Condensed tricyclic derivatives for treating psychotic disorders

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula pharmaceutically acceptable salts thereof, where ---- independently denotes a single or double bond; ring Q is imidazole, triazole (for example 1,2,3-triazole or 1,3,4-triazole), tetrazole or oxadiazole; B denotes C(R7)(R8) or C(R7), where if the bond between B and Y is a single bond, B denotes C(R7)(R8), and when the bond between B and Y is a double bond, B denotes C(R7); Y denotes C(R7), C(R7)(R8) or O, where if the bond between B and Y is a single bond, Y denotes C(R7)(R8) or O, and when the bond between B and Y is a double bond, B denotes C(R7); Z1 denotes -CH2-, -(CH2)2-, -CH2CH-CH3-, where Z1 is bonded on the left side to a nitrogen atom or -(CH2)3-; X denotes C(R1) or N; A denotes quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substitutes, which can be identical or different and are selected from a group comprising halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C(O)N(R3)(R4), 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; when R is present, each independently denotes halogen, C1-6-alkyl; each R1 denotes hydrogen or methyl; each R2 denotes cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5)R6, -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; R3 and R4 independently denote hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3 and R4 are bonded to the same nitrogen atom, they, together with the nitrogen atom, they form a 4-, 5- or 6-member ring which optionally contains one extra O atom in the ring; R5 denotes C1-4-alkyl; R6 denotes C3-7-cycloalkyl or C1-6-alkyl; R7 and R8 independently denote hydrogen or C1-6-alkyl; p equals 0, 1 or 2; r equals 0, 1, 2 or 3; s equals 0, 1, 2 or 3. The invention also relates to 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide, 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide, dihydrochloride 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide, 7-methyl-6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide, to use of the compound in any of claims 1-16, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 5-HT1 receptor mediated activity.

23 cl, 195 ex

 

The present invention relates to new tricyclic condensed derivatives, processes for their preparation, pharmaceutical compositions containing such compounds, and their use as medicines, inter alia, for the treatment of psychotic disorders, depressive disorders, anxiety disorders, and sexual dysfunction.

In WO 2004/046124 reveals a number benzoxazinone - compounds with affinity for the receptor type 5-HT1and/or having the activity of inhibiting re-uptake of serotonin.

A new series of compounds with high affinity to the receptor type 5-HT1and/or which are inhibitors of reuptake of serotonin.

In the first aspect of the invention relates to the compound of formula (I)

its salt or prodrug,

where

---- represents, independently, a single or double bond;

cycle Q represents a 5-membered heteroaromatic cycle or a 5-membered heterocyclic ring, each of which contains at least one nitrogen atom in the cycle, as shown in the formula (I), and optionally 1-3 additional heteroatoms in the cycle, is selected independently from oxygen, nitrogen and sulfur;

Represents a C(R7)(R8) or C(R7), where in the case when the bond connecting b and Y, assuming yet a simple link, Represents a C(R7)(R8), and when the bond connecting b and Y is a double bond, A is a C(R7);

Y is C(R7), C(R7)(R8), Or S(O)twhere in the case when the bond connecting b and Y represents a simple bond, Y is C(R7)(R8), Or S(O)tand when the bond connecting b and Y is a double bond, A is a C(R7);

Z1is a linker group of formula (A)

where

W represents -(CH=CH)-; -C(=O)-; -C(=CH2)-; -C(R7)(R8)-; -C(R7)(R8)-S(O)t-; -C(R7)(R8)-O -, or a 3-7-membered cycloalkenyl group or a 3-7-membered cycloalkenyl group, any of which optionally is substituted by 1-3 substituents, which may be the same or different, selected from halogen, hydroxy, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C1-6alkanoyl and C1-6-alkoxy; and

n and m is, independently, 0, 1, or 2;

X represents C(R1), N, or S; where when indicated by the dotted line connection attached to X represents a simple bond, X represents C(R1or N, and when indicated by the dotted line connection attached to X is a double bond, X before the hat is S;

And represents indolyl, hinely, hintline, benzofuranyl or sensational, any of which is optionally substituted by 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, hydroxy, cyano, nitro, C1-6-alkyl, halogen-C1-6-alkyl, C3-7-cycloalkyl, aryl-C1-6-alkoxy, C1-6-alkylthio,1-6-alkoxy, halogen-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-4-alkoxy, C2-6-alkenyl,3-6-quinil, halogen-C2-6-alkenyl, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -S(O)2N(R3)(R4), -N(R3)(R4), -C(NOR5R6, -N(R3)C(O)(R6), -N(R3)S(O)2(R6), -C(O)R6, -C(O)OR7, heterocyclic ring, Arora and aryl; where the group of heterocyclic ring, aroyl and aryl optionally substituted with one, two or three substituents selected, independently, from the group consisting of halogen, hydroxy, cyano, nitro, amino, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy and halogen-C1-6-alkoxy;

when R is present, each represents, independently, halogen, C1-6-alkyl, cyano, halogen-C1-6-alkyl, C1-6-alkanoyl,1-6-alkoxy, hydroxy or triptoreline;

each R1 represents hydrogen, halogen, C1-6-alkyl, cyano, halogen-C1-6-alkyl, C1-6-alkanoyl,1-6-alkoxy, hydroxy or1-6-alkoxy-C1-6-alkyl;

each R2represents hydrogen, halogen, hydroxy, cyano, nitro, C1-6-alkyl, halogen-C1-6-alkyl, C3-7-cycloalkyl, aryl-C1-6-alkoxy, C1-6-alkylthio,1-6-alkoxy, halogen-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-4-alkoxy, C2-6alkenyl,3-6-quinil, halogen-C2-6alkenyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -S(O)2N(R3)(R4), -N(R3)(R4), -C(NOR5R6, --N(R3)C(O)(R6), -N(R3)S(O)2(R6), -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, heterocyclic ring, aroyl or aryl; where the group of heterocyclic ring, aroyl or aryl optionally substituted with one, two or three substituents selected, independently, from the group consisting of halogen, hydroxy, cyano, nitro, amino, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy and halogen-C1-6-alkoxy;

R3and R4represent, independently, hydrogen; C1-6-alkyl; aryl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3and R4connected to the same nitrogen atom, together with the Ohm nitrogen form a 4-, 5-, 6 - or 7-membered cycle, optionally containing one additional atom of O, N or S in the loop;

R5represents a C1-4-alkyl, C3-7-cycloalkyl-C1-6-alkyl or C3-7-cycloalkyl;

R6represents hydrogen, halogen, cyano, C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl or1-6-alkyl;

R7and R8represent, independently, hydrogen, C1-6-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-6-alkyl or halogen-C1-6-alkyl;

R9and R10represent, independently, hydrogen, C1-6-alkyl, cyano, halogen-C1-6-alkyl, C1-6-alkanoyl,1-6-alkoxy, hydroxyl, halogen or1-6-alkoxy-C1-6-alkyl;

p is 0, 1 or 2;

r is 0, 1, 2 or 3;

s is 0, 1, 2 or 3; and

t is 0, 1 or 2.

The term "5-membered heteroaromatic cycle" denotes a 5-membered aromatic cycle containing at least one nitrogen atom in the cycle and, optionally, contains at cycle advanced 1-3 heteroatoms selected from oxygen, nitrogen and sulfur. Examples of 5-membered heteroaromatic cycles are pyrrole, imidazole, pyrazole, triazole, oxadiazole and tetrazole.

The term "5-membered heterocyclic ring" means a 5-membered heterocyclic ring, partially or fully saturated, i.e. near the case, containing at least one nitrogen atom in the cycle and, optionally, contains at cycle advanced 1-3 heteroatoms selected from oxygen, nitrogen and sulfur. Examples of such cycles, which are partially saturated, include oxazoline, isoxazoline, imidazolin, pyrrolin and pyrazolin. Examples of such cycles that are fully saturated, include pyrrolidine, imidazolidine and oxadiazolyl.

The term "heterocyclic ring" means a 5 - or 6-membered single-cycle, partially or fully saturated, where up to 5 carbon atoms are replaced by heteroatoms, selected independently from O, S and N. Examples of heterocyclic rings, which are fully saturated 5 - or 6-membered mononuclear cycles are pyrrolidine, imidazolidine, pyrazolidine, tetrahydrofuran, dioxolane, piperidine, piperazine, morpholine, thiomorpholine, tetrahydrothiophene, dioxane, tetrahydro-2H-Piran and Titian. Examples of heterocyclic rings which are partially saturated 5 - or 6-membered mononuclear cycles are oxazoline, isoxazoline, imidazolin, pyrazoline, 1,2,3,6-tetrahydropyridine and 3,6-dihydro-2H-Piran.

The term "aryl", as an independent or as part of another group, is intended, unless otherwise specified, to refer to an aromatic carbocyclic ring or a heteroaromatic cycle. Por the measures of aryl groups are phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxadiazolyl, isothiazolin, oxazolyl, thiazolyl, triazinyl, furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, azepines and naphthyl.

The term "C1-6-alkyl", as an independent or as part of another group, is intended to denote alkyl groups with one to six carbon atoms in all isomeric forms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.

The term "halogen" is used in this description to describe, unless otherwise stated, the groups selected from fluorine, chlorine, bromine and iodine.

The term "halogen-C1-6-alkyl" denotes a1-6is an alkyl group which is substituted by one or more halogen, such as CF3.

The term "C1-6-alkanoyl" means alkanoyloxy group with 1-6 carbon atoms, such as methanol (or "formyl"), ethanol (or "acetyl"), propanol, butanol, pentanol and hexanol.

The term "C1-6-alkoxy" denotes a linear or branched alkoxy group (or "alkyloxy") with one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, neopentane, sec-pentox, n-pentox, isobutoxy, tert-pentox, hexyloxy.

The term "3-7-membered cycloalkene the Vaya group" refers to cycloalkenyl groups having 3-7 carbon atoms, such as cyclohexene.

The term "3-7-membered cycloalkenyl group" refers to cycloalkenyl groups having 3-7 carbon atoms, such as cyclohexenyl.

The term "C1-6-alkylthio" denotes a linear or branched alkylthiols with one to six carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio, neopentyl, sec-pentylthio, n-pentylthio, isopentyl, tert-pentylthio and hexylthio.

The term "aryl-C1-6-alkoxy" refers to an aryl group connected with1-6-alkoxygroup. Examples include phenylmethoxy, venlafaxi, aftermarket, naftiliaki, phenylpropoxy, naftemporiki, phenylmethoxy, naftiliaki.

The term "C3-7-cycloalkyl" refers to cycloalkyl the group consisting of 3-7 carbon atoms, such as cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane and Cycloheptane.

The term "aroyl" refers to a group of the formula aryl -, where aryl has the values listed above.

The term "C2-6alkenyl" refers to an unsaturated hydrocarbon group containing one or more carbon-carbon double bonds, with two to six carbon atoms in all isomeric forms, such as ethynyl, propenyl, butenyl, pentenyl and hexenyl.

The term "C2-6-quinil" refers to the unsaturated hydrocarbon group, containing one or more carbon-carbon triple links, with two to six carbon atoms in all isomeric forms, such as PROPYNYL, butylidene, pentenyl and Pantelidis.

In one embodiment of the loop Q is an imidazole, triazole (e.g., 1,2,3-triazole or 1,3,4-triazole) or tetrazol. In another embodiment of the loop Q is an imidazole.

In one embodiment Y is C(R7), C(R7)(R8) or, in the case where, when the bond connecting b and Y represents a simple bond, Y is C(R7)(R8or Oh, and when the bond connecting b and Y is a double bond, A is a C(R7). In another embodiment, when Y is C(R7), C(R7)(R8or Oh, R7and R8represent, independently, hydrogen or C1-6-alkyl (in particular methyl or ethyl). In another embodiment R7and R8represent hydrogen.

In one embodiment of the Z1represents-CH2-, -(CH2)2-, -CH2CH(CH3)- (left side Z1attached to the nitrogen atom) or -(CH2)3-. In another embodiment Z1represents -(CH2)2-.

In one embodiment X represents C(R1or N. In another embodiment, when X represents C(R1), R1/sup> represents hydrogen, halogen or1-6-alkyl (such as methyl or ethyl). In another embodiment R1represents hydrogen or methyl. In another embodiment X represents N or CH.

In one embodiment And is finalyl or hintline, any of which is optionally substituted by 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, hydroxy, cyano, nitro, C1-6-alkyl, halogen-C1-6-alkyl, C3-7-cycloalkyl, aryl-C1-6-alkoxy, C1-6-alkylthio,1-6-alkoxy, halogen-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-4-alkoxy, C2-6-alkenyl,3-6-quinil, halogen-C2-6-alkenyl, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -S(O)2N(R3)(R4), -N(R3)(R4), -C(NOR5R6, -N(R3)C(O)(R6), -N(R3)S(O)2(R6), -C(O)R6, -C(O)OR7, heterocyclic ring, Arora and aryl; where the group of heterocyclic ring, aroyl and aryl optionally substituted with one, two or three substituents selected, independently, from the group consisting of halogen, hydroxy, cyano, nitro, amino, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy and halogen-C1-6-alkoxy. In another embodiment of the mandated the prevalence And selected from the group consisting of halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkoxy, -C(O)N(R3)(R4and-C(O)R6. In another embodiment the substituents a are selected from the group consisting of halogen (such as fluorine or chlorine), C1-6-alkyl (such as methyl, ethyl and propyl), cyano, trifloromethyl,1-6-alkoxy (such as methoxy, ethoxy or isopropoxy) and-C(O)R6. In yet another embodiment And is chenail, and substituents And are selected from the group consisting of halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkoxy and-C(O)N(R3)(R4). In yet another embodiment And is a 5-chinolin, and substituents And are selected from the group consisting of halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkoxy and-C(O)N(R3)(R4). In yet another embodiment a represents a 2-methyl-5-chinolin.

In one embodiment R, when present, represents a halogen (such as fluorine or chlorine) or (C1-6-alkyl (such as methyl or ethyl).

In one embodiment R1when he is present, represents hydrogen or C1-6-alkyl (such as methyl or ethyl).

In one embodiment, each R2represents hydrogen, cyano, C1-6-alkyl, 1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -S(O)2N(R3)(R4), -N(R3)(R4), -C(NOR5R6, -N(R3)C(O)(R6), -N(R3)S(O)2(R6), -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, a heterocyclic ring or aryl; where group a heterocyclic ring or aryl optionally substituted with one, two or three substituents selected, independently, from the group consisting of halogen, cyano, nitro, amino, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy and halogen-C1-6-alkoxy. In another embodiment, each R2represents hydrogen, cyano, C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5R6, -N(R3)C(O)(R6), -C(O)R6,

-C(O)OR7, -C(O)NHNHC(O)R6, a heterocyclic ring or aryl; where group a heterocyclic ring or aryl optionally substituted with one, two or three substituents selected, independently, from the group consisting of halogen, cyano, nitro, amino, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy and halogen-C1-6-alkoxy. In another embodiment, each R2represents a C1-6-alkyl, -C(O)N(R3)(R4or-C(O)R6.

In one embodiment, s is 1 or 2.

In one embodiment of the invention is worn to the compound of formula (I), its salt or prodrug, where

---- represents, independently, a simple bond or double bond;

a loop Q is an imidazole, triazole (e.g., 1,2,3-triazole or 1,3,4-triazole) or tetrazol;

Represents a C(R7)(R8) or C(R7), where in the case when the bond connecting b and Y represents a simple bond, A represents C(R7)(R8), and when the bond connecting b and Y is a double bond, A is a C(R7);

Y is C(R7), C(R7)(R8) or, in the case where, when the bond connecting b and Y represents a simple bond, Y is C(R7)(R8or Oh, and when the bond connecting b and Y is a double bond, A is a C(R7);

Z1represents-CH2-, -(CH2)2-, -CH2CH(CH3)- (left side Z1attached to the nitrogen atom) or -(CH2)3-;

X represents C(R1or N;

But chinolin or hintline, any of which is optionally substituted by 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, hydroxy, cyano, nitro, C1-6-alkyl, halogen-C1-6-alkyl, C3-7-cycloalkyl, aryl-C1-6-alkoxy, C1-6-alkylthio, 1-6-alkoxy, halogen-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-4-alkoxy, C2-6-alkenyl,3-6-quinil, halogen-C2-6-alkenyl, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -S(O)2N(R3)(R4), -N(R3)(R4), -C(NOR5R6, -N(R3)C(O)(R6), -N(R3)S(O)2(R6), -C(O)R6, -C(O)OR7, heterocyclic ring, Arora and aryl; where the group of heterocyclic ring, aroyl and aryl optionally substituted with one, two or three substituents selected, independently, from the group consisting of halogen, hydroxy, cyano, nitro, amino, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy and halogen-C1-6-alkoxy;

R, when present, represents a halogen (such as fluorine or chlorine) or (C1-6-alkyl (such as methyl or ethyl);

R1when present, represents hydrogen or C1-6-alkyl (such as methyl or ethyl);

each R2represents hydrogen, cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -S(O)2N(R3)(R4), -N(R3)(R4), -C(NOR5R6, -N(R3)C(O)(R6), -N(R3)S(O)2(R6), -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6the heterocycle is ical ring or aryl; where group a heterocyclic ring or aryl optionally substituted with one, two or three substituents selected, independently, from the group consisting of halogen, cyano, nitro, amino, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy and halogen-C1-6-alkoxy;

R3and R4represent, independently, hydrogen; C1-6-alkyl; aryl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3and R4connected to the same nitrogen atom, together with the nitrogen atom form a 4-, 5-, 6 - or 7-membered cycle, optionally containing one additional atom of O, N or S in the loop;

R5represents a C1-4-alkyl, C3-7-cycloalkyl-C1-6-alkyl or C3-7-cycloalkyl;

R6represents hydrogen, halogen, cyano, C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl or1-6-alkyl;

R7and R8represent, independently, hydrogen, C1-6-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-6-alkyl or halogen-C1-6-alkyl;

R9and R10represent, independently, hydrogen, C1-6-alkyl, cyano, halogen-C1-6-alkyl, C1-6-alkanoyl,1-6-alkoxy, hydroxyl, halogen or1-6-alkoxy-C1-6-alkyl;

p is 0, 1 or 2;

r is 0, 1, 2 or 3;

s is 0, 1 or 2; and

t is 0, 1 or 2.

In one embodiment of the invention relates to the compound of formula (I), its salt or prodrug, where

---- represents, independently, a simple bond or double bond;

a loop Q is an imidazole, triazole (e.g., 1,2,3-triazole or 1,3,4-triazole) or tetrazol;

Represents a C(R7)(R8) or C(R7), where in the case when the bond connecting b and Y represents a simple bond, A represents C(R7)(R8), and when the bond connecting b and Y is a double bond, A is a C(R7);

Y is C(R7), C(R7)(R8) or, in the case where, when the bond connecting b and Y represents a simple bond, Y is C(R7)(R8or Oh, and when the bond connecting b and Y is a double bond, A is a C(R7);

Z1represents -(CH2)2-;

X represents CH or N;

But chinolin or hintline, any of which is optionally substituted by 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkoxy, -C(O)N(R3)(R4and-C(O)R6;

R, when present, represents the second halogen (such as fluorine or chlorine) or (C 1-6-alkyl (such as methyl or ethyl);

R1when present, represents hydrogen or C1-6-alkyl (such as methyl or ethyl);

each R2represents hydrogen, cyano, C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5R6, -N(R3)C(O)(R6), -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, a heterocyclic ring or aryl; where group a heterocyclic ring or aryl optionally substituted with one, two or three substituents selected, independently, from the group consisting of halogen, cyano, nitro, amino, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy and halogen-C1-6-alkoxy;

R3and R4represent, independently, hydrogen; C1-6-alkyl; aryl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3and R4connected to the same nitrogen atom, together with the nitrogen atom form a 4-, 5-, 6 - or 7-membered cycle, optionally containing one additional atom of O, N or S in the loop;

R5represents a C1-4-alkyl, C3-7-cycloalkyl-C1-6-alkyl or C3-7-cycloalkyl;

R6represents hydrogen, halogen, cyano, C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl or1-6-alkyl;

R7and R8represent the th, independently, hydrogen, C1-6-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-6-alkyl or halogen-C1-6-alkyl;

p is 0, 1 or 2;

r is 0, 1, 2 or 3; and

s is 0, 1 or 2.

In one embodiment of compounds of formula (I) are selected from

dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (example 14);

dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (example 15);

dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-c][1,4]benzoxazine (example 24);

dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (example 83);

dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (example 89);

dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (example 91);

dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}tetrazolo[1,5-a]quinoline (example 94);

dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (example 97);

dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(3-methyl-1,2,4-oxadiazol-5-yl)imidazo[1,5-a]ginoli is a (example 105);

dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide (example 109);

dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (example 122);

dihydrochloride of N,7-dimethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (example 124) and

dihydrochloride of 7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (example 125);

or their pharmaceutically acceptable salts or free bases.

In another embodiment the compound is a hydrochloride of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (example 14).

In another embodiment the compound is a 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (example 14, free base).

In another embodiment the compound is a hydrochloride of 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (example 91).

In another embodiment the compound is a hydrochloride of 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide (example 109).

According to another aspect, the invention relates to the compound of formula (I) or its headlight is asepticheski acceptable salt,

where

And represents indolyl, hinely, hintline, benzofuranyl or benzothiazyl, where these groups optionally substituted by 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, hydroxy, cyano, nitro, C1-6-alkyl, halogen-C1-6-alkyl, C3-7-cycloalkyl, aryl-C1-6-alkoxy, C1-6alkanoyl,1-6-alkylthio,1-6-alkoxy, halogen-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-4-alkoxy, C2-6-alkenyl,3-6-quinil, halogen-C2-6-alkenyl, C(O)N(R3)(R4), C(O)N(R3)-C1-6-alkoxy, S(O)2N(R3)(R4), N(R3)(R4); C(NOR5R6N(R3)C(O)(R4), N(R3)S(O)2(R4), C(O)R7C(O)OR7, heterocycle, Arola or aryl, where arolina or heterocyclic group optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy and halogen-C1-6-alkoxy;

Represents a C(R7)(R8) or C(R7);

X represents C(R1), N or S;

Y is C(R7), C(R7)(R8), Or S(O)t;

Z1represents a group of the Sabbath.

where n and m is, independently, 0, 1, or 2 and W is a 3-7-membered cycloalkenyl group or a 3-7-membered cycloalkenyl group, optionally substituted by 1-3 substituents, which may be the same or different and are selected from halogen, hydroxy, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C1-6alkanoyl or1-6-alkoxy; or W represents -(CH=CH)-; -C(=O)-; -C(=CH2)-; -C(R7)(R8)-; -C(R7)(R8)-S(O)t- or-C(R7)(R8)-O-;

cycle Q represents a 5-membered heteroaromatic cycle or a 5-membered heterocyclic ring containing at least one nitrogen atom and optionally additionally containing 1-3 heteroatom selected from oxygen, nitrogen and sulfur;

---- represents, independently, a simple bond or double bond, provided that when

(a) X represents N or C(R1), the link ----connected with X represents a simple bond;

(b) Y is C(R2)(R3), N(R2), O, or S(O)tthe link ----connected to Y represents a simple bond;

R represents, independently, halogen, C1-6-alkyl, cyano, halogen-C1-6-alkyl, C1-6-alkanoyl,1-6-alkoxy, hydroxy or triptoreline;

R1(a) represents hydrogen, C 1-6-alkyl, cyano, halogen-C1-6-alkyl, C1-6-alkanoyl,1-6-alkoxy, hydroxy or1-6-alkoxy-C1-6-alkyl;

R2represents hydrogen, halogen, hydroxy, cyano, nitro, C1-6-alkyl, halogen-C1-6-alkyl, C3-7-cycloalkyl, aryl-C1-6-alkoxy, C1-6-alkanoyl,1-6-alkylthio,1-6-alkoxy, halogen-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkoxy-C1-4-alkoxy, C1-6alkenyl,3-6-quinil, halogen-C1-6alkenyl, =O, C(O)N(R3)(R4), C(O)N(R3)-C1-6-alkoxy, S(O)2N(R3)(R4), N(R3)(R4); C(NOR5R6N(R3)C(O)(R4), N(R3)S(O)2(R4), C(O)R7C(O)OR7, heterocycle, aroyl or aryl, where arolina or heterocyclic group optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C1-6-alkyl, halogen-C1-6-alkyl, C1-6-alkoxy and halogen-C1-6-alkoxy;

R3and R4represent, independently, hydrogen, C1-6is alkyl, aryl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-6-alkyl or together with N, NR3R4or form a 4-, 5-, 6 - or 7-membered azacyclonol group, optionally containing Azazelle one will augment the capacity atom O N or S containing 3-8 carbon atoms (including the carbon atoms contained in any(s) optional(s) Deputy(ies) of azazil);

R5represents a C1-4-alkyl, C3-7-cycloalkyl-C1-6-alkyl or C3-7-cycloalkyl;

R6represents hydrogen, halogen, cyano, C3-7-cycloalkyl-C1-6-alkyl or C3-7-cycloalkyl or1-6-alkyl;

R7and R8represent, independently, hydrogen, C1-6-alkyl or halogen-C1-6-alkyl;

R9and R10represent, independently, hydrogen, C1-6-alkyl, cyano, halogen-C1-6-alkyl, C1-6-alkanoyl,1-6-alkoxy, hydroxyl, halogen or1-6-alkoxy-C1-6-alkyl;

p is 0, 1 or 2;

r is 1, 2 or 3;

s is 1, 2 or 3;

t is 0, 1 or 2.

The term "substituted" means substitution of one or more groups. When groups you can choose from a number of alternative groups of the selected group may be the same or different.

The term "independently" means that when the number of possible substituents chosen several substituents, such substituents may be the same or different.

The compounds of formula (I) can form salts accession acids or bases. It should be borne in mind that for use in medicine, the salts must be is pharmaceutically acceptable. Suitable pharmaceutically acceptable salts are obvious to experts in this field and include the salts described in Berge et al., J. Pharm. Sci., 1977, 66, 1-19. When the compounds of formula (I) contain a basic center, they can form salts accession acids with suitable inorganic or organic acids. Examples of suitable inorganic acids are hydrochloric, Hydrobromic, sulphuric, nitric, uudistoodetena, metaphosphoric or phosphoric acid. Examples of suitable organic acids are succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, triperoxonane, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfonate, sotynova, mucus, gentisic, isonicotinoyl, sugar, glucuronic, Voronova, glutamic, ascorbic, Anthranilic, salicylic, phenylacetic, almond, albanova (AMOVA), econsultancy, Pantothenic, stearic, Sultanova, alginic, galacturonic acid and arylsulfonic acid (for example, benzolsulfonat, p-toluensulfonate, methanesulfonate or naphthalenesulfonate acid). When the compounds of formula (I) contain an acid center, they can form salts joining bases with alkali metals, alkaline earth metals and suitable organic base is I. Examples of suitable organic bases are N,N-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine), lysine and procaine. Some compounds of formula (I) can form salts accession acids with less than one equivalent, one equivalent or more than one equivalent of acid (for example, salt is a dihydrochloride). Salts of compounds of formula (I) include all possible stoichiometric and non-stoichiometric forms. Salts with physiologically acceptable anion or cation are included in the scope of the invention, they may be applicable intermediate compounds for obtaining physiologically acceptable salts and/or applied to non-targets, for example in situations in vitro. In one embodiment the salt is a physiologically acceptable salt.

Professionals in this field should be borne in mind that some containing protective groups derivatives of compounds of formula (I), which can be obtained before the final stage of the removal of the protective group may not possess pharmacological activity as such, but in some cases can be entered and subsequently to metabolize in the body to form compounds of the invention which are pharmacologically active. Therefore, such derivatives can be described as PR the medication. In addition, some compounds of formula (I) may act as prodrugs of other compounds of formula (I). All containing protective groups, derivatives and prodrugs of the compounds of formula (I) is included in the scope of the invention. Examples of suitable prodrugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp. 499-538, in Topics in Chemistry, Chapter 31, pp. 306-316, and in "Design of Prodrugs"by H. Bundgaard, Elsevier, 1985, Chapter 1 (included in this description as references). Professionals in this field should also be borne in mind that some groups, known to specialists in this field as progroup, for example, described by H. Bundgaard in "Design of Prodrugs" (included in this description by reference), can be replaced with the appropriate functional groups, when such functional groups present in the compounds of the invention. In one embodiment, the prodrugs of the compounds of the invention include esters, complex esters, carbonates, complex palefire, esters of phosphates, complex nitroethane, ester sulfates, sulfoxidov, amides, carbamates, azo compounds, phosphamide, glycosides, ethers, acetals and ketals.

Hereinafter in the description of the compounds of formula (I), their salts and prodrugs, as defined in any aspect of the invention (except intermediate compounds in chemical methods), called soy is inanami of the invention.

Compounds of the invention can be obtained in crystalline and non-crystalline form. If the connections are in crystalline form, they can be hydrated or solvated. In the scope of the invention included a stoichiometric hydrate or solvate, as well as compounds containing variable amounts of water and/or solvent.

Compounds of the invention can also exist in different polymorphic forms.

Some compounds of the invention can exist in stereoisomeric forms (e.g., geometric or (CIS-TRANS) isomers, diastereomers and enantiomers), and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated by methods known to experts-chemists, or any given isomer may be obtained by asymmetric synthesis.

The invention also extends to any and all tautomeric forms and mixtures thereof. In the scope of the present invention includes all such isomers, including mixtures.

The invention also includes all suitable isotopic variations of the compounds of the invention. Isotopic variant of the compound of the invention is defined as a variant, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass, the usual found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N17O,18O,31P,32P,35S18F and36Cl, respectively. Some isotopic variants according to the invention, for example options that include a radioactive isotope, such as3N or14With, applicable in medicine and/or in the study of distribution in the tissue of the substrate. Isotopes tritium, i.e3N, and carbon-14, i.e14With, are suitable because of their easy access and discovery. Further, substitution with isotopes such as deuterium, i.e2N, may provide some therapeutic advantages resulting from greater resistance to metabolism, such as increased half-life existence in vivo or reduced the need for dosage, and, therefore, may be appropriate in some circumstances. Isotopic variations of the compounds of the invention can generally be obtained by the conventional procedures, such as illustrated in the ways or methods of preparation, are described in the examples and descriptions below, using appropriate isotopic variations of suitable reagents.

In the description of the General formulas are denoted by Latin num is mi (I), (II), (III), (IV), etc. Subgroups such General formulas are denoted as (Ia), (Ib), (Ic), etc, ... (IVa), (IVb), (IVc), etc.

The compounds of formula (Ia), i.e. compounds of formula (I), where Z1represents a-CH(R7)-[CH(R9)]m- (where m is 0, 1 or 2), can be obtained according to the reaction scheme 1. The compounds of formula (II) enter into an interaction with compounds of the formula (III) in the presence of a suitable reductant, such as triacetoxyborohydride sodium. The interaction is typically carried out in an aprotic solvent (such as a simple ether, for example tetrahydrofuran, halogenated hydrocarbons such as 1,2-dichloroethane, N,N-dimethylformamide or acetonitrile) at room temperature.

Scheme 1

Some compounds of formula (III) are known (see published application for international patent application WO2004/046124), or they can be obtained by procedures similar to those described in WO2004/046124. Other compounds of formula (III) can be obtained using procedures similar to those described in the descriptions 47, 116, 142, 143, 146, 150, 151 and 163.

The compounds of formula (II) can be obtained by oxidative cleavage of compounds of formula (IV) according to reaction scheme 2. Oxidative cleavage can be carried out using catalytic osmium tetroxide in aqueous tetrahydrofuran followed by the addition of periodate on the rija at room temperature. Other methods include ozonolysis using ozone followed by treatment with a suitable reducing agent (such as dimethyl sulfide).

Scheme 2

The compounds of formula (IVa) can be obtained from compounds of formula (V) interaction with diethylphosphate in the presence of a base (for example, tert-butoxide potassium) at low temperature (such as 120 ºC) followed by the addition With1-6-allylisothiocyanate and bases (for example, tert-butoxide potassium) (see reaction scheme 3). This interaction is usually carried out in an aprotic solvent such as N,N-dimethylformamide.

Scheme 3

The compounds of formula (IVb) can be obtained according to reaction scheme 4. The compounds of formula (V) is treated with a suitable base (e.g. sodium hydride) in a suitable solvent (such as DMF), and then treated with R2C(O)CHR2Cl cooling (for example, at 0 ° C), and obtain the compounds of formula (VI). Treatment of compounds of formula (VI) with ammonium acetate in acetic acid under the influence of microwave radiation gives the compounds of formula (IVb).

Scheme 4

The compounds of formula (IVc) can be obtained according to reaction scheme 5. The compounds of formula (V) enter into interaction with the reagent Laussane (Lawesson) in toluene at above the Noah temperature (for example, toluene/boiling under reflux), and obtain the compounds of formula (VIIa). Processing (VIIa) methyliodide in acetone in the presence of a suitable base (e.g. potassium hydroxide), followed by processing dimethylacetal of aminoacetaldehyde in dry ethanol gives the compounds of formula (VIII). Cyclization in acidic medium (for example, concentrated hydrochloric acid in methanol) gives compounds of formula (IVc).

Scheme 5

The compounds of formula (IVd) can be obtained from compounds of formula (VII) according to reaction scheme 6. Treatment of (VII) with hydrazine monohydrate in ethanol at elevated temperature (e.g., 80 ° C) with subsequent processing (MeO)3R2under the influence of microwave radiation gives the compounds of formula (IVd).

Scheme 6

The compounds of formula (IVe) can be obtained according to reaction scheme 7. The compounds of formula (VII) is treated with hydroxylamine hydrochloride and sodium acetate in dry ethanol and obtain the compounds of formula (IX). Then the compounds of formula (IX) is treated with carbonyl diimidazol in dry tetrahydrofuran and get the compounds of formula (IVe).

Scheme 7

The compounds of formula (IVf) can be obtained intramolecular 1,3-bipolar cyclopentadiene compounds of the formula (X) according to reaction scheme 8. Simocatta usually carried out in an organic solvent (for example, toluene).

Scheme 8

The compounds of formula (X) can be obtained by procedures similar to the procedures described in description 2, 37, 38 and 39.

The compounds of formula (IVg) can be obtained according to reaction scheme 9 from compounds of formula (VIIa). Typical conditions of interaction described in the descriptions 19, 131, 133 and 135.

Scheme 9

The compounds of formula (IVh) can be obtained according to reaction scheme 10 from compounds of formula (XI). Typical conditions of interaction described in the descriptions 87, 88, 89, 90, 107 and 108.

Scheme 10

The compounds of formula (IVi) can be obtained according to reaction scheme 11 from compounds of formula (XI). Typical conditions of interaction described in the descriptions 88 and 92.

Scheme 11

The compounds of formula (IVj) can be obtained according to reaction scheme 12 from compounds of formula (XI). Typical conditions of interaction described in the descriptions 88, 94, 95 and 96.

Scheme 12

The compounds of formula (IVk) can be obtained according to reaction scheme 13 of compounds of formula (XI). Typical conditions of interaction described in the descriptions 101, 102 and 103.

Scheme 13

The compounds of formula (XI) can be obtained according to procedures similar to the procedures which, described in the description of 88.

The compounds of formula (V) (see scheme of reactions 3, 4 and 5) can be obtained according to reaction scheme 14 of the compounds of formula (XII). Typical conditions of interaction include heating (XII) in the presence of iron powder and ammonium chloride. The interaction is typically carried out in a solvent or mixture of solvents at a temperature in the range of 60-100ºC. Suitable solvents are mixtures of water and alcohol (e.g. methanol or ethanol).

Scheme 14

The compounds of formula (Va) can be obtained according to reaction scheme 15. A typical interaction conditions for the first stage are interacting with BrCH(R7)C(=O)NH2in the presence of a suitable base (such as potassium carbonate) in a suitable solvent (such as acetone). A typical interaction terms for the second stage are the interaction in the presence of copper iodide and N,N-dimethylethylenediamine and a suitable base (such as potassium carbonate) in a suitable solvent (such as NMP) at elevated temperature (such as 150 º C).

Scheme 15

The compounds of formula (Vb) can be obtained according to reaction scheme 16 from compounds of formula XIII. Typical conditions of interaction described in the descriptions 71 and 72.

Scheme 16

With the organisations of the formula (XIII) are commercially available, or you can get them using procedures known to the experts-chemists, from readily available starting materials.

The compounds of formula (XIIa) can be obtained according to the reaction scheme 17 the interaction of compounds of the formula (XIV) with a suitable base (such as sodium hydride) followed by treatment of the compound of formula (Hal)-CH2-C(O)O-C1-4-alkyl, where Hal represents a halogen (such as bromine).

Scheme 17

The compounds of formula (XIV), where m is equal to 1, can be obtained by procedures similar to those described in descriptions 1 and 2.

Compounds of General formula (I) can be obtained according to reaction scheme 18, when the compounds of formula (XV) (where Hal represents a halogen, such as chlorine, bromine) enter into an interaction with compounds of the formula (III). Interaction conditions include heating in the presence of a base (e.g. sodium carbonate or potassium carbonate) and, optionally, a catalyst such as sodium iodide, in a suitable solvent (such as 1-methyl-2-pyrrolidone or methyl isobutyl ketone).

Scheme 18

The compounds of formula (Ib), i.e. compounds of formula (I)where Y represents Oh or-CH2-and represents-CH2-can be obtained from compounds of formula (XVI) according to the reaction scheme 19. The compounds of formula (XVI), you can enter what about the interaction in terms similar to that described for schemes of reactions 3 and 4, and to obtain the compound of formula (Ib).

Scheme 19

The compounds of formula (XVI) can be obtained by the interaction of the compounds of the formula (III) with soedinenii formula (XVII) according to the reaction scheme 20. The terms of cooperation are as described for reaction scheme 18.

Scheme 20

It should be borne in mind that the compounds of formula (I) or (IV) can be converted into other compounds of formula (I) or (IV) methods of synthesis known in the art. Examples of such transformations are described below.

a) the compounds of formula (I) or (IV)where one or more R2represent CO2N, can be obtained by hydrolysis of the corresponding compounds in which R2is a CO2R7. Typically, the hydrolysis is carried out in the presence of a base (e.g. sodium hydroxide) in aqueous methanol at high temperatures and/or with the use of microwave radiation.

b) Compounds of formula (I) or (IV), where R2represents C(O)N(R3)(R4), can be obtained by the interaction of the corresponding compounds in which R2constitutes a suitable activated carboxylic group, with a compound of the formula NH(R3)(R4). Suitable activated carboxylic groups include allalone, the mixed anhydrite, the activated ester (such as a thioester) group or a group derived formed between a carboxyl group and agent combinations (such as tetrafluoroborate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea). Typically, the interaction is carried out at room temperature and in an aprotic solvent such as a hydrocarbon solvent, halogenated hydrocarbon solvent (such as dichloromethane) or an ether (such as tetrahydrofuran)in the presence of a suitable base (such as diisopropylethylamine or dimethylamine).

(C) Compounds of formula (I) or (IV), where R2represents-C(O)N(C1-6-alkyl)O-C1-6-alkyl, can be obtained by the interaction of the corresponding compounds in which R2represents-CO2R7with trimethylaluminum and the hydrochloride of N,O-di-C1-6-alkylhydroxylamines at room temperature.

d) the compounds of formula (I) or (IV), where R2represents-C(O)R6can be achieved by interaction of the corresponding compounds in which R2represents-C(O)N(C1-6-alkyl)O-C1-6-alkyl, with the appropriate Grignard reagent in an organic solvent at low temperature.

(e) Compounds of formula (I) or (IV), where R2represents a 3-methyl-5-isoxazolyl, can be obtained in two stages, at first it is rather the interaction of the corresponding compounds, in which R2represents-C(O)R6with dimethylacetal N,N-dimethylacetamide at elevated temperature (such as 150 º C), and then by treatment with hydroxylamine hydrochloride in a suitable solvent (such as ethanol) at elevated temperature (such as 150 º C).

f) Compounds of the formula (I) or (IV), where R2represents a 3-methyl-1H-pyrazole-5-yl, can be obtained in two stages, first by the interaction of the corresponding compounds in which R2represents-C(O)R6with dimethylacetal N,N-dimethylacetamide at elevated temperature (such as 150 º C), and then by treatment with hydrazine monohydrate in a suitable solvent (such as ethanol) at elevated temperature (such as 150 º C).

(g) Compounds of formula (I) or (IV), where R2represents cyano, can be obtained by the interaction of the corresponding compounds in which R2represents-C(O)NH2with the anhydride triperoxonane acid in the presence of organic bases (e.g. pyridine). The interaction usually takes place in an aprotic solvent such as tetrahydrofuran, at 0 ° C.

h) Compounds of the formula (I) or (IV), where R2represents hydrogen, can be obtained by decarboxylation of compounds of formula (I) or (IV)in which R2is a CO2N. The reaction can osushestvleniya in an organic solvent such as a halogenated aromatic hydrocarbon).

i) the compounds of formula (I) or (IV), where R2represents a 3-methyl-1,2,4-oxadiazol-5-yl, can be obtained by interaction of the corresponding compounds of formula (I) or (IV)in which R2is a CO2R7with oxime methylcarbamate in the presence of a suitable base (such as sodium hydride).

