine-4-yl)-1H-benzo[d]imidazol-2(3H)-he instead furan-3-ylmethanone. MS (DCI/NH3) m/z 484 (M+H)+.

EXAMPLE 435

4-{3-[(4-methylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 1-methylpiperazine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 367 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1,46-of 1.52 (m, 4H), 2,24 (s, 3H), 2,29-of 2.34 (m, 2H), 2,37-to 2.42 (m, 4H), 2,54-2,62 (m, 2H), 3,61-to 3.73 (m, 4H), was 4.02 (s, 2H), 7,35-7,39 (m, 1H), 7,39-the 7.43 (m, 2H), 7,51 (s, 1H).

EXAMPLE 436

4-{3-[(4-ethylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 1-ethylpiperazin instead furan-3-ylmethanone. MS (DCI/NH3) m/z 381 (M+H)+.

EXAMPLE 437

4-{3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]benzoyl}piperazine-1-carbaldehyde

Specified in the title compound receive in accordance with the method of example 308, using piperazine-1-carbaldehyde instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 381 (M+H)+.

EXAMPLE 438

4-{3-[(4-acetylpiperidine-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 1-(piperazine-1-yl)Etalon instead furan-3-yl is ethanamine. MS (DCI/NH3) m/z 395 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1,44-of 1.57 (m, 4H), of 2.09 (s, 3H), 2,28-2,39 (m, 2H), of 2.51-of 2.66 (m, 2H), 3,39-to 3.73 (m, 8H), is 4.03 (s, 2H), was 7.36-7,39 (m, 1H), 7,43 (t, J=7,02 Hz, 2H), 7,54 (s, 1H).

EXAMPLE 439

4-(3-{[4-(2-hydroxyethyl)piperazine-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 2-(piperazine-1-yl)ethanol instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 397 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1,42-of 1.55 (m, 4H), 2,27-is 2.37 (m, 2H), 2,50-2,62 (m, 6H), 2,69 (t, J=5,80 Hz, 2H), 3,54 of 3.75 (m, 4H), to 3.89 (t, J=5,80 Hz, 2H), was 4.02 (s, 2H), 7,35-7,38 (m, 1H), 7,39-the 7.43 (m, 2H), 7,50 (s, 1H).

EXAMPLE 440

4-{3-[(4-phenylpiperazin-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 1-phenylpiperazine instead furan-3-ylmethanone. MS (DCI/NH3) m/z 429 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1,44-of 1.57 (m, 4H), 2,27-to 2.42 (m, 2H), 2,52-of 2.66 (m, 2H), is 3.08-3,20 (m, 4H), 3,68-a 3.83 (m, 4H), Android 4.04 (s, 2H), 6,91 (t, J=7,32 Hz, 1H), 6,98 (d, J=to 7.93 Hz, 2H), 7,28-7,34 (m, 2H), 7,37-7,41 (m, 1H), 7,44 (t, J=of 7.48 Hz, 1H), 7,46-7,49 (m, 1H), EUR 7.57 (s, 1H).

EXAMPLE 441

4-{3-[(4-pyridine-2-reparation-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 1-(pyridin-2-yl)piperazin is instead furan-3-ylmethanone. MS (DCI/NH3) m/z 430 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1,46-of 1.55 (m, 4H), to 2.29-2.40 a (m, 2H), 2,52-to 2.65 (m, 2H), 3,53-3,63 (m, 4H), 3,64-of 3.78 (m, 4H), a 4.03 (s, 2H), 6,66 (DD, J=of 6.71, 4,58 Hz, 1H), 6.73 x (d, J=8.54 in Hz, 1H), 7,37-7,41 (m, 1H), 7,43 (d, J=7,63 Hz, 1H), 7,45-of 7.48 (m, 1H), 7,49-rate of 7.54 (m, 1H), EUR 7.57 (s, 1H), 8,29 (DD, J=4,88, 1,22 Hz, 1H).

EXAMPLE 442

4-{3-[(4-pyrimidine-2-reparation-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 2-(piperazine-1-yl)pyrimidine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 431 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1,42-to 1.59 (m, 4H), and 2.26-2.40 a (m, 2H), 2,50-of 2.66 (m, 2H), 3,62-3,74 (m, 4H), 3,82-3,91 (m, 4H), a 4.03 (s, 2H), 6,55 (t, J=4,73 Hz, 1H), 7,38 (d, J=5,80 Hz, 1H), 7,40 was 7.45 (m, 1H), 7,45-7,49 (m, 1H), EUR 7.57 (, 1H), scored 8.38 (d, J=4,88 Hz, 2H).

EXAMPLE 443

4-[3-({4-[2-(2-hydroxyethoxy)ethyl]piperazine-1-yl}carbonyl)benzyl]-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 2-(2-(piperazine-1-yl)ethoxy)ethanol instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 441 (M+H)+.

EXAMPLE 444

4-(3-{[4-(2-forfinal)piperazine-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 1-(2-forfinal)piperazine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 447 (M+H)+ .

EXAMPLE 445

4-(3-{[4-(4-forfinal)piperazine-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 1-(4-forfinal)piperazine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 447 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ 1,44-of 1.56 (m, 4H), 2,30-2,39 (m, 2H), 2,53-2,63 (m, 2H), 3,02-of 3.12 (m, 4H), 3,68-3,81 (m, 4H), of 4.05 (s, 2H), 6,93-6,97 (m, 2H),? 7.04 baby mortality-to 7.09 (m, 2H), 7,37-7,41 (m, 1H), 7,44 (t, J=7,32 Hz, 1H), 7,46-7,51 (m, 1H), EUR 7.57 (s, 1H).

EXAMPLE 446

4-(3-{[4-(2-chlorophenyl)piperazine-1-yl]carbonyl}benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 1-(2-chlorophenyl)piperazine instead of furan-3-ylmethanone. MS (DCI/NH3) m/z 463 (M+H)+.

EXAMPLE 447

4-{3-[(4-methyl-1,4-diazepan-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 308, using 1-methyl-4-(piperazine-1-yl)ASEAN instead furan-3-ylmethanone. MS (DCI/NH3) m/z 381 (M+H)+;1H NMR (500 MHz, D2O/pyridine-d5): δ of 1.44 to 1.48 (m, 1H), 1,48-is 1.51 (m, 4H), 1,92 is 2.01 (m, 2H), 2,28-of 2.36 (m, 2H), of 2.51 is 2.55 (m, 2H), 2,58 (s, 3H), of 2.64 (t, J=5,65 Hz, 1H), 2,84-to 2.94 (m, 2H), 3,64-3,71 (m, 3H), 3,88-to 3.92 (m, 1H), 4,01 (s, 2H), 7,33-7,39 (m, 1H), 7,39-7,41 (m, 1H), 7,41 was 7.45 (m, 1H), 7,51 (s, 1H).

EXAMPLE 448

4-[3-(1,1-dioxido-1,2-diazinon-2-yl)-4-terbisil]-5,6,7,8-tet is hydrophilizing-1(2H)-he

EXAMPLE 448A

3-(1,1-dioxido-1,2-diazinon-2-yl)-4-forbindelse

Specified in the title compound receive in accordance with the method of example 300A, using 1,4-butanesultone instead of 5-methylpyrrolidinone. MS (DCI/NH3) m/z 258 (M+H)+.

EXAMPLE 448B

4-[3-(1,1-dioxido-1,2-diazinon-2-yl)-4-terbisil]-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 448A, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 392 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1.57 in-1,71 (m, 4H), 1,75-to 1.87 (m, 2H), 2,13-of 2.24 (m, 2H), 2,34 is 2.46 (m, 4H), 3,16 of 3.28 (m, 2H), 3.46 in-to 3.58 (m, 2H), 3,92 (s, 2H), 7.23 percent (DD, J=8,13, to 2.18 Hz, 1H), of 7.48 (d, J=to 7.93 Hz, 1H), EUR 7.57 (d, J=1,59 Hz, 1H), was 12.61 (ush. s, 1H).

