Dihydropyridophthalazinone inhibitors of poly(adp-ribose)polymerase

FIELD: chemistry.

SUBSTANCE: claimed invention relates to field of organic chemistry, namely to novel compound of formula (I), where Y and Z, each independently, are selected from group, consisting of: a) phenyl, if necessary substituted with 1 or 2 R6; b) pyridine, imidazole, thiazole, furan, triazole, quinoline or imidazopyridine, if necessary substituted with 1 R6; and c) substituent, independently selected from group, consisting of hydrogen, C1-C6alkyl or pyperidine; R1, R2 and R3, each independently selected from group, consisting of hydrogen and halogen; A and B is each independently selected from hydrogen, OH and C1-C6alkyl; RA and RB are independently selected from group, consisting of hydrogen, C1-C6alkyl and C3-C8cycloalkyl; or RA and RB together with atom, to which they are attached, form 4-6-membered heterocycle, if necessary having additionally one heteroatom or functional heterogrpoup, selected from group, consisting of -O-, -NH, -N(C1-C6-alkyl)- and -NCO(C1-C6-alkyl)-, and 6-membered heterocycle can be additionally substituted with one or two C1-C6-alkyl groups; R4 and R5, each stands for hydrogen; and each R6 is selected from Br, Cl, F, I, C1-C6-alkyl, pyrrolidine, if necessary substituted with one C1-C6-alkyl, C1-C6alkoxy, halogen-C1-C6alkyl, hydroxyl-C1-C6alkylene, -(NRARB)C1-C6alkylene and (NRARB)carbonyl; or to its individual isomer, stereoisomer or enantiomer, or their mixture, if necessary pharmaceutically acceptable salt. Invention also relates to compound of formula (II), particular compounds of formula (I) and (II), pharmaceutical composition and industrial product based on compound of formula (I) and (II), method of treating said pathological conditions, method of obtaining formula (I) compound and to intermediate compound of formula 3.

EFFECT: novel compounds, useful as inhibitors of poly(ADP-ribose)polymerase, are obtained.

50 cl, 1 tbl, 159 ex

 

CROSS-REFERENCE

This application claims the priority of provisional patent application U.S. 61/173088 filed April 27, 2009; 61/151036, filed February 9, 2009, and 61/086687, filed August 6, 2008, which is fully incorporated into the present description by reference.

The SCOPE of the INVENTION

In the present application describes compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme poly(ADP-ribose)polymerase (PARP).

The LEVEL of TECHNOLOGY

The family of poly(ADP-ribose)polymerase (PARP) includes approximately 18 proteins, all of which demonstrate a certain level of homology in their catalytic domain but differ in their cellular functions (Ame et al, BioEssays., 26(8), 882-893 (2004)). PARP-1 and PARP-2 are unique members of this family, as their catalytic activity stimulated by breaks of DNA chains.

PARP is involved in the transduction of signals DNA damage through its ability to recognize and quickly contact breaks single or double DNA strand (D Amours, et al, Biochem. J., 342, 249-268 (1999)). She participates in various related DNA functions, including gene amplification, division, differentiation, apoptosis of cells, the repair of cut is s DNA bases, as well as the effects on telomere length and chromosome stability (d'adda di Fagagna, etal, Nature Gen., 23(1), 76-80 (1999)).

The INVENTION

The invention relates to compounds, compositions and methods for modulating the activity of PARP. Among the compounds described herein include compounds that are inhibitors of PARP. It also described the use of such compounds, compositions and methods for treating diseases, disorders or conditions associated with the activity of PARP.

In some embodiments, the communication according to the invention have the structure of Formula (I) and Formula (II) and their pharmaceutically acceptable salts, solvate, esters, acids and prodrugs. In some embodiments implementing the invention relates to compounds having the structure of Formula (I) and Formula (II), which are inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP).

Here 8-B,Z-2-R4-4-R1-5-R2-6R3-7R5-9-A,Y-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-ones, 8-B,Z-5-R2-9-A,Y-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-ones, in which A, B, Z, Y, R1, R2, R3, R4and R5described next. In some embodiments implementing the invention includes isomers, including enantiomers and diastereoisomers, and chemically protected forms of compounds representing the structure of Formula (I) and Formula (II).

Formula (I) is the following:

Formula (I)

in which:

Y and Z, each independently selected from the group consisting of:

(a) aryl, if necessary substituted by 1, 2 or 3 R6; eachR6selected from OH, NO2, CN, Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, C2-C8geterotsiklicheskie; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl, arylalkyl,3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB,(NRARB)C1-C6alkylene,(NRARB)carbonyl,(NRARB)carbonylation,(NRARB)sulfonyl and (NRARB)sulfonylurea;

b) heteroaryl, if necessary substituted by 1, 2 or 3 R6;

c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, quinil, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, hydroxyalkyl is on, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic alkylsulfonyl, arylsulfonyl, heteroarylboronic, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea;

R1,R2and R3each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, quinil, cyano, halogenoalkane, halogenoalkane, hydroxyl, hydroxyalkyl, nitro, NRARB, NRARBalkylene and (NRARB)carbonyl;

A and B, each independently, selected from hydrogen, Br, Cl, F, I, OH, C1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl, and doesn't mean IT;

RAand RBindependently selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylsulphonyl; or RAand RBtogether with the atom to which they are attached, form a 3-10-membered heterocycle, in case of need, having from one to three gets is of automob or functional heterogroup, selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl)-, -N(aryl)-, -N(aryl-C1-C6-the alkyl-)-, -N(substituted-aryl-C1-C6-the alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6--alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl -) -, and-S - or S(O)q-where q=1 or 2 and the 3-10-membered heterocycle may be substituted by one or more substituents;

R4and R5each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, halogenoalkane, hydroxyalkyl and (NRARB)alkylene;

and its isomers, salts, solvate, chemically protected forms, and prodrugs.

Formula (II) is the following:

Formula (II)

in which:

Y denotes aryl or heteroaryl, if necessary substituted by at least one of R6;

Z represents aryl, if necessary substituted by at least oneR6;

A and B, each independently, selected from hydrogen, Br, Cl, F, I, OH,C1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8 cycloalkyl, and doesn't mean IT;

R6selected from OH, NO2, CN, Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, C2-C8geterotsiklicheskie;C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl, arylalkyl, C3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation-(NRARB)sulfonyl and (NRARB)sulfonylurea;

R2selected from hydrogen, Br, Cl, I or F;

RAand RBindependently selected from the group consisting of hydrogen, C1-C6of alkyl, C3-C8cycloalkyl and alkylsulphonyl; or RAand RBtogether with the atom to which they are attached, form a 3-10-membered heterocycle, in case of need, having from one to three heteroatoms or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl)-, -NCO(C3-C8-cycloalkyl)-, -N(Ari is a), -N(aryl-C1-C6-the alkyl-)-, -N(substituted-aryl-C1-C6-the alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl -) -, and-S - or S(O)q-where q=1 or 2 and the 3-10-membered heterocycle may be substituted by one or more substituents; or its pharmaceutically acceptable salt, MES or prodrug.

In some embodiments implementing the invention relates to compounds of Formula (I) or their therapeutically acceptable salts, in whichR1, R2, R3independently selected from the group consisting of hydrogen, alkyl and halogen;R4denotes hydrogen, and R5selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, halogenoalkane, hydroxyalkyl and (NRARB)alkylene; RAand RBindependently selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylsulphonyl; or RAand RBtogether with the atom to which they are attached, form a 3-10-membered heterocycle, in case of need, having from one to three heteroatoms or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl)-, -N(aryl)-, -N(aryl-C1-C6-the alkyl-)-, -N(substituted-aryl-C1-C6-the alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1 -C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl -) -, and-S - or S(O)q-where q=1 or 2 and the 3-10-membered heterocycle may be substituted by one or more substituents.

In one embodiment, the invention relates to the compound of Formula (I)in which Y represents aryl. In another embodiment, the aryl is a phenyl. In another embodiment, phenyl is substituted by at least one of R6selected from Br, Cl, F, or I. In one embodiment, aR6means F. In one embodiment, phenyl is substituted by at least one of R6selected from (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In one embodiment, R6is (NRARB)C1-C6alkylene. In another embodiment, C1-C6alkyl selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene and tert-butylene. In yet another embodiment, C1-C6alkyl represents methylene. In another embodiment, RAand RBdenote, each independently, hydrogen, C1-C6alkyl or C3-C8cycloalkyl. In one embodiment, C1-C6 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In one embodiment, With1-C6alkyl represents methyl. In another embodiment, With1-C6alkyl represents ethyl. In yet another embodiment, C3-C8cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In yet another embodiment, C3-C8cycloalkyl is cyclopropyl. In another embodiment, R6denotes hydroxyalkyl. In one embodiment, hydroxyalkyl selected from CH2OH, CH2CH2OH, CH2CH2CH2OH, CH(OH)CH3CH(OH)CH2CH3CH2CH(OH)CH3and CH2CH2CH2CH2OH. In another embodiment, RAand RBtogether with the nitrogen to which they are attached, form a 6-membered heterocycle, having 1 heteroatom or functional heterogroup selected from the group consisting of-O-, -NH or-N(C1-C6the alkyl). In yet another embodiment, the functional heterogroup represents-N(C1-C6alkyl). In another embodiment, C1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, aC1-C6lcil represents methyl. In one embodiment, Y represents heteroaryl, if necessary substituted by at least oneR6. In another embodiment, heteroaryl selected from furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazol, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, cinoxacin, quinoline and isoquinoline. In yet another embodiment, heteroaryl is an imidazole. In another embodiment, the imidazole substituted C1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In one embodiment, heteroaryl represents a furan. In another embodiment, heteroaryl is a thiazole. In yet another embodiment, heteroaryl represents a 1,3,4-oxadiazole. In another embodiment, heteroaryl substituted C1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, aC1-C6alkyl represents methyl. In one embodiment, Z is oznachaet aryl. In another embodiment, the aryl is a phenyl. In another embodiment, phenyl is substituted by at least oneR6selected from Br, Cl, F, or I. In another embodiment, aR6means F. In another embodiment, aR6denotes Cl. In one embodiment, phenyl is substituted by at least oneR6selected from (NRARB)C1-C6alkylene,(NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In another embodiment, R6means (NRARB)C1-C6alkylen. In yet another embodiment, C1-C6alkyl selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene and tert-butylene. In another embodiment, C1-C6alkyl represents methylene. In another embodiment, RAand RBdenote, each independently, hydrogen,aC1-C6alkyl or C3-C8cycloalkyl. In one embodiment, C1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In yet anotherVarian is e implementation of R Aand RBtogether with the nitrogen to which they are attached, form a 6-membered heterocycle, having 1 heteroatom or functional heterogroup selected from the group consisting of-O-, -NH or-N(C1-C3the alkyl). In another embodiment, the functional heterogroup represents-N(C1-C3alkyl). In one embodiment, aC1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In one embodiment, Z represents heteroaryl, if necessary substituted by at least one of R6. In another embodiment, heteroaryl selected from furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazol, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, cinoxacin, quinoline and isoquinoline. In yet another embodiment, heteroaryl is an imidazole. In another embodiment, the imidazole substituted C1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, aC1- 6alkyl represents methyl. In one embodiment, heteroaryl is furan. In another embodiment, heteroaryl is a thiazole. In yet another embodiment, heteroaryl represents a 1,3,4-oxadiazole. In another embodiment, heteroaryl substituted C1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In yet another embodiment, C1-C6alkyl represents methyl. In another embodiment, aR2denotes hydrogen. In another embodiment, R2selected from F, Cl, Br and I. In another embodiment, aR2denotes F.

In one embodiment, the invention relates to the compound of Formula (I)in which A stands for hydrogen. In another embodiment, A stands With1-C6alkyl. In another embodiment, A is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentile and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl may be substituted by OH, NO2CN5Br, Cl, F and I. In another embodiment, A represents methyl. In yet another embodiment, A is selected from F, Cl, Br and I. In another embodiment, assests is A means of C3-C8cycloalkyl. In another embodiment, a means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, A is substituted by OH, NO2or CN. In another embodiment, B represents C1-C6alkyl. In another embodiment, B is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentile and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl may be substituted by OH, NO2, CN, Br, Cl, F and I. In one embodiment, the invention relates to the compound of Formula (I)in which B represents hydrogen. In another embodiment, B represents methyl. In yet another embodiment, B is selected from F, Cl, Br and I. In another embodiment, B represents C3-C8cycloalkyl. In another embodiment, B denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, A is substituted by OH, NO2or CN. In another embodiment, the invention relates to the compound of Formula (I)in which A represents hydrogen and B is selected from Br, Cl, F, I, C1-C6of alkyl,C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl,C3-C8cycloalkyl, alkoxy, alkoxyalkyl mo the ut to be substituted by at least one Deputy, selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl. In another embodiment, the invention relates to the compound of Formula (I)in which B is hydrogen and A is selected from Br, Cl, F, I, C1-C6of alkyl,C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl. In yet another embodiment, both A and B denote hydrogen. In another embodiment, both A and B are selected from Br, Cl, F, I, C1-C6of alkyl,C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl.

In one embodiment, the invention relates to the compound of Formula (II)in which Y represents aryl. In another embodiment, the aryl is a phenyl. In another embodiment, phenyl is substituted by at least one of R6selected from Br, Cl, F, or I. In one embodiment, R6denotes F. odnawiane implementation phenyl substituted by at least one of R 6selected from (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In one embodiment, R6means (NRARB)C1-C6alkylen. In another embodiment, C1-C6alkyl selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene and tert-butylene. In yet another embodiment, C1-C6alkylene represents methylene. In anotherembodiment, RAand RBdenote, each independently, hydrogen, C1-C6alkyl or C3-C8cycloalkyl. In one embodiment, C1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In one embodiment, aC1-C6alkyl represents methyl. In another embodiment, C1-C6alkyl represents ethyl. In yet another embodiment, C3-C8cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In another embodiment, C3-C8cycloalkyl is cyclopropyl. In another embodiment, R6denotes hydroxyalkyl. In one embodiment, the wasp is estline hydroxyalkyl selected from CH 2OH, CH2CH2OH, CH2CH2CH2OH, CH(OH)CH3CH(OH)CH2CH3CH2CH(OH)CH3and CH2CH2CH2CH2OH. In anotherembodiment, RAand RBtogether with the nitrogen to which they are attached, form a 6-membered heterocycle, having 1 heteroatom or functional heterogroup selected from the group consisting of-O-, -NH or-N(C1-C6the alkyl). In yet another embodiment, the functional heterogroup represents-N(C1-C6alkyl). In another embodiment, C1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In one embodiment, Y represents heteroaryl, if necessary substituted by at least one of R6. In another embodiment, heteroaryl selected from furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazol, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, cinoxacin, quinoline and isoquinoline. In yet another embodiment, heteroaryl is an imidazole. In another embodiment is sushestvennee the imidazole substituted With 1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, aC1-C6alkyl represents methyl. In one embodiment, heteroaryl represents a furan. In another embodiment, heteroaryl is a thiazole. In yet another embodiment, heteroaryl represents a 1,3,4-oxadiazole. In another embodiment, heteroaryl substituted C1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, aC1-C6alkyl represents methyl. In one embodiment, Z represents aryl. In another embodiment, the aryl is a phenyl. In another embodiment, phenyl is substituted by at least oneR6selected from Br, Cl, F, or I. In another embodiment, R6means F. In another embodiment, R6denotes Cl. In one embodiment, phenyl is substituted by at least oneR6selected from (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In another embodiment, realized is I R 6means (NRARB)C1-C6alkylen. In yet another embodiment, C1-C6alkylene selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene and tert-butylene. In another embodiment, C1-C6alkyl represents methylene. In anotherembodiment, RAand RBdenote, each independently, hydrogen, C1-C6alkyl or C3-C8cycloalkyl. In one embodiment, C1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In yet anotherembodiment, RAand RBtogether with the nitrogen to which they are attached, form a 6-membered heterocycle, having 1 heteroatom or functional heterogroup selected from the group consisting of-O-, -NH or-N(C1-C6the alkyl). In another embodiment, the functional heterogroup represents-N(C1-C6alkyl). In one embodiment, C1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In another embodiment, R2means in dorog. In another embodiment, R2selected from F, Cl, Br and I. In another embodiment, R2denotes F.

In one embodiment, the invention relates to the compound of Formula (II), in which A stands for hydrogen. In another embodiment, A represents C1-C6alkyl. In another embodiment, A is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentile and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl may be substituted by OH, NO2, CN, Br, Cl, F and I. In another embodiment, A represents methyl. In yet another embodiment, A is selected from F, Cl, Br and I. In another embodiment, A represents C3-C8cycloalkyl. In another embodiment, a means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, A is substituted by OH, NO2or CN. In one embodiment, the invention relates to the compound of Formula (II), in which B denotes hydrogen. In another embodiment, B represents C1-C6alkyl. In another embodiment, B is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentile and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, isop the filing, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl may be substituted by OH, NO2, CN, Br, Cl, F and I. In another embodiment, B represents methyl. In yet another embodiment, B is selected from F, Cl, Br and I. In another embodiment, B isC3-C8cycloalkyl. In another embodiment, B denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, A is substituted by OH, NO2or CN. In another embodiment, the invention relates to the compound of Formula (II)in which A represents hydrogen and B is selected from Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl. In another embodiment, the invention relates to the compound of Formula (II)in which B is hydrogen and A is selected from Br, Cl, F, I, C1-C6of alkyl,C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl,C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl andC -C8cycloalkyl. In yet another embodiment, both A and B denote hydrogen. In another embodiment, both A and B are selected from Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, andC1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl.

In another aspect the invention relates to a compound selected from:

or its pharmaceutically acceptable salt, MES or prodrug.

In another aspect the invention relates to a compound selected from:

or its pharmaceutically acceptable salt, MES or prodrug.

In another aspect the invention relates to a compound selected from:

or its pharmaceutically acceptable salt, MES or prodrug.

In another embodiment, the invention relates to a compound selected from:

or its pharmaceutically acceptable salt, MES or prodrug.

In another embodiment, the invention relates to a compound selected from the following compounds:

(8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8S,9R)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[43,2-de]phthalazine-3(7H)-he,

(8R,9S)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8R,9S)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8S,9R)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8R,9S)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8R,9S)-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he and

(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

or in pharmaceutical preparations is automatic acceptable salt, the MES or the prodrug.

In another aspect the invention relates to pharmaceutical compositions comprising a compound of Formula (I) and Formula (II) or its pharmaceutically acceptable salt, pharmaceutically acceptable MES or pharmaceutically acceptable prodrug and a pharmaceutically acceptable carrier, excipient, binder or diluent.

In one aspect, the invention relates to a method of inhibiting poly(ADP-ribose)polymerase (PARP) in a patient, for which there is a need to PARP inhibition, comprising the administration to a patient a therapeutically effective amount of the compounds of Formula (I) and Formula (II).

In another aspect, the invention relates to a method of treatment of the disease, facilitated by PARP inhibition, comprising the administration to a patient a therapeutically effective amount of the compounds of Formula (I) and Formula (II).

In one embodiment, the disease is selected from the group consisting of the following diseases: vascular disease; septic shock; ischaemic injury; reperfusion injury; neurotoxicity; hemorrhagic shock; inflammatory diseases; multiple sclerosis; secondary effects of diabetes; and acute treatment of cytotoxicity after cardiovascular surgery.

In another aspect, the invention relates to a method of treating cancer, including BB is doing the patient a therapeutically effective amount of the compounds of Formula (I) and Formula (II) in combination with ionizing radiation, one or more chemotherapeutics or their combination,

In one embodiment, the compound of Formula (I) and Formula (II) is administered simultaneously with ionizing radiation, one or more chemotherapeutics or their combination. In another embodiment, the compound of Formula (I) and Formula (II) is injected alternately with the use of ionizing radiation, one or more chemotherapeutic agents or combinations thereof.

In another aspect the invention relates to a method of treating cancer in which there is a shortage of dependent homologous recombination (HR) pathways repair breaks double DNA strand breaks (DSB), which includes the introduction to the patient a therapeutically effective amount of the compounds of Formula (I) and Formula (II).

In one embodiment, the cancer comprises one or more cancer cells having a reduced or abrogated ability to recover DNA DSB by HR relative to normal cells. In another embodiment, the cancer cells have a BRCA1 or BRCA2 deficient phenotype. In another embodiment, the cancer cells detect the deficiency in BRCA1 or BRCA2. In another embodiment, the patient is heterozygous in respect of mutations in a gene, encoding a component of the HR dependent pathway DSB repair DNA. In yet another embodiment, the patient who is heterozygous in respect of mutations in BRCA1 and/or BRCA2. In one embodiment, the cancer is a cancer of the breast, ovary, pancreas, or prostate cancer. In another embodiment, the treatment includes in addition to the introduction of ionizing radiation or chemotherapeutic agents.

In one aspect the invention relates to the use of compounds of Formula (I) and Formula (II) in the composition of the medicinal product for the treatment of mediated poly(ADP-ribose)polymerase disease or condition.

In another aspect the invention relates to an industrial product comprising packaging material, a compound of Formula (I) and Formula (II) and label, and the compound is effective for modulating the activity of the enzyme poly(ADP-ribose)polymerase, or for treatment, prevention and / or alleviate one or more symptoms of a poly(ADP-ribose)polymerase-dependent or poly(ADP-ribose)polymerase-mediated disease or condition, and the connection is packaged in a packaging material, and on the label indicates that the compound or its pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable MES, or pharmaceutical composition comprising such a compound is used to modulate the AK is Yunosti poly(ADP-ribose)polymerase, or for treatment, prevent or alleviate one or more symptoms of a poly(ADP-ribose)polymerase-dependent or poly(ADP-ribose)polymerase-mediated disease or condition.

DETAILED description of the INVENTION

PARP plays a significant role in facilitating DNA repair, control of RNA transcription, oposredovanii cell death and the regulation of the immune response. PARP inhibitors show efficacy in multiple models of the disease, especially in models of damage during ischemia-reperfusion injury, inflammatory diseases, degenerative diseases, protection from above side effects of cytotoxic compounds and potentiation of cytotoxic cancer therapy. They are effective in preventing damage during ischemia-reperfusion injury in models of myocardial infarction, stroke, other neural trauma, and organ transplantation, as well as reperfusion of the eye, kidney, intestine and skeletal muscle. These inhibitors are effective in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation, such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also demonstrated benefit in several models of degenerative diseases, including diabetes and Parkinson's disease. PARP inhibitors facilitate gepetto the sicnosti after overdose peroxyacetyl, toxicity to the heart and kidneys manifested doxorubicin and antitumor means, on the basis of platinum, as well as damage the skin sulfur mustards. In various cancer models have shown that PARP inhibitors potentiate radiotherapy and chemotherapy, increasing apoptosis of cancer cells, limiting tumor growth, reducing metastasis and prolonging the survival of animals with cancer.

In some embodiments implementing the invention relates to compounds of Formula (I)

Formula (I)

or their therapeutically acceptable salts, in which R1, R2and R3each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, quinil, cyano, halogenoalkane, halogenoalkane, hydroxyl, hydroxyalkyl, nitro, NRARB, NRARBalkylene and (NRARB)carbonyl;

RAand RBindependently selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylsulphonyl; or RAand RBtogether with the atom to which they are attached, form a 3-10-membered heterocycle, in case of need, having from one to three heteroatoms or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl-, -N(aryl)-, -N(aryl-C1-C6-the alkyl-)-, -N(substituted-aryl-C1-C6-the alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6--alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl -) -, and-S - or S(O)q-where q=1 or 2 and the 3-10-membered heterocycle may be substituted by one or more substituents; R4and R5each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, halogenoalkane, hydroxyalkyl and (NRARB)alkylene;

A and B, each independently, selected from hydrogen, Br, Cl, F, I, HE, C1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl, and doesn't mean IT;

Y and Z, each independently selected from the group consisting of:

(a) aryl, if necessary substituted by 1, 2 or 3 substituents R6; R6selected from OH, NO2, CN, Br, Cl, F, I, C1-C6of alkyl,C3-C8cycloalkyl, C2-C8geterotsiklicheskie; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl, arylalkyl,3-C8the CEC is alkylaryl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea;

b) heteroaryl, if necessary substituted by 1, 2 or 3 substituentsR6; R6has the values defined above;

c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, quinil, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, hydroxyalkyl, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic, alkylsulfonyl, arylsulfonyl, heteroarylboronic, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea; or their pharmaceutically acceptable salts, MES or prodrug.

In some embodiments implementing the invention relates to compounds of Formula (I), or their therape is almost acceptable salt, in which R1,R2,R3independently selected from the group consisting of hydrogen, alkyl and halogen; R4denotes hydrogen, and R5selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, halogenoalkane, hydroxyalkyl and (NRARB)alkylene; RAand RBindependently selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylsulphonyl; or RAand RBtogether with the atom to which they are attached, form a 3-10-membered heterocycle, in case of need, having from one to three heteroatoms or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl)-, -N(aryl)-, -N(aryl-C1-C6-the alkyl-)-, -N(substituted-aryl-C1-C6the alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl -) -, and-S - or S(O)q-where q=1 or 2 and the 3-10-membered heterocycle may be substituted by one or more substituents; A and B each independently selected from hydrogen, Br, Cl, F, I, O, C1-C6of alkyl, C3-C3cycloalkyl, alkoxy, alkoxyalkyl With1-C6alkyl, C3-C3cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C 1-C6the alkyl and C3-C8cycloalkyl, and doesn't mean HE; Y and Z each independently selected from the group consisting of:

(a) aryl, if necessary substituted by 1,2 or 3R6; and each of R6selected from OH, NO2, CN, Br, Cl, F, IC1-C6of alkyl,C3-C3cycloalkyl,C2-C3geterotsiklicheskie;C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl, arylalkyl,C3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea;

b) heteroaryl, if necessary substituted by 1,2 or 3R6;

c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, quinil, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, hydroxyalkyl is on, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic, alkylsulfonyl, arylsulfonyl, heteroarylboronic, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea; or their pharmaceutically acceptable salts, MES or prodrug.

In some embodiments implementing the invention relates to compounds of Formula (I) or their therapeutically acceptable salts, in which R1, R2and R3independently selected from the group consisting of hydrogen, alkyl and halogen; R4and R5denotes hydrogen; RAndand RInindependently selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylsulphonyl; or RAand RBtogether with the atom to which they are attached, form a 3-10-membered heterocycle, in case of need, having from one to three heteroatoms or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl)-, -N(aryl)-, -N(aryl-C1-C6-the alkyl-)-, -N(substituted-aryl-C1-C6the alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl -) -, and-S - or S(O)q-where q=1 or 2 and the 3-10-linnagaleriis may be substituted by one or more substituents; A and B, each independently, selected from hydrogen, Br, Cl, F, IC1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, andC1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, FI, C1-C6the alkyl and C3-C8cycloalkyl; Y and Z each independently selected from the group consisting of:

(a) aryl, if necessary substituted by 1, 2 or 3 R6; and each of R6selected from OH, NO2CN5Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, C2-C8geterotsiklicheskie; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl, arylalkyl, C3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea;

b) heteroaryl, if necessary, replaced by the CSOs 1,2 or 3 R 6;

c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, quinil, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, hydroxyalkyl, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic, alkylsulfonyl, arylsulfonyl, heteroarylboronic, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea; or their pharmaceutically acceptable salts, MES or prodrug.

In some embodiments implementing the invention relates to compounds of Formula (I) or their therapeutically acceptable salts, in which R1, R2, R3,R4and R5denote hydrogen; RAandRBindependently selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylsulphonyl; or RAand RBtogether with the atom to which they are attached, form a 3-10-membered heterocycle, in case of need, having from one to three heteroatoms or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl)-, -N(aryl)-, -N(aryl-C1-C6the alkyl-)-, -N(C is displaced-aryl-C 1-C6the alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl -) -, and-S - or S(O)q-where q=1 or 2 and the 3-10-membered heterocycle may be substituted by one or more substituents; A and B each independently selected from hydrogen, Br, Cl, F, I, OH, C1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, andC1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, CI, F, I, C1-C6the alkyl andC3-C8cycloalkyl, and doesn't mean HE; Y and Z each independently selected from the group consisting of:

(a) aryl, if necessary substituted by 1, 2 or 3 R6; and each of R6selected from OH, NO2, CN, Br, Cl, F, IC1-C6of alkyl, C3-C3cycloalkyl,C2-C8geterotsiklicheskie; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl, arylalkyl,C3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocycle the si, heterozygotic, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea;

b) heteroaryl, if necessary substituted by 1,2 or 3R6;

c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, quinil, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, hydroxyalkyl, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic, alkylsulfonyl, arylsulfonyl, heteroarylboronic, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea; or their pharmaceutically acceptable salts, MES or prodrug.

In one embodiment, the invention relates to the compound of Formula (I)in which R1, R2, R3each independently selected from the group consisting of hydrogen, alkyl and halogen; R4denotes hydrogen, and R5selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, halogenoalkane, hydroxyalkyl and (NRARB)alkylene; and what its isomers, salts, solvate, chemically protected forms, and prodrugs.

In another embodiment, the invention relates to the compound of Formula (I)in which R1, R2, R3each independently selected from the group consisting of hydrogen, alkyl and halogen; R4and R5represent hydrogen; and its isomers, salts, solvate, chemically protected forms, and prodrugs.

In another embodiment, the invention relates to the compound of Formula (I)in which R1, R2, R3, R4represent hydrogen, and R5denotes alkyl.

In yet another embodiment, the invention relates to the compound of Formula (I) : R1, R2, R3, R4represent hydrogen; and R5denotes methyl.

In one embodiment, the invention relates to the compound of Formula (I)in which R1, R2and R3denote hydrogen.

In another embodiment, the invention relates to the compound of Formula (I)in which Y and Z, each independently selected from the group consisting of:

a) phenyl, if necessary substituted by 1, 2 or 3 R6;

b) pyridyl, if necessary substituted by 1, 2 or 3 R6; and

c) a substituent independently selected from the group consisting of hydrogen, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkyl, cyclol the sludge, cycloalkenyl, halogenoalkane, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic,(NRARB)alkylene, (NRARB)carbonyl and (NRARB)carbonylation.

In another embodiment, the invention relates to the compound of Formula (I)in which Y and Z, each independently selected from the group consisting of

a) phenyl, if necessary substituted by 1, 2 or 3 R6;

b) imidazole, if necessary substituted by 1, 2 or 3 R6; and

c) a substituent independently selected from the group consisting of hydrogen, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic, (NRARB)carbonyl, (NRARB)alkylene and (NRARB)carbonylation.

In yet another embodiment, the invention relates to the compound of Formula (I)in which Y and Z, each independently selected from the group consisting of

d) phenyl, if necessary substituted by 1, 2 or 3 R6;

e) a triazole, if necessary substituted by 1, 2 or 3 R6; and

f) a substituent independently selected from the group consisting of hydrogen, alkoxyalkyl, alkoxycarbonyl, and the Qila, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic,(NRARB)carbonyl, (NRARB)alkylene and (NRARB)carbonylation.

In one embodiment, the invention relates to the compound of Formula (I), in whichR5denotes hydrogen or alkyl. In another embodiment, aR5denotes hydrogen. In another embodiment, R5represents C1-C6alkyl. In another embodiment, R5indicatesCH3. in another embodiment, R5denotes CH2CH3.

In another embodiment, the invention relates to the compound of Formula (I)in which R4denotes hydrogen or alkyl. In another embodiment, R4denotes hydrogen.

In one embodiment, aR2selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, quinil, cyano, halogenoalkane, halogenoalkane, hydroxyl, hydroxyalkyl-nitro, NRARB, NRARBalkylene and (NRARB)carbonyl. In another embodiment, aR2denotes a halogen selected from F, Cl, Br and I. In another variant of the implementation of R 2denotes fluorine. In one embodiment, R2denotes hydrogen.

In another embodiment, R3selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, quinil, cyano, halogenoalkane, halogenoalkane, hydroxyl, hydroxyalkyl, nitro, NRARB, NRARBalkylene and (NRARB)carbonyl. In another embodiment, R3denotes hydrogen. In some embodiments, the implementation of R3selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, quinil, cyano, halogenoalkane, halogenoalkane, hydroxyl, hydroxyalkyl, nitro, NRARB, NRARBalkylene and (NRARB)carbonyl. In another embodiment, R3denotes hydrogen.

Also there are disclosed compounds of the Formula (I)in which Z represents aryl, if necessary substituted by 1, 2 or 3 R6; and each of R6selected from OH, NO2, CN, Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, C2-C8geterotsiklicheskie; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl, arylalkyl, C3-C8cycloalkenyl, halogenoalkane, halogenate is a, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In one embodiment, the invention relates to the compound of Formula (I)in which Z denotes if necessary substituted phenyl. In one embodiment, Z represents phenyl. In another embodiment, phenyl, if necessary substituted by at least one of R6selected from OH, NO2, CN, Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, C2-C8geterotsiklicheskie; C1-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl, arylalkyl, C3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)is arbonia, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In another embodiment, R6means (NRARB)alkylen. In another embodiment, R6denotes CH2(NRARB). In another embodiment, R6denotes CH2(NRARB), where NRARBindicates azetidin, pyrrolidine, piperidine or morpholine. In another embodiment, RAdenotes H or alkyl. In another embodiment, RArepresents C1-C6alkyl. In another embodiment, RAdenotes CH3. In another embodiment, RBdenotes H or alkyl. In one embodiment, RBrepresents C1-C6alkyl. In another embodiment, RBdenotes CH3. In another embodiment, R6denotes CH2NHCH3. In another embodiment,aR6denotes CH2NCH3CH3. In one embodiment, R6means (C=O)heteroseksualci(C=O)alkyl. In one embodiment, R6means (C=O)heteroseksualci(C=O)alkyl, in which heterocytolysine group has at least one heteroatom selected from O, N and S. In another embodiment, heterocyclyl the ilen group has two atoms N. In another embodiment, R6means (C=O)heteroseksualci(C=O)alkyl, in which alkyl is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl and tert-butyl. In one embodiment, the alkyl is cyclopropyl. In another embodiment, the alkyl represents isopropyl. In one embodiment, R6denotes. In another embodiment, R6does.

Here are the compounds of Formula (I)in which Z denotes if necessary substituted heteroaryl. In one embodiment, heteroaryl selected from pyridine, pyrimidine, pyrazine, pyrazole, oxazole, thiazole, isoxazol, isothiazole, 1,3,4-oxadiazole, pyridazine, 1,3,5-triazine, 1,2,4-triazine, cinoxacin, benzimidazole, benzotriazole, purine, 1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole, imidazole, thiophene, furan, isobenzofuran, pyrrole, indolizine, isoindole, indole, indazole, isoquinoline, quinoline, phthalazine, naphthiridine, heatline, cinnoline and pteridine. In one embodiment, Z represents pyridine. In another embodiment, Z denotes if necessary substituted pyridine.

Also disclosed are the compounds of Formula (I)in which Y denotes aryl, if necessary C is displaced 1,2 or 3 R 6; and each of R6selected from OH, NO2, CN, Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, C2-C5geterotsiklicheskie; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl,C2-C6the quinil, aryl, arylalkyl,C3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In one embodiment, the invention relates to the compound of Formula (I)in which Y denotes an if necessary substituted phenyl. In one embodiment Y represents phenyl. In another embodiment, the phenyl may be substituted by at least oneR6selected from OH, NO2, CN, Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, C2-C8geterotsiklicheskie; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl is, arylalkyl, C3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In another embodiment, R6denotes CH2(NRARB). In another embodiment, RAdenotes H or alkyl. In another embodiment, RArepresents C1-C6alkyl. In another embodiment, RAdenotes CH3. In another embodiment, RBdenotes H or alkyl. In one embodiment, RInindicatesC1-C6alkyl. In another embodiment, RBdenotes CH3. In another embodiment, R6indicatesCH2NHCH3. In another embodiment, R6denotes CH2NCH3CH3. In one embodiment, R6means (C=O)heteroseksualci(C=O)alkyl. In one embodiment, R6means (C=O)heteroseksualci(C=O)alkyl, cotranslationally group has at least one heteroatom, selected from O, N and S. In another embodiment, heterocytolysine the group has two atoms N. In another embodiment, R6means (C=O)heteroseksualci(C=O)alkyl, in which alkyl is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl and tert-butyl. In one embodiment, the alkyl is cyclopropyl. In another embodiment, the alkyl represents isopropyl. In one embodiment, R6does. In another embodiment, R6does.

Here are the compounds of Formula (I)in which Y denotes an if necessary substituted heteroaryl. In one embodiment, heteroaryl selected from pyridine, pyrimidine, pyrazine, pyrazole, oxazole, thiazole, isoxazol, isothiazole, 1,3,4-oxadiazole, pyridazine, 1,3,5-triazine, 1,2,4-triazine, cinoxacin, benzimidazole, benzotriazole, purine, 1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole, imidazole, thiophene, furan, isobenzofuran, pyrrole, indolizine, isoindole, indole, indazole, isoquinoline, quinoline, phthalazine, naphthiridine, heatline, cinnoline and pteridine. In one embodiment, Y represents pyridine. In another embodiment, Y denotes if necessary substituted pyridine. In about the nom embodiment, Y represents an imidazole. In another embodiment, Y denotes if necessary substituted imidazole. In one embodiment, Y represents the triazole. In another embodiment, Y denotes if necessary substituted triazole.

In one embodiment, Y represents the Deputy, is independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, quinil, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, hydroxyalkyl, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylboronic, arylcarbamoyl, heteroarylboronic, alkylsulfonyl, arylsulfonyl, heteroarylboronic, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In one embodiment, Y represents alkyl. In another embodiment, Y represents C1-C6alkyl. In another embodiment, Y is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In another embodiment, Y represents isopropyl.

Also disclosed are the compounds of Formula (I)in which Y denotes an if necessary substituted heteroseksualci. In one embodiment, heteroseksualci selected and is of pyrrolidinyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothieno, tetrahydropyranyl, dihydropyrrole, tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, dioxane, piperazinil, azetidine, oxetane, tatania, homopiperazine, oxetanyl, tapanila, oxazepine, diazepine, thiazepine, 1,2,3,6-tetrahydropyridine, 2-pyrroline, 3-pyrroline, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-DIOXOLANYL, pyrazoline, dithienyl, dithiolane, dihydropyrrole, dihydrothieno, dihydrofurane, pyrazolidine, imidazoline, imidazolidine, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[4.1.0]heptenyl, 3H-indolyl and chinoiserie. In another embodiment, heteroseksualci selected from pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinil, pyrazolidine, tetrahydrofuranyl, tetrahydrothiophene, 1,3-oxathiolane, indolinyl, isoindolyl, morpholinyl and pyrazoline. In another embodiment, heteroseksualci is piperidinyl.

In another aspect the invention relates to the compound of Formula (IA):

Formula (IA)

or its therapeutically acceptable salt, MES or prodrug, in which R1, R2and R3each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl,alkyl, cycloalkyl, quinil, cyano, halogenoalkane, halogenoalkane, hydroxyl, hydroxyalkyl, nitro, NRARB; NRARBalkylene and (NRARB)carbonyl;

RAand RBindependently selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylsulphonyl; or RAandRBtogether with the atom to which they are attached, form a 3-10-membered heterocycle, in case of need, having from one to three heteroatoms or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl)-, -N(aryl)-, -N(aryl-C1-C6-the alkyl-)-, -N(substituted-aryl-C1-C6-the alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6--alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl -) -, and-S - or S(O)q-where q=1 or 2 and the 3-10-membered heterocycle may be substituted by one or more substituents; R4and R5each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, halogenoalkane, hydroxyalkyl and (NRARB)alkylene;

A and B, each independently, selected from hydrogen, Br, Cl, F, I, O, C1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by IU is greater least one Deputy, selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl, and doesn't mean IT;

Y is selected from the group consisting of:

(a) aryl, if necessary substituted by 1,2 or 3 substituentsR6; R6selected from OH, NO2, CN, Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl,C2-C8geterotsiklicheskie; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl, arylalkyl,C3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics,C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea;

b) heteroaryl, if necessary substituted by 1,2 or 3 substituents R6; R6selected independently from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, quinil, aryl, arylalkyl, cycloalkyl, cycloalkenyl, cyano, halogenoalkane, halogen is Qila, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, geterotsiklicheskie, heterocyclics, heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea;

c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, quinil, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, hydroxyalkyl, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic, alkylsulfonyl, arylsulfonyl, heteroarylboronic, (NRARB)alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea; and

n means an integer from 0 to 4;

or its pharmaceutically acceptable salt, MES or prodrug of this.

In another embodiment, the invention relates to the compound of Formula (IA)having the structure:

or its pharmaceutically acceptable salt, MES or prodrugs is.

In one embodiment, the invention relates to the compound of Formula (IA)in which Y represents aryl. In another embodiment, Y represents heteroaryl. In another embodiment, the aryl denotes phenyl. In another embodiment, the invention relates to the compound of Formula (IA), in which phenyl is substituted by at least oneR6. In another embodiment, phenyl is substituted by at least oneR6selected from Br, Cl, F, or I. In one embodiment, R6means F. In one embodiment, the invention relates to the compound of Formula (IA), in which phenyl is substituted by at least oneR6selected from (NRARB)C1-With6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In one embodiment, R6means (NRARB)C1-C6alkylen. In another embodiment, C1-C6alkylene selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene and tert-butylene. In yet another embodiment, C1-C6alkylene represents methylene. In anotherembodiment, RAand RBdenote, each independently, hydrogen, C1-C6al is Il or C3-C8cycloalkyl. In one embodiment, C1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In one embodiment, aC1-C6alkyl represents methyl. In another embodiment, C1-C6alkyl denotes ethyl. In one embodiment, the invention relates to the compound of Formula (IA)in which C3-C8cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In yet another embodiment, C3-C8cycloalkyl is cyclopropyl. In one embodiment, the invention relates to the compound of Formula (IA)in which R6 denotes hydroxyalkyl. In one embodiment, hydroxyalkyl selected from CH2OH, CH2CH2OH, CH2CH2CH2OH, CH(OH)CH3CH(OH)CH2CH3CH2CH(OH)CH3and CH2CH2CH2CH2OH. In anotherembodiment, RAand RBtogether with the nitrogen to which they are attached, form a 6-membered heterocycle, having 1 heteroatom or functional heterogroup selected from the group consisting of-O-, -NH or-N(C1-Salkil). In yet another embodiment, the functional heterogroup represents-N(C1-C6alkyl). In d the natives embodiment, C 1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl.

In one embodiment, the invention relates to the compound of Formula (IA)in which Y denotes heteroaryl, if necessary substituted by at least oneR6. In another embodiment, heteroaryl selected from furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazol, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazol, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, cinoxacin, quinoline and isoquinoline. In yet another embodiment, heteroaryl is an imidazole. In another embodiment, the substituted imidazoleC1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In one embodiment, heteroaryl represents a furan. In another embodiment, the group heteroaryl is a thiazole. In yet another embodiment, heteroaryl represents a 1,3,4-oxadiazole. In another embodiment, assests is of heteroaryl substituted C1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl.

In one embodiment, the invention relates to the compound of Formula (IA)in which A and B are, each independently, selected from hydrogen, Br, Cl, F, I, HE, C1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl, and not mean IT.

In yet another embodiment, the invention relates to a compound selected from:

or its pharmaceutically acceptable salt, MES or prodrug.

In one embodiment, the invention relates to the compound of Formula (I)in which Y denotes heteroaryl selected from furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazol, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, hinokio is a, quinoline and isoquinoline. In another embodiment, Y represents an imidazole. In yet another embodiment, the imidazole substituted C1-C6the alkyl. In another embodiment, C1-C6alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, aC1-C6alkyl represents methyl. In another embodiment, the invention relates to the compound of Formula (I)in which Y denotes a substituted imidazole group, and Z is selected from aryl or heteroaryl. In another embodiment, Z represents aryl. In another embodiment, the aryl is a phenyl. In another embodiment, the aryl is a phenyl, substituted with halogen. In another embodiment, Z represents heteroaryl. In another embodiment, heteroaryl represents furan, pyridine, pyrimidine, pyrazin, imidazole, thiazole, isothiazol, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazol, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, cinoxacin, quinoline and isoquinoline. In another embodiment, heteroaryl is an imidazole. In another embodiment, the imidazole substituted C1-C6the alkyl. In another embodiment is sushestvennee C 1-C6alkyl represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl.

In another embodiment, the invention relates to the compound of Formula (I)in which Y denotes a triazole. In yet another embodiment, the triazole substituted C1-C6the alkyl. In another embodiment, group C1-C6alkyl represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In another embodiment, the invention relates to the compound of Formula (I)in which Y denotes a substituted group of triazole, and Z is selected from aryl or heteroaryl. In another embodiment, Z represents aryl. In another embodiment, the aryl is a phenyl. In another embodiment, the aryl is a phenyl, substituted with halogen. In another embodiment, Z represents heteroaryl. In another embodiment, heteroaryl represents furan, pyridine, pyrimidine, pyrazin, imidazole, thiazole, isothiazol, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazol, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine 1,3,5-triazine, thienothiophene, cinoxacin, quinoline and isoquinoline. In another embodiment, heteroaryl is a triazole. In another embodiment, the triazole substituted C1-C6the alkyl. In another embodiment, C1-C6alkyl represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl is stands.

In another embodiment, the compound is selected from

or their pharmaceutically acceptable salts, MES or prodrugs.

In one aspect the invention relates to the compound of Formula (II):

Formula (II)

in which:

Y denotes aryl or heteroaryl, if necessary substituted by at least one of R6;

Z represents aryl, if necessary substituted by at least one of R6; R6selected from OH, NO2, CN, Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, C2-C8geterotsiklicheskie; C2-C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl,C2-C6the quinil, aryl, arylalkyl, C3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroanalogs is, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea;

R2selected from hydrogen, Br, Cl, I, or F;

A and B, each independently, selected from hydrogen, Br, Cl, F, I, O, C1-C6of alkyl,C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl,C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl, and doesn't mean IT;

RAndand RInindependently selected from the group consisting of hydrogen, C1-C6of alkyl, C3-C8cycloalkyl and alkylsulphonyl; or RAndand RIntogether with the atom to which they are attached, form a 3-10-membered heterocycle, in case of need, having from one to three heteroatoms or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl)-, -NCO(C3-C8-cycloalkyl)-, -N(aryl)-, -N(aryl-C1-C6-the alkyl-)-, -N(substituted-the Rila-C 1-C6-the alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6--alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl -) -, and-S - or S(O)q-where q=1 or 2 and the 3-10-membered heterocycle may be substituted by one or more substituents; or its pharmaceutically acceptable salt, MES or prodrug.

In one embodiment, the invention relates to the compound of Formula (II)in which Y represents aryl. In another embodiment, the aryl is a phenyl. In another embodiment, phenyl is substituted by at least one of R6selected from Br, Cl, F, or I. In one embodiment, R6means F. In one embodiment, phenyl is substituted by at least one of R6selected from (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In one embodiment, R6means (NRARB)C1-C6alkylen. In another embodiment, C1-C6alkylene selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene and tert-butylene. In yet another embodiment, C1-C6alkylene represents methylene. In another embodiment, RAand RInmark, everyone is ezavisimo, hydrogen, C1-C6alkyl or C3-C8cycloalkyl. In one embodiment, C1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In one embodiment, C1-C6alkyl represents methyl. In another embodiment, C1-C6alkyl represents ethyl. In yet another embodiment, C3-C8cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In another embodiment, C3-C8cycloalkyl is cyclopropyl. In another embodiment, R6denotes hydroxyalkyl. In one embodiment, hydroxyalkyl selected from CH2OH, CH2CH2OH, CH2CH2CH2OH, CH(OH)CH3CH(OH)CH2CH3CH2CH(OH)CH3and CH2CH2CH2CH2OH. In another embodiment, RAand RIntogether with the nitrogen to which they are attached, form a 6-membered heterocycle, having 1 heteroatom or functional heterogroup selected from the group consisting of-O-, -NH or-N(C1-C6the alkyl). In yet another embodiment, the functional heterogroup represents-N(C1-C6alkyl). In another embodiment, C1-C6alkyl selected from methyl, who stated, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl.

In one embodiment, the invention relates to the compound of Formula (II)in which Y denotes heteroaryl, if necessary substituted by at least one of R6. In another embodiment, heteroaryl selected from furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazol, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, cinoxacin, quinoline and isoquinoline. In yet another embodiment, heteroaryl is an imidazole. In another embodiment, the imidazole substituted C1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In one embodiment, heteroaryl is furan. In another embodiment, heteroaryl is a thiazole. In yet another embodiment, heteroaryl represents a 1,3,4-oxadiazole. In another embodiment, heteroaryl substituted C1-C6the alkyl selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl.

In one embodiment, the invention relates to the compound of Formula (II)in which Z represents aryl. In another embodiment, the aryl is a phenyl. In another embodiment, phenyl is substituted by at least one of R6selected from Br, Cl, F, or I. In another embodiment, R6means F. In another embodiment, R6denotes Cl. In one embodiment, phenyl is substituted by at least oneR6selected from (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB)sulfonylurea. In another embodiment, R6means (NRARB)C1-C6alkylen. In yet another embodiment, C1-C6alkylene selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene and tert-butylene. In another embodiment, C1-C6alkylene represents methylene. In the following embodiment, RAand RBdenote, each independently, hydrogen, C1-C6alkyl or C3-C8cycloalkyl. In one embodiment, is sushestvennee C 1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In another embodiment, RAndand RIntogether with the nitrogen to which they are attached, form a 6-membered heterocycle, having 1 heteroatom or functional heterogroup selected from the group consisting of-O-, -NH or-N(C1-C6the alkyl). In another embodiment, the functional heterogroup represents-N(C1-C6alkyl). In one embodiment, C1-C6alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In another embodiment, C1-C6alkyl represents methyl. In another embodiment, R6denotes CH2(NRARB), where NRARBindicates azetidin, pyrrolidine, piperidine or morpholine. In another embodiment, R2denotes hydrogen. In another embodiment, R2selected from F, Cl, Br and I. In another embodiment, R2denotes F.

In one embodiment, the invention relates to the compound of Formula (II)in which A and B denote hydrogen. In another embodiment, A and B are independently selected from hydrogen and C1-C6is Lila.

In another embodiment, the invention relates to the compound of Formula (II)in which Z represents aryl and Y is independently selected from the group consisting of

a) phenyl, if necessary substituted by 1, 2 or 3 R6;

b) imidazole, if necessary substituted by 1, 2 or 3 R6;

c) a triazole, if necessary substituted by 1, 2 or 3 R6; and

d) substituent, independently selected from the group consisting of hydrogen, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic, (NRARB)alkylen(NRARB)carbonyl.

In another embodiment, the invention relates to the compound of Formula (II)in which Z represents phenyl and Y is independently selected from the group consisting of

e) phenyl, if necessary substituted by 1, 2 or 3 R6;

f) imidazole, if necessary substituted by 1, 2 or 3 R6;

g) a triazole, if necessary substituted by 1, 2 or 3 R6; and

h) substituent, independently selected from the group consisting of hydrogen, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylboron the La, arylcarbamoyl, heteroarylboronic, (NRARB)alkylen(NRARB)carbonyl.

In another embodiment, the invention relates to the compound of Formula (II)in which Z represents phenyl, substituted by 1, 2 or 3 R6and Y are independently selected from the group consisting of

i) phenyl, if necessary substituted by 1, 2 or 3 R6;

j) imidazole, if necessary substituted by 1, 2 or 3 R6;

k) triazole, if necessary substituted by 1, 2 or 3 R6; and

l) substituent, independently selected from the group consisting of hydrogen, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkyl, cycloalkyl, cycloalkenyl, halogenoalkane, oxo, geterotsiklicheskie, geterotsiklicheskikh, alkylcarboxylic, arylcarbamoyl, heteroarylboronic, (NRARB)alkylen(NRARB)carbonyl.

In another embodiment, A is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentile and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl may be substituted by OH, NO2, CN, Br, Cl, F and I. In another embodiment, A represents methyl. In yet another embodiment, A is selected from F, Cl, Br and I. In another embodiment, A represents C3-C8cycloalkyl. In each the m of the embodiment, A stands for IT. In another embodiment, a means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, A is substituted by OH, NO2or CN. In another embodiment, A stands for hydrogen. In another embodiment, B represents hydrogen. In another embodiment, B isC1-C6alkyl. In another embodiment, B is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentile and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl may be substituted by OH, NO2, CN, Br, Cl, F and I. In another embodiment, B represents methyl. In yet another embodiment, B is selected from F, Cl, Br and I. In another embodiment, B represents C1-C8cycloalkyl. In another embodiment, B denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, A is substituted by OH, NO2or CN. In another embodiment, the invention relates to the compound of Formula (II)in which A represents hydrogen and B is selected from Br, Cl, F, I, C1-C6of alkyl,C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least about is him Deputy, selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl. In another embodiment, the invention relates to the compound of Formula (II)in which B is hydrogen and A is selected from Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl. In yet another embodiment, both A and B denote hydrogen. In the following embodiment, and A and B are selected from Br, Cl, F, I, HE, C1-C6of alkyl,C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl, and not mean IT.

It also described the stereoisomers of compounds of Formula (I), (IA) or (II), such as enantiomers, diastereomers and mixtures of enantiomers or diastereomers. In one embodiment, the invention relates to a stereoisomer of the compounds of Formula (II)having the structure:

in which:

p> Y denotes aryl or heteroaryl, if necessary substituted by at least oneR6;

Z represents aryl, if necessary substituted by at least oneR6;

A and B, each independently, selected from hydrogen, Br, Cl, F, I, HE, C1-C6of alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl, and C1-C6alkyl, C3-C8cycloalkyl, alkoxy, alkoxyalkyl can be substituted by at least one Deputy, is selected from OH, NO2, CN, Br, Cl, F, I, C1-C6the alkyl and C3-C8cycloalkyl, and doesn't mean IT;

R6selected from OH, NO2, CN, Br, Cl, F, I, C1-C6of alkyl, C3-C8cycloalkyl, C2-C8geterotsiklicheskie; C2-C3alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, C2-C6the quinil, aryl, arylalkyl, C3-C8cycloalkenyl, halogenoalkane, halogenoalkane, hydroxyalkyl, oxo, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatic, heteroaromatic, heterocyclics, C2-C8heterozygosity, heterocyclics, heterocycly, NRARB, (NRARB)C1-C6alkylene, (NRARB)carbonyl, (NRARB)carbonylation, (NRARB)sulfonyl and (NRARB )sulfonylurea;

R2selected from hydrogen, Br, Cl, I or F;

RAand RBindependently selected from the group consisting of hydrogen, C1-C6the alkyl,C3-C8cycloalkyl and alkylsulphonyl; or RAandRBtogether with the atom to which they are attached, form a 3-10-membered heterocycle, in case of need, having from one to three heteroatoms or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl)-, -NCO(C3-C8-cycloalkyl)-, -N(aryl)-, -N(aryl-C1-C6-the alkyl-)-, -N(substituted-aryl-C1-C6-the alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6--alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl -) -, and-S - or S(O)q-where q=1 or 2 and the 3-10-membered heterocycle may be substituted by one or more substituents; or its pharmaceutically acceptable salt, MES or prodrug.

In one embodiment, the invention relates to a stereoisomer of the compounds of Formula (II)shown above, having the substituents shown above, and R2denotes fluorine. In another embodiment, the invention relates to the compound of Formula (II)shown above, having the substituents shown above, and Y represents an imidazole. In another embodiment, after retina relates to the compound of Formula (II) shown above, having the substituents mentioned above, and the imidazole Y substituted C1-C6the alkyl. In another embodiment, With1-C6alkyl represents methyl. In yet another embodiment, the invention relates to the compound of Formula (II)shown above, having the substituents shown above, and Y denotes a triazole. In another embodiment, the invention relates to the compound of Formula (II)shown above, having the substituents shown above, and triazole Y substituted C1-C6the alkyl. In another embodiment, C1-C6alkyl represents methyl. In another embodiment, the invention relates to the compound of Formula (II)shown above, having the substituents shown above, and the group Y represents aryl. In another embodiment, the invention relates to the compound of Formula (II)shown above, having the substituents shown above, and the aryl Y is phenyl. In another embodiment, phenyl substituted with halogen. In another embodiment, the halogen is a F. In another embodiment, the halogen is selected from Br, Cl, and I. In yet another embodiment, the invention relates to the compound of Formula (II)shown above, having the substituents shown above, and Z represents aryl. Even on the nom embodiment, the invention relates to the compound of Formula (II), shown above, having the substituents shown above, and the aryl Z represents phenyl. In another embodiment, phenyl Z substituted by halogen selected from F, Br, Cl, and I. In another embodiment, phenyl substituted Z F. In another embodiment, phenyl substituted Z C1-C6alkylen(NRARB). In another embodiment, C1-C6alkylene represents methylene. In yet another embodiment, NRARBindicates azetidin.

In one embodiment, the invention relates to a compound selected from the following compounds:

(8S,9R)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8R,9S)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8R,9S)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8R,9S)-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8S,9R)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8R,9S)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-37H)-he,

(8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

(8S,9R)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2Η-pyrido[4,3,2-de]phthalazine-3(7H)-he and

(8R,9S)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,

or its pharmaceutically acceptable salt, MES or prodrug.

In one aspect the invention relates to a compound selected from the following compounds:

9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8,9-bis(4-((methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8,9-di(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8,9-di(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8,9-di(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8,9-bis(3-((methylamino)methyl)phenyl)-8)9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-(is hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8,9-bis(3-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(piperidine-3-yl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(piperidine-4-yl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8,9-bis(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-(hydroxymethyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(3-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-di is Idro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((methylamino)methyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-(hydroxymethyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-((methylamino)methyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((methylamino)methyl)phenyl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H-he;

9-(4-((methylamino)methyl)phenyl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-(hydroxymethyl)phenyl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((methylamino)methyl)phenyl)-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-(hydroxymethyl)phenyl)-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-((methylamino)methyl)phenyl)-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-phenyl-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-phenyl-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-phenyl-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

5-fluoro-9-phenyl-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

5-fluoro-9-(3-((methylamino)methyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-((dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

5-fluoro-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-((dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-he;

5-fluoro-9-(4-((is, ethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-he;

9-(3-((dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-he;

8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-he;

5-fluoro-9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-he;

5-fluoro-8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-he;

7-methyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

7-ethyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-phenyl-9-(thiazol-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-phenyl-8-(4-(piperazine-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-e]phthalazine-3(7H)-he;

8,9-bis(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(1-ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-phenyl-9-(1-propyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((diethylamino)methyl)phenyl)-8-(4-((diethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-phenyl-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-phenyl-8-(piperidine-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-phenyl-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8,9-bis(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8,9-bis(3-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(3-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2Η-pyrido[4,3,2-de]phthalazine-3(7H)-he;

5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(1-methyl-1H-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-forfinal)-9-methyl-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-forfinal)-9-(1,4,5-trimethyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-forfinal)-9-(1-methyl-1Η-1,2,3-triazole-4-yl) - 8.9bn-dihydro-2Η-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4,5-dimethyl-4H-1,2,4-triazole-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4,5-dimethyl-4H-1,2,4-triazole-3-yl)-8-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7Η)-he;

8-(4-chlorophenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(1-methyl-1H-imidazol-2-yl)-8-(4-(trifluoromethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-forfinal)-9-(thiazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(1-those who-1H-imidazol-2-yl)-8-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((4-ethyl-3-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-forfinal)-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-forfinal)-8-(4-(piperazine-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-forfinal)-8-(4-((3-methylpiperazin-1-yl)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-forfinal)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-forfinal)-9-(4-methyl-4H-1,2,4-triazole-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-forfinal)-9-(1-methyl-1H-imidazo[4,5-C]pyridine-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

5-chloro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8,9-bis(4-((dimethylamino)methyl)phenyl)-5-fluoro-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((3,4-dimethylpiperazine-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H-he;

8-(4-((3,5-dimethylpiperazine-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-phenyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-phenyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(1-methyl-1Η-imidazol-2-yl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-forfinal)-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-forfinal)-8-(quinoline-6-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-9-(4-methoxyphenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-(diethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((diethylamino)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-chlorophenyl)-8-(4-(diethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(E)-6-fluoro-4-((1-methyl-1H-imidazol-2-yl)methylamino)isobenzofuran-1(3H)-he;

5-fluoro-9-(4-forfinal)-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-9-(4-ethylphenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)Fe who yl)-9-(4-isopropylphenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-((dimethylamino)methyl)phenyl)-9-(4-(trifluoromethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-(diethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-forfinal)-8-(4-(1-methylpyrrolidine-2-yl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-forfinal)-8-(4-(pyrrolidin-2-yl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

8-(4-forfinal)-9-methyl-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-forfinal)-8-(lΗ-imidazol-2-yl) - 8.9bn-dihydro-2Η-pyrido[4,3,2-de]phthalazine-3(7Η)-he;

5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

9-(4-forfinal)-9-hydroxy-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8S,9R)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8R,9S)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8R,9S)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)he;

(8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8S,9R)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2!4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8R,9S)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8R,9S)-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;

(8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he; and

(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H) -; or a pharmaceutical acceptable salt, MES or prodrug.

In some embodiments implementing the invention relates to pharmaceutical compositions comprising the compounds of Formula (I), (IA) or (II), or stereoisomers, or pharmaceutically acceptable salt, pharmaceutically acceptable MES, pharmaceutically acceptable prodrug, and a pharmaceutically acceptable carrier, excipient, binder or diluent.

Some embodiments of relate to a method of inhibiting PARP in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) is whether its therapeutically acceptable salts.

In one embodiment, the invention relates to a method of treating diseases, facilitated by PARP inhibition, comprising the administration to a patient a therapeutically effective amount of the compounds of Formula (I), (IA) or (II). In some embodiments, the implementation of a disease selected from the group consisting of: vascular disease; septic shock; ischaemic injury; reperfusion injury; neurotoxicity; hemorrhagic shock; inflammatory diseases; multiple sclerosis; secondary effects of diabetes and acute treatment of cytotoxicity after cardiovascular surgery.

In some embodiments implementing the invention relates to a method of treatment of cancer, comprising the administration to a patient a therapeutically effective amount of the compounds of Formula (I), (IA) or (II).