(j) the compounds of formula (I) or (IV), where R2represents-C(=NOMe)R6you can get in two stages by the interaction of the corresponding compounds of formula (I) or (IV)in which R2represents C(O)R6with hydrochloride methoxylamine in a suitable solvent (such as ethanol) at an elevated temperature.

(k) Compounds of formula (I) or (IV), where R2represents-C(O)NH-NHC(O)Me, can be obtained by the interaction of the corresponding compounds of formula (I) or (IV)in which R2is a CO2R7with acetohydrazide in a suitable solvent (such as DCM) at low temperature (such as 0 ° C).

(l) Compounds of formula (I) or (IV), where R2represents 5-methyl-1,3,4-oxadiazol-2-yl, can be obtained by the interaction of the corresponding compounds of formula (I) or (IV)in which R2represents-C(O)NH-NHC(O)Me (see k), with triperoxonane (triflic) anhydride in a suitable solvent (such as pyridine) at low temperature (such as 0 ° C).

m) Soy is inane formula (I) or (IV), where R2represents a 1,3-oxazol-5-yl, can be obtained in two stages from the corresponding compounds of formula (I) or (IV)in which R2is a CO2R7. In the first stage, the ether is reduced to the aldehyde using lithium aluminum hydride at low temperature (such as 0 ° C) in a suitable solvent (such as THF). In the second stage, the aldehyde is treated with p-toluensulfonate.

Professionals in this field should be borne in mind that it may be necessary to protect certain reactive substituents while some of the above procedures. You can use the standard methods for the introduction and removal of protective groups, such as described in T.W. Greene, Protective groups in organic synthesis, New York, Wiley (1981). For example, primary amines can be protected in the form of phthalimide, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl or trailerville derivatives. The carboxyl group can be protected in the form of ester groups. Aldehyde or catography can be protected as acetals, ketals, thioacetals or tionately. The removal of such protective groups reach using conventional procedures well known in the field. For example, protective groups such as tert-butoxycarbonyl, can be removed using acid such as hydrochloric or trip orokana acid, in a suitable solvent, such as dichloromethane, diethyl ether, isopropanol or mixtures thereof.

Pharmaceutically acceptable salts can be obtained in the usual way by interacting with the corresponding acid or acid derivative.

Other details of obtaining compounds of formula (I) are given in the description hereinafter in the examples section.

As indicated above, the compounds of the invention have a high affinity to the receptor type 5-HT1and/or are inhibitors of reuptake of serotonin and, respectively, applicable in the treatment or prevention of diseases and conditions mediated by modulation of receptor type 5-HT1and/or receptor reuptake of serotonin.

Therefore, according to another aspect, the invention relates to the compound of the invention for use as a medicinal product, respectively, of a medicinal product for human use.

According to another aspect, the invention relates to the use of compounds of the invention when getting drugs for treating or preventing a disease or condition mediated by modulation of the receptor 5-HT1and/or receptor reuptake of serotonin.

In one embodiment the disease or condition that can oposredovanie modulation of the receptor 5-HT1and/or receptor surface is ornago absorption of serotonin, choose from the list, which includes a disease or condition listed below [the numbers in brackets after the diseases listed below, refer to the classification code in Diagnostic and Statistical Manual of Mental Disorders, 4thEdition, published by American Psychiatric Assotiation (DSM-IV), and/or International Classification of Diseases, 10thEdition (ICD-10)].

i) Psychotic disorders such as schizophrenia including the subtypes paranoid type (295.30), destructive type (295.10), catatonic type (295.20), undifferentiated type (295.90) and residual type (295.60)); disorder schizophrenic form (295.40); schizoaffective disorder (295.70) including the subtypes bipolar type and depressive type); delusion disorder (297.1) including the subtypes of erotomania, megalomania, jealousy, persecution, somatic type, mixed type and unspecified type); brief psychotic disorder (298.8); distributed psychotic disorder (297.3); psychotic disorder due to a General treatment General Medical Condition (including the subtypes with delusions and hallucinations); psychotic disorder caused by substances (including the subtypes with delusions (293.81) and with hallucinations (293.82)), and psychotic disorder without other definition (298.9).

ii) Depression and mood disorders, such as depressive episodes (including major depressive episode, unikalny episode a mixed episode and hypomanic episode; depressive disorders (including major depressive disorder, delimitable disorder (300.4), depressive disorder not otherwise defined (311)); bipolar disorders including bipolar I disorder, bipolar II disorder (i.e. large recurring depressive episodes with hypomanic episodes) (296.89), cyclothymic disorder (301.13) and bipolar disorder do not have a different definition (296.80); other mood disorders including mood disorder due to a General mode of treatment (293.83)which includes the subtypes with depressive features, with an episode reminiscent of major depressive disorder, with manic features and with mixed features); mood disorder caused by substances (including the subtypes with depressive features, with manic features and with mixed features)and mood disorder, no other definition (296.90).

iii) Disorder anxiety disorder such as social anxiety; panic attack; agoraphobia, panic disorder; agoraphobia without panic disorder in disorder (300.22); specific phobia (300.29) (including the subtypes animal type, natural environment type of damage during the injection of the blood (Blood-Injection-Injury), psychogenic types, etc the Gogo type); social phobia (300.23); obsessive-compulsive disorder (300.3); post-traumatic stress disorder (309.81), acute stress (308.3); disorder generalized anxiety (300.02), anxiety disorder due to a General mode of treatment (293.84), anxiety disorder induced substance, anxiety disorder, no other definition (300.00).

iv) Disorders caused by substances, such as disorders in the application of substances (including dependence on substances, addiction to substances and substance misuse); disorders caused by substances (including intoxication, withdrawal syndrome, delirium, caused by the substance, sustainable dementia, caused by the substance, sustainable amnestic disorder induced substance, psychotic disorder, caused by a substance called substance mood disorder induced substance, anxiety disorder induced substance sexual dysfunction caused by substance a sleep disorder and hallucinogen sustainable preceptive disorder"freeze frames"); disorders related to alcohol (including alcohol dependence (303.90), alcohol abuse (305.00), alcohol intoxication (303.00), the syndrome of withdrawal from alcohol (291.81), alcohol intoxication delirium, withdrawal delirium alcohol-induced alcohol sustainable dementia caused by alcohol is sustainable amnestic disorder alcohol-induced psychotic disorder, alcohol-induced mood disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder and is associated with alcohol disorder without other definition (291.9)); disorders associated with amphetamine (or amphetamine-like substances) (for example, amphetamine dependence (304.40), methamphetamine abuse (305.70), amphetamine intoxication (292.89), the syndrome of withdrawal from amphetamine (292.0), delirium amphetamine intoxication caused by amphetamine psychotic disorder caused by amphetamine mood disorder caused by amphetamine disorder anxiety caused by amphetamine sexual dysfunction caused by amphetamine sleep disorder and is associated with amphetamine disorder without other definition (292.9)); disorders associated with caffeine (including caffeine intoxication (305.90), caused by caffeine anxiety disorder, caused by caffeine sleep disorder and associated with caffeine disorder without other definition (292.9)); disorders associated with preparations of hemp (including dependence on drugs of cannabis (304.30), misuse of drugs cannabis (305.20), intoxication with drugs of cannabis (292.89), the delirium of intoxication of preparation is Tami from hemp, called hemp psychotic disorder caused by drugs of cannabis disorder anxiety and related products from hemp disorder without other definition (292.9)); disorders associated with cocaine (including cocaine dependence (304.20), cocaine abuse (305.60), cocaine intoxication (292.89), the syndrome of withdrawal from cocaine (292.0), cocaine delirium of intoxication caused by cocaine, psychotic disorder, cocaine related mood disorder, cocaine related disorder anxiety caused by cocaine sexual dysfunction caused by cocaine sleep disorder and is associated with a cocaine disorder without other definition (292.9)); disorders associated with hallucinogens (including zavisimosti from hallucinogen (304.50), the abuse of hallucinogens (305.30), hallucinogen intoxication (292.89), hallucinogen sustainable preceptive disorder ("snapshots") (292.89); delirium hallucinogenic intoxication-induced psychotic disorder hallucinogen-induced hallucinogen mood disorder caused by hallucinogen disorder and anxiety associated with the disorder hallucinogen, no other definition (292.9)); disorders associated with volatile drugs (including dependence on volatile drug (304.60), abuse of l is tokimi drugs (305.90), intoxication fugitive drug (292.89), the delirium of intoxication fugitive drug induced volatile drug resistant dementia caused by volatile drug psychotic disorder caused by volatile drug mood disorder caused by volatile drug disorder and anxiety associated with volatile drug disorder without other definition (292.9)); disorders associated with nicotine (including nicotine dependence (305.1), the syndrome of withdrawal from nicotine (292.0) and associated with nicotine disorder without other definition (292.9)); disorders associated with opioids (including opioid dependence (304.00), abuse opioids (305.50), opioid intoxication (292.89), the syndrome of withdrawal from opioids (292.0), delirium opioid intoxication caused by opioid psychotic disorder caused by opioid mood disorder-induced sexual dysfunction opioid-induced opioid disorder of sleep and associated with opioid use disorder without other definition (292.9)); disorders associated with phencyclidine (or benzylidenemalonate substances) (including phencyclidine dependence (304.60), abuse of phencyclidine (305.90), phencyclidine intoxication (292.89), delirium phencyclidine intoxication caused by phencyclidine psychotic disorder, is caused by phencyclidine mood disorder, caused by phencyclidine disorder and anxiety associated with the disorder phencyclidine, no other definition (292.9)); disorders associated with sedative, hypnotic or anxiolytic agents (including dependence on sedatives, hypnotics or anxiolytics (304.10), abuse sedative, hypnotic or anxiolytic agents (305.40), intoxication sedative, hypnotic or anxiolytic agents (292.89), the syndrome of withdrawal from sedatives, hypnotics or anxiolytics (292.0), intoxication delirium sedative, hypnotic or anxiolytic means, delirium syndrome withdrawal from sedatives, hypnotics or anxiolytics, called sedative, hypnotic or anxiolytic means of sustainable dementia caused sedative, hypnotic or anxiolytic means of sustainable amnestic disorder caused sedative, hypnotic or anxiolytic means psychotic disorder caused sedative, hypnotic or anxiolytic means mood disorder caused by the sedative, hypnotic or anxiolytic means disorder anxiety caused sedative, hypnotic or anxiolytic means sexual dysfunction caused by the sedative, with otbornye or anxiolytic means a sleep disorder and is associated with sedative, hypnotic or anxiolytic means disorder, no other definition (292.9)); disorders associated with multiple substances (including dependence on multiple substances (304.80)), and related disorders other (or unknown) substance (including anabolic steroids, steroids, volatile nitrates and nitric oxide).

v) sleep Disorders, such as primary sleep disorders, such as dyssomnia (including primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), sleep disorders related to breathing (780.59), disorder circadian rhythm sleep (307.45) and dyssomnia, no other definition (307.47)); primary sleep disorders such as parasomnias (including disorder nightmares (307.47), a disorder of fear in a dream (307.46), disorder of walking in my sleep (307.46) and parasomnia, no other definition (307.47); sleep disorders related to another mental disorder (including insomnia related to another mental disorder (307.42)and hypersomnia related to another mental disorder (307.44); sleep disorder due to a General mode of treatment and is caused by substances a sleep disorder (including the subtypes insomniacal type gipertoniceskaja type parasomnias type and mixed type).

vi) Disorders associated with eating, such as neuro-mental anorexi the (307.1) including the subtypes restricting type and binge eating/purging of the bowels (Binge-Eating/Purging Type); neuropsychiatric bulimia nervosa (307.51) including the subtypes laxative type and mislabeling type; obesity; compulsive eating disorder; binge eating and eating disorder without other definition (307.50).

vii) Disorders from a number of autism, including autistic disorder (299.00), Asperger disorder, disorder Rett, child disintegrative disorder and pervasive developing disorder, no other definition.

viii) Disorder attention deficit/hyperactivity disorder (including the subtypes of the disorder attention deficit/hyperactivity disorder combined type (314.01), disorder attention deficit/hyperactivity type of primary inattention (314.00), disorder attention deficit/hyperactivity hyperactiveimpulsive type (314.01) and disorder attention deficit/hyperactivity, no other definition (314.9)); hyperkinetic disorder; disruptive behavior disorder, such as behavioral disorder (including the subtypes of occurrence of disorders in childhood (321.81), the appearance of disorder in adolescence (321.82) and unidentified appearance of disorder (312.89), oppositional defiant disorder (313.81) and disruptive behaviour disorder, no other definition); and teak disorders, such as rastra the STV Tourette (307.23).

ix) Personality disorders including the subtypes paranoid personality disorder (301.0), schizoid personality disorder (301.20), personality disorder in schizophrenia (301.22), antisocial personality disorder (301.7), borderline personality disorder (301.83), mimic personality disorder (301.50), narcissistic (301.81), avoidance (301.82), dependent (301.86), obsessive-compulsive personality disorder (301.4) and personality disorder, no other definition (301.9).

x) Improving perception, including the treatment of worsening perception of other diseases, such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with impairment of perception, such as Alzheimer's disease.

xi) Sexual dysfunction, such as disorders of sexual desire (including the hypoactive sexual desire disorder (302.71), and sexual aversion (302.79); sexual arousal disorder (including sexual arousal disorder in women (302.72) and erectile dysfunction in men (302.72)); orgasmic disorders (including orgasmic disorder in women (302.73), orgasmic disorder in men (302.74) and premature ejaculation (302.75)); pain during sexual intercourse (including dyspareunia (302.76) and vaginismus (306.51)); sexual dysfunction not having another the distribution (302.70); a paraphilia (including exhibitionism (302.4), fetishism (302.81), frottage (302.89), pedophilia (302.2), sexual masochism (302.83), sexual sadism (302.84), transvestity fetishism (302.3), voyeurism (302.82) and paraphilia not having other definition (302.9); gender identity disorder (including gender identity disorder in children (302.6) and gender identity disorder in adolescents or adults (302.85)and sexual disorder without other definition (302.9).

In another embodiment the disease or condition, which may be mediated by modulation of the receptor 5-HT1and/or receptor re-absorption of serotonin, which are selected from the above group (i), (ii), (iii) and (xi).

In another embodiment sexual dysfunction is premature ejaculation.

It should be borne in mind that in this description, references to "treatment" refer to the prevention of relapse and the suppression or attenuation of symptoms (weak, moderate or strong), and for treatment of established conditions. The compound of the invention can be introduced as a chemical substance, but the active ingredient is typically present in the form of pharmaceutical compositions.

Compounds of the invention can be used for the treatment or prevention of psychotic disorders in combination with the following means: i) antipsychotics; ii) karstenia means in the case of extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergic tools (such as amantadine); (iii) antidepressants; (iv) anxiolytics and v) amplifiers perception, such as cholinesterase inhibitors (such as takin, donepezil, rivastigmine and galantamine).

Compounds of the invention can be used in combination with antidepressants for the treatment or prevention of depression and mood disorders.

Compounds of the invention can be used for treating or preventing bipolar illness, in conjunction with the following means: i) mood stabilizers; (ii) antipsychotics and (iii) antidepressants.

Compounds of the invention can be used for the treatment or prevention of anxiety disorders in combination with the following means: (i) anxiety and (ii) antidepressants.

Compounds of the invention can be used for treating or preventing sexual dysfunction in conjunction with the following means: (i) inhibitors of phosphodiesterase V, for example vardenafil and sildenafil; ii) dopamine agonists/inhibitors transfer of dopamine, such as apomorphine and buproprion; (iii) antagonists, alpha-adrenergic receptors, such as phentolamine; (iv) agonists, prostaglandins, such as alprostadil; v) agonists dough is Theron, such as testosterone; (vi) the transfer inhibitors serotonin, for example inhibitors of reuptake of serotonin; (vii) the transfer inhibitors of norepinephrine, such as reboxetine, and viii) agonists at 5-HT1A, for example flibanserin.

Compounds of the invention can be used for treating or preventing sexual dysfunction in women, in combination with the same resources, which are defined in the case of sexual dysfunction in men, as well as agonist of estrogen, such as estradiol.

Antipsychotic drugs include typical antipsychotics (e.g. chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixene, haloperidol, molindone and loxapine) and atypical antipsychotics (eg, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone and amisulpride).

Drugs antidepressants include inhibitors of reuptake of serotonin (such as citalopram, ESCITALOPRAM, fluoxetine, paroxetine, sertraline femoxetine, fluvoxamine, indalpine and zimeldine); dual inhibitors of reuptake of serotonin/norepinephrine (such as venlafaxine, DULOXETINE and milnacipran): inhibitors of reuptake of norepinephrine (such as reboxetine and venlafaxine); tricyclic antidepressants (such as Amitri tilin, clomipramine, imipramine, maprotiline, nortriptyline, and trimipramine); monoamine oxidase inhibitors (such as isocarboxazid, moclobemide, phenelzine and tranilcipromin) and other tools (such as bupropion, mianserin, mirtazapine, nefazodone, and trazodone).

Medications mood stabilizers include lithium, sodium valproate/valproate acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, tiagabine.

Anxiolytic drugs include benzodiazepines, such as alprazolam and lorazepam.

In addition, the compounds of the invention can be introduced in combination with antagonists of 5-HT3(such as ondansetron, granisetron and metoclopramide); serotonin agonists such as sumatriptan, rauwolscine, yohimbine and metoclopramide) and antagonists of NK-1.

It should be borne in mind that the combination or composition of compounds according to the invention can be introduced simultaneously (either in the same or in different dosage forms), separately or sequentially.

According to another aspect of the invention relates to pharmaceutical compositions containing the compound of the invention in combination with one or more pharmaceutically acceptable carriers, diluents and/or excipients. Carrier, diluent and/or excipient should be acceptable in the sense of compatibility with other ingredients comp the positions and not be irritants to their recipient.

Compounds of the invention can be introduced in conventional dosage forms obtained by combining the compounds of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the field. Such procedures may include mixing, granulating and compressing or dissolving the ingredients, respectively, for the desired product.

The pharmaceutical compositions according to the invention can be formulated for administration in any way, and include compositions in a form adapted for oral, local or parenteral administration to mammals, including humans.

The composition can be obtained for insertion in any way. The composition can be in the form of tablets, capsules, powders, granules, pellets, creams or liquid preparations such as solutions or suspensions for oral administration or in sterile solutions or suspensions for parenteral administration.

The local composition of the present invention can be presented in the form of, for example, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to facilitate penetration of the medicinal product and emollients in which asah and creams.

The composition can also contain conventional carriers, such as cream or ointment, and ethanol or alerby alcohol in the case of lotions. Such media can contain from about 1% to about 98% of the composition. Often they will make up about 80% of the composition.

Tablets and capsules for oral administration may represent a standard dosage form and may contain conventional excipients such as binding agents, for example syrup, Arabian gum, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletiruemye lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; substances that contribute to the scattering, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Liquid preparations for oral administration may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for restore with water or other suitable vehicle before use. Such liquid preparations may contain conventional DOB is Cai, such as suspendresume substances, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, gel, aluminum stearate or hydrogenated edible fats, emulsifying agents, for example lecithin, monooleate sorbitan or Arabian gum; non-aqueous environment (which may include edible oils), for example almond oil, esters of fatty acids and, for example, glycerol, propylene glycol or ethyl alcohol; preservatives, for example methyl - or propyl-p-hydroxybenzoate or sorbic acid, and, if desirable, normal corrigentov or dyes.

Suppositories will contain the usual bases for suppositories, for example cocoa butter or other glycerides.

For injecting liquid standard dosage form is obtained using the compound and a sterile environment, and is typical of water. Connection, depending on the environment and concentration, can be either suspended or dissolved in the medium. Upon receipt of the solutions the compound can be dissolved in water for injection, sterilizing the solution by filtration before filling a suitable vial or ampoule and sealed shut.

Mainly substances, such as local anesthetic, preservative or buferiruemoi substances can be dissolved in the environment. In order to improve the color stability, the e l e C the composition can be frozen after filling of the vial and remove the water in the vacuum. Then dry liofilizovannye powder, sealed in a bottle, and you can provide an accompanying vial of water for injections to restore the liquid composition before use. Parenteral suspensions receive essentially the same manner except that the compound is suspended in the environment instead of being dissolved, and sterilization cannot be done by filtering. The connection can be sterilized by exposure to ethylene oxide before suspendirovanie in sterile water. Mainly, the composition includes a surfactant or wetting agent to facilitate uniform distribution of the connection.

The compositions may contain from 0.1 wt.%, accordingly, 10-60 wt.%, the active material, depending on the method of introduction. When the compositions comprise a standard dosage form, each unit will contain, respectively, 50-500 mg of the active ingredient. The dosage used for the treatment of adults, will, therefore, vary from 10 to 3000 mg per day, for example, will be 1500 mg per day, depending on the method and frequency of administration. This dosage corresponds to 0.1-50 mg/kg per day.

Professionals in this field should be borne in mind that the optimal quantity is the primary objective and the interval between the introduction of individual dosages of the compounds of the invention will be determined by the nature and degree of the condition, which are treated, the form, manner and place of administration and the particular type of mammal, which is treated, and that their optimums can be determined by conventional methods. Professionals in this field should also be borne in mind that the optimal course of treatment, i.e. the number of doses of the compounds of the invention given per day for a certain number of days, can set the specialists in the field using conventional treatment of analytical tests.

All publications, including patents and patent applications, and other works cited in this description are included as references.

It should be borne in mind that the invention includes additional aspects listed below. The embodiments described for the first aspect also apply to these additional aspects. Diseases and conditions described above, in appropriate cases, refer to these additional aspects.

i) a Compound of the invention for use in the treatment or prevention of a disease or condition mediated by modulation of the receptor 5-HT1and/or receptor reuptake of serotonin.

ii) a Method of treating or preventing the disease or condition in a mammal mediated by modulation of the receptor 5-HT1and/or receptor re-absorption of serotonin, which includes an effective introduction to the icesta compounds of the invention.

Examples

The invention is illustrated by the examples described below.

In the procedures described hereinafter, after the name of each source of the substance typically contains a link to the description. This link is provided solely in aid specialist-chemist. The original substance is not necessary to receive from the party, to which reference is made.

Compounds were named using the software for chemical names ACD/Name PRO 6.02 (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

Proton nuclear magnetic resonance spectrum (NMR) register or on a Varian instrument at 300, 400 or 500 MHz or on a Bruker instrument at 300 MHz. Chemical shifts are indicated in ppm (δ) using the line of residual solvent as internal standard. The spectrogram of splitting the display in the notation s - singlet, d - doublet, t - triplet, Quartet, m - multiplet, user. broadened. NMR spectra recorded in the temperature interval from 25 to 90ºC. When finding multiple conformers, chemical shifts lead to the most abundant conformer.

Mass spectra (MS) are obtained on a quadrupole mass spectrometer 4 II (Micromass UK) or mass spectrometer Agilent MSD 1100, working on the type of ionization ES(+) and ES(-), or mass spectrometer Agilent LC/MSD 1100, working on the type of ionization ES(+) and ES(-), in combination with a device for HPLC series Agilent 1100 [LC/MS ES(+): analysis carried out on a Supelcosil ABZ + Plus (33×4.6 mm, 3 μm) (mobile phase 100% [water + 0.1% HCO2N] for 1 min, then from 100% [water + 0.1% HCO2N] to 5% [water + 0.1% HCO2N] and 95% [CH3CN] in 5 min, finally under these conditions for 2 min; T = 40 ºC, flow rate = 1 ml/min; LC/MS - ES(-): analysis carried out on a Supelcosil ABZ + Plus (33×4.6 mm, 3 μm) (mobile phase 100% [water + 0.05% of NH3] for 1 min, then from 100% [water + 0.05% of NH3] to 5% [water + 0.05% of NH3] and 95% [CH3CN] in 5 min, finally under these conditions for 2 min; T = 40 ºC, flow rate = 1 ml/min]. In the mass spectra is only one peak in the molecular cluster ions.

Flash chromatography on silica gel carried out on silica gel 230-400 mesh mesh (supplied by Merck AG Darmstadt, Germany), or pre-filled cartridges Varian Mega Be-Si, or pre-filled cartridges with silica Biotage.

Cartridges SPE-SCX represent the extraction column with ionoobmennoi solid phase, supplied by Varian. The eluent used with cartridges SPE-SCX is methanol followed by the application of a 2 N solution of ammonia in methanol.

Some ways to get do the cleaning with the use or non-automated device for flash chromatography (Flash+) Biotage, or automated systems for flash chromatography (Horizon). All these devices operate with cartriges Biotage Silica.

Cartridges SPE-Si presented Aut an extraction column with the solid phase of silicon dioxide, supplied by Varian.

(+/-)-BINAP- racemic 2,2-(diphenylphosphino)-1,1-binaphthyl
1,2-DCE and DCE- 1,2-dichloroethane
SN- cyclohexane
DAST- TRIFLUORIDE (diethylamino)sulfur
DBU- 1,8 - diazabicyclo[5.4.0]undec-7-EN
DCM- dichloromethane
DEOXOFLUOR- TRIFLUORIDE bis(2-methoxymethyl)uminosity
DIPEA- N,N-diisopropylethylamine
DMF- N,N'-dimethylformamide
EDC×HClhydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
Add- ethylenediaminetetraacetic acid
NMP- 1-methyl-2-pyrrolidone
rt- room temperature
TBTU- tetrafluoroborate O-(Ben is triazol-1-yl)-N,N,N',N'-tetramethylurea
Thea- triethylamine
TFK- triperoxonane acid
THF- tetrahydrofuran
Triton- hydroxide designed

Description 1. 2-Nitrophenyl-2-propen-1-silt ether (D1)

To a solution of 2-NITROPHENOL (100 g, 719,4 mmol) in acetone (1.4 l) in the atmosphere N2add allylbromide (68,5 ml, 791,4 mmol, 1.1 EQ.) and K2CO3(110 g, 791,4 mmol, 1.1 EQ.). A heterogeneous mixture is heated to boiling under reflux and stirred for 16 hours. The mixture is cooled to room temperature, and the solids filtered and washed with Et2O. the combined organic phases are concentrated in vacuo and get named in the title compound (132 g, 737,4 mmol) as a pale orange viscous oil, which is used in the next stage without additional purification. MS (ES) m/z: 180,10 [MH+]. C9H9NO3requires 179,17.1H-NMR (300 MHz, CDCl3) δ: 7,76 (m, 1H), 7,43 (m, 1H), 7,01-6,92 (m, 2H), 5,94 (m, 1H), 5,42 (m, 1H), 5,26 (m, 1H), with 4.64-4,59 (m, 2H).

Description 2. 2-Nitro-6-(2-propen-1-yl)phenol (D2)

2-Nitrophenyl-2-propen-1-silt ester (D1) (132 g, 737,4 mmol) is stirred and heated on a sand bath is reflux while at 200 ° C (internal temperature of 180 160º) for 26 hours. After cooling, the crude reaction product is purified by filtration through a layer of silica (1 kg) with elution with a gradient of mixtures of cyclohexane/ethyl acetate (100:0 to 80:20) and get named in the title compound as a pale yellow oil (89 g, 68%). MS (ES) m/z: 180,10 [MH+]. C9H9NO3requires 179,17.1H-NMR (300 MHz, CDCl3) δ: 10,86 (s, 1H), to $ 7.91 (m, 1H), 7,38 (m, 1H), 6,84 (m, 1H), 5,94 (m, 1H), 5,07-free 5.01 (m, 2H), 3.43 points is 3.40 (m, 2H).

Description 3. Methyl-{[2-nitro-6-(2-propen-1-yl)phenyl]oxy}acetate (D3)

To a solution of 2-nitro-6-(2-propen-1-yl)phenol (D2) (76 g, 424,6 mmol) in acetone (600 ml) with stirring at room temperature and under nitrogen atmosphere add methylbromide (42.2 ml, 445,8 mmol, of 1.05 equiv.) and K2CO3(61,6 g, 445,8 mmol, of 1.05 EQ.). The mixture is heated at 60 ° C and stirred for 3.5 hours. The mixture is cooled, the solid is filtered off and the solution concentrated in vacuo. The residue is dissolved in ethyl acetate (1 l) and extracted with 1 N NaOH solution (3×200 ml), water (1×200 ml) and brine (1×200 ml). The combined organic layers are dried (MgSO4) and concentrated in vacuo, and get named in the title compound as a viscous pale yellow oil, which was used in the next stage without additional purification. MS (ES) m/z: 252,10 [MH+]. C12H13NO5requires 251,24.1H-NMR (300 MHz, CDCl3) δ: 7,66 (m, 1H), 7,39 (m, 1H), 7,14 (m, 1H), ,88 (m, 1H), 5,10-of 4.95 (m, 2H), 4,56 (s, 2H, in), 3.75 (s, 3H), 3,49-of 3.46 (m, 2H).

Description 4. 8-(2-Propen-1-yl)-2H-1,4-benzoxazin-3(4H)-he (D4)

To a solution of methyl-{[2-nitro-6-(2-propen-1-yl)phenyl]oxy}acetate (D3) (109 g, 434 mmol) in a mixture of Meon/N2O) (1:1, 1.8 l) was added with stirring iron powder (145 g, 2.6 mol, 6 EQ.) and NH4Cl (232 g, 4,34 mol, 10 EQ.). The mixture is heated at 80 ° C and stirred for 3.5 hours and then cooled to about 40ºC. The mixture is filtered through celite using a mixture Meon/DCM (1:1, 1 l) as eluent. The solvent is evaporated to dryness and then add DCM (2 l). The organic phase is washed with saturated aqueous ammonium chloride, water and brine. Mixed organic phase is dried (Na2SO4and discolor, adding carbon powder. The mixture is filtered, the filtrate evaporated in vacuo, and get the remainder, which is cleaned on a layer of silica with a gradient of mixtures of cyclohexane/ethyl acetate(4:1 - 1:1), and you get named in the title compound (70 g, 86%) as a white solid. MS (ES) m/z: 190,10 [MH+]. C11H11NO2requires 189,21.1H-NMR (300 MHz, CDCl3) δ: 8,10-a 7.85 (users, 1H), 6,91-6,84 (m, 2H), 6,66 (m, 1H), 5,95 (m, 1H), 5,10-5,00 (m, 2H), br4.61 (s, 2H), 3,40-to 3.36 (m, 2H).

5. Ethyl-6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D5)

To a solution of 8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-she (D4) (170 mg, 0.9 m is ol) and tert-butoxide potassium (110 mg, 0.9 mmol) in dry DMF (5 ml) at 0 ° C add diethylphosphate (0.15 ml, 1.8 mmol). After 10 minutes, add a solution of ethylisothiocyanate (0.15 ml, 1.35 mmol) and tert-butoxide potassium (152 mg, 1.35 mmol) in dry DMF (2 ml). The reaction mixture was stirred at 60 ° C for 6 hours, then cooled and quenched the reaction with water (5 ml). DMF is evaporated under vacuum, the crude reaction product is purified on SPE cartridge-Si c-elution with a mixture of 30% ethyl acetate in cyclohexane and get named in the title compound as a white solid (132 mg, 52%). MS (ES) m/z: RUB 285.2 [MH+]. C16H16N2O3requires at 284.3.1H-NMR (300 MHz, CDCl3) δ: 8,2 (s, 1H), 7,55 (d, 1H), and 7.3 (d, 1H), 7,2 (t, 1H), and 6.25 (m, 1H), 5,7 (s, 2H), 5,2-5,3 (m, 2H)and 4.65 (q, 2H), 3,65 (d, 2H), 1,6 (t, 3H).

Description 6. Ethyl-6-(2-oxoethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D6)

To a solution of ethyl-6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D5) (77 mg, 0.27 mmol) in a mixture of THF/water (2:1, 1.5 ml) was added with stirring the osmium tetroxide (0.2 ml of 4 wt.% solution in water, 0,125 EQ.). After 10 minutes add periodate sodium (145 mg, of 0.68 mmol) and the reaction mixture is stirred for 2 hours. After evaporation of THF, the residue partitioned between water (10 ml) and DCM (3×10 ml). The organic layers are combined, dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si c is lirovanie a mixture of 4% methanol in DCM and get named in the title compound as a white solid (52 mg, 67%).1H-NMR (300 MHz, CDCl3) δ: 9,8 (s, 1H), 8 (s, 1H), and 7.4 (t, 1H), 7-7,1 (m, 2H), and 5.5 (s, 2H), 4,35 (kV, 2H), and 3.8 (s, 2H), 1,4 (t, 3H).

Description 7. 6-(2-Propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (D7)

A solution of ethyl-6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D5) (900 mg, 3,17 mmol) in a mixture of methanol and 1m sodium hydroxide solution (1:1, 60 ml) is stirred at 60 ° C for 30 minutes. The cooled reaction mixture is neutralized with acetic acid and then cooled to 0OC. The crude reaction product is collected by filtration, washed with methanol and dried, and get named in the title compound as a white solid (570 mg, 70%).1H-NMR (300 MHz, CDCl3) δ: 8,55 (s, 1H), of 7.75 (d, 1H), 7,05-to 7.15 (m, 2H), and 5.8 (m, 1H), and 5.5 (s, 2H), a 5.0 to 5.1 (m, 2H), 3.45 points (d, 2H).

Description 8. N,N-Dimethyl-6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (D8)

1-Hydroxybenzotriazole (80 mg, 0.59 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (113 mg, 0.59 mmol) are added to a solution of 6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (D7) (150 mg, 0.59 mmol) and dimethylamine (0,35 ml of 2 M solution in THF, 0.7 mmol) in a solution of DMF/DCM (2:1, 6 ml). The reaction mixture was stirred at room temperature for 4 hours, DMF was removed the cartridge SPE-SCX (elution with methanol, then 2 N solution of ammonia in methanol). Then the crude reaction product on isout on the cartridge SPE-Si c-elution with a mixture of 5% methanol in DCM and get named in the title compound as a white solid (68 mg, 41%). MS (ES) m/z: 284,2 [MH+]. C16H16N2O3requires is 283.3.1H-NMR (300 MHz, CDCl3) δ: a 7.85 (s, 1H), 7,35 (d, 1H), 7,05 (d, 1H), 6,95 (t, 1H), 5,95 (m, 1H), and 5.5 (s, 2H), of 5.05 (m, 2H), 3,6 (s, 3H), of 3.45 (d, 2H), 3,1 (s, 3H).

Description 9. N,N-Dimethyl-6-(2-oxoethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (D9)

N-Oxide 4-methylmorpholine (50 mg, 0.42 mmol) and osmium tetroxide (50 μl of 4 wt.% solution in water, a 0.035 EQ.) added to a solution of N,N-dimethyl-6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (D8) (60 mg, 0.21 mmol) in a mixture of acetone/water (8:1, 2.25 ml). The reaction mixture is stirred for 4 hours and then the reaction quenched with a saturated aqueous sodium sulfite (10 ml). After 30 minutes stirring, the mixture is extracted with ethyl acetate (3×10 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, and receive the intermediate compound 6-(2,3-hydroxypropyl)-N,N-dimethyl-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (40 mg, 0.14 mmol, 60%), which is dissolved in a mixture of THF/water (1:1, 2 ml) without further purification. Add periodate sodium (43 mg, 0.21 mmol) and the mixture is stirred for 1 hour. After evaporation of THF, the residue is treated with water (10 ml) and DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The crude substance is purified by chromatography with elution with a 2% solution of methanol in DCM, and the floor is given the corresponding 6-[2,2-bis(metiloksi)ethyl]-N,N-dimethyl-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (25 mg). Hydrolysis of the acetal HCl (0.15 ml, 1 M solution in diethyl ether and subsequent evaporation of volatile substances give named the title compound (20 mg) as a white solid.1H-NMR (300 MHz, CDCl3) δ: of 9.75 (s, 1H), and 7.8 (s, 1H), 7,45 (t, 1H), 7,05 (d, 1H), 6.75 in (d, 1H), and 5.5 (s, 2H), 3,55 (s, 3H), and 3.8 (s, 2H), 3,1 (s, 3H).

Description 10. N-Cyclopentyl-6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (D10)

Named in the title compound are obtained from the output 21% according to the General procedure descriptions 8, from 6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (D7) (150 mg, 0.59 mmol) and cyclopentylamine (70 μl, 0.07 mmol). MS (ES) m/z: 324 [MH+]. C19H21N3O2requires 323,4.1H-NMR (300 MHz, CDCl3) δ: a 7.85 (s, 1H), and 7.3 (d, 1H), 6,9-7,1 (m, 3H), 5,95 (m, 1H), of 5.55 (s, 2H), of 5.05 (m, 2H), 4,35 (kV, 1H), 3.45 points (d, 2H), 2-2,1 (m, 2H), of 1.45 to 1.8 (m, 6H).

Description 11. N-Cyclopentyl-6-(2-oxoethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (D11)

N-oxide 4-methylmorpholine (28 mg, 0.24 mmol) and osmium tetroxide (29 μl of 4 wt.% solution in water, a 0.035 EQ.) added to a solution of N-cyclopentyl-6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (D10) (37 mg, 0.12 mmol) in a mixture of acetone/water (8:1, 2.25 ml). The reaction mixture is stirred for 4 hours and then the reaction quenched with a saturated aqueous sodium sulfite (10 ml). After 0 minutes of mixing, the mixture is extracted with ethyl acetate (3×10 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, and receive the intermediate compound 6-(2,3-hydroxypropyl)-N-cyclopentyl-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (38 mg, 0.14 mmol, 90%), which is dissolved in a mixture of THF/water (1:1, 2 ml) without further purification. Add periodate sodium (34 mg, 0.16 mmol) and the mixture is stirred for 1 hour. After evaporation of THF, the residue is treated with water (10 ml) and DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, and get named in the title compound as a white solid (25 mg), used without further purification.1H-NMR (300 MHz, CDCl3) δ: 9,8 (s, 1H), and 7.8 (s, 1H), 7,45 (t, 1H), between 6.7 and 7.1 (m, 3H), and 5.5 (s, 2H), 4,4 (kV, 1H), and 3.8 (s, 2H), 1,4-1,9 (m, 8H).

Description 12. 6-(2-Propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin (D12)

A mixture of 6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (D7) (120 mg, 0.47 mmol) and 1,2-dichlorobenzene (1.5 ml) is irradiated in the microwave reactor (PersonalChemistry ErmysTM Optimiser, 300 W, 250º, 10 minutes). The solvent is removed on the cartridge SPE-SCX (elution with methanol, then 2 N solution of ammonia in methanol) and get named in the title compound as a white solid (61 mg, 100%). MS (ES) m/z: 213,2 [MH+]. C13H12N2O requires 212,3.1H-NMR (300 MHz, CDCl3) δ: 8,6 (s, 1H), and 7.6 (d, 1H), 7,2-7,35 (m, 3H), and 6.25 (m, 1H) 5,5 (s, 2H), 5,35 (m, 2H), 3,65 (d, 2H).

Description 13. 4H-Imidazo[5,1-c][1,4]benzoxazin-6-ylacetamide (D13)

Named the title compound is obtained in 30% yield according to the procedure of description 11, from 6-(2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazine (D12) (60 mg, 0.28 mmol). The reaction mixture is stirred for 3 days, and for good conversion to the intermediate compound 3-(4H-imidazo[5,1-c][1,4]benzoxazin-6-yl)-1,2-propandiol required additional amount of osmium tetroxide (50 μl, was 0.026 EQ.) and N-oxide 4-methylmorpholine (66 mg, 0,56 mmol).1H-NMR (300 MHz, CDCl3) δ: 9,8 (s, 1H), 8,15 (s, 1H), 7.7 (d, 1H), 7,3 was 7.45 (m, 3H), and 5.5 (s, 2H, in), 3.75 (s, 2H).

Description 14. 8-(3-Hydroxypropyl)-2H-1,4-benzoxazin-3(4H)-he (D14)

To a solution of 8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-she (D4) (2.5 g, 13,2 mmol) in dry THF (45 ml) at 0 ° C is added dropwise a 1.6 M solution of disimilarity in THF (18 ml, 29 mmol). The solution is stirred for 4 hours at 0 ° C and then overnight at room temperature. The reaction mixture was diluted with ethanol (8,7 ml) and then added dropwise an aqueous solution of sodium hydroxide (6 M, 3 ml) and hydrogen peroxide (aqueous 35 wt.% the solution, 6 ml). The mixture was stirred at 50ºC for 2 hours and then cooled to room temperature, diluted with water (300 ml) and extracted with ethyl acetate (3×300 ml). United organic layers are dried (Na2SO4and concentrate vacuume. The crude reaction product is purified on SPE cartridge-Si c-elution with a mixture of 40% cyclohexane in ethyl acetate, and get named in the title compound as a white solid (1.9 g, 69%).1H-NMR (300 MHz, CDCl3) δ: 8,1 (users, 1H), 6,9 (m, 2H), of 6.65 (d, 1H), 4,6 (s, 2H), 3,6 (t, 2H), and 2.7 (t, 2H), 1.8 m (DD, 2H).