EXAMPLE 449

8-[4-fluoro-3-(2-oxoazetidin-1-yl)benzyl]pyrido[2,3-d]pyridazin-5(6H)-he

Specified in the title compound receive in accordance with the method of example 101, using the compound obtained in example 415, instead of the compound obtained in example 103. MS (ESI) m/z 325 (M+H)+.

EXAMPLE 450

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

Specified in the title compound obtained as TFU salt according to the method of example 414, using the compound obtained in example 370, instead of the compound obtained in example 369. MS (ESI) m/z 294 (M+H)+.

4-(1-(4-fluoro-3-(2-oxoazetidin-1-yl)phenyl)ethyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 101, using the compound obtained in example 412, instead of the compound obtained in example 103. MS (ESI) m/z 342 (M+H)+;1H NMR (300 MHz, DMSO-d6): of 1.41 (d, J=7,12 Hz, 3H), 1,44-to 1.67 (m, 4H), 1,84-of 2.08 (m, 1H), 2,34 (m, 2H), 2,53-to 2.74 (m, 1H), 3,11 (t, J=4,58 Hz, 2H), 3.72 points-3,88 (m, 2H), 4,22 (sq, J=is 6.78 Hz, 1H), for 6.81-to 6.95 (m, 1H), 7,18 (DD, J=11.87 per, 8,48 Hz, 1H), 7,76 (DD, J=7,46, 2.37 Hz, 1H), 12,70 (s, 1H).

EXAMPLE 452

1-{3-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}pyrrolidin-2,5-dione

Specified in the title compound receive in accordance with the method of example 2, 3 and 4, using 3-nitrobenzaldehyde instead of 4-fluoro-3-nitrobenzaldehyde. MS (DCI/NH3) m/z 256 (M+H)+.

EXAMPLE 453

N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-2-(2-oxopyrrolidin-1-yl)ndimethylacetamide

Specified in the title compound obtained as TFU salt according to the method of example 136 using the compound obtained in example 2 instead of the compound obtained in example 89, and 2-(2-oxopyrrolidin-1-yl)acetic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 356 (M+H)+. MS (DCI/NH3) m/z 399 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,53-to 1.67 (m, 4H), 1,89-to 2.06 (m, 2H), and 2.26 (t, J=7,97 Hz, 2H), 2,31 is 2.43 (m, 4H), 3,39-3,47 (m, 2H) 3,86 (s, 2H), 4,07 (s, 2H), 6,93-6,99 (m, 1H), 7,18 (DD, J=10,85, 8,48 Hz, 1H), 7,71 (DD, J=7,46, 2,03 Hz, 1H), 9,82 (ush. s, 1H), 12,61 (ush. s, 1H).

EXAMPLE 454

N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide

Specified in the title compound obtained as TFU salt according to the method of example 136 using the compound obtained in example 2 instead of the compound obtained in example 89, and 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 356 (M+H)+. MS (DCI/NH3) m/z 458 (M+H)+.

EXAMPLE 455

N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-5-oxohexanoate

Specified in the title compound obtained as TFU salt according to the method of example 136 using the compound obtained in example 2 instead of the compound obtained in example 89, and 5-oxohexanoyl acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 386 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,53-of 1.65 (m, 4H), 1,67 and 1.80 (m, 2H), 2,08 (s, 3H), 2,28-of 2.34 (m, 2H), 2,34-to 2.41 (m, 4H), 2,42-2,49 (m, 2H), 3,85 (s, 2H), 6,82-of 6.96 (m, 1H), 7,15 (DD, J=10,85, 8,48 Hz, 1H), to 7.67 (DD, J=7,46, 1.70 Hz, 1H), 9,60 (ush. s, 1H), 12,61 (ush. s, 1H).

EXAMPLE 456

N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-3-methoxypropane

Specified in the title compound obtained as TFU salt in accordance with the methods of the IR of example 136, using the compound obtained in example 2 instead of the compound obtained in example 89, and 3-methoxypropanol acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 360 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,55-of 1.66 (m, 4H), 2,30 is 2.43 (m, 4H), 2,60 (t, J=6,10 Hz, 2H), 3,23 (s, 3H)and 3.59 (t, J=6,27 Hz, 2H), 3,86 (s, 2H), 6,85-6,99 (m, 1H), 7,16 (DD, J=10,85, 8,48 Hz, 1H), 7,74 (DD, J=7,46, 1.70 Hz, 1H), for 9.64 (ush. s, 1H), 12,61 (ush. s, 1H).

EXAMPLE 457

N-{2-fluoro-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenyl}-N'-phenylenediamine

Specified in the title compound obtained as TFU salt according to the method of example 136 using the compound obtained in example 2 instead of the compound obtained in example 89, and 5-oxo-5-(phenylamino)pentane acid instead of 1-methylcyclopropane acid. MS (DCI/NH3) m/z 463 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,55-to 1.67 (m, 4H), 1,83-of 1.94 (m, 2H), 2,31-to 2.40 (m, 6H), 2.40 a at 2.45 (m, 2H), 3,85 (s, 2H), 6,89-of 6.96 (m, 1H), 6,98-7,06 (m, 1H), 7,15 (DD, J=10,85, 8,48 Hz, 1H), 7.24 to 7,32 (m, 2H), to 7.59 (d, J=7,46 Hz, 2H), 7,71 (DD, J=7,97, of 1.53 Hz, 1H), 9,67 (ush. s, 1H), 9,88 (ush. s, 1H), br12.62 (ush. s, 1H).

EXAMPLE 458

Benzyl 2-(dimethylamino)-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenylcarbamate

EXAMPLE 458 A

4-(dimethylamino)-N-methoxy-N-methyl-3-nitrobenzamide

To a solution of 4-fluoro-3-nitrobenzoic acid (5 g, of 27.0 mmol) in dimethylformamide (100 ml) is added N,O-dimethylhydroxylamine hydrochlo the ID (5,93 g, of 60.8 mmol) and triethylamine (17,0 ml, 122 mmol). To the mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11,65 g of 60.8 mmol) and hydroxybenzotriazole (9,31 g of 60.8 mmol) and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture is concentrated and distributed between ethyl acetate (150 ml) and saturated salt solution (150 ml). The organic layers are concentrated on a rotary evaporator and the crude product was purified flash chromatography (elution with 40% ethyl acetate in hexano), getting mentioned in the title compound. MS (DCI/NH3) m/z 254 (M+H)+.

EXAMPLE 458B

3-amino-4-(dimethylamino)-N-methoxy-N-methylbenzamide

A solution of the compound obtained in example 458A (2,34 g, 9,24 mmol)in tetrahydrofuran (40 ml) is treated with Raney Nickel (2.0 g, Raney Nickel 2800, suspension in water) at room temperature in an atmosphere of hydrogen (balloon) for 16 hours. The catalyst is filtered off and the filtrate evaporated. The rest is used in the next stage without additional purification.

EXAMPLE 458C

Benzyl 2-(dimethylamino)-5-(methoxy(methyl)carbarnoyl)phenylcarbamate

To a solution of the compound obtained in example 458B, in a mixture of tetrahydrofuran (20 ml) and water (20 ml) is added cesium carbonate (6,02 g, 18,58 mmol) and benzylchloride (1.5 ml, 10,16 mmol). The reaction mixture was stirred at room temperature in those who tell 16 hours and then evaporated. The residue is distributed between ethyl acetate (100 ml) and saturated salt solution (75 ml). The organic layer was washed with saturated salt solution and concentrated. The resulting oil purified flash chromatography (elution with 40% ethyl acetate in hexano), getting mentioned in the title compound. MS (DCI/NH3) m/z 358 (M+H)+.