Some embodiments of relate to a method for potentiation of cytotoxic cancer therapy in a patient comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

In some embodiments implementing the invention relates to a method of treatment of cancer, comprising the administration to a patient a therapeutically effective amount of the compounds of Formula (I), (IA) or (II) in combination with ionizing radiation or one or more chemo is terapevticheskii means. In some embodiments, the implementation of the connection described here, is used simultaneously with ionizing radiation or one or more chemotherapeutic agents. In other embodiments, implementation of the connection described here are used sequentially with ionizing radiation or one or more chemotherapeutic agents.

In some embodiments implementing the invention relates to a method of treating cancer which comprises the administration to a patient a therapeutically effective amount of the compounds of Formula (I), (IA) or (II) in combination with ionizing radiation and one or more chemotherapeutic agents. In some embodiments, the implementation of the connection described here, is used simultaneously with ionizing radiation and one or more chemotherapeutic agents. In other embodiments, implementation of the connection described here are used sequentially with ionizing radiation and one or more chemotherapeutic agents.

Some embodiments of refer to the way a patient of leukemia, colon cancer, glioblastoma, lymphoma, melanoma, breast cancer or cervical cancer, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

In some is, some embodiments implement the invention relates to a method of treatment of cancer, where there is a shortage of dependent homologous recombination (HR) pathways repair breaks double DNA strand breaks (DSB), which includes an introduction to the patient a therapeutically effective amount of the compounds of Formula (I), (IA) or (II). In some embodiments, the implementation of the cancer involves one or more cancer cells having a reduced or abrogated ability to recover DNA DSB by HR relative to normal cells. In some embodiments, the implementation of the cancer cells have a BRCA1 or BRCA2 deficient phenotype. In some embodiments, the implementation of the cancer cells deficient in relation to BRCA1 or BRCA2. In some embodiments, the implementation of the methods according to the invention include the treatment of a man who is heterozygous in respect of mutations in a gene, encoding a component of the HR dependent pathway DSB repair DNA. In some embodiments, the implementation of the individual is heterozygous in respect of mutations in BRCA1 and/or BRCA2. In some embodiments implement a method of treating cancer includes treatment of breast cancer, ovarian cancer, pancreatic cancer and/or prostate cancer. In some embodiments implement a method of treating cancer further includes the use of ionizing radiation or chemotherapeutic agents.

The primary function of system repair of mismatched DNA does not match reparaci the (MMR) and consists in removing the individual not the same bases and loops insertion-deletions, which can occur during DNA replication. Loop insertion-deletions (indels) are formed due to the appearance or disappearance of short repeating units within microsatellite sequences, also known as microsatellite instability (MSI). Required at least six different MMR proteins. To recognize mismatches protein MSH2 forms heterodimer either MSH6 or MSH3 depending on the type of damage that must be fixed (MSH6 are required to correct the mismatch only basis, whereas MSH3, and MSH6 can help fix loops insertion-deletions (indels). Heterodimer MLH1 and PMS2 coordinates the interaction between the recognition of mismatches and other proteins required for MMR. These additional proteins may include at least exonuclease 1 (EXO1), perhaps the helicase(s), the core antigen of proliferating cells (PCNA), single-stranded DNA binding protein (RPA), and DNA polymerase δ and ε. In addition to PMS2, MLH1 may heterodimerization with two additional proteins, MLH3 and PMS1. Recent observations show that PMS2 is required to correct the mismatch only basis, and as PMS2, and MLH3, both involved in the correction loops insertion-deletions (indels). Known additional homologues of the human MMR proteins that are required for other functions, p is by MMR. These proteins include MSH4 and MSH5, which are required for meiotic (and possibly mitotic) recombination, but is assumed to not participate in MMR.

Mutations germinal way human MMR genes cause predisposition to hereditary non-polyposis colorectal cancer, colon cancer (HNPCC), one of the most common syndromes of cancer in humans. An excess of colon cancer and a specific spectrum of extraintestinal cancer diagnosed at an early age and transmitted as an autosomal dominant trait, is the clinical definition of the syndrome. MSI, a sign of HNPCC, occurs in approximately 15%-25% of cases of sporadic tumors of the colon and rectum, and other organs. According to the international standards, a high degree of MSI (MSI-H) is defined as instability in two or more of the five loci or ≥30% to 40% of all the studied microsatellite loci, whereas instability in a smaller number of loci is referred to as low MSI (MSI-L). MSI occurs in a significant proportion (from 2% to 50% of tumors) non-HNPCC cancer (e.g. breast cancer, prostate and lung). Based on the proportions of volatile markers in the cases of these cancers can be categorised MSS, MSI-L and MSI-H by analogy with cancer HNPCC. In one embodiment, the invention relates to a method of treating cancer, wherein nabludaetsa deficit path repair of DNA mismatches. In another embodiment, the invention relates to a method of treating cancer, demonstrating microsatellite instability due to reduced or impaired DNA repair pathway. In another embodiment, the invention relates to a method of treating cancer, demonstrating genomic instability due to reduced or impaired DNA repair pathway.

Some embodiments of relate to the treatment of the damage of ischemia-reperfusion injury associated with, but not limited to, myocardial infarction, stroke, other neural trauma, and organ transplantation, in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of relate to a method of treating reperfusion including, but not limited to, reperfusion of the eye, kidney, gut and skeletal muscle in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of relate to a method of treatment of inflammatory diseases, including, but not limited to, arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic ence is Palit, sepsis, toxic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of relate to a method of treating immunological diseases or disorders such as rheumatoid arthritis and septic shock in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of relate to the treatment of degenerative diseases, including, but not limited to, diabetes and Parkinson's disease, in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of relate to a method of treating hypoglycemia in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of relate to a method of treating retroviral infection in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) his or therapist who Cesky acceptable salt.

Some embodiments of relate to the treatment of hepatotoxicity after overdose peroxyacetyl in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of relate to method of treatment toxicity to the heart and kidneys caused by doxorubicin and antitumor means of platinum-based, patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of relate to the treatment of skin lesions caused by sulfur mustard, in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt to obtain drugs for inhibition of the enzyme PARP patient.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt for a drug to inhibit the growth of the tumor the patient.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt for a medicinal product for the treatment of cancer patients.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt for a medicinal product for the treatment of leukemia, colon cancer, glioblastomas, lymphomas patient.

Some embodiments of relate to the treatment of degenerative diseases, including, but not limited to, diabetes, and Parkinson's disease, in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt to obtain drugs for potentiation of cytotoxic cancer therapy in a patient comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt for a medicinal product is for treatment of injury ischemia-reperfusion, associated with, but not limited to, myocardial infarction, stroke, other neural trauma, and organ transplantation, in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt to obtain drugs for treating reperfusion including, but not limited to, reperfusion of the eye, kidney, gut and skeletal muscle in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt for a medicinal product for the treatment of inflammatory diseases, including, but not limited to, arthritis, gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

is some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt to obtain drugs for treating immunological diseases or disorders such as rheumatoid arthritis and septic shock in a mammal, comprising administration to the patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt to obtain drugs for the treatment of hypoglycemia in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt to obtain drugs for the treatment of retroviral infection in a patient, comprising the administration to a patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt to obtain drugs for the treatment of hepatotoxicity after overdose paroxetie is anilide the patient, includes introduction to the patient a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt to obtain drugs for the treatment of toxicity to the heart and kidneys caused by doxorubicin and antitumor means of platinum-based, patient, comprising the administration to a mammal a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

Some embodiments of refer to the use of compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt for a medicinal product for the treatment of skin lesions caused by sulfur mustard, in a patient, comprising the administration to a mammal a therapeutically acceptable amount of the compounds of Formula (I), (IA) or (II) or a therapeutically acceptable salt.

The invention relates to industrial products, including packaging material, a compound according to the invention that is effective to modulate the activity of the enzyme poly(ADP-ribose)polymerase, or for treatment, prevention and / or alleviate one or more symptoms of a poly(ADP-ribose)polymerisates the independent or poly(ADP-ribose)polimeraza.posle disease or condition, inside of the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable MES, are used to modulate the activity of poly(ADP-ribose)polymerase, or for treatment, prevention and / or alleviate one or more symptoms of a poly(ADP-ribose)polymerisations or poly(ADP-ribose)polymerase-mediated disease or condition.

Any combination of the groups described above for the various variables included in the scope of the invention.

In one embodiment, the invention relates to pharmaceutical compositions comprising the compound, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable MES of any of the compounds according to the invention. In some embodiments, the implementation of the pharmaceutical compositions optionally include a pharmaceutically acceptable diluent, excipient or binder. In some embodiments, the implementation of the pharmaceutical composition additionally comprises a second pharmaceutically active ingredient.

In one embodiment, the ARP-mediated disease or condition in a patient or PARP-dependent disease or condition in a patient represent cancer or non-cancerous disorder. In some embodiments, the implementation of the disease or condition is iatrogenic.

In some embodiments implementing the invention relates to methods for reducing/inhibiting the activity of PARP in a patient, which includes the introduction of a patient at least once an effective amount of the compounds described herein.

Some embodiments of the invention relate to methods of correction, including reducing and/or inhibiting activityPARP, directly or indirectly, in a patient, comprising the administration to a patient at least once an effective amount of at least one compound described herein.

In other embodiments implementing the invention relates to methods for treating PARP-mediated condition or disease comprising the administration to a patient at least once an effective amount of at least one compound described herein.

Some options for implementation include the use of compounds described herein, in getting medicines for the treatment of a disease or condition in a patient, in which the activity of at least one PARP protein contributes to the pathology and/or symptoms of the disease or condition.

In any of the above embodiments have the following options for implementation, the cat is where the introduction is carried out enterline, parenteral or both ways, and:

(a) an effective amount of the compound administered to the patient systemically;

(b) an effective amount of the compound administered to the patient orally;

(c) an effective amount of the compound administered to the patient intravenously;

(d) an effective amount of the compound is administered by inhalation;

(e) an effective amount of the compound administered nasal introduction;

(f) an effective amount of the compound administered to the patient by injection;

(g) the effective amount of the compound administered to the patient tapicerki (dermal route);

(h) an effective amount of compound injected eye introduction; and/or

(i) an effective amount of the compound administered to the patient rectally.

In any of the above embodiments are further embodiments of which include a separate injection of an effective amount of the compound, including further embodiments of, in which the compound is administered to a patient (i) once; (ii) repeatedly after a certain period in one day; (iii) continually; or (iv) continuously.

In any of the above embodiments are further embodiments of which include repeated administration of an effective amount of the compound, including further embodiments of which:

(i) compound is administered in a single the public dose;

(ii) the interval between repeated injections is 6 hours;

(iii) the compound is administered to the patient every 8 hours.

Other or alternative options for implementing the method includes a rest period from the introduction of the medicinal product, in which the introduction of the connection is temporarily stopped or dose of the compound is temporarily reduced; at the end of the rest period from the introduction of medicines introduction connection resume. In some embodiments, the implementation of the duration of the rest period from the introduction of the drug varies from 2 days to 1 year.

In any of the above embodiments involving the treatment of proliferative disorders, including cancer, are further embodiments of which include the introduction of at least one additional means selected from among alemtuzumab, arsenic trioxide, asparaginase (Paglierani or not-Paglierani), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin/doxorubicin/idarubitsina, irinotecan, fludarabine, 5-fluorouracil inside the body, gemtuzumab, methotrexate, paclitaxel, Taxol®, temosolomida, Tg and classes of drugs including hormones (an antiestrogen, an antiandrogen, or analogues gonadotropinreleasing hormone, such checkinterface, for example, alpha interferon, nitrogen mustards such as busulfan, melphalan or mechlorethamine, retinoids, such as tretinoin, topoisomerase inhibitors, such as irinotecan or topotecan, an inhibitor of tyrosine kinases, such as, for example, gefinitib or imatinib, and means to treat signs or symptoms induced by such therapy including allopurinol, filgrastim, granisetron/ondansetron/palonosetron and dronabinol.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following description. It should be understood, however, that the description and specific examples, showing some embodiments of provided for illustration only, since various changes and modifications within the spirit and scope of the present description will be apparent from this detailed description.

There are described compounds, methods of making such compounds, pharmaceutical compositions and medicaments that include such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the activity of PARP.

There are described compounds having activity against inhibition of the enzyme poly(ADP-ribose)polymerase (PARP). In some embodiments, with the organisations have a structure of Formula (I), (IA) or (II).

The enzyme PARP-1 mammals is a multidomain protein. PARP-1 is involved in the transduction of signals DNA damage through its ability to recognize and quickly contact breaks single or double DNA chain. D Amours, et al, Biochem. J., 342, 249-268 (1999); and Virag et al. Pharmacological Reviews, vol. 54, no. 3, 375-429 (2002) included here by reference for such disclosure.

The family of poly(ADP-ribose)polymerases includes approximately 18 proteins, all of which demonstrate a certain level of homology in their catalytic domain but differ in their cellular functions. PARP-1 and PARP-2 are unique members of the family that their catalytic activity is stimulated by breaks in the DNA chain. Ame et al., BioEssays., 26(8), 882-893 (2004) included here by reference for such disclosure.

PARP-1 is involved in various related DNA functions, including gene amplification, division, differentiation, apoptosis of cells, the repair of cut DNA bases, as well as the impact on telomere length and chromosome stability. d'adda di Fagagna et al, Nature Gen., 23(1), 76-80 (1999) included here by reference for such disclosure.

Studies of the mechanism by which PARP-1 modulates the DNA repair and other processes, identify its importance in the formation of chains of poly(ADP-ribose) within the cell nucleus. Associated with DNA, activated PARP-1 used in the ABOVE +to synthesize poly(ADP-ribose) on various nuclear proteins target, including topoisomerases, histones and directly PARP. Althaus, F. R. and Richter, C, ADP-Ribosylation of Proteins: Enzymology and Biological Significance, Springer-Verlag, Berlin (1987); and Rhun, et al, Biockem. Biophys. Res. Commun., 245, 1-10 (1998) included here by reference for such disclosure.

Poly(ADP-ribosyl)licensing is also associated with malignant transformation. For example, the activity of PARP-1 higher in isolated nuclei SV40-transformed fibroblasts, while and leukemia cells, and cancer cells of the colon show higher enzyme activity than the equivalent normal cells and the mucous membrane of the colon. In addition, malignant tumors prostate cancer have elevated levels of active PARP compared to benign prostate cells, which is associated with higher levels of genetic instability. Miwa, et al, Arch Biochem. Biophys., 181, 313-321 (1977); Burzio, et al., Proc. Soc. Exp. Biol. Med., 149, 933-938 (1975); Hirai, et al, Cancer Res., 43, 3441-3446 (1983); and Mcnealy, et al., Anticancer Res., 23, 1473-1478 (2003) included here by reference for such disclosure.

In cells treated with alkylating agents, inhibition of PARP leads to a pronounced increase breaks the chains of DNA and destroy cells. Inhibitors of PARP-1 also enhances the effects of response to radiation suppressing reparaz the Yu potentially lethal damage. PARP inhibitors are also effective in radio-sensitization of hypoxic tumor cells. On some lines, tumor cells, chemical inhibition of PARP activity is also associated with a marked sensitization to very low doses of radiation.

In addition, animals with knockout by PARP-1 (PARP-/-) show genomic instability in response to alkylating agents and γ-irradiation. Data indicate that PARP-1 and PARP-2 have overlapping and nepovtorimymi each other functions in maintaining genomic stability, which makes them both interesting targets. Wang, et al, Genes Dev., 9, 509-520 (1995); Menissier de Murcia, et al, Proc. Natl. Acad. Sci USA, 94, 7303-7307 (1997); and Menissier de Murcia, et al, EMBO. J., 22(9), 2255-2263 (2003) included here by reference for such disclosure.

PARP-1 also plays a role in some vascular diseases, such as, for example, septic shock, ischemic damage and neurotoxicity. DNA damage by oxygen radicals, which leads to breaks in the DNA chain, which are then recognized by PARP-1, is the main factor of such painful conditions, as shown by studies of inhibitor of PARP-1. PARP also plays a role in the pathogenesis of hemorrhagic shock. Cantoni, et al, Biochim. Biophys. Acta, 1014, 1-7 (1989); Szabo, et al, J. Clin. Invest., 100, 723-735 (1997); Cosi, et al, J Neurosci. Res., 39, 3846 (1994); Said et al., Proc. Natl. Acad. ScI U.S.A., 93, 4688-4692 (1996); and Liaudet, et al, Proc. Natl. Acad. Sci. U.S.A., 97(3), 10203-10208 (2000) included here by reference and in respect of such disclosure.

In addition, efficient retroviral infection of mammalian cells is blocked by inhibition of the activity of PARP-1. This inhibition infections recombinant retroviral vector occurs in various cell types. In some embodiments, the implementation of inhibitors of PARP-1 are used in antiviral therapies and in the treatment of cancer. Gaken, et al, J. Virology, 70(6), 3992-4000 (1996) are included here by reference for such disclosure.

In addition, in some embodiments, the implementation of the inhibition of PARP-1 delays the onset of aging characteristics in human fibroblasts. Out of touch with any theory, this may be due to the role PARP plays in controlling the function of telomeres. Rattan and Clark, Biochem. Biophys. Res. Comm., 201(2), 665-672 (1994); and d'adda di Fagagna et al, Nature Gen., 23(1), 76-80 (1999) included here by reference for such disclosure.

In some embodiments, the implementation of the PARP inhibitors are relevant for the treatment of inflammatory bowel disease, ulcerative colitis and Crohn's disease. Szabo C, Role of Poly(ADP-Ribose) Polymerase Activation in the Pathogenesis of Shock and Inflammation, In PARP as a Therapeutic Target; Ed J. Zhang, 2002 by CRC Press; 169-204; Zingarelli, B, et al, Immunology, 113(4), 509-517 (2004); and Jijon, H. B., et al, Am. J. Physiol. Gastrointest. Liver Physiol, 279, G641-G651 (2000) included here by reference for such disclosure.

In some embodiments, the implementation of PARP inhibitors, such as compounds of Formula I, (IA) or (II), can be used for: (a) preventing or inhibiting the formation of chains of poly(ADP-ribose), for example, by inhibiting the activity of cellular PARP (PARP-1 and/or PARP-2); (b) treatment of vascular disease; septic shock; ischaemic injury, both cerebrocortical and cardiovascular; reperfusion injury, both cerebrocortical and cardiovascular; neurotoxicity, including acute and chronic treatment of stroke and Parkinson's disease; hemorrhagic shock; inflammatory diseases, such as arthritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease; multiple sclerosis; secondary effects of diabetes; as well as acute treatment of cytotoxicity after cardiovascular surgery or diseases, facilitated by inhibition of the activity of PARP; (c) use as an adjunct in cancer therapy or for potentiating tumour cells for treatment with ionizing radiation and/or chemotherapeutic agents.

In some embodiments, the communication according to the invention, such as, for example, the compounds of Formula (I), (IA) or (II)used in the combined anticancer therapies (or addition) along with alkylating agents, such as methylmethanesulfonate (MMS), temozolomide and dacarbazine (DTIC), also with inhib the torus topoisomerase-1, such as topotecan, irinotecan, rubitecan, eksteen, lurtotecan, gimatecan, diflomotecan (gamecaptain); and 7-substituted non-silaturahmi; 7-silyl camptothecins, BNP 1350; and non-camptothecine inhibitors topoisomerase-I, such as indolocarbazole, as well as dual inhibitors of topoisomerase I and II, such as benzophenone, XR 11576/576 MLN and banteringly. In some embodiments, the implementation of such a combination is administered, such as intravenous fluids or oral introduction depending on the method of introduction of specific tools.

In some embodiments, the implementation of PARP inhibitors, such as, for example, the compounds of Formula (I), (IA) or (II)used in the treatment of diseases, facilitated by the inhibition of PARP, which includes an introduction to the patient a therapeutically effective amount of the compounds according to the invention, and in one embodiment in the form of pharmaceutical compositions. In some embodiments, the implementation of PARP inhibitors, such as, for example, the compounds of Formula (I), (IA) or (II)used in the treatment of cancer, which includes an introduction to the patient a therapeutically effective amount of the compounds according to the invention in combination, and in one embodiment in the form of a pharmaceutical composition, simultaneously or sequentially with radiotherapy (ionizing radiation) or chemical is therapeutic means.

In some embodiments, the implementation of PARP inhibitors, such as, for example, the compounds of Formula (I), (IA) or (II)used in obtaining medications for the treatment of cancer, in which there is a shortage of dependent homologous recombination (HR) pathways repair breaks double DNA strand breaks (DSB), or for the treatment of a patient suffering from cancer, in which there is a shortage of HR-dependent DSB activity DNA repair, which includes the introduction of the indicated patient a therapeutically effective amount of compound according to izobreteny.

HR-dependent DSB way DNA repair restores denitive breaks (DSB) in DNA through homologous mechanisms, reforming continuous DNA helix. Components of HR-dependent DSB way DNA repair include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM 002878), DMCl (NM 007068), XRCC2 (NM_005431), XRCC3 (NM 005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCAl (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MREl 1A (NM_005590) and NBSl (NM_002485). Other proteins involved in HR-dependent DSB way DNA repair include regulatory factors, such as EMSY. Components of HR is also described in Wood et al., Science, 291, 1284-1289 (2001), which is included here by reference for such disclosure. K. K. Khanna and S. P. Jackson, Nat. Genet. 27(3): 247-254 (2001); and Hughes-Davies, et al., Cell, 115, pp 523-535 also included here by reference for such disclosure.

In some embodiments, the wasp is estline cancer, where there is a shortage of HR-dependent DSB activity DNA repair, includes one or more cancer cells that have reduced or abrogated ability to recover DNA DSB through this way compared with normal cells, i.e. the activity of HR-dependent DSB way DNA repair is reduced or absent in one or more cancer cells.

In some embodiments, the implementation of the activity of one or more components of HR-dependent DSB way DNA is absent in one or more cancer cells of a person with cancer where there is a shortage of HR-dependent DSB activity DNA repair. Components of HR-dependent DSB way DNA repair include the above components.

In some embodiments, the implementation of the cancer cells have BRCA1 and/or BRC A2-deficient phenotype, that is, the activity of the BRCA1 and/or BRCA2 genes in cancer cells is reduced or absent. In some embodiments, the implementation of the cancer cells with this phenotype are scarce in relation to BRCA1 and/or BRCA2 genes, that is, the expression and/or activity of the BRCA1 and/or BRCA2 genes in cancer cells is reduced or absent, for example, by mutation or polymorphism in the coding nucleic acid, or as a result of amplification, mutation or polymorphism in a gene encoding a regulatory factor, for example, EMSY gene, which encodes a regulatory factor BRCA2, or is the result of epigenetic mechanism, such as methylation of the promoter of the gene.

BRCA1 and BRCA2 are tumor suppressor, the wild-type allele which is frequently lost in tumors heterozygous carriers. Mutations in BRCA1 and/or BRCA2 genes associated with breast cancer. Amplification of EMSY gene, which encodes a BRCA2-binding factor associated with breast cancer and ovarian cancer. Jasin M., Oncogene, 21(58), 8981-93 (2002); Tutt, et at, Trends Mol Med., 8(12), 571-6, (2002); and Radice, P. J., Exp Clin Cancer Res., 21(3 Suppl), 9-12 (2002) included here by reference for such disclosure.

Carriers of mutations in BRCA1 and/or BRCA2 have an increased risk of cancer of the ovary, prostate and pancreas.

In some embodiments, the implementation of the individual is heterozygous for one or more changes, such as mutations and polymorphisms in BRCA1 and/or BRCA2 genes or their regulators. Detection of changes in the BRCA1 and BRCA2 genes are described, for example, in EP 699 754, EP 705 903, Neuhausen, S. L. and Ostrander, E. A,, Genet. Test, 1, 75-83 (1992); Janatova M., etal, Neoplasma, 50(4), 246-50 (2003), which are included here by reference for such disclosure. Determining amplification of BRCA2-binding factor EMSY described in Hughes-Davies, et al, Cell, 115, 523-535).

In some cases, mutations and polymorphisms associated with cancer detected at the level of nucleic acid, detecting the presence of the variant nucleic acid sequence, or at the protein level, detecting the presence of variant (i.e. mu is Anta or allelic variant of the polypeptide.

DEFINITION

If not stated otherwise, all technical and scientific terms used herein have the default value related to the subject. When there are many definitions for terms used is predominantly used in this section. If reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the Internet can come and go, but equivalent information can be found by searching the Internet. Link to this shows the availability and accessibility of such information.

It should be understood that the foregoing General description and following detailed description are only for example and explanation and are not restrictive to any of the stated objects. In this application the use of the singular includes the plural unless specifically stated otherwise. It should be noted that in the description and appended claims, the singular number include the plural, unless the context clearly requires otherwise. In this application the use of "or" means "and/or"unless stated otherwise. In addition, the use of the term "including"as well as other forms, such as "include", "includes" and "included", has no ogranichitel the aqueous character.

If not specified, uses conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, techniques of recombinant DNA and pharmacology. If not given a specific definition, use the standard nomenclature used in this connection, and standard laboratory procedures and techniques of analytical chemistry, chemistry of organic synthesis and medicinal and pharmaceutical chemistry. In some cases, standard techniques are used for chemical syntheses, chemical analyses, receipt, preparation and delivery of pharmaceuticals and treatment of patients. In some embodiments, the implementation of standard techniques are used for recombinant DNA, synthesis of oligonucleotide and tissue culture and transformation (e.g., electroporation, lipofection). In some embodiments, the implementation of the reaction and methods purification is carried out, for example, with the use of sets in accordance with the specification of the manufacturer or, as commonly used, or as described here.

Throughout the application and in the attached claims, the following terms have the following meanings:

The term "alkenyl" in the framework of the invention, means a hydrocarbon with a straight, branched chain, or cyclic (also known as "cycloalkenyl")containing 2-10 carbon atoms and containing at m is d one carbon-carbon double bond, formed by removal of two hydrogen atoms. In some embodiments, implementation, depending on the structure of alkenyl represents a monovalent radical or the divalent radical (i.e., albaniles). In some embodiments, the implementation alkeneamine groups can be substituted. Illustrative examples of alkenyl include, but are not limited to, ethynyl, 2-propenyl 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-Heptene and 3-Setenil.

The term "alkoxy" in the context of the invention means an alkyl, as defined here, attached to the parent molecular group through an oxygen atom. Illustrative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy.

The term "alkyl" in the context of the invention means a hydrocarbon with a straight, branched chain or cyclic (in this case, it is also known as "cycloalkyl")containing 1-10 carbon atoms. Illustrative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-etylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

The term "C1-C6-alkyl" in the context of the invention means a hydrocarbon with a straight, branched chain or Ilichevsky (in this case, it is also known as "cycloalkyl")containing 1-6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cicloral, n-butyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclopentyl and n-hexyl.

The term "cycloalkyl" in the context of the invention means a monocyclic or polycyclic radical containing only carbon and hydrogen, and includes those which are saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative examples of loops include, but are not limited to, the following groups:

In some embodiments, implementation, depending on the structure cycloalkyl group is a monovalent radical or the divalent radical (for example, cycloalkenes group).

The term "cycloalkyl group" within the framework of the invention relates to groups which may be substituted by 1, 2, 3, or 4 substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulphonyl, alkylcarboxylic, alkylthio, alkylthiomethyl, quinil, carboxy, cyano, formyl, halogenoalkane, halogenoalkane, halogen, hydroxyl, hydroxyalkyl, mercapto, oxo, -NRARAThe (NR ARB)carbonyl.

The term "cycloalkenyl" in the context of the invention means cycloalkyl group, as defined here, attached to the parent molecular group through an alkyl group, as defined here. Representative examples of cycloalkenyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylmethyl.

The term "carbocyclic" in the context of the invention refers to a compound that contains one or more covalently closed ring structures, and in which the atoms which form the basis of the ring are all carbon atoms.

The term "carbocycle" in the framework of the invention relates to a ring, in which each of the atoms forming the ring is a carbon atom. Carbocyclic rings include, which is formed by three, four, five, six, seven, eight, nine or more than nine carbon atoms. Carbocycle can be overridden.

The term "alkoxyalkyl" in the context of the invention means at least one alkoxy group, as defined here, attached to the parent molecular group through an alkyl group, as defined here. Illustrative examples of alkoxyalkyl include, but are not limited to, 2-methoxyethyl, 2-ethoxyethyl, tert-butoxyethyl and methoxymethyl.

The term "alkoxyaryl the sludge" in the context of the invention means an alkoxy group, as defined here, attached to the parent molecular group through a carbonyl group, as defined here. Illustrative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl.

The term "alkoxycarbonyl" in the context of the invention means alkoxycarbonyl group, as defined here, attached to the parent molecular group through an alkyl group, as defined here.

The term "alkylaryl" in the context of the invention means an alkyl group, as defined here, attached to the parent molecular group through a carbonyl group, as defined here. Illustrative examples of alkylcarboxylic include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopent.

The term "alkylcarboxylic" in the context of the invention means alkylcarboxylic group, as defined here, attached to the parent molecular group through an oxygen atom. Illustrative examples of alkylcarboxylic include, but are not limited to, atomic charges, ethylcarbonate and tert-BUTYLCARBAMATE.

The term "alkylthio" or "dialkoxy" in the context of the invention means an alkyl group, as defined here, attached to the parent molecular group through a sulfur atom. Illustrative is the reamers, alkylthio include, but not limited to, methylthio, ethylthio, butylthio, tert-butylthio and hexylthio.

The term "alkylthiomethyl" in the context of the invention means allylthiourea, as defined here, attached to the parent molecular group through an alkyl group, as defined here. Illustrative examples of alkylthiomethyl include, but are not limited to, methylthiomethyl, 2-(ethylthio)ethyl, butylthioethyl and exitialis.

The term "quinil" in the context of the invention means a hydrocarbon with a straight, branched chain, containing 2-10 carbon atoms and containing at least one carbon-carbon triple bond. In some embodiments, the implementation alkyline groups can be substituted. Illustrative examples of quinil include, but are not limited to, acetylenyl, 1-PROPYNYL, 2-PROPYNYL, 3-butynyl, 2-pentenyl and 1-butynyl.

The term "aromatic" in the context of the invention refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n denotes an integer. In some embodiments, the implementation of the aromatic ring formed by five, six, seven, eight, nine or more than nine atoms. In other embodiments, implementation of the aromatic compounds may be substituted. The term includes monocyclic or condensed polycyclic (i.e., rings which share common is minye pairs of carbon atoms) group.

The term "aryl" in the context of the invention refers to the aromatic ring, in which each of the atoms forming the ring is a carbon atom. In some embodiments, the implementation of the aryl ring formed by five, six, seven, eight, nine or more than nine carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthrene, anthracene, fluorene and indenyl.

In some embodiments, the implementation of the term "aryl" in the context of the invention means an aryl which may be substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulphonyl, alkylcarboxylic, alkylthio, alkylthiomethyl, quinil, carbonyl, cyano, formyl, halogenoalkane, halogenoalkane, halogen, hydroxyl, hydroxyalkyl, mercapto, nitro, -NRARAand (NRARB)carbonyl.

The term "arylalkyl" in the framework of the invention, means an aryl group, as defined here, attached to the parent molecular group through an alkyl group, as defined here. Illustrative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, -phenylpropyl, 1-methyl-3-phenylpropyl and 2-naphthas-2-ileti.

The term "carbonyl" in the framework of the invention, means the group-C(O)-

The term "carboxy" in the context of the invention means a group-COOH.

The term "cyano" in the context of the invention means the group-CN.

The term "formyl" in the context of the invention means the group-C(O)H.

The term "halogen" in the context of the invention means-Cl, -Br, -I or-F.

The term "mercapto" in the context of the invention means the group-SH.

The term "nitro" in the context of the invention means a group-NO2.

The term "hydroxy" in the context of the invention means a group-IT.

The term "oxo" in the context of the invention means a group =O.

The term "communication" or "simple connection" in the context of the invention refers to a chemical bond between two atoms, or two groups, when the atoms connected by a bond shall be considered part of a larger substructure.

The terms "halogenated", "halogenoalkanes", "halogenoalkanes and halogenoalkane" in the framework of the invention include alkyl, alkeline, alkyline and alkoxy structures in which at least one hydrogen is replaced by halogen atom. In some embodiments, the implementation in which two or more hydrogen atoms replaced by halogen atoms, the halogen atoms are the same. In other embodiments, the implementation in which two or more hydrogen atoms replaced by halogen atoms, the halogen atoms are not the same. The terms "foralkyl and feralcode include halogenated, halogenoalkane group, according to the government, in which the halogen is fluorine. In some embodiments, the implementation of halogenoalkane can be overridden.

The term "alkylamine" refers to the group-N(alkyl)xHywhere x and y are selected from x=1, y=1 and x=2, y=0. In some embodiments, implementation, when x=2, alkyl groups, together with the N atom to which they are attached, may form a cyclic ring system.

The term "amide" as part of the invention is a chemical group with the formula-C(O)other or-NHC(O)R, where R is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and geterotsiklicheskie (attached through a ring carbon). In some embodiments, the implementation of the amide group forms a link between amino acid or molecule, peptide and compound described herein, thereby forming a prodrug. In some embodiments, the implementation of the amine or carboxyl side chain of the compounds described herein, liderovna.

The term "ester" refers to a chemical group with the formula-COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and geterotsiklicheskie (attached through a ring carbon). In some embodiments, the implementation of any hydroxyl or carboxyl side chain of the compounds described herein, etherification.

Ter the ins "heteroalkyl" "heteroalkyl and heteroalkyl" in the framework of the invention include, if necessary, substituted alkyl, alkanniny and alkynylaryl radicals in which one or more atoms of the skeletal chain selected from an atom other than carbon, for example, oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof.

The term "heteroatom" in the context of the invention refers to an atom other than carbon or hydrogen.

Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In the variants of implementation, in which there are two or more heteroatoms, these two or more heteroatoms are the same, or some or all of the two or more heteroatoms are different from others.

The term "ring" in the context of the invention refers to any covalently closed structure. Rings include, for example, carbocycle (for example, Ariely and cycloalkyl), heterocycles (for example, heteroaryl and heterocicluri), aromatic ring (for example, Ariely and heteroaryl) and non-aromatic rings (for example, cycloalkyl and heterocicluri). In some embodiments, the implementation of the rings can be substituted. In some embodiments, the implementation of the rings are part of a ring system.

In the framework of the invention, the term "ring system" refers to two or more rings in which two or more of the rings are condensed. The term "condensed" refers to the structures, the cat is where two or more rings share one or more common links.

The terms "heteroaryl" or alternatively, "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. N-containing heteroaromatic" or "heteroaryl" group refers to an aromatic radical, in which at least one of the skeletal atoms of the ring is a nitrogen atom. In some embodiments, the implementation of polycyclic heteroaryl group condensed or not condensed. Examples of heteroaryl groups include, but are not limited to, the following groups:

In some embodiments, implementation, depending on the structure of the heteroaryl group is a monovalent radical or the divalent radical (that is, heteroarenes group).

The term "heteroaryl" means a heteroaryl group that is substituted by 0, 1, 2, 3 or 4 substituents, independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulphonyl, alkylcarboxylic, alkylthio, alkylthiomethyl, alkynylaryl, carboxy, cyano, formyl, halogenoalkane, halogenoalkane, halogen, hydroxyl, hydroxyalkyl, mercapto, nitro, -NRARBand -(NRARB)carbonyl.

The term "heteroaromatic" in the context of the invention means heteroaryl, as defined here, p is soedinenii to the parent molecular group through an alkyl group, as defined here. Illustrative examples of heteroaromatic include, but are not limited to them, pyridinylmethyl.

The term "heteroseksualci" or "the non-aromatic heterocycle" in the context of the invention refers to non-aromatic ring in which one or more atoms forming the ring is a heteroatom. "Heteroseksualci" or "the non-aromatic heterocycle" refers to cycloalkyl group, which includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the implementation of radical condensed with aryl or heteroaryl. In some embodiments, the implementation heterocytolysine ring formed by three, four, five, six, seven, eight, nine or more than nine atoms. In some embodiments, the implementation heterocytolysine rings can be substituted. In some embodiments, the implementation of heterocicluri contain one or more carbonyl or thiocarbonyl group, such as, for example, oxo - and thio-containing groups. Examples of heterocyclization include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioamide, cyclic carbamates, tetrahydrothiopyran, 4H-Piran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiin, 1,4-oxathiin, 1,4-axation, tetrahydro-1,4-t is asin, 2H-1,2-oxazin, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperidin, as dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrrolin, pyrrolidine, pyrrolidone, pyrrolidin, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiol, 1,3-ditiolan, isoxazolin, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolan. Illustrative examples geterotsiklicheskikh groups, also called non-aromatic heterocycles include, but are not limited to, the following groups:

The term heteroseksualci also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides and oligosaccharides.

The term "heterocycle" refers to heteroaryl, and heteroseksualci used here, refers to groups containing one to four heteroatoms selected from O, S and N, each heterocyclic group has from 4 to 10 atoms in its ring system, and provided that the ring of the specified group does not contain two adjacent O atom or s Each time the specified number of carbon atoms in the heterocycle (for example, C1-C6a heterocycle), at least one other atom (the heteroatom) must be present in coleta designations as "C1-C6a heterocycle"refer only to the number of carbon atoms in the ring and do not relate to the total number of atoms in the ring. In some embodiments, the implementation assumes that the ring of the heterocycle has an additional heteroatoms in the ring. Designations such as "4-6-membered heterocycle"refer to the total number of atoms contained in the ring (that is, four-, five - or six-membered ring, in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms). In some embodiments, implementation of the heterocycles that have two or more heteroatoms, these two or more heteroatoms are identical or different. In some embodiments, the implementation of the heterocycles can be substituted. In some embodiments, the implementation of the accession to the heterocycle via heteroatom or via a carbon atom. Heterocytolysine groups include groups having only 4 atoms in their ring system, but heteroaryl group must have at least 5 atoms in their ring system. Heterocyclic groups include benzododecinium ring system. An example of a 4-membered heterocyclic group is azetidinol (obtained from the of seidina). Example 5-membered heterocyclic group is thiazolyl. Example 6-membered heterocyclic group is pyridyl, and example 10-membered heterocyclic group is chinoline. Examples geterotsiklicheskikh groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothieno, tetrahydropyranyl, dihydropyran, tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, dioxane, piperazinil, azetidine, oxetane, titanyl, homopiperazine, oxetanyl, tepanil, oxazepines, diazepines, thiazepines, 1,2,3,6-tetrahydropyridine, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, pyrazolines, dithienyl, dithiolane, dihydropyran, dehydration, dihydrofurane, pyrazolidine, imidazoline, imidazolidinyl, 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes, 3H-indolyl, and finalizing. Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolin, pyrrolyl, chinoline, ethenolysis, indolyl, benzimidazolyl, benzofuranyl, indolinyl, indazoles, indolizinyl, phthalazine, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinol, oxadiazolyl, thiadiazolyl, furutani, benzofurazanyl, benzothiophene, benzothiazole, benzoxa is alil, hintline, honokalani, naphthyridines and properidine. In some embodiments, the implementation of the above groups derived from the above groups and is C-attached or N-attached where such is possible. For example, in some embodiments, the implementation group derived from pyrrole, is a pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, in some embodiments, the implementation of the group derived from imidazole, represents imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). Heterocyclic groups include benzododecinium ring systems and ring systems substituted with one or two oxo (=O) groups, such as pyrrolidin-2-it. In some embodiments, implementation, depending on the structure of the heterocyclic group is a monovalent radical or the divalent radical (i.e. heterocycle group).

The heterocycles described herein, substituted by 0, 1, 2, 3 or 4 substituents, independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulphonyl, alkylcarboxylic, alkylthio, alkylthiomethyl, quinil, carboxy, cyano, formyl, halogenoalkane, halogenoalkane, halogen, hydroxyl, hydroxyalkyl, mercapto, nitro, -ΝRA RBand -(NRARB)carbonyl.

The term "heterocyclics" refers to geteroseksualnoe group, as defined here, attached to the parent molecular group through an alkoxy group.

The term "heterozygosity" refers to geteroseksualnoe group, as defined here, attached to the parent molecular group through alkylthio group.

The term "heterocyclic" refers to geteroseksualnoe group, as defined here, attached to the parent molecular group through an oxygen atom.

The term "heterozygotic" refers to geteroseksualnoe group, as defined here, attached to the parent molecular group through a sulfur atom.

The term "heteroaromatic" refers to a heteroaryl group, as defined here, attached to the parent molecular group through an alkoxy group.

The term "heteroaromatic" refers to a heteroaryl group, as defined here, attached to the parent molecular group through alkylthio group.

The term "heteroaromatic" refers to a heteroaryl group, as defined here, attached to the parent molecular group through an oxygen atom.

The term "heteroaromatic" refers to a heteroaryl group, as defined here, attached to the parent forefront of the polar group through a sulfur atom.

In some embodiments, the implementation of the term-membered ring" encompasses any cyclic structure. The term "member" refers to the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridine, Piran and thiopyran represent a 6-membered ring, and cyclopentyl, pyrrole, furan, and thiophene are 5-membered rings.

The term "non-aromatic 5, 6, 7, 8, 9, 10, 11 or 12-bicyclic heterocycles" in the context of the invention means heteroseksualci, as defined here, consists of two carbocyclic rings fused together on the same carbon atom (with the formation of the Spiro structure) or on different carbon atoms (in which two rings share one or more common links), having from 5 to 12 atoms in its full ring system, where one or more atoms forming the ring is a heteroatom. Illustrative examples of non-aromatic 5, 6, 7, 8, 9, 10, 11 or 12-bicyclic heterocyclic rings include, but are not limited to, 2-azabicyclo[2.2.1]heptenyl, 7-azabicyclo[2.2.1]heptenyl, 2-azabicyclo[3.2.0]heptanes, 3-azabicyclo[3.2.0]heptenyl, 4-azaspiro[2.4]heptanol, 5-azaspiro[2.4]heptanol, 2-oxa-5-azabicyclo[2.2.1]heptenyl, 4-azaspiro[2.5]octenyl, 5-azaspiro[2.5]octenyl, 5-azaspiro[3.4]octenyl, 6-azaspiro[3.4]octenyl, 4-oxa-7-azaspiro[2.5]octenyl, 2-azabicyclo[2.2.2]octenyl, 1,3-Diaz is bicyclo[2.2.2]octenyl, 5-azaspiro[3.5]nonanal, 6-azaspiro[3.5]nonanol, 5-oxo-8-azaspiro[3.5]nonanal, octahydrocyclopenta[c]pyrrolyl, octahydro-1H-hemolysins, 2,3,4,6,7,9a-hexahydro-1H-hemolysins, decahydrated[1,2-a]azepine, decahydro-1H-pyrido[1,2-a]azocine, 1-azabicyclo[2.2.1]heptenyl, 1-azabicyclo[3.3.1]nonanal, hinokitiol and 1-azabicyclo[4.4.0]decenyl.

The term "hydroxyalkyl" in the context of the invention means that at least one hydroxyl group, as defined here, attached to the parent molecular group through alkylenes group, as defined here. Illustrative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethylene, 3-hydroxypropyl and 4-hydroxylation.

The term "NRANRB" in the context of the invention means two groups,RAandRBthat are attached to the parent molecular group through a nitrogen atom.RAandRBdenote, each independently, hydrogen, alkyl and alkylaryl. Illustrative examplesNRARBinclude, but are not limited to, amino, methylamino, acetylamino, acetylecholine.

The term "(NRANRB)carbonyl" in the context of the invention means a groupRARBas defined here, attached to the parent molecular group through a carbonyl group, as opredelennosti. Illustrative examples of (NRARB)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.

The term "NRCNRD" in the context of the invention means two groups, RCandRDthat are attached to the parent molecular group through a nitrogen atom. RCandRDdenote, each independently, hydrogen, alkyl and alkylaryl. Illustrative examplesNRCRDinclude, but are not limited to, amino, methylamino, acetylamino, acetylecholine.

The term "(NRCNRD)carbonyl" in the context of the invention means a groupRCRDas defined here, attached to the parent molecular group through a carbonyl group, as defined here. Illustrative examples of (NRCRD)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.

In the framework of the invention, the term "mercaptan" refers to the group alkyl)S.

In the framework of the invention, the term "group" refers to a particular segment or functional group of the molecule. Chemical groups often recognize as chemical objects included in or attached to a molecule.

In the framework of the invention, the term "sulfinil" apply the K-S(=O)-R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and geterotsiklicheskie (attached through a ring carbon).

In the framework of the invention, the term "sulfonyl" refers to-S(=O)2-R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and geterotsiklicheskie (attached through a ring carbon).

In the framework of the invention, the term "O carboxy" refers to a group of the formula RC(=O)O-.

In the framework of the invention, the term "C carboxy" refers to a group of the formula-C(=O)OR.

In the framework of the invention, the term "acetyl" refers to a group of the formula-C(=O)CH3.

In the framework of the invention, the term "trihalomethanes" refers to a group of the formula X3CS(=O)2-, where X denotes a halogen.

In the framework of the invention, the term "isocyanate" refers to a group of the formula NCO.

In the framework of the invention, the term "thiocyanato" refers to a group of the formula-CNS.

In the framework of the invention, the term "isothiocyanato" refers to a group of the formula-NCS.

In the framework of the invention, the term "S sulfonamide" refers to a group of the formula-S(=O)2NR2.

In the framework of the invention, the term "N sulfonamide" refers to a group of the formula RS(=O)2NH-.

In the framework of the invention, the term "trihalomethane" refers to a group of the formula X 3CS(=O)2NR-.

In the framework of the invention, the term "O carbamyl" refers to a group of the formula-OC(=O)NR2.

In the framework of the invention, the term "N carbamyl" refers to a group of formula ROC(=O)NH-.

In the framework of the invention, the term "O thiocarbamyl" refers to a group of the formula-OC(=S)NR2.

In the framework of the invention, the term "N thiocarbamyl" refers to a group of formula ROC(=S)NH-.

In the framework of the invention, the term "C amido" refers to a group of the formula-C(=O)NR2.

In the framework of the invention, the term "N-amido" refers to a group of the formula RC(=O)NH-.

In the framework of the invention Deputy "R"standing separately and without marking the number refers to the Deputy selected from alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and non-aromatic heterocycle (attached through a ring carbon).

The term "substituted" means that the referent group may be substituted (substituted or unsubstituted) one or more additional groups, individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic group, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, aaltio, alkylsulfonate, arylsulfonate, alkylsulfonate, arylsulfonate, cyano, halogen, carbonyl, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhalogenated, perfluoroalkyl, silili amino, including mono - and disubstituted amino groups, and their protected derivatives. For example, the additional substituents areLsRswhere each Lsindependently selected from-O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(=O)2NH-, -NHS(=O)2, -OC(O)NH-, -NHC(O)O-, -(substituted or unsubstitutedC1-C6the alkyl), or -(substituted or unsubstituted C2-C6alkenyl); and eachRsindependently selected from N (substituted or unsubstituted lower alkyl), (substituted or unsubstituted lower cycloalkyl), heteroaryl or heteroalkyl.

The term "protective group" refers to the deleted group, which modifies the reactivity of a functional group such as hydroxyl, ketone or amine, against undesirable reactions during synthesis and can be later removed. Examples of protective groups for hydroxy groups include, but are not limited to, methylthiomethyl, tert-dimethylallyl, tert-butyldiphenylsilyl, ethers, such as methoxymethyl, and esters, including acetyl, benzoyl and the like, Examples of the protective groups of the ketone include, but are not limited to, ketals, oximes, O-substituted oximes, for example, O-benzyl, the oxime, O-phenylthiomethyl the oxime, 1-isopropoxycarbonyl the oxime and the like, Examples of protective groups for amines include, but are not limited to, the requirement is-butoxycarbonyl (Vos) and carbobenzoxy (Cbz).

The term "if necessary substituted" in the context of the invention means that the referent group substituted with zero, one, or more substituents, as defined here.

The term "protected hydroxy" refers to a hydroxyl group protected by a protective group for hydroxy group, as defined above.

In some embodiments, the communication according to the invention exist as stereoisomers, which contain asymmetric or chiral centers. Stereoisomers are defined as (R) or (S) depending on the configuration of substituents around the chiral carbon atom. The term (R) and (S)used here, refers to the configuration as defined in EJPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45:13-30 included in the present description by reference. Embodiments of described herein, specific include various stereoisomers and mixtures thereof. Stereoisomers include enantiomers, diastereomers and mixtures of enantiomers or diastereomers. In some embodiments, the implementation of the individual stereoisomers of the compounds obtained artificially from commercially available starting materials that contain asymmetric or chiral centers, or the racemic mixtures with further separation. These methods of separation are illustrated (1) addition of a mixture of enantiomers to Hira is gnome supporting means, separation of the resulting mixture of diastereomers by recrystallization or chromatography and the separation of the optically pure product from the auxiliary means or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic column.

The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same type of activity. In some situations, the compounds exist as tautomers. All tautomers are included within the concept of the compounds according to the invention. In some embodiments, the implementation of the compounds described herein exist in resolutional, as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein, are also disclosed here.

Throughout the description of the group and their deputies chosen in some embodiments, the implementation to ensure stable groups and connections.

Obtaining these compounds

In some embodiments, the implementation of the compounds described herein are synthesized using any of the methods of synthesis, including standard methods of synthesis and reduced the Oba synthesis, as described here. In some embodiments, the implementation uses the following synthesis methods.

The formation of covalent bonds by reaction of an electrophile with a nucleophile

Selected examples of covalent linkages and functional groups of the precursors that lead to them, are listed in the Table titled "Examples of covalent linkages and precursors. Functional group precursor is shown as an electrophilic group and a nucleophilic group. In some embodiments, the functional group on the organic substance attached directly or attached via any suitable spacer or linker, as defined below.

Table 1
Examples of covalent linkages and precursors
Product covalent bindingThe electrophileNucleophile
CarboxamideActivated estersAmines/anilines
CarboxamideArylazideAmines/anilines
CarboxamideAcylhomoserine Amines/anilines
EstersAcylhomoserineAlcohols/phenols
EstersAllnutriAlcohols/phenols
CarboxamideAllnutriAmines/anilines
EminiAldehydesAmines/anilines
The hydrazonesAldehydes or ketonesHydrazines
OximesAldehydes or ketonesHydroxylamine
The bonds alkylaminesAlkylhalogenideAmines/anilines
EstersAlkylhalogenideCarboxylic acids
The thioethersAlkylhalogenideThiols
EthersAlkylhalogenide Alcohols/phenols
The thioethersThe alkyl sulphonatesThiols
EstersThe alkyl sulphonatesCarboxylic acids
EstersThe alkyl sulphonatesAlcohols/phenols
EstersAnhydridesAlcohols/phenols
CarboxamideAnhydridesAmines/anilines
ThiophenolThe aryl halidesThiols
ArylamineThe aryl halidesAmines
The thioethersAsendinThiols
Esters Bronevoy acidBoronateGlycols
CarboxamideCarboxylic acidsAmines/anilines
Carboxylic acidsAlcohols

HydrazinesThe hydrazidesCarboxylic acids
N-allodapini or anhydridesCarbodiimideCarboxylic acids
EstersDiazoalkanesCarboxylic acids
The thioethersEpoxidesThiols
The thioethersHalogenatedThiols
AmatriainHalogenfreiAmines/anilines
Simple trainline estersHalogenfreiAlcohols/phenols
AmidineComplex imidiatelyAmines/anilines
UreaIsocyanates Amines/anilines
UrethanesIsocyanatesAlcohols/phenols
ThioureaIsothiocyanatesAmines/anilines
The thioethersMaleimideThiols
Fosfatnye estersPhosphoramiditeAlcohols
Silovye estersSilicaliteAlcohols
The bonds alkylaminesThe sulfonatesAmines/anilines
The thioethersThe sulfonatesThiols
EstersThe sulfonatesCarboxylic acids
EthersThe sulfonatesAlcohols
SulfonamidesSulphonylchlorideAmines/anilines
Sul the courses sulphonylchloridePhenols/alcohols

In General, carbon electrophiles can be attacked complementary nucleophiles, including carbon nucleophiles, and the attacking nucleophile brings an electron pair to the carbon electrophile, forming a new bond between the nucleophile and the carbon electrophile.

Suitable carbon nucleophiles include, but are not limited to, alkyl, alkenyl, aryl and quinil Grignard, organolithium, organozinc, reagents alkyl-, alkenyl-, aryl - and quinil-tin (organostannic), reagents alkyl-, alkenyl-, aryl - and quinil-boron hydride (organoborane and organoboronic); these carbon nucleophiles have the advantage that they are kinetically stable in water or polar organic solvents. Other carbon nucleophiles include pastorality, enol and enolate reagents; these carbon nucleophiles have the advantage that they are relatively easily obtained from the predecessors. Carbon nucleophiles, when they are used in combination with carbon electrophiles, generate new carbon-carbon linkages between carbon nucleophile and the carbon electrophile.

Non-carbon nucleophiles suitable for combination with carbon electrophiles include, but are not limited to, primary and secondary s is Bered, thiols, thiolate and thioethers, alcohols, alcoholate, azides, semicarbazides, etc. These non-carbon nucleophiles, when they are used in combination with carbon electrophiles, usually produce communication through the heteroatom (C-X-C), in which X denotes a heteroatom, such as oxygen or nitrogen.

The use of protective groups

The term "protective group" refers to chemical groups that block some or all reaktsionnosposobnykh group and hinder the participation of such groups in chemical reactions until the protective group is removed. In some embodiments, the implementation is used in more than one protective group. In more specific embodiments, the implementation of each of the protective group is removed in different ways. Protective groups that hatshepsuts in a totally different reaction conditions, meets the requirement of differential removal. In various embodiments, the implementation of the protective group is removed by acid, base, or by hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are labile to acid and, in some embodiments, the implementation used to protect reaktsionnosposobnykh carboxy - and hydroxy-groups in the presence of amino groups protected with Cbz groups, which are removed by hydrogenolysis, and the Fmoc groups, which are labile to base the Oia. In some embodiments, the implementation reaktsionnosposobnykh group, carboxylic acid and hydroxy groups are blocking groups labile to a base, such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate, or carbamates, which are stable to acid and base, but are removed by hydrolysis.

In some embodiments, the implementation reaktsionnosposobnykh group, carboxylic acid and hydroxy-group block hydrolytically removable protective groups such as benzyl, while in some embodiments, the implementation of an amino group, capable of forming hydrogen bonds with the acid labile blocking to the base groups such as Fmoc. In various embodiments, implementation reaktsionnosposobnykh the carboxylic acid group is protected by conversion into simple ester derivatives, as illustrated here, or they blocked removed by oxidation protective groups such as 2,4-dimethoxybenzyl, while in some embodiments, the implementation of co-existing amino groups blocked labile to fluoride silil the carbamates.

In some cases, the allyl-blocking groups can be used in the presence of protective groups for acids and bases, since the latter are a hundred is strong. In some embodiments, the implementation of such groups are then removed by catalysts based on metal or pi-acid. For example, in some embodiments, the implementation is blocked by allyl carboxylic acid is subjected to removal of the protective group using Pd°-catalyzed reaction in the presence of acid-labile tert-BUTYLCARBAMATE or labile to the base of the acetate protective group for an amine. In some embodiments, the implementation of the protective group is a resin to which is attached a connecting or intermediate connection. Until the balance is attached to the resin, the functional group is blocked and cannot react. After separation from the resin, the functional group is available to participate in reactions.

In some embodiments, the implementation of blocking/protective group selected from, as a non-limiting example:

Other protective groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999.

The compounds of Formula (I)

In some embodiments, the implementation of the compounds of Formula (I), consisting of Ia-If, receive a variety of ways, as described inThe synthesis schemes 1 and 2. In each schema variables (e.g., R1,R2, R3, R4,R5, Y and Z) corresponds to the same definition as the criminal code is mentioned above, while R stands for alkyl and Y' is the same or a different group defined by Y, and Z' is the same or a different group defined Z. In some embodiments, the communication synthesized using methodology similar to that described below, by means of suitable alternative raw materials.

In some embodiments, the implementation of the compounds of Formula Ia and Ib)in which Y is identical to Z, synthesized according toThe scheme of synthesis 1. Thus, the intermediate connection3whereR5denotes hydrogen, carry out the condensation of 4-aminoazobenzene-1(3H)-it1with aldehyde2in the presence of a base, preferably of an alcoholate of an alkali metal, in suitable solvents such as ethyl acetate or ethylpropane, at ambient temperature or at elevated temperature. The compounds of Formula Ia, in which R5denotes hydrogen, receiving, processing intermediate connection3the hydrazine hydrate at ambient temperature or at elevated temperature. The compounds of Formula Ia, in whichR5denotes alkyl or substituted alkyl, are obtained from the compounds of Formula Ia, in whichR5denotes hydrogen, by the reaction of reductive amination with R7-CHO, whereR7means Alki is, substituted alkyl. In some embodiments, the implementation of obtaining compounds of the Formula Ib take further modification of the Ia. Through the transformation of suitable functional groups on the group and YZ obtain the compounds of Formula Ib with different Y' and Z' 2 - or 3 - positions.

The scheme of synthesis 1

In some embodiments, the implementation of the compounds of Formula (Ic and Id) are synthesized according toThe scheme of synthesis of 2. For example, the intermediate connection5get condensation reagent1with aldehyde4in the presence of water absorbent substance, such as sodium sulfate or magnesium sulfate at elevated temperature. Subsequent reaction of the condensation of this intermediate with another aldehyde in the presence of a base, preferably of an alcoholate of an alkali metal, in suitable solvents such as ethyl acetate or ethylpropane, at ambient temperature or at elevated temperature, provides an intermediate connection6whereR5denotes hydrogen. The compounds of Formula Ic, in whichR5denotes hydrogen, receiving, processing intermediate connection6the hydrazine hydrate at ambient temperature or at elevated temperature. The compounds of Formula Ic, in whichR5denotes alkyl,substituted alkyl, obtained from compounds of the Formula Ic, in whichR5denotes hydrogen, by the reaction of reductive amination withR7-CHO, whereR7denotes alkyl or substituted alkyl. In some embodiments, the implementation of obtaining compounds of Formula Id take further modification of the Ic. Through appropriate transformations of functional groups on the group Y, and Z get the compounds of Formula Ic with different Y' and Z' are at positions 2 or 3.

Scheme of synthesis of 2

Some pharmaceutical terms

The term "acceptable" on the composition, composition or ingredient, in the framework of the invention, means having no permanent harmful effect on General health being treated patient.

In the framework of the invention, the term "selective binding compound" refers to a compound that selectively binds to any portion of the one or more target proteins.

In the framework of the invention, the term "selectively binds" refers to the ability of the selective binding of the compound to contact with the protein target, such as, for example, PARP, with greater affinity than it binds to non-target protein. In some embodiments, the implementation of specific binding refers to binding to a target with an affinity that is at least AP is sustained fashion in 10, about 50, about 100, about 250, about 500, about 1000 or more times greater than the affinity for namesti.

In the framework of the invention, the term "protein-target" refers to a molecule or part of a protein that can be associated selective binding connection. In some embodiments, the implementation of the protein target is an enzyme poly(ADP-ribose)polymerase (PARP).

In the framework of the invention, the term "treatment" includes therapeutic and/or preventive measures, for example, inhibition, delay or delay of onset of a symptom of disease or impairment, a full or partial reduction of the symptom or the disease condition and/or relief, improve, reduce, or cure of diseases or disorders and/or symptoms.

In the framework of the invention, the relief of symptoms of specific disorders introduction of a specific compound or pharmaceutical composition refers to any decrease in the severity, delay the onset, slow progression, or shorten the duration, permanent or temporary, lasting or transient that can be attributed to or associated with the introduction of the compound or composition.

In the framework of the invention, the term "modulator" refers to a compound that alters the activity of the molecule. For example, the modulator includes the t connection, which causes an increase or decrease in specific activity of the molecule compared to the magnitude of the activity in the absence of the modulator. In some embodiments, the implementation of the modulator is an inhibitor, which reduces the value of one or more activities of the molecule. In some embodiments, the implementation of the inhibitor completely prevents one or more of the activities of the molecule. In some embodiments, the implementation of the modulator is an activator, which increases the magnitude of the at least one activity of the molecule. In some embodiments, the realization of the presence of the modulator leads to activity which does not occur in the absence of the modulator.

In the framework of the invention, the term "selective modulator" refers to a compound that selectively modulates the target activity.

In the framework of the invention, the term "PARP" belongs to the family of the enzyme poly(ADP-ribose)polymerase, which includes approximately 18 proteins, particularly poly(ADP-ribose)polymerase-1 (PARP-1) and poly(ADP-ribose)polymerase-2 (PARP-2).

In the framework of the invention, the term "selective PARP modulator" refers to a compound that selectively modulates at least one activity associated with the enzyme poly(ADP-ribose)polymerase (PARP). In various embodiments, the implementation of selective modulator selectively meters delerue activity of PARP-1, PARP-2 and PARP-1 and PARP-2 or more members of the family of the enzyme poly(ADP-ribose)polymerase (PARP).

In the framework of the invention, the term "a method of inhibiting PARP" refers to a method of inhibiting the activity of one or more members of the family of the enzyme poly(ADP-ribose)polymerase (PARP). In the framework of the invention, the term "PARP inhibition refers to inhibition of the activity of one or more members of the family of the enzyme poly(ADP-ribose)polymerase (PARP).

In the framework of the invention, the term "correction activity of the enzyme poly(ADP-ribose)polymerase" refers to correction of the activity of one or more members of the family of the enzyme poly(ADP-ribose)polymerase (PARP).

In the framework of the invention, the term "selectively modulates" refers to the ability of the selective modulator to modulate the target activity to a greater extent than it modulates the inappropriate activity. In some embodiments, the implementation of target activity selectively modulated, for example, from about 2 times to about 500 times more, in some embodiments, the implementation of approximately 2, 5, 10, 50, 100, 150, 200, 250, 300, 350, 400, 450 or more than 500 times.

In the framework of the invention, the term "target activity" refers to biological activity that can be modulated by selective modulator. Some examples of target activities include, but are not limited to the trading of them, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or associated with inflammation processes and alleviating one or more symptoms associated with the disease or condition.

In the framework of the invention, the term "agonist" refers to a compound whose presence leads to the biological activity of the protein, which is the same as the biological activity, the following from the presence of the natural ligand for the protein, such as, for example, PARP.

In the framework of the invention, the term "partial agonist" refers to a compound whose presence leads to the biological activity of the protein, which has the same type as the following from the presence of the natural ligand for the protein, but lower values.