Description 15. 8-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-2H-1,4-benzoxazin-3(4H)-he (D15)

To a solution of 8-(3-hydroxypropyl)-2H-1,4-benzoxazin-3(4H)-she (D14) (0.5 g, 2.4 mmol) in dry DMF (35 ml) was added imidazole (1.6 g, 24 mmol) and tert-butyldimethylsilyl (3.5 g, 24 mmol). The reaction mixture was stirred at room temperature for 4 hours, then the reaction is quenched with saturated aqueous NaHCO3(200 ml) and the mixture extracted with ethyl acetate (3×200 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si c-elution with a mixture of 30% cyclohexane in ethyl acetate and get named in the title compound (containing ~50% DMF). The connection used in the next stage without additional purification. MS (ES) m/z: 322,2 [MH+]. C17H27NO3Si requires 321,5.1H-NMR (300 MHz, CDCl3) δ: 8,3 (s, 1H), 8 (s, 1H DMF)and 6.9 (m, 2H), 6,7 (d, 1H), 4,6 (s, 2H), and 3.7 (t, 2H), 2,95 (3H, DMF), and 2.8 (3H, DMF), to 2.65 (t, 2H), and 1.9 (m, 2H), and 0.9 (s, 9H), 0 (s, 6H).

Description 16. Ethyl-6-(3-hydroxypropyl)-4H-imidazo[5,1-c]1,4]benzoxazin-3-carboxylate (D16)

Named the title compound is obtained in yield of 24% according to the procedure of description 5, from 8-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2H-1,4-benzoxazin-3(4H)-she (D15) (2.4 mmol). The crude reaction product is purified on SPE cartridge-SCX (elution with methanol, then 2 N solution of ammonia in methanol). MS (ES) m/z: 303,2 [MH+]. C16H18N2O4requires 302,3.1H-NMR (500 MHz, DMSO-d6) δ: 8 (s, 1H), and 7.3 (d, 1H), and 7.1 (d, 1H), 6,9 (t, 1H), and 5.5 (s, 2H), 4,3 (kV, 2H), and 3.7 (t, 2H), and 2.8 (t, 2H), 1.8 m (m, 2H), 1,4 (t, 3H).

Description 17. Ethyl-6-(3-oxopropyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D17)

To a solution of ethyl-6-(3-hydroxypropyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D16) (170 mg, 0,56 mmol) in DCM (5 ml) is added by portions periodan dess-Martin (263 mg, 0,56 mmol). The reaction mixture was stirred at room temperature for 2 hours, filtered, the reaction is quenched with water (10 ml) and the mixture extracted with DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, and get named in the title compound (160 mg, 100%), which is used without further purification. MS (ES) m/z: 301,2 [MH+]. C16H16N2O4requires 300,3.1H-NMR (300 MHz, CDCl3) δ: 9,8 (s, 1H), and 8.2 (m, 1H), 7,6-8 (m, 3H), and 5.5 (s, 2H), 4,35 (kV, 2H), 3 (m, 2H), and 2.7 (m, 2H) 1,4 (t, 3H).

Description 18. 8-(2-Propen-1-yl)-2H-1,4-benzoxazin-3(4H)-tion (D18)

A mixture of 8-(2-propen-yl)-2H-1,4-benzoxazin-3(4H)-she (D4) (2 g, 10.5 mmol) and reagent Laussane (2.2 g, 5.3 mmol) in dry toluene (35 ml) is heated at the boil under reflux for 1 hour. The mixture is cooled to room temperature and the solvent is evaporated in vacuum. The crude substance is purified by chromatography on silica gel with elution with a mixture of 10% cyclohexane in ethyl acetate and get named in the title compound as a white solid (1.9 g, 88%).1H-NMR (300 MHz, CDCl3) δ: 9,6 (s, 1H), 6,85 (m, 2H), 6.75 in (m, 1H), and 5.8 (m, 1H), of 5.05 (m, 2H), and 4.75 (s, 2H), 3,35 (d, 2H).

Description 19. 3-(Methylthio)-8-(2-propen-1-yl)-2H-1,4-benzoxazin (D19)

To a mixture of 8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-thione (D18) (100 mg, 0.49 mmol) and potassium hydroxide (69 mg, of 1.23 mmol) in acetone (2 ml) add methyliodide (46 μl, of 0.74 mmol) in two doses with an interval of 15 minutes. The reaction mixture is heated at the boil under reflux for 2 hours, cooled, filtered to remove potassium iodide and evaporated in vacuum. The crude substance is purified by chromatography on silica gel with elution with a mixture of 10% cyclohexane in ethyl acetate and get named in the title compound as a colourless oil (70 mg, 65%). MS (ES) m/z: 220,2 [MH+]. C12H13NOS requires 219,3.1H-NMR (300 MHz, CDCl3) δ: 7.2V (m, 1H), 6,9 (users, 2H), 5,9 (m, 1H), 5 (m, 2H), and 4.5 (s, 2H), and 3.3 (d, 2H), and 2.5 (s, 3H).

Description 20. N-[2,2-Bis(metiloksi)ethyl]-8-(2-propen-1-yl)-2H-1,4-Benz is casin-3-amine (D20)

A mixture of 3-(methylthio)-8-(2-propen-1-yl)-2H-1,4-benzoxazine (D19) (180 mg, 0.82 mmol) and dimethylacetal of aminoacetaldehyde (134 μl, of 1.23 mmol) in dry ethanol (5 ml) is heated at the boil under reflux for 9 hours. Volatile matter is evaporated in vacuo, the crude reaction product is purified by chromatography on silica gel with elution with a mixture of 40% ethyl acetate in cyclohexane and get named in the title compound as a colourless oil (93 mg, 41%). MS (ES) m/z: making up 277.3 [MH+]. C15H20N2O3requires 276,3.1H-NMR (300 MHz, CDCl3) δ: 7.2V (m, 1H), 6,9 (users, 2H), 5,9 (m, 1H), 5 (m, 2H), and 4.5 (s, 2H), and 3.3 (d, 2H), and 2.5 (s, 3H).

Description 21. 6-(2-Propen-1-yl)-4H-imidazo[2,1-c][1,4]benzoxazin (D21)

A mixture of N-[2,2-bis(metiloksi)ethyl]-8-(2-propen-1-yl)-2H-1,4-benzoxazin-3-amine (D20) (90 mg, 0.33 mmol) and conc. hydrochloric acid (0.8 ml) in methanol (1 ml) heated to boiling under reflux for 3 hours. After concentration in vacuo the residue is dissolved in DCM (20 ml), the solution washed with aqueous saturated solution of NaHCO3(15 ml), dried (Na2SO4) and evaporated in vacuo. The crude substance is purified by chromatography on silica gel with elution with a mixture of 35% ethyl acetate in cyclohexane and get named in the title compound as a yellow solid (65 mg, 92%). MS (ES) m/z: 213,3 [MH+]. C13H12Nsub> 2O requires 212,3.1H-NMR (300 MHz, CDCl3) δ: 7,4 (users, 1H), 7,2 (users, 2H), 7,05 (users, 2H), 5,95 (m, 1H), 5,3 (s, 2H), 5,1 (m, 2H), 3.45 points (d, 2H).

Description 22 and 23

4H-Imidazo[2,1-c][1,4]benzoxazin-6-ylacetamide (D22)

4H-Imidazo[2,1-c][1,4]benzoxazin-6-carbaldehyde (D23)

Named the title compound is obtained using the procedure described in the description of the 11 on the basis of 6-(2-propen-1-yl)-4H-imidazo[2,1-c][1,4]benzoxazine (D21) (200 mg, of 0.94 mmol). The reaction mixture is stirred for 2 days, and requires an additional amount of osmium tetroxide (200 μl, 0.03 EQ.) and N-oxide 4-methylmorpholine (250 mg, 2.1 mmol). The reaction gives a mixture of two aldehydes D22 and D23 (~7:3), which is used in the next stage. MS (ES) m/z: D22 215,3 [MH+], C12H10N2O2requires 214,3; for D23 201,3 [MH+], C11H8N2O2requires 200,2.1H-NMR (300 MHz, CDCl3) δ: 10,5 (s, 1H D23), and 9.8 (s, 1H D22), and 7.7 (m, 1H D23), 7.5 (m, 1H D23), 7-7,4 (m, 5H D22+3H D23), to 5.4 (s, 2H D23 in), 5.25 (s, 2H D22), and 3.8 (s, 2H D22).

Description 24. 1-Methyl-6-(2-propen-1-yl)-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin (D24)

A solution of 8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-thione (D18) (1,38 g of 6.71 mmol) in absolute ethanol (50 ml) is added dropwise within 1 hour at 80 ° C to a solution of hydrazine monohydrate (8 ml) in absolute ethanol (50 ml). The reaction mixture is stirred at the boil under reflux (80 is C) for 40 minutes and concentrated in vacuo and receive the intermediate hydrazone compound (3E)-8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-it, which was immediately used in the next stage without any further purification. The hydrazone is mixed with triethylorthoformate (15 ml) and heated with stirring at 150 º C for 10 minutes when exposed to microwave radiation. The reaction mixture is evaporated in vacuo, the residue is purified flash chromatography on silica gel with elution with a mixture of 5% methanol in DCM and get named in the title compound as a pale yellow solid (0,78 g, 51%). MS (ES) m/z: 228,20 [MH+]; C13H13N3O requires 227,27.1H-NMR (300 MHz, CDCl3) δ: of 7.36 (d, 1H), 7,11-7,03 (m, 2H), 6,01 of 5.84 (m, 1H), 5.25 in (s, 2H), 5.08 to free 5.01 (m, 2H), 3.43 points (d, 2H), was 2.76 (s, 3H).

Description 25. (1-Methyl-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-6-yl)acetaldehyde (D25)

N-Oxide 4-methylmorpholine (145 mg, 1,24 mmol) and osmium tetroxide (0,20 ml of 4 wt.% solution in water) are added to a solution of 1-methyl-6-(2-propen-1-yl)-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazine (D24) (142 mg, of 0.62 mmol) in a mixture of acetone/water (8:1, 9 ml). The resulting reaction mixture was stirred at room temperature overnight, evaporated in vacuum and then the residue purified flash chromatography on silica gel with elution with a mixture of 5% methanol in DCM, and receive the intermediate compound 3-(1-methyl-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-6-yl)-1,2-propandiol (97 mg, 60%) as a white solid. The resulting material dissolved in a mixture of THF/water (1:1, 3 is l), add periodate sodium (197 mg, of 0.92 mmol) and the resulting mixture was stirred at room temperature for 1 hour. After evaporation of THF, the residue is treated with water (10 ml) and DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, and get named in the title compound as a white solid (50 mg, 35%), which can be used without additional purification. MS (ES) m/z: 230,20 [MH+]. C12H11N3O2requires 229,24.1H-NMR (300 MHz, CDCl3) δ: 9,78 (s, 1H), 7,49 (d, 1H), 7,15 for 7.12 (m, 2H), 5,28 (s, 2H), 3,82 (s, 2H), and 2.79 (s, 3H).

Description 26. 4-(2-Oxopropyl)-8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-he (D26)

Sodium hydride (159 mg, 60%, mass./mass., suspension in mineral oil, 3,98 mmol) at 0OC was added parts to the solution of 8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-she (D4) (500 mg, to 2.65 mmol) and 1-chloro-2-propanone (253 μl, 3,17 mmol) in dry DMF (6 ml). The reaction mixture is left to warm to room temperature and stirred for 7 hours and then the reaction quenched with water (10 ml)and the mixture extracted with ethyl acetate (3×30 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, get the crude reaction product, which was purified flash chromatography on silica gel with elution with a mixture of DCM/acetone (95/5), and get named in the title compound as white is th solid (314 mg, 49%). MS (ES) m/z: 246,20 [MH+]. C14H15NO3requires 245,28.1H-NMR (300 MHz, CDCl3) δ: 6,95-6,85 (m, 2H), of 6.49 (m, 1H), 5,95 (m, 1H), 5.08 to free 5.01 (m, 2H), 4,67 (s, 4H), 3,39 (m, 2H), 2,54 (s, 3H).

Description 27. 2-Methyl-6-(2-propen-1-yl)-4H-imidazo[2,1-c][1,4]benzoxazin (D27)

To a solution of 4-(2-oxopropyl)-8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-she (D26) (63 mg, 0,257 mmol) in glacial acetic acid (1 ml) is added ammonium acetate (396 mg, 5,14 mmol). The mixture is irradiated in the microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 150 º C, 10 min), then diluted with ethyl acetate (10 ml), poured into a mixture of ice water (10 ml) and alkalinized with an aqueous solution of ammonium hydroxide (3 ml). The mixture is extracted with ethyl acetate (3×20 ml), the combined organic layers are dried (Na2SO4), and remove the solvent under reduced pressure. The crude substance is purified flash chromatography on silica gel with elution with a mixture of DCM/acetone (95/5), and get named in the title compound (47 mg, 81%). MS (ES) m/z: 227,10 [MH+]. C14H14N2O requires 226,28.1H-NMR (300 MHz, CDCl3) δ: 7,09-6,94 (m, 4H), 5,95 (m, 1H), 5,19 (s, 2H), 5,06-5,00 (m, 2H), 3,39 (m, 2H), and 2.26 (s, 3H).

Description 28. (2-Methyl-4H-imidazo[2,1-c][1,4]benzoxazin-6-yl)acetaldehyde (D28)

Named in the header connection receive according to the procedure of description 6 based on 2-methyl-6-(2-propen-1-yl)-4H-imidazo[2,1-c][1,4]benzoxazine (D27). The reaction product is extracted with a yield of 36% of flash is-chromatography on silica gel using as eluent a mixture of ethyl acetate/cyclohexane (1/1). MS (ES) m/z: 229,20 [MH+]. C13H12N2O2requires 228,25.1H-NMR (300 MHz, CDCl3) δ: 9,77 (s, 1H), 7,22-6,91 (m, 4H), of 5.24 (s, 2H), of 3.77 (s, 2H), 2,31 (s, 3H).

Description 29. 4-(1-Methyl-2-oxopropyl)-8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-he (D29)

A mixture of 8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-she (D4) (500 mg, to 2.65 mmol), 3-chloro-2-butanone (294 μl, only 2.91 mmol, 1.1 EQ.) and K2CO3(402 mg, only 2.91 mmol, 1.1 EQ.) in dry acetone (15 ml) is heated at the boil under reflux for 4 hours. Add another 3-chloro-2-butanone (294 μl, only 2.91 mmol, 1.1 EQ.) and K2CO3(402 mg, only 2.91 mmol, 1.1 equiv.) and the reaction mixture is heated to boiling under reflux for 18 hours. The mixture is cooled to room temperature, the solid is filtered and washed with acetone (50 ml)and the combined filtrates concentrated in vacuo. The crude substance is purified flash chromatography on silica gel with elution with a mixture of DCM/acetone 95/5) and get named in the title compound (626 mg, 91%) as a pale yellow viscous oil. MS (ES) m/z: of 260.2 [MH+]. C15H17NO3requires 259,31.1H-NMR (300 MHz, CDCl3) δ: of 6.96-6,85 (m, 2H), 6,66 return of 6.58 (m, 1H), to 5.93 (m, 1H), 5,16-5,00 (m, 3H), 4,70-to 4.52 (m, 2H), 3,38 (m, 2H), 2,12 (s, 3H)and 1.51 (m, 3H).

Description 30. [4-(1-Methyl-2-oxopropyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl]acetaldehyde (D30)

Named in the title compound recip shall comply with the exit 64% according to the procedure describe 6, on the basis of 4-(1-methyl-2-oxopropyl)-8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-she (D29) (195 mg, 0,753 mmol). The reaction product is purified flash chromatography on silica gel using as eluent a mixture of ethyl acetate/cyclohexane (1/1).1H-NMR (300 MHz, CDCl3) δ: 9,72 (s, 1H), 6,93 (m, 1H), 6,85 (m, 1H), of 6.68 (m, 1H), 5,12 (m, 1H), 4,59 (m, 2H), 3,71 (s, 2H), 2,11 (s, 3H), 1,50 (m, 3H).

Description 31. 4-(1-Methyl-2-oxopropyl)-8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-he (D31)

Named in the title compound obtained as white solid with a yield of 92% according to the General procedure described in example 1, from [4-(1-methyl-2-oxopropyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl]acetaldehyde (D30) (127 mg, 0,487 mmol). The reaction product is purified flash chromatography on silica gel with elution with a gradient of mixtures of DCM/methanol (99/1-98/2). MS (ES) m/z: 473,40 [MH+]. C28H32N4O3requires 472,59.1H-NMR (500 MHz, DMSO-d6) δ: at 8.36 (d, 1H), 7,60 (m, 2H), 7,40 (d, 1H), 7,12 (DD, 1H),? 7.04 baby mortality (m, 3H), 4.95 points (quart, 1H), 4,7 (DD, 2H), 3,05 (users, 4H), 2,85 (t, 2H), 2,75 (users, 4H), 2,65 (m, 5H), of 2.08 (s, 3H), of 1.41 (d, 3H).

Description 32. Methyl-[3-oxo-8-(2-propen-1-yl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (D32)

Named the title compound is obtained in yield of 95% according to the General procedure descriptions 26. In accordance with this 8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-he (D4) (1.0 g, from 5.29 mmol) in DMF (15 ml) obrabatyvayutsya (651 μl, to 6.88 mmol, 1.3 EQ.) and sodium hydride (318 mg, 60% wt./mass. suspension in oil, 7,94 mmol, 1.5 EQ.). The mixture is stirred for 6 hours and the crude reaction product is purified flash chromatography on silica gel using as eluent a mixture of ethyl acetate/cyclohexane (1/4). MS (ES) m/z: 262,2 [MH+]. C14H15NO4requires 261,28.1H-NMR (300 MHz, CDCl3) δ: of 6.96-6.90 to (m, 2H), 6,65-6,60 (m, 1H), 5,95 (m, 1H), 5,10-free 5.01 (m, 2H), 4,67 (s, 2H), of 4.66 (s, 2H), of 3.78 (s, 3H), 3,39 (m, 2H).

Description 33. Methyl[3-oxo-8-(2-oxoethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (D33)

Named the title compound is obtained in yield 66% according to the General procedure descriptions 6 on the basis of methyl-[3-oxo-8-(2-propen-1-yl)-2,3-dihydro-4H-1,4-benzoxazin-yl]acetate (D32) (1.0 g, a 3.83 mmol). The reaction product is purified flash chromatography on silica gel using as eluent a mixture of ethyl acetate/cyclohexane (3/7).1H-NMR (300 MHz, CDCl3) δ: 9,74 (m, 1H), 6,98 (m, 1H), to 6.88 (m, 1H), of 6.71 (m, 1H), and 4.68 (s, 2H), 4,67 (s, 2H), 3,79 (s, 3H), 3,74 (m, 2H).

Description 34. Methyl-(8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate (D34)

Named in the title compound are obtained from the output 90% according to the procedure of example 1, from methyl[3-oxo-8-(2-oxoethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (D33) (300 mg, to 1.14 mmol). The reaction product is purified flash chromatography on silica gel with blueraven is eaten with gradient mixtures of DCM/methanol (99/1-98/2). MS (ES) m/z: 475,20 [MH+]. C27H30N4O4requires 474,56.1H-NMR (300 MHz, CDCl3) δ: of 8.37 (m, 1H), 7,71 (m, 1H), 7,58 (m, 1H), 7,24 (m, 1H), 7,07 (m, 1H), 6,95 (m, 2H), only 6.64 (m, 1H), 4,70 (s, 2H), of 4.66 (s, 2H), 3,79 (s, 3H), and 3.16 (users, 4H), 2,98-2,74 (osirm, 8H), by 2.73 (s, 3H).

Description 35. (8-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (D35)

To a suspension of methyl-(8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate (D34) (300 mg, 0,633 mmol) in methanol (5 ml) is added 2 N NaOH solution in methanol (5 ml). The mixture is stirred at room temperature for 4 hours and then add water (10 ml). The methanol is evaporated under reduced pressure and the residue acidified with 6 N hydrochloric acid (5 ml). The mixture contribute to the cartridge SPE-SCX (elution with a mixture of water/methanol, 1:1, then 2 N solution of ammonia in methanol) and get named in the title compound as a white solid (290 mg, 99%). MS (ES) m/z: 461,2 [MH+]. C26H28N4O4requires 460,54.1H-NMR (300 MHz, DMSO-d6) δ: 8.30 to (m, 1H), 7,58-7,52 (m, 2H), 7,34 (m, 1H), 7,07 (m, 1H), 6.90 to-to 6.80 (m, 2H), 6.75 in (m, 1H), 4,60 (s, 2H), is 4.21 (s, 2H), 3,01 (users, 4H), 2,84-2,53 (osirm, 11H).

Description 36. 8-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-4-(3,3,3-Cryptor-2-oxopropyl)-2H-1,4-benzoxazin-3(4H)-he (D36)

To a suspension of (8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-oxo-2,3-dihydr is-4H-1,4-benzoxazin-4-yl)acetic acid (D35) (115 mg, 0.25 mmol) in toluene (10 ml) at room temperature add oxalicacid (64 μl, 0.75 mmol, 3 EQ.) and a drop of DMF. The suspension is heated at 60 ° C for 3 hours. Removal of the solvent under reduced pressure gives the crude acid chloride, which integrate directly in the subsequent interaction. To a suspension of the crude acid chloride (120 mg, 0.25 mmol) in DCM (10 ml) at room temperature add triperoxonane anhydride (315 μl, 1.5 mmol, 6 equiv.) and pyridine (162 μl, 2 mmol, 8 EQ.). After stirring for 2 hours, add water (15 ml) and then the reaction mixture was alkalinized by adding NaHCO3(saturated aqueous solution, 10 ml). The organic phase is separated and the remaining aqueous phase is extracted with DCM (3×50 ml). The combined organic phases are dried (MgSO4) and evaporated under reduced pressure, and get the crude reaction product, which was subjected to column flash chromatography on silica gel with elution with a mixture of DCM/methanol (97/3), and get named in the title compound D36 (hydrate ketone) as a yellow solid (79 mg, 60%). MS (ES) m/z: 531,1 [MH+]. C27H29F3N4O4requires 530,55.1H-NMR (300 MHz, DMSO-d6) δ: of 8.37 (m, 1H), of 7.70 (m, 1H), 7,58 (m, 1H), 7.23 percent (m, 1H), 7,08-for 6.81 (m, 4H), 5,15-4,20 (m, 4H), 3,14 (users, 4H), 2.95 and-2,60 (osirm, 11H).

Description 37. 2-(2-butyn-1 yloxy)-1-nitro-3-(2-prop is-1-yl)benzene (D37)

A mixture of 2-nitro-6-(2-propen-1-yl)phenol (D2) (500 mg, and 2.79 mmol), 1-bromo-2-butyne (269 μl, of 3.07 mmol, 1.1 EQ.) and K2CO3(424 mg, of 3.07 mmol, 1.1 EQ.) in acetone (20 ml) heated to boiling under reflux for 4 hours. The mixture is cooled to room temperature, and then the solids filtered and washed with acetone (30 ml). The combined organic phase was concentrated in vacuo, the crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (1/9) and get named in the title compound (640 mg, 99%).1H-NMR (300 MHz, CDCl3) δ: the 7.65 (m, 1H), 7,39 (m, 1H), 7,13 (m, 1H), 5,90 (m, 1H), 5,11-5,02 (m, 2H), 4,60 (m, 2H), 3,49 (m, 2H), 1.77 in (s, 3H).

Description 38. [2-(2-butyn-1 yloxy)-3-(2-propen-1-yl)phenyl]amine (D38)

To a solution of 2-(2-butyn-1 yloxy)-1-nitro-3-(2-propen-1-yl)benzene (D37) (640 mg, 2.77 mmol) in glacial acetic acid (10 ml) is added iron powder (619 mg, 11.1 mmol, 4 equiv.) at room temperature and the mixture is stirred for 16 hours. The solvent is evaporated in vacuo and to the residue is added ethyl acetate (50 ml). Precipitated precipitated substance is removed by filtration and the filtrate is successively extracted with 1 N NaOH solution (10 ml) and brine (10 ml), then dried (MgSO4) and evaporated in vacuo, and get named in the title compound (540 mg, 97%). MS (ES) m/z: 202,10 [MH+]. C13H15NO there is a need for the t 201,27. 1H-NMR (300 MHz, CDCl3) δ: 6,86 (m, 1H), 6,61-6,53 (m, 2H), 5,94 (m, 1H), 5,10-free 5.01 (m, 2H), of 4.44 (m, 2H), 3,82 (users, 2H), 3,40 (m, 2H), 1,87 (m, 3H).

Description 39. 1 Azido-2-(2-butyn-1 yloxy)-3-(2-propen-1-yl)benzene (D39)

A solution of sodium nitrite (72 mg, 1.05 mmol, of 1.05 equiv.) in water (1 ml) with vigorous stirring and cooling with a mixture of ice/water is added dropwise to a suspension of [2-(2-butyn-1 yloxy)-3-(2-propen-1-yl)phenyl]amine (D38) (201 mg, 1 mmol) in 4 N HCl (3 ml). The mixture is then neutralized by adding an aqueous solution of NaHCO3and gradually at 5ºC add a solution of sodium azide (65 mg, 1 mmol, 1 EQ.) in water (1 ml). After 30 minutes the mixture is extracted with diethyl ether (3×20 ml)and the combined organic phases are dried (MgSO4) and evaporated under reduced pressure, and get named in the title azide (222 mg, 98%), which is used in the next stage without additional purification.1H-NMR (300 MHz, CDCl3) δ: 7,02 (m, 1H), of 6.96-6.87 in (m, 2H), 5,90 (m, 1H), 5,10-of 4.95 (m, 2H), 4,55 (s, 2H), of 3.45 (m, 2H), 1,80 (s, 3H).

Description 40. 3-Methyl-6-(2-propen-1-yl)-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazin (D40)

A solution of 1-azido-2-(2-butyn-1 yloxy)-3-(2-propen-1-yl)benzene (D39) (222 mg, 0.98 mmol) in toluene (8 ml) is heated at the boil under reflux for 2.5 hours. Then the solvent is evaporated under reduced pressure, the residue is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (1/4) and get the named the title compound (183 mg, 82%). MS (ES) m/z: 228,20 [MH+]. C13H13N3O requires 227,27.1H-NMR (300 MHz, CDCl3) δ: 7,86 (m, 1H), 7,10-7,00 (m, 2H), 5,90 (m, 1H), 5.25 in (s, 2H), of 5.05-to 4.98 (m, 2H), 3,39 (m, 2H), 2,33 (s, 3H).

Description 41. (3-Methyl-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazin-6-yl)acetaldehyde (D41)

Named the title compound is obtained in yield 66% according to the procedure of description 6 based on 3-methyl-6-(2-propen-1-yl)-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazine (D40) (183 mg, 0,806 mmol). The reaction product is purified flash chromatography on silica gel using as eluent a mixture of ethyl acetate/cyclohexane (2/3). MS (ES) m/z: 230,10 [MH+]. C12H11N3O2requires 229,24.1H-NMR (300 MHz, CDCl3) δ: 9,72 (s, 1H), 7,97 (m, 1H), and 7.1 (m, 2H), 5,26 (s, 2H), 3,74 (s, 2H), 2,33 (s, 3H).

Description 42. The oxime (3E)-8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-she (D42)

A mixture of 8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-thione (D18) (108 mg, of 0.53 mmol), hydroxylamine hydrochloride (55 mg, of 0.79 mmol, 1.5 EQ.) and sodium acetate (65 mg, of 0.79 mmol, 1.5 EQ.) in dry ethanol (5 ml) is heated at the boil under reflux for 40 minutes. Add water (15 ml), ethanol is removed under reduced dwaleni and the aqueous layer was extracted with DCM (3×30 ml). The combined organic layers are dried (MgSO4) and remove the solvent under reduced dwaleni. Column flash chromatography on silica gel (ethyl acetate/cyclohexane, 1/4) gives named for the head of the compound as a white solid (105 mg, 97%). MS (ES) m/z: 205,10 [MH+]. C11H12N2O2requires 204,23.1H-NMR (300 MHz, CDCl3) δ: PC 6.82 (m, 1H), 6,70 (m, 1H), 6,63 (m, 1H), 6,16 (s, 1H), 5,90 (m, 1H), 5,02-of 4.95 (m, 2H), 4,51 (s, 2H), 3,32 (m, 2H).

Description 43. 6-(2-Propen-1-yl)-4H-[1,2,4]oxadiazol[3,4-c][1,4]benzoxazin-1-he (D43)

The oxime (3E)-8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-she (D42) (108 mg, 0,529 mmol) in dry THF (4 ml) is treated with carbonyl diimidazol (94 mg, 0,582 mmol, 1.1 EQ.) while boiling under reflux for 1 hour and then treated with carbonyl diimidazol (94 mg, 0,582 mmol). After 2 hours boiling under reflux, the solvent is removed under reduced dwaleni, the residue is dissolved in DCM (20 ml), the solution washed with water (10 ml), dried (Na2SO4) and evaporated under reduced pressure. The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (1/4), and get named in the title compound (115 mg, 94%).1H-NMR (300 MHz, CDCl3) δ: 7,98 (m, 1H), 7,32 (m, 1H), 7,12 (m, 1H), 5,97 (m, 1H), 5,20-5,00 (m, 4H), 3.43 points (m, 2H).

Description 44. (1-Oxo-4H-[1,2,4]oxadiazol[3,4-c][1,4]benzoxazin-6-yl)acetaldehyde (D44)

Named the title compound is obtained in 71% yield according to the procedure describe 6, from 6-(2-propen-1-yl)-4H-[1,2,4]oxadiazol[3,4-c][1,4]benzoxazin-1-it (D43) (115 mg, 0.50 mmol). The reaction product is purified flash chromatography on Sealy is agile using as eluent a mixture of ethyl acetate/cyclohexane (1/4). 1H-NMR (300 MHz, CDCl3) δ: 9,72 (s, 1H), 8,00 (m, 1H), 7,14-7,02 (m, 2H), of 5.05 (s, 2H), 3,76 (s, 2H).

Description 45. 2-(Trifluoromethyl)-5-chinainternational (D45)

To a solution of 2-(trifluoromethyl)-5-chinoline (1.07 g, of 5.03 mmol) and pyridine (2,05 ml of 25.1 mmol) in dry DCM (20 ml) under cooling with ice add anhydride triftormetilfullerenov acid (1,34 ml, with 8.05 mmol). The mixture is heated to room temperature and continue stirring for 2 hours. Add water (15 ml) and the mixture extracted with DCM (3×20 ml). The combined organic layers are dried (MgSO4) and evaporated in vacuo, and get named in the title compound as a yellowish oil (1,61 g, 93%). MS (ES) m/z: 346 [MH+]. C11H5F6NO3S requires 345,22.1H-NMR (300 MHz, DMSO-d6) δ: an 8.70 (d, 1H), with 8.33 (d, 1H), to 8.20 (d, 1H), 8,03 (2H, m).

Description 46. 1,1-Dimethylethyl-4-[2-(trifluoromethyl)-5-chinoline]-1-piperidinecarboxylate (D46)

A mixture of 2-(trifluoromethyl)-5-chinainternational (D45) (1,61 g, and 4.68 mmol), Cs2CO3(to 2.29 g, 7,02 mmol), Pd(OAc)2(147 mg, 0,655 mmol) of (+/-)-BINAP (436 mg, 0,702 mmol) and N-BOC-piperazine (1.39 g, of 7.48 mmol) in dry toluene (20 ml) was stirred at 90ºC during the night. After cooling to room temperature, add aqueous saturated solution of NH4Cl (25 ml) and the mixture extracted with ethyl acetate (3×30 ml). The combined organic layers are dried (MgSO4and pariva the t in vacuum. The residue is purified column chromatography on silica gel with elution with a gradient of mixtures of cyclohexane/ethyl acetate (9:1-0:1), and get named in the title compound as a yellow oil (1.27 g, 71%). MS (ES) m/z: 382 [MH+]. C19H22F3N3O2requires 381,40.1H-NMR (300 MHz, CDCl3) δ: 8,65 (d, 1H), 7,9 (d, 1H), and 7.7 (m, 2H), 7,2 (d, 1H), 3,6-3,8 (m, 4H), 3,0-3,1 (m, 4H), and 1.5 (s, 9H).

Description 47. 5-(1-Piperazinil)-2-(trifluoromethyl)quinoline (D47)

A solution of 1,1-dimethylethyl-4-[2-(trifluoromethyl)-5-chinoline]-1-piperidinecarboxylate (D46) (1.27 g, of 3.33 mmol) in a mixture of TFWC/THF (1:3, 20 ml) was stirred at room temperature overnight. After evaporation the crude substance is purified on SPE cartridge-SCX (elution with methanol, then 2 N solution of ammonia in methanol) and get named in the title compound (888 mg, 95%) as a yellow solid. MS (ES) m/z: 282 [MH+]. C14H14F3N3requires 281,28.1H-NMR (300 MHz, CDCl3) δ: 8,7 (d, 1H), 7,9 (d, 1H), and 7.7 (m, 2H), 7,2 (m, 1H), 3,2-3,0 (m, 9H).

Description 48. (2-E,Z)-2-Butene-1-yl-2-nitrophenyloctyl ether (D48)

To a solution of 2-NITROPHENOL (5,1 g, 363 mmol) in acetone (45 ml) add Cotillard (3.9 ml, 40.0 mmol, 1.1 EQ.) and K2CO3(5.5 g, 40.0 mmol, 1.1 EQ.). The heterogeneous mixture is heated at the boil under reflux for 18 hours. The mixture is cooled and concentrated in vacuo. To the end of tirovannoj the reaction mixture was added 1 M NaOH solution (200 ml) and the reaction product is extracted with ethyl acetate (2×100 ml). The combined organic extracts washed with 1 M NaOH solution (2×100 ml), water (1×100 ml) and brine (1×100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to dryness. Get an 8/2 mixture of stereoisomers named the title compound as an orange oil, which can be used in the next stage without additional purification.1H-NMR (300 MHz, CDCl3) δ: 7,81 (m, 1H), 7,45 (m, 1H), 7,06 (m, 1H), 6,98 (m, 1H), of 5.92-to 5.58 (m, 2H), 4,74 (m, 2H, stereoisomer 1), 4,60 (m, 2H, stereoisomer 2), of 1.74 (m, 3H).

Description 49. 2-(1-Methyl-2-propen-1-yl)-6-NITROPHENOL (D49)

(2-E,Z)-2-Butene-1-yl-2-nitrophenyloctyl ether (D48) (6.0 g, 31,1 mmol) is stirred and heated under reflux on a sand bath at 200ºC for 5 hours. After cooling, the crude reaction product is purified on SPE cartridge-Si elution with mixtures of cyclohexane/ethyl acetate (100:0-80:20) and get named in the title compound (964 mg, 16%).1H-NMR (300 MHz, CDCl3) δ: 11,04 (s, 1H), 7,98 (d, 1H), 7,47 (d, 1H), 6.90 to (t, 1H), 6,02 (m, 1H), 5,11-of 5.05 (m, 2H), 4.00 points (m, 1H), 1,33 (d, 3H).

Description 50. Methyl{[2-(1-methyl-2-propen-1-yl)-6-nitrophenyl]oxy}acetate (D50)

To a stirred solution of 2-(1-methyl-2-propen-1-yl)-6-NITROPHENOL (D49) (343 mg, 1.77 mmol) in acetone (10 ml) at room temperature add methylbromide (of 0.18 ml of 1.95 mmol) and K2CO3(269 mg, of 1.95 mmol). The mixture heating is t by boiling under reflux for 3 hours and quenched the reaction with water (20 ml). The reaction product is extracted with ethyl acetate (2×20 ml), the extracts dried over Na2SO4and concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si (cyclohexane/ethyl acetate 90:10) and get named in the title compound (486 mg, quantities.) in the form of a yellow oil.1H-NMR (300 MHz, CDCl3) δ: 7,71 (d, 1H), of 7.48 (d, 1H), 7.23 percent (m, 1H+CDCl3), 5,96 (m, 1H), 5,14-to 4.92 (m, 2H), 4.75 V-4,48 (d+d, 2H), 4.09 to (m, 1H), 3,82 (s, 3H), of 1.38 (d, 3H).

Description 51. 8-(1-Methyl-2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-he (D51)

To a solution of methyl{[2-(1-methyl-2-propen-1-yl)-6-nitrophenyl]oxy}acetate (D50) (486 mg, to 1.83 mmol) in a mixture of Meon/N2About (1:1, 8 ml) was added with stirring iron powder (614 mg, 11.0 mmol) and NH4Cl (979 mg, and 18.3 mmol). The mixture is heated at 80 ° C and stirred for 4 hours, and then filtered through celite using as eluent a mixture of Meon/DCM (1:1, 1 l). Volatile organic compounds are removed in vacuum and the remaining aqueous solution extracted with DCM (2×50 ml). The combined organic extracts dried (Na2SO4) and concentrated in vacuo, and get named in the title compound (280 mg, 80%) as a light brown solid, which can be used in the next stage without additional purification.1H-NMR (300 MHz, CDCl3) δ: 7,79 (users, 1H), 7,00-PC 6.82 (m, 2H), is 6.61 (m, 1H), 6,00 (m, 1H), 5,11-4,96 (m, 2H), 4,58, 2H), 3,82 (m, 1H), 1,31 (d, 3H).

Description 52. Ethyl-6-(1-methyl-2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D52)

To a solution of 8-(1-methyl-2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-she (D51) (545 mg, 2.68 mmol) and tert-butoxide potassium (300 mg, 2.68 mmol) in dry DMF (8 ml) at 0 ° C add diethylphosphate (0,80 ml, are 5.36 mmol). After 20 minutes, add a solution of ethylisothiocyanate (of 0.44 ml, 4.02 mmol) and tert-butoxide potassium (451 mg, 4.02 mmol) in dry DMF (3.2 ml). The reaction mixture was stirred at 60 ° C for 8 hours, then cooled and quenched the reaction with water (20 ml). The reaction product is extracted with ethyl acetate (2×20 ml), the combined organic extracts dried over Na2SO4and concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si elution with a mixture of 30% ethyl acetate in cyclohexane and get named in the title compound as a white solid (200 mg, 25%).1H-NMR (300 MHz, CDCl3) δ: 7,98 (s, 1H), 7,32 (d, 1H), 7,12 (d, 1H), 7,01 (t, 1H), 5,98 (m, 1H), of 5.53 (s, 2H), 5,14-free 5.01 (m, 2H), and 4.40 (q, 2H), 3,91 (m, 1H), 1,41 (t, 3H), of 1.32 (d, 3H).

Description 53. Ethyl-6-(1-methyl-2-oxoethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D53)

N-oxide 4-methylmorpholine (196 mg, 1,68 mmol) and osmium tetroxide (50 μl of 4 wt.% solution in water) are added to a solution of ethyl-6-(1-methyl-2-propen-1-yl)-4H-imidazo[5,1-c][1,4]benzoxa the n-3-carboxylate (D52) (200 mg, 0.67 mmol) in a mixture of acetone/water (8:1, and 16.7 ml). The reaction mixture is stirred for 18 hours and then the reaction quenched with a saturated aqueous solution of sodium sulfite (20 ml). After 30 minutes stirring, the mixture is extracted with ethyl acetate (3×20 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, and get ethyl-6-(2,3-dihydroxy-1-methylpropyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (200 mg, of 0.60 mmol, 90%), which is dissolved in a mixture of THF/water (1:1, 17 ml) without further purification. Add periodate sodium (272 mg, of 1.27 mmol) and the mixture is stirred for 2 hours. After evaporation of THF, the residue is treated with water (30 ml) and ethyl acetate (3×20 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, and get named in the title compound (151 mg, 84%) as a white solid, which is used in the next stage without additional purification.1H-NMR (300 MHz, CDCl3) δ: to 9.70 (s, 1H), 7,98 (s, 1H), 7,40 (d, 1H), 7,15-7,0 (d+t, 2H), 5,61 of 5.39 (d+d, 2H), to 4.38 (q, 2H), with 3.89 (m, 1H), 1,49 to 1.31 (t+d, 6H).