EXAMPLE 458D

Benzyl 2-(dimethylamino)-5-formylphenylboronic

A solution of the compound obtained in example 458C (2,89 g, 8.1 mmol)in anhydrous tetrahydrofuran (20 ml) is treated with lithium aluminum hydride (a 1.0 M solution in tetrahydrofuran, to 8.1 ml, 8.1 mmol) at 0°C for 10 minutes. The reaction is quenched with water and the mixture is distributed between ethyl acetate and dilute HCl solution. The organic layer was washed with saturated salt solution and concentrated on a rotary evaporator. The resulting oil purified flash chromatography (elution: 20% ethyl acetate in hexano), getting mentioned in the title compound. MS (DCI/NH3) m/z 299 (M+H)+.

EXAMPLE 458E

Benzyl 2-(dimethylamino)-5-[(4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl]phenylcarbamate

Specified in the title compound receive in accordance with the method of example 300B, using the compound obtained in example 458D, instead of the compound obtained in example 300A. MS (DCI/NH3) m/z 433 (M+H)+.

EXAMPLE 459

8-(4-fluoro-3-(2-oxoazetidin-1-yl)benzyl)-1,2,3,4-tetr is hydroperiod[3,2-d]pyridazin-5(6H)-he

Specified in the title compound receive in accordance with the method of example 414, using the compound obtained in example 449, instead of the compound obtained in example 369. MS (ESI) m/z 329 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1.61 of to 1.76 (m, 2H), 2,33 (t, J=6,35 Hz, 2H), 3,12 (t, J=4,56 Hz, 2H), 3,17 (m, 2H), of 3.77 (s, 2H), 3,81 (sq, J=4,36 Hz, 2H), 6,32 (s, 1H), 6.87 in-7,01 (m, 1H), 7,17 (DD, J=11,90, of 8.33 Hz, 1H), 7,78 (DD, J=7,54, 2.38 Hz, 1H), RS 11.80 (s, 1H).

EXAMPLE 460

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

EXAMPLE 460A

3-(3-bromo-4-forfinal)-3-methoxy-4,5,6,7-tetrahydrothiopyran-1(3H)-he

To a solution of 2-bromo-1-fluoro-4-yogashala (13,23 g, 44 mmol) in anhydrous tetrahydrofuran (30 ml) is added chloride Isopropylamine (2.0 M solution in tetrahydrofuran, 24,18 ml of 48.4 mmol) at -20°C. After addition the reaction mixture was stirred at 0°C for 3 hours and added to a solution of 3,4,5,6-tetrahydrophthalic anhydride (between 6.08 g, 40 mmol) in anhydrous tetrahydrofuran (60 ml) at -78°C. the Mixture is stirred for 2 hours, then add saturated aqueous solution of ammonium chloride and the resulting reaction mixture was then stirred at room temperature for 30 minutes. The reaction mixture was added anhydrous magnesium sulfate and the mixture is filtered. The filtrate is concentrated. Thionyl chloride (10.4 ml, 142 mol) are added dropwise to methanol (40 ml) at -10°C and the solution stirred PR is 0°C for 30 minutes. Then, to the obtained solution of thionyl chloride add the remainder of the filtrate in anhydrous methanol (15 ml). The reaction mixture was stirred at room temperature overnight and then evaporated. The residue is dissolved in methylene chloride (40 ml) and treated with triethylamine (5,58 ml) at 0°C for 1 hour. Water is added and the mixture washed with sodium hydrogen carbonate solution, a saturated solution of salt and water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The remainder is shared by flash chromatography (ethyl acetate in hexane elution gradient: 10-35%), getting mentioned in the title compound. MS (DCI/NH3) m/z 341, 343 (M+H)+.

EXAMPLE 460B

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

A solution of the compound obtained in example 460A (9.5 g, 27.8 mmol), and hydrazine monohydrate (1,76 ml, and 36.2 mmol) in ethanol (70 ml) is refluxed for 4 hours. After cooling to room temperature the solid product is collected by filtration, washed with ethanol and dried, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 323, 325 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,57-of 1.65 (m, 2H), 1,66-of 1.74 (m, 2H), 2,34 (t, J=5,75 Hz, 2H), 2,45 (t, J=x 6.15 Hz, 2H), 7,45 (t, J=8,72 Hz, 1H), 7,49-of 7.55 (m, 1H), 7,80 (DD, J=6,74, 2.38 Hz, 1H), 12,85 (ush. s, 1H).

EXAMPLE 461

4-[4-fluoro-3-(2-oxoazetidin-1-yl)phenyl]-5,6,7,8-tetrahydropyrazin-1(2H)-he/u>

EXAMPLE 461A

2-(benzoyloxymethyl)-4-(3-bromo-4-forfinal)-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in example 460 (2.0 g, to 6.19 mmol)in anhydrous dimethylformamide (30 ml) is added tert-piperonyl potassium (1M solution in tetrahydrofuran, of 6.50 ml, 6.5 mmol). The solution was stirred at room temperature for 30 minutes and add benzylcarbamoyl ether (1,163 g, the 7.43 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and partitioned between water and ethyl acetate. The organic phase is washed with water and evaporated. The remainder is shared by flash chromatography (ethyl acetate in hexane elution gradient: 20-60%), getting mentioned in the title compound. MS (DCI/NH3) m/z 443 (M+H)+.

EXAMPLE 461B

2-(benzoyloxymethyl)-4-(4-fluoro-3-(2-oxoazetidin-1-yl)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he

In a tubular microwave reactor load connection example 461A (137 mg, 0,309 mmol), Tris(dibenzylideneacetone)dipalladium(0) (28,3 mg, 0,031 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (26.9 mg, 0.046 mmol), 2-azetidinone (44 mg, 0,619 mmol) and rejonowy potassium phosphate (98 mg, 0,464 mmol). Add anhydrous dioxane (3 ml). The suspension is rinsed with nitrogen and closed microwave partition. The reaction mixture was kept in a microwave reactor CEM Explorer® (Mathews, NC) at 200°C for 50 minutes. After cooling, the reaction mixture is distributed between ethyl acetate and a saturated solution of salt. The organic phase is washed with water and evaporated. The remainder is shared by flash chromatography (ethyl acetate in hexane elution gradient: 20-70%), getting mentioned in the title compound. MS (DCI/NH3) m/z 434 (M+H)+.

EXAMPLE 461C

4-[4-fluoro-3-(2-oxoazetidin-1-yl)phenyl]-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of the compound obtained in example 461B (140 mg, 0,323 mmol), in methanol (10 ml) under nitrogen atmosphere add 20% palladium hydroxide-on-carbon (80 mg). The resulting suspension is rinsed with hydrogen and stirred under hydrogen atmosphere (balloon) at 50°C for 4 hours. The mixture is filtered and the filtrate evaporated. The residue is recrystallized from methanol (4 ml), getting mentioned in the title compound. Uterine fluid is shared by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 250×of 2.54 column, mobile phase A: 0.1% OF TFU in H2O; B: 0.1% OF TFU in CH3CN; gradient 0-100%), receiving the additional amount specified in the title compounds. MS (DCI/NH3) m/z 314 (M+H)+;1H NMR (400 MHz, DMSO-d6), δ 1,57-to 1.63 (m, 2H), 1,67-of 1.74 (m, 2H), 2,33 (t, J=of 5.83 Hz, 2H), 2,45 (t, J=6,14 Hz, 2H), 3,14-3,18 (m, 2H), 3,86-3,90 (m, 2H), 7,16-7,21 (m, 1H), 7,34 (DD, J=11,66, 8,59 Hz, 1H), to 7.93 (DD, J=7,52, 2.30 Hz, 1H), 12,89 (s, 1H).