In the framework of the invention, the term "antagonist" or "inhibitor" refers to the connection, the presence of which leads to a decrease of the biological activity of the protein. In some embodiments, the realization of the presence of the antagonist leads to complete inhibition of the biological activity of the protein, such as, for example, the enzyme poly(ADP-ribose)polymerase (PARP).

In the framework of the inventionIC50refers to the amount, concentration or dosage of a particular test compound that achieves a 50%inhibition of the maximum response,such as modulation of PARP, in the test, which measure such a reaction.

In the framework of the invention, EC50refers to a dosage, concentration or amount of a particular test compound that causes a dose-dependent response on 50% of the maximum intensity of the specific response induced, provoked or potenziruemoe specific test connection.

The term "cancer" in the context of the invention refers to abnormal growth of cells which tend to uncontrolled cell proliferation and, in some cases, to metastasize. The types of cancer include, but are not limited to, solid tumors such as tumors of the bladder, bowel, brain, breast, membrane of the uterus, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid gland), prostate, skin (melanoma) or hematological tumors (such as leukemia).

The term "carrier" in the context of the invention refers to a relatively non-toxic chemical compounds or tools that facilitate the incorporation of compounds into cells or tissues.

The terms "co-administration" or the like within the framework of the invention encompass the introduction of the selected therapeutic agents to the individual patient and include treatment regimens in which the means to impose the same or different is the way of administration or at the same or at different times.

The term "diluent" refers to chemical compounds that are used for dilution target compounds prior to delivery. Diluents include chemical compounds used to stabilize the connection, because they provide a more stable environment. Salt dissolved in the buffer solutions (which can also provide control or maintain pH), are used as diluents in some embodiments of implementation, including, but not limited to, phosphate buffered saline solution.

The terms "effective amount" or "therapeutically effective amount" in the context of the invention relate to a sufficient number of input means or connections, which to some extent eliminates one or more symptoms being treated disease or condition. The result includes the reduction and/or alleviation of the signs, symptoms or causes of disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of composition comprising a compound as disclosed here, is necessary in order to provide a clinically significant reduction in painful symptoms. An appropriate "effective" amount in any individual case, determine the use of the UYa any suitable method, such as the study of the rise of the doses.

The terms "enhance" or "enhancing" in the context of the invention means to increase or prolong the strength or duration of the desired effect. Thus, in relation to enhance the effect of therapeutic agents, the term "amplification" refers to the ability to increase or prolong, either the strength or duration of the effect of other therapeutic agents in the system. "Effective enhancement amount" in the context of the invention refers to the amount that is appropriate to enhance the effect of another therapeutic agent in a desirable system.

The term "enzymatically degradable linker" in the framework of the invention relates to unstable or erodible relations, which are one or more enzymes.

The term "inflammatory disorders" refers to diseases or conditions that are characterized by one or more symptoms of pain (dolor, from the generation of harmful substances and excitation of the nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid) and loss of function (functio laesa, which may be partial or complete, temporary or permanent). Inflammation takes many forms and includes, but is not limited to, inflammation, which is the way the second one or more of the following: acute, sticky, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrous, Central, granulomatous, hyperplastic, hypertrophic interstitial, metastatic, necrotic, obliterating, parenchymatous, plastic, productive, proliferating, pseudomembranous, acute, sclerosing, sero-fibrinous, serous, simple, specific, subacute, chronic, toxic, traumatic, and/or ulcers. Inflammatory disorders further include, without being limited by them, those that affect the blood vessels (polyarteritis, temporal arteritis diagnostics); the joint (arthritis: crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter); gastrointestinal tract (Crohn's disease, ulcerative colitis); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus).

The term "PARP-mediated" in the context of the invention refers to conditions or disorders that are facilitated by one or more members of the family of the enzyme poly(ADP-ribose)polymerase (PARP).

The terms "set" and "industrial product" are used as synonyms.

"Metabolite" of the compounds disclosed here, is a derivative of this compound, which is formed in the metabolism of compounds. The term "Akti is hydrated metabolite" refers to a biologically active derivative compounds which is formed in the metabolism of compounds. The term "product" in the context of the invention refers to the amount of processes (including, but not limited to, hydrolytic reactions and reactions catalyzed by enzymes), in which a particular substance is changed by the body. Thus, in some cases, enzymes produce certain structural changes in the connection. In some embodiments, the implementation of the metabolites of the compounds disclosed here are identified either by the introduction of compounds to the owner and analysis of tissue samples of the host, or by incubation of compounds with hepatic cells in vitro and analysis of the obtained compounds.

The term "modulates" in the context of the invention means interacts with the target, directly or indirectly, with the change in the activity of the target, including, as example, the increased activity of the target, the inhibition of the activity of the target, limit the activity of the target or the extension activity of the target.

"Pharmaceutically acceptable" or "therapeutically acceptable" in the context of the invention refers to a material, such as a carrier or diluent that does not abrogate the biological activity or properties of the compound, and is relatively non-toxic. In some cases, non-toxic and does not impede the activity and properties of materials include materials that is when they are administered to man, do not cause significant undesirable biological effects and/or does not interact harmful way with any of the components of the composition in which they are contained.

The term "pharmaceutically acceptable salt" or "therapeutically acceptable salt" refers to a composition of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some cases, pharmaceutically acceptable salts receive by entering the compound described herein, reaction with acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, etc. In some cases, pharmaceutically acceptable salts receive by entering the compound having an acid group described here, in the reaction with base to obtain salt, such as ammonium salt, a salt of an alkali metal such as sodium salt or potassium salt, alkaline earth metal, such as a salt of calcium or magnesium salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, Tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine and the like, or other methods defined previously.

The term "pharmacist the ical combination" in the context of the invention means a product, the resulting mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound described herein, and the co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound described herein, and the co-agent is administered to a patient as separate objects at the same time, competitive or sequentially with no specific time intervals, and this introduction provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, for example, the introduction of three or more active ingredients.

The term "pharmaceutical composition" refers to a mixture of the compounds described herein, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspendresume agents, thickeners and/or excipients. The pharmaceutical composition facilitates the introduction of the compound into the body. In the art there are many methods of introducing compounds, including, but not limited to: intravenous, oral,aerosol, parenteral, ocular, pulmonary and topical administration.

"Prodrug" refers to a vehicle that is converted to the original drug in vivo. Prodrugs are often useful because, in some situations, it is easier to enter than the original drug. In some cases, the prodrug is bioavailable by oral administration whereas the parent compound does not possess this property. In some cases, the prodrug has improved solubility in pharmaceutical compositions compared to the original drug. An example, without limitation, of a prodrug is a compound described herein that is administered as an ester (the"prodrug")to facilitate passage through the cell membrane where water solubility does harm to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active object that has penetrated into the cell where water-solubility is beneficial. A further example of a prodrug may be a short peptide (polyaminoamide)associated with the acid group or amino group, where the peptide is metabolized to reveal the active group. In some embodiments, the implementation with the introduction of in vivo prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active form of soy is inane. In some embodiments, the implementation of the enzyme prodrug is metabolized in one or more stages or processes to the biologically, pharmaceutically or therapeutically active form of the compound. To obtain prodrugs pharmaceutically active compound modified so that the active connection is established when introduced in vivo. In some embodiments, the implementation of the prodrug designed in such a way to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of the medicinal product or to alter other characteristics or properties of the drug.

The term "person" or "patient" includes mammals, and memleketim. Examples of mammals include, but are not limited to, any member of the class of mammals: human, non-human primates, such as chimpanzees and other apes and nonhuman apes; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and Guinea pigs, etc. are Examples of memleketim include, but are not limited to, birds, fish, etc. In one embodiment, the methods and HDMI the Nations according to the invention the mammal is a human.

The terms "treat" or "treatment" in the context of the invention include alleviating, reducing, or alleviating the symptoms of the disease or condition, preventing additional symptoms, relief or prevention of major metabolic causes of symptoms, inhibiting the disease or condition, for example, stopping the development of the disease or condition, relieving the disease or condition, the regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, prophylactically and/or therapeutically.

The pharmaceutical composition/composition

In some embodiments, the implementation of the pharmaceutical compositions comprise any way, including using one or more physiologically acceptable carriers comprising excipients and/or auxiliary AIDS that facilitate the preparation of the active compounds in pharmaceuticals. In some embodiments, the implementation of suitable composition depends on the selected route of administration. In various embodiments, the implementation uses any suitable technique, carriers and excipients.

The invention relates to pharmaceutical compositions that include a compound described herein and a pharmaceutically acceptable diluent(s), excipient(s) and/or Eitel(and). In addition, in some embodiments, the implementation of the compounds described herein are administered as pharmaceutical compositions in which compounds described herein are mixed with other active ingredients, as in combination therapy.

The pharmaceutical composition within the invention relates to mixtures of the compounds described herein, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspendresume agents, thickeners and/or excipients. In some embodiments, the implementation of the pharmaceutical composition facilitates the introduction of the compound into the body. In some embodiments, the implementation in practice of the methods of treatment or use according to the invention includes the introduction or use of pharmaceutical compositions comprising a therapeutically effective amount of the compounds according to the invention. In some embodiments, the implementation of the methods of treatment according to the invention includes the introduction of such a pharmaceutical composition to a mammal having a disease or condition to be treated. In one embodiment, the mammal is a human. In some embodiments, the implementation of a therapeutically effective amount varies widely depending on the severity of the disease, the age and relative health p is of they, potential connections in use and other factors. In various embodiments, the communication described here, are used individually or in combination with one or more therapeutic tools as components of mixtures.

In some embodiments, the implementation of the pharmaceutical compositions according to the invention are for intravenous injection. In some aspects, compositions for intravenous injection according to the invention are aqueous solutions, and, in some embodiments, the implementation in a physiologically compatible buffer solution such as a solution of Hank, ringer's solution, or physiological saline buffer. In some embodiments, the implementation of the pharmaceutical compositions according to the invention are for insertion through the mucous. In some aspects, the compositions for administration through mucosa include wetting agents, suitable for barrier through which to penetrate. In some embodiments, the implementation of the pharmaceutical compositions according to the invention are for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, and in one embodiment, the physiologically compatible buffers or excipients.

In some embodiments, the implementation of the pharmaceutical compositions according to the invention are for oral introduction the deposits. In some aspects of the form according to the invention for oral administration include compounds described here are prepared with pharmaceutically acceptable carriers or excipients. Such carriers enable the preparation of the compounds described herein in the form of tablets, powders, pills, tablets, capsules, liquids, gels, syrups, elixirs, casic, suspensions and the like, for oral ingestion by a patient receiving the treatment.

In some embodiments, the implementation of pharmaceutical preparations for oral use get, mixing one or more solid excipient with one or more compounds described herein, if necessary, grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain the core of pills or tablets. Suitable excipients include, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; preparations of cellulose, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragakant, methylcellulose, microcrystalline cellulose, hypromellose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If it is desirable, if necessary add the keys disintegrator, such as the transverse cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.

In some embodiments implementing the invention relates to pharmaceutical compositions prepared in the form of a dragee cores with suitable coatings. In some embodiments, the implementation for molding a suitable coatings are used concentrated solutions of sugars, and if necessary they contain gum Arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, solutions varnishes and suitable organic solvents or solvent mixtures. In some embodiments, the implementation of dyes and/or pigments added to the tablets, pills and/or coating, for example, identify or okharakterizovanie different combinations of active doses connection.

In some embodiments, the implementation of the pharmaceutical drugs used orally include capsules of the two put each other halves, made of gelatin, and also soft sealed capsules made of gelatine and a softener, such as glycerol or sorbitol. In some embodiments, the implementation of the capsules of the two put each other halves contain active ingredients mixed with a filler, such galactose, binders, such as starches, and/or lubricants such as talc or magnesium stearate and, if necessary, stabilizers. In some embodiments, the implementation in soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as non-volatile liquid oil, liquid paraffin, or liquid polyethylene glycols. In addition, if necessary, may be added as stabilizers. In some embodiments, the implementation of the compositions for oral administration are in dosages suitable for such administration.

In some embodiments, the implementation of the pharmaceutical compositions according to the invention are for buccal or sublingual administration. In some embodiments, the implementation of the buccal or sublingual compositions take the form of tablets, dispersible tablets, or gels, prepared in the usual way. In some embodiments, the implementation of parenteral injections include bolus injection or continuous infusion. In some embodiments, the implementation of the compositions for injection are presented in a standard dosage form, e.g., in ampoules or in multi-dose containers with an added preservative. In some embodiments, the implementation of the pharmaceutical composition described herein is in a form suitable for parenteral injection, such as sterile is Uspenskii, solutions or emulsions in oily or aqueous carriers, and, if necessary, provides tools for preparation, such as suspendida, stabilizing and/or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In some embodiments, the implementation of the suspensions of the active compounds receive as appropriate oily suspension for injection. Suitable lipophilic solvents or carriers include non-volatile liquid oil such as sesame oil, or synthetic esters of fatty acids, such as etiloleat or triglycerides, or liposomes. In some embodiments, the implementation of the water suspension injections contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. If necessary, the suspension can also contain suitable stabilizers or tools that increase the solubility of the compounds to provide a very concentrated solutions. In alternative embodiments, the active ingredient is in powder form for recovery with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

In some embodiments, the communication, described is here enter tapicerki. In some embodiments, the communication described here are in the form of various tapicerki entered compositions, such as solutions, suspensions, lotions, gels, pastes, containing the medicinal substance sticks, balms, creams or ointments. Such pharmaceutical compounds, if necessary, contain a fluidizing agents, stabilizers, means amplifying toychest, buffers and/or preservatives.

In some embodiments, the implementation of the pharmaceutical compositions according to the invention are for percutaneous introduction of the compounds described herein. In some embodiments, the implementation of the introduction of such compositions involves the use of devices for the percutaneous delivery and transdermal patches for the delivery. In some embodiments, the implementation arrangements are lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in the polymer or adhesive. These patches include designed for continuous, pulsating, or on demand delivery of pharmaceutical products. In some embodiments, the implementation of the percutaneous delivery of the compounds described herein, using iontophoretic patches, etc. In some embodiments, the implementation of transdermal patches provide controlled delivery is connected to the second invention, such as, for example, the compounds of Formula (I), (IA) or (II). In some embodiments, the implementation of the absorption rate slows down when using speed control membranes or capturing compound in a polymer matrix or gel. On the contrary, amplifiers absorption, if necessary, are used to enhance absorption. Power absorption and carrier include absorbable pharmaceutically acceptable solvents that help the passage of compounds through the skin. For example, transdermal devices are in the form of a bandage comprising a support element, a reservoir containing the compound, if necessary with the media, if necessary, controlling the speed barrier to deliver the compound to the skin of the host with a controlled and predetermined rate over a long period of time, and means for fixing the device on the skin.

In some embodiments, the implementation of the pharmaceutical compositions according to the invention are for administration by inhalation. In some embodiments, the implementation of such pharmaceutical compositions for inhalation, the compounds described herein are in the form of an aerosol or powder. In some embodiments, the implementation of the pharmaceutical compositions described herein, are delivered in the form of an aerosol dispenser of the Germa the ranks of the blocks or nebulizer, with the use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In some aspects of the pressurized aerosol, the unit dosage is determined using a valve to release a measured quantity. In some embodiments, the implementation consists of capsules and cartridges of, such as, only as an example, gelatin for use in an inhaler or insufflator containing a powder mix of the compound described herein and a suitable base powder, such as lactose or starch.

In some embodiments, the implementation of the compounds described herein are prepared in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel suppositories or held enema. In some embodiments, the implementation of rectal compositions, if necessary, contain a regular basis suppositories, such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In some form of suppository these compositions are first melted low-melting wax, such as, but not limited to it, a mixture of glycerides of fatty acids, if necessary in combination with cocoa butter.

In various embodiments, assests is of the pharmaceutical compositions comprise the usual way, using one or more physiologically acceptable carriers including excipients and auxiliary tools, which facilitate processing of the active compounds in pharmaceutically acceptable preparations. In some embodiments, the implementation of suitable composition depends on the selected route of administration. In various embodiments, the implementation uses any suitable technique, carriers and excipients. In some embodiments, the implementation of a pharmaceutical composition comprising a compound described herein, to receive the usual way, for example, by means of conventional mixing, dissolving, granulating, drazhirovanija, otmuchivanie, emulsifying, encapsulating, gripping or pressing.

In some embodiments, the implementation of the pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and connection described herein as an active ingredient, in the form of free acid or free base form or in the form of pharmaceutically acceptable salts. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. In some situations, the connection is written here, exist as tautomers. All tautomers are included within the concept of the compounds represented here. Additionally, in the scope of the invention included solvated and not solvated forms of the compounds described herein. Solvated compounds include those which are solvated with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein, are also disclosed here. In some embodiments, the implementation of the pharmaceutical compositions described herein include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution promoters, salts for regulating osmotic pressure and/or buffers. In additional embodiments, the implementation of the pharmaceutical compositions described herein can also contain other therapeutically valuable substances.

Methods for producing compositions containing the compounds described herein include the preparation of compounds with one or more inert pharmaceutically acceptable excipients or carriers, receiving solid, semi-solid or liquid forms. Solid compositions include, but are not limited to, powders, tablets, dispersive granules, capsules, pills and suppositories. Riccicomoto include solutions in which the compound is dissolved, the emulsion comprising a compound or a solution containing liposomes, micelles, or nanoparticles containing compounds, as disclosed here. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. In various embodiments, the implementation of the compositions are in liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to use, or in the form of emulsions. These compositions, if necessary, contain minor amounts of nontoxic auxiliary substances such as wetting agents or emulsifiers, bothersome tools, etc.

In some embodiments, the implementation of a composition comprising a compound described herein, takes the form of a liquid, where the means are present in solution, in the suspended state, or in both States. In some embodiments, implementation, when the composition is administered in the form of a solution or suspension, the first component is present in the solution, and the second part means is in the form of particles in a suspended condition in the liquid matrix. In some embodiments, the implementation of the liquid composition comprises a gel. In other embodiments, implementation of the liquid composition is water.

Suitable aqueous suspension, if necessary, provides the one or more polymers as suspendida agents. Suitable polymers include water-soluble polymers such as cellulose polymers, for example, hypromellose and water-insoluble polymers, such as cross stitched containing carboxyl group of the polymer. Suitable compositions, if necessary, include mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (polymer of acrylic acid), poly(methylmethacrylate), polyacrylamide, polycarbophil, copolymer of acrylic acid/butyl acrylate, sodium alginate and dextran.

Suitable compositions, if necessary, include solubilizing means to facilitate the solubility of the compounds described herein. The term "solubilizer tool usually includes tools that lead to the formation of a micellar solution or a true solution. Solubilizing tools include some acceptable nonionic surfactants, such as Polysorbate 80, and ophthalmologist acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

Suitable compositions, if necessary, include one or more regulating pH of funds or bothersome funds, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as hydroxide n is sodium, the sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and Tris-hydroxyethylaminomethyl; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in the quantity necessary to maintain the pH of the composition within a reasonable range.

Suitable compositions, if necessary, include one or more salts in an amount necessary to maintain the osmolality of the composition into an acceptable range. Such salts include salts, which are cations of sodium, potassium or ammonium and the anion chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

Some suitable compositions, if necessary, include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances, such as merfen and thiomersal; stable chlorine dioxide; and Quaternary ammonium bases, such as benzalconi chloride, cetyltrimethylammonium bromide, pyridinium chloride.

Some suitable compositions, if necessary, include one or more surfactants to increase the physical stability or other C the order. Suitable nonionic surfactants include glycerides of fatty acids and polyoxyethylene vegetable oils, for example, polyoxyethylenated (60) gidrirovannoe castor oil; and polyoxyethylenated alkalemia esters and alkylphenolate esters, for example, octoxynol 10, octoxynol 40.

Some suitable compositions, if necessary, contain one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, only as an example, ascorbic acid and sodium metabisulfite.

In some embodiments, the implementation of the composition in the form of aqueous suspensions packaged in single dose in beyond re-sealing capacity. In an alternative implementation options are amenable to re-sealing capacity c multiple doses, usually when the composition includes a preservative.

In a different implementation is used by any delivery system for hydrophobic pharmaceutical compounds. Liposomes and emulsions are examples of the basics for shipping or carriers for hydrophobic drugs. In some embodiments, the implementation uses some organic solvents, such as N-organic. In some embodiments, the communication taking out Aut, using system slow release, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agent. Various slow release materials are used in embodiments of the invention. In some embodiments, the implementation capsule delayed release release the connection within a few weeks up to over 100 days. In some embodiments, implementation, depending on the chemical nature and the biological stability of therapeutic reagent used additional strategies for protein stabilization.

In some embodiments, the implementation of the compounds or compositions can, if necessary, to include antioxidants, metal agents for the formation of chelate compounds, tiradera connections, and other conventional stabilizers. Examples of such stabilizers include, but are not limited to: (a) from about 0.5% to about 2% wt./about. glycerol, (b) from about 0.1% to about 1% wt./about. methionine, (c) from about 0.1% to about 2% wt./about. monodiglyceride, (d) from approximately 1 mm to approximately 10 mm EDTA, (e) from about 0.01% to about 2% wt./about. ascorbic acid, (f) from 0.003% to about 0.02% wt./about. Polysorbate 80, (g) from about 0.001% to about 0.05% weight./about. is riservata 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) polysulphate of pentosan and other heparinoid, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

Methods of administration and modes of treatment

In some embodiments, the communication described here are used in the receipt or production of pharmaceuticals for the treatment of diseases or conditions that are mediated by the enzyme poly(ADP-ribose)polymerase (PARP) or in which inhibition of the enzyme poly(ADP-ribose)polymerase (PARP) leads to alleviation of the disease or condition. In some embodiments implement a method of treating any of the diseases or conditions described herein in a patient includes an introduction to the specified patient pharmaceutical compositions containing at least one compound described herein, or its pharmaceutically acceptable salt, pharmaceutically acceptable Ν-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable MES, in therapeutically effective amounts.

In some embodiments, the implementation of the composition containing the compound(I)described herein are administered for prophylactic and/or therapeutic treatment. In some therapeutic applications, compositions are administered to a patient already is tragoudia the disease or condition, in a quantity sufficient to cure or at least partially stop the development of symptoms of the disease or condition. In some embodiments, the implementation of amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's condition, body weight and response to drugs, and the judgment of the prescribing treatment. In some cases, a medical professional can determine such therapeutically effective amounts of conventional experimentation (including, but not limited to, clinical trial lifting dose).

In some prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of specific diseases, disorders or conditions. In some embodiments, implementation of the entered number is defined as a "prophylactically effective amount or dose." In some embodiments, the application of the exact number of input connections depend on the health of the patient, body weight, etc. In some embodiments, the medical worker can define such prophylactically effective amount of an ordinary experimentation (for example, clinical testing of lifting dose). In some the options for implementation with the introduction of the patient effective amounts for this application will depend on the severity and course of the disease, breach or condition, previous therapy, the patient's condition and reaction to drugs, and the judgment of the prescribing treatment.

In some cases, the patient's condition does not improve or does not significantly improved due to the introduction of the compounds or compositions described herein, and, at the discretion of the physician, the introduction of compounds can be used chronically, that is, for an extended period of time, including the period up to the lifetime of the patient, to facilitate or otherwise control or limit the symptoms of the disease or condition in a patient.

In some cases, when the patient's condition improves or basically not improved, according to the discretion of the physician, the introduction of compounds can be carried out continuously; alternatively, the dose of injected drugs may be temporarily reduced or temporarily suspended for a certain length of time (i.e., "rest period from the introduction of medicines"). In some embodiments, the implementation of the rest period from the introduction of the drug varies from 2 days to 1 year, including, as example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 30 days or 365 days. Reduce dose during the rest period from the introduction of drugs includes the reduction of from about 10% to about 100%, including, as example, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or approximately 100%.

In some embodiments, the implementation, as soon as see the improvement of the condition of the patient, if necessary, give the maintenance dose. In some embodiments, the implementation of the dosage, for example, maintenance dose, or frequency of administration, or both, decrease, depending on the symptoms, to a level at which you are saving the improvement of the diseases, disorders or conditions. In some embodiments, implementation, however, the patients, if necessary, give intermittent treatment on a long-term basis upon any recurrence of symptoms.

In some embodiments, the implementation of a number of given means, which corresponds to an effective amount varies depending on such factors as the particular compound, disease or condition and it is resnosti, identity (e.g., body weight) of the patient or host. In some embodiments, the effective amount is, however, determined from private circumstances surrounding the case, including, for example, a particular tool that is administered, route of administration, the condition being treated, and treatment of the patient or host. In some embodiments, implementation, however, the doses used for the treatment of an adult person, are in the range of from about 0.02 to about 5000 mg per day, in the particular embodiment, from about 1 to about 1500 mg per day. In various embodiments, the implementation of the desired dose may be presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more podos in the day.

In some embodiments, the implementation of the pharmaceutical compositions described herein are standard dosage form, suitable for only the introduction of precise dosages. In some cases, a standard dosage form, the composition is divided into uniform doses containing appropriate quantities of one or more compounds. In some embodiments, the implementation of the dosage form is in the Orme packaging, containing individual quantities of the composition. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. In some embodiments, the implementation of the composition in the form of aqueous suspensions packaged in single dose in beyond re-sealing capacity. In an alternative implementation options are amenable to re-sealing the container containing multiple doses, usually when the composition includes a preservative. Just as an example, formulations for parenteral injection in some embodiments, the implementation presented in a standard dosage form, which include, but are not limited to, vials or containers with multiple doses, with added preservative.

In some embodiments, the implementation of the daily dosages appropriate for the compounds described herein are from about 0.01 to about 2.5 mg/kg of body weight. In some embodiments, the implementation of the indicated daily dosage in the larger patient, including, but not limited to, humans, is in the range from about 0.5 mg to about 100 mg, and preferably administered in divided doses, including, but not limited to, up to four times per day, or in the form of sustained release. In some embodiments, the implementation of the right standard dosage forms for oral administration comprise from about 1 to about 50 mg of the active ingredient. The above ranges are only recommended, because the number of variables in regard to an individual treatment regime is large, and significant deviations from these recommended values are quite common. In some embodiments, the implementation of the dosage might be modified depending on many variables, not limited to the activity of the used compound, disease or condition being treated, the route of administration, the requirements of the individual patient, the severity of the disease or condition being treated, and the judgment practice.

In some embodiments, the implementation of the toxicity and therapeutic efficacy of such therapeutic regimens determined in accordance with standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the definition of aLD50(the dose lethal to 50% of the population) andED50(the dose therapeutically effective in 50% of the population). The ratio of the dose between toxic and therapeutic effects is therapeutic index and it can be expressed as the ratio betweenLD50andED50. In some embodiments, the communication indicating a high therapeutic indices are preferred. In some the options for implementation of the data obtained from tests on cell culture and animal studies, are used to construct the dose range for use in humans. In some embodiments, the implementation of the dosage of such compounds lies within a range of circulating concentrations that includeED50with minimal toxicity. In some embodiments, the implementation of the dosage varies within this range depending on the dosage form and the route of administration.

Combined treatment

In some cases, at least one compound described herein are preferably administered in combination with another therapeutic agent. Just as an example, if one of the side effects experienced by a patient upon receiving one of the compounds described here, is inflammation, then, in some embodiments, the implementation in combination with the initial therapeutic agent is preferably introduced anti-inflammatory agent. In some embodiments, the implementation of therapeutic effectiveness of one of the compounds described herein can be enhanced by the introduction of adjuvant (ie, in some embodiments, the implementation separately adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therape the political benefit for the patient uvelichivatsa). In some embodiments, the implementation of the benefit for the patient is increased by introducing one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. In some embodiments, implementation, regardless subjected to the treatment of diseases, disorders or conditions, the total benefit received by the patient in the combined treatment is additive or synergistic.

In some embodiments, the implementation of therapeutically effective dose range, when drugs are used in combinations. In some embodiments, the implementation of therapeutically effective doses of drugs and other tools for use in the combined treatment regimens define any suitable way, for example, using metronomical introduction, that is, by introducing more frequent, but lower doses to minimize toxic side effects. In some embodiments, the implementation of a combined treatment regimen described herein, encompasses treatment regimens in which the introduction of a PARP inhibitor described herein, begin before, during or after treatment with a second agent described above, and continues until any time during treatment with a second agent or after the second treatment environments is the your. It also includes treatments in which a PARP inhibitor described herein, and the second tool used in combination, administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combined treatment further includes periodic treatment, which start and stop at different times to facilitate clinical monitoring of the patient. For example, in some embodiments, the implementation of the PARP inhibitor described herein, the combined treatment is administered once a week at the beginning of treatment, reducing then the frequency of introduction to once in two weeks, and reducing the frequency of the next as needed.

In some embodiments implementing the invention relates to compositions and methods for combination therapy. In accordance with one aspect, the pharmaceutical compositions disclosed here is used in the treatment PARP-mediated disease or condition or a disease or condition which is alleviated by the inhibition of PARP. In accordance with the private aspects, the pharmaceutical compositions disclosed here is used to treat vascular disease; septic shock; ischaemic injury; reperfusion injury; neurotoxicity; hemorrhagic shock; inflammatory diseases; multiple sclerosis; secondary is x effects of diabetes; and acute treatment of cytotoxicity after cardiovascular surgery. In the private aspect, the pharmaceutical compositions disclosed here is used in combination, simultaneously or sequentially with ionizing radiation or one or more chemotherapeutic agents.

In some embodiments, the implementation of the combination therapy described herein are used as part of a specific treatment regimen to ensure a favorable impact from the joint action of PARP inhibitor described herein, and concurrent treatment. It should be understood that the mode of administration for the treatment, prevention or relief of the condition(s)for which you want relief, may be modified in accordance with various factors.

In some combination therapies described herein, dosages of the compounds, added together, will vary depending on the type of joint used drugs, specific drugs, subjected to treatment of the disease or condition, etc. In some embodiments, the implement when used in conjunction with one or more biologically active means, disclosed here, the compound is administered either simultaneously with the biologically active agent(s), or sequentially. In some aspects, in which the means of introducing p is therefore the attending physician will decide on the appropriate sequence of introduction of the protein in combination with a biologically active agent(s).

In various embodiments, the implementation of multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. In some cases, the introduction is simultaneous, and many therapeutic agents, if necessary, is introduced into a single unified form, or in multiple forms (just as an example, either as a single pill or as two separate pills). In some embodiments, the implementation of one of therapeutic agents given in multiple doses, or both given as multiple doses. In some cases, the introduction is not simultaneous, the timing between the multiple doses varies as a non-limiting example, from more than zero weeks to less than four weeks. In addition, combination methods, compositions and formulations should not be limited to using only two tools; the use of multiple therapeutic combinations also are assumed according to the invention.

In other embodiments, the communication described herein are used in combination with procedures that provide additional or synergistic benefit to the patient. T is like as an example, it is expected that patients will receive therapeutic and/or prophylactic benefit in the methods described herein, and pharmaceutical composition of the compounds disclosed here, and/or combinations with other therapeutic tool, combined with genetic testing to determine whether this person is a carrier of a mutant gene, which is known that it correlates with sexually transmitted diseases or conditions.

In some embodiments, the communication described herein and combination therapies are administered before, during or after the occurrence of a disease or condition. In some embodiments, the implementation timing of the introduction of a composition containing a compound varies. Thus, for example, in some embodiments, the communication is used as a prophylactic and continuously injected patients with a propensity to develop conditions or diseases in order to prevent this disease or condition. In some embodiments, the communication and the composition is administered to the patient during or as soon as possible after onset of symptoms. In some embodiments, the implementation of the introduction connections begin within the first 48 hours of onset of symptoms within the first 6 hours after onset of symptoms or within 3 hours of pashapavlya symptoms. The initial introduction is carried out by any practical means, such as, for example, intravenous injection, bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal introduction and the like, or combinations thereof. In some embodiments, the implementation of the connection type as fast as it really is once the disease or condition is detected or suspected, and for the length of time necessary for treatment of the disease, such as from about 1 month to about 3 months. In some embodiments, the implementation of the duration of treatment varies for each patient, and duration determine, using any criteria. In some embodiments, the implementation of the compound or the composition containing the compound is administered for at least 2 weeks, from about 1 month to about 5 years, or within about 1 month to about 3 years.

Other combined therapy

In some embodiments, the implementation described here, the methods of treatment with PARP-mediated conditions or diseases, such as proliferative disorders, including cancer, to enable the administration to a patient compounds, pharmaceutical compositions or drugs described herein, in combination the at least one additional tool, selected from the group consisting of alemtuzumab, arsenic trioxide, asparaginase (Paglierani or not-Paglierani), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin/doxorubicin/idarubitsina, irinotecan, fludarabine, 5-fluorouracil inside the body, gemtuzumab, methotrexate, paclitaxel, Taxol®, temosolomida, Tg, or classes of drugs including hormones (an antiestrogen, an antiandrogen, or analogs of gonadotropin-releasing hormone, such as interferons such as alpha interferon, nitrogen mustards such as busulfan, melphalan or mechlorethamine, retinoids, such as tretinoin, topoisomerase inhibitors, such as irinotecan or topotecan, an inhibitor of tyrosine kinases, such as, for example, gefinitib or imatinib, and means to treat signs or symptoms induced by such therapy including allopurinol, filgrastim, granisetron/ondansetron/palonosetron and dronabinol.

Sets/Industrial products

For use in therapeutic applications described herein, kits and industrial products are also described here. In various embodiments, the implementation of such kits comprise a carrier, package, or container that is separated from the receiving one or more containers, such as and the pools, tubes and the like, and each of the containers includes one of the separate elements that are used in the way described here. Suitable containers include, for example, vials, ampoules, syringes, and test tubes. In some embodiments, the implementation of the capacity formed from various materials, such as glass or plastic.

In some embodiments, the implementation of industrial products according to the invention contain packing materials. Packaging materials for use in packaging pharmaceutical products include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected composition and the intended route of administration and treatment.

In some embodiments, the implementation of capacity(and)described herein includes one or more compounds described herein, if necessary in the composition or in combination with another agent as disclosed here. Capacity(s), if necessary, is sterile inlet (for example, in some embodiments, the implementation of the capacity is the bag for intravenous solution or vial having a stopper which can be pierced by a needle for subcutaneous injection). Such sets, if necessary, include a connection with an identifying description or etikett the th, or instructions relating to its use in the methods described here.

In some embodiments, the implementation of a set includes one or more additional containers, each with one or more of various materials (such as reagents, if necessary, in a concentrated form, and/or devices)desirable from a commercial and user standpoint for use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; media, packaging, capacity, labels, capsules and/or tubes, showing the composition and/or instructions for use, and insert with instructions for use. If necessary, may include a set of instructions.

In some embodiments, the implementation of the label affixed to the container or attached to the vessel. In some embodiments, the implementation of the label is on a container when letters, numbers or other characters forming the label attached, molded or treated directly in the container; a label attached to the container when it is present within the receiving tank or carrier that also holds the container, e.g., as a package insert. In some embodiments, the implementation of the label indicates that the content should be the La specific therapeutic applications. In some embodiments, the implementation of the label shows the instructions for use of the content, for example, in the ways described here.

In some embodiments, the implementation of the pharmaceutical composition is presented in a pack or dispenser that contains one or more standard dosage forms containing the compound according to the invention. In some embodiments, the implementation of the packaging contains a metal or plastic film, as in the case of blister packs. Device in the form of a package or dispenser if necessary accompanied by instructions for administration. In some embodiments, the implementation of the package or dispenser is accompanied by a notice associated with the container in form prescribed by a government Agency monitoring the manufacture, use or sale of pharmaceuticals, and this notice reflects approval by the specified body form of the medicinal product for medical or veterinary use. In some embodiments, the implementation of such notification is, for example, a label approved by the U.S. Food and Drug Administration, or an insert for a proven product. In some embodiments, the implementation of the composition containing the compound according to the invention consists in a compatible pharmaceutical carrier and placed in a suitable eating the awn, labeled for treatment of the identified condition.

EXAMPLES

The following Examples are intended to illustrate various embodiments as defined in the attached claims. In some embodiments, the communication receive various ways of synthesis. All publications, patents and patent applications, cited herein fully incorporated by reference.

EXAMPLE 1

Example 1a: Parenteral composition

To obtain a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of water-soluble salts of the compounds described here, was dissolved in DMSO and then mixed with 10 ml of 0.9% sterile saline. The mixture include in a standard dosage form suitable for administration by injection.

Example 1b: Oral Composition

To obtain a pharmaceutical composition for oral delivery, 100 mg of the compounds described herein are mixed with 750 mg of starch. The mixture was included in the oral dosage form, such as a hard gelatin capsule, which is suitable for oral administration.

Example 1c: Composition for sublingual administration (Solid tablet dispersible)

To obtain a pharmaceutical composition for buccal delivery, such as a solid tablet, a mixture of 100 mg of a compound described herein, with 20 mg of powdered sugar mixed, with 1.6 ml of light corn syrup, 2.4 ml distilled water, and 0.42 ml mint extract. The mixture was gently mixed and poured into the mold to form tablet suitable for buccal administration.

Example 1d: Composition for inhalation

To obtain a pharmaceutical composition for delivery by inhalation, 20 mg of the compounds described herein are mixed with 50 mg of anhydrous citric acid and 100 ml of 0.9% sodium chloride solution. The mixture was included in a dosage form for delivery by inhalation, such as a nebulizer, which is suitable for administration by inhalation.

Example 1E: Rectal composition in gel form

To obtain a pharmaceutical composition for rectal delivery, 100 mg of the compounds described herein are mixed with 2.5 g of methylcellulose (1500 MPa), 100 mg of methylparaben, 5 g of glycerin and 100 ml of purified water. The resulting mixture in the form of a gel is then included in the dosage form for rectal delivery, such as syringes, which are suitable for rectal administration.

Example 1f: Topical composition in gel form

To obtain a topical pharmaceutical composition in the form of gel 100 mg of the compounds described herein are mixed with 1.75 g of hydroxypropyl cellulose, 10 ml of propylene glycol, 10 ml of isopropylmyristate and 100 ml of purified alcohol USP. The resulting gel mixture is then included in a container such as a tube, which is the tsya suitable for topical administration.

Example 1g: Composition ophthalmic solution

To obtain a pharmaceutical composition in the form of ophthalmic solution, 100 mg of the compounds described herein are mixed with 0.9 g of NaCl in 100 ml of purified water and filtered using a filter with a pore size of 0.2 micron. Received isoosmotic solution is then included in the forms for ophthalmic delivery, such as containers for eye drops, which are suitable for ocular administration.

Example 2

8,9-Diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 2A

4-Nitrosobenzene-1(3H)-he

A suspension of sodium borohydride (0,757 g, 20 mmol) in anhydrous tetrahydrofuran (120 ml) was cooled to 0°C. Then the suspension was added dropwise a solution of 4-nitrobenzofurazan-1,3-dione (6,18 g, 32 mmol) in anhydrous tetrahydrofuran (30 ml). After the addition the mixture was stirred at this temperature for 3 hours. The reaction mixture was extinguished 3h. hydrochloric acid (up to pΗ 1). To the mixture was added water (40 ml) and was stirred for 1 hour. The tetrahydrofuran was removed under reduced pressure. The residue was separated between water (150 ml) and ethyl acetate (150 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate, concentrated, give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=20:1-2:1)to give 4-NITR isobenzofuran-1(3H)-he (4,2 g, yield 73%) in the form of a solid white color. MS (ESI) m/z: 180 (M+1)+.1H-NMR (400 MHz, CDCl3) δ 5,77 (s, 3H), 7,32-7,34 (d, J=8,4 Hz, 1H), 7,81-a 7.85 (t, J=8.0 Hz, 1H), 8,29 (d, J=8.0 Hz, 1H), 8,55 (d, J=8.0 Hz, 1H).

Example 2B

4-Aminoazobenzene-1(3H)-he

A suspension of 4-nitroazobenzene-1(3H)-she (1.0 g, to 5.58 mmol) and 10% Pd/C (0.1 g) in ethyl acetate (30 ml) was cleaned in 1 ATM. hydrogen and stirred at 25°C for 3 hours. The mixture was filtered, and the filtrate was concentrated, obtaining 4-aminoazobenzene-1(3H)-he (0.8 g, yield 96%) in the form of a solid off-white color. MS (ESI) m/z: 150 (M+1)+.1H-NMR (400 MHz, CDCl3) δ 3,82 (users, 1H), 5,19 (s, 3H), 6,91-to 6.95 (m, 1H), 7,32 and 7.36 (m, 2H).

Example 2C

4-Oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-aminoazobenzene-1(3H)-she (0.4 g, 2.68 mmol) and benzaldehyde (0,72 g, 6.7 mmol) in ethylpropylamine (20 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (248 mg, 10.72 mmol) in methanol (20 ml)]. After the addition the mixture was heated under reflux for 16 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water, acidified 1H. hydrochloric acid to pH 6, then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous Sul is an atom of sodium and concentrated, give crude product. The crude product was purified preparative HPLC, receiving 4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (256 mg, yield 27%) and 4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (140 mg, yield 14%) in the form of a solid of light yellow color. 4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl: MS (ESI) m/z: 358 (M+1)+.1H-NMR (400 MHz, CDCl3) δ 3,86 (s, 3H), 3.95 to 3,98 (d, J=16.4 Hz, 1H), 4,81-4,84 (d, J=12,8 Hz, 1H), 4,89 (users, 1H), 6,72-6,77 (m, 2H), 6.90 to-6,93 (m, 2H), 7,11-7,21 (m, 8H), 7,34 and 7.36 (t, J=7.8 Hz, 1H).

Example 2D

8,9-Diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (100 mg, mmol) in hydrazine monohydrate (25 ml) was heated under reflux for 20 hours. The mixture was diluted with water (30 ml), extracted with ethyl acetate (30 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 20:1 to 8:1)to give 8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (15.6 mg, yield 16%) in the form of a solid white color. MS (ESI) m/z: 340 (M+1)+.1H-NMR (400 MHz, CDCl3) δ 4,22-of 4.25 (d, J=9.6 Hz, 1H), 4,66-4,69 (d, J=9.6 Hz, 1H), 7,02-7,06 (m, 3H), 7,16-7,26 (m, 8H), EUR 7.57-to 7.61 (t, J=7.8 Hz, 1H), 7,74-7,76 (d, J=7,6 Hz, 1H), 9,82 (s, 1H).

Example 3

Example 3A

2,3-bis(4-((Diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 2,3-bis(4-((diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-aminoazobenzene-1(3H)-she (298 mg, 2 mmol) and 4-(diethoxylate)benzaldehyde (1.04 g, 5 mmol) in ethylpropylamine (15 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (184 mg, 8 mmol) in methanol (15 ml)]. After the addition the mixture was stirred at 25°C for 16 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1-10:1)to give 2,3-bis(4-((diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 2,3-bis(4-((diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (240 mg only, exit 21%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 562 (M+1)+(2,3-bis(4-((diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl); 576 (M+1)+(2,3-bis(4-((diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate).

Example 3B

8,9-bis(4-(Diethoxylate)phenyl-,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2,3-bis(4-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2,3-bis(4-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (240 mg, 0.43 mmol) in hydrazinoacetate (5 ml) and methanol (5 ml) was stirred at 40°C for 2 hours. The mixture was cooled to ambient temperature and filtered, obtaining 8,9-bis(4-(diethoxylate)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (120 mg, yield 52%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 544 (M+1)+. MS (ESI) m/e 381 [M+Η]+.

Example 3C

4,4'-(3-Oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzamide

A mixture of 8,9-bis(4-(diethoxylate)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7Η)-she (120 mg, 0.22 mmol) in 3h. hydrochloric acid (5 ml) was stirred at ambient temperature for 3 hours. The mixture is then neutralized (podslushivaet) with potassium carbonate to pH 8. The resulting suspension was filtered, getting 4,4'-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzamide (80 mg, yield 97%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 396 (M+1)+.

Example 3D

8,9-bis(4-((Methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4,4'-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzamide (80 mg, 0.21 mmol) and 27% alcoholic solution of methylamine (94 mg, 0.82 mmol) in methanol (10 ml) was stirred the ri ambient temperature for 40 minutes The mixture then was cooled to 0°C. was Added sodium borohydride (24 mg, 0.64 mmol). After the addition the mixture was stirred at ambient temperature for 4 hours. The methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated, receiving 8,9-bis(4-((methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (29.5 mg, yield 33%) in the form of a solid of light yellow color.1H-NMR (400 MHz, DMSO-d6) δ of 2.20 (d, J=8,8 Hz, 6H), 3,52-of 3.53 (d, J=2.4 Hz, 4H), or 4.31-to 4.33 (d, J=6,4 Hz, 1H), 4,76-of 4.77 (d, J=6,4 Hz, 1H), 7,06-was 7.08 (d, J=6,4 Hz, 2H), 7,12-7,17 (m, 5H), 7,35-7,38 (t, J=6.4 Hz, 2H), 7,49-EUR 7.57 (t, J=10.0 Hz, 1H); LC-MS (ESI) m/z: 426 (M+1)+.

Example 4

8,9-di(Pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 4A

4-Oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-aminoazobenzene-1(3H)-she (149 mg, 1 mmol) and nicotinamide (268 mg, 2.5 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (93 mg, 4 mmol) in methanol (3 ml)]. After the addition the mixture was stirred at 25°C for 16 hours. The mixture is extinguished with water (5 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, isusually over anhydrous sodium sulfate and concentrated, give crude product. The crude product was purified preparative HPLC, receiving 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (60 mg, yield 17%) and 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (4 mg, yield 1%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 360 (M+1)+(4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl), 374 (M+1)+(4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate).

Example 4B

8,9-di(Pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (60 mg, 0,17 mmol) in hydrazinoacetate (7 ml) was heated under reflux for 4 hours. Then the mixture was cooled to ambient temperature, and the solvent was removed in vacuum to give crude product. The crude product was purified prep-HPLC, getting 8,9-di(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-one (15 mg, yield 68%) in the form of a solid of light yellow color.1H-NMR (400 MHz, DMSO) δ 4,46-4,48 (d, J=8,4 Hz, 1H), 4,90 to 4.92 (d, J=8,4 Hz, 1H), 7,16-7,20 (m, 3H), 7,32-7,34 (d, J=5,2 Hz, 2H), 7,40-7,42 (d, J=8,4 Hz, 1H), 7,55 (s, 1H), to 7.59-7,63 (t, J=8.0 Hz, 1H), 8,40-8,40 (d, J=5,2 Hz, 2H), 8,44-to 8.45 (d, J=5,2 Hz, 2H). LC-MS (ESI) m/z: 342(M+1)+.

Example 5

8,9-di(Pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Por the measures 5A

4-Oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-aminoazobenzene-1(3H)-she (298 mg, 2 mmol) and nicotinamide (535 mg, 5 mmol) in ethylpropylamine (15 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (184 mg, 8 mmol) in methanol (15 ml)]. After the addition the mixture was stirred at 25°C for 16 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate = 100:1 to 10:1)to give 4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (480 mg only, exit 67%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 360 (M+1)+(4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl); 374 (M+1)+(4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate).

Example 5B

8,9-di(Pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-5-meth is carboxylate and 4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (480 mg, of 1.34 mmol) in hydrazinoacetate (20 ml) and methanol (5 ml) was heated under reflux for 2 hours. The mixture then was cooled to ambient temperature and filtered, obtaining 8,9-di(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-(320 mg, yield 68%) in the form of a solid of light yellow color.1H-NMR (400 MHz, DMSO-d6) δ 4,51-a 4.53 (d, J=8,4 Hz, 1H), 4,89-4,91 (d, J=8,4 Hz, 1H), 7.18 in-7,20 (m, 1H), 7.24 to 7,27 (m, 1H), 7,31-7,33 (m, 1H), 7,43-7,44 (m, 1H), 7,60 (s, 1H), 7,58-7,63 (m, 2H), 7,79-7,81 (m, 1H), 8,32-to 8.34 (m, 2H), to 8.41-8,43 (m, 1H), 8,45-8,46 (d, J=1.6 Hz, 1H); LC-MS (ESI) m/z: 342 (M+1)+.

Example 6

8,9-di(Pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 6A

4-Oxo-2,3-di(pyridin-2-yl)-1,2,3, 4-tetrahydroquinolin-5-methylcarbamoyl and 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-aminoazobenzene-1(3H)-she (149 mg, 1 mmol) and nicotinamide (268 mg, 2.5 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (93 mg, 4 mmol) in methanol (3 ml)]. After the addition the mixture was stirred at 25°C for 16 hours. The mixture is extinguished with water (5 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3), combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product is CT was purified preparative HPLC, getting 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (72mg, yield 20%) and 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (14 mg, yield 3%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 360 (M+1)+(4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl); 374 (M+1)+(4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate).

Example 6B

8,9-di(Pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (68 mg, 0,19 mmol) in hydrazinoacetate (7 ml) was heated under reflux for 4 hours. Then the mixture was cooled to ambient temperature, and the solvent was removed in vacuum to give crude product. The crude product was purified prep-HPLC, getting 8,9-di(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (24 mg, yield 37%) in the form of a solid of light yellow color.1H-NMR (400 MHz, DMSO) δ 5,42-5,43 (d, J=5,2 Hz, 1H), 5,56-to 5.57 (d, J=5,2 Hz, 1H), 7,30-to 7.32 (d, J=8.0 Hz, 1H), 7,37-7,39 (d, J=8.0 Hz, 1H), 7,63-7,66 (t, J=6,6 Hz, 1H), 7.68 per-of 7.70 (m, 2H), 7,78-7,80 (d, J=7.2 Hz, 1H), 7,87-7,89 (d, J=8.0 Hz, 1H), 8,11-8,16 (m, 2H), 8,66-8,67 (d, J=4,8 Hz, 1H), total of 8.74-8,76 (d, J=5.6 Hz, 1H); LC-MS (ESI) m/z: 342 (M+1)+.

Example 7

9-Isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 7A

(E)-4-(Benzo is linename) isobenzofuran-1(3H)-he

4-aminoazobenzene-1(3H)-he (600 mg, 4 mmol), benzaldehyde (427 mg, 4 mmol) was added to methanol (20 ml) and stirred under reflux overnight, then the mixture was evaporated under reduced pressure, and the residue was dried in vacuum. Received 600 mg of the crude product (E)-4-(benzylideneamino)isobenzofuran-1(3H)-it is used in the next stage of the synthesis without further purification.

Example 7B

3-Isopropyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

Was added 4-(benzylideneamino)isobenzofuran-1(3H)-he (237 mg, 1 mmol), Isobutyraldehyde (216 mg, 3 mmol), methanolate sodium (162 mg, 3 mmol) and ethylpropane (20 ml)and the mixture was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4) and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether/ethyl acetate= 20:1 to 5:1). Received 35 mg solids 3-isopropyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate, (yield: 11%). LC-MS (ESI) m/z: 308 (M+1)+.

Example 7C

9-Isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Added 3-isopropyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (35 mg, 1 mmol) and hydrazinoacetate (20 ml)and the mixture was stirred at 40°C for 3 hours. The resulting mixture ek who was tragically with ethyl acetate (100 ml ×4) and concentrated, was purified preparative HPLC. Received 7 mg solids 9-isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (yield: 15%).1H-NMR (400 MHz, DMSO-d6): δ 0,82-of 0.83 (d, J=5,2 Hz, 3H), 1,15-1,17 (d, J=5,2 Hz, 3H), 1,89-of 1.93 (m, 1H), 2.71 to 2,73 (d, J=6.0 Hz, 1H), a 4.83 (s, 1H), 7,11-7,26 (m, 7H), 7,51-rate of 7.54 (m, 2H), 12,11 (s, 1H). LC-MS (ESI) m/z: 306 (M+1)+.

Example 8

9-(4-((Methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 8A

1-(4-(Diethoxylate)phenyl)-N-methylmethanamine

A mixture of 4-(diethoxylate)benzaldehyde (1.04 g, 5 mmol) and methylamine (solution 27-32% in methanol, 2.3 g, 20 mmol) in methanol (20 ml) was stirred at ambient temperature for 40 minutes. The mixture was cooled to 0°C, sodium borohydride (0,284 g, 7.5 mmol) was added parts. After the addition the mixture was stirred at ambient temperature for 4 hours. The methanol was removed under reduced pressure. The residue was separated between water (50 ml) and ethyl acetate (50 ml). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude 1-(4-(diethoxylate)phenyl)-N-methylmethanamine (1.1 g) in the form of a light yellow oil, which was used in the next stage without far the necks of cleaning. LC-MS (ESI) m/z: 224 (M+1)+.

Example 8B

4-(Diethoxylate)benzyl(methyl)benzylcarbamoyl

To a stirred solution of 1-(4-(diethoxylate)phenyl)-N-methylmethanamine (1.1 g, 4.9 mmol) and triethylamine (0.75 g, 7,35 mmol) in anhydrous dichloromethane (10 ml) at 0°C was added benzyl carbonochloridic (1.0 g, 5,88 mmol). After the addition the mixture was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (50 ml), washed with water (50 ml × 3), brine (50 ml), dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 100:1 to 20:1)to give 4-(diethoxylate)benzyl(methyl)benzylcarbamoyl (1.0 g, yield 57% for two steps) in the form of a light yellow oil.1H-NMR (400 MHz, CDCl3) δ: 3,82 (users, 1H), 5,19 (s, 3H), 6,91-to 6.95 (m, 1H), 7,32 and 7.36 (m, 2H); LC-MS (ESI) m/z: 358 (M+1)+.

Example 8C

4-Formylmethyl(methyl)benzylcarbamoyl

A mixture of 4-(diethoxylate)benzyl(methyl)benzylcarbamoyl (1.0 g, 2.8 mmol) in 3h. hydrochloric acid (50 ml) was stirred at ambient temperature for 1 h Then the mixture was neutralized with potassium carbonate. The resulting mixture was extracted with ethyl acetate (100 ml ×4), the organic phase is washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and concentrated, gaining 4 forlivesi the(methyl) benzylcarbamoyl (730 mg, 92%).1H-NMR (400 MHz, CDCl3) δ: 2,94 (d, 3H), 4,572 (d, 2H), 5,18 (d, 2H), 7,32-7,39 (m, 7H), to 7.84 (m, 2H), 10,00 (s, 1H); LC-MS (ESI) m/z: 284 (M+1)+.

Example 8D

3-(4-(((Benzyloxycarbonyl)(methyl)amino)methyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of 4-formylmethyl(methyl)benzylcarbamoyl (566 mg, 2 mmol) and 4-(benzylideneamino)isobenzofuran-1-it (474 mg, 2 mmol) in ethylpropylamine (15 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (184 mg, 8 mmol) in methanol (15 ml)]. After the addition the mixture was stirred at 25°C for 18 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate = 100:1 to 10:1)to give a mixture of 3-(4-(((benzyloxycarbonyl)methyl)amino)methyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 3-(4-(((benzyloxycarbonyl)methyl)amino)methyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (220 mg, yield 20%in the form of a solid of light yellow color. LC-MS (ESI) m/z: 535 (M+1)+and 549 (M+1)+.

Example 8E

Methyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrid the[4,3,2-de]phthalazine-9-yl)benzyl)benzylcarbamoyl

A mixture of 3-(4-(((benzyloxycarbonyl)amino(methyl))methyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (220 mg, of 0.94 mmol) in hydrazinoacetate (50 ml) and methanol (5 ml) was stirred at 40°C for 24 hours. The mixture was cooled to ambient temperature and filtered, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=3:1)to give methyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)benzyl)benzylcarbamoyl (80 mg, yield 16%). LC-MS (ESI) m/z: 517 (M+1)+.

Example 8F

9-(4-((Methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of methyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)benzyl)benzylcarbamoyl (80 mg, 0.26 mmol), 10% Pd/C (20 mg) in methanol (50 ml) was stirred at ambient temperature for 4 hours. The solution mixture was then filtered and evaporated under reduced pressure. The residue was purified preparative HPLC. Received 3 mg of 9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she and 6 mg of 9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she, exit 9%. For 9-(4-((methylamino)methyl)-phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it:1H-NMR (400 MHz, CD3OD) δ: 2,50 (s, 3H), a 3.87 (s, 2H), to 4.38 (d 1H), of 4.75 (d, 1H), 7,15-7,17 (m, 2H), 7,19-7,25 (m, 5H), 7,27-7,28 (m, 3H), EUR 7.57 (d, 1H), 7,65 (t, 1H). LC-MS (ESI) m/z: 383 (M+1)+. For 9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it:1H-NMR (400 MHz, CD3OD) δ: 2,31 (s, 6H), of 3.57 (s, 2H), 4,33 (d, 1H), 4,73 (d, 1H), 7,10 for 7.12 (m, 2H), 7,19-7,21 (m, 6H), 7,26-7,27 (m, 2H), 7,58 (d, 1H), to 7.64 (t, 1H). LC-MS (ESI) m/z: 397 (M+1)+.

Example 9

9-(3-((Methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 9A

3-(3-(Diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (474 mg, 2 mmol) and 4-(diethoxylate)benzaldehyde (418 mg, 2 mmol) in ethylpropylamine (20 ml) was cooled to 0°C. Then was added dropwise a sodium methylate in methanol solution [sodium (148 mg, 8 mmol) in methanol (2 ml)], and the mixture was stirred at ambient temperature overnight. The resulting mixture was evaporated under reduced pressure. The residue was extracted with ethyl acetate (100 ml ×3), and the combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography on columns (silica gel, petroleum ether/ethyl acetate= 50:1 to 5:1)to give 3-(3-(diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (230 mg, yield 25%) in the form of a solid yellow color./p>

Example 9B

9-(3-(Diethoxylate)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

3-(3-(Diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (300 mg, of 0.65 mmol) in hydrazinoacetate (20 ml) was stirred at 45°C for 4 hours. The resulting mixture was filtered, receiving 9-(3-(diethoxylate)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (95 mg, yield 33%) in the form of a solid white color.1H-NMR (400 MHz, DMSO-d6) δ; 1,04-a 1.08 (t, J=7.0 Hz, 6H), 3.27 to 3,31 (square, 4H), 4,34 is 4.36 (d, J=8,8 Hz, 1H), 4,74 was 4.76 (d, J=8,8 Hz, 1H), of 5.34 (s, 1H), was 7.08 (s, 1H), 7,14-7,24 (m, 7H), 7,27-7,29 (m, 2H), 7,37-7,39 (d, J=7.2 Hz, 1H), the 7.43 (s, 1H), 7,56-of 7.60 (t, J=8.0 Hz, 1H), 12,15 (s, 1H); LC-MS (ESI) m/z: 442 (M+1)+.

Example 9C

3-(3-Oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)benzaldehyde

A mixture of 9-(3-(diethoxylate)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (90 mg, 0.20 mmol) in 3h. hydrochloric acid (12 ml) was stirred at ambient temperature for 20 hours. Then the mixture was podslushivaet to pΗ 8 with potassium carbonate. The resulting suspension was extracted with ethyl acetate, getting 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)benzaldehyde (66 mg, yield 88%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 368 (M+1)+.

Example 9D

9-(3-((Methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-PI is IDO[4,3,2-de]phthalazine-9-yl)benzaldehyde (66 mg, 0.18 mmol) and 27% alcohol solution of methylamine (83 mg, to 0.72 mmol) in methanol (15 ml) was stirred at ambient temperature for 1 hour. The mixture then was cooled to 0°C was added sodium borohydride (11 mg, 0.27 mmol). After the addition the mixture was stirred at ambient temperature for 4 hours. The methanol was removed under reduced pressure. The residue was purified preparative HPLC, receiving 9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-(34 mg, yield 49%) in the form of a solid of light yellow color.1H-NMR (400 MHz, MeOD-d4) δ; to 2.55 (s, 3H), 4.04 the-4,13 (square, 2H), 4,36-to 4.38 (d, J=9.6 Hz, 1H), 4,74 was 4.76 (d, J=8,8 Hz, 1H), 7.18 in-7,24 (m, 6H), 7,25-7,35 (m, 4H), 7,56-7,58 (d, J=7,6 Hz, 1H), 7,62-7,66 (t, J=8 Hz, 1H); LC-MS (ESI) m/z: 383 (M+1)+.

Example 10

8-(4-((Methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 10A

(E)-4-(4-(Diethoxylate)benzylideneamino)isobenzofuran-1(3H)-he

4-aminoazobenzene-1(3H)-he (600 mg, 4 mmol), 4-(ethoxy(methoxy)methyl)benzaldehyde (1.6 g, 8 mmol) and 1 g of magnesium sulfate was added to 40 ml of dichloromethane and stirred under reflux overnight, then the mixture was evaporated under reduced pressure, and the residue was dried in vacuum, receiving 600 mg of the crude product (E)-4-(4-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-it, which without further purification was used at the next stage.

Example 10B

2-(4-(Dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

(E)-4-(4-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-he (600 mg, 1 mmol), benzaldehyde (616 mg, 3 mmol), methanolate sodium (414 mg, 7.6 mmol) and ethylpropane (20 ml) was added and the mixture was stirred at ambient temperature overnight. The mixture then was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4) and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate= 20:1 to 5:1)to give 120 mg of a solid product 2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (yield: 22%). LC-MS (ESI) m/z: 432 (M+1)+.

Example 10C

8-(4-(Dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To 2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (120 mg, 0.28 mmol) was added hydrazinoacetate (20 ml) and the mixture was stirred at 40°C for 3 hours. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered, received 89 mg solids 8-(4-(dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (yield: 78%). LC-MS (ESI) m/z: 414 (M+1)+.

Example 10D

4-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde

8-(4-(dimethoxymethyl)phenyl)-9-dryer is l-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-ONU (89 mg, 0.22 mmol) was added 20 ml of hydrochloric acid (3 mol/l) and the mixture was stirred at ambient temperature for 2 hours. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered, received 59 mg of a solid product 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde; yield: 73%. LC-MS (ESI) m/z: 368 (M+1)+.

Example 10E

8-(4-((Methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (59 mg, 0.16 mmol) was added methanamine (20 ml)and the mixture was stirred at ambient temperature for 2 hours. Then was added 30 mg of sodium borohydride and stirred for another 2 hours. The resulting mixture was evaporated under reduced pressure and was purified preparative HPLC. Got to 11.5 mg of 8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (yield: 19%).1H-NMR (400 MHz, CD3OD) δ: 2,66 (s, 3H), 4,33 is 4.35 (d, J=8 Hz, 1H), a 4.83-4,85 (d, J=7,6 Hz, 1H), 7,10 for 7.12 (m, 2H), 7,15-7,22 (m, 4H), 7,34-7,42 (m, 4H), 7,55-EUR 7.57 (m, 1H), 7,63-to 7.67 (m, 1H). LC-MS (ESI) m/z: 383 (M+1)+.