Description 54. 2-Bromo-5-forfinal-2-propen-1-silt ether (D54)

2-Bromo-5-terfenol (10 mmol), allylbromide (1 ml, 1.1 EQ.) and K2CO3(1.5 g, 1.1 EQ.) in acetone (100 ml) is stirred at 60 ° C over night. Then the reaction mixture was concentrated under reduced pressure, washed with aqueous solution of NH4 Cl (100 ml) and extracted with Et2O (3×75 ml). The combined organic phases are washed with 1 M aqueous NaOH solution (100 ml), dried over Na2SO4and concentrate, and get named in the title compound as a yellow oil (1.50 g, 90%).1H-NMR (300 MHz, CDCl3) δ: 7,35-7,30 (m, 1H), 6,50-6,30 (m, 2H), 5,95-of 5.75 (m, 1H), 5.25 in (d, 1H), 5,15 (d, 1H), and 4.40 ppm (d, 2H).

Description 55. 1-Bromo-4-fluoro-2-(2-propen-1-yloxy)benzene (D55)

To a solution of 2-bromo-5-forfinal-2-propen-1-silt ether (D54) (213 mg, 1 mmol) in heptane (100 ml), cooled to 0 ° C, under stirring is added dropwise 2 ml of a 1 M solution of diethylaluminium (2.0 EQ.) in hexane. The resulting mixture was warmed to room temperature and stirred for 1 hour. The mixture is then cooled to 0 ° C and add 1 M hydrochloric acid (50 ml). The reaction mixture was extracted with Et2O (3×50 ml)and the collected organic phases are washed with H2O (75 ml), dried over Na2SO4filter and concentrate. The crude substance is purified flash chromatography on silica gel using a mixture of cyclohexane/ethyl acetate (98:2) and get named in the title compound (120 mg, 60%).1H-NMR (300 MHz, CDCl3) δ: 7,25 (m, 1H), 6,55 (t, 1H), 6,00-5,70 (m, 1H), ceiling of 5.60 (s, 1H), 5,10-of 4.95 (m, 2H), 3.40 in ppm (d, 2H).

Description 56. (3-Bromo-6-fluoro-2-hydroxyphenyl)acetaldehyde (D56)

Periodate sodium (7,4 g, to 34.7 mmol) is added under stirring PR is room temperature to 1-bromo-4-fluoro-2-(2-propen-1-yloxy)benzene (D55) (4.0 g, 17.3 mmol) in THF (70 ml) and N2O (70 ml). After 5 minutes add 4 wt.% the solution OsO4in N2Of (6.3 ml, 5 mol.%). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture is successively washed with Et2O (100 ml), N2O (100 ml) and aqueous solution of Na2S2O3(100 ml) and then dried over Na2SO4. The crude substance is purified by chromatography on silica gel using a mixture of cyclohexane/ethyl acetate (95:5) and get named in the title compound as a colourless solid (2.0 g, 50%). On the basis of NMR spectra obtained substance is identified as a mixture of approximately 30/70 named the title product 7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-ol.1H-NMR (300 MHz, CDCl3) δ: 9,7 (s, 1H), 7,38 (DD, 1H), 6,65 (t, 1H), 5,78 (users, 1H), of 3.80 ppm (s, 2H).1H-NMR (300 MHz, CDCl3) δ: 7,20-7,30 (m, 1H), 6,65 (t, 1H), 6,2 (users, 1H), 3,55 (d, 1H), of 3.45 (DD, 1H), 3,20 ppm (DD, 1H).

Description 57. 6-Bromo-3-fluoro-2-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenol (D57)

2-Methyl-5-(1-piperazinil)quinoline (1,46 g, 6.4 mmol) and (3-bromo-6-fluoro-2-hydroxyphenyl)acetaldehyde (D56) (1.50 g, 6.4 mmol) was stirred at room temperature in DCM (10 ml) for 30 min and then add Na2SO4(0,91 g, 6.4 mmol). The resulting mixture was stirred at room temperature e is e for 30 min, then add triacetoxyborohydride sodium (1.35 g, 6.4 mmol) and the mixture is stirred over night. The reaction mixture was poured into an aqueous solution of NH4Cl (50 ml) and extracted with DCM (3×50 ml). The collected organic phases are washed with aqueous solution of NH4Cl (75 ml) and N2O (75 ml), then dried over Na2SO4and concentrate. The crude substance is purified by chromatography on silica gel using a mixture of DCM/Meon (98:2) and get named in the title compound as a yellow solid (2.0 g, 70%). MS (ES/+) m/z: 444 [MH+]. C22H24FBrN3O requires 443.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.75 (d, 1H), 7,65 (t, 1H), 7,40-7,25 (m, 2H), 7,15 (d, 1H), 6,50 (t, 1H), 3,30 was 2.25 (m, 12H), to 2.75 ppm (s, 3H).

Description 58. 2-[(2-Bromo-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)oxy]ndimethylacetamide (D58)

2-Bromo-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenol (D57) (444 mg, 1 mmol), 2-bromoacetamide (151 mg, 1.1 mmol) and K2CO3(145 mg, 1.1 mmol) dissolved in acetone (10 ml) and stirred at 60 ° C over night. After evaporation under reduced pressure type H2O (50 ml) and the resulting mixture extracted with DCM (3×50 ml). The combined organic phases are washed with H2O (50 ml), dried over Na2SO4and concentrate. The crude substance is purified by chromatography on silica gel with what ispolzovaniem mixture of DCM/Meon (96:4) and get named in the title compound as a colourless solid (400 mg, 86%). MS (ES/+) m/z: 503 [MH+]. C24H26BrFN4O2requires 502.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,55 (t, 1H), 7,40 (DD, 1H), 7,30-7,20 (m, 1H), 7,05 (d, 1H), 6,85 (t, 1H), and 4.5 (s, 2H), 3,5 (users, 2H), 3,10-2,6 (m, 15H).

Description 59. 7-Fluoro-8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-he (D59)

2-[(2-Bromo-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)oxy]ndimethylacetamide (D58) (400 mg, 0.80 mmol), CuI (152 mg, 0.80 mmol), N,N'-dimethylethylenediamine (71 mg, 0.80 mmol) and K2CO3(220 mg, 1.6 mmol) is suspended in NMP (5 ml) and stirred at 150 º C for 1 hour. The reaction mixture is purified on a cartridge SPE(SCX) and then by chromatography on silica gel using a mixture of DCM/Meon (96:4) and get named in the title compound as a colourless solid (200 mg, 60%). MS (ES/+) m/z: 421 [MH+]. C24H25FN4O2requires 420.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), and 7.9 (s, 1H), 7.7 (d, 1H), and 7.6 (t, 1H), 7,2 (m, 1H), 7,0 (d, 1H), 6,5-6,7 (m, 2H), 4,6 (s, 2H), 3,2 (users, 4H), of 3.0 to 2.6 ppm (m, 11H).

Description 60. 2-[(2-Bromo-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)oxy]propanamide (D60)

Sodium hydride (37 mg, 60%, mass./mass., dispersion in mineral oil) is carefully added to 6-bromo-3-fluoro-2-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenol (D57) (400 mg, of 0.93 mmol) in dioxane (3 is l). The obtained yellow solution was stirred at room temperature for 10 minutes and then add 2-bromopropionate (140 mg, 1.05 mmol). The reaction mixture is heated at 120 ºC when exposed to microwave radiation for 30 min, then diluted with Meon (1 ml) and purified by SPE(SCX), and get named in the title compound (100%). MS (ES/+) m/z: 498 [MH+]. C25H29BrN4O2requires 498.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,55 (t, 1H), 7,40 (d, 1H), 7,30-6,85 (m, 4H), 4,85 (kV, 1H), 3,5 (users, 2H), 3,10-2,6 (m, 15H), a 1.45 (d, 3H).

Description 61. 2-Methyl-8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-he (D61)

2-[(2-Bromo-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)oxy]propanamide (D60) (370 mg, of 0.74 mmol), CuI (141 mg, of 0.74 mmol), N,N'-dimethylethylenediamine (65 mg, of 0.74 mmol) and K2CO3(195 mg, 1.5 mmol) is suspended in NMP (5 ml) and stirred at 150 º C for 1 hour. The reaction mixture is purified by SPE(SCX) and then by chromatography on silica gel using a mixture of DCM/Meon (97:3) and get named in the title compound as a colourless solid (150 mg, 50%). MS (ES/+) m/z: 417 [MH+]. C25H28N4O2requires 416.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,61 (users, 1H), to 8.41 (d, 1H), 7,35 (d, 1H), 7,60 (t, 1H), 7,35-7,25 (m, 1H), 7,10 (d, 1H), of 7.96-6,86 (m, 2H), 6,76 of 6.66 (m, 1H), 4,7 (m, 1H), 3,1-2,6 (m, 15H), and 1.63 (d, 3H).

Description 62. 6-Bromo-3-fluoro-2-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)phenol (D62)

5-(1-Piperazinil)-2-(trifluoromethyl)quinoline (D47) (211 mg, 1 mmol) and (3-bromo-6-fluoro-2-hydroxyphenyl)acetaldehyde (D56) (231 mg, 1 mmol) was stirred at room temperature in DCM (3 ml) for 30 min, and then add Na2SO4(142 mg, 1 mmol). The resulting mixture was stirred at room temperature for 30 min, then add triacetoxyborohydride sodium (212 mg, 1 mmol) and the mixture is stirred over night. The reaction mixture was poured into an aqueous solution of NH4Cl (50 ml) and extracted with DCM (3×50 ml). The combined organic phases are washed with aqueous solution of NH4Cl (50 ml) and N2About (50 ml), dried over Na2SO4and concentrate. The crude substance is purified by chromatography on silica gel using a mixture of DCM/Meon (99:1) and get named in the title compound as a yellow solid (298 mg, 60%). MS (ES/+) m/z: 499 [MH+]. C22H20BrF4N3O requires 498.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,65 (d, 1H), of 7.96 (d, 1H), 7,8-in 7.7 (m, 2H), between 7.4 and 7.3 (m, 2H), 6.48 in (t, 1H), 3,1 and 2.9 (m, 12H).

Description 63. 2-{[6-Bromo-3-fluoro-2-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)phenyl]oxy}ndimethylacetamide (D63)

6-Bromo-3-fluoro-2-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)Hairdryer is l (D62) (285 mg, of 0.57 mmol), 2-bromoacetamide (86 mg, 0,63 mmol) and K2CO3(226 mg, 1,71 mmol) in acetone (10 ml) was stirred at 40 ºC for 48 hours. After removal of the solvent under reduced pressure type H2O (20 ml) and the mixture extracted with DCM (3×25 ml). The combined organic phases are washed with H2O (40 ml), dried over Na2SO4and concentrate. The crude substance is purified by chromatography on silica gel using a mixture of DCM/Meon (96:4), and get named in the title compound as a colourless solid (200 mg, 63%). MS (ES/+) m/z: 556 [MH+]. C24H23BrF4N4O2requires 555.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,65 (d, 1H), of 7.90 (m, 1H), and 7.7 (m, 2H), and 7.4 (m, 1H), 7,20 (m, 1H), 7,0 (users, 1H), 6,85 (t, 1H), 6,65 (users, 1H), and 4.5 (s, 2H), 3,1) of 2.6 (m, 12H).

Description 64. 7-Fluoro-8-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-2H-1,4-benzoxazin-3(4H)-he (D64)

2-{[6-Bromo-3-fluoro-2-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)phenyl]oxy}ndimethylacetamide (D63) (200 mg, 0.36 mmol), CuI (68 mg, 0.36 mmol), N,N'-dimethylethylenediamine (32 mg, 0.36 mmol) and K2CO3(100 mg, to 0.72 mmol) suspended in NMP (5 ml) and stirred at 150 º C for 1 hour. The reaction mixture is purified by SPE(SCX) and then by chromatography on silica gel using a mixture of DCM/Meon (96:4), and get called in the header joint is in the form of a solid (165 mg, 100%). MS (ES/+) m/z: 475 [MH+]. C24H22F4N4O2requires 474.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,65 (d, 1H), of 7.70 (m, 1H), 7,8-to 7.6 (m, 3H), 7,2 (m, 1H), 6,7-6,6 (m, 2H), 4,6 (s, 2H), 3,1) of 2.6 (m, 12H).

Description 65. 6-Bromo-3-fluoro-2-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}phenol (D65)

2-Methyl-5-(1-piperazinil)hinzelin (180 mg, of 0.79 mmol) and (3-bromo-6-fluoro-2-hydroxyphenyl)acetaldehyde (D56) (180 mg, of 0.79 mmol) was stirred at room temperature in DCM (10 ml) for 30 min, and then add Na2SO4(112 mg, of 0.79 mmol). The resulting mixture was stirred at room temperature for 30 min, then add triacetoxyborohydride sodium (167 mg, of 0.79 mmol) and the mixture is stirred over night. The reaction mixture was poured into an aqueous solution of NH4Cl (50 ml) and then extracted with DCM (3×40 ml). The combined organic phases are washed with aqueous solution of NH4Cl (30 ml) and N2O (30 ml), then dried over Na2SO4and concentrate. The crude substance is purified by chromatography on silica gel using a mixture of DCM/Meon (98:2) and get named in the title compound as a yellow solid (210 mg, 60%). MS (ES/+) m/z: 445 [MH+]. C21H22BrFN4O requires 444.1H-NMR (300 MHz, CDCl3) δ (ppm): 9,5 (s, 1H), 7,78 (t, 1H), 7.62mm (d, 1H), 7,34-7,25 (m, 2H), 7,13 (d, 1H), 6,47 (t, 1H), 3,4-2,8 (m, 15H).

Description is 66. 2-[(6-Bromo-3-fluoro-2-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}phenyl)oxy]ndimethylacetamide (D66)

6-Bromo-3-fluoro-2-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}phenol (D65) (210 mg, 0.47 mmol), 2-bromoacetamide (74 mg, 0.52 mmol) and K2CO3(186 mg, of 1.41 mmol) in acetone (10 ml) was stirred at 40 ºC for 48 hours. After removal of the solvent under reduced pressure type H2O (30 ml) and the resulting mixture extracted with DCM (3×25 ml). The combined organic phases are washed with H2O (40 ml), dried over Na2SO4and concentrate. The crude reaction product is purified by chromatography on silica gel using a mixture of DCM/Meon (95:5) and get named in the title compound as a solid (200 mg, yield 85%). MS (ES/+) m/z: 502 [MH+]. C23H25BrFN5O2requires 501.1H-NMR (300 MHz, CDCl3) δ (ppm): 9,5 (s, 1H), of 7.75 (t, 1H), 7,55 (t, 1H), and 7.4 (m, 1H), 7,05 (d, 1H), 6,9 (users, 1H), 6,8 (t, 1H), 5,75 (users, 1H), and 4.5 (s, 2H), 3,1-2,6 (m, 15H).

Description 67. 7-Fluoro-8-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-he (D67)

2-[(6-Bromo-3-fluoro-2-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}phenyl)oxy]ndimethylacetamide (D66) (200 mg, 0.40 mmol), CuI (76 mg, 0.40 mmol), N,N'-dimethylethylenediamine (35 mg, 0.40 mmol) and K2CO3(105 mg, 0.80 mmol) suspended in NMP (5 ml) and stirred 150º for 1 hour. The reaction mixture is purified by SPE(SCX) and then by chromatography on silica gel using a mixture of DCM/Meon (96:4), and get named in the title compound as a solid (90 mg, 53%). MS (ES/+) m/z: 422 [MH+]. C23H24FN5O2requires 421.1H-NMR (300 MHz, CDCl3) δ (ppm): 9,5 (s, 1H), 7,8-in 7.7 (m, 2H), 7,55 (d, 1H), 7,05 (d, 1H), 6,7-6,5 (m, 2H), 4,6 (s, 1H), 3,1-2,6 (m, 15H).

Description 68. 1,1-Dimethylethyl-4-(2-formyl-5-chinoline)-1-piperidinecarboxylate (D68)

To a solution of 1,1-dimethylethyl-4-(2-methyl-5-chinoline)-1-piperidinecarboxylate (D165) (4,51 g of 13.8 mmol) in dioxane (20 ml) was added selenium dioxide (1,83 g, 16.5 mmol). The mixture was stirred at 90ºC for 1.5 hours, cooled to room temperature, filtered and evaporated. The residue is purified column flash chromatography with elution with a mixture of cyclohexane/ethyl acetate (9:1-1:1) and get named in the title compound as a yellow solid (3,35 g, 71%). MS (ES; m/z): 342 [MH+]. C19H23N3O3requires 341,41.1H-NMR (300 MHz, CDCl3) δ: 10,20 (s, 1H), 8,63 (d, 1H), 7,98 (kV, 2H), 7,71 (t, 1H), 7,21 (d, 1H), 3,69 (users, 4H), 3,03 (users, 4H), to 1.48 (s, 9H).

Description 69. 1,1-Dimethylethyl-4-(2-cyano-5-chinoline)-1-piperidinecarboxylate (D69)

To a solution of 1,1-dimethylethyl-4-(2-formyl-5-chinoline)-1-piperidinecarboxylate (D68) (522 mg, 1,52 IMO the ü) in 20% aqueous ammonia solution (15 ml) and THF (3 ml) is added iodine (427 mg, by 1.68 mmol). The mixture is stirred at room temperature for 1 hour. Then add an aqueous solution of Na2S2O3(5%, 10 ml) and the reaction product extracted with DCM (3×15 ml). The organic layer is dried (MgSO4), filtered and evaporated in vacuum. The residue is purified by chromatography on silica gel with elution with mixtures of cyclohexane/ethyl acetate(8:2 - 0:1), and you get named in the title compound as a yellow solid (265 mg, 51%). MS (ES; m/z): 339 [MH+]. C19H22N4O2requires 338,41. NMR (1H, 300MHz, DMSO-d6) δ: an 8.70 (d, 1H), of 7.97 (d, 1H), 7,79 (m, 2H), was 7.36 (m, 1H), 3,57 (users, 4H), 2.95 and (m,4H), of 1.40 (s, 9H).

Description 70. 5-(1-Piperazinil)-2-hinolincarbonova (D70)

A solution of 1,1-dimethylethyl-4-(2-cyano-5-chinoline)-1-piperidinecarboxylate (D69) (1.04 g, a 3.06 mmol) in a mixture of TFWC/DCM (20 ml, 1:3) was stirred at room temperature overnight. After evaporation the crude substance is purified on SPE-SCX and receives a yellow solid (633 mg, 87%). Analysis by HPLC/MS shows a second product (28%, m/z 312). The resulting material can be used in the next stage without additional purification. MS (ES; m/z): 239 [MH+]. C14H14N4requires 238,29.

Description 71. 2-Oxo-1,2,3,4-tetrahydro-5-chinainternational (D71)

1,1,1-Cryptor-N-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (1,21 g, 3,39 mmol) is added in portions under stirring at 0 ° C to a suspension of 5-hydroxy-3,4-dihydro-2(1H)-chinoline (Davos, commercially available) (460 mg, 2.82 mmol) in CH3CN (25 ml) and triethylamine (492 μl, of 3.53 mmol). The reaction mixture is stirred for 15 hours at room temperature, then the reaction quenched with water (20 ml) and the mixture extracted with DCM (3×50 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si elution with a mixture of cyclohexane/ethyl acetate (7:3) and get named in the title compound (812 mg, 97%). MS (ES) m/z: 296,00 [MH+]. C10H8F3NO4S requires 295,24.1H-NMR (300 MHz, CDCl3) δ: 7,92 (users, 1H), 7,28 (m, 1H), 6,97 (m, 1H), 6,76 (m, 1H), is 3.08 (t, 2H), 2,68 (t, 2H).

Description 72. 5-(2-Propen-1-yl)-3,4-dihydro-2(1H)-chinoline (D72)

To a solution of 2-oxo-1,2,3,4-tetrahydro-5-chinainternational (D71) (919 mg, of 3.12 mmol) in dry DMF (9 ml) at room temperature add allyltrimethylsilane (1,16 ml, 3,74 mmol), LiCl (3 mg, 2%) and tetrakis(triphenylphosphine)palladium(0) (361 mg, 10%). The reaction mixture was stirred at 100ºC for 2 hours, then cooled, quenched the reaction with water (10 ml) and the mixture extracted with DCM (3×50 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, get crude about the SPS reaction, which purified flash chromatography on silica gel with elution with a mixture of cyclohexane/ethyl acetate (7:3) and get named in the title compound (496 mg, 85%). MS (ES) m/z: 188,10 [MH+]. C12H13NO require 187,24.1H-NMR (300 MHz, CDCl3) δ: 7,93 (users, 1H), 7,13 (t, 1H), to 6.88 (d, 1H), 6,65 (d, 1H), 6,00-by 5.87 (m, 1H), 5,11-of 4.95 (m, 2H), 3,42-to 3.38 (m, 2H), equal to 2.94 (t, 2H), 2,62 (t, 2H).

Description 73. (2-Oxo-1,2,3,4-tetrahydro-5-chinolin)acetaldehyde (D73)

Named in the title compound are obtained from the output 63% according to the procedure describe 6, starting from 5-(2-propen-1-yl)-3,4-dihydro-2(1H)-Hinayana (D72) (380 mg, 2.03 mmol). The reaction product is purified flash chromatography on silica gel using as eluent a mixture of ethyl acetate/cyclohexane (1:1). MS (ES) m/z: 190,1 [MH+]. C11H11NO2requires 189,21.1H-NMR (300 MHz, CDCl3) δ: 9,73 (t, 1H), 7,68 (users, 1H), 7,19 (t, 1H), 6.90 to (d, 1H), of 6.71 (d, 1H), of 3.77 (d, 2H), 2,88 (t, 2H), 2.63 in (d, 2H).

Description 74. 5-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-3,4-dihydro-1(1H)-chinoline (D74)

Named the title compound is obtained in 75% yield according to the General procedure of example 1, from (2-oxo-1,2,3,4-tetrahydro-5-chinolin)acetaldehyde (D73) (242 mg, 1.28 mmol). The crude reaction product is purified flash chromatography on silica gel with gradienta of methanol in DCM (1-3%), and get called in reception is e compound (384 mg, 75%). MS (ES) m/z: 401,20 [MH+]. C25H28N4O requires 400,52.1H-NMR (500 MHz, DMSO-d6) δ: 10,01 (s, 1H), 8.34 per (acsis, 1H), 7,58 (m, 2H), 7,37 (d, 1H), to 7.09 (m, 1H), 7,07 (t, 1H), at 6.84 (d, 1H), 6,72 (DD, 1H), 3,03 (users, 4H), 2,89(t, 2H), 2,80 (m, 2H), 2,74 (users, 4H), of 2.54 (m, 2H), 2,44 (t, 2H), 2,63 (users, 3H).

Description 75. 5-Methyl-2-nitrophenyl-2-propen-1-silt ether (D75)

Named in the title compound are obtained from quantitative yield (2.5 g), following the procedure of description 1, starting from 5-methyl-2-NITROPHENOL (2.0 g, 13 mmol).1H-NMR (300 MHz, CDCl3) δ: 7,71 (d, 1H), 6,77-6,72 (m, 2H), 5,95 (m, 1H), 5,46-5,23 (m, 2H), br4.61-4,58 (m, 2H), 2,33 (s, 3H).

Description 76. 3-Methyl-6-nitro-2-(2-propen-1-yl)phenol (D76)

Named the title compound is obtained in yield 68% (1.7 g), following the procedure of description 2, starting from 5-methyl-2-nitrophenyl-2-propen-1-silt ether (D75) (2.5 g, 13 mmol).1H-NMR (300 MHz, CDCl3) δ: 11,06 (s, 1H), 7,89 (d, 1H), 6,78 (d, 1H), 5,95 (m, 1H), of 5.05-is 4.93 (m, 2H), 3,52-to 3.49 (m, 2H), is 2.37 (s, 3H).

Description 77. Methyl{[3-methyl-6-nitro-2-(2-propen-1-yl)phenyl]oxy}acetate (D77)

Named in the title compound, receive, following the procedure of description 3, based on 3-methyl-6-nitro-2-(2-propen-1-yl)phenol (D76) (1.7 g, 8,81 mmol). MS (ES) m/z: 266,1 [MH+]. C13H15NO5requires 265,26.1H-NMR (300 MHz, CDCl3) δ: 7,71 (d, 1H), was 7.08 (d, 1H), 5,95 (m, 1H), 5,10-to 4.81 (m, 2H), br4.61 (s, 2H), 3,81 (s, 3H), 3,59-3,55 (m, 2H), a 2.36 (s, 3H).

Description 78. 7-Methyl-8-(2-p is open-1-yl)-2H-1,4-benzoxazin-3(4H)-he (D78)

Named the title compound is obtained in yield of 48% (860 mg), following the procedure describing 4, on the basis of methyl{[3-methyl-6-nitro-2-(2-propen-1-yl)phenyl]oxy}acetate (D77) (2,33 g, 8,81 mmol). MS (ES) m/z: to 204.1 [MH+]. C12H13NO2requires 203,24.1H-NMR (300 MHz, CDCl3) δ: 7,79 (users, 1H), 6,77 (d, 1H), 6,56 (d, 1H), of 5.89 (m, 1H), 5,02-4,88 (m, 2H), 4,58 (s, 2H), 3,42-3,39 (m, 2H, in), 2.25 (s, 3H).

Description 79. (7-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)acetaldehyde (D79)

Named the title compound is obtained in yield of 48% (860 mg), following the procedure describing 6, from 7-methyl-8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-she (D78) (2,33 g, 8,81 mmol). MS (ES) m/z: 206,1 [MH+]. C11H11NO3requires 205,21.1H-NMR (300 MHz, CDCl3) δ: to 9.70 (s, 1H), 7,79 (users, 1H), for 6.81 (d, 1H), 6,66 (d, 1H), 4,56 (s, 2H, in), 3.75 (s, 2H), of 2.38 (s, 3H).

Description 80. 7-Methyl-8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-he (D80)

Named in the title compound, receive, following the General procedure of reductive amination of example 1, based on (7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)acetaldehyde (D79) (242 mg, 1.28 mmol). The crude reaction product is purified flash chromatography on silica gel with gradienta of methanol in DCM (1-3%) and get named in the title compound (384 mg, 75%). MS (ES) m/z: 417,20 [MH+]. C25H8 N4O2requires 416,52.1H-NMR (300 MHz, CDCl3) δ: 10,52 (s, 1H), with 8.33 (d, 1H), EUR 7.57 (m, 2H), 7,35 (d, 1H), to 7.09 (m, 1H), 6,74 (d, 1H), 6,63 (d, 1H), 4.53-in (s, 2H), 3.04 from (users, 4H), 2,81-of 2.64 (m, 6H), 2,62 (s, 3H), 2,38-to 2.57 (m, 2H), 2,24 (s, 3H).

Description 81. 5-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-3,4-dihydro-2(1H)-chinoline (D81)

To a solution of 5-hydroxy-3,4-dihydro-2(1H)-Hinayana (640 mg, 3.93 mmol) in DMF (3.5 ml) under stirring at room temperature add tert-butyldimethylsilyloxy (651 mg, 4,32 mmol) and imidazole (321 mg, 4,71 mmol). After 4 hours, add water (10 ml) and the mixture extracted with DCM (3×70 ml). The combined organic layers are dried (Na2SO4), concentrated in vacuo, and get named in the title compound (997 mg, 91%), which is used in the next stage without additional purification. MS (ES) m/z: 278,2 [MH+]. C15H23NO2Si requires 277,44.1H-NMR (300 MHz, CDCl3) δ: 7.62mm (users, 1H), 7,03 (t, 1H), of 6.52 (d, 1H), 6,36 (d, 1H), 2.95 and (t, 2H), 2,61 (t, 2H), of 1.03 (s, 9H), of 0.25 (s, 6H).

Description 82. Ethyl-6-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D82)

Named in the header connection receive according to the procedure of example 80, from 5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3,4-dihydro-2(1H)-Hinayana (D81) (997 mg, 3.6 mmol). The crude reaction product is purified flash chromatography on silica gel with elution mixture is Yu ethyl acetate/cyclohexane (4:6) and get named in the title compound (992 mg, 74%). MS (ES) m/z: 373,2 [MH+]. C20H28N2O3Si requires 372,54.1H-NMR (300 MHz, CDCl3) δ: 7,99 (s, 1H), 7,21 (t, 1H), to 7.09 (d, 1H), 6,77 (d, 1H), to 4.41 (q, 2H), and 3.31 (t, 2H), with 2.93 (t, 2H), of 1.44 (t, 3H), of 1.05 (s, 9H), or 0.27 (s, 6H).

Description 83. Ethyl-6-hydroxy-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D83)

To a solution of ethyl-6-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D82) (642 mg, at 1.73 mmol) in THF (20 ml) is added tetrabutylammonium fluoride (3,45 ml of 1 M solution in THF, of 3.45 mmol) and the resulting solution was stirred at room temperature. After 2 hours, add a saturated solution of ammonium chloride (10 ml), THF removed in vacuo and the resulting mixture extracted with DCM (4×100 ml). The combined organic layers are dried (Na2SO4), concentrated in vacuo and get named in the title compound (446 mg, 100%), which can be used in the next stage without additional purification. MS (ES) m/z: 259,1 [MH+]. C14H14N2O3requires 258,28.1H-NMR (300 MHz, DMSO-d6) δ: 10,07 (users, 1H), 8,72 (s, 1H), 7,27 (d, 1H), 7,17 (t, 1H), at 6.84 (d, 1H), 4.26 deaths (kV, 2H), 3,18 (t, 2H), 2,82 (t, 2H), of 1.30 (t, 3H).

Description 84. Ethyl-6-{[(trifluoromethyl)sulfonyl]oxy}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D84)

Named in the header connection receive according to the procedure descriptions 71, is stepping down from ethyl-6-hydroxy-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D83) (446 mg, of 1.73 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of dichloromethane/methanol (97:3), then by SCX cartridge and get named in the title compound (491 mg, 73%). MS (ES) m/z: 391,0 [MH+]. C15H13F3N2O5S requires 390,34.1H-NMR (300 MHz, CDCl3) δ: 8,03 (s, 1H), 7,55-7,40 (m, 2H), 7,26 (m, 1H), to 4.41 (q, 2H), 3,39 (t, 2H), 3,06 (t, 2H), USD 1.43 (t, 3H).

Description 85. Ethyl-6-(2-propen-1-yl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D85)

Named in the title compound are obtained from quantitative yield according to the procedure descriptions 72, based on ethyl-6-{[(trifluoromethyl)sulfonyl]oxy}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D84) (491 mg, of 1.26 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (7:3) and get named in the title compound (354 mg, Quant.). MS (ES) m/z: 283,2 [MH+]. C17H18N2O2requires 282,34.1H-NMR (300 MHz, CDCl3) δ: 7,99 (s, 1H), 7,40-7,28 (m, 2H), 7,13 (d, 1H), 5,95 (m, 1H), 5,13-of 4.95 (m, 2H), and 4.40 (q, 2H), 3,47 (m, 2H), 3,30 (t, 2H), 2,89 (t, 2H), USD 1.43 (t, 3H).

Description 86. Ethyl-6-(2-oxoethyl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D86)

Named the title compound is obtained in yield of 85% (305 mg), following the procedure describing 6, based on ethyl-6-(2-PR is pen-1-yl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D85) (354 mg, 1.25 mmol).1H-NMR (300 MHz, CDCl3) δ: 9,77 (t, 1H), 8,01 (s, 1H), 7,46 (d, 1H), 7,35 (m, 1H), 7,14 (d, 1H), 4,39 (kV, 2H), 3,86 (d, 2H), 3,32 (t, 2H), and 2.83 (t, 2H), USD 1.43 (t, 3H).

Description 87. 5-(2-Propen-1-yl)quinoline (D87)

To a mixture of 5-brainline (1.5 g, from 7.24 mmol), Tris(dibenzylideneacetone)diplegia(0) (331 mg, 0.36 mmol) and triphenylphosphine (760 mg, 2.9 mmol) in toluene (50 ml) add allyltrimethylsilane (2.4 ml, 8 mmol). The reaction mixture was stirred overnight at 120 ºC and then the reaction quenched with water (30 ml) and 1 N hydrochloric acid (10 ml). The organic layer is extracted with 1 M hydrochloric acid (3×20 ml), then the combined aqueous phase is alkalinized solid NaHCO3and then extracted with DCM (3×50 ml). The combined organic extracts dried over anhydrous Na2SO4and evaporated in vacuum. The crude substance is purified on SPE cartridge-Si elution with a mixture of 5% ethyl acetate in cyclohexane and get named in the title compound as a pale yellow solid (1 g, 81%). MS (ES) m/z: USD 170.1 [MH+]. C12H11N requires 169,23.1H-NMR (300 MHz, CDCl3) δ: rate of 8.75 (t, 1H), to 8.20 (d, 1H), a 7.85 (d, 1H), 7,45 (t, 1H), 5,95 to 5.8 (m, 1H), 5,0-to 4.8 (m, 2H), 3,65 (d, 2H).

Description 88. N-Oxide of 5-(2-propen-1-yl)quinoline (D88)

To a solution of 5-(2-propen-1-yl)quinoline (D87) (6 g, 35.5 mmol) in DCM (100 ml) at 0 ° C add 3-chloroperbenzoic acid (55%, and 13.4 g of 42.6 mmol). The reaction mixture was stirred at room temperature is 2 hours and then the reaction quenched with saturated aqueous NaHCO 3(100 ml). The mixture is extracted with DCM (3×50 ml)and the combined organic extracts dried over anhydrous Na2SO4and evaporated in vacuum. The crude substance is purified on SPE cartridge-Si elution with a mixture of 40% ethyl acetate in cyclohexane and get named in the title compound as a pale brown solid (5.4 g, 82%). MS (ES) m/z: 186,2 [MH+]. C12H11NO require 185,24.1H-NMR (300 MHz, CDCl3) δ: 8,7 (users, 1H), 8,50 (users, 1H), 7,9 (users, 1H), 7,7 (users, 1H), 7.5 (users, 1H), and 7.3 (users, 1H), 6 (users, 1H), 5,1 (d, 1H), 5.0mm (d, 1H), 3,8 (users, 2H).

Description 89. Eternita[5-(2-propen-1-yl)-2-chinoline]acetate (D89)

To a mixture of N-oxide of 5-(2-propen-1-yl)quinoline (D88) (2 g, the 10.8 mmol) and acetic anhydride (5 ml) is added dropwise ethylnitrosourea (1.3 ml, with 11.9 mmol). After 30 min stirring observe the formation of the precipitate, the reaction is quenched with water (10 ml) and the mixture filtered. The solid is washed with methanol (10 ml) and dried in vacuum, and get named in the title compound as a yellow solid (1.4 g, 43%). MS (ES) m/z: 301,1 [MH+]. C16H16N2O4requires 300,31.1H-NMR (300 MHz, CDCl3) δ: 8,2 (userd, 1H), 7,7-of 7.4 (m, 3H), 7,3 (userd, 1H), 6,1-5,9 (osirm, 1H), 5,2-4,9 (osirm, 2H), 4,5-4,3 (osirm, 2H), 3,7 (users, 2H), 1,4-1,3 (osirm, 3H).

Description 90. Ethyl-6-(2-propen-1-yl)imidazo[1,5-a]quinoline-3-carboxylate (D90)

To the mixture eternita[5-(2-propen-1-yl)-2-chinoline]acetate (D89) (550 mg, to 1.83 mmol) and glacial acetic acid (15 ml) is added zinc powder (720 mg, 11 mmol). The reaction mixture was stirred at room temperature for 4 hours, then the reaction quenched with water (50 ml), the mixture was diluted with DCM (50 ml), cooled to 0 ° C and neutralized solid NaHCO3. The aqueous layer was separated and extracted with DCM (2×50 ml), and then the combined organic phases are washed with saturated aqueous NaHCO3(3×50 ml), dried over anhydrous Na2SO4and evaporated in vacuum. The intermediate connection ethylamino[5-(2-propen-1-yl)-2-chinoline]acetate fast process triethylorthoformate (5 ml) and heated with stirring at 150 º C for 7 min under the influence of microwave radiation. The resulting reaction mixture is passed through a SCX cartridge to remove triethylorthoformate and then purified on SPE cartridge-Si elution with a mixture of 50% ethyl acetate in cyclohexane and get named in the title compound as a pale yellow solid (245 mg, 48%). MS (ES) m/z: 281,20 [MH+]. C17H16N2O2requires 280,33.1H-NMR (300 MHz, CDCl3) δ: 8,6 (s, 1H)and 8.1 (d, 1H), 7,9 (d, 1H), 7.5 to about 7.6 (m, 2H), and 7.3 (d, 1H), 6,0 was 5.9 (m, 1H), 5,1 (d, 1H), 5.0mm (d, 1H), of 4.45 (q, 2H), and 3.8 (d, 2H), 1,4 (t, 3H).

Description 91. Ethyl-6-(2-oxoethyl)imidazo[1,5-a]quinoline-3-carboxylate (D91)/u>

To a solution of ethyl-6-(2-propen-1-yl)imidazo[1,5-a]quinoline-3-carboxylate (D90) (245 mg, 0.88 mmol) in a mixture of THF/water (2:1, 9 ml) was added with stirring the osmium tetroxide (0.63 ml of 4 wt.% solution in water). After 10 minutes add periodate sodium (470 mg, 2.2 mmol) and the reaction mixture was stirred for another 20 min After evaporation of THF, the residue is treated with water (10 ml) and ethyl acetate (3×10 ml). The organic layers are combined, dried (Na2SO4) and concentrated in vacuo, and get named in the title compound (220 mg). The crude reaction product can be used without further purification in the next stage.1H-NMR (300 MHz, CDCl3) δ: 9,8 (s, 1H), and 8.7 (s, 1H), 8,15 (d, 1H), with 8.05 (d, 1H), 7,65 (t, 1H), and 7.3 (m, 2H), of 4.45 (q, 2H), 4,15 (s, 2H), 1,4 (t, 3H).

Description 92. 6-(2-Propen-1-yl)tetrazolo[1,5-a]quinoline (D92)

A mixture of N-oxide of 5-(2-propen-1-yl)quinoline (D88) (500 mg, 2.7 mmol) and methanesulfonamide (to 0.22 ml, 2.7 mmol) in dry acetonitrile (5 ml) is stirred for 3 hours at room temperature. To the suspension is added dropwise trimethylsilyl (0,36 ml, 2.7 mmol) and the mixture is then heated to boiling under reflux for 24 hours. Evaporation in vacuo of volatiles and purification cartridge SPE-Si elution DCM give named the title compound (318 mg, 56%). MS (ES) m/z: 211,1 [MH ]. C12H10N4requires 210,2.1H-NMR (300 MHz, CDCl3) δ: 8,6 (d, 1H)and 8.1 (d, 1H), from 7.9 to 7.7 (m, 2H), and 7.6 (d, 1H), 6,1-5,9 (m, 1H), 5,15 (d, 1H), 5.0mm (d, 1H), and 3.8 (d, 2H).

Description 93. Tetrazolo[1,5-a]quinoline-6-ylacetamide (D93)

To a solution of 6-(2-propen-1-yl)tetrazolo[1,5-a]quinoline (D92) (100 mg, 0.48 mmol) in a mixture of THF/water (2:1, 4.5 ml) was added with stirring the osmium tetroxide (0,34 ml of 4 wt.% solution in water). After 10 minutes add periodate sodium (256 mg, 1.2 mmol) and the reaction mixture is stirred for 15 more minutes After evaporation of THF, the residue is treated with water (10 ml) and ethyl acetate (3×10 ml). The organic layers are combined, dried (Na2SO4) and concentrated in vacuo. Processing raw materials with a mixture of DCM/ethyl acetate (1:1, 2 ml) gives named the title compound (62 mg, 61%). MS (ES) m/z: 213,1 [MH+]. C11H8N4O requires 212,2.1H-NMR (300 MHz, DMSO-d6) δ: 9,8 (s, 1H), and 8.6 (d, 1H), 8.3 (l, 1H)and 8.1 (d, 1H), 7,95 (t, 1H), 7.7 (d, 1H), and 4.5 (s, 2H).

Description 94. 5-(2-Propen-1-yl)-2(1H)-chinoline (D94)

To a solution of N-oxide of 5-(2-propen-1-yl)quinoline (D88) (670 mg, 3.62 mmol) in DMF (12 ml) is added under stirring triperoxonane anhydride (5,1 ml, and 36.2 mmol). The mixture is stirred at room temperature overnight, then the reaction is quenched with saturated aqueous NaHCO3(20 ml) and the mixture extracted with ethyl acetate (3×20 ml). Together the major organic phase is dried over Na 2SO4and then evaporated in vacuum. The crude substance is cleaned at cartrigde SPE-Si elution with a mixture of 30% cyclohexane in ethyl acetate and get named in the title compound as a white solid (360 mg, 54%).1H-NMR (300 MHz, CDCl3) δ: 13,4 (s, 1H), and 8.2 (d, 1H), 7.5 (t, 1H), and 7.4 (d, 1H), and 7.3 (d, 1H), 6,8 (d, 1H), 6,1-5,9 (m, 1H), and 5.2 (d, 1H), 5.0mm (d, 1H), and 3.7 (d, 2H).