EXAMPLE 462

2-fluoro-5-[(5-oxo-5,6-digitope the IDO[2,3-d]pyridazin-8-yl)methyl]benzamide

EXAMPLE 462A

Methyl 2-fluoro-5-((5-oxo-5,6-dihydropyrido[3,2-d]pyridazin-8-yl)methyl)benzoate

Specified in the title compound receive in accordance with the method of example 66C, using the compound obtained in example 415, instead of the compound obtained in example 66B. MS (DCI/NH3) m/z 314 (M+H)+.

EXAMPLE 462B

2-fluoro-5-[(5-oxo-5,6-dihydropyrido[2,3-d]pyridazin-8-yl)methyl]benzamide

A solution of the compound obtained in example 462A (1 g, 3.2 mmol)in 7N ammonia solution in methanol (5 ml) maintained at 70°C overnight and cooled to room temperature. The solid product is collected by filtration, washed with methanol and dried, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 299 (M+H)+.

EXAMPLE 463

8-(3-amino-4-terbisil)pyrido[2,3-d]pyridazin-5(6H)-he

A mixture of 1,5N aqueous solution of KOH (2 ml) and 3 g of ice is treated with bromine (80 mg, 0.5 mmol) at -10°C for 10 minutes. To the mixture of the compound obtained in example 462 (100 mg, 0.3 mmol). The reaction mixture is additionally stirred at -10°C for 10 minutes and then heated to 65°C and maintained at this temperature for 1 hour. After cooling, the mixture is distributed between ethyl acetate and a saturated solution of salt. The organic phase is washed with saturated salt solution and evaporated to a volume of approximately 10 ml of the Solid product Sobir the Ute filtering, washed with methanol and dried, obtaining mentioned in the title compound. MS (DCI/NH3) m/z 271 (M+H)+.

EXAMPLE 464

8-[4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl]-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

EXAMPLE 464A

6-(benzoyloxymethyl)-8-(3-bromo-4-terbisil)pyrido[3,2-d]pyridazin-5(6H)-he

A solution of the compound obtained in example 415 (1 g, 3 mmol)in anhydrous dimethylformamide (100 ml) is treated with tert-piperonyl potassium (1N solution in tetrahydrofuran, 3 ml, 3 mmol) at room temperature for 30 minutes. Then add benzyloxyaniline (0.6 g, 3.6 mmol) and the mixture is stirred at room temperature overnight. The reaction is quenched with water and the reaction mixture is distributed between ethyl acetate and a saturated solution of salt. The organic layer was washed with saturated salt solution and evaporated. The residue is purified flash chromatography (85% ethyl acetate in hexane)to give specified in the title compound. MS (DCI/NH3) m/z 454 (M+H)+.

EXAMPLE 464B

6-(benzoyloxymethyl)-8-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)pyrido[3,2-d]pyridazin-5(6H)-he

Specified in the title compound receive in accordance with the method of example 101, using the compound obtained in example 464A, instead of the compound obtained in example 103. MS (ESI) m/z 459 (M+H)+.

EXAMPLE 464C

8-[4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl]-2,3,4,6-then it is carbonated is raperito[2,3-d]pyridazin-5(1H)-he

A mixture of compound of example 464B (130 mg, 0.28 mmol), 5% platinum-on-carbon (25 mg), 5% Pd(OH)2on carbon (25 mg), concentrated aqueous HCl (66 μl) and dimethylformamide (10 ml) is stirred reactor high pressure at room temperature in a hydrogen atmosphere with a pressure of 40 pounds per square inch within 48 hours. Volatile components are removed, the remainder is shared by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0.1% TFWC/CH3CN/H2O)receiving specified in the title compound in the form of TFU salt. MS (ESI) m/z 343 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,57-of 1.81 (m, 2H), 2,01-to 2.18 (m, 2H), 2.26 and is 2.46 (m, 4H), 3,17 (m, 2H), and 3.72 (t, J=6,94 Hz, 2H), 3,84 (s, 2H), to 6.39 (s, 1H), 7,16-7,19 (m, 1H), 7.18 in-7,25 (m, 1H), 7,29 (DD, J=7,54, to 1.98 Hz, 1H), 11,89 (s, 1H).

EXAMPLE 465

Methyl-2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]benzoate

Specified in the title compound obtained as TFU salt according to the method of example 414, using the compound obtained in example 462A, instead of the compound obtained in example 369. MS (ESI) m/z 318 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,61 is 1.75 (m, 2H), 2,34 (t, J=x 6.15 Hz, 2H), 3,17 (m, 2H), 3,44 (s, 3H), of 3.84 (s, 2H), to 6.39 (s, 1H), 7,27 (DD, J=10,91, 8.53 Hz, 1H), 7,46-7,56 (m, 1H), 7,76 (DD, J=7,14, 2.38 Hz, 1H), 11,84 (s, 1H).

EXAMPLE 467

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

Specified in the title compound obtained as TFU salt in soo is according to the method of example 414, using the compound obtained in example 463, instead of the compound obtained in example 369. MS (ESI) m/z 275 (M+H)+;1H NMR (300 MHz, DMSO-d6): 1,62-of 1.74 (m, 2H), 2,35 (t, J=6,27 Hz, 2H), 3,10-of 3.23 (m, 2H), 3,69 (s, 2H), 4,91 (s, 2H), and 6.25 (s, 1H), 6,45-is 6.54 (m, 1H), only 6.64 (DD, J=8,82, 2,03 Hz, 1H), 6,92 (DD, J=11,53, 8,48 Hz, 1H), 11,93 (s, 1H).

EXAMPLE 468

2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]benzoic acid

Specified in the title compound receive in accordance with the method of example 288, using the compound obtained in example 465, instead of the compound obtained in example 266. MS (ESI) m/z 304 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,61-to 1.77 (m, 2H), 2,34 (t, J=6,10 Hz, 2H), 3,06-of 3.25 (m, 2H), 3,84 (s, 2H), 6,36 (s, 1H), 7,22 (DD, J=10,85, 8,48 Hz, 1H), 7,39-7,52 (m, 1H), 7,73 (DD, J=7,12, 2.37 Hz, 1H), 11,82 (s, 1H) 13,19 (s, 1H).

EXAMPLE 470

N-ethyl-2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]benzamide

Specified in the title compound is obtained in the form of TFU salt according to the method of example 48, using the compound obtained in example 468, instead of the compound obtained in example 48C, and ethylamine instead of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 331 (M+H)+;1H NMR (300 MHz, DMSO-d6): of 1.09 (t, J=7,14 Hz, 3H), 1,58-of 1.74 (m, 2H), 2,34 (t, J=x 6.15 Hz, 2H), 3,12-3,20 (m, 2H), 3,20 to be 3.29 (m, 2H), 3,82 (s, 2H), to 6.39 (s, 1H), 7,19 (DD, J=10,31, of 8.33 Hz, 1H), 7,30-7,38 (m, 1H), 7,47 (DD, J=6,74, 2.38 Hz, 1H), 8.17-a 8,29 (m, 1H), 11,88 with, 1H).

EXAMPLE 471

N-cyclobutyl-2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]benzamide

Specified in the title compound obtained as TFU salt according to the method of example 48, using the compound obtained in example 468, instead of the compound obtained in example 48C, and cyclobutanone instead of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 357 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1.56 to 1.77 in (m, 4H), 1,90-2,10 (m, 2H), 2,12-of 2.28 (m, 2H), 2,33 (t, J=6,35 Hz, 2H), 3,05-of 3.25 (m, 2H), 3,81 (s, 2H), 4,27 is 4.45 (m, 1H), 6.35mm (s, 1H), 7,18 (DD, J=10,31, of 8.33 Hz, 1H), 7,26-7,37 (m, 1H), 7,42 (DD, J=6,74, 2.38 Hz, 1H), 8,49 (d, J=rate of 7.54 Hz, 1H), 11,84 (s, 1H).