Example 11

8,9-bis(3-((Methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 11A

2,3-bis(3-(Diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-and noisebusters-1(3H)-she (298 mg, 2 mmol) and 3-(diethoxylate)benzaldehyde (0,83 g, 4 mmol) in ethylpropylamine (15 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (184 mg, 8 mmol) in methanol (15 ml)]. After the addition the mixture was stirred at 25°C for 18 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 100:1 to 10:1)to give a mixture of 2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (370 mg, yield 33%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 562 (M+1)+and 576 (M+1)+.

Example 11B

8,9-bis(3-(Diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (370 mg, 0.59 mmol) in hydrazinoacetate (5 ml), and methanol (5 ml) was stirred at 40°C for 2 hours. The mixture was cooled to ambient temperature and filter the Lee, getting 8,9-bis(3-(diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (250 mg, yield 77%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 544 (M+1)+.

Example 11C

3,3'-(3-Oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzamide

A mixture of 8,9-bis(3-(diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (120 mg, 0.46 mmol) in 3h. hydrochloric acid (5 ml) was stirred at ambient temperature for 3 hours. The mixture was then podslushivaet to pΗ=8 with potassium carbonate. The resulting suspension was filtered, getting 3,3'-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzamide (160 mg, yield 88%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 396 (M+1)+.

Example 11D

8,9-bis(3-((Methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3,3'-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzamide (100 mg, 0.25 mmol) and 27% alcohol solution of methylamine (122 mg, 1.07 mmol) in methanol (15 ml) was stirred at ambient temperature for 40 minutes the Mixture was then cooled to 0°C. was Added sodium borohydride (31 mg, 1.00 mmol). After the addition the mixture was stirred at ambient temperature for 4 hours. The methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated, receiving 8,9-bis(3-((methylamino)m is Teal)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (20 mg, exit 19%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ; 2,62-2,63 (d, J=4.0 Hz, 6H), 4,12-4,13 (d, J=10,8 Hz, 4H), 4,42-of 4.44 (d, J=8,4 Hz, 1H), 4,84-a 4.86 (d, J=8,4 Hz, 1H), 7,20-7,24 (m, 2H), 7,29-7,33 (m, 6H), 7,52 (s, 1H), EUR 7.57-of 7.60 (DD, J1=8.0 Hz, J2=1.2 Hz, 1H), 7,65-of 7.69 (t, J=7,6 Hz, 1H); LC-MS (ESI) m/z: 426 (M+1)+.

Example 12

9-(4-(Hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 12A

3-(4-(Diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 3-(4-(diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (474 mg, 2 mmol) and 4-(diethoxylate)benzaldehyde (0.40 g, 2.4 mmol) in ethylpropylamine (15 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (184 mg, 8 mmol) in methanol (15 ml)]. After the addition the mixture was stirred at 25°C for 18 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 100:1 to 10:1)to give 3-(4-(diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl the t and 3-(4-(diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (430 mg, yield: 47%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 460 (M+1)+and 474 (M+1)+.

Example 12B

9-(4-(Diethoxylate)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(4-(diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 3-(4-(diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (430 mg, of 0.94 mmol) in hydrazinoacetate (10 ml) and methanol (5 ml) was stirred at 40°C for 24 hours. The mixture was cooled to ambient temperature and filtered, receiving 9-(4-(diethoxylate)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (270 mg, yield: 65%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 442 (M+1)+.

Example 12C

4-(3-Oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)benzaldehyde

A mixture of 9-(4-(diethoxylate)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (270 mg, 0.61 mmol) in 3h. hydrochloric acid (10 ml) was stirred at ambient temperature for 3 hours. The mixture was then podslushivaet to pΗ=8 with potassium carbonate. The resulting suspension was filtered, obtaining 4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)benzaldehyde (140 mg, yield: 69%) in the form of a solid of light yellow color.

Example 12D

9-(4-(Hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(3-oxo-8-phenyl-3,7,8,9-is etrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)benzaldehyde (140 mg, 0.42 mmol) and 27% alcohol solution of methylamine (194 mg, was 1.69 mmol) in methanol (15 ml) was stirred at ambient temperature for 40 minutes Then the mixture was cooled to 0°C. was Added sodium borohydride (48 mg, of 1.26 mmol). After the addition the mixture was stirred at ambient temperature for 4 hours. TLC (petroleum ether/ethyl acetate=2:1)showed that the reaction was complete. The methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated, receiving 9-(4-(hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (20 mg, yield: 13%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ; 4,33 is 4.35 (d, J=8.0 Hz, 1H), 4.53-in (s, 2H), 4,74 was 4.76 (d, J=8.0 Hz, 1H), 7,08-7,10 (d, J=8.0 Hz, 2H), 7.18 in-7,24 (m, 6H), 7,27-7,29 (d, J=6,8 Hz, 2H), 7,54-7,56 (d, J=7,6 Hz, 1H), 7,62-7,66 (t, J= 8.0 Hz,, 1H); LC-MS (ESI) m/z: 370 (M+1)+.

Example 13

9-(3-(4-Isobutylpyrazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-and 8,9-bis(3-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 13A

4-Isobutylpyrazine-1-tert-butylcarbamoyl

To a solution of somaclonal acid (6,608 g, 75 mmol) in anhydrous dichloromethane (130 ml) was added triethylamine (8,33 g of 82.5 mmol), 1-hydroxybenzotriazole (rate of 10,125 g, 75 mmol)and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (of 14.25 g, 75 mmol). After the add is placed and the mixture was stirred at ambient temperature for 40 minutes. The mixture then was cooled to 0°C, the connection1(13,97 g, 75 mmol) was added parts. After the addition the mixture was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (200 ml), washed with saturated sodium bicarbonate (150 ml ×2), 10% citric acid (150 ml), brine (100 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 4-isobutylpyrazine-1-tert-butylcarbamoyl (15 g, yield: 78%) in the form of a solid white color. LC-MS (ESI) m/z: 257 (M+1)+.

Example 13B

2-Methyl-1-(piperazine-1-yl)propane-1-he

To a stirred mixture of 4-isobutylpyrazine-1-tert-BUTYLCARBAMATE (6.8 g, of 26.5 mmol) in methanol (15 ml) at 0°C was added the hydrochloride/methanol (30 ml, 3M)). After the addition the mixture was stirred at ambient temperature overnight. The mixture was concentrated, obtaining 2-methyl-1-(piperazine-1-yl)propane-1-he (5.5 g, yield: 100%) in the form of a solid off-white color.1H-NMR (400 MHz, CDCl3) δ: 3,82 (users, 1H), 5,19 (s, 3H), 6,91-to 6.95 (m, 1H), 7,32 and 7.36 (m, 2H); LC-MS (ESI) m/z 157 (M+1)+.

Example 13C

3-(4-Isobutylpyrazine-1-carbonyl)benzaldehyde

To a solution of 3-formylbenzoate acid (750 mg, 5 mmol) in anhydrous dichloromethane (15 ml) was added triethylamine (1,263 g, 12.5 mmol), 1-hydroxybenzotriazole (0,743 g, 5.5 mmol)and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1,05 is, 5.5 mmol). After the addition the mixture was stirred at ambient temperature for 40 minutes. Then the mixture was cooled to 0°C, was added 2-methyl-1-(piperazine-1-yl)propane-1-he (1.06 g, 5.5 mmol). After the addition the mixture was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (50 ml), washed with saturated sodium bicarbonate (50 ml ×2), 10% citric acid (50 ml), brine (30 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 3-(4-isobutylpyrazine-1-carbonyl)benzaldehyde (1.44 g, yield: 95%) in the form of a resin. LC-MS (ESI) m/z: 289 (M+1)+.

Example 13D

3-(3-(4-Isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 2,3-bis(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of 3-(4-isobutylpyrazine-1-carbonyl)benzaldehyde (288 mg, 1 mmol) and 4-(benzylideneamino)isobenzofuran-1(3H)-she (237 mg, 1 mmol) in ethylpropylamine (7.5 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (92 mg, 4 mmol) in methanol (7.5 ml)]. After the addition the mixture was stirred at 25°C for 18 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers washed with the salt solution, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:10)to give 3-(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (110 mg, yield 20%) and 2,3-bis(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (90 mg, yield 12%in the form of solid particles of light-yellow color. LC-MS (ESI) m/z: 540 (M+1)+and 722 (M+1)+.

Example 13E

9-(3-(4-Isobutylpyrazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (110 mg, 0.20 mmol) in hydrazinoacetate (5 ml) and methanol (2 ml) was stirred at 25°C for 4 hours. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified preparative HPLC, receiving 9-(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (12 mg, yield: 11%) in the form of a solid white color.1H-NMR (400 MHz, CD3OD) δ; 0,96-0,98 (d, J=6.8 Hz,6H), 2,68-2,95 (m, 2H), 3,28-3,55 (m, 7H), 4,19-4,22 (d, J=10.0 Hz, 1H), 4,54-of 4.57 (d, J=10.4 Hz, 1H), 7.03 is-7,20 (m, 10H), 740-7,50 (m, 2H); LC-MS (ESI) m/z: 522 (M+1)+.

Example 13F

8,9-bis(3-(4-Isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2,3-bis(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (90 mg, 0.12 mmol) in hydrazinoacetate (5 ml) and methanol (2 ml) was stirred at 25°C for 4 hours. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified preparative HPLC, getting 8,9-bis(3-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (3.2 mg, yield: 4%) in the form of a solid white color.1H-NMR (400 MHz, CD3OD) δ: 0,95-0,97 (square, 12H), 2,80-is 2.88 (m, 2H), 2,98-is 3.08 (m, 3H), 3.33 and-of 3.53 (m, 13H), to 4.23-4.26 deaths (d, J=10.4 Hz, 1H), 4,62 with 4.64 (d, J=10.0 Hz, 1H), 7,02-7,46 (m, 11H); LC-MS (ESI) m/z 704 (M+1)+.

Example 14

9-(piperidine-3-yl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Suspension 8,9-di(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (120 mg, 0.35 mmol) and platinum oxide (IV) (60 mg) in methanol (20 ml) was cleaned in 20 ATM. hydrogen and stirred at 50°C for 24 hours. The mixture was filtered, and the filtrate was concentrated, give crude product. The crude product was purified preparative HPLC, receiving 9-(piperidine-3-yl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-what irido[4,3,2-de]phthalazine-3(7H)-he (4 mg, yield: 4%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ, 1,19-of 1.32 (m, 2H), 1,60-1,65 (m, 2H), 1,94-of 1.97 (d, J=10.0 Hz, 1H), 2,31 is 2.43 (m, 2H), 2,82-2,85 (d, J=12,4 Hz, 1H), 3,02 was 3.05 (d, J=12 Hz, 1H), 3,29-of 3.32 (DD, J1=2,8 Hz, J2=8,4 Hz, 1H), 4,25-4.26 deaths (d, J=2,8 Hz, 1H), 7,02-7,05 (DD, J1=0.8 Hz, J2=8,8 Hz, 1H), 7,22-7,25 (m, 1H), 7,40-7,53 (m, 3H), 8,25-8,29 (m, 2H); LC-MS (ESI) m/z: 348 (M+1)+.

Example 15

9-(piperidine-4-yl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 8,9-di(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (120 mg, 0.35 mmol), platinum oxide (IV) (60 mg) and concentrated hydrochloric acid (0.3 ml) in methanol (20 ml) was stirred at 50°C under 20 MPa. of hydrogen. The mixture was filtered, and the filtrate was concentrated, give crude product. The crude product was purified preparative HPLC, receiving 9-(piperidine-4-yl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (17.6 mg, yield: 16%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ 1.25 and 1.39 in (m, 1H), 1,40-of 1.52 (m, 1H), 1,60-1,70 (m, 1H), 1,75-of 1.84 (m, 1H), 1,89-to 1.98 (m, 1H), 2,50-to 2.57 (m, 1H), 2,60-of 2.66 (m, 1H), 3,09-is 3.21 (m, 2H), 3,34-3,37 (DD, J1=8 Hz, J2=2.4 Hz, 1H), 4,24 (d, J=2 Hz, 1H), 7,02? 7.04 baby mortality (DD, J1=8 Hz, J2=0.8 Hz, 1H), 7,09-7,11 (DD, J1=4,8 Hz, J2= 1.2 Hz, 2H), 7,41-the 7.43 (DD, J1=7,6 Hz, J2=0.8 Hz, 1H), 7,50-rate of 7.54 (t, J=8 Hz, 1H), 8.30 to-8,32 (DD, J1=4.4 Hz, J2=1,6 Hz, 2H); LC-MS (ESI) m/z: 348 (M+1)+.

Example 16

8,9-bis(4-((Dimethylamino)methyl)phenyl) - 8.9bn-digit the on-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 16A

1-(4-(Diethoxylate)phenyl)-N,N-dimethylethanamine

A mixture of 1-(4-(diethoxylate)benzaldehyde (of 2.08 g, 10 mmol) and dimethylamine (33%aqueous solution, is 2.74 g, 20 mmol) in methanol (20 ml) was stirred at ambient temperature for 40 minutes. The mixture was cooled to 0°C, sodium borohydride (or 0.57 g, 15 mmol) was added parts. After the addition the mixture was stirred at ambient temperature for 4 hours. The methanol was removed under reduced pressure. The residue was separated between water (50 ml) and ethyl acetate (50 ml). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, obtaining 1-(4-(diethoxylate)phenyl)-N,N-dimethylethanamine (1.8 g) in the form of a light yellow oil, which was used in the next stage without further purification. MS (ESI) m/z: 237 (M+1)+.

Example 16B

4-((Dimethylamino)methyl)benzaldehyde

To a solution of 1-(4-(diethoxylate)phenyl)-N,N-dimethylethanamine (1.0 g, 4 mmol) in methanol (5 ml)was added dropwise at 0°C a solution of hydrochloric acid-methanol (10 ml). The reaction solution was stirred at ambient temperature overnight. Then the methanol was removed in vacuum, obtaining 4-((dimethylamino)methyl)benzaldehyde (0,68g, yield 99%) in the form of a light yellow oil.1H-NMR (00 MHz, CDCl3): δ of 2.26 (s, 6H), 3,50 (s, 2H), 7,49 (d, J=6,4 Hz, 2H), to 7.84 (d, J=6,4 Hz, 2H), 10 (s, 1H). LC-MS (ESI) m/z: 164 (M+1)+.

Example 16C

2,3-bis(4-((Dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-((dimethylamino)methyl)benzaldehyde (539 mg, 3.3 mmol) and 4-aminoazobenzene-1(3H)-she (223 mg, 1.5 mmol) in ethylpropylamine (14 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (138 mg, 6 mmol) in methanol (4 ml)]. After the addition the mixture was stirred at ambient temperature for 20 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 100:1 to 10:1)to give a mixture of 2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (165 mg) in the form of a solid of light yellow color.

Example 16D

8,9-bis(4-((Dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

a Mixture of 2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (165 mg, 0.34 mmol) in hydrazinoacetate (12 ml) and methanol (5 ml) was stirred at 40°C for 6 hours. The mixture was filtered, give crude product. The crude product was purified preparative HPLC, getting 8,9-bis(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (or 33.7 mg, yield: 22%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ; 2,04 (s, 6H), was 2.05 (s, 6H), 3,19-3,20 (m, 2H), 3,24-3,26 (m, 2H), 4.09 to-4,11 (d, J=8,8 Hz, 1H), to 4.52-of 4.54 (d, J=8,8 Hz, 1H), 6,88-of 6.90 (m, 2H), 6,99-a 1.01 (m, 7H), 7,42-7,46 (m, 2H). LC-MS (ESI) m/z: 454 (M+1)+.

Example 17

9-(4-(4-(Cyclopropanecarbonyl) piperazine-1-carbonyl)phenyl)-8-(4((methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 17A

4-(Cyclopropanecarbonyl)piperazine-1-tert-butylcarbamoyl

A mixture of compound piperazine-1-tert-BUTYLCARBAMATE (3,725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 ml) was cooled to 0°C, then was added dropwise cyclopropanecarbonyl chloride (2.30 g, 22 mmol). After the addition the mixture was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (100 ml), washed with 10%citric acid (50 ml), then saturated sodium bicarbonate (50 ml), brine (100 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 4-(cyclopropanecarbonyl)piperazine-1-tert-butylcarbamoyl (3.7 g, yield 73%) in the particulate form in the society of white. 1H-NMR (400 MHz, CDCl3) δ (ppm): 0,76 is 0.81 (m, 2H), 0,98-of 1.03 (m, 2H), 1,49 (s, 9H), 1,69 is 1.75 (m, 1H), 3.46 in-of 3.48 (m, 4H), 3,63-the 3.65 (m, 4H); LC-MS (ESI) m/z: 255 (M+1)+.

Example 17B

Cyclopropyl(piperazine-1-yl)methanon hydrochloride

To a stirred mixture of compound 4-(cyclopropanecarbonyl)piperazine-1-tert-BUTYLCARBAMATE (3.7 g, 14.5 mmol) in methanol (15 ml) at 0°C was added the hydrochloride/methanol (15 ml, 3M)). After the addition the mixture was stirred at ambient temperature overnight. The mixture was concentrated, getting cyclopropyl(piperazine-1-yl)methanon hydrochloride (2,74 g, yield 100%) in the form of a solid off-white color.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0,71-0,76 (m, 4H), 1,96-2,03 (m, 1H), 3.04 from-and 3.16 (m, 4H), 3,69-4,08 (m, 4H), 9,58 (s, 2H); LC-MS (ESI) m/z: 155 (M+1)+.

Example 17C

4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde

To a stirred mixture of 4-formylbenzoate acid (900 mg, 6 mmol) in anhydrous dichloromethane (30 ml) was added triethylamine (1,52 mg, 15 mmol), 1-hydroxybenzotriazole (891 mg, 6.6 mmol)and then 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (1,254 g, 6.6 mmol). After the addition the mixture was stirred at ambient temperature for 40 minutes. Then the mixture was cooled to 0°C, and added parts cyclopropyl (piperazine-1-yl)methanon hydrochloride (1,259 g, 6.6 mmol). After the addition the mixture was stirred at ambient temperature during the course the e night. The mixture was diluted with dichloromethane (50 ml), washed with saturated citric acid (100 ml ×2), then saturated sodium bicarbonate (100 ml ×2), brine (50 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (810 mg, yield 80%) in the form of a light yellow oil.1H-NMR (400 MHz, CDCl3) δ (ppm): 0.79, which is of 0.85 (m, 2H), 1.00 m of-1.04 (m, 2H), 1,72 and 1.80 (m, 1H), 3,41-3,81 (m, 8H), 7,58-of 7.60 (d, J=8.0 Hz, 1H), 7.95 is-of 7.97 (d, J=8.0 Hz, 1H), 10,07 (s, 1H); LC-MS (ESI) m/z: 287 (M+1)+.

Example 17D

4-(4-(Diethoxylate)benzylideneamino)isobenzofuran-1(3H)-he

To a stirred mixture of 4-(diethoxylate)benzaldehyde (3.75 g, 18 mmol) and anhydrous sodium sulfate (21,3 g, 150 mmol) in anhydrous dichloromethane (300 ml) at 0°C was added 4-aminoazobenzene-1(3H)-he (2.24 g, 15 mmol). After the addition the mixture was stirred at ambient temperature for 6 days. The mixture was filtered and the precipitate washed with dichloromethane (50 ml ×3). The filtrate was concentrated, give crude product. The crude product was washed with petroleum ether, receiving 4-(4-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-he (4.3 g, yield 84%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 340 (M+1)+.

Example 17E

3-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of 4-(4-(is eloprofessional)piperazine-1-carbonyl)benzaldehyde (859 mg, 3 mmol) and 4-(4-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-she (1,018 g, 3 mmol) in ethylpropylamine (40 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (276 mg, 12 mmol) in methanol (8 ml)]. After the addition the mixture was stirred at ambient temperature for 20 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:10)to give 3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (500 mg, yield 26%). LC-MS (ESI) m/z 640 (M+1)+.

Example 17F

9-(4-(4-(cyclopropanecarbonyl)piperazine derivatives-1-carbonyl)phenyl)-8-(4-(diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (526 mg, 0.82 mmol) in 85%wage hydrazinoacetate (4 ml) and methanol (3 ml) was stirred at 25°C for 2 hours. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers washed the Li salt solution, dried over anhydrous sodium sulfate and concentrated, receiving 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (330 mg, yield 65%) in the form of a solid yellow color.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0,72-0,76 (m, 4H), 1,09 by 1.12 (m, 6H), 1,99 (s, 1H), 3,39-to 3.73 (m, 12H), 4,70 (s, 1H), of 5.40 (s, 1H), of 5.99 (s, 1H), 6,68-7,31 (m, 9H), 7,41-to 7.61 (m, 3H), 12,19 (s, 1H); LC-MS (ESI) m/z: 622 (M+1)+.

Example 17G

4-(9-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde

A mixture of 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (280 mg, 0.45 mmol) in 3h. hydrochloric acid (10 ml) was stirred at ambient temperature for 3 hours. Then the mixture was neutralized with potassium carbonate. The resulting suspension was filtered, obtaining 4-(9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (220 mg, yield 89%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 548 (M+l)+.

Example 17Η

9-(4-(4-(Cyclopropanecarbonyl) piperazine-1-carbonyl)phenyl)-8-(4((methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]nafta is asin-8-yl)benzaldehyde (80 mg, 0.15 mmol) and 27% alcohol solution of methylamine (50 mg, 0.44 mmol) in methanol (10 ml) was stirred at ambient temperature for 40 minutes Then the mixture was cooled to 0°C. was Added sodium borohydride (8,3 mg, 0.23 mmol). After the addition the mixture was stirred at this temperature for 2 hours. The methanol was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product. The crude product was purified preparative HPLC, receiving 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4 ((methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (6.4 mg, yield 7%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): 0,83-of 0.91 (m, 4H), 1,94-2,03 (m, 1H), 2,66 of 2.68 (d, J=6.0 Hz, 3H), 3,35-with 3.79 (m, 8H), 4,11 (s, 2H), 4,42-of 4.44 (d, J=7,6 Hz, 1H), 4,88-of 4.90 (d, J=7.2 Hz, 1H), 7,21-7,26 (m, 3H), 7.29 trend was 7.36 (m, 4H), 7,41-the 7.43 (d, J=8,4 Hz, 2H), 7,55-EUR 7.57 (d, J=7.2 Hz, 1H), 7,63-to 7.67 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 563 (M+1)+.

Example 18

9-(4-(4- (cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4 ((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (80 mg, 0.15 mmol) and 27% solution of dimethylamine (62 mg, 0.44 mmol) in methanol (10 ml) was stirred at ambient temperature for 40 minutes the ATEM and the mixture was cooled to 0°C. Was added sodium borohydride (8,3 mg, 0.22 mmol). After the addition the mixture was stirred at this temperature for 2 hours. The methanol was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product. The crude product was purified preparative HPLC, receiving 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4 ((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (4.2 mg, yield 5%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): 0,73-of 0.79 (m, 4H), of 1.84 (m, 1H), 2,69 (s, 6H), 3,47-and 3.72 (m, 8H), 4,14 (s, 2H), or 4.31-to 4.33 (d, J=8.0 Hz, 1H), 7,12-7,35 (m, 9H), 7,47-7,58 (m, 2H); LC-MS (ESI) m/z: 577 (M+1)+.

Example 19

8-(4-(Hydroxymethyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 20

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 19A

4-Isobutylpyrazine-tert-butyl-1-carboxylate

To a solution of somaclonal acid (6,608 g, 75 mmol) in anhydrous dichloromethane (130 ml) was added triethylamine (8,33 g of 82.5 mmol), 1-hydroxybenzotriazole (rate of 10,125 g, 75 mmol)and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (of 14.25 g, 75 mmol). After the addition the mixture was stirred at ambient temperature for 40 minutes. Then a mixture of what was ladli to 0°C and added parts piperazine-1-tert-butylcarbamoyl (13,97 g, 75 mmol). After the addition the mixture was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (200 ml), washed with saturated sodium bicarbonate (150 ml ×2), 10%citric acid (150 ml), brine (100 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 4-isobutylpyrazine-1-tert-butyl carboxylate (15 g, yield 78%) in the form of a solid white color.1H-NMR (400 MHz, CDCl3) δ (ppm): 1,13-to 1.14 (d, J=6.8 Hz, 6H), of 1.47 (s, 9H), 2,75-2,82 (m, 1H), 3.43 points-to 3.58 (m, 4H); LC-MS (ESI) m/z: 257(M+1)+.

Example 19B

2-Methyl-1-(piperazine-1-yl)propane-1-he

To a stirred mixture of 4-isobutylpyrazine-1-tert-BUTYLCARBAMATE (6.8 g, of 26.5 mmol) in methanol (15 ml) at 0°C was added a mixture of hydrochloride/methanol (30 ml, 3M)). After the addition the mixture was stirred at ambient temperature overnight. The mixture was concentrated, obtaining 2-methyl-1-(piperazine-1-yl)propane-1-he (5.5 g, yield 100%) in the form of a solid off-white color.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0,99-1,00 (d, J=6.4 Hz, 6H), 2,84-2,89 (m, 1H), 3,03-of 3.07 (d, 4H), 3,68-3,74 (d, 4H), 9,58 (s, 2H); LC-MS (ESI) m/z 157 (M+1)+.

Example 19C

4-(4-Isobutylpyrazine-1-carbonyl)benzaldehyde

To a stirred mixture of 4-formylbenzoate acid (1.5 g, 10 mmol) in anhydrous dichloromethane (30 ml) was added triethylamine (2,52 g, 25 mmol), 1-hydroxybenzotriazole (1.5 g, 11 mmol), then 1-et is l-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.1 g, 11 mmol). After the addition the mixture was stirred at ambient temperature for 40 minutes. Then the mixture was cooled to 0°C was added 2-methyl-1-(piperazine-1-yl)propane-1-he (2,12 g, 11 mmol). After the addition the mixture was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (50 ml), washed with saturated citric acid (100 ml ×2), then saturated sodium bicarbonate (100 ml ×2), brine (50 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 4-(4-isobutylpyrazine-1-carbonyl)benzaldehyde (2 g, yield 70%) in the form of a light yellow oil.1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.15 (d, 6H), 2,80 (users, 1H), 3,39-of 3.80 (m, 8H), 7,58 (d, J=8.0 Hz, 1H), 7,95 (d, J=8.0 Hz, 1H), 10,07 (s, 1H); LC-MS (ESI) m/z: 289 (M+1)+.

Example 19D

2-(4-(Diethoxylate)phenyl)-3-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of 4-(4-isobutylpyrazine-1-carbonyl)benzaldehyde (950 mg, 3.3 mmol) and (E)-4-(4-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-he (1,018 g, 3 mmol) in ethylpropylamine (40 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (345 mg, 12 mmol) in methanol (8 ml)]. After the addition the mixture was stirred at ambient temperature for 24 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue RA is tarali in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate = 10:1 to 1:10)to give 2-(4-(diethoxylate)phenyl)-3-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (491 mg, yield 25%).

Example 19E

8-(4-(Diethoxylate)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-(diethoxylate)phenyl)-3-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (491 mg, 0.77 mmol) in 85%wage hydrazinoacetate (4 ml) and methanol (3 ml) was stirred at 25°C during the night. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, obtaining 8-(4-(diethoxylate)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (365 mg, yield 77%) in the form of a solid yellow color.

Example 19F

4-(9-(4-(4-(Isobutylpyrazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde

A mixture of 8-(4-(diethoxylate)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he is (365 mg, 0.59 mmol) in 3h. hydrochloric acid (10 ml) was stirred at ambient temperature for 3 hours. Then the mixture was neutralized with potassium carbonate. The resulting suspension was filtered, give crude product. The crude product was purified preparative HPLC, obtaining 4-(9-(4-(4-(isobutylpyrazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (80 mg, yield 28%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): 1,11-of 1.13 (d, J=6.8 Hz, 6H), 2.95 and-3,14 (users, 1H), 3,38-of 3.80 (m, 8H), 4,37-and 4.40 (d, J=7.2 Hz, 1H), 4.75 V-of 4.77 (d, J=7,6 Hz, 1H), 7,20-7,33 (m, 9H), EUR 7.57-to 7.59 (d, J=7,6 Hz, 1H), 7,60-7,76 (t, J=8.0 Hz,, 1H), 9,92 (s, 1H); LC-MS (ESI) m/z: 550 (M+1)+.

Examples 19G 20

8-(4-(Hydroxymethyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-8-(4-((dimethylamino)methyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of compound7(50 mg, 0.09 mmol) and 33%aqueous solution of dimethylamine (25 mg, 0.18 mmol) in methanol (10 ml) was stirred at ambient temperature for 40 minutes Then the mixture was cooled to 0°C. was Added sodium borohydride (5 mg, 0.13 mmol). After the addition the mixture was stirred at this temperature for 2 hours. TLC (petroleum ether/ethyl acetate=2:1) showed that the reaction was complete. The methanol was removed under reduced pressure. The remainder of promyshlennyy ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product. The crude product was purified preparative HPLC, receiving 8-(4-((dimethylamino)methyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (4 mg, yield 9%) and 8-(4-(hydroxymethyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (16 mg, yield 36%) in the form of solid particles of light-yellow color. 8-(4-((Dimethylamino)methyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he:1H-NMR (400 MHz, CD3OD) δ (ppm): 1,10-of 1.12 (d, J=6.8 Hz, 6H), 2,80 (s, 6H), 2,96-3,00 (users, 1H), 3.33 and-3,70 (m, 8H), of 4.12 (s, 2H), 4,43-of 4.44 (d, J=7,6 Hz, 1H), 4,89-4,91 (d, J=7,6 Hz, 1H), 7,22-7,27 (m, 3H), 7,31-7,37 (m, 4H), 7,42-7,44 (d, J=8.0 Hz, 2H), 7,56-7,58 (d, J=7.2 Hz, 1H), of 7.64-7.68 per (t, 7= 8.0 Hz, 1H); LC-MS (ESI) m/z: 579 (M+1)+. 8-(4-(hydroxymethyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he:1H-NMR (400 MHz, CD3OD) δ (ppm): 1,10-of 1.12 (d, J=6.4 Hz, 6H), 2.95 and (users, 1H), 3.33 and-3,81 (m, 8H), 4,39-to 4.41 (d, J=8,2 Hz, 1H), 4.53-in (s, 2H), 4,77-rate 4.79 (d, J=7,6 Hz, 1H), 7,20-7,30 (m, 9H), 7,55-EUR 7.57 (DD, J1=8.0 Hz, J2=1.0 Hz, 1H), 7,63-to 7.67 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 552 (M+1)+.

Example 21

9-(4-(4-(Cyclopropanecarbonyl)piperazine derivatives-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 21A

(E)-4-(Benzylideneamino)isobenzofuran-1(3H)-he

To a stirred mixture of benzaldehyde (1,91 g, 18 mmol) and anhydrous sulfate is sodium (21,3 g, 150 mmol) in anhydrous dichloromethane (100 ml) at 0°C was added 4-aminoazobenzene-1(3H)-he (2.24 g, 15 mmol). After the addition the mixture was stirred at ambient temperature for 6 days. The mixture was filtered and the precipitate washed with dichloromethane (50 ml ×3). The filtrate was concentrated, give crude product. The crude product was washed with petroleum ether, obtaining (E)-4-(benzylideneamino)isobenzofuran-1(3H)-he (to 3.38 g, yield 95%) in the form of a solid white color.1H-NMR (400 MHz, CDCl3) δ (ppm): 5,41 (s, 2H), was 7.36-7,37 (d, J=7,6 Hz, 1H), 7,49-to 7.59 (m, 4H), to 7.77 for 7.78 (d, J=7,6 Hz, 1H), 7,92-7,94 (d, J=8.0 Hz, 2H), 8,55 (s, 1H). LC-MS (ESI) m/z: 238 (M+1)+.

Example 21B

3-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of compound 4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (429 mg, 1.5 mmol) and (E)-4-(benzylideneamino)isobenzofuran-1(3H)-he ((355,5 mg, 1.5 mmol) in ethylpropylamine (12 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (138 mg, 6 mmol) in methanol (12 ml)]. After the addition the mixture was stirred at 25°C for 18 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and who has centriole, give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:10)to give 3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (90 mg, yield 11%). LC-MS (ESI) m/z: 538 (M+1)+.

Example 21C

9-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (90 mg, 0.16 mmol) in 85%wage hydrazinoacetate (5 ml) and methanol (2 ml) was stirred at 25°C for 4 hours. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified preparative HPLC, receiving 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (18 mg, yield 22%) in the form of a solid white color.1H-NMR (400 MHz, CD3OD) δ (ppm): 0,86-0,94 (m, 4H), 2,00 (s, 1H), 3.33 and-3,82 (m, 8H), to 4.41-4,43 (d, J=8,4 Hz, 1H), 4,78-4,80 (d, J=8,4 Hz, 1H), 7,21-7,27 (m, 6H), 7,30-7,35 (m, 4H), 7,58-of 7.60 (m, 1H), 7,65-of 7.69 (t, J=8.0 Hz, 4H); LC-MS (ESI) m/z: 520 (M+1)+.

Example 22

9-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 2A

3-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (286 mg, 1 mmol) and (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (237 mg, 1 mmol) in ethylpropylamine (7.5 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (92 mg, 4 mmol) in methanol (7.5 ml)]. After the addition the mixture was stirred at 25°C for 18 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:10)to give 3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (64 mg, yield 12%). LC-MS (ESI) m/z: 538 (M+1)+.

Example 22B

9-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (64 mg, 0.12 mmol) in 85%wage hydrazinoacetate (5 ml) and methanol (2 ml) was stirred at 25°C in accordance with the s 4 hours. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified preparative HPLC, receiving 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-(8 mg, yield 13%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): 0,73-0,81 (m, 4H), 1,18-1,19 (m, 1H), 3,20-3,71 (m, 8H), 4,23-of 4.25 (d, J=10.0 Hz, 1H), 4,59-br4.61 (d, J=8,4 Hz, 1H), 7,08-7,26 (m, 10H), 7,45-rate of 7.54 (m, 2H); LC-MS (ESI) m/z: 520(M+1)+.

Example 23

9-(3-((Dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)benzaldehyde (45 mg, 0.12 mmol) and 33%solution of dimethylamine (50.2 mg, 0,366 mmol) in methanol (5 ml) was stirred at ambient temperature for 1 hour. Then the mixture was cooled to 0°C, was added in portions sodium borohydride (6,95 mg, 0,184 mmol). After the addition the mixture was stirred at this temperature for 2 hours. The methanol was removed under reduced pressure. The residue was purified preparative HPLC, receiving 9-(3-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (21 mg, yield 44%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): at 2.59 (s, 3H), of 2.75 (s, 3H), 4,11-427 (square, 2H), or 4.31-4,34 (d, J=10.4 Hz, 1H), 4,68-4,71 (d, J=10.4 Hz, 1H), 7,17-7,30 (m, 9H), 7,33-7,37 (t, J=7,6 Hz, 1H), 7,56-7,58 (d, J=7,6 Hz, 1H), 7,60-to 7.64 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 396 (M+1)+.

Example 24

8-(3-((Methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 24A

(E)-4-(3-(Diethoxylate)benzylideneamino)isobenzofuran-1(3H)-he

To a stirred mixture of 3-(diethoxylate)benzaldehyde (3.75 g, 18 mmol) and anhydrous sodium sulfate (21,3 g, 150 mmol) in anhydrous dichloromethane (300 ml) at 0°C was added 4-aminoazobenzene-1(3H)-he (2.24 g, 15 mmol). After the addition the mixture was stirred at ambient temperature for 6 days. The mixture was filtered and the precipitate washed with dichloromethane (50 ml ×3). The filtrate was concentrated, give crude product. The crude product was washed with petroleum ether, obtaining (E)-4-(3-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-he (3.1 g, yield 61%) in the form of a solid white color. LC-MS (ESI) m/z: 340 (M+1)+.

Example 24B

2-(3-(Diethoxylate)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 2-(3-(diethoxylate)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(3-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-she (678 mg, 2 mmol) and benzaldehyde (212 mg, 2.2 mmol) in ethylpropylamine (20 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (183 mg, 8 mmol) in methanol is (10 ml)]. After the addition the mixture was stirred at ambient temperature for 24 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:10)to give a mixture of 2-(3-(diethoxylate)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2-(3-(diethoxylate)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (160 mg, yield 17%).

Example 24C

8-(3-(Diethoxylate)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(3-(diethoxylate)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2-(3-(diethoxylate)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (160 mg, 0.36 mmol) in 85%wage hydrazinoacetate (4 ml) and methanol (3 ml) was stirred at 25°C during the night. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, obtaining 8-(3-(diethoxylate)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (90 mg, yield 58%) in the form of a solid yellow the Board. LC-MS (ESI) m/z: 442 (M+1)+.

Example 24D

3-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde

A mixture of 8-(3-(diethoxylate)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (90 mg, 0.21 mmol) in 3h. hydrochloric acid (10 ml) was stirred at ambient temperature for 3 hours. Then the mixture was neutralized with potassium carbonate. The resulting suspension was filtered, getting 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (40 mg, yield 50%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CDCl3) δ (ppm): 4,24 (d, J=7,6 Hz, 1H), 4,77 (d, J=7,6 Hz, 1H), 4,85 (users, 1H), 7,01-7,03 (m, 2H), 7,08-7,10 (m, 1H), 7,21-7,24 (m, 3H), 7,37-7,39 (m, 2H), to 7.61-the 7.65 (m, 1H), 7,74 to 7.75 (m, 2H), 7,79-7,81 (m, 1H), 9,59 (users, 1H), 9,92 (s, 1H). LC-MS (ESI) m/z: 368 (M+1)+.

Example 24E

8-(3-((Methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (40 mg, 0.11 mmol) and 27% alcohol solution of methylamine (28 mg, 0.23 mmol) in methanol (10 ml) was stirred at ambient temperature for 40 minutes Then the mixture was cooled to 0°C. was Added sodium borohydride (7 mg, 0.18 mmol). After the addition the mixture was stirred at this temperature for 2 hours. The methanol was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate is the end of what was tarawali, give crude product. The crude product was purified preparative HPLC, receiving 8-(3-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (4 mg, yield 10%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): 2,44 (s, 6H), 3,99 (m, 2H), 4,21 (m, 1H), 4,69 (m, 1H), 6,98-7,00 (d, J=7.2 Hz, 1H), 7,05-7,10 (m, 4H), 7,21-of 7.23 (m, 3H), 7,31 (s, 1H), 7,46-of 7.48 (d, J=8.0 Hz, 1H), 7,51-7,53 (m, 1H). LC-MS (ESI) m/z: 383 (M+1)+.

Example 25

8-(4-((Dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 25A

2-(4-(Dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

To a solution of (E)-4-(4-(dimethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-she (600 mg, 1 mmol) and benzaldehyde (616 mg, 3 mmol) in ethylpropylamine (20 ml) was added methanolate sodium (414 mg, 7.6 mmol)and the mixture was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4) and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate 20:1-5:1)to give a solid white color, representing 2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (120 mg, yield 22%). LC-MS (ESI) m/z: 432 (M+1)+.

Example 25B

8-(4-(Dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-the n

Was added 2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (120 mg, 0.28 mmol) and 85%hydrazinoacetate (20 ml)and the mixture was stirred at 40°C for 3 hours. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered, obtaining 8-(4-(dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (89 mg, yield 78%). LC-MS (ESI) m/z: 414 (M+1)+.

Example 25C

4-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde

Added 8-(4-(dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (89 mg, 0.22 mmol) and 20 ml of 3n. hydrochloric acid, and the mixture was stirred at ambient temperature for 2 hours. The resulting mixture was neutralized with potassium carbonate and then filtered, obtaining 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (59, yield 73%). LC-MS (ESI) m/z: 368.

Example 25D

8-(4-((Dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Was added 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (59 mg, 0.16 mmol) and dimethylamine (5 ml)and the mixture was stirred at ambient temperature for 2 hours. Then was added 20 mg of sodium borohydride and stirred for another 2 hours. The resulting mixture was evaporated under reduced pressure and was purified preparative HPLC, receiving 8-(4-((di is ethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (20 mg, yield 32%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): to 2.18 (s, 6H), 4,28-4,30 (d, J=8 Hz, 1H), 4.72 in-4,74 (d, J=8 Hz, 1H), 7,06-was 7.08 (m, 2H), 7,13-7,20 (m, 6H), 7.23 percent-of 7.25 (m, 2H), 7,54-the 7.65 (m, 2H). LC-MS (ESI) m/z: 397 (M+1)+.

Example 26 and 27

8-(4-(Morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Was added 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (59 mg, 0.16 mmol) and morpholine (42 mg)and the mixture was stirred at ambient temperature for 2 hours. Then was added 20 mg of sodium borohydride and stirred for another 2 hours. The resulting mixture was evaporated under reduced pressure and was purified preparative HPLC, receiving 8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-(8 mg, yield 11%) and 8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-(7 mg, yield 12%). 8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he:1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2,31 (s, 4H), to 3.36 (s, 4H), 3,61-3,63 (m, 4H), 4,15-4,17 (d, J=10 Hz, 1H), 4,58-br4.61 (d, J=10 Hz, 1H), 4,79 (s, 1H), 6,94-7,19 (m, 10H), 7,51-of 7.55 (m, 1H), 7.68 per-of 7.70 (m, 1H), 7,63 (s, 1H). LC-MS (ESI) m/z: 439 (M+1)+.

8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he:1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4,21-of 4.25 (m, 1H), 4.63 to-4,70 (m, 1H), a 4.86 (s, 1H), 6,97-7,06 (m, 3H), 7,11-7,26 (m, 7H), 7,58 to 7.62 (m, 1H), 7,75-to 7.77 (m, 1H). LC-MS (ESI) m/z: 370 (M+1)+.

Examples 28 and 29

9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 28A

3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde

To a stirred mixture of 3-formylbenzoate acid (450 mg, 3 mmol) in anhydrous dichloromethane (20 ml) was added triethylamine (758 mg, 7.5 mmol), 1-hydroxybenzotriazole (466 mg, of 3.45 mmol)and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (629 mg, of 3.45 mmol). After the addition the mixture was stirred at ambient temperature for 40 minutes. Then the mixture was cooled to 0°C, and added parts cyclopropyl(piperazine-1-yl)methanon hydrochloride (629 mg, 3.3 mmol). After the addition the mixture was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (50 ml), washed with saturated citric acid (100 ml ×2), then saturated sodium bicarbonate (100 ml ×2), brine (50 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (810 mg, yield 94%) in the form of a light yellow oil.1H-NMR (400 MHz, CDCl3) δ (ppm): 0.79, which is of 0.85 (m, 2H), 1.00 m of-1.04 (m, 2H), of 1.73 to 1.76 (m, 1H), 3,47-of 3.77 (m, 8H), 7,62-7,66 (t, J=7,6 Hz, 1H), 7,7-7,72 (d, J=1.6 Hz, 1H), 7.95 is-7,98 (m, 2H), 10,1 (s, 1H); LC-MS (ESI) m/z: 287 (M+1)+.

Example 28B

3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (940 mg, 3.3 mmol) and (E)-4-(4-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-she (1,018 g, 3 mmol) in ethylpropylamine (40 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (345 mg, 15 mmol) in methanol (8 ml)]. After the addition the mixture was stirred at ambient temperature for 24 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:10)to give 3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (425 mg, yield 22%).

Example 28C

9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(di is oxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (425 mg, 0.67 mmol) in 85%wage hydrazinoacetate (4 ml) and methanol (3 ml) was stirred at 25°C during the night. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, receiving 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (290 mg, yield 70%) in the form of a solid yellow color.

Example 28D

4-(9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde

A mixture of 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (290 mg, 0.48 mmol) in 3h. hydrochloric acid (10 ml) was stirred at ambient temperature overnight. Then the mixture was neutralized with potassium carbonate. The resulting suspension was filtered, give crude product. The crude product was purified preparative HPLC, obtaining 4-(9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (20 mg, yield 8%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): 0,83-of 0.91 (m, 4H), 1,94-2,03 (m, 1H), 3,18 is 3.23 (m, 1H), 3.46 in-3,82 (m, 7H), 4,42 (d, J=7,6 Hz, 1H), 4,87 (d, J=7,4 Hz, 1H), 7,22-7,41 (m, 7H), 7,52-rate of 7.54 (d, J=8.0 Hz, 2H), 7,60 (d, 1H), 9,94 (, 1H); LC-MS (ESI) m/z: 54 (M+1) +.

Examples 28E and 29E

9-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (20 mg, 0.04 mmol) and 33%aqueous solution of dimethylamine (10 mg, 0.07 mmol) in methanol (10 ml) was stirred at ambient temperature for 40 minutes Then the mixture was cooled to 0°C. was Added sodium borohydride (2 mg, 0.06 mmol). After the addition the mixture was stirred at this temperature for 2 hours. The methanol was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product. The crude product was purified preparative HPLC, obtaining the compound 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (4 mg, yield 19%) and 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (2 mg, yield 9%) in the form of solid particles of light-yellow color. 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl)-,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he: 1H-NMR (400 MHz, CD3OD) δ (ppm): 0,83-of 0.91 (m, 4H), 1,94-2,03 (m, 1H), 2,81 (s, 6H), 3,18 is 3.23 (m, 1H), 3,35-with 3.79 (m, 7H), 4.26 deaths (s, 2H), and 4.40 (d, J=7,6 Hz, 1H), 4,82 (d, J=7.2 Hz, 1H), 7,22-7,29 (m, 4H), 7,31-7,33 (m, 1H), 7,37 was 7.45 (m, 4H), 7,58-of 7.60 (d, J=8.0 Hz, 1H), of 7.64-7.68 per (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 577 (M+1)+.

9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he:1H-NMR (400 MHz, CD3OD) δ (ppm): 0,83-of 0.91 (m, 4H), 1,94 is 2.01 (m, 1H), 3,11-3,14 (m, 1H), 3,35-with 3.79 (m, 7H), 4,37-and 4.40 (d, J=10.0 Hz, 1H), 4,55 (s, 2H), to 4.38 (d, J=7,6 Hz, 1H), 4,73 was 4.76 (d, J=9.6 Hz, 1H), 7,12 (s, 1H), 7,20-7,30 (m, 7H), 7,34-7,38 (t, J=8.0 Hz, 1H), 7,56-7,58 (d, J=7,6 Hz, 1H), 7,62-7,66 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 550 (M+1)+.

Example 30

9-(4-(4-Isobutylpyrazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (40 mg, 0.07 mmol) and 33%aqueous solution of dimethylamine (17 mg, 0.14 mmol) in methanol (10 ml) was stirred at ambient temperature for 40 minutes Then the mixture was cooled to 0°C. was Added sodium borohydride (4 mg, 0.11 mmol). After the addition the mixture was stirred at this temperature for 2 hours. The methanol was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product. The crude product was purified preparative HPLC, floor the tea compound 9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (18 mg, yield 49%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): 1,10-of 1.12 (d, J=6.8 Hz, 6H), to 2.67 (s, 3H), 2,81 (users, 1H), 3.33 and-3,70 (m, 8H), of 4.12 (s, 2H), 4,43-of 4.75 (d, J=7,6 Hz, 1H), 4,88 (d, J=7,4 Hz, 1H), 7,22-7,27 (m, 3H), 7,31-7,37 (m, 4H), 7,42-7,44 (d, J=8.0 Hz, 2H), 7,56-7,58 (d, J=7.2 Hz, 1H), of 7.64-7.68 per (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 579 (M+1)+.

Example 31

9-(3-(4-Isobutylpyrazine-1-carbonyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 31A

3-(4-Isobutylpyrazine-1-carbonyl)benzaldehyde

To a solution of 3-formylbenzoate acid (750 mg, 5 mmol) in anhydrous dichloromethane (15 ml) was added triethylamine (1,263 g, 12.5 mmol), 1-hydroxybenzotriazole (0,743 g, 5.5 mmol)and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (of 1.05 g, 5.5 mmol). After the addition the mixture was stirred at ambient temperature for 40 minutes. Then the mixture was cooled to 0°C, was added 2-methyl-1-(piperazine-1-yl)propane-1-he hydrochloride (1.06 g, 5.5 mmol). After the addition the mixture was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (50 ml), washed with saturated sodium bicarbonate (50 ml ×2), 10%citric acid (50 ml), brine (30 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 3-(4-isobutylpyrazine-1-carbonyl)benzaldehyde (1.44 g, yield 95%) in the form of resin.1H-NMR (400 MHz, CDCl3) δ (ppm: 1,13-to 1.14 (d, J=6.8 Hz, 6H), 2,80 (s, 1H), 3.46 in-of 3.80 (m, 8H), 7,62-7,66 (t, J=7,6 Hz, 1H), 7,69-7,71 (d, J=7,6 Hz, 1H), 7,94 (s, 1H), of 7.96-to 7.99 (DD, J1=7,6 Hz, J2= 1.2 Hz, 1H), 10,06 (s, 1H); LC-MS (ESI) m/z: 289 (M+1)+.

Example 31B

(E)-4-(Pyridine-4-ylmethylamino)isobenzofuran-1(3H)-he

A mixture of 4-aminoazobenzene-1(3H)-it (894 mg, 6 mmol), isonicotinamide (2,568 g, 24 mmol) and anhydrous sodium sulfate (3.6 g) in anhydrous ethanol (70 ml) was heated under reflux for two days. The mixture was cooled to ambient temperature and filtered. The filtrate was concentrated, give crude product. The crude product was washed with petroleum ether, obtaining (E)-4-(pyridine-4-ylmethylamino)isobenzofuran-1(3H)-he (1.1 g, yield 77%) in the form of a solid white color.1H-NMR (400 MHz, CDCl3) δ (ppm): 5,44 (s, 1H), 7,40-7,42 (d, J=7,6 Hz, 1H), to 7.59-7,63 (t, J=7,6 Hz, 1H), to 7.77-7,79 (d, J=5.6 Hz, 2H), 7,84-7,86 (d, J=7,6 Hz, 1H), 8,54 (s, 1H), 8,81-8,82 (d, J=4,8 Hz, 1H); LC-MS (ESI) m/z: 239 (M+1)+.

Example 31C

3-(3-(4-Isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of 3-(4-isobutylpyrazine-1-carbonyl)benzaldehyde (288 mg, 1 mmol) and (E)-4-(pyridine-4-ylmethylamino)isobenzofuran-1(3H)-she (238 mg, 1 mmol) in ethylpropylamine (7.5 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (92 mg, 4 mmol) in methanol (7.5 ml)]. After the addition the mixture was stirred at 25°C for 18 h the owls. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:10)to give 3-(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (140 mg, yield 26%). LC-MS (ESI) m/z: 541 (M+1)+.

Example 31D

9-(3-(4-Isobutylpyrazine-1-carbonyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(3-(4-isobutyryl piperazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (140 mg, 0.26 mmol) in 85%wage hydrazinoacetate (10 ml) and methanol (3 ml) was stirred at 25°C for 4 hours. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified preparative HPLC, obtaining the compound 9-(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (11 mg, yield 8%) in the form of a solid white color.1H-NMR (400 MHz, CD3OD) δ (ppm): 1,11-of 1.13 (m, 6H), 2.95 and-298 (m, 1H), 3,26-3,68 (m, 8H), 4,40 was 4.42 (d, J=8,4 Hz, 1H), 4,82-4,84 (d, J=8,4 Hz, 1H), 7,19-to 7.32 (m, 4H), of 7.36-7,39 (m, 3H), to 7.59-to 7.68 (m, 2H), to 8.41-8,42 (d, J=6.0 Hz, 2H); LC-MS (ESI) m/z: 523 (M+1)+.

According to the synthetic strategy shown inThe scheme of synthesis IandThe scheme of synthesis IIand a suitable experimental procedure as described in Examples 2-31, and using different aldehydes2and the appropriate 4-aminoazobenzene-1(3H)-it1received the following connections.

Example 32

9-(3-((Dimethylamino)methyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 33

9-(3-((Methylamino)methyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 34

9-(4-((Dimethylamino)methyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 35

9-(3-(Hydroxymethyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 36

9-(4-((Methylamino)methyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 37

9-(3-((Dimethylamino)methyl)phenyl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 38

9-(3-((Methylamino)methyl)phenyl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 39

9-(4-((Dimethylamino)methyl)phenyl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 40

9-(4-((Methylamino)methyl)phenyl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

The use of the 41

9-(3-(Hydroxymethyl)phenyl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 42

9-(3-((Dimethylamino)methyl)phenyl)-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 43

9-(3-((Methylamino)methyl)phenyl)-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 44

9-(3-(Hydroxymethyl)phenyl)-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 45

9-(4-((Dimethylamino)methyl)phenyl)-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 46

9-(4-((Methylamino)methyl)phenyl)-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 47

9-Phenyl-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 48

9-Phenyl-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 49

9-Phenyl-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 50

5-fluoro-9-phenyl-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 51

9-(3-((Dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 52

5-fluoro-9-(3-((methylamino)methyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 53

9-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 54

5-fluoro-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 55

9-(4-((Di is ethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine

Example 56

5-fluoro-9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine

Example 57

9-(3-((Dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine

Example 58

8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine

Example 59

5-fluoro-9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine

Example 60

5-fluoro-8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine

Example 61

7-Methyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A solution of 8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (1.04 mmol) in methanol (20 ml) was treated with formaldehyde (37 wt.% in water, 270 μl, 3.61 mmol) at ambient temperature over night. Added cyanoborohydride sodium (228 mg, 3.61 mmol)and the solution was stirred at ambient temperature for 3 hours. After concentration under reduced pressure, the residue was dissolved in a mixture triperoxonane acid and water and was purified HPLC, receiving 7-methyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he is a good solution.

Example 62

7-Ethyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

In accordance with the experimental conditions shown in Example 61, substituting formaldehyde, acetic aldehyde, obtained target compound 7-ethyl-8,9-diphenyl-89-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he.

Example 63

5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 63A

5-fluoro-2-methyl-3-nitromethylene

To conc. the solution Η2SO4(700 ml) at-5-0°C was added parts of 5-fluoro-2-methylbenzoic acid (80 g, 520 mmol). Then at-5-0°C was added dropwise a mixture of conc.HNO3(60,4 g, 624 mmol) in conc.Η2SO4(60 ml) over a period of approximately 1.5 hours. After the addition the mixture was stirred at this temperature for 2 hours. TLC (petroleum ether/EtOAc=1:1) showed that the reaction was complete. The mixture was poured into crushed ice with vigorous stirring and the precipitate was collected by filtration. The residue was dissolved in EtOAc, washed with saline, dried over anhydrousNa2SO4concentrated, obtaining the crude product 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g). The solution of this crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g) in dry methanol (500 ml) was cooled to 0°C was added dropwiseSOCl2(64,52 g, USD 542.3 mmol). After the addition the mixture was heated under reflux for 16 hours. TLC (petroleum ether/EtOAc=1:1) showed that the reaction was complete. The solvent was removed under reduced pressure to give crude product. The crude product was purified by chromatography on silica gel (petroleum ether until the mixture petroleum ether/EtOAc=50:1)to give 5-fluoro-2-METI the-3-nitromethylene (28 g, the output 25% for two steps) in the form of a solid white color.1H-NMR (400 MHz, CDCl3) δ (ppm): at 2.59 (s, 3H), of 3.95 (s, 3H), 7,60-7,63 (DD, 1H), 7,74-to 7.77 (DD, 1H); LC-MS (ESI) m/z: 214 (M+1)+. 216 (M+3)+.

Example 63B

6-Fluoro-4-nitrosobenzene-1(3H)-he

A mixture of 5-fluoro-2-methyl-3-nitromethylene (28 g, 130,5 mmol), NBS (27.8 g, of 156.6 mmol) and BPO (3.13 g, 13,1 mmol) inCCl4(400 ml) was heated under reflux overnight. TLC (petroleum ether/EtOAc=15:1) showed that the starting material was completely consumed. Was added water (200 ml), and CCl4was removed under reduced pressure. The residue was extracted with DCM (200 ml ×3). The combined organic layers were washed with saline, dried over Na2SO4concentrated, give crude 2-(methyl bromide)-5-fluoro-2-methyl-3-nitromethylene (36 g, yield 94%) in the form of a brown oil. A mixture of 2-(methyl bromide)-5-fluoro-2-methyl-3-nitromethylene (36 g, 123 mmol) in 1,4-dioxane (250 ml) and water (62.5 ml) was heated under reflux for 4 days. TLC (petroleum ether/EtOAc=15:1) showed that the starting material was completely consumed. The dioxane was removed under reduced pressure. The residue was extracted with EtOAc (300 ml ×4). The combined organic layers were washed with saline, dried overNa2SO4and concentrated give crude product. The crude product was purified by gel-chromatography (PE is Romanovo ether to a mixture of petroleum ether/EtOAc=5:1), getting 6-fluoro-4-nitrosobenzene-1(3H)-he (19.2 g, yield 79%) in the form of a solid white color.1H-NMR (400 MHz, CDCl3) δ (ppm): 5,74 (s, 2H), 7,97-7,98 (DD, 1H), 8,24-of 8.27 (DD, 1H); LC-MS (ESI) m/z: 198 (M+1)+.

Example 63C

4-Amino-6-floridalottery-1(3H)-he

A suspension of 6-fluoro-4-nitrosobenzene-1(3H)-she (9.6 g, of 48.7 mmol) and Pd/C (10%, 1 g) in EtOAc (300 ml) was stirred at 25°C under 1 atmosphere of hydrogen for 12 hours. TLC (petroleum ether/EtOAc=2:1) showed that the reaction was complete. The mixture was filtered and the precipitate washed with EtOAc (100 ml ×3). The filtrate was concentrated, obtaining 4-amino-6-floridalottery-1(3H)-he (7.5 g, yield 92%) in the form of a solid white color.1H-NMR (400 MHz, CDCl3) δ (ppm): 3,85 (users, 2H), 5,14-of 5.15 (d, 2H), 6,62-of 6.65 (DD, 1H), 6,98-7,00 (DD, 1H); LC-MS (ESI) m/z: 168 (M+1)+.

Example 63D

(E)-4-(Benzylideneamino)-6-floridalottery-1(3H)-he

To a stirred mixture of benzaldehyde (4,125 g, and 29.9 mmol) and anhydrous magnesium sulfate (36 g, 299 mmol) in anhydrous acetonitrile (200 ml) at 0°C was added 4-amino-6-floridalottery-1(3H)-he (5 g, and 29.9 mmol). After the addition the mixture was stirred at ambient temperature for 6 days. The mixture was filtered and the precipitate washed with ethyl acetate (50 ml ×3). The filtrate was concentrated, give crude product. The crude product was washed with petroleum ether, obtaining (E)-4-(benzylideneamino)-6-floridalottery-1(3H)-he (5 g, yield: 66%).1NMR (400 MHz, CDCl3) δ (ppm): of 5.40 (s, 2); 7,11-7,14 (DD, 1H), 7,44-7,46 (DD, 2H), 7,53-to 7.59 (m, 3H), 7,93-to 7.95 (m, 2H), 8,54 (s, 1H); LC-MS (ESI) m/z: 256 (M+1)+.

Example A

7-Fluoro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(benzylideneamino)-6-floridalottery-1(3H)-she (2 g, 7.8 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (0,949 g, 8,63 mmol) in ethylpropylamine (50 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol [sodium (722 mg, 31,37 mmol) in ethanol (30 ml)]. After the addition the mixture was stirred at ambient temperature for 2 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:10)to give 7-fluoro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (141 mg).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.18 to to 1.22 (t, 3H), and 3.31 (s, 3H), 4,174,21 (square, 2H), 4,621 with 4.65 (d, 2H), 5,17-5,20 (d, 1H), 6.48 in-6,51 (DD, 1H), 6,70-of 6.73 (m, 2H), 6,86 (s, 1H), 7.24 to 7,30 (m, 3H), 7,42-7,44 (t, 2H), 7,76 (s, 1H); LC-MS (ESI) m/z: 394 (M+1)+.

Example 63F

5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

The mixture ftor-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (141 mg) in 85%wage hydrazinoacetate (10 ml) and methanol (10 ml) was stirred at 45°C during the night. The methanol was removed under reduced pressure. The mixture was filtered and washed with water, receiving 5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-(11 mg, yield: 9%).1H-NMR (400 MHz, CD3OD) δ (ppm): to 3.34 (s, 3H)and 4.65 (d, J=8.0 Hz, 1H), 4,94 (d, J=8.0 Hz, 1H), for 6.81 (s, 1H), 6,88-7,02 (m, 2H), 7,18 (DD, 1H), 7,28-7,29 (m, 3H), 7,34 and 7.36 (m, 2H);19F-NMR (400 MHz, CD3OD) δ: -105,70 (C); LC-MS (ESI) m/z: 362 (M+1)+.

Example 64

5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 64 A

(E)-6-Fluoro-4-(4-verbindingenmee)isobenzofuran-1(3H)-he

4-amino-6-floridalottery-1(3H)-he (1.5 g, 8.98 mmol), 4-forbindelse (1,67 g, 13,47 mmol) and 12.75 gMgSO4added to 40 ml of DCM and stirred under reflux overnight, then the mixture was evaporated under reduced pressure, and the residues were dried under vacuum. Received 850 mg (E)-6-fluoro-4-(4-verbindingenmee)isobenzofuran-1(3H)-it.1H-NMR (400 MHz, CDCl3) δ (ppm): lower than the 5.37 (s, 2), 7,09 for 7.12 (DD, 1H), 7,19-of 7.23 (t, 2H), 7,43 was 7.45 (DD, 1H), 7,92-to 7.95 (m, 2H), 8,49 (s, 1H); LC-MS (ESI) m/z: 274 (M+1)+.

Example V

7-fluoro-2-(4-forfinal)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

Added (E)-6-Fluoro-4-(4-verbindingenmee)isobenzofuran-1(3H)-he (850 mg, of 3.13 mmol), 1-methyl-1H-imidazole-2-carbaldehyde (342 mg, of 3.13 mmol), methanolate sodium (851 mg, to 12.52 mmol) and ethylpropane (50 ml)and the mixture paramesh the Wali at ambient temperature over night. Then the mixture was evaporated under reduced pressure and was extracted with EtOAc (4×100 ml) and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether: EtOAc 20:1 to 5:1). Received 20 mg of 7-fluoro-2-(4-forfinal)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate. LC-MS (ESI) m/z: 412 (M+1)+.