Description 95. 5-(2-Propen-1-yl)-2(1H)-finalistin (D95)

A mixture of 5-(2-propen-1-yl)-2(1H)-Hinayana (D94) (1.1 g, 6 mmol) and reagent Laussane (1.2 g, 3 mmol) in dry toluene (30 ml) is heated at the boil under reflux for 30 minutes the Mixture is cooled to room temperature and the solvent is evaporated in vacuum. The crude substance is cleaned at cartrigde SPE-Si elution with a mixture of 30% ethyl acetate in cyclohexane and get named in the title compound as a white solid (0.96 g, 80%). MS (ES) m/z: 202,1 [MH+]. C12H11NS requires 201,3.1H-NMR (300 MHz, CDCl3) δ: 12,5 (s, 1H), and 7.8 (d, 1H), 7,6-to 7.3 (m, 3H), and 7.1 (d, 1H), from 6.0 to 5.8 (m, 1H), of 5.05 (d, 1H), 4.95 points (d, 1H), and 3.7 (d, 2H).

Description 96. 1-Methyl-6-(2-propen-1-yl)[1,2,4]triazolo[4,3-a]quinoline (D96)

A solution of 5-(2-propen-1-yl)-2(1H)-chinaindia (D95) (150 mg, 0.75 mmol) in absolute ethanol (1 ml) at 100ºC is added dropwise to a solution of hydrazine monohydrate (1 ml) in absolute ethanol (1 ml). The resulting reaction mixture peremeci is up at 100 º C for 6 hours and concentrated in vacuo, and receive the intermediate hydrazone compound 5-(2-propen-1-yl)-2(1H)-quinoline, which is immediately used in the next stage without additional purification. The hydrazone is mixed with triethylorthoformate (2 ml) and heated with stirring at 150 º C for 10 min under the influence of microwave radiation. The reaction mixture is purified on a SCX cartridge and then by chromatography (SPE cartridge-Si) with elution with a mixture of 10% methanol in DCM. Named the title compound is obtained after the processing in diethyl ether (110 mg, 65%). MS (ES) m/z: 224,1 [MH+]. C14H13N3requires 223,3.1H-NMR (300 MHz, CDCl3) δ: 8,2 (d, 1H), and 7.8-7.5 (m, 3H), and 7.4 (d, 1H), 6,2 to 6.0 (m, 1H), and 5.2 (d, 1H), 5.0mm (d, 1H), and 3.8 (d, 2H), 3,2 (s, 3H), and 1.6 (d, 3H).

Description 97. (1-Methyl[1,2,4]triazolo[4,3-a]quinoline-6-yl)acetaldehyde (D97)

N-oxide 4-methylmorpholine (98 mg, 0.28 mmol) and osmium tetroxide (106 μl of 4 wt.% solution in water, a 0.035 EQ.) added to a solution of 1-methyl-6-(2-propen-1-yl)[1,2,4]triazolo[4,3-a]quinoline (D96) (94 mg, 0.42 mmol) in a mixture of acetone/water (8:1, 4.5 ml). The reaction mixture is stirred for 4 hours and then the reaction quenched with a saturated aqueous solution of sodium sulfite (15 ml). After 30 minutes stirring, the mixture is extracted with DCM (3×20 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, and receive the intermediate compound 3-(1-methyl[1,2,4]Tria is olo[4,3-a]quinoline-6-yl)-1,2-propandiol (80 mg), which is dissolved in a mixture of THF/water (1:1, 2 ml) without further purification. Add periodate sodium (133 mg, of 0.62 mmol) and acetone (1 ml)and the mixture stirred for 10 min. After evaporation of THF, the residue is treated with water (10 ml) and DCM (3×20 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo (using methanol to improve dissolution in DCM) and get named in the title compound as a white solid. (Analysis method1H NMR shows a mixture of compounds - 40% (1-methyl[1,2,4]triazolo[4,3-a]quinoline-6-yl)acetaldehyde plus 60% of 1-(metiloksi)-2-(1-methyl[1,2,4]triazolo[4,3-a]quinoline-6-yl)ethanol; 35 mg). The mixture is used without further purification.1H-NMR (300 MHz, CDCl3) (1-methyl[1,2,4]triazolo[4,3-a]quinoline-6-yl)acetaldehyde: δ a 9.9 (s, 1H), 8.3 (l, 1H), and 7.8 to 7.4 (m, 4H), 4,0 (d, 2H), 3,2 (s, 3H); and 1-(metiloksi)-2-(1-methyl[1,2,4]triazolo[4,3-a]quinoline-6-yl)ethanol: δ of 8.2 (d, 1H), 7,8 (d, 1H), and 7.8 to 7.4 (m, 3H), 5,9 (users, 1H), 3,4 (s, 3H), 3,3 (users, 2H), 3,1 (s, 3H).

Description 98. Ethyl-6-(2-propen-1-yl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D98)

Following the procedure describe 90, eternita[5-(2-propen-1-yl)-2-chinoline]acetate (D89) (1.2 g, 4 mmol) in glacial acetic acid (15 ml) is injected into the interaction with zinc powder (1,57 g, 24 mmol) for 2 hours. Part of the crude intermediate substances ethylamino[5-(2-propen-yl)-2-chinoline]acetate (200 mg) quickly dissolved in hydrochloric acid (2.5 ml, 37%), and after 5 min stirring is added dropwise a solution of sodium nitrite (62 mg in 1.5 ml water). After interaction within 2 hours of precipitated precipitated substance is filtered off and purified on SPE cartridge-Si elution with a mixture of 50% ethyl acetate in cyclohexane, and get named in the title compound (68 mg). MS (ES) m/z: 282,20 [MH+]. C16H15N3O2requires 281,3.1H-NMR (300 MHz, CDCl3) δ: 8,8 (d, 1H), 8,15 (d, 1H), 8.0 a (d, 1H), and 7.6 (d, 1H), 6,2 to 6.0 (m, 1H), and 5.2 (d, 1H), 5,1 (d, 1H), 4,6 (kV, 2H), 3,9 (d, 2H), 1.5 a (t, 3H).

Description 99. Ethyl-6-(2-oxoethyl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D99)

To a solution of ethyl-6-(2-propen-1-yl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D98) (64 mg, 0.23 mmol) in a mixture of THF/water (2:1, 3 ml) with stirring, add the osmium tetroxide (0.16 ml of a 4 wt.% solution in water). After 15 minutes add periodate sodium (122 mg, or 0.57 mmol) and the reaction mixture is stirred for 1 hour. The reaction mixture was diluted with water (5 ml) and extracted with DCM (3×10 ml). The organic layers are combined, dried (Na2SO4) and concentrated in vacuo. The crude substance is purified on SPE cartridge-Si elution with a mixture of 40% cyclohexane in ethyl acetate and get named in the title compound (37 mg, 57%).1H-NMR (300 MHz, CDCl3) δ: 9,85 (s, 1H), 8,9 (d, 1H), 8,15 (d, 1H), from 7.9 to 7.7 (m, 2H), and 4.5 (q, 2H), 4.2V (s, 2H), 1.5 a(t, 3H).

Description 100. 1,1-DIMET latil-4-[2-(deformity)-5-chinoline]-1-piperidinecarboxylate (D100)

To a solution of 1,1-dimethylethyl-4-(2-formyl-5-chinoline)-1-piperidinecarboxylate (D68) (1,015 g of 2.97 mmol) in DCM (10 ml) at room temperature add TRIFLUORIDE (diethylamino)sulfur (DAST) (428 μl, of 3.27 mmol). After 4 hours add DAST (194 μl, 1,49 mmol) and continue stirring for another 1 hour. The reaction is quenched with water (30 ml) and the mixture extracted with DCM (3×30 ml). The organic layer is dried (MgSO4) and evaporated in vacuo to a residue, which was purified column flash chromatography by elution with mixtures of cyclohexane/ethyl acetate (9:1-8:2), and get named in the title compound (886 mg, 82%) as a yellow solid. MS (ES; m/z): 364 [MH+]. C19H23F2N3O2requires 363,41.1H-NMR (300 MHz, CDCl3) δ: 8,65 (d, 1H), to 7.84 (d, 1H), to 7.67 (m, 2H), 7,17 (d, 1H), 6.75 in (t, 1H), 3,68 (osirm, 4H), to 3.02 (osirm, 4H), for 1.49 (s, 9H).

Description 101. Methyl-3-oxo-2-[5-(2-propen-1-yl)-2-chinoline]butanoate (D101)

To a mixture of N-oxide of 5-(2-propen-1-yl)quinoline (D88) (2.0 g, 10,81 mmol) and acetic anhydride (5 ml) add methylacetoacetate (1.3 ml), maintaining the internal temperature below 30ºC. The reaction mixture was stirred at 30 º C overnight and then poured into a mixture of ice water. Precipitated precipitated substance is filtered off, washed with water and then dried in vacuum at 40 ºC, and get named in connection in the form of a yellow solid (2,94 g, 96%). MS (ES) m/z: 284 [MH+]. C17H17NO3requires is 283.3.

Description 102. Methyl[5-(2-propen-1-yl)-2-chinoline]acetate (D102)

Methyl-3-oxo-[5-(2-propen-1-yl)-2-chinoline]butanoate (D101) (2.83 g, 10 mmol) was added with stirring over the course of 10 minutes to a 10% HCl solution (10 ml). After stirring for 20 minutes at room temperature, the reaction mixture was alkalinized with 10% potassium carbonate solution in water (35 ml) and then extracted with DCM (3×50 ml). The organic layer is dried over Na2SO4and then evaporated in vacuum. The residue is purified flash chromatography by elution with mixtures of 10% cyclohexane in ethyl acetate to 25% cyclohexane in ethyl acetate and get named in the title compound as an orange liquid (1,62 g, 67%). MS (ES) m/z: 242 [MH+]. C15H15NO2requires 241,3.

Description 103. Methyl-6-(2-propen-1-yl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D103)

To a mixture of methyl[5-(2-propen-1-yl)-2-chinoline]acetate (D102) (620 mg) and ethyl[5-(2-propen-1-yl)-2-chinoline]acetate (100 mg, obtained according to the procedure described above for the D102, but based on ethylacetoacetate in the description 101) (only 2.96 mmol) in dry acetonitrile (15 ml) at 0 ° C add DBU (0,464 ml, 3.1 mmol) and p-acetamidobenzenesulfonyl (768 mg, 3.1 mmol). The reaction mixture was stirred for 20 min and then quench the reaction at 0 ° C solution of ammonium chloride (20 ml). The mixture is extracted with DCM (3×20 ml)and the organic layer dried over Na2SO4and then evaporated in vacuum. The residue is purified flash chromatography by elution with mixtures of 10% cyclohexane in ethyl acetate to 20% cyclohexane in ethyl acetate, and get named in the title compound as a white solid (500 mg, 63%). MS m/z: 268 [MH+]. C15H13N3O2requires 267,3. HPLC detect the presence of ≈10% ethyl-6-(2-propen-1-yl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate.

Description 104. Methyl-6-(2-oxoethyl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D104)

To a solution of methyl-6-(2-propen-1-yl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D103) (450 mg, 1,68 mmol) in a mixture of THF/water (2:1, 21 ml) with stirring, add the osmium tetroxide (1.9 ml of a 4 wt.% solution in water). After 30 minutes add periodate sodium (900 mg, is 4.21 mmol) and the reaction mixture is stirred for 30 minutes, the Reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (3×30 ml). The organic layers are combined, dried (Na2SO4) and concentrated in vacuo. The crude substance is purified on SPE cartridge-Si elution with a mixture of 50% cyclohexane in ethyl acetate and get named in the title compound (360 mg, 80%).1H-NMR (300 MHz, CDCl3) δ: 9,9 (s, 1H), 8,9 (d, 1H), and 8.2 (d, 1H), 7,8 (m, 2H), 7,6 (users, 1H), 4.2V (s, 2H), 4,1 (s, 3H).

Description 105. the Teal-1-methyl-6-(2-propen-1-yl)imidazo[1,5-a]quinoline-3-carboxylate (D105)

To the mixture eternita[5-(2-propen-1-yl)-2-chinoline]acetate (D89) (1 g) and glacial acetic acid (25 ml) is added zinc powder (1.4 g). The reaction mixture was stirred at room temperature for 2 hours and then filtered. To 14 ml of filtered solution add triethylorthoformate (10 ml) and heated with stirring at 150 º C for 7 min under the influence of microwave radiation (Personal Chemistry EmrysTM Optimiser, 300 watts). The reaction mixture is evaporated in vacuum and then the residue is purified on SPE cartridge-Si elution with a mixture of 50% ethyl acetate in cyclohexane, and get named in the title compound as a pale yellow solid (210 mg). MS (ES) m/z: 295,1 [MH]+. C18H18N2O2requires 294,4.

Description 106. Ethyl-1-methyl-6-(2-oxoethyl)imidazo[1,5-a]quinoline-3-carboxylate (D106)

To a solution of ethyl-1-methyl-6-(2-propen-1-yl)imidazo[1,5-a]quinoline-3-carboxylate (D105) (205 mg, 0.7 mmol) in a mixture of THF/water (2:1, 6 ml) with stirring, add the osmium tetroxide (0.5 ml of 4 wt.% solution in water). After 10 minutes add periodate sodium (372 mg, of 1.74 mmol) and the reaction mixture is stirred for 30 minutes. The reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (3×15 ml). The organic layers are combined, dried (Na2SO4and concentrate in vacuo the E. The crude substance is purified on SPE cartridge-Si elution with a mixture of 30% cyclohexane in ethyl acetate and get named in the title compound as a white solid (90 mg, 43%). MS (ES) m/z: 297,2 [MH]+. C17H16N2O3requires 296,3.

Description 107. 5-Bromo-6-methylinosine (D107)

Named the title compound is obtained in yield 86%, following the procedure described in Chem. Heterocycl. Compd. (Engl. Transl.), 1988, vol. 24(8), 892. MS (ES) m/z: 222,0 [MH+]. C10H8BrN requires 221,08.

Description 108. 6-Methyl-5-(2-propen-1-yl)quinoline (D108)

To a solution of 5-bromo-6-methylinosine (D107) (5.6 g, to 25.2 mmol) in dry toluene (40 ml) at room temperature add Halliburton (8.5 ml, 27.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.4 g, 5%). The reaction mixture was stirred at 125º for 5 hours, then cooled, quenched the reaction with water (40 ml) and the mixture extracted with DCM (3×100 ml). The organic layers are dried (Na2SO4) and concentrated in vacuo, get the crude reaction product, which was purified on SPE cartridge-Si elution with a mixture of cyclohexane/ethyl acetate (15:5), and get named in the title compound (3,74 g, 81%). MS (ES) m/z: 184,10 [MH+]. C13H13N requires 183,25.

Description 109. 6-Methyl-5-(2-propen-1-yl)quinoline (D109)

Named the title compound is obtained in yield 82% according to the procedure used to receive the connection in the description 88, on the basis of 6-methyl-5-(2-propen-1-yl)quinoline (D108). MS (ES/+) m/z: 200,1 [MH+]. C13H13NO require 199,25.

Description 110. Ethyl[6-methyl-5-(2-propen-1-yl)-2-chinoline](nitro)acetate (D110)

Named the title compound is obtained in yield of 36% according to the synthesis procedure used to obtain the connection in the description 89 on the basis of 6-methyl-5-(2-propen-1-yl)quinoline (D109). The crude substance is purified on SPE cartridge-Si elution with a mixture of 0.5% Meon in DCM. MS (ES/+) m/z: 315,0 [MH+]. C17H18N2O4requires 314,34.

Description 111. Ethyl-7-methyl-6-(2-propen-1-yl)imidazo[1,5-a]quinoline-3-carboxylate (D111)

To a chilled on ice suspension of ethyl[6-methyl-5-(2-propen-1-yl)chinoline](nitro)acetate (D110) (300 mg, 0.95 mmol) in glacial acetic acid (4 ml) was added parts of zinc (374 mg, 5.7 mmol). After adding zinc reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The zinc is filtered off and washed with water (30 ml). The solution is poured into 1 M solution edtc (50 ml) and alkalinized to pH 8, 1 M NaOH solution. Then the whole solution was adjusted to pH 6 and extracted with EtOAc (2×30 ml). The combined organic phases are washed with 1 M NaOH solution (40 ml), dried over anhydrous Na2SO4and evaporated in vacuum. Temporarily the second connection ethylamino[6-methyl-5-(2-propen-1-yl)-2-chinoline]acetate fast process triethylorthoformate (4 ml) and heated with stirring at 150 º C for 10 min under the influence of microwave radiation. Light yellow solid, which precipitated precipitated from the reaction mixture, collected by filtration and washed with ether, and receive 80 mg named in the title compounds as a pale yellow solid. The filtrate is passed through a SCX cartridge to remove triethylorthoformate and then cleaned on cartrigde SPE-Si elution with a mixture of 20% ethyl acetate in cyclohexane, and get named in the title compound (100 mg, 35.8 per cent).1H-NMR (300 MHz, CDCl3) δ: 8,5 (s, 1H)and 8.1 (d, 1H), 7,9 (d, 1H), 7.5 (d, 1H), and 7.6 (d, 1H), and 7.3 (d, 1H), 6,1-5,9 (m, 1H), 5,1 (d, 1H), and 4.8 (d, 1H), of 4.45 (q, 2H), and 3.8 (d, 2H), of 2.45 (s, 3H), 1,4 (t, 3H).

Description 112. Ethyl-7-methyl-6-(2-oxoethyl)imidazo[1,5-a]quinoline-3-carboxylate (D112)

Named in the header connection receive according to the synthesis procedure used to obtain the connection in the description 91 based on ethyl-7-methyl-6-(2-propen-1-yl)imidazo[1,5-a]quinoline-3-carboxylate (D111). The crude substance is cleaned at cartrigde SPE-Si elution with mixtures of 50-100% ethyl acetate in cyclohexane, and get named in the title compound with a yield of 75%.1H-NMR (300 MHz, CDCl3) δ: 9,85 (s, 1H), 8,65 (s, 1H)and 8.1 (d, 1H), 8.0 a (d, 1H), 7.5 (d, 1H), and 7.4(d, 1H), and 4.5 (q, 2H), 4.2V (s, 2H), and 2.5 (s, 3H), 1,4 (t, 3H).

Description 113. (2Z)-3-(Dimethylamino)-1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-yl)-2-butene-1-he (D113)

+]. C33H37N5O2requires 535,69.

Description 114. 2-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-4-intraformational (D114)

1,1,1-Cryptor-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (2,54 g, 7,11 mmol) is added in portions with stirring to a chilled on ice suspension of 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-4-ol (WO 2000071517) (1.28 g, of 5.92 mmol) and triethylamine (1,10 ml, 7,89 mmol) in dry CH3CN (40 ml). The reaction mixture was stirred over night at room temperature, then the reaction quenched with water (30 ml) and the mixture extracted with EtOAc (3×30 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture is purified on a Horizon-Si elution with a mixture of 30% EtOAc in hexane, and get named in the title compound (1.60 g, 4,60 mmol, yield 78%) as a white solid. MS (ES) m/z: 349,1 [MH+]. C12H7F3 2O5S requires 348,26.

Description 115. 1,1-Dimethylethyl-4-[2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-4-yl]-1-piperidinecarboxylate (D115)

A mixture of 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-4-intraformational (D114) (1.31 g, 3,76 mmol), Cs2CO3(1.84 g, 5,64 mmol), Pd(OAc)2(84,41 g, 0.38 mmol), (+/-)-BINAP (0.35 g, 0,56 mmol) and N-BOC-piperazine (0,91 g, 4,88 mmol) in dry toluene (40 ml) was stirred at 100 º C for 4 hours. After cooling to room temperature, add aqueous saturated solution of NH4Cl (30 ml) and the mixture extracted with ethyl acetate (3×30 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo. The residue is purified on Biotage Si with elution with a mixture of cyclohexane/ethyl acetate, 70/30, and get named in the title compound (0,94 g of 2.44 mmol, yield 65%) as a yellow oil.1H-NMR (300 MHz, DMSO) δ: 7,8 (s, 1H), and 7.4 (m, 2H), and 7.8 (d, 1H), 3,5-3,4 (osirm, 4H), and 3.3 (s, 3H), 3,2-3,1 (osirm, 4H), and 1.4 (s, 9H).

Description 116. 1-[2-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-4-yl]piperazine (D116)

A solution of 1,1-dimethylethyl-4-[2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-4-yl]-1-piperidinecarboxylate (D115) (0,83 g of 2.16 mmol) in a mixture of TFWC/THF (1:3, 12 ml) was stirred at room temperature overnight. After evaporation the crude substance is purified on a SCX cartridge (elution met the Nole, and then 2 N solution of ammonia in methanol) and get named in the title compound (0,77 g, yield 92%) as a yellow solid. MS (ES; m/z): 285,1 [MH+]. C15H16N4O2requires 284,32.

Description 117. Ethyl-2-[8-(2-propen-1-yl)-2H-1,4-benzoxazin-3-yl]hydrazinecarboxamide (D117)

A mixture of 8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-thione (D18) (1 mmol, 203 mg) and ethylcarbazole (3 mmol, 312 mg) in anhydrous ethanol (4 ml) is refluxed for 4.5 hours. The reaction mixture is cooled to room temperature and the resulting solid is filtered off and treated with ethyl ether. Named the title compound is obtained in 75% yield (210 mg). MS (ES) m/z: 276,2 [MH+]. C14H17N3O3requires 275,3.

Description 118. 6-(2-Propen-1-yl)-2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-he (D118)

A solution of ethyl-2-[8-(2-propen-1-yl)-2H-1,4-benzoxazin-3-yl]hydrazinecarboxamide (D117) (80 mg, 0,291 mmol) in DMF (1 ml) is heated under stirring at 200ºC for 10 minutes under the influence of microwave radiation. The solution is concentrated and the obtained solid is treated with diethyl ether, and get named in the title compound (50 mg, 74%). MS (ES) m/z: 230,0 [MH+]. C12H11N3O2requires 229,2.

Description 119. 2-Methyl--(2-propen-1-yl)-2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-he (D119)

To a solution of 6-(2-propen-1-yl)-2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-it (D118) (60 mg, 0.26 mmol) and iodomethane (20 µl, 0.31 mmol) in dry DMF (3 ml) at 0 ° C add sodium hydride (15 mg, 60% wt./mass., suspension in mineral oil, and 0.37 mmol). The reaction mixture was left to warm to room temperature and stirred for 1 hour, then the reaction quenched with water (5 ml) and the mixture extracted with DCM (3×15 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, and get named in the title compound (66 mg), which can be used in the next stage without additional purification. MS (ES) m/z: 244,0 [MH+]. C13H13N3O2requires 243,2.

Description 120. (2-Methyl-1-oxo-2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-6-yl)acetaldehyde (D120)

Named in the header connection receive according to the procedure of description 6 based on 2-methyl-6-(2-propen-1-yl)-2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-it (D119) (64 mg, 0.26 mmol). The crude reaction product used in the next stage without additional purification.1H-NMR (400 MHz, CDCl3) δ: 9,77 (s, 1H), 8,24 (m, 1H), 7,14 (m, 1H), 7,05 (m, 1H), to 5.03 (s, 2H), of 3.78 (s, 2H), 3,54 (s, 3H).

Description 121. 7-Methyl-8-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-he (D121)

Named the title compound is obtained in yield 92%, following the General procedure of example 1, based on (7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)acetaldehyde (D79) (100 mg, 0,488 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (165 mg, 0,732 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of mixtures of methanol in DCM (2-3%), and get named in the title compound (186 mg, 92%). MS (ES) m/z: 416,10 [MH+]. C26H29N3O2requires 415,53.

Description 122. 6-Methyl-2-oxo-1,2,3,4-tetrahydro-5-chinainternational (D122)

Named in the title compound, receive, following the procedure describing 71, starting from 5-hydroxy-6-methyl-3,4-dihydro-2(1H)-Hinayana [see Organic Preparations and Procedures International, 25(2), 223-8, 1993] (2.0 g, 11.3 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (7/3), and get named in the title compound (3.9 g). MS (ES) m/z: 310,00 [MH+]. C11H10F3NO4S requires 309,26.

Description 123. 6-Methyl-5-(2-propen-1-yl)-3,4-dihydro-2(1H)-chinoline (D123)

Named in the title compound, receive, following the procedure describing 72, from 6-methyl-2-oxo-1,2,3,4-tetrahydro-5-chinainternational (D122) (3.5 g, 11.3 mmol). The crude reaction product is purified flash x is matography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (7/3) and processing diethyl ether, and you get named in the title compound (1.97 g, 85%). MS (ES) m/z: 202,10 [MH+]. C13H15NO require 201,27.

Description 124. Ethyl-7-methyl-6-(2-propen-1-yl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D124)

Named in the title compound, receive, following the procedure of example 80, using 6-methyl-5-(2-propen-1-yl)-3,4-dihydro-2(1H)-Hinayana (D123) (700 mg, of 3.48 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (1/1) and get named in the title compound (863 mg, 84%). MS (ES) m/z: 297,10 [MH+]. C18H20N2O2requires 296,37.

Description 125. Ethyl-7-methyl-6-(2-oxoethyl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D125)

Named in the title compound, receive, following the procedure in the description of the receiving D6, using ethyl-7-methyl-6-(2-propen-1-yl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D124) (863 mg, of 2.92 mmol). The crude reaction product is purified flash chromatography on silica gel with elution by ethyl acetate and get named in the title compound (602 mg, 69%).1H-NMR (300 MHz, CDCl3) δ: ppm was 1.43 (t, 3H), of 2.35 (s, 3H), 2,85 (t, 2H), 3,32 (t, 2H), 3,91 (s, 2H), and 4.40 (q, 2H), 7,22 (d, 1H), was 7.36 (d, 1H), 8,02 (s, 1H), 9,78 (s, 1H).

Description 126. 6-(2-Propen-1-yl)-4H-tetrazolo[5,1-C][1,4]benzoxazin (D126)

A solution of hydrazine hydrate is added (380 μl, 12.2 mmol) in dry THF (2 ml) is treated at 20 ° C by adding dropwise a solution of 8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-thione (D18) (500 mg, of 2.44 mmol) in THF (25 ml). After stirring for 1.5 hours the solvent is removed under reduced pressure and get the intermediate hydrazone, which is used in the next stage without additional purification. To a suspension of hydrazone (495 mg, 2,44 mmol) in 0.5 N HCl (15 ml) at 5 º C is added dropwise a solution of sodium nitrite (252 mg, 3,66 mmol) in water (2 ml). After stirring for 4 hours the mixture was neutralized with saturated solution of NaHCO3and extracted with DCM (3×30 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (2/8) and get named in the title compound (235 mg, 45%). MS (ES) m/z: 215,10 [MH+]. C11H10N4O requires 214,23.

Description 127. 5-(2-Propen-1-yl)-3,4-dihydro-2(1H)-finalistin (D127)

Named in the title compound, receive, following the procedure of description 18, using 5-(2-propen-1-yl)-3,4-dihydro-2(1H)Hinayana (D72) (404 mg, of 2.16 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (4/6) is getting called in the title compound (290 mg, 66%). MS (ES) m/z: 204,10 [MH+]. C12H13NS requires 203,31.

Description 128. 6-(2-Propen-1-yl)-4,5-dihydrotetrazolo[1,5-a]quinoline (D128)

Named in the title compound, receive, following the procedure describing 126, starting from 5-(2-propen-1-yl)-3,4-dihydro-2(1H)-chinaindia (D127) (290 mg, 1,43 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (3/7), and get named in the title compound D128 (225 mg, 74%). MS (ES) m/z: 213,10 [MH+]. C12H12N4requires 212,25.

Description 129. 4H-Tetrazolo[5,1-c][1,4]benzoxazin-6-ylacetamide (D129)

Named in the title compound, receive, following the procedure describing the receipt D6, using 6-(2-propen-1-yl)-4H-tetrazolo[5,1-a]quinoline (D126) (235 mg, of 1.09 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (4/6) and get named in the title compound (144 mg, 61%).1H-NMR (300 MHz, CDCl3) δ ppm of 3.77 (s, 2H), to 5.56 (s, 2H), 7,14 (d, 2H), of 7.90 (t, 1H), 9,72 (s, 1H).

Description 130. 4,5-Dihydrotetrazolo[1,5-a]quinoline-6-ylacetamide (D130)

Named in the title compound, receive, following the procedure describing 6, using 6-(2-propen-1-yl)-4,5-dihydrotetrazolo[1,5-a]is inoline (D128) (225 mg, 1.06 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with mixtures of ethyl acetate/cyclohexane (4/6-10/0) and get named in the title compound (132 mg, 58%).1H-NMR (300 MHz, CDCl3) δ ppm 2.95 points (t, 2H), 3.27 to (t, 2H), 3,82 (s, 2H), 7,19 (m, 1H), 7,38 (m, 1H), of 7.97 (d, 1H), 9,72 (s, 1H).

Description 131. 2-(Methylthio)-5-(2-propen-1-yl)-3,4-dihydroquinoline (D131)

Named in the title compound, receive, following the procedure describing 19 using 5-(2-propen-1-yl)-3,4-dihydro-2(1H)-henrician (D127) (150 mg, of 0.74 mmol). The crude reaction product used in the next stage without additional purification. MS (ES) m/z: 218,10 [MH+]. C13H15NS requires 217,33.

Description 132. Ethyl-(2E/Z)-nitro[8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-ilidene]ethanoate (D132)

To a mixture of 3-(methylthio)-8-(2-propen-1-yl)-2H-1,4-benzoxazine (D19) (441 mg, a 2.01 mmol) and ethylnitrosourea (2,23 ml of 20.1 mmol) at room temperature and under nitrogen atmosphere add the Triton-B (40% solution in methanol, 841 µl, a 2.01 mmol). The reaction mixture is heated at 50 º C for 2 hours, then the reaction quenched with water (10 ml)and the mixture extracted with DCM (3×30 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo, and get the crude reaction product, which was purified flash chromatography on silica gel with elution by the mixture of utilized the t/cyclohexane (1/9) and get named in the title compound (411 mg, 67%) as a mixture of E/Z isomers. MS (ES) m/z: 305,10 [MH+]. C15H16N2O5requires 304,30.

Description 133. Ethyl-(2E/Z)-nitro[5-(2-propen-1-yl)-3,4-dihydro-2(1H)hyalinized]ethanoate (D133)

Named in the title compound, receive, following the procedure describing 132, using 2-(methylthio)-5-(2-propen-1-yl)-3,4-dihydroquinoline (D131) (261 mg, 1.20 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (1/9) and get named in the title compound (264 mg, 73%) as a mixture of E/Z isomers. MS (ES) m/z: 303,20 [MH+]. C16H18N2O4requires 302,33.

Description 134. Ethyl-6-(2-propen-1-yl)-4H-[1,2,3]triazolo[5,1-c]benzoxazin-3-carboxylate (D134)

To a solution of ethyl-(2E/Z)-nitro[8-(2-propen-1-yl)-2H-1,4-benzoxazin-3(4H)-ilidene]ethanoate (D132) (280 mg, 0,921 mmol) in glacial acetic acid (3 ml) at 0 ° C, add zinc (356 mg, of 5.53 mmol). The reaction mixture is heated to room temperature and stirred for 45 minutes, then cooled to 5 º C, and add trichloroacetic acid (30 mg, 0,184 mmol) and amyl nitrate (151 mg, 1.28 mmol). The reaction mixture is heated to room temperature and stirred for 1.5 hours, then the reaction quenched with water (10 ml)and the mixture extracted with DCM (3×30 ml). The combined organization is a mini-layers are dried (Na 2SO4) and concentrated in vacuo, and get the crude reaction product, which is purified first on a SCX cartridge and then flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (2/8), and get named in the title compound (154 mg, 58%). MS (ES) m/z: 286,00 [MH+]. C15H15N3O3requires 285,30.

Description 135. Ethyl-6-(2-propen-1-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D135)

Named in the title compound, receive, following the procedure describing 134, using ethyl(2E/Z)-nitro[5-(2-propen-1-yl)-3,4-dihydro-2(1H)hyalinized]ethanoate (D133) (200 mg, to 0.662 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohexane (2/8), and get named in the title compound (97 mg, 52%). MS (ES) m/z: 284,00 [MH+]. C16H17N3O2requires 283,33.

Description 136. Ethyl-6-(2-oxoethyl)-4H-[1,2,3]triazolo[5,1-C][1,4]benzoxazin-3-carboxylate (D136)

Named in the title compound, receive, following the procedure of description 6 using ethyl-6-(2-propen-1-yl)-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazin-3-carboxylate (D134) (154 mg, 0,540 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of ethyl acetate/cyclohex is an (2/8), and you get named in the title compound (96 mg, 62%).1H-NMR (300 MHz, CDCl3) δ ppm of 1.37 (t, 3H), 3,76 (s, 2H), and 4.40 (q, 2H), to 5.57 (s, 2H), 7,12 (m, 2H), 8,01 (m, 1H), 9,72 (s, 1H).

Description 137. Ethyl-6-(2-oxoethyl)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D137)

Named in the title compound, receive, following the procedure describing the receipt D6, using ethyl-6-(2-propen-1-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D135) (97 mg, 0,343 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with mixtures of ethyl acetate/cyclohexane (2/8-4/6) and get named in the title compound (71 mg, 73%).1H-NMR (300 MHz, CDCl3) δ ppm of 1.40 (t, 3H), 2,87 (t, 2H), 3.33 and (t, 2H), 3,83 (s, 2H), to 4.41 (q, 2H), 7,18 (m, 1H), 7,38 (m, 1H), 8,12 (d, 1H), 9,73 (s, 1H).

Description 138. 6-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carbaldehyde (D138)

To a solution of N-methyl-N-(metiloksi)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E25) (120 mg, 0,234 mmol) in dry THF (1 ml), cooled to 0 ° C, with stirring LiAlH4(0,117 ml of 1 M solution in THF, 0,117 mmol)and the resulting mixture is stirred for 1 hour at 0OC. The reaction is quenched with water and then the reaction mixture was extracted with ethyl acetate (3×20 ml). The combined organic is such layers are dried (Na 2SO4) and evaporated in vacuo, and the crude oil purified on SPE cartridge-Si (2 g) with elution with a mixture of 2% methanol in DCM, and get named in the title compound as a white solid (77 mg, 75%). MS (ES) m/z: 454,4 [MH+]. C27H27N5O3requires 453,54.

Description 139. (2Z)-3-(Dimethylamino)-1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-yl)-2-butene-1-he (D139)

The free base of the hydrochloride of 1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-yl)ethanone (E) (85 mg, of 0.182 mmol) suspended in dimethylacetal N,N-dimethylacetamide, and the mixture is exposed to microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 150 º C, 5 min + 5 min). Precipitated precipitated from the reaction mixture creamy solid is collected by filtration and treated with ethyl ether, and get named in the title compound (67 mg, 69%). MS (ES) m/z: 537,3 [MH+]. C32H36N6O2requires 536,68.

Description 140. 1,1-Dimethylethyl-4-hydroxy-4-(5-chinoline)-1-piperidinecarboxylate (D140)

5-Bromohydrin (2 g, 0,0096 mol) in an atmosphere of N2at 70 º C added under stirring to a solution of n-BuLi (12 ml, 1.6 M solution in hexane, 0,0192 mmol) in 20 ml of a mixture of dry THF:diethyl ether (1:1). The reaction mixture plumage is eshivot 30 minutes, then add a solution of 1,1-dimethylethyl-4-oxo-1-piperidinecarboxylate (1.9 grams, 0,0095 mol) in THF (20 ml) and the reaction mixture was stirred for another 30 minutes. The reaction mixture is heated to 0 ° C, then quench the reaction with water and the mixture extracted with ethyl acetate (3×20 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and receive 2 g of the crude substance. The resulting mixture was purified on a column of Horizon (40 M) with elution with a mixture of 10% ethyl acetate in cyclohexane, and get named in the title compound as a cream solid (1.9 g, 60%). MS (ES) m/z: 329,2 [MH+]. C19H24N2O3requires 328,41.

Description 141. 1,1-Dimethylethyl-4-fluoro-4-(5-chinoline)-1-piperidinecarboxylate (D141)

1,1-Dimethylethyl-4-hydroxy-4-(5-chinoline)-1-piperidinecarboxylate (D140) (100 mg, 0.3 mmol)dissolved in dry DCM (3 ml), add-78º with stirring to a solution of DEOXOFLUOR (0,144 ml of 50% solution in THF, 0,335 mmol) in dry DCM (3 ml). The reaction mixture is stirred for 2 hours at-78º and then for 1 hour at room temperature. The reaction is quenched with saturated solution of NH4Cl and the reaction mixture extracted with DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and get the crude substance. The resulting mixture was purified on a cartridge is SPE-Si (2 g) with elution with a mixture of 2% methanol in DCM, and you get named in the title compound as a white foam (85 mg, 83%). MS (ES) m/z: 331,2 [MH+]. C19H23FN2O2requires 330,4.

Description 142. 5-(4-Fluoro-4-piperidinyl)quinoline (D142)

1,1-Dimethylethyl-4-fluoro-4-(5-chinoline)-1-piperidinecarboxylate (D141) (170 mg, 0.51 mmol) dissolved in a mixture of TFWC/DCM (3:1, 6.2 ml) and stirred over night at room temperature. The solvent is evaporated in vacuo, and the crude mixture was purified on SPE cartridge-SCX (2 g) (elution with methanol, then 2 N solution of ammonia in methanol), and get named in the title compound as a white solid (90 mg, 76%). MS (ES) m/z: 231,1 [MH+]. C14H15FN2requires 230,28.

Description 143. 2-(Deformity)-5-(1-piperazinil)quinoline (D143)

A solution of 1,1-dimethylethyl-4-[2-(deformity)-5-chinoline]-1-piperidinecarboxylate (D100) (886 mg, 2,438 mmol) in a mixture of TFWC/DCM (10 ml, 1:1) was stirred at room temperature overnight. After evaporation the crude substance is purified by extraction on SCX and get named in the title compound (616 mg, 96%) as a yellow solid. MS (ES) m/z: 264 [MH+]. C14H15F2N3requires 263,29.1H-NMR (300 MHz, CDCl3) δ: 8,65 (d, 1H), 7,80 (d, 1H), 7,66 (m, 2H), 7,17 (d, 1H), 6,74 (t, 1H), 3,1 (m, 9H).

Description 144. 1,1-Dimethylethyl-4-[2-(g is proximity)-5-chinoline]-1-piperidinecarboxylate (D144)

A solution of 1,1-dimethylethyl-4-(2-formyl-5-chinoline)-1-piperidinecarboxylate (D68) (1,505 g, to 4.41 mmol) and sodium borohydride (834 mg, 22.05 mmol) in ethanol (20 ml) is stirred for 5 hours at room temperature. The mixture is evaporated in vacuum and the residue is dissolved in water (100 ml). The suspension is extracted with DCM (3×100 ml) and the extract washed with brine (100 ml). The organic layer is dried (MgSO4) and evaporated, and get named in the title compound (1,515 g quantities.). MS (ES) m/z: 344 [MH+]. C19H25N3O3requires 343,42.1H-NMR (300 MHz, CDCl3) δ: 8,4 (m, 1H), and 7.7 (m, 1H), 7,6 (m, 1H), 7,2 (m, 1H), and 7.1 (m, 1H), 4,9 (m, 2H), 4,4 (s, 1H), 3,7 (osirm, 4H), 3.0 a (osirm, 4H), and 1.4 (s, 9H).

Description 145. 1,1-Dimethylethyl-4-[2-(permitil)-5-chinoline]-1-piperidinecarboxylate (D145)

DAST (636 μl, 782 mg, 4,852 mmol) are added to a chilled (-78º) solution of 1,1-dimethylethyl-4-[2-(hydroxymethyl)-5-chinoline]-1-piperidinecarboxylate (D144) (1,515 g, to 4.41 mmol) in DCM (20 ml). After 1.5 hours, add another DAST (289 μl, 355 mg of 2.20 mmol) and continue stirring for another 3 hours while the reaction mixture is heated to room temperature. The reaction is quenched with water (100 ml)and the mixture extracted with DCM (100 ml). The organic layer is dried (MgSO4) and evaporated in vacuo. The residue is purified column flash chromatography (cyclohexane:EtOAc, 9:18:2), and you get named in the title compound (1,087 g, 71%) as a yellow solid. MS (ES) m/z: 346 [MH+]. C19H24FN3O2requires 345,42.1H-NMR (300 MHz, CDCl3) δ: 8,56 (d, 1H), 7,74 (d, 1H), 7,6 (m, 2H), to 7.09 (d, 1H), 5,62 (d, 2H), 3,68 (osirm, 4H), 3.0 a (osirm, 4H), to 1.48 (s, 9H).