EXAMPLE 472

2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]-N-(2-pyrrolidin-1-retil)benzamid

Specified in the title compound obtained as TFU salt according to the method of example 48, using the compound obtained in example 468, instead of the compound obtained in example 48C, and 2-(pyrrolidin-1-yl)ethanamine instead of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 400 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ of 1.63 to 1.76 (m, 2H), 1,76-of 1.93 (m, 2H), 1.93 and is 2.10 (m, 2H), 2,34 (t, J=6,10 Hz, 2H), 2,61 was 2.76 (m, 2H), 2,96-of 3.12 (m, 2H), 3,12-up 3.22 (m, 2H), 3.25 to 3.40 in (m, 2H), 3,52-3,68 (m, 2H), 3,84 (s, 2H), 6.35mm (s, 1H), to 7.25 (DD, J=10,85, 8,48 Hz, 1H), 7,33-7,49 (m, 1H), EUR 7.57 (DD, J=7,12, 2.37 Hz, 1H), 8,31-of 8.50 (m, 1H), 11,84 (s, 1H).

EXAMPLE 473

8-(4-fluoro-3-{[4-(morpholine-4-ylcarbonyl)piperazine-1-and the]carbonyl}benzyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-he

Specified in the title compound is obtained in the form of TFU salt according to the method of example 48, using the compound obtained in example 468, instead of the compound obtained in example 48C, and morpholino(piperazine-1-yl)methanon instead of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 485 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1.60-to of 1.78 (m, 2H), 2,35 (t, J=x 6.15 Hz, 2H), 3,05 of 3.28 (m, N), 3,51-to 3.58 (m, 4H), 3,60-3,70 (m, 2H), 3,82 (s, 2H), 6,41 (s, 1H), 7,16-7,29 (m, 2H), 7,29-7,37 (m, 1H), 11,92 (s, 1H).

EXAMPLE 474

N-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]phenyl}-N'-phenylenediamine

Specified in the title compound is obtained in the form of TFU salt according to the method of example 136 using the compound obtained in example 467, instead of the compound obtained in example 89, and 5-oxo-5-(phenylamino)pentane acid instead of 1-methylcyclopropane acid. MS (ESI) m/z 464 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ of 1.62 and 1.75 (m, 2H), 1,81 is 1.96 (m, 2H), 2,34 (t, J=7,12 Hz, 4H), 2,42 (t, J=8,14 Hz, 2H), 3,09-up 3.22 (m, 2H), of 3.77 (s, 2H), 6.30-in (s, 1H), 6,93-7,07 (m, 1H), 7,14 (DD, J=10,85, 8,48 Hz, 1H), 7,22-7,34 (m, 3H), to 7.59 (d, J=7,80 Hz, 2H), 7.68 per-to 7.77 (m, 1H), 9,62 (s, 1H), 9,87 (s, 1H), 11,82 (s, 1H).

EXAMPLE 475

1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]phenyl}pyrrolidin-2,5-dione

EXAMPLE 475A

4-(2-fluoro-5-((5-oxo-5,6-dihydropyrido[3,2-d]pyridazin-8-yl)methyl)phenylamino)-4-oxobutanoic acid

Specified in the title compound receive in accordance with the method of example 3 using the compound obtained in example 463, instead of the compound obtained in example 2. MS (ESI) m/z 371 (M+H)+.

EXAMPLE 475B

1-(2-fluoro-5-((5-oxo-5,6-dihydropyrido[3,2-d]pyridazin-8-yl)methyl)phenyl)pyrrolidin-2,5-dione

Specified in the title compound receive in accordance with the method of example 4 using the compound obtained in example 475 A, instead of the compound obtained in example 3. MS (ESI) m/z 353 (M+H)+.

EXAMPLE 475C

1-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]phenyl}pyrrolidin-2,5-dione

Specified in the title compound receive in accordance with the method of example 414, using the compound obtained in example 475B, instead of the compound obtained in example 369. MS (ESI) m/z 357 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,58-of 1.78 (m, 2H), 2,33 (t, J=6,27 Hz, 2H), 2,72-2,90 (m, 4H), 3,07 is 3.23 (m, 2H), 3,84 (s, 2H), 6,34 (s, 1H), 7,13 (DD, J=6,95, 2.20 Hz, 1H), 7,27-7,37 (m, 1H), 7,37-the 7.43 (m, 1H), 11,83 (s, 1H).

EXAMPLE 476

N-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]phenyl}-3-methoxypropane

Specified in the title compound is obtained in the form of TFU salt according to the method of example 136 using the compound obtained in example 467, instead of the compound obtained in example 89, and 3-methoxypropanol acid instead of 1-m is telekompaniebis acid. MS (ESI) m/z 361 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,63-of 1.74 (m, 2H), 2,33 (t, J=x 6.15 Hz, 2H), 2,60 (t, J=x 6.15 Hz, 2H), 3,09-is 3.21 (m, 2H), 3,24 (s, 3H)and 3.59 (t, J=x 6.15 Hz, 2H), of 3.77 (s, 2H), 6,33 (s, 1H), 6,93-7,05 (m, 1H), 7,14 (DD, J=10,91, 8.53 Hz, 1H), 7,69-7,80 (m, 1H), 9,63 (s, 1H), 11,85 (s, 1H).

EXAMPLE 477

N-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]phenyl}-5-oxohexanoate

Specified in the title compound obtained as TFU salt according to the method of example 136 using the compound obtained in example 467, instead of the compound obtained in example 89, and 5-oxohexanoyl acid instead of 1-methylcyclopropane acid. MS (ESI) m/z 387 (M+H)+;1H NMR (300 MHz, DMSO-d6): 1,64-of 1.80 (m, 4H), of 2.08 (s, 3H), 2,27-2,39 (m, 4H), 2,42-of 2.50 (m, 2H), 3,10-of 3.23 (m, 2H), of 3.77 (s, 2H), 6,34 (s, 1H), 6,94? 7.04 baby mortality (m, 1H), 7,13 (DD, J=10,85, 8,48 Hz, 1H), 7,66-7,71 (m, 1H), 9,58 (s, 1H), up 11,86 (s, 1H).

EXAMPLE 478

N-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]phenyl}-3-phenoxypropane

Specified in the title compound obtained as TFU salt according to the method of example 136 using the compound obtained in example 467, instead of the compound obtained in example 89, and 3-phenoxypropanol acid instead of 1-methylcyclopropane acid. MS (ESI) m/z 423 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,55-of 1.74 (m, 2H), 2,33 (t, J=x 6.15 Hz, 2H), 2,84 (t, J=x 6.15 Hz, 2H), is 3.08 3.21-in (m, 2H), of 3.78 (s, 2H), 4,24 (t, J=x 6.15 Hz, 2H), 6,6 (s, 1H), 6,88-of 6.96 (m, 3H), 6,97-7,05 (m, 1H), 7,16 (DD, J=10,91, 8.53 Hz, 1H), 7,25-7,31 (m, 2H), to 7.77 (DD, J=7,54, to 1.98 Hz, 1H), 9,79 (s, 1H), 11,89 (s, 1H).