Example 64C

5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Added 7-fluoro-2-(4-forfinal)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (20 mg, 0,048 mmol) and hydrazine (3 ml), MeOH (20 ml) and the mixture was stirred at ambient temperature for 3 hours. The resulting mixture was evaporated under reduced pressure to 5 ml and then filtered; received 5.6 mg of 5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it.1Η-NMR (400 MHz, CD3OD) δ (ppm): at 3.35 (s, 3H)and 4.65 (d, 1H), 4.95 points (d, 1H), 6,84 (s, 1H), 6.87 in-6,91 (m, 2H), 7,02 (t, 2H), 7,17-7,20 (m, 1H), 7,37-7,40 (m, 1H). LC-MS (ESI) m/z: 380 (M+1)+.

Example 65

8-(4-((Dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 65A

2-(4-(Diethoxylate)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-she (678 mg, 2 mmol), 1-methyl-1H-imidazole-2-carbaldehyde (22 mg, 2.2 mmol), ethanolate sodium (544 mg, 8.0 mmol) and ethylpropylamine (50 ml) was stirred at ambient temperature for 3 hours Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4), and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate= 20:1 to 1.5:1)to give 2-(4-(diethoxylate)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate in the form of a solid (50 mg, yield 5%). LC-MS (ESI) m/z: 478 (M+1)+.

Example 65 B

8-(4-(Diethoxylate)phenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-(diethoxylate)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (490 mg, of 1.03 mmol), methanol (20 ml) and hydrazinoacetate (2 ml) was stirred at 25°C for 3 hours. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered, received 250 mg of 8-(4-(diethoxylate)phenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it is in the form of solid, yield 55%. LC-MS (ESI) m/z: 446 (M+1)+.

Example 65C

4-(9-(1-Methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde

A mixture of 8-(4-(diethoxylate)phenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it (50 mg, 0.11 mmol) and 2 ml of hydrochloric acid (BC) was stirred at ambient temperature for 2 hours. The reaction mixture was neutralized K2CO3to pΗ 7 and then filtered, received 29 mg of 4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde, yield 70%. LC-MS (ESI) m/z: 372 (M+1)+.

Example 65D

8-(4-((Dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (80 mg, 0.22 mmol), acetic acid (60 μl) and 27%solution dimethylamino alcohol (2.5 ml, 15 mmol) in acetonitrile (7 ml) was stirred at ambient temperature for 4 h Then the mixture was cooled to 0°C. was Added aNaBH3CN (36 mg, 0.67 mmol). After the addition the mixture was stirred at ambient temperature for 4 hours. The methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated, receiving 8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (30 mg, yield 34%) in the form of a solid white color.1H-NMR: (400 MHz, DMSO-d6) δ (ppm): 2,11 (s, 6H), to 3.36 (s, 2H), 3,37 (s, 3H)and 4.65 (d, J=10.4 Hz, 1H), 4.92 in (d, J=10.4 Hz, 1H), 6,76 (s, 1H), 6.89 in (s, 1H), 7,20 (d, J=7,6 Hz, 3H), 7,35 (d, J=8.0 Hz, 2H), 7,43 (d, J=6,8 Hz, 1H), a 7.62 (t, J=7.8 Hz, 1H); LC-MS (ESI) m/z: 401 (M+1)+.

Example 66

9-(1-Isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]ptalis the h-3(7H)-he

Example 66A

Ethyl 3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 1H-imidazole-5-carbaldehyde (800 mg, 8.3 mmol), 2-jumprope (1.7 g, 10 mmol) and potassium carbonate (1.4 g) in DMF (30 ml) was heated to 50°C during the night. The mixture was evaporated under reduced pressure and then extracted with ethyl acetate (100 ml ×4). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, obtaining 1-isopropyl-1H-imidazole-5-carbaldehyde (1.1 g), LC-MS (ESI) m/z: 139 (M+1)+. This compound (1.1 g, 8.0 mmol) and (E)-4-(benzylideneamino)isobenzofuran-1(3H)-he (1.7 g, 7.2 mmol) was added to ethylpropane (50 ml), then at 0°C was added sodium ethylate. The mixture was stirred over night at ambient temperature. The mixture was concentrated, and the residue was extracted with ethyl acetate (100 ml ×4). The organic layer was dried over anhydrous sodium sulfate, purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:1)to give 3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (770 mg, 30%yield). LC-MS (ESI) m/z: 404 (M+1)+.

Example 66B

9-(1-Isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A suspension of 3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (770 mg, 1.9 mmol) and hydrazinoacetate (6 ml, 85%) add the Yali in methanol (10 ml) and stirred at 50°C during the night. The mixture was filtered, and the solid is white washed with methanol and dried, obtaining 9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (90 mg, yield 13%).1H-NMR (400 MHz, DMSO-d6,) δ (ppm): 0,82-0,84 (d, J=6.8 Hz, 3H), 1,27-of 1.29 (d, J=6.4 Hz, 3H), 3,30-to 3.33 (t, J=6,6 Hz, 1H), 4,67-4,70 (d, J=11.2 Hz, 1H), 4.92 in-4,95 (d, J=11.2 Hz, 1H), 6,80 (s, 1H), 7,01 (s, 1H), 7,16-to 7.18 (s, 1H), 7,24-7,28 (m, 3H), 7,31 (s, 1H), was 7.36-7,39 (m, 3H), 7,55-to 7.59 (m, 1H); LC-MS (ESI) m/z: 372 (M+1)+.

Example 67

9-(4-Methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 67A

1-Benzyl-4-methyl-1H-imidazole-2-carbaldehyde

To a solution of 4-methyl-1H-imidazole (1 g, 5.8 mmol) in 6 ml of TΗF cooled to -50°C, was added n-BuLi (2.9 ml, 625 mmol). The mixture was stirred at -50°C~40°C for 2 h Then was cooled to -78°C and was added dropwise to DMF (0,87 ml). After the addition the ice bath was removed and the mixture was stirred at ambient temperature for 30 minutes the mixture was evaporated under reduced pressure to 10 ml and then filtered; the crude product was purified by chromatography on columns, receiving 1-benzyl-4-methyl-1H-imidazole-2-carbaldehyde (450 mg, yield 38%). LC-MS (ESI) m/z: 201 (M+1)+.

Example 67B

3-(1-Benzyl-4-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of 1-benzyl-4-methyl-1H-imidazole-2-carbaldehyde (450 mg, 2.25 mmol), (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (640 mg, 2.7 mmol), m is canaleta sodium (207 mg, 9 mmol) and ethylpropylamine (25 ml) was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (4×100 ml) and concentrated, obtaining 3-(1-benzyl-4-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (250 mg, yield 25%). LC-MS (ESI) m/z: 438 (M+1)+.

Example 67C

9-(1-Benzyl-4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(1-benzyl-4-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (250 mg, or 0.57 mmol) and hydrazinoacetate (3 ml) was stirred at ambient temperature for 5 hours. The resulting mixture was evaporated under reduced pressure to 15 ml and then filtered; the filtrate was concentrated, receiving 9-(1-benzyl-4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he is solid white (40 mg, yield 16%). LC-MS (ESI) m/z: 434 (M+1)+.

Example 67D

9-(4-Methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 9-(1-benzyl-4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it (40 mg, 0.09 mmol) and the catalyst based on palladium hydroxide on carbon (40 mg, 20 wt.%) in anhydrous methanol (15 ml) was purged with hydrogen (1 bar) at ambient temperature for 12 hours. The mixture was filtered, and the filter is Rath concentrated, give crude product, which was purified prep-HPLC, receiving 9-(4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-(27 mg, yield 87%).1H-NMR (400 MHz, CD3OD) δ (ppm): 2,22 (DD, 3H), 4,77-a 4.86 (m, 2H), 7,06 (s, 1H), 7,20 (m, 1H), was 7.36 (t, 5H), at 7.55 (d, 1H), 7.62mm (t, 1H); LC-MS (ESI) m/z: 344 (M+1)+.

Example 68

8-Phenyl-9-(thiazol-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 68A

4-Oxo-2-phenyl-3-(thiazol-5-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of thiazole-5-carbaldehyde (500 mg, 4 mmol), (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (960 mg, 4 mmol), methanolate sodium (375 mg, 16,1 mmol) and ethylpropylamine (30 ml) was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (4×100 ml), and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate 10:1 to 1:1)to give 4-oxo-2-phenyl-3-(thiazol-5-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (110 mg, yield 7%). LC-MS (ESI) m/z: 379 (M+1)+.

Example 68B

8-Phenyl-9-(thiazol-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

4-Oxo-2-phenyl-3-(thiazol-5-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (110 mg, 0.29 mmol) and hydrazinoacetate (2 ml) was added to methanol (10 ml)and the mixture was stirred at ambient temperature for 4 hours. The resulting mixture was evaporated under eigendom pressure to 10 ml and then filtered; the filtrate was concentrated, receiving 8-phenyl-9-(thiazol-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (13 mg, yield 13%) in the form of a solid white color.1H-NMR (400 MHz, CD3OD) δ (ppm): 4,67 (d, 1H), 4,78 (d, 1H), 7,10-7,19 (m, 4H), 7,24 (t, 2H), 7,45-7,56 (m, 2H), 8,76 (s, 1H); LC-MS (ESI) m/z: 347 (M+1)+.

Example 69

9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 69A

3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (948 mg, 4 mmol) and furan-3-carbaldehyde (422 mg, 4.4 mmol) in ethylpropylamine (30 ml) was cooled to 0°C. Then was added dropwise a solution of ethoxide sodium in ethanol [sodium (368 mg, 16 mmol) in ethanol (20 ml)]. After the addition the mixture was stirred at ambient temperature for 2 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate = 10:1 to 1:1)to give 3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (80 mg, yield: 5%). LC-MS (ESI) m/z: 362 (M+1)+.

Example 69B

9-(Furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]falasi is -3(7H)-he

A mixture of 3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (80 mg) in 85%wage hydrazinoacetate (10 ml) and methanol (10 ml) was stirred at 45°C during the night. The methanol was removed under reduced pressure. The crude product was purified preparative HPLC, receiving 9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (5 mg, yield 7%).1H-NMR (400 MHz, CD3OD) δ (ppm): 4,19 (d, J=8.0 Hz, 1H), 4,67 (d, J=8.0 Hz, 1H), of 6.26 (s, 1H), 7,07-7,21 (m, 7H), 7,30 (s, 1H), 7,27 (m, 1H), 7,41 (d, 1H), 7,51 (m, 1H); LC-MS (ESI) m/z: 330 (M+1)+.

Example 70

8-(4-((4-Ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (200 mg, 0.54 mmol) in dichloromethane (30 ml) was added acetic acid (1 ml) followed by addition of 1-ethylpiperazine (121 mg, and 1.63 mmol). After the addition the mixture was stirred at ambient temperature overnight. Then the mixture was cooled to 0°C. was Added NaBH(OAc)3(173 mg, 0.81 mmol). After the addition the mixture was stirred at this temperature for 12 hours. Dichloromethane was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product. The crude product was purified preparative HPLC, receiving 8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,32-de]phthalazine-3(7H)-he (135 mg, yield 47%) in the form of a solid white color.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1,22 (t, 3H), 2,36 is 2.44 (m, 1H), 2,74-3,11 (m, 8H), 4,01-4,10 (m, 3H), 4,33 (DD, 1H), 4,78 (DD, 1H), 7,13-7,31 (m, 10H), 7,37 (d, 1H), 7,47 (s, 1H), 7,58 (t, 3H); LC-MS (ESI) m/z: 452 (M+1)+.

Example 71

9-Phenyl-8-(4-(piperazine-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (200 mg, 0.54 mmol) in dichloromethane (30 ml) at ambient temperature was added acetic acid (196 mg, 3,24 mmol) and piperazine-1-tert-butylcarbamoyl (304 mg, and 1.63 mmol) and was stirred over night. Then to the mixture at 0°C was added NaBH(OAc)3(173 mg, 0.81 mmol), was stirred for one day. The reaction mixture was extinguished aqueous sodium bicarbonate solution, was extracted with dichloromethane. The combined organic layer was washed with saline, dried over anhydrous sodium sulfate, concentrated, give crude product, which was purified flash chromatography, obtaining the solution. To the resulting solution is concentrated to approximately 50 ml) at ambient temperature was added conc. HCl (10 ml) and stirred over night. The mixture was extracted with ethyl acetate three times, the aqueous phase was concentrated, receiving 9-phenyl-8-(4-(piperazine-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (127 mg, yield 46%).1NAMR (400 MHz, DMSO-d6) δ (ppm): 3,47 (users, 7H), of 3.60 (m, 1H), 4,32 (s, 2H), to 4.38 (d, 1H), a 4.83 (d, 1H), 5,41 (users, 2H), 7,19 (m, 6H), from 7.24 (m, 3H), 7,55 (m, 4H), 9,87 (users, 2H), 12,20 (s, 1H); LC-MS (ESI) m/z: 438 (M+1)+.

Example 72

8-(1-Methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 72A

(E)-4-((1-Methyl-1H-imidazol-2-yl)methylamino)benzofuran-1(3H)-he

To stir a mixture of 1-methyl-1H-imidazole-2-carbaldehyde (2.5 g, 23 mmol) and anhydrous sodium sulfate (26,9 g, 190 mmol) in anhydrous dichloromethane (500 ml) at 0°C was added 4-aminoazobenzene-1(3H)-he (2.8 g, 19 mmol). After the addition the mixture was stirred at ambient temperature for 6 days. The mixture was filtered and the precipitate washed with dichloromethane (50 ml ×3). The filtrate was concentrated, give crude product. The crude product was washed with petroleum ether, receiving(E)-4-((1-methyl-1H-imidazol-2-yl)methylamino)benzofuran-1(3H)-he (5 g, yield 98%) in the form of a solid white color. LC-MS (ESI) m/z: 242 (M+1)+.

Example 72B

2-(1-Methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-((1-methyl-1H-imidazol-2-yl)methylamino)benzofuran-1(3H)-she (241 mg, 1 mmol) and benzaldehyde (116 mg, 1.1 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [on the bacilli (92 mg, 4 mmol) in methanol (5 ml)]. After the addition the mixture was stirred at ambient temperature for 2 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:10)to give a mixture of 2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (87 mg, yield: 24%). LC-MS (ESI) m/z: 362 (M+1)+, 376 (M+1)+.

Example 72C

8-(1-Methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (87 mg) in 85%wage hydrazinoacetate (4 ml) and methanol (10 ml) was stirred at ambient temperature overnight. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified prep-In the LC, receiving 8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-(34 mg, yield 42%) in the form of a solid yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): to 3.41 (s, 3H), of 4.49 (d, 1H), 5,35 (d, 1H), 7.18 in-7,20 (m, 2H), 7,26-7,29 (m, 1H), 7,33-7,35 (m, 3H), 7,40 (d, 1H), to 7.61 (d, 1H), 7,71 to 7.75 (m, 2H); LC-MS (ESI) m/z: 344 (M+1)+.

Example 73

9-(1-Methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 73A

3-(1-Methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (500 mg, 2.1 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (255 mg, 2.3 mmol) in ethylpropylamine (20 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol [sodium (194 mg, 8.4 mmol) in ethanol (10 ml)]. After the addition the mixture was stirred at ambient temperature for 2.5 hours. The mixture is extinguished with water (20 ml), and the solvent was removed in vacuum. The residue was dissolved in water and filtered; the precipitate was washed with water, then with ethyl acetate, getting 3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate in the form of a solid yellow color. The solid was dried in vacuum at 50°C (140 mg, yield 18%).1H-NMR (400 MHz, DMSO-d6,) δ (ppm): 1.18 to to 1.21 (t, J=7.2 Hz, 3H), and 3.31 (s, 3H), 4,16-4,19 (m, 2H), 4,564,59 (d, J=13,2 Hz, 1H), 5,14-5,17 (d, J=13,2 Hz, 1H), 6,54-6,56 (d, J=12 Hz, 1H), 6,72 (s, 1H), 6,86 (s, 1H), 6,98-of 6.99 (d, J=4,8 Hz, 1H), 7.24 to to 7.9 (m, 3H), 7,34-7,38 (t, J=8.0 Hz, 1H), 7,42-7,44 (d, J=12 Hz, 2H), 7,49 (s, 1H); LC-MS (ESI) m/z: 376 (M+1)+.

Example V

9-(1-Methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (140 mg) in 85%wage hydrazinoacetate (3 ml) and methanol (5 ml) was stirred at ambient temperature for 2 days. The resulting mixture was filtered, and the residue was washed with water (20 ml) and methanol (5 ml)to give a solid white color. The solid was dried in vacuum at 50°C, receiving 9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (95 mg, yield 74%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.40 in (s, 3H), with 4.64-of 4.67 (d, J=10,8 Hz, 1H), 4.92 in-4,94 (d, J=10.4 Hz, 1H), 6,72 (s, 1H), 6.87 in (s, 1H), 7,15-7,17 (d, J=8,4 Hz, 2H), 7,26-7,30 (m, 3H), 7,38 (s, 3H), 7,55-to 7.59 (t, J=7,6 Hz, 1H), 12,15 (s, 1H); LC-MS (ESI) m/z: 344 (M+1)+.

Example 74

8,9-bis(1-Methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example A

2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-aminoazobenzene-1(3H)-he (298 mg, 2 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (440 mg, 4 mmol) in ethylpropylamine (20 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol [sodium (184 mg, 8 mmol) in ethanol (10 ml)]. After the addition the mixture was stirred at ambient temperature for chasov. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 5:1 to 1, ethyl acetate:methanol= 50:1 to 25:1, a hydrate of ammonium 1 ml)to give 2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (120 mg, 16% yield). LC-MS (ESI) m/z: 380 (M+1)+.

Example 74B

8,9-bis(1-Methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2,3-bis(1-methyl-1H-imidazol~2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (120 mg) in 85%wage hydrazinoacetate (2 ml) and methanol (3 ml) was stirred at ambient temperature for 3.5 hours. The solvent is evaporated and was added methanol (1 ml), filtered and the precipitate washed with methanol (2 ml)to give a solid white color. The solid was dried in vacuum at 50°C, receiving 8,9-bis(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (45 mg, yield 41%).1H-NMR (400 MHz, CD3OD) δ (ppm): 3.46 in (s, 3H), 3,49 (s, 3H), 4,78-to 4.81 (d, J=12.0 Hz, 1H), 5.08 to-5,11 (d, J=12.0 Hz, 1H), 6,69 (s, 1H), 6,76-6,79 (m, 3H), 6,99-7,02 (d, J=7,6 Hz, 1H), 7,42-7,49 (m, 2H); LC-MS (ESI) m/z: 348 (M+1)+.

Example 75

9-(1H-Imidazol-2-yl)-8-FeNi is 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 75A

9-(1-Benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

3-(1-Benzyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (3.7 g, 8,46 mmol) in hydrazinoacetate (25 ml) and methanol (100 ml) was stirred at ambient temperature for 5 hours. The resulting mixture was filtered, receiving 9-(1-benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it is in the form of a solid white color (950 mg, yield 27%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): br4.61 with 4.64 (d, J=11.2 Hz, 1H), 4,99-5,12 (m, 1H), 6,83-6,89 (m, 4H), 7,14-7,28 (m, 11H), was 7.36-7,38 (d, J=7,6 Hz, 1H), 7,54-7,58 (t, J=8.0 Hz, 7H), 12,20 (s, 1H). LC-MS (ESI) m/z: 420 (M+1)+.

Example 75B

9-(1H-Imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 9-(1-benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (200 mg, 0.48 mmol), catalyst (20% Pd(OH)2/C (100 mg) in methanol (15 ml), purified 1 ATM. hydrogen and stirred at 40°C during the night. Then the solution mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was washed with methanol, receiving 9-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it is in the form of a solid light-yellow color (114 mg, yield 72%).1H-NMR (400 MHz, DMSO-d6) δ: to 4.41-4,43 (d, J=8.0 Hz, 11H), 4,98-5,00 (d, J=8,8 Hz, 1H), 6,68-of 6.73 (m, 1H), 6,86-6,97 (m, 1H), 7,12-7,14 (d, J=8.0 Hz, 1H), 7,20-7,37 (m, 7H), 7,54-7,58 (t, J=8.0 Hz, 1H), 11,77 (s, 1H), 12,19 (s, 1H; LC-MS (ESI) m/z: 330 (M+1)+.

Example 76

9-(1-Ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 76A

1-Ethyl-1H-imidazole-2-carbaldehyde

To a suspension of 1H-imidazole-2-carbaldehyde (480 mg, 5 mmol) and potassium carbonate (936 mg, 6 mmol) in N,N-dimethylformamide (7 ml) was added Iodate (829 mg, 6 mmol) and the mixture was heated at 50°C for 5 hours. The solvent was removed under reduced pressure. The residue was separated between water (30 ml) and ethyl acetate (30 ml). The aqueous layer was extracted with ethyl acetate (20 ml × 3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, obtaining 1-ethyl-1H-imidazole-2-carbaldehyde in the form of a light yellow oil (520 mg, yield 84%).1H-NMR (400 MHz, CDCl3) δ (ppm): 1,42 of 1.46 (t, J=7.2 Hz, 3H), 4,42-4,47 (square, 2H), 7,19 (s, 1H), 7,29 (s, 1H), 9,82 (s, 1H). LC-MS (ESI) m/z: 125 (M+1)+.

Example 76B

3-(1-Ethyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

1-ethyl-1H-imidazole-2-carbaldehyde (520 mg, 4,19 mmol) was added (E)-4-(benzylideneamino)isobenzofuran-1(3H)-he (994 mg, 4,19 mmol), methanolate sodium (385 mg, is 16.8 mmol) and ethylpropane (15 ml)and the mixture was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4) and concentrated. The crude product of cleansing and chromatography on columns (silica gel, petroleum ether/ethyl acetate= 20:1 to 5:1). Received 190 mg of 3-(1-ethyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate. LC-MS (ESI) m/z: 390 (M+1)+.

Example 76C

9-(1-Ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

3-(1-Ethyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbazole (190 mg, 0.49 mmol) and hydrazinoacetate (2 ml) was added to methanol (15 ml)and the mixture was stirred at ambient temperature for 3 hours. The methanol is evaporated and then filtered. The filtrate was concentrated, receiving 9-(1-ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he is solid white (50 mg, yield 28%).1H-NMR (400 MHz, DMSO-d6) δ (ppm); to 0.96 (t, 3H), 3,74-with 3.79 (m, 2H), br4.61 (d, 1H), 4.95 points (d, 1H), 6,78 (DD, 1H), 6,91 (DD, 1H), 7,16 (d, 1H), 7.23 percent-7,31 (m, 4H), 7,37 (s, 3H), EUR 7.57 (t, 1H). LC-MS (ESI) m/z: 358 (M+1)+.

Example 77

8-Phenyl-9-(1-propyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 77A

1-Propyl-1H-imidazole-2-carbaldehyde

1H-imidazole-2-carbaldehyde (800 mg, 8.3 mmol), 1-jumprope (1.7 g, 10 mmol) and potassium carbonate (1.4 g) was added in DMF (30 ml), and the mixture was heated to 50°C during the night. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, obtaining 1-PDEC the l-1H-imidazole-2-carbaldehyde (1.1 g). LC-MS (ESI) m/z 139 (M+1)+.

Example 77B

4-Oxo-2-phenyl-3-(1-propyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a mixture of 1-propyl-1H-imidazole-2-carbaldehyde (1.1 g, 8.0 mmol) and (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (1.7 g, 7.2 mmol) was added ethylpropane (50 ml)and then sodium methylate was added at 0°C. the Mixture was stirred over night at ambient temperature. The mixture was concentrated, and the residue was extracted with ethyl acetate (100 ml ×4). The organic layer was dried over anhydrous sodium sulfate, purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:1)to give 4-oxo-2-phenyl-3-(1-propyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (770 mg, 30%yield). LC-MS (ESI) m/z: 404 (M+1)+.

Example 77C

8-Phenyl-9-(1-propyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a suspension of 4-oxo-2-phenyl-3-(1-propyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (770 mg, 1.9 mmol) and hydrazinoacetate (6 ml, 85%) was added methanol (10 ml) and stirred at 50°C during the night. The mixture was filtered, and the solid is white washed with methanol and dried in vacuum, obtaining 8-phenyl-9-(1-propyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (260 mg, yield 37%).1H-NMR (400 MHz, DMSO-d6,) δ (ppm): 0,59-of 0.62 (t, J=7,4 Hz, 1H), 1,23-of 1.40 (m, 2H), 3,62-and 3.72 (m, 2H), 4,58-br4.61 (d, J=11.2 Hz, 1H), equal to 4.97-4,99 (d, J=11 Hz, 1H), 6,79 (s, 1H), 6.89 in (s, 1H), 7,16-to 7.59 (m, 8H), 12,15 (s, 1H); LC-MS (ESI) m/z: 372 (M+1)+.

Example 78

9-(1-Methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 78A

3-(1-Methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (474 mg, 2 mmol) and 1-methyl-1H-imidazole-5-carbaldehyde (220 mg, 2 mmol) in ethylpropylamine (20 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol [sodium (184 mg, 8 mmol) in ethanol (10 ml)]. After the addition the mixture was stirred at ambient temperature for 3 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 5:1 to 3:7)to give 3-(1-methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (170 mg, yield 23%). LC-MS (ESI) m/z: 376 (M+1)+.

Example 78B

9-(1-Methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(1-methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (170 mg) in 85%wage hydrazinoacetate (3 ml) and methanol ( ml) was stirred at ambient temperature for 5 hours. Was filtered and the precipitate washed with methanol (2 ml)to give a solid white color. The solid was dried in vacuum at 50°C, receiving 9-(1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (70 mg, yield 46%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3,50 (s, 3H), to 4.52-of 4.54 (d, J=9,2 Hz, 1H), a 4.83-4,85 (d, J=9,2 Hz, 1H), 6,66 (s, 1H), 7,17-7,19 (d, J=7,6 Hz, 1H), 7,25-to 7.32 (m, 3H), of 7.36-7,44 (m, 5H), 7,56-of 7.60 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 348 (M+1)+.

Example 79

9-(3-((Diethylamino)methyl)phenyl)-8-(4-((diethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4,4'-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzamide (200 mg, 0.5 mmol) and diethylamine (146 mg, 2.0 mmol) in methanol (10 ml) was stirred at ambient temperature for 40 minutes Then the mixture was cooled to 0°C. was Added sodium borohydride (56 mg, 1.5 mmol). After the addition the mixture was stirred at ambient temperature for 2 hours. The methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated, give crude product. The crude product was purified preparative HPLC, receiving 9-(3-((diethylamino)methyl)phenyl)-8-(4-((diethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he is solid white (76 mg, yield 29%).1H-NMR (400 MHz, CD3OD) δ (ppm): of 1.28 and 1.33 (m, 12H), 3,13-3,19 (m, 8H), 4,27 (s, 4H), 4,40 was 4.42 (d, J=7,6 Hz, 1H), 4,84-a 4.86 (d, J=7,6 Hz, 1H), 7,22-7,27 (m, 3H), 7,38-7,41 (m, 6H), 7,56-the 7.65 (m, 2H); LC-MS (ESI) m/z: 510 (M+1)+.

Example 80

9-(3-((4-Methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a stirred solution of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)benzaldehyde (150 mg, 0.4 mmol) in dry dichloromethane (10 ml) was added acetic acid, then 1-methylpiperazine (121 mg, 1.2 mmol). After the addition the mixture was stirred at ambient temperature for 1 hour. Then the mixture was cooled to 0°C. was Added sodium borohydride (130 mg, 0.2 mmol). After the addition the mixture was stirred at this temperature for 3 hours. Dichloromethane was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product. The crude product was purified prep-HPLC, receiving 9-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he is solid white (22 mg, yield 12%).1H-NMR (400 MHz, CD3OD) δ (ppm): 2,31 (s, 3H), 2,36-2,48 (m, 8H), 3,37-of 3.48 (DD, 2H), 4,30 (DD, 1H), 4,71 (DD, 1H), 7,01 (s, 1H), 7,05 (DD, 1H), 7,17-of 7.23 (m, 5H), 7,25-7,28 (m, 2H), 7,56 (DD, 1H), to 7.61-the 7.65 (t, 1H); LC-MS (ESI) m/z: 452 (M+1)+.

Example 81

8-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example A

2-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-3-enyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

4-Aminoazobenzene-1(3H)-he (372,5 mg, 2.5 mmol), 4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (645 mg, 2.5 mmol) and 1 g MgS4was added in 40 ml of dichloromethane and stirred under reflux overnight, then the mixture was evaporated under reduced pressure, and the residues were dried under vacuum. 385 mg (E)-4-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzylideneamino)isobenzofuran-1(3H)-she. A mixture of (E)-4-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzylideneamino)isobenzofuran-1(3H)-she (385 mg, of 0.92 mmol), benzaldehyde (97.9 mg, 0.97 mmol), methanolate sodium (199 mg, 3,68 mmol) and ethylpropylamine (10 ml) was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4), and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate 20:1 to 5:1)to give 300 mg of 2-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate. LC-MS (ESl) m/z: 538 (M+1)+.

Example 81B

8-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (300 mg, 0.55 mmol) and hydrazinoacetate (3 ml) var is stirred at ambient temperature for 3 hours. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered; the filtrate was concentrated, give crude product. The crude product was purified prep-HPLC, receiving 8-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he is solid white (4 mg, yield 19%).1H-NMR (400 MHz, DMSO-d6) δ (ppm); 0,71-0,74 (m, 4H), of 1.97 (t, 1H), 3.46 in is 3.76 (m, 8H), 4,36 (DD, 1H), a 4.83 (DD, 1H), 7,13-of 7.23 (m, 6H), 7,30 (m, 2H), 7,38 (m, 3H), 7,47 (s, 1H), to 7.59 (t, 1H), 12,17 (s, 1H); LC-MS (ESI) m/z 520 (M+1)+.

Example 82

9-Phenyl-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 82A

4-Oxo-3-phenyl-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(pyridine-4-ylmethylamino)isobenzofuran-1(3H)-she (1,71 g, 7,18 mmol) and benzaldehyde (837 mg, 7.9 mmol) in ethylpropylamine (50 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol [sodium (660 mg, 28.7 mmol) in ethanol (35 ml)]. After the addition the mixture was stirred at ambient temperature for 2 hours. The mixture is extinguished with water (20 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (150 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica compound is a gel, petroleum ether/ethyl acetate= 5:1 to 1:1)to give 4-oxo-3-phenyl-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (340 mg, yield 13%). LC-MS (ESI) m/z: 373 (M+1)+.

Example 82B

9-Phenyl-8-(pyridin-4-yl)-859-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-oxo-3-phenyl-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (340 mg) in 85%wage hydrazinoacetate (6 ml) and methanol (3 ml) was stirred at ambient temperature for 2 hours. After evaporation of solvent was added to the water. Was filtered and the precipitate washed with water (5 ml), then ethyl acetate, getting a solid white color. The solid was dried in vacuum at 50°C, receiving 9-phenyl-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (150 mg, yield: 48%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): to 4.38-and 4.40 (d, J=7,6 Hz, 1H), 4,84-7,86 (d, J=8.0 Hz, 1H), 7,15-7,25 (m, 6H), 7,30-7,31 (m, 2H), 7,39-7,41 (d, J=7,6 Hz, 1H), 7,51-7,52 (s, 1H), to 7.59 to 7.62 (t, J=8.0 Hz, 1H), 8,43-8,44 (d, J=6.0 Hz, 2H), 12,19 (s, 1H); LC-MS (ESI) m/z: 341 (M+1)+.

Example 83

9-Phenyl-8-(piperidine-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 9-phenyl-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (150 mg, 0.4 mmol), conc. ΗCl (0.6 ml) and monohydrate platinum (IV) (40 mg) in methanol (30 ml) was purified 50 bar of hydrogen at 50°C for 18 hours. Then the mixture was filtered. The solvent was removed in vacuum to give crude oil, which was purified preparative HPLC, floor the tea 9-phenyl-8-(piperidine-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (95 mg, yield 62%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1,24-of 1.41 (m, 1H), 1,49-to 1.59 (m, 1H), 1,69-of 1.78 (m, 2H), 1,98 is 2.01 (d, J=13,2 Hz, 1H), 2,67-of 2.86 (m, 2H), 3,22-of 3.31 (m, 3H), 4,18 (s, 1H), 7,05-was 7.08 (m, 3H), 7,14-7,21 (m, 2H), 7.24 to 7,28 (m, 2H), 7,31-7,33 (d, J=7.2 Hz, 1H), 7,52-7,56 (t, J=8.0 Hz, 1H), 8,19-8,24 (m, 1H), 8,54-8,56 (m, 1H), 12,30 (s, 1H); LC-MS (m/z 347 (M+1)+.

Example 84

9-Phenyl-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 84A

4-Oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

4-Aminoazobenzene-1(3H)-he (600 mg, 4 mmol), picolinamides (856 mg, 8 mmol) and 1 gMgS4was added in 40 ml of dichloromethane, and the mixture was stirred under reflux overnight, then the mixture was evaporated under reduced pressure, and the residues were dried under vacuum. Received 476 mg(E)-4-(pyridine-2-ylmethylamino) isobenzofuran-1(3H)-she. A mixture of (E)-4-(pyridine-2-ylmethylamino)isobenzofuran-1(3H)-she (476 mg, 2 mmol), benzaldehyde (212 mg, 2 mmol), methanolate sodium (432 mg, 8 mmol) and ethylpropylamine (40 ml) was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4), and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate 20:1 to 5:1)to give 30 mg of 4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamate; output 5%. LC-MS (ESI) m/z: 459 (M+1)+

Example 84B

9-Phenyl-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (30 mg, 0.08 mmol) and hydrazinoacetate (1 ml) was stirred at ambient temperature for 3 hours. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered. Received 10 mg of 9-phenyl-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she, exit 37%.1H-NMR (400 MHz, CDCl3) δ (ppm): 4,60 (d, 1H), 4,86-4,88 (m, 1H), total of 5.21 (s, 1H), of 6.96 (DD, 1H), 7,08-7,17 (m, 4H), 7,22-7,28 (m, 3H), 7,46-7,49 (m, 1H), 7,60 (t, 1H), 7,73 (DD, 1H), 8,59 (d, 1H), made up 9.77 (s, 1H); LC-MS (ESI) m/z: 341 (M+1)+.

Example 85

8-(4-((4-Methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (150 mg, 0.4 mmol), N-methyl-piperazine (123 mg, 1.2 mmol) and acetic acid (120 mg, 1.2 mmol) in methanol (50 ml) was stirred at ambient temperature for 60 minutes and Then the mixture was cooled to 0°C. was Added triacetoxyborohydride sodium (130 mg, 0.6 mmol). After the addition the mixture was stirred at ambient temperature overnight. The methanol was removed under reduced pressure. The crude product was purified prep-HPLC, receiving 8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (36 mg, yield 19%).1H-NMR (400 MHz, CDsub> 3OD) 5 (ppm): to 2.29 (s, 3H), 2,12-2,73 (users, 8H), 3,47 (s, 2H), 4,30 (d, J=8.0 Hz, 1H), 4,74 (d, J=8.0 Hz, 1H), 7,08-7,10 (m, 2H), 7.18 in-7,21 (m, 6H), 7.23 percent-of 7.25 (m, 2H), 7,55-EUR 7.57 (d, J=8.0 Hz, 1H), 7,62-to 7.64 (m, 1H). LC-MS (ESI) m/z: 452 (M+1)+.

Example 86

8,9-bis-(4-Forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 86A

2-(4-(Dimethoxymethyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl, 2-(4-(dimethoxymethyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate and 2,3-bis-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl

A mixture of (E)-4-(4-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-she (1,36 g, 4 mmol), 4-forventelige (546 mg, 4.4 mmol), methanolate sodium (864 mg, 16 mmol) and ethylpropylamine (25 ml) was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4), and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate= 20:1 to 1:1)to give 440 mg of a mixture of 2-(4-(dimethoxymethyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate, 2-(4-(dimethoxymethyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate and 2,3-bis-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate.

Example 86B

8,9-bis-(4-Forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-4-(dimethoxymethyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbonate, 2-(4-(dimethoxymethyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate and 2,3-bis-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate (440 mg) and hydrazinoacetate (20 ml) was stirred at ambient temperature overnight. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered. Received 400 mg of crude product. To a solution of this crude product (400 mg) in dichloromethane was added triperoxonane acid (1 ml) at 0°C. the Mixture was stirred at ambient temperature for 1 hour. Then the mixture was neutralized with potassium carbonate. The mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate 10:1 to 1:1)to give 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (80 mg) and 8,9-bis(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (36 mg). 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde: LC-MS (ESI) m/z: 368 (M+1)+. 8,9-bis(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he:1H-NMR (400 MHz, CD3OD) δ (ppm); the 4.29 (d, J=8.0 Hz, 1H), 4,70 (d, J=8.0 Hz, 1H), 6,92-7,00 (m, 4H), 7,08-7,10 (m, 2H), 7,20-7,20 (m, 1H), 7,28-to 7.32 (m, 2H), to 7.59 (m, 1H) 7,63-to 7.67 (m, 1H),19F-NMR (400 MHz, CD3OD) δ (ppm): -116,77, -118,23; LC-MS (ESI) m/z: 376 (M+1)+.

Example 87

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (80 mg, 0.21 mmol), amine (47 mg, 1.04 mmol) and acetic acid (62 mg, 1.04 mmol) in methanol (50 ml) was stirred at ambient temperature for 60 minutes and Then the mixture was cooled to 0°C. was Added sodium cyanoborohydride (20 mg, 0.3 mmol). After the addition the mixture was stirred at ambient temperature overnight. The methanol was removed under reduced pressure. The crude product was purified prep-HPLC, receiving 8-(4-((dimethylamino)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (21 mg, yield 24%).1H-NMR (400 MHz, CD3OD) δ (ppm): 2,82 (s, 6H), 4.26 deaths (s, 2H), 4,32 (d, J=8.0 Hz, 1H), 4,77 (d, J=8.0 Hz, 1H), 6,93-to 6.95 (m, 2H), 7,10-7,11 (m, 2H), 7.23 percent (m, 1H), 7,40-7,41 (m, 4H), to 7.59 (d, J=8.0 Hz, 1H), 7,65 (t, J=8.0 Hz, 1H),19F-NMR (400 MHz, CD3OD) δ (ppm): -77,09, -118,00; LC-MS (ESI) m/z: 415 (M+1)+.

Example 88

8-(4-Forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 88A

2-(4-Forfinal)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a stirred mixture of 4-forventelige (3 g, of 20.4 mmol) and anhydrous sodium sulfate (29 g, of 20.4 mmol) in anhydrous dichloro is not (200 ml) at 0°C was added 4-aminoazobenzene-1(3H)-he (3.04 from g, 24.5 mmol). After the addition the mixture was stirred at ambient temperature for 6 days. The mixture was filtered and the precipitate washed with dichloromethane (50 ml ×3). The filtrate was concentrated, give crude product. The crude product was washed with petroleum ether, obtaining (E)-4-(4-verbindingenmee)isobenzofuran-1(3H)-he (4,25 g, yield 81%); LC-MS (ESI) m/z: 256 (M+1)+. A mixture of (E)-4-(4-verbindingenmee)isobenzofuran-1(3H)-she (2,53 g, 10 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (1,21 g, 11 mmol) in ethylpropylamine (50 ml) was cooled to 0°C. Then was added dropwise a solution of ethoxide sodium in ethanol [sodium (1 g, 44 mmol) in ethanol (30 ml)]. After the addition the mixture was stirred at ambient temperature for 2 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1: 10)to give 2-(4-forfinal)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (210 mg, yield 5%). LC-MS (ESI) m/z: 394 (M+1)+.

Example 88B

8-(4-Forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-forfinal)3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (210 mg) in 85%wage hydrazinoacetate (10 ml) and methanol (10 ml) was stirred at 45°C during the night. The methanol was removed under reduced pressure. The mixture was filtered and washed with water, receiving 8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (36 mg, yield 19%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.42 points (s, 3H), of 4.66 (d, J=8.0 Hz, 1H), 4.95 points (d, J=8.0 Hz, 1H), 6,72 (s, 1H), 6.89 in (s, 1H), 7,11-7,17 (m, 3H), 7,30 (s, 1H), 7,40 (d, 1H), 7,43-7,44 (m, 2H), 7,58 (d, 1H), 12,17 (s, 1H);19F-NMR (400 MHz, DMSO-d6) δ (ppm): -114,58; LC-MS (ESI) m/z: 362 (M+1)+.

Example 89

8,9-bis(3-((Dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 89A

3-(Diethoxylate)benzaldehyde

A mixture of isophthalic aldehyde (21,44 g, 160 mmol), ammonium chloride (0.34 g, 6.38 mmol) in anhydrous ethanol (23,2 g, 480 mmol) was cooled to 0°C, then was added dropwise triethoxysilane. After the addition the mixture was heated to 40°C and was stirred for two days. The mixture was filtered, and the filtrate was concentrated, give crude product. The crude product was purified by chromatography on columns (silica gel, petroleum ether/ethyl acetate = 200:1 to 100:1)to give 3-(diethoxylate)benzaldehyde (25.4 g, yield 76%) in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ (ppm): 1,23-of 1.27 (m, 6H), 3,53-to 3.67 (m, 4H), to 5.58 (s, 1H), 7,52-7,56 (t, J=7,6 Hz, 1H), 7,74-to 7.77 (DD, J1=7,6 Hz, J2=3,6 Hz, 1H), 8,00 (s, 1H), 10,04 (s, 1H); LC-MS (ESI) m/z: 209 (M+1)+.

Example 89B

2,3-bis(3-(Diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl and 2,3-bis(3(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-aminoazobenzene-1(3H)-she (298 mg, 2 mmol) and 3-(diethoxylate)benzaldehyde (0,83 g, 4 mmol) in ethylpropylamine (15 ml) was cooled to 0°C. Then was added dropwise a solution of sodium methylate in methanol [sodium (184 mg, 8 mmol) in methanol (15 ml)]. After the addition the mixture was stirred at 25°C for 18 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (50 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate =100:1 to 10:1)to give a mixture of 2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (370 mg, together, yield 33%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 562 (M+1)+, 576 (M+1)+.

Example 89C

8,9-bis(3-(Diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamate and 2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (370 mg, 0.59 mmol) in hydrazinoacetate (5 ml) and methanol (5 ml) was stirred at 50°C for 2 hours. The mixture of the cooling gap is Ali to ambient temperature and filtered, getting 8,9-bis(3-(diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (250 mg, yield 77%) in the form of a solid of light yellow color.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0,99-a 1.08 (m, 12H), 3.27 to to 3.33 (m, 8H), 4,28-or 4.31 (d, J=8,8 Hz, 1H), 4,74 was 4.76 (d, J=8,4 Hz, 1H), 5,31-5,32 (d, J=6,8 Hz, 2H),? 7.04 baby mortality (s, 1H), 7,12-7,26 (m, 7H), 7,31-the 7.43 (m, 3H), 7,56-of 7.60 (t, J=8,0 Hz, 1H); LC-MS (ESI) m/z: 544 (M+1)+.

Example 89D

3,3'-(3-Oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,8-diyl)dibenzamide

A mixture of 8,9-bis(3-(diethoxylate)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (120 mg, 0.46 mmol) in 3h. hydrochloric acid (5 ml) was stirred at ambient temperature for 2 hours. Then the mixture was podslushivaet to pΗ=8 with potassium carbonate. The resulting suspension was filtered, getting 3,3'-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,8-diyl)dibenzamide (160 mg, yield 88%) in the form of a solid of light yellow color.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4,57-4,59 (d, J=9.6 Hz, 1H), 4,98-5,00 (d, J=9,2 Hz, 1H), 7,20-7,22 (d, J=7,6 Hz, 1H), 7,42-7,52 (m, 5H), 7,60-to 7.77 (m, 5H), 7,89 (s, 1H), 9,90 (s, 1H), to 9.93 (s, 1H), 12,08 (s, 1H); LC-MS (ESI) m/z: 396 (M+1)+.

Example 89E

8,9-bis(3-((Dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3,3'-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,8-diyl)dibenzamide (60 mg, 0.16 mmol) and a 32% solution of dimethylamine (135 mg, 0.96 mmol) in methanol (10 ml) was stirred at ambient temperature for 40 minutes For the eat and the mixture was cooled to 0°C. Was added sodium borohydride (18.2 mg, 0.48 mmol). After the addition the mixture was stirred at ambient temperature for 2 hours. The methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated, give crude product. The crude product was purified preparative HPLC, getting 8,9-bis(3-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (18.6 mg, yield 26%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): 2,61-to 2.67 (m, 12H), 4,10-to 4.15 (m, 4H), 4,25-4,27 (d, J=9.6 Hz, 1H), 4,67-4,69 (d, J=10.0 Hz, 1H), 7,05-7,29 (m, 7H), 7,29-7,39 (m, 2H), 7,49-rate of 7.54 (m, 2H); LC-MS (ESI) m/z: 454(M+1)+.

Example 90

9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-1H-pyrido[4,3,2-de]phthalazine-9-yl)benzaldehyde (70 mg, 0,19 mmol) and cyclopropylamine (worth 32.55 mg, or 0.57 mmol) in anhydrous methanol (10 ml) was stirred at ambient temperature for 1.5 hours. Then the mixture was cooled to 0°C, sodium borohydride (10,82 mg, 0,286 mmol) was added parts. After the addition the mixture was stirred at this temperature for 2 hours. The methanol was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 ml), was extracted with 1N. hydrochloric acid (20 ml), the aqueous layer was separated. The organic layer was washed for 1H. hydrochloric acid (20 ml). United water the layers were podslushivaet to pΗ 9 potassium carbonate, were extracted with ethyl acetate (25 ml ×4). The combined organic layers were dried over anhydrous sodium sulfate and concentrated, receiving 9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-one (15 mg, yield 19%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): 0,19-0,29 (m, 4H), 1,74 and 1.80 (m, 1H), 3,55 (s, 2H), 4,16-4,19 (d, J=8,8 Hz, 1H), 4,60-to 4.62 (d, J=8,8 Hz, 1H), 6,88-of 6.90 (d, J=7,6 Hz, 1H), 6,95 (s, 1H), 7,01-7,10 (m, 6H), 7,13-to 7.15 (m, 2H), 7,42-7,44 (d, J=7,6 Hz, 1H), of 7.48 to 7.75 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 408 (M+1)+.

Example 91

8-(3-((Dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (50 mg, 0.14 mmol) and 1M solution of dimethylamine (0.5 ml, 0.41 mmol) in methanol (10 ml) was stirred at ambient temperature for 40 minutes Then the mixture was cooled to 0°C. was Added sodium cyanoborohydride (13 mg, 0.20 mmol) and acetic acid (40,8 mg of 0.68 mmol). After the addition the mixture was stirred at 0°C for 2 hours. The methanol was removed under reduced pressure. The residue was dissolved in 1N. hydrochloric acid and washed with ethyl acetate. The mother liquor was podslushivaet to pΗ 8 and extracted with ethyl acetate. The solvent was removed, receiving 8-(3-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-(34 mg, yield 64%) in the form of a solid light-W is logo color. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2,17 (s, 6H), 3,17-3,41 (square, 2H), or 4.31 (d, J=8.0 Hz, 1H), 4,74 (d, J=8.0 Hz, 1H), 7,08-7,10 (m, 2H), 7,13-7,25 (m, 8H), 7,55-EUR 7.57 (d, J=8.0 Hz, 1H), to 7.61-the 7.65 (m, 1H). LC-MS (ESI) m/z: 397 (M+1)+.

Example 92

8-(3-(Morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (40 mg, 0.11 mmol), research (28 mg, 0.33 mmol) and acetic acid (33 mg, 0,mol) in methanol (50 ml) was stirred at ambient temperature for 40 minutes Then the mixture was cooled to 0°C. was Added triacetoxyborohydride sodium (35 mg, 0.16 mmol). After the addition the mixture was stirred at 0°C for 2 hours. The methanol was removed under reduced pressure. The residue was dissolved in 1N. hydrochloric acid and washed with ethyl acetate. The mother liquor was podslushivaet to pΗ 8 and extracted with ethyl acetate. The solvent was removed, receiving 8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he (31 mg, yield 66%) in the form of a solid of light yellow color.1H-NMR (400 MHz, CD3OD) δ (ppm): 2,23-of 2.24 (m, 4H), 3,32-3,43 (square, 2H), 4,30 (d, J=8.0 Hz, 1H), 4,74 (d, J=8.0 Hz, 1H), 7,08-7,10 (m, 2H), 7,13-7,19 (m, 6H), 7,21-7,25 (m, 1H), 7,31-7,33 (m, 1H), 7,55-EUR 7.57 (d, J=8.0 Hz, 1H), 7,62-to 7.64 (m, 1H). LC-MS (ESI) m/z: 439 (M+1)+.

Example 93

8-(4-(Azetidin-1-ylmethyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 93A

2-(4-(Diethoxylate)phenyl)-3-(4-forfinal)4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of (E)-4-(4-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-she (10.8 g, 31.9 per mmol) and 4-forventelige (3,95 g, 31.9 per mmol) in ethylpropylamine (150 ml) at 0°C was added sodium ethylate (8,66 g, 127,4 mmol in ethanol (60 ml). Then the mixture was stirred at ambient temperature for 5 hours. The resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4), and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate = 20:1 to 1:1)to give the crude product (4,2 g, yield 26%). LC-MS (ESI) m/z: 492 (M+1)+.

Example 93B

8-(4-(Diethoxylate)phenyl)-9-(4-forfinal)8.9bn-dihydro-2Η-pyrido[4,3,2-de]phthalazine-3(7H)-he

Crude 2-(4-(diethoxylate)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (4,2 g, 8,54 mmol) and hydrazinoacetate (5 ml) was added to methanol (60 ml)and the mixture was stirred at ambient temperature for 16 hours. The resulting mixture was concentrated under reduced pressure to a volume of 40 ml and then filtered, obtaining the crude target compound (3.0 g, yield 76%). LC-MS (ESI) m/z: 460 (M+1)+.

Example 93C

4-(9-(4-Forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde

To a solution of crude 8-(4-(diethoxylate)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (3.0 g, 6,53 mmol) in water (10 ml) at 0°C was added hydrochloric Ki the lot (1H., 50 ml). The mixture was stirred at ambient temperature for 4 hours. Then the mixture was neutralized with potassium carbonate. The mixture was extracted with ethyl acetate (200 ml ×3). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, obtaining the crude target compound (2.5 g, yield 98%). LC-MS (ESI) m/z: 386 (M+1)+.

Example 93D

8-(4-(Azetidin-1-ylmethyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a stirred solution of crude 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (930 mg, 2,42 mmol) in DCM (120 ml) was added acetic acid (0.3 ml), then azetidin (670 mg, of 11.8 mmol), after adding the mixture was stirred at ambient temperature overnight. Then the mixture was cooled to 0°C and was added NaBH(OAc)3(764 mg, 3.62 mmol). After the addition the mixture was stirred at this temperature for 6 hours. DCM was removed under reduced pressure. To the residue was added water, then at 25°C hydrochloric acid (5 ml). The mixture was stirred at ambient temperature for 0.5 hours. The mixture was extracted with ethyl acetate (100 ml ×3). The aqueous layer was neutralized with potassium carbonate and filtered, obtaining the target compound in the form of a solid white (500 mg, yield 49%). LC-MS (ESI) m/z: 427 (M+1)+.1H-NMR (400 MHz, DMSO-d6)δ (ppm): 2,24-2,49 (m, 2H), 3,85-was 4.02 (m, 4H), 4,25 (d, 2H), to 4.38 (d, 1H), 4,80 (d, 1H) 7.03 is (t, 2H), 7,14-7,20 (m, 3H), of 7.36-7,39 (m, 5H), 7,47 (s, 1H), to 7.59 (t, 1H) at 10.64 (s, 1H), 12,18 (s, 1H).

Example 94

5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 94A

7-fluoro-2-(4-forfinal)-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of (E)-6-fluoro-4-(4-verbindingenmee)isobenzofuran-1(3H)-she (4 g, 14.6 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (4.1 g, 36,9 mmol) in ethylpropylamine (220 ml) at 37°C was added EtONa (sodium 940 mg of 40.9 mmol)in 70 ml of ethanol, then the mixture was stirred at 40°C for 6 hours. The resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4). the extract was concentrated to dryness, to give crude product, which was purified by chromatography on columns (silica gel, dichloromethane:methanol= 200:1 to 100:1), getting a solid green color (1,02 g, yield 14%). LC-MS (ESI) m/z: 413 (M+1)+.

Example 94B

5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a solution of 7-fluoro-2-(4-forfinal)-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (840 mg, 2.04 mmol) in methanol (2 ml) was added hydrazinoacetate (1 ml)and the mixture was stirred at 25°C for 10 hours. The mixture is then filtered, obtaining a solid white color (650 mg, yield 84%). LC-M (ESI) m/z: 381 (M+1) +.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3,66 (s, 3H), equal to 4.97-5,04 (m, 2H), 6,91-6,94 (DD, J1=11.2 Hz, J2=2.4 Hz, 1H), 7,06-to 7.09 (DD, J1= 8,8 Hz, J2=2.4 Hz, 1H), 7,14-to 7.18 (m, 3H), 7,47-7,51 (m, 2H), 7,72 (s, 1H), 7,80 (s, 1H), 12,35 (s, 1H).

Example 95

9-(1-Methyl-1H-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 95A

3-(1-Methyl-1H-1,2,4-triazole-5-yl)-4-oxo-2-phenyl-1,2,3, 4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (1.78 g, 7.5 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (1.01 g, 9,16 mmol) in ethylpropylamine (110 ml) at 40°C was added EtONa (sodium (490 mg, 21 mmol) in 35 ml of ethanol, then the mixture was stirred at 41°C for 3 hours. The resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (150 ml ×4), and concentrated. The crude product was purified by chromatography on columns (silica gel, dichloromethane:methanol= 200:1 to 50:1)to give a solid green color (400 mg, yield 14%). LC-MS (ESI) m/z: 377 (M+1)+

Example 95B

9-(1-Methyl-1Η-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2Η-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a solution of 3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (400 mg, 1.06 mmol) in methanol (8 ml) was added hydrazinoacetate (0.5 ml)and the mixture is then stirred at 25°C for 10 hours. The mixture was filtered, getting solid white (110 mg, 30%yield). L-MS (ESI) m/z: 345 (M+1) +.1H-NMR (400 MHz, DMSO-d6) δ (ppm): of 3.77 (s, 3H), 4,48-of 4.49 (d, J=6,4 Hz, 1H), 5,16-5,19 (d, J=6,4 Hz, 1H), 7,40-7,42 (m, 2H), 7,54-7,58 (t, 1H), 7,74 (s, 1H), 12,23 (s, 1H).

Example 96

8-(4-((Dimethylamino)methyl)phenyl)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 96A

2-(4-((dimethylamino)methyl)phenyl)-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-she (of 2.21 g, 7.5 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (1.01 g, 9,16 mmol) in ethylpropylamine (110 ml) at 40°C was rapidly added EtONa (sodium (490 mg, 21 mmol) in 35 ml of ethanol, then the mixture was stirred at 45°C for 3 hours. The resulting mixture was evaporated under reduced pressure, extracted with ethyl acetate (200 ml ×3) and then the extract was concentrated. The crude product was purified by chromatography on columns (silica gel, dichloromethane:methanol= 100:1 to 10:1), obtaining the solid green (510 mg, yield 16%). LC-MS (ESI) m/z: 434 (M+1)+.

Example 96B

8-(4-((Dimethylamino)methyl)phenyl)-9-(1-methyl-1Η-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2 Η-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a solution of 2-(4-((dimethylamino)methyl)phenyl)-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (506 mg, at 1.17 mmol) in methanol (3 ml) was added hydrazinoacetate (1 ml)and the mixture was stirred at 25°C for 10 hours. The mixture is filter the Wali, getting a solid white color (225 mg, yield 48%). LC-MS (ESI) m/z: 402 (M+1)+.1H-NMR (400 MHz, DMSO-40 δ (ppm): 2,10 (s, 6H), to 3.33 (s, 2H), to 3.58 (s, 3H), 4,88 to 4.92 (m, 2H), 7,20-7,22 (m, 3H), 7,34-7,40 (m, 4H), 7,54 to 7.62 (t, J=8,4 Hz, 1H), 7,79 (s, 1H), 12,20 (s, 1H).

Example 97

8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 97A

2-(4-((Dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-floridalottery-1(3H)-she (2,34 g, 7.5 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (1.01 g, 9,16 mmol) in ethylpropylamine (110 ml) at 40°C was added EtONa (sodium (500 mg, 21 mmol) in 35 ml of ethanol, then the mixture was stirred at 48°C for 3 hours. The resulting mixture was evaporated under reduced pressure, extracted with ethyl acetate (250 ml ×3) and concentrated. The crude product was purified by chromatography on columns (silica gel, dichloromethane:methanol= 50:1 to 10:1)to give a solid green color (160 mg, yield of 4.7%). LC-MS (ESI) m/z: 452 (M+1)+.

Example 97B

8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a solution of 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (160 mg, 0.35 mmol) in methanol (2 ml) was added Hydra is thinmanager (0.5 ml), and the mixture was stirred at 25°C for 10 hours. The mixture was filtered, obtaining the target compound in the form of a solid white color (45 mg, 30%yield). LC-MS (ESI) m/z: 420 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2,10 (s, 6H), to 3.36 (s, 2H)and 3.59 (s, 3H), 4,91-4,99 (m, 2H), 6,91-to 6.95 (DD, J1=11.2 Hz, J2=2.4 Hz, 1H), 7,05-was 7.08 (DD, J1=9,2 Hz, J2=2.4 Hz, 1H), 7,20-of 7.23 (d, J=8.0 Hz, 2H), 7,35-7,37 (d, J=8.0 Hz, 2H), 7,72 (s, 1H), 7,79 (s, 1H), of 12.33 (s, 1H).

Example 98

8-(4-Forfinal)-9-methyl-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 98A

2-(4-Forfinal)-3-methyl-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A solution of 2-(4-forfinal)-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (100 mg, 0.25 mmol) and potassium carbonate (70 mg, 0.51 mmol) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 1 hour. Then the solution was cooled to 0°C was added dropwise at 0°C for 1 hour a solution of iodomethane (0.1 ml) in N,N-dimethylformamide (1 ml), and stirred at ambient temperature overnight. The mixture is extinguished with water (30 ml), extracted with ethyl acetate, washed with saline, and then the extract was evaporated to give crude product, which was used in the next stage without further purification (80 mg, yield 77%), LC-MS (ESI) m/z: 409 (M+1)+.

Example 98B

8-(4-Forfinal)-9-methyl-9-(1-meth is l-1Η-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2Η-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-forfinal)-3-methyl-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (80 mg, 0,19 mmol) in 85%wage hydrazinoacetate (5 ml) and methanol (1 ml) was stirred under reflux overnight. The resulting solution was cooled and filtered, the precipitate washed with methanol (2 ml)to give a solid white color, which was dried under vacuum at 55°C, obtaining the target compound (40 mg, yield 54%). LC-MS (ESI) m/z: 377 (M+1)+;1H-NMR (400 MHz, DMSO-d6,) δ (ppm): 1,83 (s, 3H), of 2.86 (s, 3H), br4.61 (s, 1H), 6,88-6,92 (m, 2H), 7,11-7,169 (t, J=8,8 Hz, 2H), 7,19-7,22 (d, J=8.0 Hz, 1H), 7,41 (s, 1H), 7,47-7,49 (m, 1H), 7,60-to 7.64 (t, J=8.0 Hz, 1H), 7,72 (s, 1H), 12,40 (s, 1H).

Example 99

8-(4-Forfinal)-9-(1,4,5-trimethyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 99A

1,4,5-Trimethyl-1H-imidazol

To a cold suspension of formaldehyde (21 ml, 0.3 mol), methylamine hydrochloride (36.5 g, 540 mmol) and ammonium hydroxide (150 ml) was added butandiol (15,8 ml, 180 mmol) and the mixture is then stirred at 100°C for 30 minutes After cooling to ambient temperature the reaction mixture was extracted with dichloromethane. The organic layers were dried Na2SO4, and the solvent was removed on a rotary evaporator. The crude product was purified by chromatography (dichloromethane/methanol=100:1), receiving 1,4,5-trimethyl-1H-imidazole.1H-NMR (400 MHz, CDCl3) δ (ppm): 2,11 (s, 3H), of 2.15 (s, 3H), 3,49 (s, 3H), and 7.8 (s, 1H).

Example 99B

1,4,5-Trimethyl-1H-imidazole-2-carbaldehyde

To a solution of 1,4,5-trimethyl-1H-imidazole (550 mg, 5 mmol) in dry tetrahydrofuran (15 ml) at -40°C was added dropwise n-BuLi (3 ml, 2.5 M in hexane). After stirring for 2 hours at this temperature, to the solution at -70°C was added dried DMF (840 mg, 11.5 mmol). The obtained yellow suspension was stirred at -70°C for 1 hour, then at 0°C for 0.5 hours and extinguished with water with ice. The mixture was extracted with ethyl acetate, and the organic extracts were driedNa2SO4, after which it was evaporated, getting oil residue. The residue was purified on a column of silica gel (petroleum ether:ethyl acetate=3:1)to give 340 mg of a solid substance of white color, yield: 50%.1H-NMR (400 MHz, CDCl3) δ (ppm): 2,21 (s, 1H), 2,25 (s, 1H), 3,90 (s, 1H), to 9.66 (s, 1H). LC-MS (ESI) m/z: 138 (M+1)+.

Example 99C

2-(4-Forfinal)-4-oxo-3-(1,4,5-trimethyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

The mixture of compounds (E)-4-(4-verbindingenmee)isobenzofuran-1(3H)-she (510 mg, 2.0 mmol) and 1,4,5-trimethyl-1H-imidazole-2-carbaldehyde (304 mg, 2.2 mmol) in ethylpropylamine (20 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (184 mg, 8.0 mmol) in ethanol (10 ml)). After the addition the mixture was stirred at ambient temperature for 2.5 hours. The mixture is extinguished with water (20 ml), and Rast is oritel was removed under reduced pressure. The residue was dissolved in water and was extracted with ethyl acetate (100 ml ×3), then the extract was washed with water, brine and evaporated, the crude product was purified by chromatography, getting solid yellow (150 mg, yield: 18%). LC-MS (ESI) m/z: 421 (M+1)+.