Description 146. 2-(Permitil)-5-(1-piperazinil)quinoline (D146)

A solution of 1,1-dimethylethyl-4-[2-(permitil)-5-chinoline]-1-piperidinecarboxylate (D145) (1,087 g, 3,147 mmol) in a mixture of TFWC/DCM (15 ml, 1:2) was stirred at room temperature overnight. After evaporation the crude substance is purified by extraction on SCX and get named in the title compound (725 mg, 94%) as a yellow solid. MS (ES) m/z: 246 [MH+]. C14H16FN3requires 245,30.1H-NMR (300 MHz, CDCl3) δ: 8,56 (d, 1H), 7,72 (d, 1H), 7,6 (m, 2H), 7,10 (d, 1H), 5,62 (d, 2H), 3,1 (osirm, 9H).

Description 147. 5-(4-{[(1,1-Dimethylethyl)oxy]carbonyl}-1-piperazinil)-2-quinoline-carboxylic acid (D147)

1,1-Dimethylethyl-4-(2-formyl-5-chinoline)-1-piperidinecarboxylate (D68) (1.0 g, of 2.93 mmol, 1 EQ.) dissolved in DMSO (12 ml) and the mixture is cooled to 5ºC. Add buffer solution (3 ml; pH 3 citric acid/sodium hydroxide/hydrochloric acid). To the resulting yellow suspension at 5 º C for 1 hour is added dropwise a 1 M aqueous solution of NaClO2(4 ml, 1,36 EQ.). The mixture is then stirred at 25 OC in those which begins 1 hour. Analysis by TLC indicates incomplete reaction. Add dropwise 1 M aqueous solution of NaClO2(12 ml) and DMSO (2 ml). After 1 hour stirring at 25 mixture is diluted with water (10 ml) and extracted with AcOEt (2×10 ml). The organic layer is dried (Na2SO4), evaporated, and the residue chromatographic on silica gel (230-400 mesh mesh) by elution with a mixture of DCM/methanol, 9/1, and get named in the title compound (0,876 g, 83%) as a yellow oil. C19H23N3O4requires 357,41.1H-NMR (300 MHz, CDCl3) δ: to 8.62 (d, 1H), of 8.06 (d, 1H), a 7.85 (d, 1H), 7,69 (t, 1H), 7,25 (d, 1H), 3,59 (osirm, 4H), 2,98 (osirm, 4H), USD 1.43 (s, 9H).

Description 148. 1,1-Dimethylethyl-4-{2-[(dimethylamino)carbonyl}-5-chinoline}-1-piperidinecarboxylate (D148)

A solution of 5-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinil)-2-quinoline-carboxylic acid (D147) (219 mg, 0,753 mmol), EDC×HCl (216 mg, 1,129 mmol), HOBt (173 mg, 1,129 mmol) and dimethylamine (2.0 M solution in THF, a 1.88 ml, 3,765 mmol) in dry DMF (5 ml) was stirred at room temperature for 20 hours. The reaction mixture was diluted with DCM (20 ml) and washed with saturated solution of NaHCO3(20 ml). The organic layer is dried (MgSO4) and evaporated in vacuo, and get named in the title compound (171 mg, 75%). The product can be used crude in the next stage.

Description 149. 1,1-Dimethylethyl-4-{2-[(methylamino)is arbonyl]-5-chinoline}-1-piperidinecarboxylate (D149)

Named the title compound (296 mg, 87%) receive procedure descriptions 148 using 5-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinil)-2-quinoline-carboxylic acid (D147) (376 mg, 1,052 mmol) and methylamine (2.0 M/THF). Named in the title compound used in the next stage without additional purification.

Description 150. N,N-Dimethyl-5-(1-piperazinil)2-chinainternational (D150)

A solution of 1,1-dimethylethyl-4-{2-[(dimethylamino)carbonyl]-5-chinoline}-1-piperidinecarboxylate (D148) (171 mg, 0,444 mmol) in a mixture of DCM contains 10% TFOC (5 ml) was stirred at room temperature overnight. After evaporation the crude substance is purified by extraction on SCX and get named in the title compound (102 mg, 81%). MS (ES; m/z): 285 [MH+]. C16H20N4O requires 284,36.

Description 151. N-Methyl-5-(1-piperazinil)-2-chinainternational (D151)

A solution of 1,1-dimethylethyl-4-{2-[(methylamino)carbonyl]-5-chinoline}-1-piperidinecarboxylate (D149) (296 mg, 0,770 mmol) in a mixture of DCM contains 10% TFOC (5 ml) was stirred at room temperature overnight. After evaporation the crude substance is purified by extraction on SCX and get named in the header of the reaction product (96 mg, 46%). MS (ES; m/z): 271 [MH+]. C15H18N 4O requires 270,33.

Description 152 and 153. 2-Methyl-2-[(1S)-1-phenylethyl]-4-piperidinol (D152 and D153)

Named in the title compound D152 and D153 receive according to the experimental procedure described in WO2004/094380. The crude mixture was purified on a Biotage column (65M) with elution with a mixture of 15% ethyl acetate in cyclohexane and get diastereoisomer D152 and D153 in the form of a pale yellow oil. Diastereoisomer 1 (D152):1H NMR (500 MHz, CHLOROFORM-d) δ ppm was 1.15 (d, J=5,86 Hz, 3H), of 1.34 (d, J=6,83 Hz, 3H), 2,16-2,39 (m, 3H), 2,60 is 2.80 (m, 3H), 3,35-of 3.42 (m, 1H), was 4.02 (q, 1H), 7.24 to 7,28 (m, 1H), 7,34 (t, 2H), 7,45 (d, J=6,83 Hz, 2H); Diastereoisomer 2 (D153):1H NMR (500 MHz, CHLOROFORM-d) δ ppm of 1.05 (d, J=6,83 Hz, 3H), USD 1.43 (d, J=6,83 Hz, 3H), 2,10-2,12 (m, 1H), 2,29-of 2.36 (m, J=12,69 Hz, 1H), of 2.51-2,60 (m, 2H), 2,92-3,00 (m, 2H), 3,14-3,20 (m, 1H), 3,92 (kV, 1H), 7.24 to 7,29 (m, 1H), 7,31-7,38 (m, 4H).

Description 154. Acetate 2-methyl-4-piperidinol (D154)

2-Methyl-1-[(1S)-1-phenylethyl]-4-piperidinol (diastereoisomer 1) (D152) (18 g, 0,083 mol) is dissolved in acetic acid (90 ml) under nitrogen atmosphere in the flask for hydrogenation. Add 10% Pd/C (900 mg, 5%, mass./mass.), and the reaction mixture is vigorously stirred in a Parr apparatus at a pressure of H24 psi for 2 days. The catalyst is filtered off, the solution evaporated in vacuum and get named in the title salt acetate as a pale yellow oil (14 g, 97%). MS (ES) m/z: 114,1 [MH+]. C6H11NO require 113,16.

Description 155. Azet the t 2-methyl-4-piperidinol (D155)

Named in the title compound are obtained from the output 100% according to the experimental procedure for obtaining the description 154, based on 2-methyl-2-[(1S)-1-phenylethyl]-4-piperidinol (diastereoisomer 2) (D153). MS (ES) m/z: 114,1 [MH+]. C6H11NO require 113,16.

Description 156. 1,1-Dimethylethyl-2-methyl-4-oxo-1-piperidinecarboxylate (D156)

To a solution of the acetate of 2-methyl-4-piperidinol (D154) (14 g, of 0.081 mol) in 1 M NaOH solution (30 ml) is added di-tert-BUTYLCARBAMATE (18 g, of 0.081 mol) and the reaction mixture was stirred over night at 20 ° C. The reaction mixture was diluted with ethyl acetate (50 ml) and extracted several times (50 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and receive the crude oil which is purified on a layer of silica with elution with a mixture of 11% ethyl acetate in cyclohexane, and get named in the title compound (6,95 g, 40%) as a pale yellow oil. MS (ES) m/z: 214,1 [MH+]. C11H19NO3requires 213,28.

Description 157. 1,1-Dimethylethyl-2-methyl-4-oxo-1-piperidinecarboxylate (D157)

Named in the header connection receive according to the experimental procedure for obtaining the description 56, on the basis of the acetate of 2-methyl-4-piperidinol (D155). MS (ES) m/z: 214,1 [MH+]. C11H19NO3requires 213,28.

Describes the e 158. 1,1-Dimethylethyl-2-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylic (D158)

To a solution of 1,1-dimethylethyl-2-methyl-4-oxo-1-piperidinecarboxylate (D156) (6,95 g, 0,0325 mol) in dry THF (60 ml) under cooling at-78º add LiHDMS (35,8 μl of 1 M solution in hexane, 0,0358 mol), and then add dropwise a solution of 1,1,1-Cryptor-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (11.5g, 0,0325 mol) in THF (60 ml). After 30 minutes at-78º the reaction mixture is heated to room temperature and then stirred for 4 hours. Add a saturated solution of NH4Cl (200 ml) and the mixture extracted with ethyl acetate (3×100 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and receive 10 g of the crude substance. The resulting mixture was purified on a column of Horizon (65M) with elution with a mixture of 3% ethyl acetate in cyclohexane, and get a mixture of 1:1 double bond regioisomers in the form of a cream solid. MS (ES) m/z: 246,1, 290,0, 346,0 [MH+]. C12H18F3NO5S requires 345,3.

Description 159. 1,1-Dimethylethyl-6-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylic (D159)

Named in the header connection receive according to the experimental procedure descriptions 158, based on 1,1-dimethylethyl-2-methyl-4-oxo-1-piperidinecarboxylic is a (D157). MS (ES) m/z: 246,1, 290,0, 346,0 [MH+]. C12H18F3NO5S requires 345,3.

Description 160. 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (D160)

A mixture of 2-methyl-5-chinainternational (receipt described in WO 2004/046124 A1) (13.5 g, 0.046 mol), bis(pinacolato)Debora (13 g, 0,051 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.88 g, 0,0023 mol), 1,1'-bis(diphenylphosphino)ferrocene (1.27 g, 0,0023 mol) and potassium acetate (13.5 g, was 0.138 mol) in dry 1,4-dioxane (120 ml) is heated overnight at 80 ° C. The solvent is evaporated to dryness, and the crude substance is purified on a column of Horizon (65M) with elution with a mixture of 10% ethyl acetate in cyclohexane, and get named in the title compound as a cream solid (10 g, 81%). MS (ES) m/z: 270,2 [MH+]. C16H20BNO2requires 269,15.

Description 161 (racemic mixture). 1,1-Dimethylethyl-6-methyl-4-(2-methyl-5-chinoline)-3,6-dihydro-1(2H)-pyridinecarboxylic (D161)

The mixture of regioisomers double bond 1,1-dimethylethyl-2-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylic (D158) (1,65, 4,778 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (D160) (1.35 g, 5,017 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.39 g, 0,4778 mol) and potassium acetate (2 g, 14,33 mmol) in dry DMF (100 ml) is heated at boiling the situation under reflux for 4 hours. The solvent is evaporated to dryness, and the crude substance is purified on a column of Horizon (40M) with elution with a linear gradient, starting with a mixture of 10% ethyl acetate in cyclohexane and to a mixture of 30% ethyl acetate in cyclohexane, and get named in the title compound as a cream solid (736 mg, 45%). MS (ES) m/z: 339,2 [MH+]. C21H26N2O2requires 338,45.

Description 162 (racemic mixture of enantiomers). 1,1-Dimethylethyl-2-methyl-4-(2-methyl-5-chinoline)-1-piperidinecarboxylate (D162)

1,1-Dimethylethyl-6-methyl-4-(2-methyl-5-chinoline)-3,6-dihydro-1(2H)-pyridinecarboxylic (D161) (736 mg, 2,17 mmol) dissolved in 95% ethanol (8.5 ml) in a hydrogenation flask. Add 10% Pd/C (84 mg) and the reaction mixture is vigorously stirred under atmospheric pressure of hydrogen for 9 days. The catalyst is filtered off and the solution evaporated in vacuo. The crude substance is purified on a column of Horizon (40M) with elution with a linear gradient starting from 100% cyclohexane and to a mixture of 20% ethyl acetate in cyclohexane, and get named in the title compound as a white solid (350 mg, 47%). MS (ES) m/z: 341,3 [MH+]. C21H28N2O2requires 340,46.

Description 163 (racemic mixture of enantiomers). 2-Methyl-5-(2-methyl-4-piperidinyl)chinoline (D163)

1,1-D is methylethyl-2-methyl-4-(2-methyl-5-chinoline)-1-piperidinecarboxylate (D162) (350 mg, 1,03 mmol) dissolved in a mixture of TFWC/DCM (3:1, 3.1 ml) and stirred over night at room temperature. The solvent is evaporated in vacuo, and the crude mixture was purified on SPE cartridge-SCX (2 g) (elution with methanol, then 2 N solution of ammonia in methanol), and get named in the title compound as a white solid (212 mg, 86%). MS (ES) m/z: 241,2 [MH+]. C16H20N2requires 240,36.

Description 164. 1,1-Dimethylethyl-4-(2-methyl-5-chinoline)-1-piperidinecarboxylate (D164)

To a solution of 2-methyl-5-(1-piperazine)quinoline (3.00 g, 13,19 mmol) in dioxane (10 ml) and a saturated aqueous solution of NaHCO3(10 ml) is added VOS2On (3,17 g, 14,52 mmol) and stirred at room temperature overnight. Add water and the reaction product is extracted with ethyl acetate (2×). The organic layer is dried (MgSO4), filtered and evaporated in vacuum, and get named in the title compound (4,51 g, Quant.). MS (ES) m/z: 328 [MH+]. C19H25N3O2(327,43).1H-NMR (300 MHz, CDCl3) δ: at 8.36 (d, 1H), 7,72 (d, 1H), 7,56 (t, 1H), 7,26 (d, 1H), 7,02 (d, 1H), 3,68 (m, 4H), to 3.00 (m, 4H), of 2.72 (s,3H), of 1.48 (s, 9H).

Description 165. 1,1-Dimethylethyl-4-(2-formyl-5-chinoline)-1-piperidinecarboxylate (D165)

To a solution of intermediate compound 164 (4,51 g, 13,77 mmol) in dioxane (20 ml) add SeO2(1,83 g, 16.2 mmol). The mixture was stirred at 90ºC for 1.5 hours, then cooled to room temperature and then filtered and evaporated. The residue is purified column flash chromatography (cyclohexane:EtOAc, 9:1-1:1), and get named in the title compound (3,35 g, 71%) as a yellow solid. MS (ES) m/z: 342 [MH+]. C19H23N3O3(341,41).1H NMR (300 MHz, CDCl3) δ: 10,20 (s, 1H), 8,63 (d, 1H), 7,98 (kV, 2H), 7,71 (t, 1H), 7,21 (d, 1H), 3,69 (users, 4H), 3,03 (users, 4H), to 1.48 (s, 9H).

Description 166. 2-Bromophenyl-2-propenyloxy ether (D166)

In a round bottom flask, equipped with a fridge, download o-bromophenol (500 g), acetone (5000 ml) and K2CO3(440 g). Then added dropwise (over 30 min) allylbromide (385 g). The mixture is heated at the boil under reflux for 2 hours. The reaction mixture is cooled and the solid is filtered off. The solution was concentrated in vacuo to 1500 ml and then added to 5000 ml of cyclohexane. The solution is again concentrated to 1500 ml and then added to 5000 ml of cyclohexane. Finally, the mixture is concentrated to 1500 ml and add 1500 ml of cyclohexane.

Description 167. 2-Bromo-6-(2-propen-1-yl)phenol

Et2AlCl in hexano (2885 ml) is added dropwise to the product of the reaction mixture descriptions 166, adjusting the temperature below 30 º C (internal temperature). Reaction control HPLC. Upon completion of the reaction, reactio the ing the mixture is cooled to 5 º C (internal temperature) and add dropwise 1 N HCl (3000 ml), controlling the beginning of the evolution of a gas (pH control). Then add dropwise water (50 ml). The phases are separated and the organic phase is extracted with cyclohexane (2500 ml). The solution is concentrated to 1500 ml in vacuo and then added to 5000 ml of THF. The solution is again concentrated to 1500 ml and then added to 5000 ml of THF. Finally, the mixture is concentrated to 3075 ml.

Description 168. (3-Bromo-2-hydroxyphenyl)acetaldehyde

Get the solution periodate sodium (1537,5 g) in water (11375 ml) and stirred over night. The solution is filtered. To a solution of 2-bromo-6-(2-propen-1-yl)phenol (D167) in THF add water (920 ml) and then K2OsO4.2H2O (1.18 g). The mixture is stirred at room temperature for 30 minutes Then added dropwise within 3 hours an aqueous solution of periodate sodium, regulara temperature so that the internal temperature remained below 20-25ºC. Reaction control HPLC. Upon completion of the reaction, to the reaction mixture are added water (5000 ml) and DCM (4000 ml). The mixture is stirred for 15 minutes the Phases are separated and the organic phase washed with water (5000 ml). To the organic phase, add Si-thiol resin (28.5 g, the acceptor heavy metals), and the solution is refluxed for 2 hours. After cooling to room temperature, the solution is passed through a CUNO filter to remove contaminants metals. ZAT is m, the solution was concentrated in vacuo to a volume of 2500 ml

Description 169. 2-Bromo-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenol

Charged to the reactor piperazine (314 g), DCM (2590 ml) and triacetoxyborohydride sodium (399,6 g). The mixture is stirred for 15 min at room temperature (formed dense solution). Added dropwise (3-bromo-2-hydroxyphenyl)acetaldehyde (D168) in DCM (370 g 2500 ml DCM), regulating the internal temperature. Reaction control HPLC. To the reaction mixture add 10% NaOH solution up until the pH becomes alkaline (approximately 1110 ml) (pH control using paper strips or pH meter). Then the phases are separated, and the organic phase washed with water (3700 ml). To the organic phase add 3700 ml of THF, the mixture is then concentrated to 3700 ml at atmospheric pressure (T = 45-55ºC). Then add 3700 ml of THF, and the mixture is again concentrated to 3330 ml at atmospheric pressure (T = 55-57º). The reaction mixture was gradually cooled to room temperature (approximately 1 hour). In the mixture contribute seed and added dropwise heptane (5550 ml). The mixture is stirred over night at room temperature. The solid is filtered off and the filter residue is washed with 925 ml of a mixture of THF/heptane, 1:2. The solid is dried in a vacuum Cabinet at 40 º C.

Description 170. 1-[(2-Bromo-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)oxy]-2-propanone/u>

Charged to the reactor 2-bromo-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenol (D169), phenol (550 g), methyl ethyl ketone (5500 ml), chloracetamide (302,5 g), potassium carbonate (325 mesh) (550 mg) and 18.6-crown-ether (17,05 g). The mixture is refluxed for 90 min (heterogeneous solution). Reaction control HPLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature. Add DCM (8250 ml) and then water (8250 ml). The organic phase is separated. The aqueous phase is checked HPLC, if it still has a certain amount of reaction product, then the aqueous phase is re-extracted with 5500 ml of DCM. To the organic phase add 5500 ml of THF and the mixture is concentrated to 5500 ml at atmospheric pressure (T = 45-55ºC). Then add 5500 ml of THF and the mixture is again concentrated to 4950 ml at atmospheric pressure (T = 55-57º). The reaction mixture was gradually cooled to room temperature (approximately 1 hour). In the mixture contribute seed and added dropwise heptane (8250 ml). The mixture is stirred over night at room temperature. The solid is filtered off and the filter residue is washed 1375 ml of a mixture of THF/heptane, 1:2. The solid is dried in a vacuum Cabinet at 40 º C.

Description 171. 8-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-he

In the reactor atmosphere is nitrogen load DMF (4750 ml), CuI (75,05 g) and N,N'-dimethylethylenediamine (97,85 g). The reaction mixture was stirred in an atmosphere of N2until then, until the mixture turns dark blue (approximately 2 hours). To the reaction mixture is added potassium carbonate (325 mesh) (306 g) and 1-[(2-bromo-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)oxy]-2-propanone (D170) (475 g). The heterogeneous mixture is heated at 110 º C (internal temperature) for 16 hours. Reaction control HPLC. The reaction mixture is cooled to room temperature and add water (9500 ml) and DCM (9500 ml). The reaction mixture was stirred at 30 º C (internal temperature) for 1 hour. The mixture is then cooled to room temperature and the phases are separated. The aqueous phase is checked HPLC, if it still have some amount of reaction product, then the aqueous phase is re-extracted 4750 ml DCM. The organic phase is washed first with a 3.5% solution of NH4OH (4750 ml) and then water (4750 ml) four times (up until HPLC no longer detects DMF). The organic phase is passed through a CUNO filter to remove contaminants metals. To the organic phase add 4750 ml of THF, and the mixture is then concentrated to 4750 ml at atmospheric pressure (T = 45-55ºC). Then add 4750 ml of THF and the mixture is again concentrated to 4750 ml at atmospheric pressure (T = 55-57º). The mixture is gradually cooled to room temperature (approximately 1 hour). In the ect make seed and added dropwise heptane (7125 ml). The mixture is stirred over night at room temperature. The solid is filtered off and the filter residue is washed 1187 ml of a mixture of THF/heptane, 1:2. The solid is dried in a vacuum Cabinet at 40 º C.

Examples

Example 1. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E1)

A mixture of ethyl-6-(2-oxoethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D6) (50 mg, 0,17 mmol) and 2-methyl-5-piperazine-1-rhinolin (58 mg, 0.21 mmol) in dry 1,2-dichloroethane (4 ml) was stirred at room temperature under nitrogen atmosphere for 15 minutes. Then add triacetoxyborohydride sodium (44 mg, 0.21 mmol) and the resulting reaction mixture is stirred for 3 hours, the reaction is quenched with saturated aqueous ammonium chloride and the mixture extracted with DCM (×3). The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified on SPE cartridge (silica gel) by elution with a mixture of 4% methanol in DCM, and receive free ground mentioned in the title compound as a white solid (61 mg, 70%). MS (ES) m/z: 498,5 [MH+]. C16H16N2O3requires 497,6.1H-NMR (300 MHz, CDCl3) δ: 8,4 (d, 1H), 8 (s, 1H), 7.7 (d, 1H), 7,55 (t, 1H), and 7.3 (d, 1H), 7,2 (m, 1H), and 7.1 (d, 1H), 6,95-7,05 (m, 2H), of 5.55 (s, 2H), 4,4 (kV, 2H), 2,7-,15 (m, 12H), and 3.7 (s, 3H), 1,4 (t, 3H). The free base (20 mg, 0.04 mmol) dissolved in dry methanol (1 ml) and treated with HCl (0,068 ml of a 1.25 M solution in methanol, 0,084 mmol) at 0OC. The resulting suspension was stirred at 0 ° C for 4 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound (20 mg, 87%) as a yellow solid.1H-NMR (500 MHz, DMSO-d6) δ: 10,67 (users, 1H), 8,8-8,6 (users, 1H), 7,89 (DD, 1H), 7,82 (s, 2H), to 7.64 (users, 1H), 7,35 (s, 1H), 7,29 (DD, 1H), 7,2 (d, 1H), 4,3 (kV, 2H), 3,76 (DD, 2H), 3,6-3,3 (m, 8H), and 2.8 (s, 3H), of 1.33 (t, 3H).

The compound of example 1 was prepared as follows.

Charged to the reactor 8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-he (D171) (274 g) and THF (2740 ml). The mixture is cooled to 0 ° C and added dropwise a 1 M solution of tert-BuOK in THF (748 ml), adjusting the temperature at 0OC. At 0OC add diethylphosphate (126 ml) and the reaction mixture was stirred at 0OC for 30 minutes, the Reaction mixture was cooled down to-5ºC and add utilitarianistic (87,7 ml) and 1 M solution of tert-BuOK in THF (811 ml), keeping the temperature below 0OC. The reaction mixture is stirred at -5 º C for 1.5 hours. Reaction control HPLC. The reaction is quenched by adding a solution of ammonium chloride (20%, 4250 ml), and then THF is evaporated to 4658 ml. Add DCM (5480 ml) and the mixture is heated to 30ºC. After stirring for 30 min phase RA is really and the aqueous phase re-extracted with DCM (2740 ml), if it is still present, the reaction product (after checking HPLC). The combined organic phases washed with water (2740 ml). The organic phase is passed through a CUNO filter to remove contaminants metals. The organic phase is concentrated to 822 ml (P=1000 mbar, T =66º), it adds 2740 ml of acetone, and the mixture is concentrated to 2192 ml (P=950 mbar, T=45-55ºC). Then add another 274 ml of acetone and the mixture is again concentrated to 1370 ml (P=950 mbar, T=55-57º). After cooling, take a sample for NMR amount of DCM. If DCM is left, the solvent exchange as long as the number of DCM will not be ≤2,25%. Then the mixture is cooled to room temperature and stirred over night. The solid is filtered off and the filter residue is washed 685 ml of acetone. The solid is dried in a vacuum Cabinet at 40 º C.

Example 2. 6-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2)

To a solution of ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E1) (220 mg, 0.44 mmol) in methanol (3 ml) is added NaOH (3 ml of 10% aqueous solution) and the resulting white suspension is heated for 5 minutes when exposed to microwave radiation at 120 ºC. The obtained pale-yellow solid is filtered off, suspended in water (15 ml) and the solution n is italist (pH 7) aqueous solution of acetic acid. The obtained precipitated in the sediment is not quite white solid is filtered off and washed with diethyl ether (3×20 ml), and get called in the header connection (has 0.168 g, 81%). MS (ES) m/z: 470,3 [MH+]. C27H27N5O3requires 469,54.1H-NMR (300 MHz, DMSO-d6) δ: 8,49 (users, 1H), 8.3 (l, 1H), 7.7 (d, 1H), 7,55 (users, 1H), 7,35 (d, 1H), 7,2 (d, 1H), 7,07 (osirm, 2H), and 5.5 (s, 2H), 3,05-2,75 (acsim, 15H).

Potassium salt of the compound of example 2 was prepared as follows.

The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E1) (115 g) are suspended in 1.5 M solution of KOH in methanol (805 ml). The suspension is heated to boiling under reflux for 1.5 hour. The reaction mixture is cooled to room temperature and filtered. The solid is washed with methanol (287,5 ml). White solid is dried in a vacuum Cabinet at 40 º C.

Example 3. The dihydrochloride of N-cyclopentyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E3)

Named in the title compound are obtained from the output 40%, following the General procedure of example 1, from N-cyclopentyl-6-(2-oxoethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (D11) (25 mg, 0.08 mmol) and 2-methyl-5-piperazine-1-rhinolin (20 mg, 0.09 mmol) (WO 2004/046124). MS (ES) m/z: 537,3 [MH+]. C32H36 N6O2requires 536,6.1H-NMR (500 MHz, DMSO-d6) δ: 10,79 (acsis, 1H), 8,67 (acsis, 1H), 8,58 (s, 1H), 7,9 (d, 1H), 7,8 (d+acsis, 3H), 7,6 (acsis, 1H), 7,32 (users, 1H), 7,24 (d, 1H), 7,15 (t, 1H), 5,59 (s, 2H), 4,18 (m, 1H), 3,7-3 (widm, 12H), 2,78 (users, 3H), 1,83 (m, 2H), 1,67 (m, 2H), of 1.52 (m, 4H).

Example 4. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine (E4)

Named in the title compound are obtained from the output 40%, following the General procedure of reductive amination of example 1, based on 4H-imidazo[5,1-c][1,4]benzoxazin-6-ylacetamide (D13) (20 mg, 0.08 mmol) and 2-methyl-5-piperazine-1-rhinolin (20 mg, 0.1 mmol). MS (ES) m/z: 426,3 [MH+]. C26H27N5O requires 425,5.1H-NMR (500 MHz, DMSO-d6) δ: at 10.64 (users, 1H), 8,64 (s, 1H), of 8.47 (d, 1H), 7,81 (d, 1H), and 7.7 (s, 2H), of 7.48 (d, 1H), and 7.3, and 7.1 (m, 3H), 7,07 (s, 1H), to 5.35 (s, 2H), 3,8-3,1 (acsim, 12H), 2,68 (s, 3H).

Example 5. The dihydrochloride ethyl-6-{3-[4-(2-methylinosine-5-yl)piperazine-1-yl]propyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E5)

Named in the title compound are obtained from the output 40%, following the General procedure of reductive amination of example 1 from ethyl-6-(3-oxopropyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D17) (20 mg, 0.08 mmol) and 2-methyl-5-piperazine-1-rhinolin (20 mg, 0.1 mmol). MS (ES) m/z: 512,4 [MH+]. C30H33N5O3/sub> requires 511,6.1H-NMR (500 MHz, DMSO-d6) δ: 10,92 (users, 1H), 8,71 (s, 1H), 8,64 (s, 1H), 7,83 (m, 3H), to 7.67 (users, 2H), 7,33 (users, 1H), 7,26 (d, 1H), 7,15 (t, 1H), 5,6 (s, 2H), 4,3 (kV, 2H), 3,64 (userd, 2H), 3,0-3,3 (acsim, 8H), 2,81 (users, 3H), 2,77 (DD, 2H), 2,12 (users, 2H), 1,33 (s, 3H).

Example 6. 6-{3-[4-(2-Methyl-5-chinoline)-1-piperazinil]propyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E6)

The dihydrochloride ethyl-6-{3-[4-(2-methylinosine-5-yl)piperazine-1-yl]propyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E5) (100 mg, 0.2 mmol) dissolved in methanol (1 ml)and add sodium hydroxide (1 ml of 1 M aqueous solution). The reaction mixture is exposed to microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 watts, 120 ºC, 5 min). The crude substance is purified on SPE cartridge-SCX and then treated triperoxonane acid (0.2 mmol), and get called in the header connection. MS (ES) m/z: 484,3 [MH+]. C28H29N5O3requires 483,6.1H-NMR (300 MHz, DMSO-d6) δ: 9,6 (users, 1H), and 8.6 (s, 1H), and 8.4 (d, 1H), and 7.8 (d, 1H), 7,65 (m, 1H), and 7.4 (d, 1H), 7-7,2 (m, 4H), of 5.55 (s, 2H), 3,0-3,7 (acsim, 10H), of 2.81 (m, 2H), 2,77 (s, 3H), 2,12 (users, 2H).

Example 7. The dihydrochloride 6-{3-[4-(2-methyl-5-chinoline)-1-piperazinil]propyl}-4H-imidazo[5,1-c][1,4]benzoxazine (E7)

6-{3-[4-(2-Methyl-5-chinoline)-1-piperazinil]propyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E6) (30 mg, 0.06 mmol) in 1-dichlorobenzene (1.5 ml) is exposed to in the microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 250º, 10 min). The solvent is removed on the cartridge SPE-SCX (elution with methanol, then 2 N solution of ammonia in methanol) and receive free ground mentioned in the title compound as a white solid (20 mg, 72%). The free base was dissolved in dry methanol (1 ml) and at 0 ° C gradually add HCl (80 μl of a 1.25 M solution in methanol, 0.1 mmol). The resulting suspension was stirred at 0 ° C for 4 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound as a yellow solid (20 mg). MS (ES) m/z: 440,4 [MH+]. C27H29N5O requires 439,6.1H-NMR (500 MHz, DMSO-d6) δ: 10,4 (users, 1H), and 8.4 (s, 1H), 8.3 (l, 1H), 7,6 to 7.75 (m, 3H), and 7.4 (d, 1H), 7,1-7,2 (m, 3H), 7 (users, 1H), 5,3 (s, 2H), 3,1-3,6 (osirm, 10H), and 2.7 (m, 2H), 2,6 (users, 3H), 2,1 (m, 2H).

Examples 8 and 9. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[2,1-c][1,4]benzoxazine (E8) dihydrochloride and 6-[4-(2-methyl-5-chinoline)-1-piperazinil]methyl}-4H-imidazo[2,1-c][1,4]benzoxazine (e)

Named in the title compound obtained as a mixture, following the General procedure of reductive amination of example 1, based on the mixture of aldehydes 4H-imidazo[2,1-c][1,4]benzoxazin-6-ylacetamide and 4H-imidazo[2,1-c][1,4]benzoxazin-6-carbaldehyde (D22 and D23) (50 mg, 0.2 mmol). Free base named header is VCE compounds E8 and e (13,8 mg and 14 mg, 20%) divided by chromatography on silica gel with elution with a mixture of 2% methanol in DCM. Free base is dissolved in dry methanol (0.5 ml) and at 0 ° C gradually add HCl (2.2 EQ. 1.25 M solution in methanol). The resulting suspension was stirred at 0 ° C for 4 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound as yellow solids.

Example 8. MS (ES) m/z: 426,3 [MH+]. C26H27N5O requires 425,5.1H-NMR (500 MHz, DMSO-d6) δ: 11,07 (users, 1H), 8,78 (osirm, 1H), with 8.05 (s, 1H), 7,88 (osirm, 2H), 7,7 (osirm, 2H), 7,38 (osirm, 1H), 7,25 (users, 1H), 7,24 (d, 1H), 7,18 (t, 1H), 5,43 (s, 2H), 3,8-3,2 (acsim, 12H), 2,84 (s, 3H).

Example 9. MS (ES) m/z: 412,4 [MH+]. C25H25N5O requires 411,5.1H-NMR (500 MHz, DMSO-d6) δ: at 10.64 (users, 1H), 8,8 (users, 1H), 8.0 a (osirm, 1H), 7,9 (users, 3H), 7,8 (users, 1H), 7.7 (d, 1H), and 7.1 to 7.4 (osirm, 3H), and 5.5 (s, 2H), and 4.5 (s, 2H), 3,8-3,1 (acsim, 8H), and 2.7 (s, 3H).

Example 10. The dihydrochloride of 1-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazine (E10)

Named the title compound is obtained in 71%yield by following the General procedure for reductive amination of example 1, on the basis of (1-methyl-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-6-yl)acetaldehyde (D25) (45 mg, 0.2 mmol) and 2-methyl-5-piperazine-1-rhinolin (54 mg, 0.24 mmol). MS (ES) m/z: 441,3 [MH+]. C 26H28N6O requires 440,6.1H-NMR (500 MHz, DMSO-d6) δ: 11,21 (users, 1H), 8,92 (users, 1H), 7,97 (users, 2H), 7,81 (userd, 1H), 7,72 (d, 1H), 7,45 (userd, 1H), 7,34 (d, 1H), 7,25 (m, 1H), 5,46 (s, 2H, in), 3.75 (d, 2H), 3,3-3,6 (osirm, 8H), 3,24 (m, 2H), 2.91 in (s, 3H), 2,74 (s, 3H).

Example 11. The dihydrochloride of 1-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazine (E11)

Named in the title compound are obtained from the output 35%, following the General procedure of reductive amination of example 1, on the basis of (1-methyl-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-6-yl)acetaldehyde (D25) (50 mg, 0.22 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (54,77 mg, 0.24 mmol). MS (ES) m/z: 440,10 [MH+]. C27H29N5O requires 439,57.1H-NMR (500 MHz, DMSO-d6) δ: 10,3 (users, 1H), 8,02 (users, 1H), 8,06 (users, 1H), 7,95 (users, 1H), 7,82 (users, 1H), 7,74 (d, 1H), to 7.64 (users, 1H), 7,34 (d, 1H), 7,25 (m, 1H), 5,46 (s, 2H), 3,76 (d, 2H), 3,80-3,10 (acsim, 6H), 2,86 (users, 3H), 2,74 (s, 3H), 2,3-2,1 (m, 5H).

Example 12. The dihydrochloride of 1-methyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazine (E12)

Named the title compound is obtained in yield of 47%, following the General procedure of reductive amination of example 1, on the basis of (1-methyl-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-6-yl)acetaldehyde (D25) (26 mg, 0.11 mmol) and 2-methyl-5-[(3R)-3-methyl-1-Pipera inyl]quinoline (40 mg, 0.16 mmol) (WO 2004/046124). MS (ES) m/z: 455,70 [MH+]. C27H30N6O requires 454,58.1H-NMR (500 MHz, DMSO-d6) δ: 10,85 (users, 1H), cent to 8.85 (users, 1H), 7,88 (users, 2H), 7,72 (users, 1H), 7,7-7,6 (users, 1H), 7,4-7,3 (users, 1H), 7,38 (d, 1H), 7,25 (m, 1H), 5,48 (s, 2H), 4-3,2 (acsim, 11H), 2,85 (users, 3H), 2,74 (s, 3H), 1,46-1,6 (2D, 3H).

Example 13. The dihydrochloride 6-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}-1-methyl-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazine (E13)

Named the title compound is obtained in yield 53%, following the General procedure of reductive amination of example 1, on the basis of (1-methyl-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-6-yl)acetaldehyde (D25) (25 mg, 0.11 mmol) and 7-fluoro-2-methyl-5-(1-piperazinil)quinoline (38 mg, 0.15 mmol) (WO 2004/046124). MS (ES) m/z: 459,30 [MH+]. C26H27N6OF requires 458,54.1H-NMR (500 MHz, DMSO-d6) δ: 10,44 (users, 1H), 8,44 (users, 1H), 7,73 (d, 1H), 7,47 (d, 1H), 7,43 (m, 1H), 7,34 (d, 1H), 7,32 (m, 1H), 7,22 (m, 1H), 5,46 (s, 2H), 3,74 (d, 2H), 3,6-3,1 (m, 10H), 2,69 (users, 3H), 2,74 (s, 3H).

Examples 14-24. A General procedure for obtaining amides

To a solution of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2) (1 EQ.) and DIPEA (1.1 EQ.) in DMF was added with stirring TBTU (1.1 equiv.) and the resulting solution was stirred for 1 hour at room temperature. Add the desired amine (1.1 EQ.) and the solution is stirred for 1 cha is and. The crude solution contribute to the cartridge SPE-SCX (elution with methanol, then 2 N solution of ammonia in methanol). After evaporation of the solvent from the ammonia fractions and processing diethyl ether extract of the free base of the desired compound in pure form. The free base was dissolved in dry methanol and treated with HCl (2.1 EQ. 1 M solution in diethyl ether) at 0OC. Evaporation of the solvent and processing diethyl ether to give the final compound in pure form.

Example 14. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E14)

To a solution of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2) (30 mg, 0.06 mmol) and DIPEA (0.012 mmol) in DMF (1 ml) was added with stirring TBTU (22,6 mg, 0.07 mmol) and the resulting solution was stirred for 1 hour at room temperature. Add hexamethyldisilazane (of 0.013 ml, 0.07 mmol) and the solution stirred for 1 hour. The excess amine is removed by use of PS-isocyanate resin, and after filtering off the resin and evaporation of the solvent the crude reaction product is purified on SPE cartridge (silica gel) by elution with a mixture of 3% methanol in DCM, and receive free ground mentioned in the title compound as a white solid substances the. The free base was dissolved in dry methanol and treated with HCl (2.1 EQ. 1 M solution in diethyl ether) at 0OC. Evaporation of the solvent and processing diethyl ether to give the target compound in pure form (22 mg, 65%). MS (ES) m/z: 469,4 [MH+]. C27H28N6O2requires 468,56.1H-NMR (300 MHz, DMSO-d6) δ: 11,4 (users, 1H), 9,05 (d, 1H), 8,59 (s, 1H), 8,08 (d, 1H), 8,01 (t, 1H), to $ 7.91 (d, 1H), to 7.84 (DD, 1H), 7,51-7,49 (userd, 2H), 7,33 (users, 1H), 7,26 (d, 1H), 7,15 (t, 1H), 5,59 (s, 2H), 3,81-3,72 (userd, 2H), 3,53-3,49 (userd, 4H), 3,43-3,39 (userd, 4H), 3,22-3,17 (m, 2H), 2,97 (s, 3H).

The free base of the compound of example 14 was prepared as follows.

6-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate potassium (E2) (63.5 g) is suspended in DMF (952,5 ml) in an atmosphere of N2. The suspension is stirred for 15 min at room temperature and then added DIPEA (23,5 ml) and TBTU (45,72 g). The suspension becomes orange-brown and after 45 min at room temperature and becomes transparent orange-brown solution. To clear the reaction mixture are added HMDS (28,5 ml) at room temperature. During the addition a white precipitate is formed and the suspension is stirred for 2 hours at room temperature. To the reaction mixture are added water (127 ml)and the suspension is stirred for 30 min and then filtered (filtration is very slow). OST the current on the filter is washed with a mixture of water/THF (2/1, 315 ml) and then MTBE (63 ml). The obtained solid is dried in a vacuum Cabinet at 40 º C for 24 hours.

The compound of example 14 (i.e. salt dihydrochloride) is also obtained from the free base as follows.

6-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (250,13 mg) suspended in a mixture of THF/N2About 90:10, vol/about. (15 ml). The mixture is heated to a temperature just below the boiling temperature under reflux and allowed to cool to about room temperature. Then add concentrated hydrochloric acid (89 ml) to the suspension, which immediately becomes yellow, and stimulated significant dissolution of solid substances. Several large agglomerates solid deep yellow/orange colors remain in solution, but they dissolved under stirring. The mixture is again heated almost to the boiling temperature under reflux, and virtually all solid enters solution, and remains homogeneous yellow solution. Upon cooling of the solution begins to fall hard yellow substance in significant amounts. The mixture is then transferred into the apparatus with cyclic temperature regime and expose cycle 0 -40 º C during the weekend for the maximum crystallization of the sample. The solid is removed by filtration and dried the 48 hours in vacuum at 40ºC.