EXAMPLE 479

N-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]phenyl}-4-oxo-4-phenylbutane

Specified in the title compound receive in accordance with the procedure of example 136 using the compound obtained in example 467, instead of the compound obtained in example 89, and 4-oxo-4-phenylbutanoate acid instead of 1-methylcyclopropane acid. MS (ESI) m/z 435 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,63-of 1.73 (m, 2H), 2,32 (t, J=5,95 Hz, 2H), 2,75-and 2.79 (m, 2H), is 3.08-3,19 (m, 2H), 3.27 to to 3.36 (m, 2H), 3,75 (s, 2H), 6,27 (s, 1H), 6,91? 7.04 baby mortality (m, 1H), 7,14 (DD, J=10,91, 8.53 Hz, 1H), 7,54 (t, J=rate of 7.54 Hz, 2H), to 7.59-of 7.69 (m, 1H), 7,70-to 7.77 (m, 1H), 7,94-8,03 (m, 2H), 9,74 (s, 1H), 11,78 (s, 1H).

EXAMPLE 481

2-[4-(benzyloxy)phenoxy]-N-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]phenyl}ndimethylacetamide

Specified in the title compound obtained as TFU salt according to the method of example 136 using the compound obtained in example 467, instead of the compound obtained in example 89, and 2-(4-(benzyloxy)phenoxy)acetic acid instead of 1-methylcyclopropane acid. MS (ESI) m/z 515 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,53-of 1.81 (m, 2H), 2,22-2,39 (m, 2H), 3,07-is 3.21 (m, 2H), of 3.78 (s, 2H), of 4.66 (s, 2H), 5,04 (s, 2H), 6,34 (s, 1H), 6,83-6,99 (m, 4H), 7,02-7,10 (m, 1H), 7,14-of 7.23 (m, 1H), 7,30-7,37 (m, 2H), 7,37-7,46 (m, 3H), the 7.65 (DD, J=7,5, to 1.98 Hz, 1H), made up 9.77 (s, 1H), 11,84 (s, 1H).

EXAMPLE 483

N-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]phenyl}-2-(4-methoxyphenoxy)ndimethylacetamide

Specified in the title compound obtained as TFU salt according to the method of example 136 using the compound obtained in example 467, instead of the compound obtained in example 89, and 2-(4-methoxyphenoxy)acetic acid instead of 1-methylcyclopropane acid. MS (ESI) m/z 438 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,63 is 1.75 (m, 2H), 2,33 (t, J=6,27 Hz, 2H), is 3.08-3.24 in (m, 2H), 3,70 (s, 3H), 3,79 (s, 2H), of 4.66 (s, 2H), 6.35mm (s, 1H), 6,84-of 6.96 (m, 4H), 7,01-7,11 (m, 1H), 7,18 (DD, J=10,85, 8,48 Hz, 1H), 7,66 (DD, J=7,63, 2.20 Hz, 1H), 9,73 (s, 1H), 11,85 (s, 1H).

EXAMPLE 484

N-cyclopropyl-2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]benzamide

Specified in the title compound obtained as TFU salt according to the method of example 48, using the compound obtained in example 468, instead of the compound obtained in example 48S, and cyclopropylamine instead of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 343 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 0,44 is 0.59 (m, 2H), 0,63-0,76 (m, 2H), 1.60-to of 1.78 (m, 2H), 2,34 (t, J=6,35 Hz, 2H), 2,74-2,90 (m, 1H), 3,09-up 3.22 (m, 2H), 3,81 (s, 2H), to 6.39 (s, 1H), 7.03 is-7,25 (m, 1H), 7,25-7,37 (m, 1H), 7,42 (DD, J=6,74, 2.38 Hz, 1H), with 8.33 (d, J=3,97 Hz, 1H), 11,89 (s, 1H).

EXAMPLE 485

8-(3-{[4-(2-ethoxyethyl)piperazine-1-yl]carbonyl}-4-terbisil)-2,3,4,6-those whom RapidRead[2,3-d]pyridazin-5(1H)-he

Specified in the title compound obtained as TFU salt according to the method of example 48, using the compound obtained in example 468, instead of the compound obtained in example 48S, and 1-(2-ethoxyethyl)piperazine instead of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 444 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ of 1.09 (t, J=9,0 Hz, 3H), 1,61 to 1.76 (m, 2H), 2,56-2,69 (m, 2H), 3,01-3,11 (m, 2H), 3,11-3,24 (m, 4H), 3,35-of 3.43 (m, 4H), 3,43-3,61 (m, 4H), 3,82 (s, 2H), 6.35mm (s, 1H), 7.18 in-7,26 (m, 1H), 7,28-7,34 (m, 1H), 7,34-7,41 (m, 1H), 11,84 (s, 1H).

EXAMPLE 486

2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[2,3-d]pyridazin-8-yl)methyl]-N-(2-piperidine-1-retil)benzamid

Specified in the title compound receive in accordance with the method of example 48, using the compound obtained in example 468, instead of the compound obtained in example 48S, and 2-(piperidine-1-yl)ethanamine instead of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 414 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,33-1,49 (m, 2H), 1,50-of 1.64 (m, 4H), of 1.62 and 1.75 (m, 2H), 2,33 (t, J=6,35 Hz, 2H), 2,54-2,82 (m, 4H), of 3.10-3.20 (m, 2H), 3,20-to 3.35 (m, 2H), 3,37-3,55 (m, 2H), 3,82 (s, 2H), 6.35mm (s, 1H), 7,20 (DD, J=10,51, 8.53 Hz, 1H), 7,33-7,44 (m, 1H), 7,53 (DD, J=7,14, 2.38 Hz, 1H), 8,51 (DD, J=4,36, of 1.59 Hz, 1H), 11,83 (s, 1H).

EXAMPLE 487

2-fluoro-5-((5-oxo-1,2,3,4,5,6-hexahydrobenzo[3,2-d]pyridazin-8-yl)methyl)-N-(2-oxo-2 - (piperidine-1-yl)ethyl)benzamide

Specified in the title compound receive in accordance with the method of example 48, IP is using the connection, obtained in example 468, instead of the compound obtained in example 48S, and 2-amino-1-(piperidine-1-yl)Etalon instead of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. MS (ESI) m/z 428 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ of 1.44 (m, 2H), 1,48-of 1.65 (m, 4H), 1,65-to 1.79 (m, 2H), 2,33 (t, J=6,27 Hz, 2H), 3,10-3,24 (m, 2H), 3,34-of 3.42 (m, 2H), 3,41-to 3.50 (m, 2H), 3,84 (s, 2H), 4,13 (d, J=5,09 Hz, 2H), 6,00-6,50 (m, 1H), 7,05-7,28 (m, 1H), 7,32-7,53 (m, 1H), 7,63 (DD, J=7,12, 2.37 Hz, 1H), 8,17 (sq, J=5,09 Hz, 1H), 11,82 (s, 1H).

EXAMPLE 490

4-{4-fluoro-3-[(4-pyrimidine-2-reparation-1-yl)carbonyl]benzyl}-5,6,7,8-tetrahydropyrazin-1(2H)-he

To a solution of compound of example 1 (100 mg, 0.33 mmol) in dimethylacetamide (5 ml) is added 2-(1H-7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate methanamine (HATU) (126 mg, 0.33 mmol) and triethylamine (92 μl, 0.66 mmol) and stirred for 20 minutes at room temperature. Then add dihydrochloride (piperazine-1-yl)pyrimidine (78 mg, 0.33 mmol) and the reaction mixture was stirred at room temperature for 16 hours. After concentration, the residual oil purified by HPLC (sorbent Bond® C-18 ODS [Agilent Technologies, Santa Clara, CA], 0-1% TFA/CH3CN/H2(O) obtaining specified in the title of the product. MS (DCI/NH3) m/z 449 (M+H)+;1H NMR (300 MHz, DMSO-d6): δ 1,53-1,71 (m, 4H), 2,32 is 2.44 (m, 4H), 3,24-3,39 (m, 2H), 3,67-of 3.78 (m, 4H), 3,79-3,88 (m, 2H), 3,93 (s, 2H), 6,67 (t, J=4,75 Hz, 1H), 7,21-of 7.23 (m, 1H), 7.24 to 7,28 (m, 1H),7,30-7,35 (m, 1H), 8,39 (d, J=of 4.75 Hz, 2 is), br12.62 (USS, 1H).