Example 99D

8-(4-Forfinal)-9-(1,4,5-trimethyl-1Η-imidazol-2-yl) - 8.9bn-dihydro-2Η-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-forfinal)-4-oxo-3-(1,4,5-trimethyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (150 mg) in 85%wage hydrazinoacetate (85%, 3 ml) and methanol (5 ml) was stirred at ambient temperature for 2 days. The resulting suspension was filtered and washed with water (20 ml) and methanol (5 ml)to give a solid white color. The solid was dried in vacuum at 50°C, obtaining the target compound (90 mg, yield 65%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1,91 is 1.96 (d, J=18 Hz, 6H), of 3.25 (s, 3H), 4,59-to 4.62 (d, J=10,8 Hz, 1H), 4.92 in-4,95 (d, J=10,8 Hz, 1H), 7,09-to 7.15 (m, 3H), 7,22 (s, 1H), was 7.36-7,38 (d, J=7,6 Hz, 1H), 7,43-7,46 (m, 2H), 7,54-7,58 (t, J=8 Hz, 1H), 12,13 (s, 1H); LC-MS (ESI) m/z: 390 (M+1)+.

Example 100

8-(4-Forfinal)-9-(1-methyl-1H-1,2,3-triazole-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 100A

(1H-1,2,3-Triazole-4-yl)methanol

TMSN3(24.8 g, 214 mmol) under nitrogen atmosphere was added to a solution of CuI (1.4 g, 0.4 mol) and prop-2-in-1-ol (8.0 g, 142,4 mmol) in DMF (160 ml) and methanol (20 ml). The reaction mixture was stirred at 100°C for 12 chaste the mixture was cooled to ambient temperature and filtered through a short Florisil and concentrated. The crude product was purified by chromatography on columns (silica gel, prewashed with triethylamine, petroleum ether:ethyl acetate 1:3 to 1:5)to give the target compound (12.7 g, 90%) in the form of a yellow oil.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.09 to (m, 2H), 4,48-4,10 (m, 1H), to 5.21-5,24 (m, 1H), 7.62mm (s, 1H); LC-MS (ESI) m/z: 100 (M+1)+.

Example 100B

(1-Methyl-1H-1,2,3-triazole-4-yl)methanol

To a solution of (1Η-1,2,3-triazole-4-yl)methanol (5.0 g, 51,5 mmol) and K2CO3(8.5 g, 62 mmol) in MeCN (190 ml) dropwise at 0°C was added iodomethyl (3.8 ml). Then the reaction mixture was stirred at ambient temperature overnight, the reaction solution was filtered and acidified to pH 6 with acetic acid, then the solvent was evaporated, obtaining the target compound (5.6 g, yield 98%) in the form of a yellow oil and used in the next stage without further purification. LC-MS (ESI) m/z: 114 (M+1)+.

Example 100C

1-Methyl-1H-1,2,3-triazole-4-carbaldehyde

(1-Methyl-1H-1,2,3-triazole-4-yl)methanol (5.6 g, 50 mmol) and activated manganese dioxide (55 g, 65 mmol) was dissolved in acetone (130 ml)and the solution was stirred at ambient temperature for 3 hours. Then the reaction mixture was filtered, the solvent was evaporated in vacuum. The residue was purified flash chromatography (silica gel, petroleum ether:ethyl acetate 5:1 to 2:1), obtaining the target compound (1.1 g, yield 20%).1H-NMR (400 MHz, D IS the CO-d 6) δ (ppm): 4,13 (m, 3H), 8,81 (s, 1H), 10,02 (s, 1H); LC-MS (ESI) m/z: 112 (M+1)+.

Example 100D

2-(4-Forfinal)-3-(1-methyl-1H-1,2,3-triazole-4-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-verbindingenmee)isobenzofuran-1(3H)-she (698 mg, 2.7 mmol) and 1-methyl-1H-1,2,3-triazole-4-carbaldehyde (334 mg, 3 mmol) in ethylpropylamine (35 ml) was cooled to 0°C. Then was added dropwise a solution of ethanolate sodium in ethanol (sodium (248 mg, up 10.8 mmol) in ethanol (15 ml)). After the addition the mixture was stirred at ambient temperature for 4 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product which was then purified by chromatography (silica gel, petroleum ether/ethyl acetate = 3:1 to 1:1), obtaining the target compound (426 mg, yield 39%). LC-MS (ESI) m/z: 395 (M+1)+.

Example 100E

8-(4-Forfinal)-9-(1-methyl-1H-1,2,3-triazole-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-forfinal)-3-(1-methyl-1H-1,2,3-triazole-4-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (113 mg, 0.28 mmol) in 85%wage hydrazinoacetate (4 ml) was stirred for 3 hours at ambient temperature. The mixture was filtered and washed with water, petrol is NYM ether and ethyl acetate, give crude product, which was purified preparative HPLC, obtaining the target compound (41 mg, yield 39%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3,93 (s, 3H), 4,50-to 4.52 (d, J=7,6 Hz, 1H), 4,96-to 4.98 (d, J=1.6 Hz, 1H), 7,09-to 7.15 (m, 3H), 7,35-7,42 (m, 4H), 7,55-EUR 7.57 (t, J=7,6 Hz, 1H), 7,72 (s, 1H); LC-MS (ESI) m/z: 363 (M+1)+.

Example 101

N,N-Dimethyl-4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzamid

Example 101A

4-Formyl-N,N-dimethylbenzamide

To a suspension of 4-formylbenzoate acid (4,00 g, to 26.7 mmol) in dry DCM (8 ml) dropwise at ambient temperature under nitrogen atmosphere was added thionyl chloride (2,92 g, 40.0 mmol) and DMF (0.6 ml). The reaction mixture was heated under reflux for 2 hours. After cooling, this mixture was added dropwise for 15 minutes in a bath of ice water to 33% dimethylamine in water (10.5 ml, 72 mmol)and the reaction mixture was stirred for 1 hour at the same temperature. The solvent was evaporated in vacuum. The residue was purified by chromatography on silica gel, obtaining the target compound (2.5 g, yield 53%) in the form of a solid yellow color.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2,86 (s, 3H), 3,30 (s, 3H), 7,60 (d, J=7,6 Hz, 2H), 7,95 (d, J=7,6 Hz, 2H), 10,04 (s, 1H); LC-MS (ESI) m/z: 178 (M+1)+.

Example 101B

(Ε)-N,N-dimethyl-4-((1-oxo-1,3-dihydroisobenzofuran-4-elimina)methyl)benzamide

4-Aminoazobenzene-1(3H)-he (2.10 g, 14.1 mmol), 4-formyl-N,N-dimethylbenzene is (2.50 g, 14.1 mmol) and dryMgSO4(9,84 g, 82 mmol) was added to acetonitrile (170 ml) and stirred under reflux overnight. The mixture was filtered, and the solvent was evaporated under reduced pressure, and the residue was recrystallized getting 3.5 g of target compound in the form of bright solids.1H-NMR (400 MHz, CDCl3) δ (ppm): a 3.01 (s, 3H), 3.15 in (s, 3H), 5,43 (s, 2H), 7,38-7,40 (d, 7= 7,6 Hz, 1H), 7,55-to 7.61 (m, 3H), 7,80-of 7.82 (d, J=7,6 Hz, 1H), of 7.96-7,98 (d, J=8 Hz, 2H), 8,58 (s, 1H); LC-MS (ESI) m/z: 308 (M+1)+.

Example 101C

2-(4-(Dimethylcarbamoyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

Added (E)-N,N-Dimethyl-4-((1-oxo-1,3-dihydroisobenzofuran-4-elimina)methyl)benzamide (924 mg, 3.0 mmol), 1-methyl-1Η-imidazole-2-carbaldehyde (363 mg, 3.3 mmol), sodium (276 mg, 12 mmol) in ethanol (30 ml) and ethylpropane (45 ml)and the mixture was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4), and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether/ethyl acetate= 20:1 to 1:2)to give the target compound in the form of a solid yellow (500 mg, yield 37%). LC-MS (ESI) m/z: 447 (M+1]+.

Example 101D

N,N-Dimethyl-4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzamid

Time to relax is 2-(4-(dimethylcarbamoyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (500 mg, 1.12 mmol) and hydrazinoacetate (8 ml)and the mixture was stirred at 40°C for 3 hours. Then the mixture was cooled to ambient temperature and filtered, obtaining the target compound (90 mg, yield 19%) in the form of a solid white color.1Η ΝMR (400 MHz, DMSO-d6) δ (ppm): 2,86 (s, 3H), 2,96 (s, 3H), 3,42 (s, 3H), 4,66-4,69 (d, J=10.4 Hz, 1H), 4,96-4,99 (d, J=10.4 Hz, 1H), 6.73 x (s, 1H), 6.89 in (s, 1H), 7,16-7,19 (m, J=7,6 Hz, 1H), 7.29 trend was 7.45 (m, 6H), 7,56-of 7.60 (t, J=and 7.6 Hz, 1H), 12,18 (s, 1H); LC-MS (ESI) m/z: 415 (M+1)+.

Example 102

9-(4,5-Dimethyl-4H-1,2,4-triazole-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 102A

Isothiocyanates

To a solution of methylamine hydrochloride (61 g, 0.9 mol) in 100 ml of water was added carbon disulfide (68,5 g, 0.9 mol). The mixture was cooled to 10°C, was added dropwise within 30 minutes, a cold solution of sodium hydroxide (72 g, 1.8 mol) in water (160 ml). After the addition the internal temperature was gradually raised to 85°C. the Solution was maintained at this temperature for 1.5 hours. The bright red solution was cooled to a temperature of 35°C~40°C, was added ethylchloride (98 g, 0.9 mol) over 1 hour with stirring. Stirring was continued for 30 minutes after adding. The mixture was defended during the night. The organic layer was separated, dried over Na2SO4and person to distil under atmospheric pressure. The fraction which boils at 115-120°C, collected in the form of colorless is kristallov (40 g, yield 61%).1H-NMR (400 MHz, CDCl3) δ (ppm); 3,29 (s, 3H).

Example 102B

2-Acetyl-N-methylhydrogensilicone

To mix the solution acetohydrazide (3.7 g, 50 mmol) in methanol (30 ml) at 0°C was added a solution of compound isothiocyanatobenzene (3,65 g, 50 mmol) in methanol (50 ml). After the addition the mixture was stirred at ambient temperature overnight. The mixture was concentrated, obtaining the crude product (7 g) in the form of a solid white color that was used in the next stage without further purification. LC-MS (ESI) m/z 148 (M+1)+.

Example 102

3,4-Dimethyl-1H-1,2,4-triazole-5(4H)-tion

To a stirred solution of crude 2-acetyl-N-methylhydrogensilicone (7 g, or 47.6 mmol) in ethanol (100 ml) was added triethylamine (14.4 g, 143 mmol). After the addition the mixture was heated under reflux overnight and then concentrated, obtaining the target compound (4,2 g, yield 65% for two steps) in the form of a solid white color that was used in the next stage without further purification.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2,28 (s, 3H), 3,38 (s, 3H), 13,40 (s, 1H). LC-MS (ESI) m/z: 130 (M+1)+.

Example 102D

3,4-Dimethyl-4H-1,2,4-triazole

A suspension of 3,4-dimethyl-1H-1,2,4-triazole-5(4H)-thione (4,2 g, 32.5 mmol) in dichloromethane (72 ml) was cooled to 0°C. was added dropwise a solution of 30% hydrogen peroxide (16,9 ml of 149.5 mmol) in acetic acid is the (44 ml). After the addition the mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved with water (20 ml), was treated with an aqueous solution of sodium hydroxide to pΗ=12, was extracted with dichloromethane (80 ml ×8). The combined organic layers were dried over anhydrous Na2SO4concentrated, obtaining the target compound (2.3 g, yield 73%) in the form of a solid brown color.1H-NMR (400 MHz, CDCl3) δ (ppm); 2,47 (s, 3H), 3,63 (s, 3H), of 8.09 (s, 1H). LC-MS (ESI) m/z: 98 (M+1)+

Example 102E

(4,5-Dimethyl-4H-1,2,4-triazole-3-yl)methanol

A mixture of 3,4-dimethyl-4H-1,2,4-triazole (2.3 g, with 23.7 mmol) and aqueous formaldehyde (5 ml) was heated to 90°C over night. The mixture was concentrated, give crude product. The crude product was purified by chromatography on silica gel (dichloromethane/methanol= 200:1 to 15:1), obtaining the target compound (2,48 g, yield 82%) in the form of a solid white color.1H-NMR (400 MHz, DMSO-d6) δ (ppm); 2,31 (s, 3H), 3,52 (s, 3H), to 4.52-of 4.54 (d, J=5,2 Hz, 2H), 5,49-the 5.51 (t, J=5,2 Hz, 1H). LC-MS (ESI) m/z: 128 (M+1)+

Example 102F

4,5-Dimethyl-4H-1,2,4-triazole-3-carbaldehyde

A mixture of 4,5-dimethyl-4H-1,2,4-triazole-3-yl)methanol (2,48 g of 19.5 mmol) and manganese oxide (IV) (17.8 g, 204,8 mmol) in dry tetrahydrofuran (72 ml) was stirred at ambient temperature overnight, the mixture was filtered and the precipitate about ivali dichloromethane (100 ml ×3). The combined filtrate was concentrated, obtaining the target compound (1.6 g, yield 66%) in the form of a solid white color.1H-NMR (400 MHz, DMSO-d6) δ (ppm); to 2.54 (s, 3H), with 3.89 (s, 3H), 10,06 (s, 2H). LC-MS (ESI) m/z: 126 (M+1)+.

Example 102G

3-(4,5-Dimethyl-4H-1,2,4-triazole-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-she (237 mg, 1 mmol) and 4,5-dimethyl-4H-1,2,4-triazole-3-carbaldehyde (150 mg, 1.2 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol [sodium (92 mg, 4 mmol) in ethanol (5 ml)]. After the addition the mixture was stirred at 10°C for 5 hours, then at 30°C for 2.5 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (30 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=5:1 then ethyl acetate/methanol=15:1), obtaining the target compound (60 mg, yield: 15%). LC-MS (ESI) m/z: 391 (M+1)+.

Example 102Η

9-(4,5-Dimethyl-4H-1,2,4-triazole-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(4,5-dimethyl-4H-1,2,4-triazole-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (60 mg) in 85%of the m hydrazinoacetate (1 ml) and methanol (3 ml) was stirred at 10°C for 2.5 hours. The mixture was purified preparative HPLC, obtaining the target compound in the form of a solid yellow (6 mg, yield: 11%).1H-NMR (400 MHz, CD3OD) δ (ppm); of 2.33 (s, 3H), on 3.36 (s, 3H), 4,79-to 4.81 (d, J=11,6 Hz, 1H), 4,99-5,02 (d, J=11,6 Hz, 1H), 7,21-of 7.23 (m, 2H), 7,31-7,33 (m, 2H), 7,45-of 7.48 (m, 2H), to 7.59-to 7.67 (m, 2H); LC-MS (ESI) m/z: 359 (M+1)+.

Example 103

9-(4,5-Dimethyl-4H-1,2,4-triazole-3-yl)-8-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 103A

3-(4,5-Dimethyl-4H-1,2,4-triazole-3-yl)-2-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-verbindingenmee)isobenzofuran-1(3H)-she (510 mg, 2 mmol) and 4,5-dimethyl-4H-1,2,4-triazole-3-carbaldehyde (275 mg, 2.2 mmol) in ethylpropylamine (20 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (184 mg, 8 mmol) in ethanol (10 ml)). After the addition the mixture was stirred at 10°C for 2 hours, then at 30°C for 4 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (30 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=3:1, then ethyl acetate/methanol=30:1)to give the target compound (170 mg, yield: 21%). LC-MS (ESI) m/z: 409 (M+1)+.

Example 103

9-(4,5-Dimethyl-4H-1,2,4-triazole-3-yl)-8-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(4,5-dimethyl-4H-1,2,4-triazole-3-yl)-2-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (170 mg) in 85%wage hydrazinoacetate (1 ml) and methanol (3 ml) was stirred at 25°C for 3 hours. The mixture was purified preparative HPLC, obtaining the target compound in the form of a solid yellow (40 mg, yield: 26%).1Η-NMR (400 MHz, DMSO-d6) δ (ppm): of 2.23 (s, 3H), 3,38 (s, 3H), 4,78-4,80 (d, J=11.0 cm Hz, 1H), 4,99-5,02 (d, J=11.0 cm Hz, 1H), 7,11-to 7.18 (m, 3H), 7,35-7,40 (m, 2H), 7,47-7,51 (m, 2H), EUR 7.57-to 7.61 (t, J=7,6 Hz, 1H), 12,19 (s, 1H); LC-MS (ESI) m/z: 377 (M+1)+.

Example 104

2-Fluoro-N,N-dimethyl-5-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzamid

Example 104A

5-(Diethoxylate)-2-perbenzoate

To a stirred solution of 2-fluoro-5-formylbenzoate (5,96 g, 40 mmol) in ethanol (5.6 g, 120 mmol) was added ammonium chloride (85,6 mg, 1.6 mmol). Once added, the mixture was cooled to 0°C and was added dropwise triethoxysilane (6,52 g, 44 mmol). After the addition the mixture was stirred at ambient temperature overnight. The mixture was concentrated, then was filtered and the precipitate washed with ethyl acetate (20 ml ×2). The filtrate was concentrated, obtaining the target compound (8.8 g, yield 98%) in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ (ppm): 1,22-of 1.29 (m, 6H), 3,50-3,70 (m, 4H), of 5.50 (s, 1H), 7,19-724 (t, J=8,8 Hz, 1H), 7,70-7,74 (m, 1H), 7,76 for 7.78 (DD, J1=6,4 Hz, J2=2.4 Hz, 1H). LC-MS (ESI) m/z: 224 (M+1)+.

Example 104B

2-Fluoro-5-formylbenzoate acid

A mixture of 5-(diethoxylate)-2-perbenzoate (8.8 g, to 39.5 mmol) in 3h. aqueous sodium hydroxide solution (100 ml) was heated to 90°C and was stirred for 8 hours. Then the mixture was cooled to ambient temperature and acidified 3h. hydrochloric acid to pH 2 and then extracted with ethyl acetate (200 ml ×4). The combined organic layers were dried over anhydrous Na2SO4and concentrated, obtaining 2-fluoro-5-formylbenzoate acid (6.6 g, yield 99%) in the form of a solid white color.1H-NMR (400 MHz, CDCl3) δ (ppm): 7,34-7,39 (DD, J1=10 Hz, J2=8,4 Hz, 1H), 8,14-8,18 (m, 1H), 8,57-8,59 (DD, J1=7,2 Hz, J2=2.4 Hz, 1H), 10,04 (s, 1H). LC-MS (ESI) m/z 169 (M+1)+.

Example 104C

2-Fluoro-5-formyl-N,N-dimethylbenzamide

To a solution of 2-fluoro-5-formylbenzoate acid (3 g, 17.8 mmol) in methylene chloride (10 ml) slowly at 0°C was added thionyl chloride (2.0 ml, for 26.7 mmol). Then cool the reaction mixture was heated under reflux for 3 hours. The solution was cooled to 0°C, was slowly added dimethylamine (40 solutions wt.% in water, 5 ml)and then stirred at ambient temperature for 1 hour. The solution was washed with water and brine, the organic layer was dried Na2SO4, the solvent was removed, receiving the desired product (2.4 g, yield 76%). LC-MS (ESI) m/z: 196 (M+1)+

Example 104D

(E)-2-fluoro-N,N-dimethyl-5-((1-oxo-1,3-dihydroisobenzofuran-4-elimina)methyl)benzamide

A solution of 2-fluoro-5-formyl-N,N-dimethylbenzamide (2.38 g, 12.2 mmol), 4-aminoazobenzene-1(3H)-she (1,82 g, 12.2 mmol), anhydrous magnesium sulfate (14,67 g, 122 mmol) in acetonitrile (100 ml) was heated under reflux for 2 days. The solution was filtered and removed in vacuo. The crude product is recrystallized from isopropanol, obtaining the target compound (1.5 g, yield: 37%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.91 in of 2.92 (d, J=0.4 Hz, 3H), of 3.07 (s, 3H), of 5.55 (s, 2H), 7,52-7,56 (t, J=8,8 Hz, 1H), to 7.67-of 7.70 (m, 2H), 7,76 for 7.78 (m, 1H), 8,02-of 8.04 (m, 1H), 8,10-to 8.14 (m, 1H), 8,83 (s, 1H); LC-MS (ESI) m/z: 327 (M+1)+.

Example 104E

2-(3-(Dimethylcarbamoyl)-4-forfinal)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

The mixture of compounds 1-methyl-1H-imidazole-2-carbaldehyde (110 mg, 1.0 mmol) and (E)-2-fluoro-N,N-dimethyl-5-((1-oxo-1,3-dihydroisobenzofuran-4-elimina)methyl)benzamide (300 mg, of 0.92 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (85 mg, 3,68 mmol) in ethanol (5 ml)). After the addition the mixture was stirred at ambient temperature for 2.5 hours. The mixture is extinguished with water (20 ml), and the solvent was removed in vacuum. The residue was dissolved in water and was extracted with etilize is that three times, washed with water, brine, and then the extract was evaporated, the crude product was purified by chromatography, getting a solid yellow color. The solid was dried in vacuum at 50°C, obtaining the target compound (130 mg, yield: 30%). LC-MS (ESI) m/z: 465 (M+1)+.

Example 104F

2-Fluoro-N,N-dimethyl-5-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzamid

A mixture of compound 2-(3-(dimethylcarbamoyl)-4-forfinal)-3-(1-methyl-1Η-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (130 mg) in hydrazinoacetate (85%, 2 ml) and methanol (5 ml) was stirred at ambient temperature for 4 hours. The resulting mixture was filtered and washed with water (20 ml) and methanol (5 ml)to give a solid white color. The solid was dried in vacuum at 50°C, obtaining the target compound (30.0 mg, 30%yield).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2,72 (s, 3H), of 2.97 (s, 3H), 3.43 points (s, 3H), 4,67-4,70 (d, J=10,8 Hz, 1H), 4.95 points is equal to 4.97 (d, J=10,8 Hz, 1H), 6,72-of 6.73 (d, J=1.2 Hz, 1H), 6.89 in-6,89 (d, J=0.8 Hz, 1H), 7,15-of 7.23 (m, 2H), 7,34-7,41 (m, 3H), of 7.48-7,49 (m, 1H), 7,56-of 7.60 (t, J=8 Hz, 1H), 12,17 (s, 1H); LC-MS (ESI) m/z: 433 (M+1)+.

Example 105

8-(4-Chlorophenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 105A

(E)-4-(4-Chlorobenzylidene)isobenzofuran-1(3H)-he

To a stirred mixture of 4-chlorobenzaldehyde (2.3 g, 16,1 mmol) and anhydrous magnesium sulfate (16 g, 134 mmol) in betwedn the m acetonitrile (200 ml) at ambient temperature was added 4-aminoazobenzene-1(3H)-he (2 g, the 13.4 mmol). After the addition the mixture was stirred under reflux overnight. The mixture was filtered and the precipitate washed with ethyl acetate (50 ml ×3). The filtrate was concentrated, give crude product. The crude product was washed with petroleum ether and recrystallized from ethyl acetate, obtaining the target compound (2 g, yield: 55%). LC-MS (ESI) m/z: 272 (M+1)+.

Example 105B

2-(4-Chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-chlorobenzylidene)isobenzofuran-1(3H)-she (500 mg, of 1.85 mmol) and N-methyl-2-imidazolecarboxaldehyde (222 mg, 2.1 mmol) in ethylpropylamine (20 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (174 mg, 7.4 mmol) in ethanol (10 ml)). After the addition the mixture was stirred at ambient temperature for 2 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1), obtaining the target compound (150 mg, yield 20%). LC-MS (ESI) m/z: 410 (M+1)+.

Example 105C

8-(4-Chlorophenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]nafta is Azin-3(7H)-he

A mixture of 2-(4-chlorophenyl)-3-(1-methyl-1Η-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (150 mg, and 0.37 mmol) in 85%wage hydrazinoacetate (4 ml) and methanol (6 ml) was stirred at ambient temperature for 2 hours the Mixture was filtered and washed with water, obtaining the target compound (89 mg, yield: 65%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3,44 (s, 3H), 4,69 (d, J=10,8 Hz, 1H), 4,96 (d, J=10,8 Hz, 1H), 6,76 (s, 1H), 6,93 (d, 1H), 7,16 (d, J=8 Hz, 1H), 7,33-7,44 (m, 6H), 7,56-of 7.60 (m, 1H), 12,19 (d, 1H); LC-MS (ESI) m/z: 378 (M+1)+.

Example 106

9-(1-Methyl-1H-imidazol-2-yl)-8-(4-(trifluoromethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 106A

(E)-4-(4-(Trifluoromethyl)benzylideneamino)isobenzofuran-1(3H)-he

To a stirred mixture of 4-(trifluoromethyl)benzaldehyde (2.8 g, 16,1 mmol) and anhydrous magnesium sulfate (16 g, 134 mmol) in anhydrous acetonitrile (200 ml) at ambient temperature was added 4-aminoazobenzene-1(3H)-he (2 g, a 13.4 mmol). After the addition the mixture was stirred under reflux overnight. The mixture was filtered and the precipitate washed with ethyl acetate (50 ml ×3). The filtrate was concentrated, give crude product. The crude product was washed with petroleum ether and recrystallized from ethyl acetate, obtaining the target compound (2.8 g, yield: 68%). LC-MS (ESI) m/z: 306 (M+1)+.

Example 106B

3-(1-Methyl-1H-imidazol-2-yl)-4-oxo-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-tinkerbell

A mixture of (E)-4-(4-(trifluoromethyl)benzylideneamino)isobenzofuran-1(3H)-it (1 g, or 3.28 mmol) and N-methyl-2-imidazolecarboxaldehyde (400 mg, 3.61 mmol) in ethylpropylamine (40 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (31 mg, 13,1 mmol) in ethanol (10 ml)). After the addition the mixture was stirred at ambient temperature for 2 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate =1:1), obtaining the target compound (150 mg, yield 8%). LC-MS (ESI) m/z: 444 (M+1)+.

Example 106C

9-(1-Methyl-1H-imidazol-2-yl)-8-(4-(trifluoromethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(1-methyl-1Η-imidazol-2-yl)-4-oxo-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (150 mg, 0.34 mmol) in 85%wage hydrazinoacetate (4 ml) and methanol (6 ml) was stirred at ambient temperature for 2 hours the Mixture was filtered and washed with water, obtaining the target compound (25 mg, yield: 18%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.46 in (s, 3H), to 4.81 (d, J=10,8 Hz, 1H), 5,07 (d, J=10,8 Hz, 1H), PC 6.82 (s, 1H), 6,97 (d, 1H), 7,16 (d, J=8 Hz, 1H), 7,41(d, J=7,6 Hz, 2H), 7,58-of 7.69 (m, 5H), 12,22 (d, 1H); LC-MS (ESI) m/z: 412 (M+1)+.

Example 107

8-(4-Forfinal)-9-(thiazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 107A

2-(4-Forfinal)-4-oxo-3-(thiazol-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-verbindingenmee)isobenzofuran-1(3H)-she (1.88 g, 7,37 mmol) and thiazole-2-carbaldehyde (1 g, 8,8 mmol) in ethylpropylamine (50 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (678 g, 29 mmol) in ethanol (30 ml)). After the addition the mixture was stirred at ambient temperature for 2 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 10:1 to 1:10)to give crude compound (180 mg). LC-MS (ESI) m/z: 397 (M+1)+.

Example 107B

8-(4-Forfinal)-9-(thiazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-forfinal)-4-oxo-3-(thiazol-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (180 mg) in 85%wage hydrazinoacetate (10 ml) and methanol (10 ml) was stirred at 45°C during the night. The methanol was removed under reduced pressure. A mixture of filtrowanie washed with water, receiving the target compound (3 mg, yield: 2%).1H-NMR (400 MHz, CD3OD) δ (ppm): 4,88 (d, J=8.0 Hz, 1H), 5,09 (d, J=8.0 Hz, 1H), 7,01 (t, 2H), 7,21 (d, 1H), was 7.36-7,40 (m, 2H), 7,47 (d, 1H), to 7.59 (d, 1H), 7,65 (t, 1H), 7,74 (d, 1H);19F-NMR (400 MHz, CD3OD) δ (ppm): -116,36 (c); LC-MS (ESI) m/z: 365 (M+1)+.

Example 108

9-(1-Ethyl-1H-imidazol-2-yl)-8-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 108A

3-(1-Ethyl-1Η-imidazol-2-yl)-2-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-verbindingenmee)isobenzofuran-1(3H)-she (765 mg, 3 mmol) and N-ethyl-2-imidazolecarboxaldehyde (372 mg, 3 mmol) in ethylpropylamine (45 ml) was cooled to 0°C. Then was added dropwise a solution of ethoxide sodium (sodium (276 mg, 12 mmol) in ethanol (45 ml)). After the addition the mixture was stirred at ambient temperature for 4 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 25:1 to 5:1), obtaining the target compound (90 mg, yield: 7%). LC-MS (ESI) m/z: 408 (M+1)+.

Example 108B

Synthesis of 9-(1-Ethyl-1H-imidazol-2-yl)-8-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it

a Mixture of 3-(1-ethyl-1H-imidazol-2-yl)-2-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-carboxylate (90 mg, 0.22 mmol) in 85%wage hydrazinoacetate (4 ml) and methanol (10 ml) was stirred for 4 hours at ambient temperature. The methanol was removed under reduced pressure. The mixture was filtered and washed with water to give crude product. The crude product was purified preparative HPLC, obtaining the target compound (a 38.5 mg, yield: 47%).1H-NMR (400 MHz, MeOD)) δ (ppm): 1,06-of 1.09 (t, J=7.2 Hz, 3H), 3,74-of 3.78 (m, 2H), 4,60-to 4.62 (d, J=11,6 Hz, 1H), 4,98-free 5.01 (d, J=11,6 Hz, 1H), 6,91-7,02 (m, 4H), 7,19-7,21 (m, 1H), 7,39-the 7.43 (m, 2H), 7,56-to 7.64 (m, 2H,); LC-MS (ESI) m/z: 376 (M+1)+.

Example 109

8-(4-((4-Ethyl-3-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (86 mg, 0.23 mmol) in dry DCM (15 ml) was added ΗOAc, then 1-ethyl-2-methylpiperazin (90 mg, 0.7 mmol), after adding the mixture was stirred at ambient temperature overnight. Then the mixture was cooled to 0°C. was Added sodium borohydride (85 mg, 1.4 mmol). After the addition the mixture was stirred at this temperature for 12 hours. DCM was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product, which was purified preparative HPLC, obtaining the target compound in the form of a solid white (90 mg, 71%yield).1H-NMR (400 MHz, DMSO-d6) δ (MD.): of 1.30 (t, 3H), of 1.42 (m, 3H), 3,23 (s, 1H), 3,47 of 3.56 (m, 6H), 3,80 (t, 2H), 4,46 (m, 3H) 4,91 (m, 10H), 7,20-7,29 (m, 3H), 7,30-to 7.32 (m, 3H), 7,46-of 7.48 (m, 3H), to 7.59 (m, 1H), 7,69 (t, 1H). LC-MS (ESI) m/z: 552(M+1)+.

Example 110

8-(4-((4-Ethylpiperazin-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (200 mg, 0.52 mmol), N-ethylpiperazine (209 mg, 1.56 mmol) and acetic acid (156 mg, 2.6 mmol) in dichloromethane (30 ml) was stirred at ambient temperature overnight. Then the mixture was cooled to 0°C was added triacetoxyborohydride sodium (165 mg, 0.78 mmol). After the addition the mixture was stirred at ambient temperature for 5 hours. Dichloromethane was removed under reduced pressure. The crude product was purified prep-HPLC, obtaining the target compound (96 mg, yield 33%).1H-NMR (400 MHz, CD3OD) δ (ppm): 1,37-of 1.41 (t, J=6.8 Hz, 3H), 3,30-to 3.34 (m, 2H), 3,47-3,86 (m, 8H), 4,36-to 4.38 (d, J=7,6 Hz, 1H), 4,46 (s, 2H), 4.80 to 4,82 (d, J=8,4 Hz,1H), 6,92-of 6.96 (m, 2H), 7,11-to 7.15 (m, 2H), 7,21-of 7.23 (m, 1H), 7,42 was 7.45 (m, 2H), 7,51-7,56 (m, 3H), 7,63-to 7.67 (m, 1H). LC-MS (ESI) m/z: 484 (M+H)+.

Example 111

4-(9-(4-Forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)-N,N-dimethylbenzamide

Example 111A

2-(4-(Dimethylcarbamoyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

Added the compound (E)-N,N-dimethyl-4-((1-oxo-1,3-dihydroisobenzofuran-4-elimina)methyl)benzamide (1,36 g, 4.4 mmol), 4-fluoro shall benzaldehyde (600 mg, 4,84 mmol), sodium (405 mg, 17.6 mmol), ethanol (40 ml) and ethylpropane (66 ml)and the mixture was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4), and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether/ethyl acetate = 20:1 to 5:1), obtaining the target compound in the form of a solid (490 mg, yield 22%). LC-MS (ESI) m/z: 461 (M+1)+.

Example 111B

4-(9-(4-Forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)-N,N-dimethylbenzamide

A mixture of 2-(4-(dimethylcarbamoyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (490 mg, 1 mmol) and hydrazinoacetate (15 ml) was stirred at 40°C for 3 hours. Then the mixture was cooled to ambient temperature and filtered, obtaining the target compound (110 mg, yield 24%) in the form of a solid white color.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2,82 (s, 1H), 2,93 (s, 1H), 4,36-to 4.38 (d, J=9,2 Hz, 1H), 4,78-4,80 (d, J=9,2 Hz, 1H), 7,01-7,03 (m, 2H), 7,14-7,19 (m, 3H), 7,25-7,28 (m, 2H), 7,32-7,40 (m, 3H), 7,45 (s, 1H), 7,56-of 7.60 (t, J=8 Hz, 1H), 12,17 (s, 1H); LC-MS (ESI) m/z: 429 (M+1)+.

Example 112

4-(8-(4-((Dimethylamino)methyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)-N,N-dimethylbenzamide

Example 112A

2-(4-(Diethoxylate)phenyl)-3-(4-(dimethylcarbamoyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxyl the lat

To a mixture of 4-formyl-N,N-dimethylbenzamide (960 mg, 5,42 mmol), (E)-4-(4-(diethoxylate)benzylideneamino)isobenzofuran-1(3H)-she (1.84 g, 5,42 mmol) and sodium methylate (499 mg, and 21.7 mmol) was added ethylpropane (30 ml)and the mixture was stirred at ambient temperature overnight. Then the mixture was evaporated under reduced pressure and was extracted with EtOAc (100 ml ×4), and concentrated. Received the crude product (250 mg). LC-MS (ESI) m/z: 545 (M+1)+.

Example 112B

4-(8-(4-(Diethoxylate)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)-N,N-dimethylbenzamide

2-(4-(Diethoxylate)phenyl)-3-(4-(dimethylcarbamoyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (250 mg, 0.46 mmol) and hydrazinoacetate (85%, 5 ml) were added in MeOH (15 ml)and the mixture was stirred at ambient temperature for 5 hours. The resulting mixture was concentrated under reduced pressure to a volume of 15 ml and then filtered; the filtrate was evaporated, obtaining the target compound in the form of a solid white color (180 mg, yield 76%). LC-MS (ESI) m/z: 513 (M+1)+.

Example 112C

4-(8-(4-Formylphenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)-N,N-dimethylbenzamide

To a solution of 4-(8-(4-(diethoxylate)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)-N,N-dimethylbenzamide (180 mg, 0.35 mmol) in acetonitrile (10 ml) was added triperoxonane acid (5 ml)was stirred during the s 30 minutes. Then the mixture was evaporated under reduced pressure, obtaining the target compound (140 mg, yield 91%). LC-MS (ESI) m/z: 439 (M+1)+.

Example 112D

4-(8-(4-((Dimethylamino)methyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)-N,N-dimethylbenzamide

To a stirred solution of 4-(8-(4-formylphenyl)-3-oxo-3,7,8,9-tetrahydro-2Η-pyrido[4,3,2-de]phthalazine-9-yl)-Ν,Ν-dimethylbenzamide (140 mg, 0.32 mmol) in dry DCM (20 ml) was added acetic acid, then dimethylamine (57 mg, 1.3 mmol). After the addition the mixture was stirred at ambient temperature overnight. Then the mixture was cooled to 0°C. was Added sodium borohydride (102 mg, 0.48 mmol). After the addition the mixture was stirred at this temperature for 12 hours. DCM was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product, which was purified preparative HPLC, obtaining the target compound in the form of a solid white color (15 mg, yield 10%).1Η-NMR (400 MHz, CD3OD) δ (ppm): 2,19 (DD, 6H), of 2.93 (s, 3H), 3,06 (s, 3H), 3,40 (DD, 2H), 4,34 (d, 1H), 4,16-7,19 (m, 5H), 7.23 percent-7,26 (m, 4H), 7,54 (d, 1H), to 7.61 (t, 1H). LC-MS (ESI) m/z: 468 (M+1)+.

Example 113

9-(4-Forfinal)-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2Η-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (150 mg, 0,39 mmol), N-methylp perazine (117 mg, at 1.17 mmol) and acetic acid (117 mg, of 1.95 mmol) in dichloromethane (20 ml) was stirred at ambient temperature overnight. Then the mixture was cooled to 0°C was added triacetoxyborohydride sodium (124 mg, of 0.58 mmol). After the addition the mixture was stirred at ambient temperature for 5 hours. Dichloromethane was removed under reduced pressure. The crude product was purified preparative HPLC, obtaining the target compound (48 mg, yield 22%).1H-NMR (400 MHz, CD3OD) δ (ppm): to 3.02 (s, 3H), 3,60-3,81 (m, 8H), 4,36-to 4.38 (d, J=7,6 Hz, 1H), 4,47 (s, 2H), 4.80 to 4,82 (d, J=7,6 Hz, 1H), 6,93-6,97 (m, 2H), 7,12-to 7.15 (m, 2H), 7,22-7,24 (m, 1H), 7,43 was 7.45 (m, 2H), 7,52-EUR 7.57 (m, 3H), of 7.64-to 7.68 (m, 1H). LC-MS (ESI) m/z: 470 (M+1)+.

Example 114

9-(4-Forfinal)-8-(4-(piperazine-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 114A

4-(4-(9-(4-Forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzyl)piperazine-1-tert-butylcarbamoyl

A mixture of 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (150 mg, 0,39 mmol), piperazine-1-tert-BUTYLCARBAMATE (218 mg, 1,17 mmol) and acetic acid (117 mg, of 1.95 mmol) in dichloromethane (20 ml) was stirred at ambient temperature overnight. Then the mixture was cooled to 0°C was added triacetoxyborohydride sodium (124 mg, of 0.58 mmol). After the addition the mixture was stirred at ambient temperature for 5 hours. Dichloromethane deletion is whether under reduced pressure. The crude product was purified flash chromatography, obtaining the target compound (70 mg, yield 32%). LC-MS (ESI) m/z: 556 (M+1)+.

Example 114B

9-(4-Forfinal)-8-(4-(piperazine-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzyl)piperazine-1-tert-BUTYLCARBAMATE (70 mg, 0.12 mmol) in solution ΗCl (g) in acetonitrile (feast upon. 10 ml) was stirred for 3 hours at ambient temperature. The mixture is then filtered, obtaining the crude product. The crude product was purified flash chromatography, obtaining the target compound in the form of a hydrochloride (35 mg, yield 60%).1H-NMR (400 MHz, CD3OD) δ (ppm): 2,63-of 2.64 (m, 4H), 3,19-is 3.21 (m, 4H), of 3.54 (s, 2H), 4,29-or 4.31 (d, J=8.0 Hz, 1H), 4,69-4,71 (d, J=8,4 Hz, 1H), 6.89 in-6,93 (m, 2H), 7,07-7,10 (m, 2H), 7,19-7,26 (m, 5H), 7,54-7,56 (m, 1H), to 7.61-7,65 (m, 1H). LC-MS (ESI) m/z: 456 (M+1)+.

Example 115

9-(4-Forfinal)-8-(4-((3-methylpiperazin-1-yl)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 115A

4-benzyl-1-tert-butyl-2-methylpiperazin-1,4, in primary forms

To a solution of 2-methylpiperazine (2.0 g, 20 mmol) in methylene chloride (15 ml) at 0°C was added dropwise benzylchloride (3.0 ml). The mixture was stirred at 0°C for 1 hour and then at ambient temperature for 2 hours. The mixture then was cooled to 0°C was added diisopropylethylamine (4,5 ml) and then (Re)2O (4.8 g, 22 mmol). The mixture was stirred is at ambient temperature over night, and then the solvent was removed on a rotary evaporator. The residue was dissolved in EtOAc, washed with water and brine, dried overNa2SO4and was purified by chromatography on a column of silica gel (EtOAc:hexane=1:9)to give an intermediate compound in the form of an oil (4.8 g, 72%). LC-MS (ESI) m/z: 357 (M+23)+.

Example 115B

2-Methylpiperazin-tert-butyl-1-carboxylate

To a solution of 4-benzyl-1-tert-butyl-2-methylpiperazin-1,4-in primary forms (4.8 g, 14.4 mmol) in methanol (25 ml) was added 480 mg of 10% Pd/C and stirred at ambient temperature under hydrogen overnight. Was filtered and concentrated, obtaining the target product (2.8 g, yield 97%) in the form of a colorless oil.1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.21 (d, J=6.8 Hz, 3H), of 1.46 (s, 9H), 2,64-2,70 (m, 1H), 2,74-2,78 (m, 1H), 2,88-a 3.01 (m, 3H), of 3.78 (d, J=12,4 Hz, 1H), 4,16 (m, 1H); LC-MS (ESI) m/z: 201 (M+1)+.

Example 115C

4-(4-(9-(4-Forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzyl)-2-methylpiperazin-1-tert-butylcarbamoyl

A mixture of 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (200 mg, 0.52 mmol) and 2-methylpiperazin-1-tert-BUTYLCARBAMATE (311 mg, 1.56 mmol) in methylene chloride (10 ml) was stirred at ambient temperature overnight, then was added NaBH3CN (129 mg, 2.1 mmol)and the mixture was stirred for another 5 hours. Concentrated and the residue was purified chromatograph is her (silica gel, petroleum ether/ethyl acetate= 3:1 to 1:1), obtaining the target compound (70 mg, yield 24%). LC-MS (ESI) m/z: 570 (M+1)+.

Example 115D

9-(4-Forfinal)-8-(4-((3-methylpiperazin-1-yl)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzyl)-2-methylpiperazin-1-tert-BUTYLCARBAMATE (70 mg, 0,123 mol) in 2 ml of ΗCl-acetonitrile was stirred for 2 hours. Concentrated and the residue was purified preparative HPLC, obtaining the target product in the form of a solid white color (30 mg, yield 52%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0,87 (d, J=6.4 Hz, 3H), 1,49 (t, J=10 Hz, 1H)and 1.83 (t, J=10 Hz, 1H), to 2.55 (m, 2H), 2,64 (m, 2H), 2,75 (m, 1H), 3,32 (s, 3H), 4,34 (d, J=9,2 Hz, 1H), 4.72 in (d, J=9,2 Hz, 1H), 6,97-7,01 (m, 2H), 7,13-7,24 (m, 7H), 7,37-7,41 (m, 2H), 7,55-to 7.59 (m, 1H), 12,15 (s, 1H); LC-MS (ESI) m/z: 470 (M+1)+.

Example 116

4-(8-(4-Forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)-N,N-dimethylbenzamide

Example 116A

3-(4-(Dimethylcarbamoyl)phenyl)-2-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

Sodium (115 mg, 5 mmol) was added to EtOH (10 ml)to give sodium ethylate. (E)-4-(4-verbindingenmee)isobenzofuran-1(3H)-he (500 mg, a 1.96 mmol) and 4-formyl-N,N-dimethylbenzamide (382 mg, of 2.16 mmol) was dissolved in ethylpropylamine (10 ml), and to the mixture at 0°C was added dropwise a solution of ateleta sodium, and then the mixture was heated to 30°C for 1 h To the reaction mixture to relax is whether water and EtOAc, the organic phase was separated, washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and then concentrated, to give crude product. The crude product was purified flash chromatography (MeOH:DCM 1:25)to give the target compound (400 mg, yield 44%). LC-MS (ESI) m/z: 461 (M+1)+.

Example 116B

4-(8-(4-Forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-9-yl)-N,N-dimethylbenzamide

A mixture of 3-(4-(dimethylcarbamoyl)phenyl)-2-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (400 mg, 0.87 mmol) and hydrazinoacetate (85%, 10 ml) was dissolved in MeOH (20 ml) and stirred at 35°C for 2 hours. The mixture was concentrated under reduced pressure. The resulting mixture was filtered, the solid washed with water and methanol, getting solid white, and solid matter was dried in vacuum at 40°C, obtaining the target compound (100 mg, yield 54%).1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2,85 (s, 3H), equal to 2.94 (s, 3H), 4,37-and 4.40 (d, 1H), 4.80 to 4,82 (d, 1H), 7,17-7,25 (m, 5H), 7,33 and 7.36 (m, 2H), 7,39-7,41 (d, 1H), 7,45 (s, 1H), EUR 7.57-to 7.61 (t, 1H), 12,19 (s, 1H); LC-MS (ESI) m/z: 429 (M+1)+.

Example 117

9-(4-Forfinal)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 117A

9-(4-Forfinal)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a stirred mixture of 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]ptalis the n-8-yl)benzaldehyde (0.1 g, 0.26 mmol) in anhydrous DCM (4 ml) at 25°C for 0.5 hours was added AcOH (94 mg, 1.56 mmol), then at 25°C was added pyrrolidine (37 mg, 0.52 mmol), was stirred over night. NaBH(OAc)3was added in an ice bath and was stirred for 5 hours. The mixture was concentrated, give crude product. The crude product was dissolved in ethyl acetate, and to this solution was added 2n. HCl (10 ml). The aqueous phase was separated and added 20%NaOH (20 ml). The mixture was extracted with ethyl acetate, and the organic phase was separated, obtaining the target compound (30 mg, yield 26%). LC-MS (ESI) m/z: 441 (M+1)+.

Example 117B

9-(4-Forfinal)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 9-(4-forfinal)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it (30 mg) in a solution of HCl/methanol (20 ml) was stirred at 25°C for 0.5 hours. The methanol was removed under reduced pressure. The mixture was filtered and washed with water, dried over night at 50°C, obtaining the target compound (24 mg, yield 74%).1H-NMR (400 MHz, CD3OD) δ (ppm): 2,00 (s, 2H), 2,16 (s, 2H), 3,14 (s, 2H), 3,41 (s, 2H), 4,32 (s, 2H), 4,35-to 4.38 (d, 1H), 4,78-4,80 (d, 1H), 6,91-to 6.95 (t, 2H), 7,10-7,13 (t, 2H), 7,22-7,24 (d, 1H), 7,42 (m, 4H), 7,56-7,58 (d, 2H), of 7.64-of 7.70 (1H); LC-MS (ESI) m/z: 441 (M+1)+.

Example 118

9-Phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 118A

2-Oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide

To a solution of 4-aminos benzofuran-1(3H)-she (4.0 g, 26.8 mmol), 2-oxo-2-phenylacetic acid (4.1 g, 26.8 mmol) and ΗBTU (15.2 g, with 40.2 mmol) in dichloromethane (240 ml) was added tea (8 ml). The reaction mixture was stirred at ambient temperature overnight. To the mixture was added to water and acidified to pΗ 6-7 1%aqueous solution of HCl, and then filtered. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was evaporated and the crude product was purified by chromatography gradient (silica gel, petroleum ether/ethyl acetate 6:1 to 3:1), obtaining the target compound (5.0 g, yield 66%). LC-MS (ESI) m/z: 282 (M+1)+.

Example 118B

N-(4-Methoxybenzyl)-2-oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide

To a solution of 2-oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide (5 g, 11.7 mmol) in DMF (48 ml) was added NaH (0,78 g of 19.5 mmol). The solution was stirred at ambient temperature for 1.5 hours followed by the addition of 1-(chloromethyl)-4-methoxybenzene (2.8 ml). After stirring at 30°C during the night to the resulting mixture were added water and podslushivaet to pH 3-4 0,5h. aq. HCl. Then added ethyl acetate, concentrated and filtered, the filtrate washed with ethyl acetate, the combined ethyl acetate layer was washed with saline, dried over anhydrous sodium sulfate, concentrated and purified flash chromatography on silica gel, obtaining the desired compound (4.7 g, yield 66%). LC-MS (ESI)m/z: 402 (M+1) +.1H-NMR (400 MHz, DMSO-d6) δ (ppm): to 3.73 (s, 3H), of 4.83-5,17 (m, 4H), 6.89 in-6,91 (d, J=8,8 Hz, 2H), 7.18 in-7,20 (m, 2H), 7.24 to 7,26 (m, 1H), 7,38-7,42 (t, 1H), 7,52-7,56 (m, 2H), 7,69-7,71 (m, 1H), 7,75-7,81 (m, 3H).

Example S

4-Hydroxy-1-(4-methoxybenzyl)-2-oxo-3-phenyl-1,2-dihydroquinoline-5-ethylcarboxylate

A mixture of N-(4-methoxybenzyl)-2-oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide (4.7 g, 11.7 mmol) and anhydrous Na2SO4(16.6 g, 117 mmol) in anhydrous ethylpropylamine (120 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (673 mg, 29.2 mmol) in anhydrous ethanol (70 ml)). After the addition the mixture was stirred at ambient temperature for 18 hours. The mixture is extinguished with water (100 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (250 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, obtaining the product (as 4.02 g, yield 80%). LC-MS (ESI) m/z: 430 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1,23-of 1.26 (t, J=6.8 Hz, 3H), of 3.69 (s, 3H), 4,21-to 4.23 (m, 2H), 5,46 (s, 1H), 6,86-to 6.88 (d, J=7,6 Hz, 2H), 7,11-to 7.18 (m, 3H), of 7.36-of 7.55 (m, 7H), 10,59 (s, 1H).

Example 118D

4-Hydroxy-2-oxo-3-phenyl-1,2-dihydroquinoline-5-ethylcarboxylate

A mixture of 4-hydroxy-1-(4-methoxybenzyl)-2-oxo-3-phenyl-1,2-dihydroquinoline-5-ethylcarboxylate (298 mg, 2 mmol) in triperoxonane acid was heated to reverse the fridge for 48 hours. After removal of solvents, the residue was washed with ethyl acetate, obtaining the target compound in the form of a solid white color (250 mg, yield 32%). LC-MS (ESI) m/z: 310 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1,25 (t, J=7.2 Hz, 3H),4,23 (sq, J=12 Hz, 2H), was 7.08 (d, J=7.2 Hz, 1H), 7,31-the 7.43 (m, 6H), 7,52 (t, J=8 Hz, 1H), accounted for 10.39 (s, 1H), 11,64 (s, 1H).

Example 118E

9-Phenyl-2H-pyrido [4,3,2-de]phthalazine to 3.8(7H,9H)-dione

4-Hydroxy-2-oxo-3-phenyl-1,2-dihydroquinoline-5-ethylcarboxylate (330 mg, 1.1 mmol) was added to the hydrazine monohydrate (1 ml) and methanol (2 ml), the mixture was stirred at 110°C for 2.5 hours in a microwave reactor. Then the mixture was cooled to ambient temperature, the solvent was evaporated in vacuum. The residue was washed with methanol and then purified by chromatography on columns (silica gel, dichloromethane/methanol from 300:1 to 50:1)to give a bright solid white (148 mg, yield 53%). LC-MS (ESI) m/z: 278 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 5,09 (s, 1H), 7,17-7,40 (m, 6H), to 7.77-7,81 (m, 2H), 11,10 (s, 1H), 12,57 (s, 1H).

Example 118F

9-Phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 9-phenyl-2H-pyrido[4,3,2-de]phthalazine to 3.8(7H,9H)-dione (80 mg, 2.2 mmol),BH3(0.7 ml, 1 mol/l in THF), dioxane (4 ml) in a sealed tube was stirred for 2 hours at 95°C in nitrogen atmosphere. The mixture is then treated with a mixture of MeOH~HCl (g) (0.2 ml), was stirred for 20 minutes at 95°C. the mixture is Then about what was ladale and podslushivaet to pH 8 Et 3N. the Solvent was removed under vacuum and the crude product was purified by chromatography on columns (silica gel, petroleum ether/ethyl acetate= 20:1 to 1:1), obtaining the target compound in the form of a solid yellow (18.3 mg, yield 24%). LC-MS (ESI) m/z: 264 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): 3,60-to 3.64 (m, 1H), 3,68-and 3.72 (m, 1H), 4,21 (t, J=5,2 Hz, 1H)1 7,09-7,11 (d, J=8 Hz, 1H), 7,16-7,29 (m, 5H), 7,53-to 7.61 (m, 2H).

Example 119

8-(4-Forfinal)-9-(4-methyl-4H-1,2,4-triazole-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 119A

2-(4-Forfinal)-3-(4-methyl-4H-1,2,4-triazole-3-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

The mixture of compounds (E)-4-(4-verbindingenmee)isobenzofuran-1(3H)-she (690 mg, 2.7 mmol) and 4-methyl-4H-1,2,4-triazole-3-carbaldehyde (300 mg, 2.7 mmol) in ethylpropylamine (20 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol [sodium (250 mg, about 10.8 mmol) in ethanol (10 ml)]. After the addition the mixture was stirred at ambient temperature for 2.5 hours, then extinguished with water (20 ml), and the solvent was removed in vacuum. The residue was dissolved in water and was extracted with ethyl acetate three times, washed with water and brine and then evaporated to give crude product, which was purified by chromatography, getting solid yellow (120 mg, yield 11%). LC-MS (ESI) m/z: 395 (M+1)+.

Example 119B

8-(4-Forfinal)-9-(4-methyl-4H-1,2,4-triazole-3-yl)-8,-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-forfinal)-3-(4-methyl-4H-1,2,4-triazole-3-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (120 mg) in 85%wage hydrazinoacetate (2 ml) and methanol (5 ml) was stirred at ambient temperature for 4 hours. Then, the solution was evaporated, the crude product was purified preparative HPLC, obtaining the target compound in the form of a solid white color (20 mg, yield 18%). LC-MS (ESI) m/z: 363 (M+1]+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3,50 (s, 3H), of 4.83-a 4.86 (d, J=11,6 Hz, 1H), 5,00-to 5.03 (d, J=11,6 Hz, 1H), 7,12-7,19 (m, 3H), 7,39-7,42 (m, 2H), 7,47-7,51 (m, 2H), 7,60-to 7.64 (t, J=8 Hz, 1H), 8,31 (s, 1H), 12,24 (s, 1H).

Example 120

8-(4-Forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 120A

2-(4-forfinal)-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of 4-(4-verbindingenmee)isobenzofuran-1(3H)-she (5.0 g, a 19.6 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (2.8 g, 25.5 mmol) in ethylpropylamine (310 ml) at ambient temperature under nitrogen atmosphere was added sodium ethylate (1.26 g, 54,9 mmol). The mixture was stirred at 55°C for 2 hours. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (150 ml ×4), and the extracts were concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate= 20:1 to 1.5:1). Got a solid product (2.4 g, yield 31%). LC-MS (ESI) m/: 395 (M+1) +.

Example 120B

8-(4-Forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

In a round bottom flask of 100 ml equipped with a thermometer and magnetic stirrer, was loaded 2-(4-forfinal)-3-(1-methyl-1Η-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (1,72 g, 4.4 mmol), methanol (15 ml) and NH2NH2(4 ml, 85%). The mixture was stirred at 25°C for 5 hours. The reaction was checked by HPLC for completion. The mixture was evaporated under reduced pressure, and methanol was added to obtain a suspension. The suspension was filtered. The obtained solid was washed with 20 ml of methanol, and dried, obtaining the target compound (1.4 g, yield 90%). LC-MS (ESI) m/z: 363 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm); the 3.65 (s, 3H), 4,93 is equal to 4.97 (m, 2H), 7,12-7,19 (m, 3H), 7,39-the 7.43 (m, 2H), 7,47-to 7.50 (m, 2H), 7,58-of 7.60 (m, 1H), 7,79 (s, 1H), 12,22 (s, 3H).

Example 121

8-(4-Forfinal)-9-(1-methyl-1H-imidazo[4,5-C]pyridine-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 121A

N-Methyl-3-nitropyridine-4-amine

To a suspension of 4-chloro-3-nitropyridine (2 g, 12.6 mmol) in dichloromethane (15 ml) was carefully added methylamine (25%solution in water, 10 ml, 63 mmol). The reaction mixture was heated to 40°C. After stirring for 1 hour the mixture was poured into water (20 ml)and the precipitate was collected by filtration and dried in vacuum, obtaining the target compound (1.9 g, yield 98%) in the form of a solid yellow the Board. LC-MS (ESI) m/z 154 (M+1)+.

Example 121B

Ν-4-Methylpyridin-3,4-diamine

A suspension of N-methyl-3-nitropyridine-4-amine (2.5 g, 16.3 mmol) and Pd/C (10%, 500 mg) in methanol (50 ml) was first made at ambient temperature over night. Then the mixture was filtered, and the filtrate was evaporated, receiving the product (1.2 g, yield 60%). LC-MS (ESF) m/z: 124 (M+1)+

Example 121C

1,2-Dimethyl-1H-imidazo[4,5-C]pyridine

The solution Ν-4-methylpyridin-3,4-diamine (2.5 g, 20.3 mmol) in acetic anhydride (25 ml) was heated under reflux overnight. Then acetic anhydride was evaporated under reduced pressure and added with 1H. hydrochloric acid. Then the mixture was extracted with dichloromethane (50 ml ×3). The aqueous layer was neutralized with sodium bicarbonate and was extracted with dichloromethane (50 ml ×3). The organic layers were concentrated, obtaining the target compound (1.9 g, yield 64%). LC-MS (ESI) m/z 148 (M+1)+.1H-NMR (400 MHz, CDCl3) δ (ppm): of 2.64 (s, 3H), 3,74 (s, 3H), 7.23 percent-of 7.24 (d, J=5,2 Hz, 1H), 8,39-to 8.41 (d, J=5,2 Hz, 1H), 8,98 (s, 1H).

Example 121D

1-Methyl-1H-imidazo[4,5-C]pyridine-2-carbaldehyde

To a solution of 1,2-dimethyl-1H-imidazo[4,5-C]pyridine (500 mg, 3,40 mmol) in dry 1,4-dioxane (7.5 ml) was added selenium dioxide (665 mg, 5,10 mmol). The mixture was heated in a microwave reactor at 130°C for 5 minutes Then the mixture was filtered and concentrated, to give crude product, which was purified by chromatography on columns (silica gel, PE is Romany ether:DCM from 10:1 to 1:1), receiving the target compound (400 mg, yield 28%). LC-MS (ESI) m/z: 162 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): 3,61 (s, 3H), 5,91 (s, 1H), to 7.67-of 7.70 (d, J=5.6 Hz, 1H), 8,39-to 8.41 (d, J=5.6 Hz, 1H), 8,93 (s, 1H).

Example 121E

2-(4-Forfinal)-3-(1-methyl-1H-imidazo[4,5-C]pyridine-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of 1-methyl-1H-imidazo[4,5-C]pyridine-2-carbaldehyde (400 mg, 2.48 mmol), (E)-4-(4-verbindingenmee)isobenzofuran-1(3H)-she (634 mg, 2.48 mmol) in ethylpropylamine (20 ml) at 0°C was added a solution of ethoxide sodium in ethanol [sodium (171 mg, 7,45 mmol) in ethanol (10 ml)]. Then the mixture was stirred at ambient temperature overnight. The mixture is then extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 25:1 to 5:1), obtaining the target compound (150 mg, yield 14%). LC-MS (ESI) m/z: 445 (M+1)+.

Example 121F

8-(4-Forfinal)-9-(1-methyl-1H-imidazo[4,5-C]pyridine-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-forfinal)-3-(1-methyl-1Η-imidazo[4,5-C]pyridine-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (150 mg, 0.34 mmol) and hydrazinoacetate (2 ml) in methanol (5 ml) was stirred at t is mperature environment for 4 hours. Then the methanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (20 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified by chromatography (silica gel, DCM/MeOH= 25:1 to 1:1), obtaining the target compound (6,7 mg, yield 5%). LC-MS (ESI) m/z: 413 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): to 3.58 (s, 3H), 4,93-of 4.95 (d, J=11,6 Hz, 1H), 5,04 is 5.07 (d, J=11,6 Hz, 1H), 6,85-of 6.90 (t, J=8,8 Hz, 2H), 7,12-7,14 (d, J=8.0 Hz, 1H), 7,38-7,44 (m, 3H); 7,49-EUR 7.57 (m, 2H), 8,19-8,21 (d, J=5.6 Hz, 1H), 8,72 (s, 1H).

Example 122

5-Chloro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example A

5-Chloro-2-methyl-3-nitrobenzoic acid

To conc. H2SO4(90 ml) at-5-0°C was added parts of 5-chloro-2-methylbenzoic acid (13,2 g, and 77.6 mmol). Then at-5-0°C was added dropwise over about 1.5 hours to a mixture of conc.HNO3(10.5 g, 1744 mmol) in conc.H2SO4(15 ml). After the addition the mixture was stirred at this temperature for 2 hours. The mixture was poured into crushed ice with vigorous stirring and the precipitate was collected by filtration. The residue was dissolved in EtOAc, washed with saline, dried over anhydrousNa2SO4and concentrated, obtaining the crude target compound (13,2 g), which used the following studies further purification.

Example 122B

5-Chloro-2-methyl-3-nitromethylene

A solution of crude 5-chloro-2-methyl-3-nitrobenzoic acid (13,2 g) in dry methanol (100 ml) was cooled to 0°C (3 ml)was added dropwise conc. H2SO4. After the addition the mixture was heated under reflux for 16 hours. After removal of the solvents under reduced pressure the crude product was purified by chromatography on silica gel (petroleum ether until the mixture petroleum ether/EtOAc=50:1)to give the target compound (6.3 g, yield 35% for two steps) in the form of a solid white color. LC-MS (ESI) m/z: 230 (M+1)+, 231(M+2)+.1H-NMR (400 MHz, CDCl3) δ (ppm): at 2.59 (s, 3H), of 3.95 (s, 3H), 7,84-a 7.85 (d, 1H), 7,98-to 7.99 (d, 1H).