The free base of the compound of example 14 was prepared as follows.

6-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (250,52 mg) suspended in a mixture of Meon/N2About 90:10, vol/about. (15 ml). The mixture is heated to a temperature just below the boiling temperature under reflux and allowed to cool to about room temperature. The mixture is again heated almost to the boiling temperature under reflux and then left to cool. The mixture is then transferred into the apparatus with cyclic temperature regime and expose cycle 0 -40 º C during the weekend for the maximum crystallization of the sample. The solid is removed by filtration and dried for 48 hours in vacuum at 40ºC.

The free base of the compound of example 14 was prepared as follows.

The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E14) (6 g) is suspended in DCM (25 ml) and add sodium bicarbonate solution (30 ml). The color of the suspension changed from yellow to white and the mixture is stirred for 30 minutes, the Solid is filtered and washed with water (15-20 ml). The filter residue is dried in a drying Cabinet at 40 º C for 12 hours, and get named in the title of the product (4 g).

Salt mesilate 6-{2-[4-(2-methyl-5-chinoline)-1-Pipa is azinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide was prepared as follows.

6-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (250,77 mg) suspended in a mixture of Meon/N2About 90:10, vol/about. (15 ml). The mixture is heated to a temperature just below the boiling temperature under reflux and allowed to cool to about room temperature. Then add methansulfonate acid (70 ml) to the suspension, which immediately becomes yellow. The mixture is again heated to a temperature just below the boiling temperature under reflux, at which all solid enters solution, and remains homogeneous yellow solution. Upon cooling of the solution begin to fall a significant amount of yellow solid. The mixture is then transferred into the apparatus with cyclic temperature regime and expose cycle 0-40ºC for maximum crystallization of the sample. The solid is removed by filtration and dried for 120 hours in vacuum at 40ºC.

Example 15. The dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E15 motorway)

Named in the title compound are obtained from the output 44% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2)following the General procedure for obtaining the amides described above, using methylamine (2 M solution in THF) MS (ES) m/z: 483,4 [MH +]. C28H30N6O2requires 482,58.1H-NMR (300 MHz, DMSO-d6) δ: 11,29 (users, 1H), 9,045 (d, 1H), at 8.60 (s, 1H), 8.07-a of 7.97 (m, 2H), 7,89 (d, 1H), 7,83 (DD, 1H), 7,49 (d, 1H), 7,37 (users, 1H), 7,24 (t, 1H), 7,15 (t, 1H), 5,59 (s, 2H), 3,70-3,38 (osirm, 10H), 3,22 is 3.15 (m, 2H), 2,96 (s, 3H), 2,74 (d, 3H).

Example 16. The dihydrochloride of N-(1-methylethyl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (e)

Named in the title compound are obtained from the output 83% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2)following the General procedure for obtaining the amides described above, using Isopropylamine. MS (ES) m/z: 511,4 [MH+]. C30H34N6O2requires 510,64.1H-NMR (300 MHz, DMSO-d6) δ: 11,41 (users, 1H), 9,07 (d, 1H), 8,61 (s, 1H), of 8.09 (d, 1H), 8,02 (t, 1H), 7,92 (d, 1H), 7,87 (s, 1H), a 7.85 (DD, 1H), 7,51 (d, 1H), 7,25 (d, 1H), 7,14 (t, 1H), 5,59 (s, 2H), 4,11-4,01 (m, 1H), 3.75 to 3,71 (userd, 2H), 3,53-3,49 (userd, 4H), 3,43-3,39 (userd, 4H), 3,22 is 3.15 (m, 2H), 2,98 (s, 3H)and 1.15 (d, 6H).

Example 17. The dihydrochloride of N-cyclopropyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E17)

Named in the title compound are obtained from the output 60% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2)following the General procedure for obtaining the amides described above, using cyclopropylamine. The (ES) m/z: 509,4 [MH +]. C30H32N6O2requires 508,62.1H-NMR (300 MHz, DMSO-d6) δ: 11,24 (users, 1H), 9,06 (d, 1H), 8,58 (s, 1H), 8,18 (d, 1H), with 8.05 (s, 1H), 8,01 (t, 1H), to $ 7.91 (d, 1H), a 7.85 (DD, 1H), 7,50 (d, 1H), 7,25 (d, 1H), 7,14 (t, 1H), 5,59 (s, 2H), 4,11-3,71 (osirm, 2H), 3,50-3,45 (userd, 4H), 3,42-3,38 (userd, 4H), 3,22 is 3.15 (m, 2H), 2,98 (s, 3H), 2,82 (m, 1H), 0,65-0,62 (userd, 6H).

Example 18. The dihydrochloride of N-cyclobutyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E18)

Named in the title compound are obtained from the output 83% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2)following the General procedure for obtaining the amides described above, using cyclobutylamine. MS (ES) m/z: of 523.4 [MH+]. C31H34N6O2requires 522,65.1H-NMR (300 MHz, DMSO-d6) δ: is 11.39 (users, 1H), 9,07 (d, 1H), to 8.62 (s, 1H), of 8.37 (d, 1H), 8,11 (d, 1H), 8,01 (t, 1H), to $ 7.91 (d, 1H), a 7.85 (DD, 1H), 7,50 (d, 1H), 7,25 (d, 1H), 7,14 (t, 1H), 5,59 (s, 2H), 4,46 is 4.35 (m, 1H), 3,78-3,71 (users, 2H), 3,56-3,49 (userd, 4H), 3,43-3,39 (userd, 4H), 3,22 is 3.15 (m, 2H), 2,98 (s, 3H), 2,17 is 2.10 (m, 4H), 1,65 is 1.58 (m, 2H).

Example 19. The dihydrochloride (cyclopropylmethyl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E19)

Named in the title compound are obtained from the output 60% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2), following the General procedure, the floor is placed amides, as described above, using cyclopropanemethylamine. MS (ES) m/z: of 523.4 [MH+]. C31H34N6O2requires 522,65.1H-NMR (300 MHz, DMSO-d6) δ: 11,50 (users, 1H), 9,05 (d, 1H), at 8.60 (s, 1H), 8,21 (users, 1H), 8,01 (t, 1H), to $ 7.91 (d, 1H), a 7.85 (DD, 1H), 7,50 (d, 1H), 7,25 (d, 1H), 7,14 (t, 1H), 5,59 (s, 2H), 3,74 (userd, 2H), 3,53-3,49 (userd, 4H), 3,42-3,38 (userd, 4H), 3,22 is 3.15 (m, 2H), 3,10 (t, 2H), 2,97 (s, 3H), 1.04 million of 1.00 (m, 1H), and 0.40 (d, 2H), 0,22 (d, 2H).

Example 20. The dihydrochloride of N-methyl-N-(1-methylethyl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E20)

Named in the title compound are obtained from the output 57% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2)following the General procedure for obtaining the amides described above, using N-methylisobutylketone. MS (ES) m/z: 525,4 [MH+]. C31H36N6O2requires 524,67.1H-NMR (300 MHz, DMSO-d6) δ: 11,37 (users, 1H), 9,05 (d, 1H), 8,61 (s, 1H), 8,08 (d, 1H), 8,01 (t, 1H), of 7.90 (d, 1H), a 7.85 (DD, 1H), 7,50 (d, 1H), 7,24 (DD, 1H), 7,15 (t, 1H), 5,52 (s, 2H), 4,11-4,01 (m, 1H), 3,71 (userd, 2H), 3,52-3,49 (userd, 4H), 3,42-3,38 (userd, 4H), 3,22 is 3.15 (m, 2H), 2,97 (s, 3H), 2,50-2,47 (users, 3H), 1,22-1,16 (osirm, 6H).

Example 21. The dihydrochloride of 3-(1-azetidinone)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine (E21)

Named in the title compound are obtained from the output 48% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]those who}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2), following the General procedure for obtaining the amides described above, using cyclobutylamine. MS (ES) m/z: 509,4 [MH+]. C30H32N6O2requires 508,62.1H-NMR (300 MHz, DMSO-d6) δ: 10,98 (users, 1H), 8,98 (userd, 1H), to 8.57 (s, 1H), 7,98-of 7.96 (userd, 2H), 7,87-7,81 (osirm, 2H), 7,47 (ushort, 1H), 7,24 (DD, 1H), 7,15 (t, 1H), 5,59 (s, 2H), 4,54 (t, 2H), 4.00 points (t, 2H), 3.75 to 3,34 (osirm, 10H), 3,20-3,15 (osirm, 2H), of 2.92 (s, 3H), a 1.96 (m, 2H).

Example 22. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(1-pyrrolidinylcarbonyl)-4H-imidazo[5,1-c][1,4]benzoxazine (E22)

Named the title compound is obtained in yield of 81% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2)following the General procedure for obtaining the amides described above, using pyrrolidine. MS (ES) m/z: of 523.4 [MH+]. C31H34N6O2requires 522,65.1H-NMR (300 MHz, DMSO-d6) δ: to 11.56 (users, 1H), 9,06 (d, 1H), to 8.57 (s, 1H), 8,10 (d, 1H), 8,02 (t, 1H), to $ 7.91 (d, 1H), 7,82 (DD, 1H), 7,51 (d, 1H), 7,24 (DD, 1H), 7,15 (t, 1H), 5,59 (s, 2H), 4,01 (t, 2H), 3.72 points userd, 2H), 3,53-3,35 (acsim, 10H), 3,21-3,17 (osirm, 2H), 2,98 (s, 3H), 1,94 is 1.75 (m, 4H).

Example 23. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(1-piperidinylcarbonyl)-4H-imidazo[5,1-c][1,4]benzoxazine (e)

Named in the title compound are obtained from the output 94% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic to the slots (E2), following the General procedure for obtaining the amides described above, using piperidine. MS (ES) m/z: 537,4 [MH+]. C32H36N6O2requires 536,68.1H-NMR (300 MHz, DMSO-d6) δ: 11,55 (users, 1H), 9,06 (d, 1H), to 8.57 (s, 1H), 8,10 (d, 1H), 8,02 (t, 1H), to $ 7.91 (d, 1H), 7,82 (DD, 1H), 7,51 (d, 1H), 7,24 (DD, 1H), 7,15 (t, 1H), of 5.53 (s, 2H), 4,46-4,05 (acsim, 2H), 3.72 points userd, 2H), 3,53-3,49 (userd, 4H), 3,44-3,35 (userd, 6H), 3,21-3,17 (osirm, 2H), 2,98 (s, 3H), 1,63-1,62 (userd, 2H), 1,54-1,53 (userd, 4H).

Example 24. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-c][1,4]benzoxazine (e)

Named in the title compound are obtained from the output 33% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E2)following the General procedure for obtaining the amides described above, using the research. MS (ES) m/z: 537,4 [MH+]. C31H34N6O3requires 538,65.1H-NMR (300 MHz, DMSO-d6) δ: 11,46 (users, 1H), 9,04 (d, 1H), 8,59 (s, 1H), of 8.06 (d, 1H), 8,00 (t, 1H), of 7.90-7,83 (m, 2H), of 7.48 (d, 1H), 7,26 (d, 1H), 7,15 (t, 1H), 5.56mm (s, 2H), or 4.31 (osirm, 4H), 3,93 of 3.56 (acsim, 6H), 3,53-3,49 (userd, 4H), 3,42-3,38 (userd, 4H), 3,22-3,17 (osirm, 2H), 2.95 and (s, 3H).

Example 25. N-Methyl-N-(metiloksi)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E25)

To a solution of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxa the Jn-3-carboxylic acid (E2) (54 mg, 0,115 mmol) and DIPEA (of 0.24 ml, was 0.138 mmol) in DMF (1 ml) under stirring at room temperature is added TBTU (41 mg, 0.12 mmol). After stirring for 1 hour add the hydrochloride of N,O-dimethylhydroxylamine (13.5 mg, was 0.138 mmol) and the reaction mixture was stirred for 1 hour. The reaction mixture contribute to the cartridge SPE-SCX (elution with methanol, then 2 N solution of ammonia in methanol) and after treatment diethyl ether get named in the title compound (40 mg, 68%). MS (ES) m/z: 513,4 [MH+]. C29H32N5O3requires 512,61.1H-NMR (300 MHz, DMSO-d6) δ: scored 8.38 (d, 1H), to 7.93 (s, 1H), 7,72 (d, 1H), EUR 7.57 (t, 1H), 7,32 (d, 1H), 7,26 (userd, 1H), 7,15 (d, 1H), 7,09-of 6.99 (m, 2H), of 5.53 (s, 2H), 3,84 (users, 3H), 3,55 (users, 3H), 3.15 in (users, 4H), 2,99-2,94 (osirm, 2H), 2,85 (users, 4H), 2,75-2,72 (osirm, 5H).

Example 26. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carbonitrile (E)

To a solution of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (free base E14) (23 mg, 0,049 mmol) in THF (0.5 ml) and pyridine (0,008 ml, 0,098 mmol) under cooling with ice and stirring triperoxonane anhydride (0,008 ml, 0,054 mmol) and the resulting solution was stirred at 0OC for 1 hour. The crude reaction mixture contribute to the cartridge SPE-SCX (elution with methanol, then 2 N races is the thief of ammonia in methanol). After evaporation of the solvent from the ammonia fractions of the resulting mixture was additionally purified on SPE cartridge (silica gel, 2 g) with elution with a mixture of DCM/methanol (98:2) and receive free ground named the title compound (7 mg, 32%) as not quite white solid. The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 451,3 [MH+]. C27H26N6O requires 450,54.1H-NMR (500 MHz, DMSO-d6) δ: of 10.93 (acsis, 1H), 8,92 (acsis, 1H), 8,79 (s, 1H), 7,95 (users, 2H), to $ 7.91 (d, 1H) 7,83 (users, 1H), 7,46 (users, 1H), 7,34 (d, 1H), 7,24 (t, 1H), 5.56mm (s, 2H), 4-3 (acsim, 12H), 2.91 in (users, 3H).

Example 27. The dihydrochloride of 2-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[2,1-c][1,4]benzoxazine (E27)

A mixture of (2-methyl-4H-imidazo[2,1-c][1,4]benzoxazin-6-yl)acetaldehyde (D28) (42 mg, 0.18 mmol) and 2-methyl-5-piperazine-1-rhinolin (63 mg, 0.28 mmol, 1.5 EQ.) in dry 1,2-dichloroethane (4 ml) was stirred at room temperature for 30 minutes, and then add triacetoxyborohydride sodium (58 mg, 0.28 mmol, 1.5 EQ.). The resulting mixture is stirred for 3 hours, the reaction is quenched with NaHCO3(10 ml saturated aqueous solution)and the mixture of extras is Giroud DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si elution with gradient mixtures of DCM/methanol (99/1-97/3) and obtain the corresponding free base named in the header, connection E27 in the form of a white solid (21 mg, 26%). To a solution of free base (21 mg, 0.05 mmol) in a mixture of Meon/DCM (3:1, 4 ml) slowly add HCl (84 ml of a 1.25 M solution in methanol) at 0OC. After 2 hours stirring at room temperature evaporation of volatiles gives named in the header, connection E27 in the form of a yellow solid. MS (ES) m/z: 440,30 [MH+]. C27H29N5O requires 439,57.1H-NMR (500 MHz, DMSO-d6) δ: 10,47 (users, 1H), 8,55 (users, 1H), 7,75 (users, 2H), 7,68 (s, 1H), 7,60 (m, 2H), 7,29 (users, 1H), 7,2 (m, 2H), are 5.36 (s, 2H), 3.75 to 3,00 (acsim, 12H), is 2.74 (s, 3H), of 2.21 (s, 3H).

Example 28. The dihydrochloride 1,2-dimethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[2,1-c][1,4]benzoxazine (E28)

To a solution of 4-(1-methyl-2-oxopropyl)-8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-she (D31) (50 mg, 0,106 mmol) in glacial acetic acid (1 ml) is added ammonium acetate (163 mg, 2,12 mmol, 20 EQ.). The mixture is exposed to microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 150 º C, 10 min), then diluted with ethyl acetate (10 ml), howling is up in a mixture of ice water (10 ml) and alkalinized with an aqueous solution of ammonium hydroxide (3 ml). The mixture is extracted with ethyl acetate (3×30 ml). The combined organic layers are dried (Na2SO4), and remove the solvent under reduced pressure. The crude substance is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-3%) and receive free ground named the title compound (44 mg, 92%). The free base (44 mg) dissolved in a mixture of Meon/DCM (3:1, 4 ml) and treated with HCl (2.2 EQ. 1.25 M solution in methanol) at 0OC. The resulting mixture was stirred at room temperature for 2 hours. Evaporation of volatiles gives named the title compound (44 mg) as a yellow solid. MS (ES) m/z: 454,40 [MH+]. C28H31N5O requires 453,59.1H-NMR (500 MHz, DMSO-d6) δ: 10,65 (acsis, 1H), 8,64 (acsis, 1H), 7,79 (users, 2H), 7,68 (d, 1H), to 7.61 (users, 1H), 7,32 (users, 1H), 7,27 (d, 1H), 7,20 (m, 1H), 5,27 (s, 2H, in), 3.75 (d, 2H), 3,70-3,00 (acsim, 10H), 2,77 (s, 3H), 2,48 (s, 3H), 2,18 (s, 3H).

Example 29. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2-(trifluoromethyl)-4H-imidazo[2,1-c][1,4]benzoxazine (E)

Named in the title compound are obtained from the output 58% in the form of a yellow solid in a manner similar to the method in example 28, from 8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4-(3,3,3-Cryptor-2-oxopropyl)-2H-1,4-benzoxazin-3(4H)-she (D36) (79 mg, 0,149 mmol) and ammonium acetate (230 mg,2,98 mmol, 20 EQ.) in acetic acid (2 ml). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-2%) and receive free ground named the title compound (42 mg, 58%). The obtained free base is treated with HCl (2.2 EQ. 1.25 M solution in Meon) and get called in the header connection. MS (ES) m/z: 494,30 [MH+]. C27H26F3N5O requires 493,54.1H-NMR (500 MHz, DMSO-d6) δ: 10,52 (acsis, 1H), total of 8.74 (s, 1H), 8,63 (acsis, 1H), 7,79 (m, 3H), to 7.61 (users, 1H), 7,30 (m, 2H), 7,22 (m, 1H), vs. 5.47 (s, 2H, in), 3.75 (d, 2H), 3,70-3,10 (acsim, 10H), 2,77 (s, 3H).

Example 30. The dihydrochloride of 3-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazine (E30)

Named the title compound is obtained in yield 81%, following the General procedure of reductive amination of example 1, from (3-methyl-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazin-6-yl)acetaldehyde (D41) (60 mg, 0,262 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-3%) and receive free ground named the title compound (93 mg, 81%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (4:1, 5 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 441,20 [MH+]. C26H28N 6O requires 440,55.1H-NMR (500 MHz, DMSO-d6) δ: 10,51 (acsis, 1H), 8,62 (acsis, 1H), to 7.93 (d, 1H), 7,78 (users, 2H), 7,60 (acsis, 1H), 7,37 (d, 1H), 7,32 (users, 1H), 7,24 (t, 1H), to 5.58 (s, 2H), 3.75 to 3,10 (acsim, 12H), was 2.76 (s, 3H), of 2.34 (s, 3H).

Example 31. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-[1,2,4]oxadiazole[3,4-c][1,4]benzoxazin-1-it (e)

Named the title compound is obtained in yield of 81% (46 mg)following the General procedure for reductive amination of example 1, on the basis of (1-oxo-4H-[1,2,4]oxadiazole[3,4-c][1,4]benzoxazin-6-yl)acetaldehyde (D44) (30 mg, 0,129 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-2%) and receive free ground named the title compound (46 mg, 81%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (5:1, 5 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 444,20 [MH+]. C25H25N5O3requires 443,51.1H-NMR (500 MHz, DMSO-d6) δ: 10,50 (acsis, 1H), 8,51 (acsis, 1H), 7,81 (d, 1H), 7,68 (users, 2H), 7,50 (acsis, 1H), 7,21-7,10 (m, 3H), 5,32 (s, 2H), 3,66-3,05 (osirm, 12H), to 2.67 (s, 3H).

Example 32. The dihydrochloride of 3-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazine (e)

Named in the header connection on ucaut with the release of 45% (25 mg), following the General procedure of reductive amination of example 1, from (3-methyl-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazin-6-yl)acetaldehyde (D41) (25 mg, 0,109 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (30 mg, 0,130 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-3%) and receive free ground named the title compound (22 mg, 45%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (4:1, 5 ml) at 0 ° C gives named in the title compound in the form of solids.1H-NMR (500 MHz, DMSO-d6) δ: 10,33 (acsis, 1H), 9,01 (acsis, 1H), 8,06 (users, 1H), to 7.93 (m, 2H), 7,82 (users, 1H), 7.62mm (users, 1H), 7.23 percent (t, 1H), to 5.58 (s, 2H), 3,39-3,10 (acsim, 9H), 2,86 (users, 3H), of 2.34 (s, 3H), of 2.20 (m, 4H).

Example 33. Hydrochloride of 1-methyl-6-(2-{4-[2-(trifluoromethyl)-5-chinoline)-1-piperazinil]ethyl}-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazine (e)

To a mixture of 5-(1-piperazinil)-2-(trifluoromethyl)quinoline (D47) (39 mg, 0,137 mmol) and (1-methyl-4H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-6-yl)acetaldehyde (D25) (21 mg, 0,092 mmol) in DCM (5 ml) add triacetoxyborohydride sodium (42 mg, 0.84 mmol). After stirring the mixture at room temperature overnight, water is added (10 ml) and the mixture extracted with DCM (3×15 ml). The combined organic layers are dried (MgSO4) and evaporated in vacuo. The residue is purified on a system of PR is paratively mass-directed HPLC with reversed phase and receive free ground mentioned in the title compound as a colourless oil (14 mg, 30%). Free base dissolved in a mixture of dry DCM/diethyl ether and treated with HCl (1.1 EQ. 1 M solution in diethyl ether). Evaporation of the solvent and diethyl ether to give the named header connection. MS (ES; m/z): 495 [MH+]. C26H25F3N6O requires 494,52.1H-NMR (400 MHz, DMSO-d6) δ: 10,85 (users, 1H), 8,86 (d, 1H), to 7.99 (d, 1H), 7,94 (d, 1H), 7,9 (d, 1H), 7,73 (DD, 1H), of 7.48 (d, 1H), 7,35 (d, 1H), 7,25 (m, 1H), vs. 5.47 (s, 2H), of 3.77 (userd, 2H), 3,6-of 3.45 (m, 4H), of 3.32 (t, 2H), 3,47 (m, 2H), 3,32 (m, 2H);19F-NMR (400 MHz, DMSO-d6) δ: -66,04.

Example 34. The dihydrochloride of N,N-dimethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E34)

Named the title compound is obtained in yield of 60%, following the General procedure described in example 1 from N,N-dimethyl-6-(2-oxoethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (D9) (20 mg, 0.07 mmol) and 2-methyl-5-piperazine-1-rhinolin (19 mg, 0,084 mmol). MS (ES) m/z: 497,3 [MH+]. C29H32N6O2requires 496,6.1H-NMR (500 MHz, DMSO-d6) δ: 11 (acsis, 1H), 8,77 (acsis, 1H), to 8.57 (s, 1H), 7,9 (users+d, 3H), 7,69 (users, 1H), was 7.36 (users, 1H), 7,25 (d, 1H), 7,15 (t, 1H), 5,54 (s, 2H), 3,7-3,2 (acsim, 12H), 2,96-2,82 (2s, 6H), 2,5 (m, 3H).

Example 35. Hydrochloride of 1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-yl)ethanone (E)

To a solution of N-methyl-N-(metiloksi)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E25) (40 mg, 0,078 mmol) in THF (1 ml) under cooling with ice and stirring, methylanisole (0,03 ml of 3 M solution in diethyl ether, 0.09 mmol)and the resulting solution was stirred for 1 hour at 0 ° C. The reaction mixture was poured into cold hydrochloric acid (2 ml of 2.5 M solution), then treated with a solution of NaHCO3(15 ml) and extracted with DCM (3×15 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and get a brown oil, which was purified on SPE cartridge (silica gel, 2 g) with elution with a mixture of DCM/methanol (98:2) and receive free ground named the title compound (22 mg, 60%) as a white solid. The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 468,4 [MH+]. C28H29N5O3requires 467,57.1H-NMR (500 MHz, DMSO-d6) δ: 11,41 (users, 1H), remaining 9.08 (d, 1H), 8,66 (d, 1H), 8,2-was 7.08 (m, 4H) 7,52 (DD, 1H), and 7.3 (DD, 1H), 7,19 (t, 1H), 5,62 (s, 2H), 4,2-3,2 (acsim, 12H), to 2.99 (s, 3H), of 2.5 (s, 3H).

Example 36. The dihydrochloride of N,N-dimethyl-6-{3-[4-(2-methyl-5-chinoline)-1-piperazinil]propyl}-4H-imidazo[5,1-c][14]benzoxazin-3-carboxamide (E36)

To a solution of 6-{3-[4-(2-methyl-5-chinoline)-1-piperazinil]propyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E6) (32 mg, 0.07 mmol) and DIPEA (23 μl, 0.13 mmol) in DMF (1 ml) was added with stirring TBTU (24 mg, of 0.075 mmol). The reaction mixture was stirred at room temperature for 1 hour, then add dimethylamine in THF (37 ál of 2 M solution of 0.075 mmol)and the solution stirred for 1 hour. The crude solution was purified on SPE cartridge-SCX (elution with methanol, then 2 N solution of ammonia in methanol), and then treated with diethyl ether and receive the corresponding free base named in the title compound as a solid (20 mg, 59%). The free base was dissolved in dry methanol (1 ml) and slowly add HCl (68 μl of 1.25 M solution in methanol, 0.09 mmol) at 0OC. The resulting suspension was stirred at 0 ° C for 4 hours. Evaporation of volatiles gives named the title compound as a yellow solid (22 mg). MS (ES) m/z: 511,4 [MH+]. C30H34N6O2requires 510,6.1H-NMR (500 MHz, DMSO-d6) δ: 10,4 (users, 1H), and 8.6 (s, 1H), and 8.4 (d, 1H), and 7.8 (d, 1H), about 7.6 to 7.7 (m, 2H), and 7.4 (users, 1H), 7,0-7,2 (m, 3H), and 5.5 (s, 2H), 3,1-3,6 (osirm, 10H), 2,9 (s, 3H), 2,5-2,8 (osirm, 8H), 2,1 (users, 2H).

Example 37. Ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxy is at (E)

A mixture of ethyl-6-(2-oxoethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D6) (62 mg, 0.27 mmol) and 2-methyl-5-piperidine-1-rhinolin (70 mg, 0.31 mmol) in dry 1,2-dichloroethane (10 ml) was stirred at room temperature under nitrogen atmosphere for 40 minutes Then add triacetoxyborohydride sodium (65 mg, 0.31 mmol)and the resulting reaction mixture is stirred for 3 hours, the reaction is quenched saturated aqueous NaHCO3(10 ml) and the mixture extracted with DCM (3×10 ml). The organic layers are combined, dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified column chromatography on silica gel with elution with a mixture of 1% methanol in DCM and get named in the title compound as a pale yellow solid (68 mg, 50%). MS (ES) m/z: 497.4 m [MH+]. C30H32N4O3requires 496,5.1H-NMR (500 MHz, CDCl3) δ: 8.30 to (d, 1H), 7,98 (s, 1H), 7,63 (d, 1H), 7,40 (d, 1H), 7,34 (DD, 1H), 7,28 (d, 1H), 7,15 (DD, 1H), 7,03 (t, 1H), of 5.53 (s, 2H), 4,39 (kV, 2H), 3,23 (m, 3H), of 2.92 (DD, 2H), by 2.73 (s, 3H), 2,65 (DD, 2H), to 2.29 (m, 2H), 1,95 (m, 4H), of 1.41 (t, 3H).

Example 38. The dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E38)

A solution of trimethylaluminum (2.0 M in hexano, 150 μl, 0.3 mmol) and methylamine (2.0 M solution in THF, 150 μl, 0.3 mmol) in DCM (1 ml) var who're asked at room temperature for 15 minutes Add ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A) (30 mg, 0.061 mmol) and continue stirring for another 3 hours at 40ºC. Upon completion of the reaction, water is added dropwise until such time as the gas will not be released and end added volume reaches approximately 3 ml Add water 1 M NaOH solution (5 ml)and the aqueous solution extracted with DCM (3×20 ml). The combined organic phases are dried (Na2SO4) and evaporated, the residue is purified by chromatography on Si gel with elution with mixtures of DCM/Meon (98:2-96:4), and receive free ground mentioned in the title compounds as a pale yellow solid (22 mg, 76%). The free base was dissolved in dry methanol (3 ml), gradually add 2.1 EQ. hydrochloric acid (1.25 M solution in Meon) and the resulting suspension is stirred for 2 hours. Evaporation of the solvent and diethyl ether to give the desired dihydrochloride salt (26 mg) as a yellow solid. MS (ES) m/z: 481,2 [MH+]. C29H31N5O2requires 480,5.1H-NMR (500 MHz, DMSO) δ: 10,67 (users, 1H), 9,24 (users, 1H), at 8.60 (s, 1H), 8,21 (DD, 1H), 8,17 (kV, 1H), of 8.06 (t, 1H), of 7.96 (d, 1H), a 7.85 (DD, 1H), 7,71 (m, 1H), 7,28 (d, 1H), 7,17 (t, 1H), 5,62 (s, 2H), 3,84 (m, 1H), 3,7-3,2 (m, 4H), 3,2 (d, 2H), 2.95 and (s, 3H), 2,77 (d, 3H), of 2.25 (q, 2H), 2,11 (d, 2H).

Example 39. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidine is l]ethyl}-3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-c][1,4]benzoxazine (E39)

A solution of trimethylaluminum (2.0 M in hexano, 150 μl, 0.3 mmol) and morpholine (30 μl, 0.3 mmol) in DCM (1 ml) was stirred at room temperature for 15 minutes Add ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A) (30 mg, 0.061 mmol) and continue stirring for another 3 hours at 40ºC. Upon completion of the reaction, water is added dropwise until such time as the gas will not be released and the final volume reaches approximately 3 ml Add water 1 M NaOH solution (5 ml) and the aqueous solution extracted with DCM (3×15 ml). The combined organic phases are dried (Na2SO4) and evaporated, the residue is purified by chromatography on Si gel with elution with mixtures of DCM/Meon (98:2-96:4), and receive free ground mentioned in the title compounds as a pale yellow solid (24 mg, 75%). The free base was dissolved in dry Meon (3 ml), gradually add 2.1 EQ. hydrochloric acid (1.25 M solution in methanol)and the resulting suspension is stirred for 2 hours. Evaporation of the solvent and diethyl ether to give the desired dihydrochloride salt (28 mg) as a yellow solid. MS (ES) m/z: 538 [MH+]. C32H37N5O3requires 537,66.1H-NMR (500 MHz, DMSO) δ: 10,7 (users, 1H), 9,2 (users, 1H), at 8.60 (s, 1H), and 8.2 (DD, 1H), 8.0 a (t, 1H), of 7.96 (d, 1H), a 7.85 (DD, 1H, 7,71 (m, 1H), 7,28 (d, 1H), 7,17 (t, 1H), 5,52 (s, 2H), 4,3 (m, 2H), 3,84 (m, 1H), 3,7-3,2 (m, 4H), 3,2 (d, 2H), 2.95 and (s, 3H), of 2.25 (q, 2H), 2,11 (d, 2H).

Example 40. 6-(2-{4-[2-(Trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E40)

A solution of ethyl ester of 6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (A) (32 mg, 0,058 mmol) and a catalytic amount of potassium cyanide in a 7 M solution of NH3in the Meon (20 ml) was stirred at room temperature for 3 days. The reaction mixture is filtered, the filtrate is evaporated in a high vacuum and get named in the title compound (18 mg, 59%) as a solid. MS (ES; m/z): 523 [MH+]. C27H25F3N6O2requires 522,53.1H NMR (400 MHz, DMSO-d6) δ: 8,79 (d, 1H), 8,54 (s, 1H), 7,95 (d, 1H), to 7.84 (m, 2H), 7,76 (d, 1H), 7,51 (DD, 1H), 7,37 (t, 1H), 7,33 (users, 1H), 7,24 (DD, 1H), and 7.1 (t, 1H), 5,54 (s, 2H), 3,31 (users, 4H), 2,89 (t, 2H), 2,79 (users, 4H)that 2.7 (m, 2H);19F NMR (400 MHz, DMSO-d6) δ: -66,05.

Example 41. The dihydrochloride of N-(metiloksi)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E)

A solution of trimethylaluminum (2.0 M in hexane, 2.4 ml, 4,82 mmol) and hydrochloride methoxylamine (402 mg, 4,82 mmol) in DCM (8 ml) was stirred at room temperature for 30 minutes. Add Aut ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E1) (400 mg, 0,803 mmol) and continue stirring for another 4 hours at 54º. Upon completion of the reaction, water is added dropwise until such time as the gas will not be released and the final volume reaches about 20 ml. of Aqueous solution is extracted with DCM (3×30 ml). In the case where the organic and inorganic phase are well separated, add water 1 M NaOH solution. The combined organic phases are dried (Na2SO4) and evaporated. The residue is treated with Et2O, and get a free base of the desired substance (284 mg, 71%). The free base (25 mg) dissolved in dry Meon (1 ml) and gradually at 0 ° C type 2.1 EQ. hydrochloric acid (1 M solution in ethyl ether). The resulting suspension is stirred for 2 h at 0OC. Evaporation of the solvent and processing in ethyl ether to give named the title compound as a yellow solid (31 mg). MS (ES) m/z: 499,6 [MH+]. C28H30N6O3requires 498,6.1H-NMR (500 MHz, DMSO-d6) δ: are 11.62 (users, 1H), 11,37 (users, 1H), 9,06 (d, 1H), to 8.62 (s, 1H), of 8.09 (d, 1H), 8,03 (t, 1H), 7,92 (d, 1H), 7,86 (DD, 1H), 7,52 (d, 1H), 7,28 (DD, 1H), 7,18 (t, 1H), 5,62 (s, 2H), 4-3,3 (acsim, 10H), of 3.69 (s, 3H), up 3.22 (DD, 2H), 2,98 (s, 3H).

Example 42. Ethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A)

To a solution of 2-methyl-5-[(3R)-3-methyl-1-piperazinil]Hino is in (WO 2004/046124) (200 mg, 0.84 mmol) and ethyl-6-(2-oxoethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (D6) (200 mg, 0.69 mmol) in DCM (10 ml) add triacetoxyborohydride sodium (178 mg, 0.84 mmol). After stirring the mixture at room temperature overnight, water is added (15 ml), and the reaction product extracted with DCM (3×20 ml). The organic layer is dried (MgSO4), filtered and evaporated in vacuum. The residue is purified column chromatography on silica gel with elution with a mixture of DCM/Meon (98:2) and get named in the title compound as a white foam (212 mg, 60%). MS (ES) m/z: 512,2 [MH+]. C30H33N5O3requires 511,6.1H-NMR (500 MHz, DMSO-d6) δ: 8,44 (d, 1H), 8,03 (s, 1H), 7,76 (d, 1H), 7.62mm (t, 1H), and 7.4 (d, 1H), and 7.3 (m, 1H), 7,2 (d, 1H), and 7.1 (m, 2H), 5,59 (s, 2H), 4,45 (quart, 2H), 3,-2,7 (acsim, 11H), 2,77 (s, 3H), of 1.46 (t, 3H), 1,2 (m, 3H).

Example 43. Ethyl-6-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E43)

Named the title compound is obtained in yield 62%, following the procedure of example 1, using 7-fluoro-2-methyl-5-(1-piperazinil)quinoline (see WO 2004/046124) (205 mg, 0.84 mmol). MS (ES) m/z: 516,6 [MH+]. C29H30FN5O3requires 515,59.1H-NMR (500 MHz, DMSO-d6) δ: with 8.33 (d, 1H), 8,03 (s, 1H), 7,39 (DD, 1H), was 7.36 (DD, 1H), 7.23 percent (d, 1H), 7,2 (DD, 1H), was 7.08 (t, 1H), 6.87 in (DD, 1H), to 5.58 (s, 2H), of 4.44 (quart., 2H), 3,18 (users, 4H), to 2.99 (DD, 2H), 2,86 (users, 4H), was 2.76 (m, 5H), 146 (t, 3H).

Example 44. Ethyl-6-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A)

Named the title compound is obtained in yield 74%, following the procedure of example 42, using 2-methyl-5-(1-piperazinil)hintline (see WO 2004/046124) (228 mg, 0.84 mmol). MS (ES) m/z: 499,1 [MH+]. C29H30FN5O3requires 498,58.1H-NMR (500 MHz, DMSO-d6) δ: being 9.61 (s, 1H), 8,03 (s, 1H), 7,79 (t, 1H), 7.62mm (d, 1H), and 7.4 (DD, 1H), 7,2 (DD, 1H), and 7.1 (m, 2H), to 5.58 (s, 2H), of 4.44 (quart., 2H), 3,25 (users, 4H), 3 (DD, 2H), 2.91 in (s, 3H), 2,87 (users, 4H), was 2.76 (DD, 2H), 1,46 (t, 3H).

Example 45. 6-{2-[(2R)-2-Methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (e)

To a solution of ethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E) (212 mg, 0.45 mmol) in Meon (4 ml) is added NaOH (4 ml of 10% aqueous solution)and the resulting white suspension is heated for 5 minutes under the influence of microwave radiation at 120 ºC. The resulting pale yellow solid is filtered off, suspended in water and the solution is neutralized (pH 7) acetic acid. Precipitated precipitated substance is filtered off and washed with diethyl ether (3×20 ml), and get named in the title compound (164 mg, 81%) as not quite white solid vedastus (ES) m/z: 484,6 [MH +]. C28H29N5O3requires 482,57.1H-NMR (300 MHz, DMSO-d6) δ: 8,53 (s, 1H), of 8.37 (d, 1H), 7,74 (DD, 1H), 7,58 (m, 2H), and 7.4 (d, 1H), 7,21 (DD, 1H), was 7.08 (m, 2H), 5,52 (s, 2H), 3,2-2,5 (m, 11H), 2,63 (s, 3H), 1,10 (d, 3H).

Example 46. Ethyl-6-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A)

Named in the title compound, receive, following the procedure of example 45, from ethyl-6-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E43) (223 mg, 0.43 mmol). MS (ES) m/z: 488,6 [MH+]. C27H26FN5O3requires 487,53.1H-NMR (300 MHz, DMSO-d6) δ: 7,63 (d, 1H), 7,42 (s, 1H), 6,78 (d, 1H), to 6.57 (d, 1H), 6,5 to 6.0 (m, 4H), 4,74 (s, 2H), 2.49 USD (s, 3H), is 2.37 (m, 4H), 2,2 (DD, 2H), 2,12 (m, 4H), 2,0 (DD, 2H).

Example 47. 6-{2-[4-(2-Methyl-5-hintline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (E)

Named in the title compound, receive, following the procedure of example 45, from ethyl-6-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E) (255 mg, 0,512 mmol). MS (ES) m/z: 488,6 [MH+]. C27H26FN5O3requires 487,53.1H-NMR (300 MHz, DMSO-d6) δ: 8,8 (s, 1H), 7,47 (s, 1H), 7,06 (t, 1H), 6,77 (d, 2H), 6,46 (d, 1H), 6,41 (d, 1H), and 6.25 (t, 1H), 4,7 (s, 2H), by 2.55 (m, 4H), 2.49 USD (s, 3H), 249 (m, 4H), of 2.36 (DD, 2H), 2,30 (DD, 2H).

An example is 48-53. A General procedure for obtaining amides

To a suspension of carboxylic acid (0.1 mmol) in DMF (1.5 ml) and DIPEA (0.11 mmol) is added TBTU (0.11 mmol) and the mixture is stirred at room temperature for 1.5 hours. Add the appropriate amine (0.11 mmol) and the reaction mixture was stirred at room temperature overnight. The crude reaction mixture was loaded onto a SCX cartridge (5 g), ammonium fraction evaporated in vacuum and get the desired amide in pure form. The free base was dissolved in dry Meon and gradually add 2.1 EQ. hydrochloric acid (1 M solution in diethyl ether) at 0OC. The resulting suspension is stirred for 2 hours at 0OC. Filtration or evaporation of the solvent and treatment with diethyl ether to give the desired salt is the dihydrochloride as a yellow solid.