EXAMPLE 491

4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)phenyl-5,6,7,8-tetrahydropyrazin-1(2H)-he

Specified in the title compound receive in accordance with the method of example 461, using 2-pyrrolidine instead of 2-azetidinone obtained in example V. MS (DCI/NH3) m/z 328 (M+H)+;1H NMR (400 MHz, CD3OD): δ 1,73-to 1.79 (m, 2H), 1,83-1,90 (m, 2H), 2,22-to 2.29 (m, 2H), 2,55-2,60 (m, 4H), 2,69 (t, J=of 5.83 Hz, 2H), 3,91 (t, J=7,06 Hz, 2H), 7,35-7,41 (m, 1H), of 7.48-7,52 (m, 1H), 7,60-to 7.64 (m, 1H).

Assume that the above examples are illustrative examples of the invention and are not intended to limit the scope of the described variants of implementation. It is also understood that modifications and changes obvious to those skilled in the art, belong to the scope and nature of the invention as defined in the attached claims.

1. The compound of formula (Ik)

or its pharmaceutically acceptable salt,
where R101, R104and R105represent H;
R102is R11where R11selected from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolinone, piperidinyl, piperazinil and azepane, and R102substituted by one or two (O) substituents;
R103is fluorine.

2. The compound according to claim 1, where R11is pyrrolidinyl; Riego pharmaceutically acceptable salt.

3. The compound according to claim 1, selected from the following compounds:
1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)pyrrolidin-2,5-dione;
4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;
4-(4-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;
4-(4-fluoro-3-(2-oxazepan-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;
1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)piperidine-2,6-dione;
4-(4-fluoro-3-(2-Oxymetazoline-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;
4-(4-fluoro-3-(2-oxopiperidin-1-yl)benzyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he; or
4-(4-fluoro-3-(2-oxopyrrolidin-1-yl)phenyl)-5,6,7,8-tetrahydropyrazin-1(2H)-he;
and their pharmaceutically acceptable salts.

4. The Union, representing 1-(2-fluoro-5-((4-oxo-3,4,5,6,7,8-hexahydronaphthalen-1-yl)methyl)phenyl)-pyrrolidin-2,5-dione; or its pharmaceutically acceptable salt.

5. Pharmaceutical composition having inhibitory activity regarding poly(D-ribose)polymerase (PARP), comprising the compound according to claim 1 and pharmaceutically acceptable excipient.

6. A method of treating cancer in a mammal, comprising an introduction to the specified mammal a therapeutically acceptable amount of a compound according to claim 1.

7. A method of reducing tumor volume in a mammal, comprising an introduction to the specified mammal therapeutics and acceptable amount of compound according to claim 1.

8. The method according to claim 6, additionally including radiation therapy.
9 the Method according to claim 6, additionally including the introduction of the chemotherapeutic drug selected from temosolomida, dacarbazine, cyclophosphamide, carmustine, melphalan, lomustina, carboplatin, cisplatin, 5-FU+/-leucovorin, gemcitabine, methotrexate, bleomycin, irinotecan, camptothecin or topotecan.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to quinoline derivatives of formula I

, or to its pharmaceutically acceptable salts, wherein X1 represents O; p represents 0, 1 or 2; each group R1 which can be identical or different and which can be located only in positions of 6- and/or 7-quinoline ring, specified in halogen, cyano, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, or in a group of formula: Q1-X2-, wherein X2 represents CO and Q1 represents pyrrolidine, q represents 0 or 1; R2 represents (1-6C)alkoxy; R3 represents hydrogen or (1-6C)alkyl; R4 represents hydrogen; R5 represents hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl; the ring A represents a 5-membor monocyclic heteroaryl ring with up to three ring heteroatoms specified in oxygen, nitrogen and sulphur; r represents 0, 1 or 2; and each group R6 which can be identical or different is specified in amino, (1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, or in a group of formula: -X6-R15 wherein X6 represents a single link and R15 represents (1-6C)alkoxy-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or in a group of formula: -X7-Q3 wherein X7 represents C(R17)2N(R17) wherein each R17 represents hydrogen and Q3 represents (3-8C)cycloalkyl, and wherein any CH2 group within the R6 group optionally carries a hydroxy group on each said group. Also, the invention refers to methods for making the compound of formula I, to a pharmaceutical composition on the basis of the compound of formula I, to applying the compound of formula I and the combinations on the basis of the compound of formula I and additional anticancer drugs.

EFFECT: there are produced new quinoline derivatives effective in treating diabetic retinopathy and disturbed cell proliferation.

15 cl, 6 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to use of 1,2,4-triazole derivatives of formula I:

, where R1, R2 and R3 independently denote hydrogen or halogen; R4 denotes C1-C6 alkyl; R5 and R6 independently denote C1-C6 alkyl or, together with a nitrogen atom to which they are bonded, form a 5-7-member heterocyclyl group, in which the 6-member heterocyclyl can further contain one oxygen or nitrogen atom and can be substituted with acetyl, C1-C6 alkyl or phyenyl; X-S-, -SO-, -SO2- or O; and n is a whole number selected from 1-8; or pharmaceutically acceptable salts, stereoisomers or solvates thereof, when producing a drug for treating or preventing sigma-1 receptor-mediated diseases or conditions, methods of producing said compounds, intermediate compounds and pharmaceutical compositions which contain compounds of formula 1.

EFFECT: improved compounds.

19 cl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds specified in cl. 1, and also to a pharmaceutical composition possessing binding activity with respect to Bcl proteins, to applying the declared compounds for preparing a drug for treating cancer and for treating a bcl-mediated disorder.

EFFECT: use of the compounds as Bcl protein inhibitors.

18 cl, 2 tbl, 41 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to specific derivatives of bicyclic amides disclosed in the claim, as well as a pharmaceutical composition.

EFFECT: compounds having protein kinase inhibiting activity, meant for use in treating protein kinase-dependant diseases, preferably proliferative diseases such as tumorous diseases.

13 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: medicine, pharmaceutics.

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

or to its pharmaceutically acceptable salt wherein the ring A represents a group presented by formula 2 R1 represents hydrogen or C1-6alkyl; R2 represents -SR5, halogen, halogenated C1-6alkyl, etc., R3 represents a group presented by formula: -CH=CH-C(RaRb)-Rc-Rd, or a group presented by formula: -(CReRf)m-C(RaRb)-Rc-Rd wherein radicals and symbols have the values presented in the patent claim, R4 represents -OR6, -CONR7R8, -NR9CONR7R8, -(CR10R11)POH, -(CR10R11)pOCONR7R8, -NR9COR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9CONR7R8, -CN, halogen or NR9(C=O)OR12; R5 represents C1-6alkyl; R6 represents -CONR7R8; each of R7 and R8 independently represents hydrogen or etc., R10 and R11 independently represents hydrogen; R12 represents C1-6alkyl; each of m and p independently represents an integer 1 to 3. This compound is applicable as a type 1 11β-hydroxysteroiddehydrogenase inhibitor.

EFFECT: invention also refers to single compounds, pharmaceutical compositions on the basis of the declared compounds, to a method for preventing and treating diabetes and the use of the compound of formula (II).