Example 122C

2-(methyl bromide)-5-chloro-3-nitromethylene

A mixture of 5-chloro-2-methyl-3-nitromethylene (6 g, to 26.2 mmol), NBS (5,1 g, 28.8 mmol) and BPO (0,63 g, 2.6 mmol) inCCl4(50 ml) was heated under reflux overnight. Was added water (200 ml), andCCl4was removed under reduced pressure. The residue was extracted with DCM (200 ml × 3). The combined organic layers were washed with saline, dried overNa2SO4and concentrated, obtaining the crude target compound (7 g, yield 87%) in the form of a brown oil, which was used in the next stage without purification.

Example 122D

6-Chloro-4-nitroazobenzene-1(3H)-he

A mixture of 2-(methyl bromide)-5-PI is the p-3 nitromethylene (7 g, of 22.8 mmol) in 1,4-dioxane (50 ml) and water (50 ml) was heated under reflux for 4 days. The dioxane was removed under reduced pressure. The residue was extracted with EtOAc (300 ml × 4). The combined organic layers were washed with saline, dried over Na2SO4and concentrated give crude product, which was purified by chromatography on silica gel (petroleum ether until the mixture petroleum ether/EtOAc=5:1), obtaining the target compound (4 g, yield 82%) in the form of a solid white color.

Example 122E

4-Amino-6-floridalottery-1(3H)-he

A suspension of 6-chloro-4-nitroazobenzene-1(3H)-she (5 g, 23.5 mmol) and Pd/C (10%, 500 mg) in EtOAc (250 ml) was stirred at 25°C under less than 1 ATM. hydrogen for 12 hours. The mixture was filtered and the precipitate washed with EtOAc (100 ml ×3). The filtrate was concentrated, obtaining the target compound (a 3.87 g, yield 90%) in the form of a solid white color. LC-MS (ESI) m/z: 184 (M+1)+.

Example 122F

(E)-4-(Benzylideneamino)-6-floridalottery-1(3H)-he

A mixture of 4-amino-6-floridalottery-1(3H)-it (1 g, 5.46 mmol), benzaldehyde (0,72 g, 6,79 mmol) and magnesium sulfate (6 g) in dichloromethane (80 ml) was stirred under reflux overnight. The mixture was evaporated under reduced pressure, and the residue was dried in vacuum. The crude product was obtained (740 mg) and used in the next stage without further purification.

Example 122G

7-the ENT-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of (E)-4-(benzylideneamino)-6-floridalottery-1(3H)-she (720 mg, of 2.66 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (330 mg, 3 mmol) in ethylpropylamine (40 ml) was added sodium ethylate (650 mg, 9.6 mmol). The mixture was stirred at ambient temperature for 3 hours. Then the mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 ml ×4), and concentrated. The crude product was purified by chromatography on columns (silica gel, petroleum ether:ethyl acetate= 20:1 to 1.5:1), obtaining the target compound in the form of a solid (170 mg, yield 15%).

Example 122Η

5-Chloro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a solution of 7-chloro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (429 mg, 1.05 mmol) in methanol (15 ml) was added hydrazinoacetate (2 ml). The mixture was stirred at 25°C for 5 hours. The resulting mixture was concentrated under reduced pressure to a volume of 10 ml and then filtered, receiving 58 mg of a solid (yield 14%). LC-MS (ESI) m/z: 378 (M+1)+; 379 (M+2)+,1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.42 points (s, 3H), 4,69 (d, 7=10.0 Hz, 1H), to 4.98 (d, J=10.4 Hz, 1H), USD 5.76 (s, 1H), 6.73 x (s, 1H), 6.89 in (s, 1H), 7,14 (s, 1H), 7,27 (DD, 4H), 7,38 (d, J=6,4 Hz, 2H), 7.62mm (s, 1H), 12,36 (s, 1H).

Example 123

8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 123A

To a stirred mixture of 4-((dimethylamino)methyl)benzaldehyde (4 g, 24.5 mmol) and anhydrous magnesium sulfate (to 15.8 g, 111,5 mmol) in anhydrous acetonitrile (100 ml) at 0°C was added 4-amino-6-floridalottery-1(3H)-he (4 g, of 22.3 mmol). After the addition the mixture was stirred under reflux for 3 days. The mixture was filtered and the precipitate washed with ethyl acetate (50 ml ×3). The filtrate was concentrated, give crude product, which was recrystallized from isopropanol, obtaining the target compound (3.7 g, yield 55%). LC-MS (ESI) m/z: 314 (M+1)+.

Example 123B

2-(4-((Dimethylamino)methyl)phenyl)-7-fluoro-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-floridalottery-1(3H)-she (500 mg, 1.6 mmol) and 4-forventelige (218 mg, of 1.76 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (110 mg, 4.8 mmol) in ethanol (5 ml)). After the addition the mixture was stirred at ambient temperature for 3 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified by chromatography (silica compound is a gel, petroleum ether/ethyl acetate=1:1), obtaining the target compound (100 mg, yield 13%). LC-MS (ESI) m/z: 465 (M+1)+.

Example 123C

8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (100 mg) in 85%wage hydrazinoacetate (0.5 ml) and methanol (2 ml) was stirred at ambient temperature overnight. The methanol was removed under reduced pressure. The crude product was purified preparative HPLC, obtaining the target compound (35 mg, yield 37%). LC-MS (ESI) m/z: 433 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): 2,12 (s, 3H), at 3.35 (s, 2H), 4,21 (d, J=8.0 Hz, 1H), with 4.64 (d, J=8.0 Hz, 1H), for 6.81-6,85 (m, 3H), 6,99-7,01 (m, 2H), 7,13-7,19 (m, 5H);19F-NMR (400 MHz, CD3OD) δ (ppm): -105,66 (C), -118,17 (s).

Example 124

8,9-bis(4-((Dimethylamino)methyl)phenyl)-5-fluoro-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 124A beaches

2,3-bis(4-((Dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6~floridalottery-1(3H)-it (1 g, 31.9 per mmol) and 4-((dimethylamino)methyl)benzaldehyde (0.52 g, 31.9 per mmol) in ethylpropylamine (50 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (220 mg, 95,8 mmol) in ethanol (20 ml)). After the addition the mixture was stirred at the temperature of environment is the first environment within 2 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified by chromatography (silica gel, dichloromethane/methanol= 10:1 to 20:3), obtaining the target compound (520 mg, yield 33%). LC-MS (ESI) m/z: 503.

Example 124B

8,9-bis(4-((Dimethylamino)methyl)phenyl)-5-fluoro-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2,3-bis(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (520 mg) in 85%wage hydrazinoacetate (10 ml) and methanol (50 ml) was stirred at 23°C during the night. The methanol was removed under reduced pressure. The mixture was filtered and washed with water, obtaining the target compound (11 mg, yield 20%). LC-MS (ESI) m/z: 472 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): is 2.09 (s, 12H), and 3.31 (s, 4H), 4,22 (d, J=8.0 Hz, 1H), 4,67 (d, J=8.0 Hz, 1H), 6,80 (DD, 1H), 6,97-of 6.99 (m, 2H), 7,06-7,11 (m, 5H), 7,14-7,16 (m, 2H);19F-NMR (400 MHz, CD3OD) δ (ppm): -105,58 (s).

Example 125

8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 125A

4-(Diethoxylate)benzaldehyde

A mixture of terephthalic aldehyde (10 g, 74,55 mmol), ammonium chloride (160 mg, 3.0 mmol) in ethanol (10.3 g, 223,6 mmol) at 0°C was added dropwise to triethoxy the Tana (12,15 g, 82 mmol). After the addition the mixture was stirred at ambient temperature overnight. The mixture was concentrated, the residue was purified by chromatography on silica gel, obtaining the target compound (7.0 g, yield 50%) in the form of a solid white color. LC-MS (ESI) m/z: 209 (M+1)+.

Example 125B

1-(4-(Diethoxylate)phenyl)-N,N-dimethylethanamine

A solution of 4-(diethoxylate)benzaldehyde (6.8 g, 32,69 mmol) and dimethylamine in 33 wt.% the solution in water (9,25 g, 98 mmol) in methanol (200 ml) was stirred at ambient temperature overnight. Sodium borohydride (1.85 g, 49 mmol) was added by portions under ice cooling. After the addition the mixture was stirred at ambient temperature for 4 hours. The mixture is extinguished with water (100 ml) and was extracted with ethyl acetate (100 ml ×3). The extract was dried over anhydrous sodium sulfate and concentrated, obtaining the crude target compound (7.0 g, yield 90%)which was used in the next stage without further purification. LC-MS (ESI) m/z: 238 (M+1)+.

Example 125C

4-((Dimethylamino)methyl)benzaldehyde

To a mixture of 1-(4-(diethoxylate)phenyl)-N,N-dimethylethanamine (7.0 g, 29.5 mmol) in hydrogen chloride (3M in water (30 ml) was stirred at ambient temperature for 5 hours. Then the mixture was extracted with ethyl acetate (50 ml ×3). The aqueous layer was podslushivaet with sodium carbonate to pH 10, extracted etelaat the Ohm (50 ml ×3), was dried with anhydrous sodium sulfate and concentrated, to give crude product (3,95 g, yield 82%). LC-MS (ESI) m/z: 164 (M+1)+.

Example 125D

(E)-4-(4-((Dimethylamino)methyl)benzylideneamino)-6-floridalottery-1(3H)-he

A solution of 4-((dimethylamino)methyl)benzaldehyde (1.0 g, 6,13 mmol), 4-amino-6-floridalottery-1(3H)-she (1,024 g, 6,13 mmol) and anhydrous magnesium sulfate (7,356 g, with 61.3 mmol) in acetonitrile (50 ml) was heated under reflux for 2 days. The solution was filtered and concentrated in vacuum. The crude product is recrystallized from isopropanol, obtaining the target compound (1,15 g, yield 60%). LC-MS (ESI) m/z: 313 (M+1)+.1H-NMR (400 MHz, CDCl3) δ (ppm): 2,28 (s, 6H), 3,52 (s, 2H), 5,38 is 5.38 (m, 2H), 7,09 for 7.12 (m, 1H), 7,42-7,44 (m, 1H), 7,46-of 7.48 (d, J=8 Hz, 2H), 7,87-7,89 (d, J=8 Hz, 2H), 8,51 (s, 1H).

Example 125E

2-(4-((Dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of benzaldehyde (75 mg, 0,705 mmol) and (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-floridalottery-1(3H)-she (220 mg, 0,705 mmol) in ethylpropylamine (5 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (65 mg, 2.82 mmol) in ethanol (3 ml)). After the addition the mixture was stirred at ambient temperature for 2.5 hours. The mixture is extinguished with water (20 ml), and the solvent was removed in vacuum. The residue was dissolved in water and was extracted with utilize the atom three times. The extract was washed with water and brine, and then the solvent was evaporated. The crude product was purified by chromatography, obtaining the target compound in the form of a solid yellow (80 mg, yield 25%). LC-MS (ESI) m/z: 447 (M+1)+.

Example 125F

8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (80 mg, 0.18 mmol) in 85%wage hydrazinoacetate (1 ml) and methanol (5 ml) was stirred at ambient temperature for 4 hours. The solvent was removed under vacuum; the crude product was purified by chromatography, obtaining the target compound in the form of a solid yellow (22 mg, 30%yield). LC-MS (ESI) m/z: 415 (M+1)+.1Η-NMR (400 MHz, DMSO-d6,) δ (ppm): 2,14 (s, 6H), to 3.36 (s, 2H), 4,18-is 4.21 (d, J=8,8 Hz, 1H), 4,67-4,69 (d, J=9,2 Hz, 1H), for 6.81-6,84 (m, 1H), 6,99-7,01 (m, 2H), 7,08-7,19 (m, 8H).

Example 126

8-(4-((3,4-Dimethylpiperazine-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 126A

3-Methylpiperazin-1-tert-butylcarbamoyl

To a solution of 2-methylpiperazine (2.0 g, 0.02 mol) and triethylamine (6 ml) in methylene chloride (15 ml) at 0°C was added dropwise (Vos)2O (4,14 g, 0.019 mol). The mixture was stirred at ambient temperature for 1 hour, and then the solvent was removed on a rotary evaporator. The residue dissolve the Yali in methylene chloride, washed with saturated sodium bicarbonate and brine, dried overNa2SO4and was purified by chromatography on columns on silica gel (DCM:MeOH:Et3N=75:1:0,2), getting a solid white color (1.65 g, 42%). LC-MS (ESI) m/z: 201 (M+1)+.

Example 126B

3,4-Dimethylpiperazine-1-tert-butylcarbamoyl

3-Methylpiperazin-tert-butylcarbamoyl (1,49 g, 7,45 mmol) and paraformaldehyde (1.12 g, is 37.2 mmol) was dissolved in a mixture of MeOH and acetic acid (5:1) at the molecular sieves. To the suspension at 25°Cadded NaBCNH3(1.88 g, to 29.8 mmol). The suspension was then heated up to 80°C for 10 hours. The mixture is then cooled, filtered and concentrated. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate. The organic solution was dried over Na2SO4and focused, getting white oil (1.2 g, 90%). LC-MS (ESI) m/z: 215 (M+1)+.

Example 126C

1,2-Dimethylpiperazine

Triperoxonane acid (7 ml) at ambient temperature was added to a solution of 3,4-dimethylpiperazine-1-tert-BUTYLCARBAMATE (1.7 g, 7,94 mmol) in methylene chloride (15 ml), then was stirred for 1 hour. The residue obtained by removing the solvent on a rotary evaporator under reduced pressure, was a target connection. LC-MS (ESI) m/z: 201 (M+1)+.1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.21 (d, J=6.8 Hz, 3H), of 1.46 (s, 9H), 2,64-,70 (m, 1H), 2,74-2,78 (m, 1H), 2,88-a 3.01 (m, 3H), of 3.78 (d, J=12,4 Hz, 1H), 4,16 (m, 1H).

Example 126D

8-(4-((3,4-Dimethylpiperazine-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (200 mg, 0.52 mmol), 1,2-dimethylpiperazine (311 mg, 1.56 mmol) in methylene chloride (10 ml) was stirred at ambient temperature overnight, then added NaBCNΗ3(129 mg, of 2.08 mmol)and the mixture was stirred for another 5 hours. After removal of solvent the residue was purified by chromatography on columns (silica gel, petroleum ether/ethyl acetate= 3:1 to 1:1), obtaining the target compound (70 mg, 26%). LC-MS (ESI) m/z: 484 (M+1)+.1H-NMR (400 MHz, CDCl3) δ (ppm): USD 1.43 (d, J=5,2 Hz, 3H), 2,84 (s, 3H), 3,29 (m, 1H), 3.33 and-3,44 (m, 6H), is 4.03 (s, 2H), 4,22 (m, 1H)and 4.65 (m, 1H), 6,91 (m, 1H), 6,97 (m, 1H), 7,00 (d, J=8 Hz, 2H), 7.23 percent-7,37 (m, 4H), 7,65 (m, 1H), to 7.77 (d, J=7.2 Hz, 1H), 9,92 (s, 1H).

Example 127

8-(4-((3,5-Dimethylpiperazine-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 127A

4-Benzyl-1-tert-butyl-2,6-dimethylpiperazine-1,4, in primary forms

To a solution of 2,6-dimethylpiperazine (2.28 g, 20 mmol) in methylene chloride (15 ml) at 0°C was added dropwise benzylchloride (3.0 ml). The mixture was stirred at 0°C for one hour, then at ambient temperature for 2 hours. The mixture was cooled to 0°C. was Added diisopropylethylamine (45 ml) and then (Re) 2O (4.8 g, 22 mmol). The mixture was stirred at ambient temperature overnight and then the solvent was removed on a rotary evaporator. The residue was dissolved in EtOAc, washed with water and brine, dried overNa2SO4and was purified by chromatography on columns on silica gel (EtOAc:hexane=1:9)to give an intermediate compound in the form of an oil (4.8 g, 72%). LC-MS (ESI) m/z: 361 (M+23)+.

Example 127B

2,6-Dimethylpiperazine-1-tert-butylcarbamoyl

To a solution of 4-benzyl-1-tert-butyl-2,6-dimethylpiperazine-1,4-in primary forms (4.8 g, 0,0144 mol) in methanol (25 ml) was added 480 mg of 10%Pd/C and stirred at ambient temperature underH2throughout the night. The resulting mixture was filtered and concentrated, obtaining the target product (2.8 g, 97%) in the form of a colorless oil. LC-MS (ESI) m/z: 215 (M+1)+,1H-NMR (400 MHz, CDCl3) δ (ppm): a 1.25 (d, J=6.8 Hz, 3H), of 1.46 (s, 9H), 1,64 (s, 1H), 2,78-2,87 (m, 4H), 3,99-of 4.05 (m, 2H).

Example 127C

(2R,6R)-4-(4-(9-(4-Forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzyl)-2,6-dimethylpiperazine-1-tert-butylcarbamoyl

A mixture of 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (200 mg, 520 mmol), 2,6-dimethylpiperazine-1-tert-BUTYLCARBAMATE (335 mg, 1.56 mmol) in methylene chloride (10 ml) was stirred at ambient temperature overnight, then added NaBCNH (129 mg, 2,08 mmol, and the mixture was stirred for another 5 hours. After removal of solvents, the residue was purified by chromatography on columns (silica gel, petroleum ether/ethyl acetate= 3:1 to 1:1), obtaining the target compound (72 mg, 24%). LC-MS (ESI) m/z: 584 (M+1)+.

Example 127D

8-(4-((3,5-Dimethylpiperazine-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of (2R,6R)-4-(4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzyl)-2,6-dimethylpiperazine-1-tert-BUTYLCARBAMATE (72 mg, 0.12 mmol) in ΗCl-CΗ3CN (2 ml) was stirred for 2 hours. After removal of solvents, the residue was purified preparative HPLC, obtaining the target product in the form of a solid white color (33 mg, 53%). LC-MS (ESI) m/z: 497 (M+1)+.1H-NMR (400 MHz, DMSO) δ (ppm): 1,02-of 1.03 (d, J=6.4 Hz, 6H), 1,58 (t, J=10 Hz, 1H), 2,66 (d, J=10 Hz, 1H), only 2.91 (t, J=6,8 Hz, 2H), 3,41 (s, 2H), 4,20 (d, J=10 Hz, 1H), 4,58 (d, J=10 Hz, 1H), to 4.98 (s, 1H), 6,97 (t, J=2.4 Hz, 2H),? 7.04 baby mortality (d, J=8.0 Hz, 1H), to 7.09 (d, J=2.4 Hz, 2H), 7,16 (d, J=2.4 Hz, 2H), 7,58 (t, J=7,6 Hz, 1H), 7,73 (d, J=7,6 Hz, 1H), 10,34 (s, 1H).

Example 128

9-Phenyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (367 mg, 1 mmol) in dry DCM (15 ml) was added acetic acid (0.2 ml), then pyrrolidine (213 mg, 3 mmol). After the addition the mixture was stirred at ambient temperature during the course the e night. Then sodium borohydride (318 mg, 1.5 mmol) was added at 0°C. After addition the mixture was stirred at this temperature for 12 hours. DCM was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product, which was purified preparative HPLC, obtaining the target compound (62 mg, yield 14%) in the form of a solid white color. LC-MS (ESI) m/z: 423 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1,82-of 1.85 (m, 2H), 1,97 (s, 2H), 3,01 was 3.05 (m, 2H), 3,26 (d, 2H), 4,27 (d, 2H), 4,36 (d, 1H), 4,84 (d, 1H), 7,13-of 7.23 (m, 6H), was 7.36-7,40 (m, 5H), of 7.48 (s, 1H), EUR 7.57-to 7.61 (t, 1H), 12,18 (s, 1H).

Example 129

8-(4-(azetidin-1-ylmethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (150 mg, 0.41 mmol) in dry dichloromethane (20 ml) and MeOH (2 ml) was added acetic acid (120 mg), then azetidin (70 mg, of 1.23 mmol). After the addition the mixture was stirred at ambient temperature overnight. Then triacetoxyborohydride sodium (131 mg, of 0.62 mmol) was added at 0°C. After addition the mixture was stirred at this temperature for 5 hours. DCM was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product, which was purified by chromatography on a column is x (silica gel, dichloromethane/methanol= 100:1 to 15:1), obtaining the target compound (84 mg, 51%yield) in the form of a solid yellow color. LC-MS (ESI) m/z: 409 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): 2,38 is 2.43 (m, 2H), 3,98 (t, J=8 Hz, 4H), 4,20 (s, 2H), 4,27 (d, J=8 Hz, 1H), 4,77 (d, J=8 Hz, 1H), 7.03 is-7,05 (m, 2H), 7,10-7,17 (m, 4H), 7,27-7,35 (m, 4H), 7,50-7,52 (m, 1H), EUR 7.57 to 7.62 (m,, 1H).

Example 130

9-(1-Methyl-1H-imidazol-2-yl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(9-(1-methyl-1Η-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2Η-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (80 mg, 0.22 mmol), acetic acid (60 μl) and pyrrolidine (1,05 g, 15 mmol) in acetonitrile (7 ml) was stirred at ambient temperature for 4 hours. To this mixture at 0°C was added aNaCNBH3(36 mg, 0.67 mmol). After the addition the mixture was stirred at ambient temperature for 4 hours. After removal of the solvents under reduced pressure, the residue was washed with ethyl acetate and filtered. The filtrate was concentrated, obtaining the target compound in the form of a solid white (21 mg, yield 22%). LC-MS (ESI) m/z: 427 (M+1)+.1H-NMR: (400 MHz, DMSO-d6& D2O) δ (ppm): of 1.66 (d, J=2,8 Hz, 4H), is 2.37 (s, 4H), to 3.38 (s, 3H), 3,50 (s, 2H), to 4.62 (d, J=10 Hz, 1H), 4,90 (d, J=10.4 Hz, 1H), 6,72 (s, 1H), 6.87 in (s, 1H), 7,15-7,20 (m, 3H), 7,29-to 7.32 (m, 3H), of 7.36-7,38 (m, 1H), 7,54-7,58 (m, 1H), 12,15 (s, 1H).

Example 131

9-(4-Forfinal)-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2de]phthalazine-3(7H)-he

Example 131A

(E)-4-((1-Methyl-1H-imidazol-2-yl)methylamino)isobenzofuran-1(3H)-he

A solution of 1-methyl-1H-imidazole-2-carbaldehyde (680 mg, 6,18 mmol), 4-aminoazobenzene-1(3H)-she (920,8 mg, 6,18 mmol) and anhydrous magnesium sulfate (7,41 g, to 61.8 mmol) in acetonitrile (100 ml) was heated under reflux for two days. The mixture was filtered, and the solvents were removed in vacuum. The crude product is recrystallized from isopropanol, obtaining the target compound (1,49 g, yield 68%). LC-MS (ESI) m/z: 242 (M+1)+.1H-NMR (400 MHz, DMSO-d6); 4,06 (s, 3H), 5,52 (s, 2H), 7,22 (s, 1H), 7,52 (s, 1H), 7,65-to 7.67 (m, 1H), 7,72-7,74 (m, 2H), 8,66 (s, 1H).

Example 131B

3-(4-Forfinal)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-forventelige (248 mg, 2 mmol) and (E)-4-((1-methyl-1H-imidazol-2-yl)methylamino)isobenzofuran-1(3H)-she (482 mg, 2 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (184 mg, 8 mmol) in ethanol (5 ml)). After the addition the mixture was stirred at ambient temperature for 0.5 hours. The mixture is extinguished with water (20 ml), and the solvent was removed in vacuum. The residue was dissolved in water and was extracted with ethyl acetate three times, washed with water and brine and then concentrated, to give crude product, which was purified by chromatography on columns, receiving solid as the color (200 mg, yield 25%). LC-MS (ESI) m/z: 394 (M+1)+

Example 131C

9-(4-Forfinal)-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(4-forfinal)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (200 mg, 0.5 mmol) in 85%wage hydrazinoacetate (1 ml) and methanol (5 ml) was stirred at ambient temperature for 4 hours. The resulting mixture was filtered and washed with water (20 ml) and methanol (5 ml)to give a solid white color, which was dried in vacuum at 50°C, obtaining the target compound (25 mg, yield 14%). LC-MS (ESI) m/z: 362 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): to 3.58 (s, 3H), to 4.52-of 4.54 (d, J=7.2 Hz, 1H), 4,94 is equal to 4.97 (m, 1H), 6,69-6,70 (m, 1H), of 6.96-6,97 (m, 1H),? 7.04 baby mortality-was 7.08 (m, 3H), 7.18 in-7,22 (m, 2H), was 7.36-7,38 (m, 2H), 7,51-of 7.55 (t, J=8.0 Hz, 1H), and 12.2 (s, 1H).

Example 132

9-(4-Forfinal)-8-(quinoline-6-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 132A

The quinoline-6-carbaldehyde

The mixture SeO2(10,89 g, 99 mmol) and 6-methylinosine (12,87 g, 90 mmol) was heated to 150°C and was stirred for 16 hours. Then it was cooled to ambient temperature and was added EtOAc (400 ml). After filtration, the filtrate was concentrated, give crude compound which was purified by chromatography (silica gel, petroleum ether/EtOAc 5:1-2:1)to give the target compound (2,87 g, yield 20%). LC-MS (ESI) m/z 158 (M+1)+.

Example 132B

(E)-4-(Quinoline-6-ylmethylamino)isobenzofuran-1(3)-he

A solution of quinoline-6-carbaldehyde (786 mg, 5.0 mmol), 4-aminoazobenzene-1(3H)-she (745 mg, 5.0 mmol) and anhydrous magnesium sulfate (6.0 g, 50.0 mmol) in acetonitrile (100 ml) was heated under reflux for two days. The solution was filtered and removed in vacuo. The crude product is recrystallized from isopropanol, obtaining the target compound (1,348 g, yield 93%). LC-MS (ESI) m/z: 289 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): to 5.57 (s, 2H), 7,63-to 7.77 (m, 4H), 8,14-is 8.16 (d, J=8,8 Hz, 1H), 8,39-8,42 (m, 1H), 8,53-8,56 (m, 2H), 8,99-9,01 (m, 2H).

Example 132C

3-(4-Forfinal)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-forventelige (248 mg, 2 mmol) and (E)-4-(quinoline-6-ylmethylamino)isobenzofuran-1(3H)-she (576 mg, 2 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (184 mg, 8 mmol) in ethanol (5 ml)). After the addition the mixture was stirred at ambient temperature for 0.5 hours. The mixture is extinguished with water (20 ml), and the solvent was removed in vacuum. The residue was dissolved in water and was extracted with ethyl acetate three times. After washing with water and brine, the solvent was removed on a rotary evaporator. The crude product was purified by chromatography, getting a solid yellow color. The solid was dried in vacuum at 50°C, obtaining the target compound (260 mg, yield 29%). LC-MS ESI) m/z: 441 (M+1) +.

Example 132D

9-(4-Forfinal)-8-(quinoline-6-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(4-forfinal)-2-(1-methyl-1Η-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (260 mg, 0.59 mmol) in 85%wage hydrazinoacetate (1 ml) and methanol (5 ml) was stirred at ambient temperature for 4 hours. The resulting mixture was filtered and washed with water (20 ml) and methanol (5 ml), obtaining the target compound in the form of a solid white (61 mg, yield 25%). LC-MS (ESI) m/z: 409 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): to 4.52-4,55 (d, J=9.6 Hz, 1H), 4,98-free 5.01 (d, J=9.6 Hz, 1H), 6,97-7,01 (m, 2H), 7,19-7,22 (m, 3H), 7,41-the 7.43 (d, J=7,6 Hz, 1H), 7,46 is 7.50 (m, 1H), 7,54 (s, 1H), to 7.59-7,63 (t, J=7,6 Hz, 1H), to 7.77-7,79 (m, 1H), to 7.84 (s, 1H), to $ 7.91-to 7.93 (m, 1H), 8,24 compared to 8.26 (d, J=7,6 Hz, 1H), cent to 8.85-8,86 (m, 1H), 12,20 (s, 1H).

Example 133

8-(4-((Dimethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 133 A

2-(4-((Dimethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-isobenzofuran-1(3H)-she (500 mg, 1.7 mmol) and 4-methylbenzaldehyde (204 mg, 1.7 mmol) in ethylpropylamine (30 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (156 mg, 6.8 mmol) in ethanol (30 ml)). After the addition the mixture was stirred at 10°C for 1 hour, then at 30°C for 3 hours. The mixture is extinguished with water (30 ml), and the solvent is dalali in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (30 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified by chromatography (silica gel, dichloromethane/methanol= 100:1 to 10:1)to give the target compound (110 mg, yield: 15%). LC-MS (ESI) m/z: 443 (M+1)+.

Example 133B

8-(4-((Dimethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (120 mg) in 85%wage hydrazinoacetate (1 ml) and methanol (3 ml) was stirred at 10°C for 2.5 hours. The mixture was purified preparative HPLC, obtaining the target compound in the form of a solid white (14 mg, yield 11%). LC-MS (ESI) m/z: 411 (M+1)+;1H-NMR (400 MHz, CD3OD) δ (ppm): to 2.18 (s, 3H), 2,31 (s, 6H), of 3.57 (s, 2H), 4,25-4,27 (d, J=8,4 Hz, 1H), 4.72 in-4,74 (d, J=8,4 Hz, 1H), 6,95-7,02 (m, 4H), 7,19-7,29 (m, 5H), 7,55-EUR 7.57 (m, 1H), 7,62-to 7.64 (t, J=8 Hz, 1H).

Example 134

9-(4-Chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 134A

3-(4-Chlorophenyl)-2-(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-isobenzofuran-1(3H)-she (588 mg, 2 mmol) and 4-chlorobenzaldehyde (281 mg, 2 mmol) in anhydrous ethylpropylamine (25 ml) ohla is given to 0°C. Was added dropwise to the sodium methylate in methanol solution (sodium (115 mg, 5 mmol) in anhydrous ethanol (10 ml)and the mixture was stirred at 25°C for 3 hours. The resulting mixture was extinguished with water (5 ml) and then evaporated under reduced pressure. The residue was extracted with ethyl acetate (100 ml ×3), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified by chromatography on columns (silica gel, dichloromethane to a mixture of dichloromethane/methanol=30:1)to give the target compound (260 mg, yield 28%) in the form of a solid yellow color. LC-MS (ESI) m/z: 463 (M+1)+.

Example 134B

9-(4-Chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(4-chlorophenyl)-2-(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (260 mg, 0,56 mmol) and hydrazinoacetate (3 ml) in methanol (20 ml) was stirred at 30°C for 4 hours. The mixture was concentrated, give crude product, which was purified preparative HPLC, obtaining the target compound (34 mg, yield 14%) in the form of a solid white color, representing the salt of formic acid. LC-MS (ESI) m/z: 431 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm); to 2.66 (s, 6H), 4,20-is 4.21 (d, J=4,8 Hz, 2H), 4,39 was 4.42 (d, J=8,8 Hz, 1H), 4,82-4,84 (d, J=8,8 Hz, 1H), 7,15-7,20 (m, 4H), 7,25-7,27 (d, 2H), 7,35-7,42 (m, 5H), 7,46 (s, 1H), 7,58 to 7.62 (t, J=8.0 Hz, 1H), 9,74 (IRS, 1H), 12,18 (s, 1H).

Example 135

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-methoxyphenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 135A

2-(4-((Dimethylamino)methyl)phenyl)-3-(4-methoxyphenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of 4-methoxybenzaldehyde (231 mg, 1.7 mmol) and (E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-she (500 mg, 1.7 mmol) in ethylpropylamine (30 ml) was added methanolate sodium (120 mg, 5.2 mmol)and the mixture was stirred at 25°C for 4 hours. Then to the mixture was added water (10 ml) and evaporated under reduced pressure was extracted with EtOAc (4×100 ml) and concentrated to dryness. The crude product was obtained (250 mg) and used for the next reaction without further purification. LC-MS (ESI) m/z: 459 (M+1)+.

Example 135B

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-methoxyphenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-((dimethylamino)methyl)phenyl)-3-(4-methoxyphenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (70 mg, 0.15 mmol) and hydrazinoacetate (1 ml) in methanol (5 ml) was stirred at ambient temperature for 5 hours. The resulting mixture was evaporated under reduced pressure to a volume of 1 ml and then filtered. The filtrate was concentrated, obtaining the target compound in the form of a solid white color (26.5 mg). LC-MS (ESI) m/z: 427 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): and 2.79(s, 6H), 3,71 (s, 3H), 4,24 (s, 2H), 4.26 deaths (d, 1H), 4,77 (d, 1H), 6,74 (d, 2H), 6,99 (d, 2H), 7.18 in-7,21 (m, 1H), 7,35-the 7.43 (m, 4H), 7,55-EUR 7.57 (m, 1H), 7,65 (t, 3H).

Example 136

8-(4-((Diethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (80 mg, 0.22 mmol), diethylamine (47 mg, of 0.65 mmol) and acetic acid (39 mg, of 0.65 mmol) in dichloromethane (50 ml) was stirred at ambient temperature for 60 minutes After cooling the mixture to 0°C was added triacetoxyborohydride sodium (or 69.3 mg, 0.33 mmol). After the addition the mixture was stirred at ambient temperature overnight. Dichloromethane was removed under reduced pressure. The crude product was purified by chromatography (silica gel, dichloromethane/methanol=50:1)to give the target compound (34 mg, yield 36%). LC-MS (ESI) m/z: 425 (M+Η)+.1H-NMR (400 MHz, CD3OD) δ (ppm): 1,10 (t, 6H), 2,64 (square, 4H), 3,70 (s, 2H), 4,30 (d, J=8.0 Hz, 1H), and 4.75 (d, J=8.0 Hz, 1H), 7,06-to 7.09 (m, 2H), 7,13-7,20 (m, 4H), 7,22-7,29 (m, 4H), 7,54-7,56 (DD, J=8.0 Hz, 1H), 7,62-to 7.64 (m, 1H).

Example 137

8-(4-((Diethylamino)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a stirred solution of 4-(9-(4-forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)benzaldehyde (260 mg, of 0.68 mmol) in dry DCM (15 ml) was added acetic acid (0.2 ml), then diethylamine (148 mg, 2.03 mmol). After the addition the mixture was stirred at the temperature of the environment and the surrounding environment during the night. Then sodium borohydride (212 mg, 1.01 mmol) was added to the mixture at 0°C. the Mixture was stirred at this temperature for 12 hours. DCM was removed under reduced pressure. The residue was washed with a mixture of ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated, give crude product, which was purified flash chromatography, obtaining the target compound in the form of a solid white color (27.3 mg, yield 9%). LC-MS (ESI) m/z: 442 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): 3,12-3,17 (m, 4H), 4,27 (s, 2H), 4,34 (d, 1H), 4,78 (d, 1H), 6,91 (t, 2H), 7,09 for 7.12 (m, 1H), 7,38 was 7.45 (m, 4H), 7,56-7,58 (m, 1H), to 7.64 (t, 1H).

Example 138

9-(4-Chlorophenyl)-8-(4-((diethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 138A

(E)-4-(4-((Diethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-he

To a stirred mixture of 4-((diethylamino)methyl)benzaldehyde (3.7 g, with 19.4 mmol) and anhydrous magnesium sulfate (11.6 g, to 96.8 mmol) in anhydrous acetonitrile (100 ml) at 0°C was added 4-aminoazobenzene-1(3H)-he (2,89 g, and 19.4 mmol). After the addition the mixture was stirred at reflux for 3 days. The mixture was filtered and the precipitate washed with ethyl acetate (50 ml ×3). The filtrate was concentrated, give crude product, which was recrystallized from isopropanol, obtaining the target compound (2.1 g, yield: 32%). LC-MS (ESI) m/z: 323 (M+1)+.

Example 138B

3-(4-Chlorophenyl)-2-(4-((diethylamino)methyl)phenyl)--oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-(4-((diethylamino)methyl)benzylideneamino)-isobenzofuran-1(3H)-she (500 mg, 1.55 mmol) and 4-chlorobenzaldehyde (218 mg, 1.55 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (107 mg, of 4.66 mmol) in ethanol (5 ml)). After the addition the mixture was stirred at ambient temperature for 3 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1)to give the crude product of the target compound (268 mg, yield 35%). LC-MS (ESI) m/z: 491 (M+1)+.

Example 138C

9-(4-Chlorophenyl)-8-(4-((diethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(4-chlorophenyl)-2-(4-((diethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (268 mg) in 85%wage hydrazinoacetate (0.5 ml) and methanol (2 ml) was stirred at 23°C during the night. The methanol was removed under reduced pressure. The crude product was purified preparative HPLC, obtaining the target compound (93 mg, yield 37%). LC-MS (ESI) m/z: 459 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0,93 (t, 6H), 2,38 (square, 4H), 3,44 (s, 2H), 4,35 (d, 1H), 4,73 (d, H), 7,13-7,19 (m, 5H), 7,22-7,25 (m, 4H), 7,38 (d, 2H), 7,41 (s, 1H), 7,56-to 7.59 (m, 1H).

Example 139

5-fluoro-8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 139A

(E)-6-Fluoro-4-((1-methyl-1H-imidazol-2-yl)methylamino)isobenzofuran-1(3H)-he

A solution of 1-methyl-1H-imidazole-2-carbaldehyde (659 mg, 6.0 mmol), 4-amino-6-floridalottery-1(3H)-she (1.0 g, 6.0 mmol) and anhydrous magnesium sulfate (7.2 g, 60,0 mmol) in acetonitrile (100 ml) was heated under reflux for 2 days. The solution was filtered, and the solvents were removed in vacuum. The crude product is recrystallized from isopropanol, obtaining the target compound (1,068 g, yield 68%). LC-MS (ESI) m/z: 260 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): Android 4.04 (s, 3H), 5,49 (s, 2H), 7,24 (s, 1H), 7,54-7,58 (m, 2H), 7,73-7,76 (m, 1H), to 8.70 (s, 1H).

Example 139B

7-fluoro-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of benzaldehyde (212 mg, 2 mmol) and (E)-6-fluoro-4-((1-methyl-1H-imidazol-2-yl)methylamino)isobenzofuran-1(3H)-she (518 mg, 2 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (184 mg, 8 mmol) in ethanol (5 ml)). After the addition the mixture was stirred at ambient temperature for 0.5 hours. The mixture is extinguished with water (20 ml), and the solvent was removed in vacuum. The residue was dissolved in water and was extracted with ethyl acetate three times. Joint the United organic layers were washed with water and brine and then evaporated to dryness, the crude product was purified by chromatography, getting a solid yellow color. The solid was dried in vacuum at 50°C, obtaining the target compound (250 mg, yield 32%). LC-MS (ESI) m/z: 394 (M+1)+.

Example 139C

5-fluoro-8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 7-fluoro-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (250 mg, 0,636 mmol) in 85%wage hydrazinoacetate (1 ml) and methanol (5 ml) was stirred at ambient temperature for 4 hours. The resulting mixture was filtered and washed with water (20 ml) and methanol (5 ml)to give a solid white color, which after drying in vacuum at 50°C gave the target compound (34,6 mg, yield 15%). LC-MS (ESI) m/z: 362 (M+1)+; 1Η NMR (400 MHz, DMSO-d6,) δ (ppm): of 3.56 (s, 3H), 4,48-of 4.49 (d, J=6.0 Hz, 1H), 5,01-to 5.03 (m, 1H), 6,70-of 6.71 (m, 1H), for 6.81-6,84 (m, 1H), 6,98-7,02 (m, 2H), 7,14-7,26 (m, 5H), 7,66-to 7.67 (m, 1H), of 12.33 (s, 1H).

Example 140

5-fluoro-9-(4-forfinal)-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 140A

7-Fluoro-3-(4-forfinal)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of 4-forventelige (248 mg, 2 mmol) and (E)-6-fluoro-4-((1-methyl-1H-imidazol-2-yl)methylamino)isobenzofuran-1(3H)-she (518 mg, 2 mmol) in ethylpropylamine (10 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (three is (184 mg, 8 mmol) in ethanol (5 ml)). After the addition the mixture was stirred at ambient temperature for 0.5 hours. The mixture is extinguished with water (20 ml)and the solvents were removed in vacuum. The residues were dissolved in water and was extracted with ethyl acetate three times. The combined organic layers were washed with water and brine. After removal of solvents, the crude product was purified flash chromatography on a column of, getting a solid yellow color, which was dried in vacuum at 50°C, obtaining the target compound (200 mg, yield: 24%). LC-MS (ESI) m/z: 412 (M+1)+.

Example 140B

5-fluoro-9-(4-forfinal)-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 7-fluoro-3-(4-forfinal)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (200 mg, 0,486 mmol) in 85%wage hydrazinoacetate (1 ml) and methanol (5 ml) was stirred at ambient temperature for 4 hours. The resulting mixture was filtered and washed with water (20 ml) and methanol (5 ml)to give a solid white color, which is then dried under vacuum at 50°C, obtaining the target compound (25,4 mg, yield 14%). LC-MS (ESI) m/z: 380 (M+1)+;1Η-NMR (400 MHz, DMSO-d6) δ (ppm): of 3.56 (s, 3H), to 4.52-a 4.53 (d, J=6,8 Hz, 1H), 5,02-5,04 (m, 1H), 6.73 x (s, 1H), 6,82-6,85 (m, 1H), 6,99-to 7.09 (m, 4H), 7.18 in-7,22 (m, 2H), 7,69 (s, 1H), 12,34 (s, 1H).

Example 141

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-ethylphenyl)8.9bn-dihydro-2H-pyrido[4,3,2-d]phthalazine-3(7H)-he

Example A

2-(4-((Dimethylamino)methyl)phenyl)-3-(4-ethylphenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-isobenzofuran-1(3H)-she (588 mg, 2 mmol) and 4-ethylbenzaldehyde (268 mg, 2 mmol) in ethylpropylamine (15 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (138 mg, 6 mmol) in ethanol (5 ml)). After the addition the mixture was stirred at ambient temperature for 3 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1)to give crude target compound (290 mg, yield 32%). LC-MS (ESI) m/z: 457 (M+1)+.

Example 141B

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-ethylphenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-((dimethylamino)methyl)phenyl)-3-(4-ethylphenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (290 mg) in 85%wage hydrazinoacetate (1 ml) and methanol (10 ml) was stirred at 30°C during the night. The methanol was removed under reduced pressure. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1), recip what I target compound (112 mg, yield 42%). LC-MS (ESI) m/z: 425 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): of 1.12 (t, 3H), 2,10 (s, 6H), 2,52 (square, 2H), 3,34 (s, 2H), or 4.31 (d, J=8.0 Hz, 1H), amounts to 4.76 (d, J=8.0 Hz, 1H),? 7.04 baby mortality (m, 4H), 7,15-7,20 (m, 3H), 7,25-7,27 (m, 2H), 7,38-7,41 (m, 3H), to 7.59-to 7.61 (m, 1H).

Example 142

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-isopropylphenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 142A

2-(4-((Dimethylamino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-isobenzofuran-1(3H)-she (588 mg, 2 mmol) and 4-isopropylbenzaldehyde (296 mg, 2 mmol) in ethylpropylamine (15 ml) was cooled to 0°C. Then was added dropwise a solution of ateleta sodium in ethanol (sodium (138 mg, 6 mmol) in ethanol (5 ml)). After the addition the mixture was stirred at ambient temperature for 3 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product which was then purified by chromatography on columns (silica gel, petroleum ether/ethyl acetate=1:1), obtaining the target compound (210 mg, yield 22%). LC-MS (ESI) m/z: 471 (M+1)+.

Example 142B

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-isopropylphenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

<> A mixture of 2-(4-((dimethylamino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (210 mg) in 85%wage hydrazinoacetate (1 ml) and methanol (10 ml) was stirred at 23°C during the night. The methanol was removed under reduced pressure. The crude product was purified flash chromatography, obtaining the target compound (72 mg, yield 37%). LC-MS (ESI) m/z: 439 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): of 1.18 (d, 3H), 1,19 (d, 3H), and 2.26 (s, 6H), 2,79-and 2.83 (m, 1H), 3,51 (d, 2H), 4,27 (d, J=8.0 Hz, 1H), 4,73 (d, J=8.0 Hz, 1H), 6,98-7,00 (m, 2H), 7,05-7,07 (m, 2H), 7.18 in-7,22 (m, 3H), 7,25-7,27 (m, 2H), 7,54-7,56 (m, 1H), 7,56-to 7.59 (m, 1H).

Example 143

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-(trifluoromethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 143A

2-(4-((Dimethylamino)methyl)phenyl)-4-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-isobenzofuran-1(3H)-she (541 mg, of 1.84 mmol) and 4-(trifluoromethyl)benzaldehyde (320 mg, of 1.84 mmol) in anhydrous ethylpropylamine (25 ml) was cooled to 0°C. Then was added dropwise a sodium ethylate in methanol solution (sodium (127 mg, 5.51 mmol) in anhydrous ethanol (10 ml)and the mixture was stirred at 25°C for 4 hours. The resulting mixture was extinguished with water (5 ml), and then the solvents evaporated under reduced pressure. The residue was extracted with ethyl acetate (100 ml ×3), and the combined organic layers were dried over anhydrous sulfate n the sodium and concentrated, give crude product, which was purified by chromatography on columns (silica gel, dichloromethane to a mixture of dichloromethane/methanol=30:1)to give the target compound (150 mg, yield 16%) in the form of a solid yellow color. LC-MS (ESI) m/z: 497 (M+1)+.

Example 143B

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-(trifluoromethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (150 mg, 0.30 mmol) and hydrazinoacetate (0.5 ml) in methanol (10 ml) was stirred at 30°C during the night. The mixture was concentrated under reduced pressure to give crude product, which was purified flash chromatography, obtaining the target compound (60 mg, yield of 34.5%) in the form of solids. LC-MS (ESI) m/z: 465 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): of 2.64 (s, 3H), 2,65 (s, 3H), 4,19-4,20 (d, J=4.0 Hz, 2H), 4.53-in-4,55 (d, J=9,2 Hz, 1H), 4,88-of 4.90 (d, J=9,2 Hz, 1H), 7,20-7,22 (d, J=7,6 Hz, 1H), 7,35-7,46 (m, 7H), to 7.50 (s, 1H), 7,56-7,63 (m, 3H), RS 9.69-9,71 (users, 1H), 12,20 (s, 1H).

Example 144

8-(4-((Diethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 144A

2-(4-((Diethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-((diethylamino)methyl)benzylideneamino)-isobenzofuran-1(3H)-she (644 mg, 2 mmol) and 4-methylbenzaldehyde (240 mg, 2 mmol) in ethylpropylamine (15 ml) was cooled to 0°C. Then p is a drop of solution was added to atlata sodium in ethanol (sodium (138 mg, 6 mmol) in ethanol (5 ml)). After the addition the mixture was stirred at ambient temperature for 3 hours. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified by chromatography on columns (silica gel, petroleum ether/ethyl acetate=1:1), obtaining the target compound (320 mg, 34% yield). LC-MS (ESI) m/z: 471 (M+1)+.

Example 144B

8-(4-((Diethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(4-((diethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (320 mg) in hydrazinoacetate (2 ml, 85%) and methanol (10 ml) was stirred at 30°C during the night. The methanol was removed under reduced pressure. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1), obtaining the target compound (85 mg, yield 29%). LC-MS (ESI) m/z: 439 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0,93 (t, 6H), of 2.20 (s, 3H), 2,39 (square, 4H), 3,42 (d, 2H), 4,27 (d, J=8.0 Hz, 1H), 4,73 (d, J=8.0 Hz, 1H), 6,98-7,00 (m, 4H), 7,15-7,17 (m, 3H), 7,22-7,24 (m, 2H), 7,35-7,38 (m, 2H), 7,54-7,56 (m, 1H), 12,12 (s, 1H).

Example 145

9-(4-Forfinal)-8-(4-(1-methylpyrrolidine-2-yl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example A

2-Oxo is irreligion-tert-butyl-1-carboxylate

To a solution of 2-pyrrolidinone (10,82 g, 127 mmol) in acetonitrile (400 ml) was added DMAP (1,53 g, 12.6 mmol), then a solution of di-tert-BUTYLCARBAMATE (33.6 g, 77,1 mmol) in acetonitrile (20 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The resulting mixture was concentrated in vacuo and the resulting oil was taken in diethyl ether. The mixture was washed successively 1H. HCl and brine. The organic phase was dried over sodium sulfate and concentrated in vacuum, obtaining the target compound in the form of a yellow oil (15 g, 64%)which was used directly in the next stage.

Example 145B

4-(4-Bromophenyl)-4-oxobutyric-BUTYLCARBAMATE

Carefully dried three-neck round bottom flask was equipped with a reflux condenser, a funnel to add and entry argon. Then this device was placed magnesium powder (7.5 g, 311 mmol, activated with iodine) and dry TΗF (300 ml), a solution of 1,4-dibromobenzene with (73,5 g, 311 mmol) in dry TΗF (200 ml) was slowly added in such a rate as to maintain boiling the mixture under reflux. After complete addition, the mixture was heated under reflux for an additional 2 hours. After cooling to ambient temperature, the solution was added at -78°C solution of 2-oxopyrrolidin-1-tert-BUTYLCARBAMATE (48 g, 260 mmol) in TΗF (320 ml), and the mixture is stirred at -78°C for 2 hours. The solution was heated to ambient temperature and was stirred for another 10 hours, and then extinguished with water. Added hydrochloric acid (1N., 100 ml)and the mixture was stirred at ambient temperature for 10 minutes. The mixture was concentrated, and the residue was separated between ethyl acetate and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuum to give crude product, which was purified by chromatography on columns (EtOAc:DCM:hexane=1:1:15), obtaining the target compound in the form of a solid white (53 g, yield 60%). LC-MS (ESI) m/z: 342 (M+1)+.

Example 145C

5-(4-Bromophenyl)-3,4-dihydro-2H-pyrrol

4-(4-Bromophenyl)-4-oxobutyl-tert-BUTYLCARBAMATE (3.42 g, 10 mmol) was stirred in TFA (10 ml) for 6 hours. Then to the mixture was added 50%NaOH solution to obtain pΗ 13-14, white precipitate was filtered, washed with water and dried, obtaining the target compound in the form of a solid white color (1.8 g, yield 80%). LC-MS (ESI) m/z: 224 (M+1)+.

Example 145D

2-(4-Bromophenyl)pyrrolidin

NaBH4(1.52 g, 40 mmol) at -41°C was added to a solution of 5-(4-bromophenyl)-3,4-dihydro-2H-pyrrole (4,48 g, 20 mmol) inH2O/Meon (30 ml, about./about. 1:4). After stirring for 4 hours, the solution was allowed to warm to ambient temperature. Once the reaction was deemed complete by TLC results, unreactedNaBH 4extinguished by the addition of 2n. HCl. The solution is then diluted with water and simple ether, and the two layers were separated. The aqueous layer was washed with an additional simple part of the ether, was podslushivaet 4M NaOH (pH 12-13) and washed with ethyl acetate. The combined organic extracts were washed with saline and then dried overNa2SO4. Evaporation of the solvent gave the crude target product in the form of a yellow oil (3.8 g, yield 84%)which was used directly in the next stage. LC-MS (ESI) m/z: 226 (M+1)+.

Example 145E

2-(4-Bromophenyl)-1-methylpyrrolidine

A mixture of 2-(4-bromophenyl)pyrrolidine (0.5 g, 2.2 mmol), formic acid (0,11 ml, 2,42 mmol), formaldehyde (0.2 ml, 2,42 mmol, 37% in water), water (4 ml) in a sealed tube was heated up to 150°C under microwave irradiation for 5 minutes. After cooling to ambient temperature the reaction mixture was extracted with EtOAc (3×15 ml), the combined organic phase was washed sequentially with saturated NaHCO3(5 ml) and brine (5 ml), dried over Na2SO4and concentrated in vacuum to give crude product (of 0.48 g, 91%)which was used directly in the next stage. LC-MS (ESI) m/z: 240 (M+1)+.

Example 145F

4-(1-Methylpyrrolidine-2-yl)benzaldehyde

To a solution of 2-(4-bromophenyl)-1-methylpyrrolidine (0.45 g, 2 mmol) in dry THF (10 ml) at -78°C until the NML was added n-BuLi (0.88 to ml, 2.2 mmol, 2.5 mol/l in hexane), after complete addition, the mixture was stirred for 1 hour, then the reaction system was added dry DMF (of 0.18 ml, 2.4 mmol), and stirring was continued for another 1 hour. Then the reaction mixture was separated between EtOAc and 1N. HCl, the aqueous solution was extracted with EtOAc (3×15 ml). The combined organic phase was washed with saline, dried over Na2SO4and concentrated in vacuum to give crude product (0.28 g, yield 74%) in the form of a yellow oil. The product was used directly in the next stage without further purification. LC-MS (ESI) m/z: 189 (M+1)+.

Example 145G

(E)-4-(4-(l-Methylpyrrolidine-2-yl)benzylideneamino)isobenzofuran-1(3H)-he

A mixture of 4-(1-methylpyrrolidine-2-yl)benzaldehyde (1.89 g, 10 mmol), 4-aminoazobenzene-1(3H)-she (1,49 g, 10 mmol) andMgSO4(12 g, 100 mmol) inCH3CN (60 ml) was heated under reflux at 120°C for 4 days. After hot filtration, CH3CN was partially removed under reduced pressure, and the formed white precipitate, the target compound was obtained by direct filtration (1.3 g, yield 41%) in the form of a solid white color. LC-MS (ESI) m/z: 440 (M+1)+.

Example 145H

3-(4-Forfinal)-2-(4-(1-methylpyrrolidine-2-yl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

A mixture of (E)-4-(4-(1-methylpyrrolidine-2-yl)benzylideneamino)-isobenzofuran-1(3H)she (0.32 g, 1 mmol), 4-forventelige (0,248 g, 2 mmol) was dissolved in dry ethylpropylamine (5 ml), to this solution was added EtONa (0,136 g, 2 mmol) in EtOH (5 ml)and the mixture was stirred at ambient temperature until the starting material disappeared on TLC test results. The reaction mixture was extinguished 0.5 ml water, the mixture was concentrated in vacuo, and the residue was purified by chromatography on columns (MeOH:DCM=1:20)to give the target compound (200 mg, yield 42%) in the form of a solid of light yellow color. LC-MS (ESI) m/z: 472 (M+1)+.

Example 145I

9-(4-Forfinal)-8-(4-(1-methylpyrrolidine-2-yl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a stirred solution of 3-(4-forfinal)-2-(4-(1-methylpyrrolidine-2-yl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (200 mg, 0.42 mmol) in MeOH (20 ml) was added N2H4.H2O (2 ml), the mixture was stirred for 4 hours and then concentrated in vacuo, and the residue was purified by chromatography (MeOH:DCM=1:20), obtaining the target compound in the form of a solid white color (45 mg, yield 24%). LC-MS (ESI) m/z: 440 (M+1)+;1H-NMR (400 MHz, CDCl3) δ (ppm): 1,67-of 1.97 (m, 3H), 2,11 (s, 3H), of 2.25 (m, 1H), 2,17-of 2.30 (m, 1H), 2,97-2,99 (m, 1H), 3,21-of 3.25 (m, 1H), 4,19-4,22 (d, J=10.4 Hz, 1H), 4,57-4,59 (d, J=10.4 Hz, 1H), 4,90 (s, 1H), 6,86-6,91 (m, 2H), 6,95-6,97 (m, 2H), 7.03 is-7,05 (d, J=7,6 Hz, 1H), 7,10 for 7.12 (d, J=8 Hz, 2H), 7,20-7,22 (d, J=8 Hz, 2H), EUR 7.57-to 7.61 (t, J=7,6 Hz, 1H), 7,74-7,76 (d, J=7,6 Hz, 1H), 9,94 (s, 1H).

Example 146

9-(4-Forfinal)-8-(4-(Pyrrhus is lidin-2-yl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 146A

2-(4-Bromophenyl)pyrrolidin-1-benzylcarbamoyl

To a solution of 2-(4-bromophenyl)pyrrolidine (of 2.26 g, 10 mmol) in dioxane (18 ml) and water (12 ml) at ambient temperature was added potassium carbonate (5,52 g, 40 mol) and benzyl chloroformate (1.88 g, 11 mmol) and was stirred over night. Then the mixture was separated between ethyl acetate and brine. The organic phase was concentrated in vacuo, and the residue was purified by chromatography on columns (silica gel, EtOAc:hexane=1:10)to give the target compound (2,95 g, 82%) in the form of a colorless oil. LC-MS (ESI) m/z: 360 (M+1)+.

Example 146B

2-(4-Formylphenyl)pyrrolidin-1-benzylcarbamoyl

In a round bottom flask of 50 ml was placed Pd(PPh3)2Cl2(70 mg, 0.1 mmol) and sodium formate (510 mg, 7.5 mmol) and was purified by carbon monoxide. DMF (7 ml) and 2-(4-bromophenyl)pyrrolidin-1-benzylcarbamoyl (1.8 g, 5 mmol) was added via syringe. The mixture is vigorously stirred at 100°C in an atmosphere of carbon monoxide within 8 hours. Then the reaction mixture was cooled to ambient temperature and was divided between the simple ether (100 ml) and water (15 ml). The organic phase is washed with water (3×15 ml), dried overNa2SO4and concentrated in vacuum. The residue was purified by chromatography on columns (silica gel, EtOAc:hexane=1:10)to give the target compound (0.31 g, yield 20%) in the form of a colorless oil. L-MS (ESI) m/z: 309 (M+1) +;1H-NMR (400 MHz, DMSO-d6) 6 (ppm): 1,73-of 1.88 (m, 3H), 2,31-to 2.41 (m, 1H), 3,57-to 3.67 (m, 2H), 4,84-of 5.06 (m, 3H), 6,84-6,86 (m, 1H), 7,12-7,34 (m, 4H), 7,41-the 7.43 (d, J=8.0 Hz, 2H), a 7.85-7,87 (d, J=8.0 Hz, 2H), 9,98-9,99 (d, J=6.0 Hz, 1H).

Example 146C

(E)-Benzyl-2-(4-((1-oxo-1,3-dihydroisobenzofuran-4-elimina)methyl)phenyl)pyrrolidine-1-carboxylate

A mixture of 2-(4-formylphenyl)pyrrolidin-1 benzylcarbamoyl (of 0.62 g, 2 mmol), 4-aminoazobenzene-1(3H)-she (0,298 g, 2 mmol),MgSO4(2.4 g, 20 mmol) inCH3CN (20 ml)was heated under reflux at 120°C for 4 days. After hot filtration, the filtrate was concentrated in vacuo, and the residue was purified by chromatography on columns (EtOAc:DCM:hexane=1:1:6)to give the target compound (0.35 g, 30%yield) in the form of a solid white color. LC-MS (ESI) m/z: 440 (M+1)+.

Example 146D

2-(4-(1-(Benzyloxycarbonyl)pyrrolidin-2-yl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of (E)-2-(4-((1-oxo-1,3-dihydroisobenzofuran-4-elimina)methyl)phenyl)pyrrolidin-1 benzylcarbamoyl (0.5 g, to 1.14 mmol) and 4-forventelige (0,284 g, 2.28 mmol) in dry ethylpropylamine (5 ml) was added EtONa (0,155 g, 2.28 mmol) in EtOH (6 ml)and the mixture was stirred at ambient temperature until the starting material disappeared, that the audit showed TLC. Then the reaction mixture was extinguished 0.5 ml water, the mixture was concentrated in vacuo, and the residue was purified chromatography the raffia on columns, receiving the target compound (130 mg, yield 20%) in the form of a solid yellow color. LC-MS (ESI) m/z: 592 (M+1)+.

Example 146E

2-(4-(9-(4-Forfinal)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8-yl)phenyl)pyrrolidin-1-benzylcarbamoyl

To a stirred solution of 2-(4-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (130 mg, 0.22 mmol) in MeOH (20 ml) was added N2Η42O (2 ml), the reaction was continued for 4 hours, then the mixture was concentrated in vacuo, and the residue was purified by chromatography (EtOAc:hexane=1:2)to give the target compound (100 mg, yield 81%) in the form of a solid white color. LC-MS (ESI) m/z: 560 (M+1)+.1H-NMR (400 MHz, CDCl3) δ (ppm): 1.77 in-1,90 (m, 3H), of 2.25 (m, 1H), 3,65-3,68 (m, 2H), 4,10-to 4.23 (m, 2H), 4,59-br4.61 (d, J=10.0 Hz, 1H), 4,90-5,14 (m, 2H), 6,82-to 7.09 (m, 10H), 7,27-to 7.32 (m, 2H), 7,37 (s, 2H), 7,60-to 7.64 (m, 1H), to 7.77-7,79 (m, 1H), being 9.61 (s, 1H).

Example 146F

9-(4-Forfinal)-8-(4-(pyrrolidin-2-yl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

2-(4-(9-(4-Forfinal)-3-oxo-3,7,8,9-tetrahydro-2Η-pyrido[4,3,2-de]phthalazine-8-yl)phenyl)pyrrolidin-1-benzylcarbamoyl (60 mg, 0,107 mmol) was dissolved in distilled methanol (15 ml)and the reaction mixture was stirred at ambient temperature in a hydrogen atmosphere in the presence of catalytic amounts of palladium on carbon (11 mg, 0.01 mmol) in 2 hours. After reacts and the catalyst was removed by filtration through a layer of celite, and the solvent was removed under reduced pressure. The residue was purified preparative TLC (MeOH:DCM=1:10)to give the target compound (5 mg, yield 11%) in the form of a white foam. LC-MS (ESI) m/z: 426 (M+1)+.1H-NMR (400 MHz, CD3OD) δ (ppm): 1,78-of 1.88 (m, 1H), 1,95-of 2.08 (m, 2H), 2,24 of-2.32 (m, 1H), 3,05-of 3.12 (m, 1H), 3,21-of 3.27 (m, 1H), 4,17-is 4.21 (m, 1H), 4,34 is 4.36 (d, J=8.0 Hz, 1H), 4.75 V-of 4.77 (d, J=8.0 Hz, 1H), 6,91-to 6.95 (m, 2H), 7,09-to 7.15 (m, 2H), 7,17-7,25 (m, 1H), 7,22-7,25 (m, 1H), 7,29-7,34 (m, 4H), 7,55-EUR 7.57 (m, 1H), 7,63-to 7.67 (m, 1H).