21 cl, 289 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new piperazine amide derivatives of formula wherein X represents N or CH; Y represents N or CH; R1 represents lower alkyl, phenyl, phenyl-lower alkyl wherein phenyl can be optionally substituted by 1-2 substitutes independently specified in a group consisting of halogen, lower alkyl; R2 represents lower alkyl, phenyl, naphthyl or heteroaryl specified in dimethylisoxazolyl, quinolinyl, thiophenyl or pyridinyl wherein phenyl or heteroaryl are optionally substituted by 1 substitute optionally specified in a group consisting of halogen, lower alkoxy group, fluor-lower alkyl, lower alkoxy-carbonyl and phenyl; R3 represents phenyl, pyridinyl or pyrazinyl wherein phenyl, pyridinyl or pyrazinyl are substituted by 1-2 substituted optionally specified in a group consisting of halogen, lower alkyl and fluor-lower alkyl; R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen, as well as to their physiologically acceptable salts. These compounds are bound with LXR alpha and LXR beta, and are applicable as therapeutic agents for treatment and/or prevention of high lipid levels, high cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non insulin dependent diabetes mellitus, metabolic syndrome, dislipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, etc.

EFFECT: preparing new piperazine amide derivatives.

15 cl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to quinoline derivatives of formula I

, or to its pharmaceutically acceptable salts, wherein X1 represents O; p represents 0, 1 or 2; each group R1 which can be identical or different and which can be located only in positions of 6- and/or 7-quinoline ring, specified in halogen, cyano, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, or in a group of formula: Q1-X2-, wherein X2 represents CO and Q1 represents pyrrolidine, q represents 0 or 1; R2 represents (1-6C)alkoxy; R3 represents hydrogen or (1-6C)alkyl; R4 represents hydrogen; R5 represents hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl; the ring A represents a 5-membor monocyclic heteroaryl ring with up to three ring heteroatoms specified in oxygen, nitrogen and sulphur; r represents 0, 1 or 2; and each group R6 which can be identical or different is specified in amino, (1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, or in a group of formula: -X6-R15 wherein X6 represents a single link and R15 represents (1-6C)alkoxy-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or in a group of formula: -X7-Q3 wherein X7 represents C(R17)2N(R17) wherein each R17 represents hydrogen and Q3 represents (3-8C)cycloalkyl, and wherein any CH2 group within the R6 group optionally carries a hydroxy group on each said group. Also, the invention refers to methods for making the compound of formula I, to a pharmaceutical composition on the basis of the compound of formula I, to applying the compound of formula I and the combinations on the basis of the compound of formula I and additional anticancer drugs.

EFFECT: there are produced new quinoline derivatives effective in treating diabetic retinopathy and disturbed cell proliferation.

15 cl, 6 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing piperazinophenols, involving reaction of piperazine, N-(β-aminoethyl)piperazine, N-(β-benzylaminoethyl)piperazine or N,N1-bis-(piperazinoethyl)ethylenediamine with a Mannich base in an aqueous medium at temperature 90-110°C in molar ratio of piperazine, N-(β-aminoethyl)piperazine, N-(β-benzylaminoethyl)piperzine:Mannich base equal to 1:0,8-2, N,N1-bis-(piperazinoethyl)ethylenediamine:Mannich base equal to 1:2 or 1:4 until release of dimethylamine stops; as well as aminomethylation of piperazine or N-(β-aminoethyl) piperazine with diphenylol propane (DPP) in the presence of formaldehyde (FA) in an aqueous medium with molar ratio piperazine: FA: DPP equal to 1:1:1 or 1:2:2 at temperature 50-90°C for 4-10 hours. Reactants react in the presence of a surfactant in amount of 2-6% of the weight of the starting piperazine, and the surfactant used is neonol, OP-7, OP-10.

EFFECT: ensuring fire safety of the process, high output of the end product which can be used as antioxidant phenol stabilisers.

1 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula 1c

, where A, B, R1, R2 and n have values given in the description, and pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions based on compounds of formula 1c, which are used as modulators of ATP-binding cassette ("ABC") transporters or fragments thereof, including cystic fibrosis transmembrane conductance regulator ("CFTR"). The present invention also relates to a method of modulating ABC-transporter activity and methods of treating ABC-transporter mediated diseases using compounds of formula 1c.

EFFECT: improved method.

32 cl, 3 tbl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 1,2,4-triazole derivatives of formula I:

, where R1, R2 and R3 independently denote hydrogen or halogen; R4 denotes C1-C6 alkyl; R5 and R6 independently denote C1-C6 alkyl or, together with a nitrogen atom to which they are bonded, form a 5-7-member heterocyclyl group, in which the 6-member heterocyclyl can further contain one oxygen or nitrogen atom and can be substituted with acetyl, C1-C6 alkyl or phyenyl; X-S-, -SO-, -SO2- or O; and n is a whole number selected from 1-8; or pharmaceutically acceptable salts, stereoisomers or solvates thereof, when producing a drug for treating or preventing sigma-1 receptor-mediated diseases or conditions, methods of producing said compounds, intermediate compounds and pharmaceutical compositions which contain compounds of formula 1.

EFFECT: improved compounds.

19 cl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention relates to specific derivatives of bicyclic amides disclosed in the claim, as well as a pharmaceutical composition.

EFFECT: compounds having protein kinase inhibiting activity, meant for use in treating protein kinase-dependant diseases, preferably proliferative diseases such as tumorous diseases.

13 cl, 115 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (IB) or to their pharmaceutically acceptable salts:

, wherein R means formula: R1 means -C(O)NR3R4, -C(O)R3 and -C(O)OR3; each R3 and R4 independently means H, C1-10 alkyl, wherein alkyl is optionally substituted by one -OH; R3 and R4 are bound together with N atoms to form a 5-6-member heterocyclic ring which additionally contains one O heteroatom; R5 means H; R6 means CN; R7 means H; W means C. What is described is a method for producing both them and intermediate compounds of formula (1-1c): , wherein: R1 means -C(O)NR3R4; R3 and R4 are specified above.

EFFECT: compounds (IB) shows DPP-IV inhibitory activity that allows them being used in a pharmaceutical composition.

9 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I),

, where groups and radicals R1, R2 independently denote H, C1-8-alkyl or C3-7-cycloalkyl, where the alkyl or cycloalkyl group can be mono- or poly-substituted with identical or different groups R11; or R2 denotes a -CH2- or -CH2-CH2- bridge which is bonded with a group Y, and R1 is as defined above, or denotes a group selected from C1-4-alkyl-CO-, C1-4-alkyl-O-CO-, (C1-4-alkyl)NH-CO- or (C1-4-alkyl)2N-CO-, where the alkyl groups can be mono- or polyfluorinated; or R1 and R2 form an alkylene bridge such that R1R2N- denotes a group selected from: azetidine, pyrrolidine, piperdine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free amino group is substituted with R13, piperidin-4-one, morpholine, thiomorpholine, 4-C1-4-alkoxy iminopiperidin-1-yl and 4-hydroxy iminopiperidin-1-yl. Wherein, when R1 and R2 form an alkylene bridge, one or more H atoms in the alkylene bridge can be substituted with identical or different groups R14, and X denotes a C1-3-alkylene bridge which can contain one, two or three identical or different C1-3-alkyl substitutes; and Y denotes a group of subformula selected from: and , where the group can be mono-substituted with a substitute R20; Z denotes -CH2-CH2- or -C(=O)-CH2-; U, V both denote CH, one of groups U, V denotes N, and the other of U, V denotes CH, where CH can be substituted with L; and L independently denotes halogen, cyano or C1-3-alkyl; and k equals 0, 1 or 2; W is selected from a group consisting of -CH2-O- and -O-CH2-; B is selected from a group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thiophenyl and thiazolyl; each of which can be mono- or poly-substituted with identical or different substitutes R20; radicals R11, R13, R14, R20 assume values given in claim 1. The invention also relates to a pharmaceutical composition containing at least one compound of formula I and having action on MCH receptor.

EFFECT: disclosed pharmaceutical compositions are useful in treating metabolic disorders or eating disorders, especially obesity, bulimia, anorexia, hyperphagia and diabetes.

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