Example 147

8-(4-Forfinal)-9-methyl-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 147A

2-(4-Forfinal)-3-methyl-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of 2-(4-forfinal)-3-(1-methyl-1Η-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (150 mg, 0.38 mmol) and cesium carbonate (268 mg, from 0.76 mmol) in DMF (10 ml) at 0°C under N2added logmean (0.2 ml, 2.28 mmol). The reaction mixture was stirred at 0°C for 4 hours and then at ambient temperature overnight. To the resulting solution was added 50 ml of water, and then extracted with ethyl acetate (100 ml ×3). The extracts were concentrated, give crude product in the form of a solid yellow (145 mg, yield 90%)which was used in the next stage without further purification. LC-MS (ESI) m/z: 408 (M+1)+.

Example 147B

8-(4-Forfinal)-9-methyl-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-37H)-he

2-(4-Forfinal)-3-methyl-3-(1-methyl-1Η-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (70 mg, 0.18 mmol) was added to the hydrazine monohydrate (5 ml)and the mixture was stirred at 67°C for 10 hours. The mixture was concentrated and was purified preparative HPLC, obtaining the target compound in the form of a solid white (9 mg, yield 14%). LC-MS (ESI) m/z: 376 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1,79 (s, 3H), 2.57 m (s, 3H), 4,50 (s, 1H), 6,68-6,69 (d, J=0.9 Hz, 1H), 6,78-PC 6.82 (m, 2H), 6,84-6,85 (d, J=0.9 Hz, 1H), 7,05-to 7.09 (m, 2H), 7,16-to 7.18 (DD, J1=8.0 Hz, J2=0.8 Hz, 1H), 7,34 (s, 1H), 7,43 was 7.45 (DD, J1=8.0 Hz, J2=0.8 Hz, 1H), EUR 7.57-to 7.61 (t, J=7,6 Hz, 1H), 12,30 (s, 1H).

Example 148

9-(4-Forfinal)-8-(1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 148A

1-Benzyl-1H-imidazole-2-carbaldehyde

To a solution of 1H-imidazole-2-carbaldehyde (240 mg, 2.4 mmol) and potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (5 ml) at 0°C was added dropwise (methyl bromide)benzene (493 mg, is 2.88 mmol). The mixture was stirred at 40°C for 4 hours. Then the mixture was filtered, evaporated to remove the acetonitrile filtrate was added EtOAc to be extracted residues, and the extract was washed with salt solution and water. The organic layer was dried anhydrous Na2SO4concentrated and chromatographically on a column of silica gel (EtOAc:hexane=1:9)to give the target compound (430 mg, yield 95%). LC-MS (SI) m/z: 187 (M+1) +.

Example 148B

(E)-4-((1-Benzyl-1H-imidazol-2-yl)methylamino)isobenzofuran-1(3H)-he

A mixture of 1-benzyl-1H-imidazole-2-carbaldehyde (430 mg, 1.48 mmol), 4-aminoazobenzene-1(3H)-she (221 mg, 1.48 mmol) and magnesium sulfate (4.3 g) in acetonitrile was heated under reflux for 48 hours. Then the mixture was filtered and evaporated to remove the solvent. The crude product is recrystallized from isopropanol, obtaining the target compound (470 mg, 65%). LC-MS (ESI) m/z: 318 (M+1)+.

Example 148C

2-(1-Benzyl-1H-imidazol-2-yl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of (E)-4-((1-benzyl-1H-imidazol-2-yl)methylamino)isobenzofuran-1(3H)-she (470 mg, 1.48 mmol) in ethyl propanate (5 ml) was added EtONa/EtOΗ (136 mg of sodium in 5 ml of ethanol) and stirred at ambient temperature under N2within 30 minutes the mixture is Then divided between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried anhydrousNa2SO4and chromatographical on a column of silica gel (EtOAc:hexane= 1:9 to 1:1), obtaining the target compound (280 mg, yield 40%). LC-MS (ESI) m/z: 470 (M+1)+.

Example 148D

8-(1-Benzyl-1Η-imidazol-2-yl)-9-(4-forfinal)8.9bn-dihydro-2Η-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 2-(1-benzyl-1H-imidazol-2-yl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (280 mg, 0.9 mmol) and hydrazinoacetate (2 ml, 85%) in methanol (4 ml) was stirred at 40°C for 2 hours and then was evaporated to half of the original volume. The mixture was filtered, and the solid is washed with ethyl acetate, obtaining the target compound (200 mg, yield 96%). LC-MS (ESI) m/z: 437 (M+1)+.

Example 148E

9-(4-Forfinal)-8-(lH-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 8-(1-benzyl-1H-imidazol-2-yl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (200 mg, 0.46 mmol) and palladium hydroxide (200 mg) in methanol (4 ml) was purged with hydrogen and stirred at 60°C for 18 hours. Then the mixture was filtered, evaporated to remove the solvent, and the solid is washed with ethyl acetate, obtaining the target compound (150 mg, yield 94%). LC-MS (ESI) m/z: 348 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): is 4.93 (d, J=8,4 Hz, 1H), total of 5.21 (d, J=8,4 Hz, 1H), 7,10 (t, J=8,4 Hz, 2H), 7,21-7,30 (m, 3H), 7,37 (s, 1H), 7,45-7,49 (m, 3H), 4,58 (d, J=10 Hz, 1H), 7,62-to 7.67 (m, 1H), 7,87 (s, 1H).

Example 149

5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 149A

7-fluoro-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of (E)-4-(benzylideneamino)-6-floridalottery-1(3H)-she (1.25 g, 4.9 mmol), anhydrous Na2SO3(1.24 g, 9,82 mmol), anhydrousNa2SO4(2 g, 14.7 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (900 mg, 8.1 mmol) in ethylpropylamine (50 ml) and 40°C was added EtONa [(sodium 316 mg, of 13.8 mmol) in 25 ml ethanol], then the mixture was stirred at 40°C for 3 hours. The resulting mixture was evaporated under reduced pressure, extracted with ethyl acetate (100 ml ×4) and concentrated to dryness. The crude product was purified by chromatography on columns (silica gel, dichloromethane:methanol= 200:1 to 50:1), obtaining the target compound in the form of a solid green color (190 mg, yield 10%). LC-MS (ESI) m/z: 395 (M+1)+.

Example 149B

5-fluoro-9-(1-methyl-1Η-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2Η-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a solution of 7-fluoro-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (186 mg, 0.47 mmol) in methanol (1 ml) was added hydrazine monohydrate (0.5 ml)and the mixture was stirred at 25°C for 15 hours. The mixture is then filtered, obtaining a solid white (40 mg, yield 24%). LC-MS (ESI) m/z: 363 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3,63 (s, 3H), 4,94-to 5.03 (m, 2H), 6,91-6,94 (DD, J1= to 11.6 Hz, J2=2.4 Hz, 1H), 7,05-was 7.08 (DD, J1=9.6 Hz, J2=2.4 Hz, 1H), 7,29-7,35 (m, 3H), 7,42-of 7.48 (m, 2H), 7,74 (s, 1H), 7,79 (s, 1H), 12,34 (s, 1H).

Example 150

9-(4-Forfinal)-9-hydroxy-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

Example 150A

3-(4-forfinal)-3-hydroxy-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a mixture of (E)-4-((1-methyl-1H-imidazol-2-yl)methylamino)-isobenzofuran-1(3H)-she (590 mg, 2.4 mmol) and 4-forventelige (300 mg, 2.4 mmol) in ethylpropylamine (20 ml) was added a solution of ateleta sodium in ethanol [sodium (220 mg, 9.6 mmol) in ethanol (10 ml)]. After the addition the mixture was stirred at ambient temperature overnight. The mixture is extinguished with water (10 ml), and the solvent was removed in vacuum. The residue was dissolved in water and then was extracted with ethyl acetate (100 ml ×4). The combined organic layers were washed with saline, dried over anhydrous sodium sulfate and concentrated, to give crude product, which was purified flash chromatography, obtaining the target compound (100 mg, yield 10%). LC-MS (ESI) m/z: 410 (M+1)+.

Example 150B

9-(4-Forfinal)-9-hydroxy-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

A mixture of 3-(4-forfinal)-3-hydroxy-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (60 mg) in 85%wage hydrazinoacetate (0.2 ml) and methanol (2 ml) was stirred at ambient temperature for 1 hour. Then the solvent was removed under reduced pressure. The residue was purified preparative TLC (methanol:dichloromethane=1:20)to give the target compound (50 mg, yield 80%). LC-MS (ESI) m/z: 378 (M+1)+;1H-NMR (400 MHz, DMSO-d6); 3,44 (s, 3H), of 5.24 (s, 1H), 6,84 (s, 1H), 6,98-7,06 (m, 4H), 7,11-7,13 (d, J=8.0 Hz, 1H), 7,38-7,42 (m, 3H), 7,46 (s, 1H), 7,56-of 7.60 (t, J=8.0 Hz, 1H).

Example 151

8-(4-Forfinal)-8-methyl-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]falasi is -3(7H)-he

Example 151A

(E)-4-(1-(4-Forfinal)ethylidene)isobenzofuran-1(3H)-he

To a solution of 4-aminoazobenzene-1(3H)-it (1 g, 6.7 mmol) and 1-(4-forfinal)ethanone (1.4 g, 10.1 mmol) in toluene (35 ml) at ambient temperature under N2added anhydrous magnesium sulfate (8.8 g, 73.7 mmol) and acetic acid (0.2 ml). The reaction mixture was stirred at 120°C for 36 hours. The reaction mixture was cooled to 90°C and filtered. Once pressed the precipitate was washed with acetonitrile, the filtrates were combined and evaporated to dryness, obtaining a solid yellow color, which was washed with petroleum ether, obtaining the target compound in the form of a solid white color (1,58 g, yield 88%). LC-MS (ESI) m/z: 270 (M+1)+.1H-NMR (400 MHz, CDCl3) δ (ppm): 2,30 (s, 3H), 5,16 (s, 2H), 7,00-7,02 (d, J=7,6 Hz, 1H), 7,13-to 7.18 (m, 2H), 7,51-7,56 (t, J=7,6 Hz, 1H), 7,66-of 7.69 (d, J=7,6 Hz, 1H), 7,99-8,03 (m, 2H).

Example V

2-(4-Forfinal)-2-methyl-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of 1-methyl-1H-imidazole-2-carbaldehyde (580 mg, 5.2 mmol) and (E)-4-(1-(4-forfinal)ethylidene)isobenzofuran-1(3H)-it (1 g, 3.7 mmol) in ethylpropylamine (20 ml) at 0°C was rapidly added EtONa [sodium (340 mg, of 14.8 mmol) in 8 ml ethanol], then the mixture was stirred at 30°C for 3 hours. To the mixture was added ethyl acetate (150 ml) and washed with water (25 ml ×3), the organic layers were combined and upari the Ali dryness, give crude product, which was purified by chromatography on columns (silica gel, dichloromethane:methanol = 200:1 to 50:1), obtaining the target compound in the form of a solid color red (120 mg, yield 8%). LC-MS (ESI) m/z: 408 (M+1)+

Example 151C

8-(4-Forfinal)-8-methyl-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

To a solution of 2-(4-forfinal)-2-methyl-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate (120 mg, 0.30 mmol) in methanol (4 ml) at ambient temperature was added hydrazine monohydrate (0.7 ml), the mixture was stirred at 30°C for 10 hours. The solvent was evaporated to give crude solid, which was washed with 14 ml of a mixture of ethyl acetate and methanol (13:1), obtaining the target compound in the form of a solid green color (40 mg, yield 36%). LC-MS (ESI) m/z 376 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.39 in (s, 3H), 3,71 (s, 3H), 4,74 (s, 1H), 6,72 (s, 1H), 7,03 (s, 1H), 7,06-7,11 (m, 2H), 7,16-7,19 (d, J=8 Hz, 1H), 7,25-7,28 (d, J=8 Hz, 1H), 7,49 (s, 1H), 7,54-7,58 (m, 3H), a 12.05 (s, 1H).

Example 152

The racemate (8R,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (8S,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she; and the racemate (8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-is on and (8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it

Example 152A

2-(4-((Dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1Η-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate

To a solution of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-floridalottery-1(3H)-she (4,2 g, 13.5 mmol) and compound 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (3.0 g, 27 mmol) in ethylpropylamine (150 ml) at 40°C was rapidly added NaOEt [sodium (870 mg, 37.8 mmol) in 70 ml ethanol], then the mixture was stirred at 48°C for 3 hours. The resulting mixture was concentrated under reduced pressure and extracted with ethyl acetate (250 ml ×3). The extract was evaporated to give crude product, which was purified by chromatography on columns (silica gel, dichloromethane:methanol= 50:1 to 10:1)to give the target compound (560 mg, yield 9%) (mixture of CIS - and TRANS-isomers). LC-MS (ESI) m/z: 452 (M+1)+.

Example 152B

The racemate (8R,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (8S,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she; and the racemate (8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it

To a solution of 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,,3,4-tetrahydroquinolin-5-ethylcarboxylate (560 mg, to 1.24 mmol, mixture of CIS - and TRANS-isomers) in methanol (2 ml) was added hydrazinoacetate (0.5 ml)and the mixture was stirred at 25°C for 10 hours. The mixture was concentrated in vacuo, and the residue was purified preparative TLC and then preparative HPLC, receiving two pairs of diastereomers in the form of solid particles of white (the racemate (8R,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (8S,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it: 20 mg, yield 4%). LC-MS (ESI) m/z: 420 (M+1)+;1H-NMR (400 MHz, DMSO-d6) δ (ppm): of 2.16 (s, 6H), is 2.88 (s, 3H), 3,34 (s, 2H), 4,73-4,74 (l, J2=4.0 Hz, 1H), 5,02-to 5.03 (d, J2=4.0 Hz, 1H), 6,92-to 6.95 (DD, J1=to 10.8 Hz, J2=2.4 Hz, 1H), 7,07-to 7.09 (DD, J1=to 10.8 Hz, J2=2.4 Hz, 1H),? 7.04 baby mortality-7,06 (d, J=7,6 Hz, 2H), 7.23 percent-of 7.25 (d, J=7,6 Hz, 2H), 7,56 (s, 1H), 7,69 (s, 1H), 12,45 (s, 1H). The racemate (8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it: 140 mg, yield 27%). LC-MS (ESI) m/z: 420 (M+1)+;1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2,10 (s, 6H), to 3.36 (s, 2H)and 3.59 (s, 3H), 4,91-4,99 (m, 2H), 6,91-to 6.95 (DD, J1=2,4, J2=11.2 Hz, 1H), 7,05-was 7.08 (DD, J1=2,4, J2=9,2 Hz, 1H), 7,20-of 7.23 (d, J=8.0 Hz, 2H), 7,35-7,37 (d, J=8.0 Hz, 2H), 7,72 (s, 1H), 7,79 (s, 1H), of 12.33 (s, 1H).

Example 153

the Racemate (8S,9S)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (8R,9R)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H-she

The racemate (8R,9S)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (600 mg, 1,67 mmol) was added to a 30% NaOH (32 ml) at ambient temperature, the mixture was stirred at 85°C for 3 hours. Then the solution was cooled to 5°C and filtered, getting 555 mg solid white, which was purified preparative HPLC, obtaining the target compound in the form of a solid white color (40 mg, yield 7%). LC-MS (ESI) m/z: 362 (M+1)+.1H-NMR (400 MHz, DMSO-d6) δ (ppm): is 2.74 (s, 3H), 4,47 (d, J=4 Hz, 1H), 4,90 (d, J=4 Hz, 1H), 6,65 (s, 1H), for 6.81 (s, 1H), 7,07-7,17 (m, 6H), 7,40-7,42 (d, J=8 Hz, 1H), 7,55-to 7.59 (t, J=8 Hz, 1H), 12,23 (s, 1H).

Examples of chiral separation

Example 154

Enantiomers (8R,9S)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she

8-(4-Forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it was dissolved in DMF, and chiral separation was performed using super-fluid chromatography (SFC) with a chiral IA column and methanol (30%) andCO2(70%) as eluents.

Example 155

Enantiomers (8R,9S)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-she (8S,9R)-5-fluoro-8-(4-fluoro who enyl)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it

5-fluoro-8-(4-forfinal)-9-(1-methyl-1Η-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it was dissolved in DMF, and chiral separation was performed using super-fluid chromatography (SFC) with a chiral IA column and methanol (20%), and CO2(80%) as eluents.

Example 156

(8R,9S)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he(8S,9R)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it was dissolved in DMF, and chiral separation was performed using super-fluid chromatography (SFC) with a chiral IA column and methanol (30%) andCO2(70%) as eluents.

Example 157

(8R,9S)-8-(4-Forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-and (8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

8-(4-Forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it was dissolved in DMF, and chiral separation was performed using super-fluid chromatography (SFC) with a chiral IA column and methanol (30%) andCO2(70%) as eluents.

Example 158

(8R,9S)-8-(4-(Azetidin-1-ylmethyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-and (8S,9R)-8-(4-(azetidin-1-ylmethyl)is enyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2 de]phthalazine-3(7H)-he

8-(4-(Azetidin-1-ylmethyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it was dissolved in methanol, and chiral separation was performed using super-fluid chromatography (SFC) with a chiral IA column and methanol (40%), and CO2(60%) as eluents.

Example 159

(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-and (8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he

8-(4-((Dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1Η-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-it was dissolved in methanol, and chiral separation was carried out using superioty chromatography (SFC) with a chiral IA column and methanol (20%) andCO2(80%) as eluents.

Biological studies

Inhibiting effects of the tested compounds against human PARP enzyme 1 was evaluated using a Universal Chemiluminescent kit for testing PARP Trevigen (Trevigen CAT#4676-096-K) according to the manufacturer's recommended Protocol.

Immediately before the test received the following reagents: A) 20× buffer for testing PARP was diluted to 1× with distilled H2O; (B) 10× PARP cocktail, which contains a mixture of biotinylated NAD NAD, was diluted by adding 10 is activated DNA and 1× for testing PARP. And PARP cocktail, and activated DNA were 1× after dilution; (C) all test compounds were initially dissolved in DMSO and then serial diluted in 1× buffer for testing PARP; (D) recombinant human PARP enzyme 1 was diluted in 1× buffer for testing PARP, to obtain 0.5 units/15 μl; (E) 10× Strap-diluent was diluted to 1× with 1× PBS/0,1% Triton X-100; (F) immediately prior to use Strap-HRP was diluted 500-fold in 1× Strap-diluent.

Chemiluminescent tests PARP activity was carried out in white tablets with 96 wells pre-coated with histones. Briefly, removed the wrapping from a number of wells were added 50 μl/well 1× PARP buffer to re-hydrate the histones, and was carried out by incubation for 30 minutes at ambient temperature. Removal 1× PARP Buffer from the wells was carried out, promaqua a number of holes with a paper towel. Added a serial dilution of test compounds of the pairs of holes in a volume of 10 μl/well. The final concentration of test compounds typically ranged from 1 to 0.0001 micron. Then recombinant human PARP enzyme 1 was added in the amount of 0.5 units of enzyme PARP 1/well in a volume of 15 μl/well. The combined volume of enzyme and inhibitor was 25 µl. A mixture of enzyme/inhibitor were incubated for 10 minutes at ambient temperature to initiate the reaction, 25 μl/well 1× PARP Cocktail was added to all wells. Control means included background well only with 1× test buffer (without PARP) and the wells without inhibitor to determine the maximum or 100%of the value of the activity of PARP. In all cases, the final reaction volume was 50 µl.

The reaction was carried out for 1 hour at ambient temperature. The tablet then washed 4 times with 200 μl/well 1× PBS/0,1% Triton X-100, using EL50 Automated Strip Washer (BIO-TEK). After washing, the wells were incubated for 60 minutes with 50 µl/well Strap-HRP, diluted 1:500 1× strap-diluent. The tablet was washed 4 times with 200 μl/well 1× PBS/0,1% Triton X-100, using EL50 Automated Strip Washer (BIO-TEK). After washing, the wells were dried, promaqua tablet paper towel. Mixed equal volumes PeroxyGlow™ A and B and add 100 ál to well. The intensity of luminescence was immediately determined in a spectrophotometer to read the tablets (EnVision, Perkin Elmer), configured for measuring chemiluminescence.

The enzyme activity in % for each compound was then calculated using the following equation:

% inhibition =control active - X×100%
control activity - negative control

The values of the IC50(the concentration which inhibited 50% of enzyme activity) for each of the tested compounds were calculated using the software GraphPad Prism5.

All tested compounds had or supposedly had inhibitory activity against the enzyme PARP. Among the tested compounds, more than 100 compounds had inhibitory activity against PARP enzyme in the test is less than 50 nm, approximately 60 of these compounds had inhibitory activity of less than 5 nm.

Test chemosensitization determines the degree to which the PARP inhibitor increases the effect of the destruction of tumor cells by cytotoxic drugs, expressed as PF50(the factor augmentation in GI50)]. 8000 LoVo cells were sown in each well of flat-bottomed tablet for micrometrology with 96 wells in a volume of 50 μl and incubated in F12K containing 10% (vol./about.) FBS (medium) overnight at 37°C. the cells were added to 50 μl of only medium, medium containing 2 μm of the inhibitor of PARP, medium containing increasing concentrations temosolomida (0-2000 μm), and medium containing 2 μm of the inhibitor of PARP and increasing concentration temosolomida (0-2000 μm). The final concentration range for temosolomida was 0-1000 μm, where applicable, the final concentration of PARP inhibitor was 1 μm, where applicable. The final concentration of the MCO was 1% in each well. The cells were allowed to grow for 5 days, after which the survival of cells was determined by staining CellTiter Glo (Promega, Madison, WI, USA). The growth of cells, determined after subtracting time values 0, expressed as a percentage of control wells containing medium with 1%DMSO.ValuesGI50(the concentration of drug that inhibited growth by 50%) was calculated from the produced by the computer curves (GraphPad Software, Inc, San Diego, California). Factor potentiation [PF50(the factor augmentationGI50)] was calculated as GI50only temosolomida/GI50temosolomida+PARP inhibitor. Reference: Thomas H,D. et al. (2007). Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial. Molecular Cancer Therapy 6, 945-956.

Most of the tested compounds had PF50more than 2X.

Research xenograft

In vivo animal antitumor efficacy

Females animicheskih mice nu/nu (8-10 weeks) were used for all studies xenograft in vivo. Mice were isolated for at least 1 week before experimental manipulation. Exponential growing cells or passaged in vivo tumor fragments were implanted subcutaneously in the right flank of Nude mice. Mice developed tumors randomized according to tumor size 6-8 mice/group in each study is AI (average tumor size ~150 mm 3). Mice were observed daily for survival, and tumors were measured twice a week in thickness in two dimensions and converted to tumor mass using the formula for an elongated ellipsoid (V=0,5×b2), where a and b are the long and the short diameters of the tumor, respectively, and assuming a density of one (1 mm3= 1 mg).

Activity is the only means: PARP inhibitors has been evaluated in xenografts Capan-1 and MX-1 in respect of the activity is the only means. Compounds were administered orally (p.o.), once a day for 28 days in medium consisting of 10% DMAc/6% Solutal/84% PBS, and the same medium was used as control. Mice were continuously checked for another 10 days after the last day of the injection.

The study combination: PARP-inhibiting compounds described herein, in a medium consisting of 10% DMAc/6% Solutal/84% PBS, either administered orally once a day for 5 days with temozolomide (17 mg/kg or 34 mg/kg, r.o., qdx5, 30 minutes after each injection of compounds) in xenograft models SW620, or administered orally, once daily for 8 days with 6 mg/kg cisplatin (once per day ip on day 3, 30 minutes after first dose of PARP inhibitors) in xenograft models MX-1. Mice were observed, and the individual tumor was measured within 30 days after the settlement is one of the introduction of PARP-inhibiting compounds.

In vivo animal study several powerful PARP-inhibiting compounds described in the Examples section, showed activity only tool in the growth of the tumor MX-I and Capan-1 when administered orally for 28 days. Several compounds, when combined with DNA-damaging agent by temozolomide significantly slowed down the development of tumors in the model SW620. In xenograft models of breast cancer MX-1, these compounds potentiate platinum drug Cisplatin, causing regression of established tumors, whereas when using comparable doses of cisplatin or PARP inhibitor individually, it was shown inhibition of tumor only in degree from mild to moderate.

BRCA2-deficient cells V-C8 or BRCA2-supplemented cells V-C8+B2

BRCA2-deficient cells V-C8 or BRCA2-supplemented cells V-C8+B2 implanted intramuscularly in the thigh 40 naked mice CD-1. Treatment was initiated when tumors reached a measurable size (the approximate diameter of the legs 11 mm). Animals received either a compound of Formula (I), (IA) or (II) (two doses of 25 or 50 mg/kg in saline)or saline (10 mg/ml) intraperitoneally injected on days 1-5, and they were checked daily for treatment (register tumor size, body weight and clinical signs); and as required after the last treatment.

ES tumor

ES cell tumors (teratoid tumors) received subcutaneous injection of 2×106cells ES atipicheskim naked mice BALB/c (nu/nu) at the age of 6-8 weeks. 40 mice were administered BRCA2-deficient ES cells or the isogenic wild-type cells. Two days after injection of cells started treatment a compound of Formula (I), (IA) or (II). For three consecutive days was introduced two intraperitoneal doses of the compounds of Formula (I), (IA) or (II) or media with an interval of 6 hours, each at a dose of 15 mg/kg per animal. This treatment was stopped for 5 days and then re-initiated for three consecutive days. Tumor growth was examined from a minimum amount of 0.2 cm3.

In vitro tests disclosed here, along with other well-known tests in vitro (Farmer et al, Nature 2005; 434:913-7: clonogenic survival assay finding that a BRCA2-deficient cell line V-C8, compared with the BRCA2 wild type control exhibited sensitivity to AG14361, a PARP-1 inhibitor, (Ki=5 nm) and NU1025, a moderately potent PARP-1 inhibitor (Ki=50 nM); & Mcabe et al, Cancer Biology &Therapy 2005; 4:9, 934-36; clonogenic survival assay using CAPAN-1 cells maintained in DMEM supplemented with FCS (20% v/v), glutamine and antibiotics showing sensitivity to PARP inhibition using KU0058684) demonstrate the activity of PARP inhibitors in the static test situation. Additionally, animal models used to analyze the dependence between tests in vitro and efficiency in vivo. Just as an example, Farmer et al. showed efficacy in vivo in blocking the growth of BRCA2-deficient about what wholey, using KU0058684, an inhibitor of PARP-1. Nature 2005; 434:913-7. This shows that inhibition of PARP-1 is the effective way of treating cancer for carriers of mutations in BRCA1/2. In addition, KU0059436, an inhibitor of PARP-1, is currently in Phase I clinical trials for patients with advanced solid tumors. Given this information, the compounds of Formula (I), (IA) or (II), which showed inhibitory effect in vitro, will probably show similar efficacy in vivo (mouse and human).

Phase II clinical trials the safety and efficacy of compounds of Formula (I), (IA) or (II)

The purpose of this phase II trial is studying the side effects and best dose of the compounds of Formula (I), (IA) or (II) and determining how well it works in treating patients with locally advanced or metastatic breast cancer or advanced ovarian cancer.

Purpose:

Primary:

A. to Determine the degree of response to the compound of Formula (I), (IA) or (II) in patients with locally advanced or metastatic breast cancer or advanced ovarian cancer who have demonstrated the expression of mutations in BRCA 1 or 2

B. to Evaluate the toxicity of the compounds of Formula (I), (IA) or (II) in these patients

Secondary:

A. to Estimate the time progression and overall survival in patients receiving treatment with the compounds is of Formula (I), (IA) or (II)

B. Study of the pharmacokinetics of the compounds of Formula (I), (IA) or (II) in these patients

C. to Assess the activity of poly(ADP-ribose)polymerase (PARP) in peripheral blood lymphocytes is heterozygous for BRCA 1 and 2 of the patient

Tertiary:

A. to Evaluate the expression of PARP, using quantitative immunological analyses by the method of Western blotting

B. to study the pharmacogenomics, including CYP2D6 and CYP3A5, transport proteins for drugs, and polymorphism in a gene encoding a direct enzyme PARP

C. to Analyze samples of the tumor biopsy (if possible) regarding the status of BRCA mutations, the activity of PARP and PARP expression

D. Analyze paraffin sections from the original diagnostic biopsy/operating procedures (if available) in respect of the status of the DNA repair enzyme, using immunohistochemical methods

E. Analyze cells derived from ascitic or pleural fluid (if available), in primary cell culture in relation to the function path repair of breaks in double-chain DNA

Patients: Acceptable patients are men and women 18 years and older

Criteria:

The characteristics of the disease:

- Histologically confirmed locally advanced or metastatic breast cancer or advanced cancer aicn the ka

- Must meet 1 of the following criteria:

Proven media known mutations of BRCA 1 or BRCA 2

Considered as very probable carrier of the mutation of BRCA 1 or 2 (score ≥20 on the Manchester criterion)

- No more than 3 prior chemotherapy regimens for patients with breast cancer or ovarian

More than 2 months since prior chemotherapy carboplatin or cisplatin for ovarian cancer

- Measurable disease, defined according to RECIST criteria and measurable by x-ray, CT-scan or NMR

Patients with bone disease should have another measurable disease for evaluation

Previously irradiated lesions cannot be used as measurable disease

- No known metastases to the brain

Not certain status hormone receptor

Characteristics of patients are:

Status characteristics WHO 0-1

- Life expectancy ≥12 weeks

- Not specified menopausal status

- Hemoglobin ≥9.0 g/DL

Absolute neutrophils ≥1500/mm3

- Platelet count ≥100000/mm3

The serum bilirubin ≤1.5 times above normal (ULN)

ALT or AST ≤2.5 times ULN (≤5 times ULN if due to tumor)

The glomerular filtration rate (GFR) ≥50 ml/min

Not pregnant and not lactating

The denier is the first test to determine pregnancy

- Fertile patients must use two effective forms of contraception (i.e., oral, injectable, or implantable hormonal contraception, intrauterine device, barrier method in the form of a condom plus spermicidal agent, or surgical sterilization) 4 weeks before (women), during, and for 6 months after (men and women) completion of study therapy

- Ability to contribute to the treatment and supervision

- The absence of benign systemic disease, including active uncontrolled infection

- No other concurrent malignancies except adequately treated carcinoma defined by biopsy in situ of the cervix, basal cell or squamous cell skin cancer or breast cancer or ovarian

Persons, survivors of cancer who underwent potentially healing therapy prior malignant process, have no symptoms of this disease for 5 years and are considered to have a low risk of recurrence, can participate in the study

- No active or unstable heart disease or history of myocardial infarction within the last 6 months

Patients with cardiovascular signs or symptoms should have the results MUGA scan or ahok is diagramme, and patients with left ventricular ejection fraction (LVEF) below the set limit of normal should be excluded

- No other condition which, in the opinion of the researcher, not allowing the patient to be a good candidate for this study

Previous competitive therapy:

- At least 4 weeks since prior radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy (6 weeks for nitrosomonas and mitomycin C)

- At least 4 weeks since prior surgery on the thoracic and/or abdominal cavity and recovery

Competitive radiation therapy to combat pain in the bones or skin lesions valid, but not within 5 days after the last dose of the investigational medicinal product

- Co-administration of bisphosphonates is valid if the dose is stable and the treatment was started at least 2 weeks prior to participation in the study

- Lack of unsolved problems of toxicity (CTCAE ≥ grade 1) from previous therapy (except alopecia)

- Lack of competitive anticancer therapy or medicines research

- Lack of competitive antibiotic tetracycline for long periods of time (short courses [5-7 days] for treatment in which eccii valid)

Study design: This study is a study of the rise doses, followed by open multifocused study. Patients are stratified according to tumor type (breast or ovarian) and mutation (BRCA 1 against BRCA 2). Patients receive the compound of Formula (I), (IA) or (II) (in one of several possible dosage) for 30 minutes once daily on days 1-5. Repeat the treatment every 21 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve stable or responding disease may receive additional courses of treatment at the discretion of the chief investigator or Drug Development Office (DDO). Patients periodically carry out blood sampling for studies of pharmacokinetics and pharmacodynamics. Samples analyzed for the quantitative determination of tumor marker (CA-125 or CA 15,3), plasma levels of the compounds of Formula (I), (IA) or (II) liquid chromatography/mass spectrometry/mass spectrometry, PARP activity and expression of protein PARP immunological analyses by the method of Western blotting. Paraffin embedded sections of the initial diagnostic biopsy is also necessary to collect and analyze in relation to the expression of PARP protein immunohistochemical methods. Pleural and ascitic fluid may be the way the Ana and analyzed for efficiency of repair of breaks in double-chain DNA immunohistochemical methods. Some patients also undergo biopsy of tumors, and the samples analyzed in relation to mutation BRCA 2, and the activity of PARP proven tests of PARP Western blot turns. After completion of study treatment, patients are followed-up for 28 days.

Primary results:

- The study of antitumor activity according to RECIST using tumor size, measured clinically or radiographically CT-scan, MRI, plain x-ray examination or other methods of visualization

The security profile

Secondary results:

The time progression and overall survival

Plasma levels of certain liquid chromatography/Mass spectrometry/Mass spectrometry

The activity of poly(ADP-ribose)polymerase (PARP), measured ex vivo using proven test

The expression of PARP using quantitative immunological analyses by the method of Western blotting

- Pharmacogenomics, including CYP2D6 and CYP3A5, transport proteins for drugs, and polymorphism in a gene encoding a directly enzymes PARP

Status of BRCA mutations, the activity and expression of PARP PARP in biopsy specimens of the tumor (if possible)

- The status of the DNA repair enzyme using immunohistochemical techniques in paraffin who's slices from the initial diagnostic biopsy/operating procedures (if available)

Function path break repair double-chain DNA in cells obtained from ascitic or pleural fluid (if available) for primary cell culture

1. The compound of Formula (I):

in which:
Y and Z, each independently selected from the group consisting of:
a) phenyl, if necessary substituted by 1 or 2 R6;
b) pyridine, imidazole, thiazole, furan, triazole, quinoline or imidazopyridine, if necessary substituted 1 R6;
c) a substituent independently selected from the group consisting of hydrogen, C1-C6the alkyl or piperidine;
R1, R2and R3each independently selected from the group consisting of hydrogen and halogen;
A and B, each independently, selected from hydrogen, OH, and C1-C6of alkyl;
RAand RBindependently selected from the group consisting of hydrogen, C1-C6the alkyl and C3-C8cycloalkyl; or
RAand RBtogether with the atom to which they are attached, form a 4-6-membered heterocycle, in case of need, having one additional heteroatom or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl) -, and-NCO(C1-C6-alkyl)-, and 6-membered heterocycle may be optionally substituted by one or two C1-C6alkyl gr is pami;
R4and R5each represent hydrogen; and
each R6selected from Br, Cl, F, I, C1-C6of alkyl, pyrrolidino, if necessary substituted by one C1-C6the alkyl, C1-C6alkoxy, halogen-(C1-C6of alkyl, hydroxy-C1-C6alkylene, -(NRARB)C1-C6alkylene and (NRARB)carbonyl; or
his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

2. The compound of Formula (II):

in which:
Y represents phenyl, thiazole, furan, imidazole, triazole or imidazopyridine, if necessary substituted by 1, 2 or 3 R6;
Z represents phenyl, if necessary substituted by 1 or 2 R6;
A and B, each independently, selected from hydrogen and C1-C6of alkyl;
each R6independently selected from Br, Cl, F, I, C1-C6of alkyl, pyrrolidino, if necessary substituted by one C1-C6the alkyl, C1-C6alkoxy, halogen-(C1-C6of alkyl, hydroxy-C1-C6alkylene, -(NRARB)C1-C6alkylene and (NRARB)carbonyl;
R2selected from hydrogen, Br, Cl, I and F;
RAand RBindependently selected from the group consisting of hydrogen, C1-C6the alkyl is C 3-C8cycloalkyl; or
RAand RBtogether with the atom to which they are attached, form a 4-6-membered heterocycle, in case of need, having one additional heteroatom or functional heterogroup selected from the group consisting of-O-, -NH, -N(C1-C6-alkyl) -, and-NCO(C1-C6-alkyl)-, and 6-membered heterocycle may be optionally substituted by one or two C1-C6alkyl groups; or
his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

3. The compound according to claim 1, in which Y denotes phenyl, substituted by 1 or 2 R6selected from Br, Cl, F and I; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

4. The compound according to claim 1, in which Y denotes phenyl, substituted by 1 or 2 R6selected from (NRARB)C1-C6alkylene and (NRARB)carbonyl; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

5. The compound according to claim 4, in which R6means (NRARB)C1-C6alkylen; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of the pharmaceutically acceptable salt.

6. The compound according to claim 5, in which C1-C6alkylene represents methylene; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

7. The compound according to claim 5, in which RAand RBdenote, each independently, hydrogen, C1-C6alkyl or C3-C6cycloalkyl; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

8. The connection according to claim 7, in which each C1-C6alkyl represents independently methyl or ethyl; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

9. The compound according to claim 4, in which (NRARB) denotes azetidin, pyrrolidine, piperidine or morpholine; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

10. The compound according to claim 1, in which R6denotes hydroxy-C1-C6alkylen; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

11. The compound according to claim 4, in which RAand RBtogether with the nitrogen to which they accession the s, form a 6-membered heterocycle having 1 additional heteroatom or functional heterogroup selected from the group consisting of-O-, -NH and-N(C1-C6of alkyl, individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

12. Connection by claim 11, in which the functional heterogroup represents-N(C1-C6alkyl); individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

13. The connection section 12, in which C1-C6alkyl represents methyl; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

14. The compound according to claim 1, in which Y represents a thiazole, furan, imidazole, triazole or imidazopyridine, if necessary substituted by 1 or 2 R6; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

15. The connection 14, in which Y denotes an imidazole or triazole group, each of which may be substituted by 1 or 2 R6; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of a pharmaceutically pickup the integral of salt.

16. The connection indicated in paragraph 15, in which the imidazole and triazole substituted C1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

17. The connection 14, in which Y denotes a furan or thiazole group, each of which may be substituted by 1 or 2 R6; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

18. The connection 17, in which the furan or thiazole substituted C1-C6the alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

19. The compound according to claim 1, in which Z represents phenyl, substituted by 1 or 2 R6selected from Br, Cl, F and I; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

20. The compound according to claim 1, in which Z represents phenyl, substituted by 1 or 2 R6selected from (NRARB)C1-C6alkylene and (NRARB)carbonyl; his individual isomer, with reasoner or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

21. Connection by claim 20, in which R6means (NRARB)C1-C6alkylen; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

22. Connection item 21, in which C1-C6alkylene represents methylene; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

23. Connection by claim 20, in which RAand RBdenote, each independently, hydrogen, C1-C6alkyl or C3-C8cycloalkyl; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

24. Connection item 23, in which C1-C6alkyl represents methyl; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

25. Connection by claim 20, in which RAand RBtogether with the nitrogen to which they are attached, form a 6-membered heterocycle, having 1 heteroatom or functional heterogroup selected from the group consisting of-O-, -NH and-N(C1-C6of alkyl, individual isomer, CTE is eaisier or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

26. Connection A.25, in which functional heterogroup represents-N(C1-C6alkyl); individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

27. Connection p, where C1-C6alkyl represents methyl; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

28. The compound according to claim 1, in which R2denotes hydrogen; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

29. The compound according to claim 1, in which R2selected from F, Cl, Br and I; his individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

30. A compound selected from the following compounds:
8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-bis(4-(methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-di(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-di(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-di(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-isopropyl-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-bis(3-((methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-(hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-bis(3-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(piperidine-3-yl)-8-(pyridin-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(piperidine-4-yl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-bis(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-(hydroxymethyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)8.9bn-dihydro-2-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(3-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(3-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-about the,
9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-phenyl-9-(thiazol-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-phenyl-8-(4-(piperazine-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-bis(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(1-ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-phenyl-9-(1-propyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-[4,3,2-de]phthalazine-3(7H)-he,
9-(1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(3-((diethylamino)methyl)phenyl)-8-(4-((diethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-phenyl-8-(pyridin-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-phenyl-8-(Pieper is DIN-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-phenyl-8-(pyridin-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-bis(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-bis(3-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(3-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(1-methyl-1H-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-forfinal)-9-methyl-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-forfinal)-9-(1,4,5-trimethyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,,2-de]phthalazine-3(7H)-he,
8-(4-forfinal)-9-(1-methyl-1H-1,2,3-triazole-4-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4,5-dimethyl-4H-1,2,4-triazole-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4,5-dimethyl-4H-1,2,4-triazole-3-yl)-8-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-chlorophenyl)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(1-methyl-1H-imidazol-2-yl)-8-(4-(trifluoromethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-forfinal)-9-(thiazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(1-ethyl-1H-imidazol-2-yl)-8-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((4-ethyl-3-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-forfinal)-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-forfinal)-8-(4-(piperazine-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-forfinal)-8-(4-((3-methylpiperazin-1-yl)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-forfinal)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-forfinal)-9-(4-methyl-4H-1,2,4-triazole-3-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-Digi the ro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-forfinal)-9-(1-methyl-1H-imidazo[4,5-C]pyridine-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
5-chloro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8,9-bis(4-((dimethylamino)methyl)phenyl)-5-fluoro-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((3,4-dimethylpiperazine-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((3,5-dimethylpiperazine-1-yl)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-phenyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(1-methyl-1H-imidazol-2-yl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-forfinal)-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-forfinal)-8-(quinoline-6-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
8-(4-(dimethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-methoxyphenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((diethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-(diethylamino)methyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-chlorophenyl)-8-(4-((diethylamino)methyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
5-fluoro-9-(4-forfinal)-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-ethylphenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-isopropylphenyl)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((dimethylamino)methyl)phenyl)-9-(4-(trifluoromethyl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-((diethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-forfinal)-8-(4-(1-methylpyrrolidine-2-yl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-forfinal)-8-(4-(pyrrolidin-2-yl)phenyl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
8-(4-forfinal)-9-methyl-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-forfinal)-8-(1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he,
9-(4-forfinal)-9-hydroxy-8-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-he,
8-(4-(azetidin-1-ylmethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he, and
5-fluoro-8-((1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
or an individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of f is matemticas acceptable salt.

31. A compound selected from the following compounds:
(8R,9S)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
(8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
(8R,9S)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
(8S,9R)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
(8R,9S)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
(8S,9R)-5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-imidazol-2-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
(8R,9S)-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
(8S,9R)-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
(8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
(8R,9S)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he; and
(8S,9R)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-forfinal)8.9bn-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-he;
or its pharmaceutically acceptable salt.

32. Connection item 30, having the name 5-fluoro-8-(4-forfinal)-9-(1-methyl-1H-1,2,4-triazole-5-yl) - 8.9bn-dihydro-2H-pyrid the[4,3,2-de]phthalazine-3(7H)-he or an individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

33. The compound according to claim 1, in which Y and Z, each independently selected from the group consisting of
a) phenyl, if necessary substituted by 1 or 2 R6;
b) imidazole, if necessary substituted 1 R6;
or an individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

34. The compound according to claim 1, in which Y and Z, each independently selected from the group consisting of
a) phenyl, if necessary substituted by 1 or 2 R6;
b) triazole, if necessary substituted 1 R6;
or an individual isomer, a stereoisomer, or enantiomer, or a mixture thereof, if necessary in the form of pharmaceutically acceptable salts.

35. Pharmaceutical composition comprising a compound according to any one of claims 1 to 34 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, excipient, binder or diluent, for use in the treatment of a patient, which requires inhibition of PARP.

36. A method of treating diseases, facilitated by PARP inhibition, comprising the administration to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 34 or the pharmaceutical to the notizie on p, in which the disease is selected from the group consisting of: vascular disease; septic shock; ischaemic injury; reperfusion injury; neurotoxicity; hemorrhagic shock; inflammatory diseases; multiple sclerosis; secondary effects of diabetes and acute treatment of cytotoxicity after cardiovascular surgery.

37. A method of treating cancer, comprising the administration to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 34 or the pharmaceutical composition according p.

38. The method according to clause 37, in which the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, prostate cancer, pancreatic cancer, hematologic cancer, leukemia, colorectal cancer, colon cancer, glioblastoma, lymphoma and melanoma.

39. The method according to clause 37, in which cancer when there is a shortage of dependent homologous recombination (HR) pathways repair breaks double DNA strand breaks (DSB), and cancer includes one or more cancer cells having a reduced or abrogated ability to recover DNA DSB by HR relative to normal cells and cancer cells have a BRCA1 or BRCA2 deficient phenotype; or cancer includes one or more cancer cells, deficient in respect of the proteins involved in the recovery of DNA DSB by HR, and cancers the e cells detect the deficiency of ATM, Rad51, Rad52, Rad54, Rad50, MRE11, NBS1, XRCC2, XRCC3, cABL, RPA, CtIP and MVS and the patient is heterozygous in respect of mutations of the gene encoding the path component repair DNA DSB by HR, where the mutation is a mutation in BRCA1 and/or BRCA2.

40. The method according to § 39, in which cancer when there is a shortage of ways to repair DNA mismatches, and cancer cells detect the deficit MutS, MutH and MutL.

41. The method according to § 39, in which the cancer shows microsatellite or genomic instability due to reduced or weakened pathways of DNA repair.

42. Industrial product comprising packaging material, a compound according to any one of claims 1 to 34 and the label, and the compound is effective for modulating the activity of the enzyme poly(ADP-ribose)polymerase, or for treatment, prevention and / or alleviate one or more symptoms of a poly(ADP-ribose)polymerase-dependent or poly(ADP-ribose)polymerase-mediated disease or condition in which the compound is packaged within the packaging material, and in which the label indicates that the compound or its pharmaceutically acceptable salt, or a pharmaceutical composition according to § 38, including such connection, used for the modulation of the activity of poly(ADP-ribose)polymerase, or for treatment, prevention and / or alleviate one or more symptoms of a poly(ADP-ribose)polymerase-chief of the independent or poly(ADP-ribose)polymerase-mediated disease or condition.

43. A method of treating cancer, comprising the administration to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 34 or the pharmaceutical composition according p in combination with ionizing radiation, one or more chemotherapeutics or their combination.

44. The method according to item 43, in which the compound is used in combination with one or more chemotherapeutics, each chemotherapeutic agent is independently selected from the group consisting of alemtuzumab, arsenic trioxide, Paglierani asparaginase, not-Paglierani asparaginase, bevacizumab, cetuximab, cisplatin, cladribine, daunorubicin/doxorubicin/idarubitsina, irinotecan, fludarabine, 5-fluorouracil inside the body, gemtuzumab, methotrexate, paclitaxel, Taxol, temosolomida, Tg, similar anti-estrogenic hormone analogue antiandrogenna hormone or analogue of gonadotropin-releasing hormone, alpha-interferon, busulfan, melphalan, mechlorethamine, tretinoin, irinotecan, topotecan, gefinitib, imatinib, allopurinol, filgrastim, granisetron/ondansetron/palonosetron and dronabinol.

45. The method according to item 43, in which the compound is used in combination with one or more chemotherapeutics, each chemotherapeutic agent independently represents the Oh alkylating agents or topoisomerase inhibitor-1.

46. The method according to item 45, in which the compound is used in combination with one or more chemotherapeutics, each chemotherapeutic agent is independently selected from the group consisting of methylmethanesulfonate, temosolomida, dacarbazine (DTIC), topotecan, irinotecan, rubitecan, Ekaterina, lurtotecan, gimatecan, diflomotecan (homogeneities), 7-substituted non-siltcoos; 7-silyl of camptothecin, BNP 1350 and XR 11576/576 MLN.

47. The method according to item 43, in which the compound is used in combination with a chemotherapeutic agent, and the chemotherapeutic agent is an irinotecan, cisplatin or temozolomide.

48. A method of obtaining a compound according to claim 1, including
a) reaction of the intermediate of formula 3

in which R denotes alkyl, with hydrazine; and
b) if necessary, the separation of the individual isomers.

49. The compound of formula 3

in which:
R represents C1-C6alkyl;
Y and Z, each independently selected from the group consisting of:
a) phenyl, if necessary substituted 1 R6;
b) pyridine, imidazole, thiazole, furan, triazole, quinoline or imidazopyridine, if necessary substituted by 1, 2 or 3 R6;
c) a substituent independently selected from the group sotoyama is made of hydrogen and C 1-C6of alkyl;
and
R1, R2and R3each independently selected from the group consisting of hydrogen and halogen;
RAand RBindependently represent C1-C6alkyl; or RAand RBtogether with the atom to which they are attached, form a 5-6-membered heterocycle, if necessary, with one additional functional heterogroup selected from the group consisting of-N(C1-C6-alkyl)-, -NCO(C1-C6-alkyl)- and-N(aryl-C1-C6-alkyl-)-;
R5denotes hydrogen; and
each R6independently selected from the group consisting of F, C1-C6of alkyl, C1-C6alkoxy, CI-C1-C6alkoxy-C1-C6of alkyl, phenylalkyl, Halogens1-C6of alkyl, (NRARB)C1-C6alkylene and (NRARB)carbonyl;
or its salt.

50. Connection § 49, selected from the group consisting of the following compounds:
4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2,3-bis(4-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2,3-bis(4-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-then it is carbonated shall rhinolin-5-ethylcarboxylate;
4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
4-oxo-2,3-di(pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
4-oxo-2,3-di(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(3-(diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(4-(diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
3-(4-(diethoxylate)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2,3-bis(3-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-(diethoxylate)phenyl)-3-(4-(4-isobutylpyrazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2-(3-(diethoxylate)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetr hydrochinon-5-methylcarbamoyl;
2-(3-(diethoxylate)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
3-(3-(4-isobutyryl piperazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
7-fluoro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
7-fluoro-2-(4-forfinal)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2-(4-(diethoxylate)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(1-benzyl-4-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
4-oxo-2-phenyl-3-(thiazol-5-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(1-benzyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
3-(1-ethyl-1H-imidazol-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
4-oxo-2-phenyl-3-(1-propyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(1-methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
4-oxo-3-phenyl-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2-(4-(dimethoxymethyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2-(4-(dimethoxymethyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2,3-bis-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2-(4-forfinal)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-methylcarbamoyl;
2,3-bis(3-(diethoxylate)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-(diethoxylate)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
7-fluoro-2-(4-forfinal)-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-((dimethylamino)methyl)phenyl)-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-FPO is phenyl)-4-oxo-3-(1,4,5-trimethyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-forfinal)-3-(1-methyl-1H-1,2,3-triazole-4-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-(dimethylcarbamoyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(4,5-dimethyl-4H-1,2,4-triazole-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(4,5-dimethyl-4H-1,2,4-triazole-3-yl)-2-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(3-(dimethylcarbamoyl)-4-forfinal)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-forfinal)-4-oxo-3-(thiazol-2-yl)-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(1-ethyl-1H-imidazol-2-yl)-2-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-(dimethylcarbamoyl)phenyl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-(diethoxylate)phenyl)-3-(4-(dimethylcarbamoyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(4-(dimethylcarbamoyl)phenyl)-2-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-forfinal)-3-(4-methyl-4H-1,2,4-triazole-3-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-forfinal)-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-shall terphenyl)-3-(1-methyl-1H-imidazo[4,5-c]pyridine-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
7-chloro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2,3-bis(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(4-forfinal)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(4-chlorophenyl)-2-(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-((dimethylamino)methyl)phenyl)-3-(4-methoxyphenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(4-chlorophenyl)-2-(4-((diethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
7-fluoro-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
7-fluoro-3-(4-forfinal)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-((dimethylamino)methyl)phenyl)-3-(4-ethylphenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-((dimethylamino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-Etiler is kilat;
2-(4-((diethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
3-(4-forfinal)-2-(4-(1-methylpyrrolidine-2-yl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
2-(1-benzyl-1H-imidazol-2-yl)-3-(4-forfinal)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate;
7-fluoro-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate; and
2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(1-methyl-1H-1,2,4-triazole-5-yl)-4-oxo-1,2,3,4-tetrahydroquinolin-5-ethylcarboxylate.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of structural formula I that possess inhibitory activity on phosphatidyl inositol-3-kinase (PI3-kinase). In formula I: B represents group of formula II:, wherein Wc represents 6-10-merous aryl, q is equal to 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, z is equal to 1; Y represents -N(R9)-; Wd represents R1 and R2 represents C1-6alkyl or halogeno; R3 represents hydrogen or C1-6alkyl; and in each case R9 independently represents hydrogen or C1-6alkyl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method for P3I-kinase inhibition in a subject, wherein the subject suffers a disease representing cancer, a bone disorder, an inflammatory disease, an immune disease, a nervous system disease, a metabolic disease, a respiratory disease, thrombosis or a cardiovascular disease.

24 cl, 11 dwg, 6 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula (I) or its pharmaceutically acceptable salt, where A stands for -CHR7-, where R7 represents hydrogen, C1-6 alkyl, optionally substituted with substituent, selected from -OH, -OR8, where R8 represents C1-6 alkyl, -NH2, -COOH and -CONH2, C6 aryl-C1 alkyl, optionally substituted with 1-3 substituents, selected from-OH, -OP(=O)(OH)2, -OP(=O)(ONa)2 and C1-6 alkyl, 5-9-member heteroaryl- C1 alkyl, C6 cycloalkyl-C1 alkyl, C6 aryl or C6 cycloalkyl; G stands for -NR6- or -O-, where R6 is independently selected from C1-6 alkyl and C2-6 alkenyl; R1 stands for -Ra-R10; where Ra stands for C1-6 alkylene and R10 represents naphthyl or 9-10-member bicyclic condensed heteroaryl, optionally substituted with substituent selected from -NH2 and halogen; R2 represents -W21-W22-Rb-R20, where W21 represents -(CO)-; W22 represents -O- or -NH-; Rb represents bond or C1-6 alkylene, optionally substituted with C1-6 alkyl; and R20 represents C1-6 alkyl, C6-10 aryl, optionally substituted woth halogen, 5-6-member heteroaryl or C6 cycloalkyl; and R3 represents C1-6 alkyl; where "heteroaryl" represents monocyclic or bicyclic aromatic radical, where 1-3 ring atoms are heteroatoms, selected from nitrogen, oxygen and sulphur, and remaining ring atoms are carbon atoms and "bicyclic condensed" means ring, bound with another ring with formation of bicyclic structure, when atoms, common for both rings, are directly bound to each other. Invention also relates to particular compounds, method of treating or preventing disorder, modulated by Wnt-signaling pathway, agent, based on (I) formula compound, intermediate compound of formula (II) , method of obtaining formula (I) compound.

EFFECT: obtained are compounds, represented by formula (I), which possess useful biological properties.

32 cl, 3 dwg, 2 tbl, 209 ex

FIELD: chemistry.

SUBSTANCE: described are novel alkyl cyclohexyl esters of 5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene derivatives of formula I where R is C1-8-alkyl, optionally substituted with a halogen, hydroxy or C1-12-alkoxy, CF3, C3-7-cycloalkyl, a 4-6-member heterocycloalkyl containing one O, R is H, C1-8-alkyl, optionally substituted with OH, -(CH2)q-Ra, where Ra is a 6-member heteroaryl containing one N, -C(O)-C1-8-alkyl, where the alkyl is optionally substituted with OH, -C(O)(CH2)qOC(O)-C1-8-alkyl, -C(O)O-C1-8-alkyl, -S(O)2-C1-8-alkyl or -S(O)2NRiRii, where Ri and Rii are identical and denote C1-8-alkyl, q=1, R3 is Cl or F, and a pharmaceutical composition containing said compounds.

EFFECT: compounds are V1a receptor antagonists and can be used in medicine.

15 cl, 69 ex, 3 tbl

FIELD: biotechnologies.

SUBSTANCE: invention refers to a method for obtaining [1S-[1α,2α,3β(1S*,2R*),5β]]-3-[7-[2-(3,4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol of formula (I) .

EFFECT: improving yield of the compound of the formula and its high quality when recrystallisation is not available.

5 cl, 1 tbl, 10 ex

FIELD: biotechnologies.

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

,

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

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

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: described are novel arylcyclohexyl esters of 5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene derivatives of formula I where R1 is phenyl, optionally substituted with cyano, C1-7-alkyl, halogen-C1-7-alkyl, C1-7-alkoxy or halogen; naphthyl, pyrazinyl or pyridazinyl; pyridinyl, optionally substituted with halogen or C1-7-alkyl, pyrimidinyl, optionally substituted with C1-7-alkyl, R2 is H, C1-8-alkyl, optionally substituted with OH or halogen, -(CH2)q-Ra, where Ra is a 6-member heteroaryl containing one N as a heteroatom, -C(O)-C1-8-alkyl, -C(O)(CH2)qNRiRii, -C(O)O-C1-8-alkyl, -S(O)2-C1-8alkyl, -S(O)2NRiRii, where Ri and Rii are identical and denote C1-8-alkyl; q =1, R3 is Cl or F, pharmaceutically acceptable salts thereof and a pharmaceutical composition containing said compounds.

EFFECT: present compounds are V1a receptor antagonists and can be used in medicine.

21 cl, 111 ex, 10 tbl

Antiviral compounds // 2505540

FIELD: biotechnologies.

SUBSTANCE: invention pertains to new compounds that have the properties of HCV virus replication inhibitor. In expression I: , A1 is C6aryl, substituted by -X1-R7; X1 is -S-; R7 is C6aryl, not necessarily substituted by one RA; Z1 is -N(RB)-; each of W1 and W2 is N; R1 is hydrogen; R3 and R4 together with carbon atoms, to which they are connected, form 6-member heterocyclic ring containing N as heteroatom, where 6-member heterocyclic ring is not necessary substituted by one RA; A2 represents C6aryl or 5-member heterocyclyl containing N as heteroatom; R2 represents -N(Rb)C(O)C(R5R6)N(R8)-T-Rd, or -LK-B; R6 and R8 together with atoms, to which they are connected, form 5-member heterocyclic ring; the values of radicals RA, R5, T, RC, RD, RD' and RD", LK, B are given in the invention's expression. Invention also pertains to pharmaceutical composition containing the said compounds, method for inhibiting HCV virus replication, method for HCV infection curing and method for obtaining the said compounds.

EFFECT: improving compound application efficiency.

25 cl, 6 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of novel pyrrolopyrazine derivatives of formula , where variables Q and R are as defined in the claim, which inhibit JAK and SYK.

EFFECT: high effectiveness when treating autoimmune and inflammatory diseases.

11 cl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-[5-(3-dimethylamino-acryloyl)-2-fluorophenyl]-N-methylacetamide of formula (I). The method is realised by reacting N-(5-acetyl-2-fluorophenyl)-N-methylacetamide of formula (VI) with excess N,N-dimethylformamide dimethylacetal (NNDMF-DMA) in the presence of a nonpolar solvent at temperature of 70-90°C. The invention discloses a method of producing a N-{2-fluoro-5-[3-(thiophene)-2-carbonyl-pyrazolo[1,5-a]pyrimidin-7-yl]phenyl}-N-methylacetamide compound of formula (II), which involves methylation of N-(5-acetyl-2-fluorophenyl)-acetamide at temperature of 15-50°C, reacting the obtained compound of formula (VI) with NNDMF-DMA, and reacting the obtained compound of formula (I) with (5-amino-1H-pyrazol-4-yl)thiophen-2-yl-methanone in glacial acetic acid at temperature of 60-90°C in the presence of an aliphatic alcohol. The invention also relates to an intermediate compound of formula (VI).

EFFECT: improved method of producing a compound which is an intermediate compound in synthesis of compounds with affinity for the GABAA receptor.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to naphthalene carboxamide derivatives of general formula I which possess the properties of protein kinase or histone deacetylase inhibitors. The compounds can find application for preparing a drug for treating inflammatory diseases, autoimmune diseases, oncological disease, diseases of the nervous system and neurodegenerative diseases, allergies, asthma, cardiovascular diseases and metabolic diseases or disease related to hormonal diseases. In general formula I: , Z represents CH or N; each of the groups R1, R2 and R3 represents hydrogen, halogen, alkyl, alkoxy or trifluoromethyl; R4 represents or X represents a benzene ring or a pyridine ring; R5 represents one or more substitutes specified in a group consisting of hydrogen, halogen, alkyl, alkoxy or trifluoromethyl. The invention also refers to a method for preparing the above compounds, a pharmaceutical preparation and using them.

EFFECT: preparing the compounds which possess the properties of protein kinase or histone deacetylase inhibitors.

13 cl, 10 tbl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).

EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.

11 cl, 1 tbl, 104 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives with anticancer activity of formulae:

, , , , ,

R2', R3', R4', R5' and R6' are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9; Y is selected from O and S; X is selected from F, Cl and Br; R8 and R9 are selected from (CH2)nCH3; R2, R3, R4 and R5 are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9, or R3 and R4 together form -Y(CH2)nY-; R1 and R1' are selected from H, Li+, Na+, K+, N+R8R9R10R11 or benzyl, where R10 and R11 are selected from H, (CH2)nYH, (CH2)nN(CnH2n+1)(CmH2m+1) or (CH2)nCH3, where n and m are integers from 0 to 4, q is an integer from 1 to 4.

EFFECT: obtaining novel compounds with anticancer activity.

37 cl, 3 dwg, 10 ex, 2 tbl

The invention relates to the technology of known derivatives hinolincarbonova acid, in particular to a method for producing derivatives of 3-hinolincarbonova acid

The invention relates to new derivatives of 5-amino-8-methyl-7-pyrrolidineethanol-3-carboxylic acids and their stereoisomers and their pharmacologically acceptable salts, have excellent antibacterial activity, and to methods for their preparation

The invention relates to a new method of obtaining quinoline-carboxylic acids and their derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), having affinity to the µ-opioid receptor and the to the ORL1 receptor, a medicinal agent containing said compounds and use thereof to obtain a medicinal agent for treating pain and other diseases. In general formula (1), Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' denote -H; R1 and R2 independently denote -CH3; R3 denotes R0, where R0 denotes C1-8-alkyl; aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR0, where R0 denotes -C1-3-alkyl; unsubstituted heteroaryl, selected from a 5-member heteroaryl with one S atom as a heteroatom; R4 denotes R0, where R0 denotes aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR0, where R0 denotes -C1-3-alkyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, mono-substituted with -S(O)2-phenyl; unsubstituted -dihydroisoindolyl or unsubstituted -indolyl; or R4 denotes -OR0 or -SR0, where R0 denotes a cycloaliphatic group selected from -C5-6-cycloalkyl; aryl, selected from unsubstituted phenyl; C1-2-alkylaryl, where aryl denotes phenyl, which is unsubstituted or mono-substituted with -OR0, where R0 denotes -C1-3-alkyl; and R5 denotes -H or -CH3.

EFFECT: obtaining a medicinal agent for treating pain and other diseases.

7 cl, 3 tbl, 22 ex

Up!