Example 48. The dihydrochloride of N-methyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E)

Named in the title compound are obtained from the output 52% according to the General procedure for obtaining amides, from 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (e) (48,3 mg, 0.1 mmol) and methylamine (by 0.055 ml of 2 M solution in THF, 0.11 mmol). MS (ES) m/z: 497,7 [MH+]. C29H32N6O2requires 496,61.1 H-NMR (500 MHz, DMSO-d6) δ: 11,51 (users, 1H), 9,14 (d, 1H), at 8.60 (s, 1H), 8,16 (m, 1H), 8,11 (d, 1H), 8,03 (t, 1H), 7,92 (d, 1H), 78,4 (d, 1H), 7.5 (d, 1H), and 7.3 (d, 1H), 7,15 (t, 1H), 5,62 (s, 2H), 4,0 and 2.9 (m, 11H), 2,99 (s, 3H), 2,74 (d, 3H), of 1.48 (d, 3H).

Example 49. The dihydrochloride 6-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}-N-methyl-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E)

Named the title compound is obtained in yield of 61% according to the General procedure for obtaining amides, based on ethyl-6-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A) (48.7 per mg, 0.1 mmol) and methylamine (by 0.055 ml of 2 M solution in THF, 0.11 mmol). MS (ES) m/z: 501,6 [MH+]. C28H29FN6O2requires 500,58.1H-NMR (500 MHz, DMSO-d6) δ: is 11.39 (users, 1H), to 8.94 (d, 1H), at 8.60 (s, 1H), 8,16 (osirm, 1H), 7,82 (m, 3H), 7,43 (d, 1H), 7,25 (d, 1H), 7,15 (t, 1H), 5,59 (s, 2H), 3.75 to is 3.40 (m, 10H), 3,2 (t, 2H), 2,93 (s, 3H), 2,74 (d, 3H).

Example 50. The dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E50)

Named in the title compound are obtained from the output 72% according to the General procedure for obtaining amides, based on ethyl-6-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A) (47 mg, 0.1 mmol) and methylamine (by 0.055 ml of 2 M solution in THF, 0.11 mmol). MS (ES) m/z: 484,6 [MH+]. C27H9 N7O2requires 483,57.1H-NMR (500 MHz, DMSO-d6) δ: 11,95, 11,14 (s, 1H), RS 9.69 (d, 1H), to 8.62 (s, 1H), 8,17 (d, 1H), 7,97 (t, 1H), to 7.84 (d, 1H), to 7.67 (d, 1H), 7,33 (d, 1H), 7,25 (DD, 1H), 7,16 (t, 1H), ceiling of 5.60 (s, 2H), 3,71 (d, 2H), 3,6 (d, 2H), 3,52, 3,4, 3,19 (widm, 8H), 3.15 in (s, 3H), of 2.75 (d, 3H).

Example 51. The dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-c][1,4]benzoxazine (e)

Named in the title compound are obtained from the output 52% according to the General procedure for obtaining amides, from 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (e) (48,3 mg, 0.1 mmol) and research (0.01 ml, 0.11 mmol). MS (ES) m/z: 553,6 [MH+]. C32H36N6O3requires 552,68.1H-NMR (500 MHz, DMSO-d6) δ: 11,7 (users, 1H), 9.15, with (d, 1H), 8,61 (s, 1H), 8,16 (d, 1H), 8,03 (t, 1H), 7,92 (d, 1H), 7,86 (d, 1H), 7,51 (d, 1H), 7,31 (d, 1H), 7,15 (t, 1H), to 5.57 (s, 2H), 4,0 and 2.9 (m, 19H), to 2.99 (s, 3H), of 1.48 (d, 3H).

Example 52. The dihydrochloride 6-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-c][1,4]benzoxazine (E)

Named the title compound is obtained in yield of 61% according to the General procedure for obtaining amides, from 6-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A) (49 mg, 0.1 mmol) and research (0.01 ml, 0.11 mmol). MS (ES) m/z: 5576 [MH +]. C31H33FN6O2requires 556,64.

Example 53. The dihydrochloride 6-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-c][1,4]benzoxazine (e)

Named in the title compound are obtained from the output 72% according to the General procedure for obtaining amides, from 6-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylic acid (A) (47 mg, 0.1 mmol) and the research (by 0.055 ml, 0.11 mmol). MS (ES) m/z: 540, 6L [MH+]. C30H33N7O3requires 539,64.

Example 54. The dihydrochloride of 3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine (E)

To a suspension of sodium hydride (85 mg, 60% suspension in oil, 0.22 mmol) in dry THF (5 ml) is added oxime methylcarbamate (17 mg, 0.22 mmol), and then after 10 minutes, add ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E1) (100 mg, 0.2 mmol). After 10 minutes add DMF (1 ml) and the reaction mixture was stirred at room temperature overnight. The reaction is quenched with water (1 ml) and the reaction mixture is extracted with ethyl acetate (3×15 ml). After drying and evaporation of organic solvents the crude substance is treated with diethyl ether and receive free the grounds mentioned in the title compound as a yellow solid (77 mg, 0.15 mmol). The resulting substance was dissolved in dry methanol and gradually add 2.1 EQ. hydrochloric acid (1 M solution in diethyl ether) at 0OC. The resulting suspension is stirred for 2 hours at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid in pure form (87 mg). MS (ES) m/z: to 508.6 [MH+]. C29H29N7O2requires 507,6.1H-NMR (500 MHz, DMSO-d6) δ: 11,22 (s, 1H), of 8.92 (d, 1H), 8,81 (s, 1H), of 7.96 (m, 3H), 7,8 (userd, 1H), 7,45 (d, 1H), 7,31 (d, 1H), 7,20 (m, 1H), 5,7 (s, 2H), 3,74 (d, 2H), 3,6-3,4 (widm, 8H), 3,21 (m, 2H), 2,90 (s, 3H), 2.40 a (s, 3H).

Example 55. The dihydrochloride ethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (E55)

A mixture of ethyl-6-(2-oxoethyl)imidazo[1,5-a]quinoline-3-carboxylate (D91) (73 mg, 0.26 mmol) and 2-methyl-5-[(3R)-3-methyl-1-piperazinil]quinoline (WO 2004/046124) (75 mg, 0.31 mmol) in 1,2-dichloroethane (4 ml) was stirred at room temperature for 30 minutes Then add triacetoxyborohydride sodium (66 mg, 0.31 mmol) and the resulting mixture is stirred over night. The crude reaction mixture was evaporated in vacuum and then the residue is purified on SPE cartridge-Si elution with a mixture of 4% Meon in DCM, and receive free ground mentioned in the title compound as a white solid (95 mg, 72). The free base (15 mg, 0.03 mmol) dissolved in dry Meon (0.5 ml) and treated with HCl (0,053 ml of a 1.25 M solution in Meon) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound (11 mg, 63%) as a yellow solid. MS (ES) m/z: 508,3 [MH+]. C31H34N5O2requires 507,6.1H-NMR (500 MHz, DMSO-d6) δ: 11,7 (users, 1H), was 9.33 (s, 1H), 9,05 (users, 1H), 8,5 (d, 2H), 8,03 (m, 4H), 7,9 (d, 1H), 7,79 (t, 1H), to 7.64 (DD, 1H), 7,52 (m, 1H), 4,37 (kV, 2H), 3,64 (osirm+water, 11H), 2,95 (s, 3H), 1.50 in (d, 2H), 1,37 (t, 3H).

Example 56. Ethyl ester of 6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (E)

To a solution of 5-(1-piperazinil)-2-(trifluoromethyl)quinoline (D47) (235 mg, 0.84 mmol) and ethyl-6-(2-oxoethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (D6) (200 mg, 0.69 mmol) in dichloroethane (10 ml) add triacetoxyborohydride sodium (178 mg, 0.84 mmol). After stirring the mixture at room temperature overnight, water is added (15 ml) and the reaction product extracted with DCM (3×20 ml). The combined organic phases are dried (MgSO4), filtered and evaporated in vacuum. The residue is purified by chromatography on silica gel with elution with a mixture of DCM/Meon (98:2) and get called in the header is VCE compound as a yellow solid (204 mg, 54%). MS (ES; m/z): 552 [MH+]. C29H28F3N5O3requires 551,57.1H-NMR (300 MHz, CDCl3) δ: RS 9.69 (d, 1H), 7,98 (s, 1H), of 7.90 (d, 1H), 7,73-to 7.67 (m, 2H), was 7.36 (d, 1H), 7,33 (m, 1H), 7,14 (d, 1H), 7,02 (t, 1H), of 5.55 (s, 2H), and 4.40 (q, 2H), 3.15 in (m, 4H), 2,98 of 2.68 (m, 8H), of 1.39 (t, 3H).

Example 57. N-Methyl-6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E)

A solution of trimethylaluminum (2.0 M in hexano, 226 μl, 0.45 mmol) and methylamine (2.0 M solution in THF, 226 μl, 0.45 mmol) in DCM (1 ml) was stirred at room temperature for 15 minutes. Add ethyl ester 6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (E) (45 mg, of 0.081 mmol) and continue stirring for another 3 hours at 40ºC. Upon completion of the reaction, water is added dropwise until such time as the gas will not be released and end added volume reaches approximately 3 ml of the Aqueous solution is extracted with DCM (3×10 ml). In the case where the organic and inorganic phases are not well separated, add water 1 M NaOH solution. The combined organic phases are dried (Na2SO4) and evaporated. The residue is purified by chromatography on silica gel with elution with mixtures of DCM/Meon (98:2-96:4), and get named in the title compound as a colourless solid (36 is g, 83%). MS (ES; m/z: 537 [MH+]. C28H27F3N6O2requires 536,56.1H-NMR (400 MHz, DMSO-d6) δ: 8,79 (d, 1H), 8,56 (s, 1H), 8,14 (kV, 1H), 7,95 (d, 1H), to 7.84 (m, 2H), of 7.75 (DD, 1H), 7,37 (Quint, 1H), 7,24 (DD, 1H), and 7.1 (t, 1H), of 5.55 (s, 2H), 3,1 (users, 4H), 2,89 (t, 2H), 2,8 (m, 4H), was 2.76 (d, 3H), to 2.67 (t, 2H);19F-NMR (400 MHz, DMSO-d6) δ:-66,05.

Example 58. N,N-Dimethyl-6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (e)

Named the title compound (12 mg, 40%) was obtained as a colorless solid using the procedure of example 57 using ethyl ether complex of 6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (E) (30 mg, 0,054 mmol) and dimethylamine. MS (ES; m/z): 551 [MH+]. C29H29F3N6O2requires 550,59.1H-NMR (400 MHz, DMSO-d6) δ: 8,79 (d, 1H), 8,55 (s, 1H), 7,65 (d, 1H), to 7.84 (d, 2H), 7,76 (DD, 1H), 7,37 (Quint, 1H), 7,24 (DD, 1H), and 7.1 (t, 1H), 5,48 (s, 2H), 3,49 (users, 3H), 3,1 (users, 4H), 2,98 (users, 3H), 2,89 (t, 2H), 2,78 (users, 4H), to 2.66 (t, 2H);19F-NMR (400 MHz, DMSO-d6) δ: -66,05.

Example 59. 3-(4-Morpholinylcarbonyl)-6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-c][1,4]benzoxazin (E)

Named the title compound (29 mg, 78%) was obtained as a colorless solid substances is and using the procedure of example 57 using ethyl ether complex of 6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (A) (35 mg, 0,063 mmol) and research. MS (ES; m/z): 593 [MH+]. C31H31F3N6O3requires 592,62.1H-NMR (400 MHz, DMSO-d6) δ: 8,79 (d, 1H), 8,56 (s, 1H), 7,95 (d, 1H), to 7.84 (m, 2H), to 7.77 (DD, 1H), 7,37 (Quint, 1H), 7,24 (DD, 1H), 7,11 (t, 1H), 5,51 (s, 2H), 4,3 (acsis, 2H), 3,66 (m, 4H), 3,6 (acsis, 2H), 3,1 (users, 4H), 2,89 (t, 2H), 2,78 (users, 4H), 2,68 (t, 2H);19F-NMR (400 MHz, DMSO-d6) δ: -66,05.

Example 60. Ethyl ester of 6-(2-{4-[2-cyano-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (E60)

To a solution of 5-(1-piperazinil)-2-hinolincarbonova (D70) (200 mg, 0,839 mmol) and ethyl-6-(2-oxoethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (D6) (250 mg, 0,873 mmol) in DCM (10 ml) add triacetoxyborohydride sodium (266 mg, of 1.26 mmol). After stirring the mixture at room temperature overnight, water is added (15 ml) and the mixture extracted with DCM (3×20 ml). The combined organic phases are dried (MgSO4), filtered and evaporated in vacuum. The residue is purified by chromatography on silica gel with elution with mixtures of ethyl acetate/Meon (1:0-9:1) and receives a yellow solid, which contains named the title compound (373 mg, purity according to HPLC/MS 75%). Part of the obtained substance (20 mg) purified by mass-directed preparative HPLC. MS (ES; m/z): 509 [MH+]. C29H28N6O3requires 508,58.1H-NMR (400 MHz, DMSO-d6-1): 2230,65 (CN), 1728,58 (CO).

Example 61. Ethyl-7-fluoro-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A)

To a solution of 7-fluoro-8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-she (D59) (200 mg, 0.48 mmol) in THF (5 ml) at 0 ° C add tert-piperonyl potassium (57 mg, 0.50 mmol). After stirring at the same temperature for 30 min, the reaction mixture was cooled to -20 ° C, and add diethylphosphate (83 μl, of 0.58 mmol). After stirring at 0 ° C for 1 hour, the reaction mixture was cooled to-78º, and add utilitarianistic (57 μl, 0.50 mmol)and then tert-piperonyl potassium (57 mg, 0.50 mmol). The reaction mixture is heated to room temperature and then stirred overnight. The mixture is then poured into brine (15 ml) and extracted with DCM (3×20 ml). The combined organic phases are dried over Na2SO4and concentrate. The crude substance is purified by chromatography on silica gel with elution with a mixture of DCM/Meon (96:4), and get named in the title compound (120 mg, 50%). MS (ES/+) m/z: 516 [MH+]. C29H30FN5O3requires 515.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,4 (d, 1H), and 7.9 (s, 1H), 7,55 (d,1H), of 7.6 (t, 1H), 7,35 (DD, 1H), and 7.3 (d, 1H), was 7.08 (d, 1H), 6,85 (t, 1H), 5,6 (s, 2H), 4,4 (kV, 2H) 3,2-2,6 (m, 15H), and 1.4 (t, 3H).

Example 62. The dihydrochloride of 7-fluoro-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-c][1,4]benzoxazine (E)

Named in the header connection receive according to the procedure of example 57, on the basis of ethyl-7-fluoro-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (free base E) and research. MS (ES/+) m/z: 557 [MH+]. C31H33FN6O3requires 556.1H-NMR (400 MHz, DMSO) δ (ppm): 10,43 (users, 1H), 8,61 (s, 1H), 8,60 (users, 1H), 7,95 (DD, 1H), 7,78 (users, 2H), 7,60 (users, 1H), 7,32 (users, 1H), 7,15 (t, 1H), 5,63 (s, 2H), 4,34 (users, 2H), 3,79 (d, 2H), 3,7-3,0 (m, 16H), 2,77 (users, 3H).

Example 63. The dihydrochloride of 7-fluoro-N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (e)

Named in the header connection receive according to the procedure of example 57, on the basis of ethyl-7-fluoro-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A) and N-methylamine. MS (ES/+) m/z: 501 [MH+]. C28H29FN6O2requires 500.1H-NMR (400 MHz, DMSO) δ (ppm): at 10.64 (users, 1H), 8,93 (users, 1H), at 8.60 (s, 1H), 8,2 (kV, 1H), 7,9 (m, 3H), 7,82 (users, 1H), 7,46 (userd, 1H), 7,15 (t, 1H), 7,15 (t, 1H), 5,67 (s, 2H), and 3.8 (d, 2H), 3,7-3,0 (m, 8H), up 3.22 (m, 2H), 2,9 (users, 3H), 2,78 (d, 3H).

Examples 64 and 65

The dihydrochloride of 7-fluoro-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E) and

the dihydrochloride of 7-fluoro-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carbonitrile (E)

A mixture of ethyl-7-fluoro-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A) (47 mg, 0.09 mmol), trimethylaluminum (230 μl of 2 M solution in hexano, 0.45 mmol) and ammonia (0,91 ml of 0.5 M solution in 1,4-dioxane, 0.45 mmol) in DCM (3 ml) is exposed to microwave radiation at 100ºC for 1 hour. The reaction mixture is dissolved in the Meon (1 ml) and purified by SPE(SCX) and then using column chromatography on silica gel with elution with a mixture of DCM/Meon (97:3) and get named in the title compound E (9 mg) and E65 (17 mg).

Example 64. MS (ES/+) m/z: 487 [MH+]. C27H27FN6O2requires 486.1H-NMR (400 MHz, DMSO) δ (ppm): 10,4 (users, 1H), 8,8 (users, 1H), 8,59 (s, 1H), 7,94 (DD, 1H), 7,85 (users, 2H), 7,72 (users, 1H), EUR 7.57 (users, 1H), 7,39 (users, 1H), was 7.36 (users, 1H), 7,15 (t, 1H), to 5.66 (s, 2H), and 3.8 (m, 2H), 3.7 to 3 (m, 10H), 2,83 (user. s, 3H).

Example 65. MS (ES/+) m/z: 469 [MH+]. C27H25FN6O requires 468.1H-NMR (400 MHz, DMSO) δ (ppm): 10,51 (user. 1H), 8,79 (s, 1H), 8,8 (user. s, 1H), to 7.99 (DD, 1H), 7,85 (users, 2H), 7,71 (users, 1H), 7,38 (users, 1H), 7,21 (t, H), 5,61 (s, 2H), 3,79 (m, 2H), 3,6-3,1 (m, 10H), 2,83 (users, 3H).

Example 66. Ethyl-4-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A)

To a solution of 2-methyl-8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-she (D61) (150 mg, 0.36 mmol) in THF (5 ml) at 0 ° C add tert-piperonyl potassium (42 mg, and 0.37 mmol). After stirring at the same temperature for 30 min the mixture is cooled to -20 ° C and add diethylphosphate (62 μl, 0.43 mmol). After stirring at 0 ° C for 1 hour, the reaction mixture was cooled to-78º and add utilitarianistic (42 μl, of 0.37 mmol)and then tert-piperonyl potassium (42 mg, and 0.37 mmol). The reaction mixture is heated to room temperature and then stirred overnight. The mixture is then poured into brine (15 ml) and extracted with DCM (3×20 ml). The combined organic phases are dried over Na2SO4and concentrate, and get the crude reaction product, which is purified using chromatography on silica gel with elution with a mixture of DCM/Meon (97:3), and get named in the title compound (60 mg, 30%). MS (ES/+) m/z: 512 [MH+]. C30H33N5O3requires 511.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,55 (t, 1H), 7.3 to 7-0 (m, 6H), 6,15 (kV, 1H), 3,2-2,6 (m, 15H), 1,5 ppm (d, 3H).

Example 67. The dihydrochloride of N,4-dimethyl-6-{2-[4-(2-methyl-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E67)

Named the title compound is obtained in yield of 42% according to the procedure of example 57, on the basis of ethyl-4-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A) and methylamine. MS (ES/+) m/z: 497 [MH+]. C29H32N6O2requires 496.1H-NMR (400 MHz, DSMO) δ (ppm): of 10.72 (users, 1H), 8,88 (users, 1H), and 8.6 (s, 1H), 8,17 (kV, 1H), to $ 7.91 (users, 2H), 7,87 (d, 1H), 7,8 (m, 1H), 7,44 (m, 1H), 7,28 (d, 1H), 7,17 (t, 1H), 6,18 (kV, 1H), 3,78 (m, 2H), 3,6-3,1 (m, 8H), 3,19 (m, 2H), 2,88 (users, 3H), 2,77 (d, 3H)and 1.51 (d, 3H).

Example 68. Ethyl-7-fluoro-6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E68)

To a solution of 7-fluoro-8-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-2H-1,4-benzoxazin-3(4H)-she (D64) (165 mg, 0.35 mmol) in THF (5 ml) at 0 ° C add tert-piperonyl potassium (350 ál of 1 M solution in THF, 0.35 mmol). After stirring at the same temperature for 30 min the mixture is cooled to -20 ° C and add diethylphosphate (60 μl, 0.42 mmol). After stirring at 0 ° C for 1 hour, the reaction mixture was cooled to-78º and add utilitarianistic (40 μl, 0.35 mmol)and then tert-piperonyl potassium (350 ál of 1 M solution in THF, 0.35 mmol). The reaction mixture is heated to room temperature and then stirred overnight. The mixture is then poured into Russ is l (15 ml) and extracted with DCM (3×20 ml). The combined organic phases are dried over Na2SO4and concentrate to a residue, which was purified using column chromatography on silica gel with elution with a mixture of DCM/Meon (97:3), and get named in the title compound (50 mg, 25%). MS (ES/+) m/z: 570 [MH+]. C29H27F4N5O3requires 569.1H-NMR (300 MHz, CDCl3) δ (ppm): 8,65 (d, 1H), of 7.70 (m, 1H), 7,8-to 7.6 (m, 3H), 7,2 (m, 1H), 6,7-6,6 (m, 2H), 5,6 (s, 2H), 4,4 (kV, 2H), 3,1) of 2.6 (m, 12H), 1,4 (t, 3H).

Example 69. The hydrochloride of 7-fluoro-N-methyl-6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E)

Named the title compound is obtained in yield of 50% according to the procedure of example 57, on the basis of ethyl-7-fluoro-6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (E68) and methylamine. MS (ES/+) m/z: 555 [MH+]. C28H26F4N6O2requires 554.1H-NMR (400 MHz, CDCl3) δ (ppm): 8,65 (d, 1H), 7,95 (d, 1H), and 7.9 (s, 1H), 7,8-in 7.7 (m, 3H), 7,35-7,25 (m, 2H), 6,85 (t, 1H), 5,6 (s, 2H), 3,1-2,6 (m, 15H).

Example 70. The hydrochloride of 7-fluoro-6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carbonitrile (E70)

A mixture of ethyl-7-fluoro-6-(2-{4-[2-(trifluoromethyl)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (whom 68) (25 mg, 0,043 mmol), trimethylaluminum (110 μl of 2 M solution in hexano, 0,213 mmol) and ammonia (0,43 ml of 0.5 M solution in 1,4-dioxans, 0,213 mmol) in DCM (3 ml) is exposed to microwave radiation at 100 º C for 1 hour. The reaction mixture is dissolved in the Meon (1 ml) and purified by SPE(SCX) and then using mass-directed preparative HPLC get named in the title compound (4 mg, 18%). MS (ES/+) m/z: 523 [MH+]. C27H22F4N6O requires 522.1H-NMR (400 MHz, CDCl3) δ (ppm): 9,7 (d, 1H), 8 (s, 1H), 7,95 (d, 1H), 7,8-in 7.7 (m, 2H), 7,4-7,25 (m, 2H), 6,9 (t, 1H), 5,6 (s, 2H), 3,1) of 2.6 (m, 12H).

Example 71. Ethyl-7-fluoro-6-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (a)

To a solution of 7-fluoro-8-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-she (D67) (90 mg, 0.21 mmol) in THF (5 ml) at 0 ° C add tert-piperonyl potassium (215 μl of 1 M solution in THF, 0.22 mmol). After stirring at the same temperature for 30 min the mixture is cooled to -20 ° C and add diethylphosphate (45 μl, 0.25 mmol). After stirring at 0 ° C for 1 hour, the reaction mixture was cooled to-78º and add utilitarianistic (29 μl, 0.21 mmol)and then tert-piperonyl potassium (215 μl of 1 M solution in THF, 0.22 mmol). The reaction mixture is heated to room temperature and then stirred overnight. Then the MCA is ü poured into brine (15 ml) and extracted with DCM (3×20 ml). The combined organic phases are dried over Na2SO4and concentrate to a residue, which was purified using chromatography on silica gel with elution with a mixture of DCM/Meon (96:4), and get named in the title compound (20 mg, 20%). MS (ES/+) m/z: 517 [MH+]. C28H29FN6O3requires 516.1H-NMR (300 MHz, CDCl3) δ (ppm): 9,5 (s, 1H), and 8.0 (s, 1H), of 7.75 (t, 1H), and 7.6 (d, 1H), between 7.4 and 7.3 (m, 1H), 7,05 (d, 1H), 6,85 (t, 1H), 5,6 (s, 2H), 4,4 (kV, 2H), 3,4-2,6 (m, 15H), a 1.45 (t, 3H).

Example 72. The dihydrochloride of 7-fluoro-N-methyl-6-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide (E72)

Named the title compound is obtained in yield of 50% according to the procedure of example 57, on the basis of ethyl-7-fluoro-6-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (a) and methylamine. MS (ES/+) m/z: 502 [MH+]. C27H28FN7O2requires 501.1H-NMR (400 MHz, DMSO) δ (ppm): 10,5 (users, 1H), 9,63 (s, 1H), at 8.60 (s, 1H), 8,18 (kV, 1H), 7,9 (m, 2H), a 7.62 (d, 1H), 7,30 (d, 1H), 7,14 (t, 1H), to 5.66 (s, 2H), 3,78 (d, 2H), 3,61 (t, 2H), 3,5-3,3 (m, 4H), 3,30 (t, 2H), 3,19 (DD, 2H), and 2.79 (s, 3H), 2,77 (d, 3H).

Example 73. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A)

A mixture of ethyl-6-(1-methyl-2-oxoethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (D53) (151 m is, 0.50 mmol) and 2-methyl-5-piperazine-1-rhinolin (WO 2004/046124) (108 mg, 0.48 mmol) in dry 1,2-dichloroethane (12.5 ml) was stirred at room temperature for 1 hour. Add triacetoxyborohydride sodium (127 mg, of 0.60 mmol) and the resulting mixture stirred for 18 hours, then the reaction quenched with water (30 ml) and the mixture extracted with ethyl acetate (3×25 ml). The combined organic phases are dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified on SPE cartridge (silica gel) by elution with a mixture of 2% Meon in DCM, and get named in the title compound as a colourless oil (200 mg, 78%). MS (ES) m/z: 512,4 [MH+].1H-NMR (300 MHz, CDCl3) δ (ppm): at 8.36 (d, 1H), 7,98 (s, 1H), 7,69 (d, 1H), 7,54 (t, 1H), 7,33 (d, 1H), 7,25-7,22 (m, 1H+CDCl3), 7,17 (d, 1H), 7,12-of 6.96 (m, 2H), 5,52 (s, 2H), 4,39 (kV, 2H), 3,51 (m, 1H), 3,10-3,0 (m, 4H), was 2.76-2,5 (m, 9H), of 1.41 (t, 3H), of 1.30 (d, 3H).

Examples 74 and 75

The dihydrochloride of N-methyl-6-{1-methyl-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide:

enantiomer 1 (E),

enantiomer 2 (E75)

A mixture of trimethylaluminum (214 μl of 2.0 M solution in hexano, 0.43 mmol) and methylamine (214 μl of 2.0 M solution in THF, 0.43 mmol) in DCM (1.7 ml) was stirred at room temperature for 15 minutes Add ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carbox the lat (free base E) (44 mg, 0,086 mmol) and continue stirring for another 2 hours at 54º. Upon completion of the reaction, water is added dropwise until such time as the gas will not be released and end added volume reaches approximately 4 ml of the Aqueous solution is extracted with DCM (3×10 ml). In the case where the organic and inorganic phase are well separated, add water 1 M NaOH solution. The combined organic phases are dried (Na2SO4) and evaporated, and receive free ground named the title compound (30 mg). Then the racemic mixture is separated prepreparation by SFC chromatography (Gilson) [CHIRALCEL AD-H, 25×2.1 cm; modifier 30% (ethanol + 0.1% Isopropylamine), flow rate = 22 ml/min; pressure bar 192; T=36º; wavelength UV 220 nm; loop = 1 ml, and get enantiomer 1 (5 mg) and enantiomer 2 (8 mg). The enantiomeric excess of both enantiomers confirm analytical SFC (Berger) conditions: chiral column CHIRALCEL AD-H, 25×0,46 cm; modifier 30% (ethanol + 0.1% Isopropylamine), flow rate = 2.5 ml/min; pressure 180 bar; T=35; wavelength UV 220 nm; loop = 10 ál.

Enantiomer 1 (E) - (a/a UV 100%, retention time of 17.5 min, ei (E.E.)=100%).

Enantiomer 2 (E75) - (a/a UV 100%, retention time 25.6 min, EE = 100%).

Free base E dissolved in dry methanol (1 ml) and slowly add HCl (8 μl of 1.25 M solution in Meon, 0.1 mmol) at 0OC. Received suspen the July stirred at 0 ° C for 4 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound as a yellow solid (4 mg).

Free base E75 dissolved in dry methanol (1 ml) and slowly add HCl (13 μl of a 1.25 M solution in Meon, 0.1 mmol) at 0OC. The resulting suspension was stirred at 0 ° C for 4 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound as a yellow solid (5.3 mg).

Enantiomer 1 (E):1H-NMR (500 MHz, DMSO-d6) δ: 9,70 (users, 1H), 8,58 (s, 1H), 8,42 (users, 1H), 8,15 (users, 1H), to 7.84 (d, 2H), to 7.67 (users, 2H), 7,46 (users, 1H), 7,34 (d, 1H), 7,19 (m, 1H), 5,62 (s, 2H), 3,8-3,1 (osirm, 11H+water)to 2.74 (d, 3H), to 2.67 (s, 3H), 1,37 (d, 3H).

Enantiomer 2 (E75):1H-NMR (500 MHz, DMSO-d6) δ: 9,48 (users, 1H), 8,58 (s, 1H), at 8.36 (m, 1H), 8,14 (d, 1H), to 7.84 (d, 2H), to 7.64 (m, 2H), 7,42 (m, 1H), 7,34 (d, 1H), 7,17 (m, 1H), 5,62 (s, 2H), 3,8-3,1 (osirm, 11H+water), 2,98 (s, 3H), 2,74 (d, 3H), 1,37 (d, 3H).

Example 76. The dihydrochloride 6-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-methyl-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazine (E)

Named in the title compound, receive, following the General procedure of reductive amination of example 1, from (3-methyl-4H-[1,2,3]triazolo[5,1-C][1,4]benzoxazin-6-yl)acetaldehyde (D41) (20 mg, 0,087 mmol) and 7-fluoro-2-methyl-5-(1-piperazinil)quinoline (WO 2004/046124) (32 mg, 0,131 mmol). The crude product is the reaction of purified flash chromatography on silica gel with elution with a gradient Meon in DCM (1-3%) and receive free ground named the title compound (27 mg, 68%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (4:1, 5 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 459,20 [MH+]. C26H27FN6O requires 458,54.1H-NMR (500 MHz, DMSO-d6) δ: 10,57 (users, 1H), charged 8.52 (userd, 1H), to 7.93 (DD, 1H), 7,53 (d, 1H), 7,47 (d, 1H), was 7.36 (DD, 1H), 7,24 (m, 2H), to 5.57 (s, 2H, in), 3.75 (d, 2H), 3,60-3,10 (acsim, 10H), by 2.73 (s, 3H), of 2.34 (s, 3H).

Example 77. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (E77)

To a solution of 5-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3,4-dihydro-2(1H)-Hinayana (D74) (334 mg, 0,835 mmol) and tert-butoxide potassium (140 mg, 1.25 mmol) in dry DMF (15 ml) at-5ºC add diethylcarbamoyl (of 0.24 ml, a rate of 1.67 mmol). After 20 minutes add solution ethylisothiocyanate (of 0.14 ml, 1.25 mmol) and tert-butoxide potassium (140 mg, 1.25 mmol) in dry DMF (2 ml). The reaction mixture was stirred at room temperature for 24 hours, then the reaction quenched with water (5 ml) and the mixture extracted with DCM (3×50 ml). The combined organic layers are dried (Na2SO4), concentrated in vacuo, and the crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-3%), and receive free ground named the title compound (116 mg, 28%). Treatment with HCl (2.2 EQ. 1.25 M solution of vmean) in methanol/DCM (1:1, 4 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 496,2 [MH+]. C30H33N5O2requires 495,62.1H-NMR (400 MHz, DMSO-d6) δ: 10,87 (users, 1H), 8,66 (users, 1H), to 8.57 (s, 1H), 7,81 (m, 3H), 7,63 (users, 1H), 7,43 (t, 1H), 7,35 (users, 1H), 7,29 (d, 1H), 4,29 (kV, 2H), 3,78 (d, 2H), 3,52-to 3.35 (m, 6H), 3,40-3,20 (m, 6H), was 3.05 (m, 2H), 2,79 (s, 3H), of 1.33 (t, 3H).

Example 78. The dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (E)

Named in the header connection receive according to the procedure of example 57, on the basis of ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (free base E77) (53 mg, 0,107 mmol) and methylamine. The crude reaction product is purified flash chromatography on silica gel with elution with a gradient Meon in DCM (1-3%) and receive free ground named the title compound (33 mg, 65%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (3:1, 4 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 481,20 [MH+]. C29H32N6O requires 480,61.1H-NMR (400 MHz, DMSO-d6) δ: 10,52 (users, 1H), 8,55 (users, 1H), 8,49 (s, 1H), 8,00 (kV, 1H), 7,79 (d, 1H), 7,76 (users, 2H), 7,58 (users, 1H), 7,41 (t, 1H), 7,32 (users, 1H), 7,27 (d, 1H), 3,79 (d, 2H), 3,52-3,30 (m, 6H), 3,40-3,20 (m, 6H), 3.00 for (m, 2H), 2,77 (2s, 6H).

Example 79. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(4-morpholinylcarbonyl)-4,5-dihydroimidazo[1,5-a]quinoline (E79)

Named the title compound is obtained in yield 82% according to the procedure of example 57, on the basis of ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (free base E77) (53 mg, 0,107 mmol) and research. The crude reaction product is purified flash chromatography on silica gel with elution with a gradient Meon in DCM (1-5%) and receive free ground named the title compound (47 mg, 82%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (4:1, 5 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 537,40 [MH+]. C32H36N6O2requires 536,68.1H-NMR (400 MHz, DMSO-d6) δ: 10,65 (users, 1H), 8,57 (users, 1H), and 8.50 (s, 1H), 7,79 (d, 1H), to 7.77 (users, 2H), 7,58 (users, 1H), 7,42 (t, 1H), 7,31 (users, 1H), 7,28 (d, 1H), 4,18 (users, 2H), 3,78 (d, 2H), 3,66 (m, 6H), 3,52-3,30 (m, 6H), 3,40-3,20 (m, 6H), to 3.00 (m, 2H), 2,77 (s, 3H).

Example 80. Ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E80)

To a solution of 7-methyl-8-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2H-1,4-benzoxazin-3(4H)-she (D80) (50 mg, 0,120 mmol) in THF (3 ml) at 0 ° C add tert-piperonyl feces is I (132 μl of 1 M solution in THF, 0,132 mmol). After stirring at 0 ° C for 20 min, the reaction mixture was cooled to -20 ° C and gradually add diethylphosphate (22 μl, 0,156 mmol). After stirring at 0 ° C for 30 min, the reaction mixture was cooled to-78º and add utilitarianistic (15 μl, 0,132 mmol)and then tert-piperonyl potassium (132 μl of 1 M solution in THF, 0,132 mmol). After stirring at ambient temperature for 4 hours the reaction is quenched with saturated aqueous NH4Cl (4 ml) and the mixture extracted with DCM (3×50 ml). The combined organic layers are dried (Na2SO4), concentrated in vacuo, the crude reaction product is purified flash chromatography on silica gel with elution with a gradient Meon in DCM (1-3%) and get named in the title compound (29 mg, 48%). MS (ES) m/z: 512,40 [MH+]. C30H33N5O3requires 511,62.

Example 81. The dihydrochloride of N,7-dimethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E)

Named in the header connection receive according to the procedure of example 57, on the basis of ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E80) (29 mg, 0.06 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient Meon in DCM (1-3%) and the floor is given free base named the title compound (24 mg, 86%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (4:1, 5 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 497,20 [MH+]. C29H32N6O2requires 496,61.1H-NMR (400 MHz, DMSO-d6) δ: 10,50 (acsis, 1H), 8,70 (acsis, 1H), 8,53 (s, 1H), 8,14 (kV, 1H), 7,80 (users, 2H), 7,72 (d, 1H), to 7.64 (acsis, 1H), 7,35 (users, 1H), 7,03 (d, 1H), to 5.58 (s, 2H), 3,79 (d, 2H), 3,60-3,10 (m, 8H), 3.15 in (m, 2H), 2,78 (s, 3H), 2,74 (d, 3H), 2,39 (s, 3H).

Example 82. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A)

Named in the title compound, receive, following the General procedure of reductive amination of example 1 from ethyl-6-(2-oxoethyl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D86) (50 mg, 0.18 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (WO 2004/046124) (60 mg, 0.26 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient Meon in DCM (1-3%) and receive free ground named the title compound (75 mg, 84%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in a mixture of Meon/DCM (4:1, 5 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 495,4 [MH+]. C31H34N4O2requires 494,64.1H-NMR (500 MHz, DMSO-d6) δ: 11,07 (users, 1H), 9,29 (userd, 1H), 8,66 (s, 1H), 8,23 (d, 1H), 8,09 (who, 1H), 7,98 (d, 1H), 7,82 (d, 1H), of 7.75 (d, 1H), 7,43 (t, 1H), 7,32 (d, 1H), 4,29 (kV, 2H), 3,85 (m, 1H), 3,80 (userd, 2H), 3,7-3,2 (osirm, 8H), 3,06 (t, 2H), 2,97 (s, 3H), 2,30 (m, 2H), 2,12 (userd, 2H), 1,33 (t, 3H).

Example 83. The dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (e)

Named in the header connection receive according to the procedure of example 57, on the basis of ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (free base E) (33 mg, 0.07 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient Meon in DCM (1-5%) and receive free ground named the title compound (25 mg, 78%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in a mixture of Meon/DCM (1:1, 2 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 480,3 [MH+]. C30H33N5O requires 479,62.1H-NMR (500 MHz, DMSO-d6) δ: of 10.25 (users, 1H), 8,72 (users, 1H), of 8.47 (s, 1H), of 7.97 (d, 1H), 7,92 (users, 1H), 7,80 (users, 1H), to 7.77 (d, 1H), to 7.61 (users, 1H), 7,50 (users, 1H), 7,38 (m, 1H), 7,26 (d, 1H), 3,78 (d, 2H), and 3.72 (m, 1H), 3,6-3,1 (osirm, 8H), 2,98 (t, 2H), 2,74 (m, 6H), 2,12 (m, 4H).

Example 84. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (E)

Named in the title compound which are square with the release of 70% of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (E) (122 mg, 0,261 mmol)following the General procedure for obtaining amides (see examples 48-53), using hexamethyldisilazane (1.1 EQ.). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in a mixture of Meon/DCM (1:1, 6 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 467,30 [MH+]. C28H30N6O requires 466,59.1H-NMR (500 MHz, DMSO-d6) δ: 10,50 (users, 1H), 8,50 (users, 1H), 8,46 (s, 1H), to 7.77 (d, 1H), 7,72 (s, 2H), 7,52 (users, 1H), 7,40 (t, 1H), 7,35 (s, 1H), 7,26 (users, 1H), 7,25 (d, 1H), 7,14 (s, 1H), 3,76 (d, 2H), 3,50 (d, 4H), 3,4-3,1 (osirm, 8H), 2,98 (t, 2H), 2,71 (s, 3H).

Example 85. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (E85)

A mixture of ethyl-6-(2-oxoethyl)imidazo[1,5-a]quinoline-3-carboxylate (D91) (30 mg, 0.11 mmol) and 2-methyl-5-piperazine-1-rhinolin (WO 2004/046124) (30 mg, 0.13 mmol) in 1,2-dichloroethane was stirred at room temperature for 30 minutes Then add triacetoxyborohydride sodium (27.5 mg, 0.13 mmol) and the resulting reaction mixture is stirred for 8 hours, the reaction is quenched with saturated aqueous NaHCO3(10 ml) and the mixture extracted with ethyl acetate (3×10 ml). The combined organic phases are dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si elution with a mixture of 2% Meon in DCM and receive free ground named is agolove compound as a white solid (17 mg, 31%). The free base (16 mg, to 0.032 mmol) dissolved in dry Meon (0.5 ml) and treated with HCl (0,057 ml of a 1.25 M solution in methanol) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound (17 mg, 94%) as a yellow solid. MS (ES) m/z: 494,20 [MH+]. C30H31N5O2requires 493,61.1H-NMR (300 MHz, DMSO-d6) δ: 10,8 (users, 1H), and 9.3 (s, 1H), 8.6 out of 8.4 (m, 2H), 7,9-7,8 (m, 2H), 7,9-to 7.6 (m, 3H), 7,6 to 7.4 (m, 2H), 7,25 (users, 1H), 4,3 (kV, 2H), 3,9-3,2 (osirm+water, 12H), and 2.8 (s, 3H), of 1.35 (t, 3H).

Example 86. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (A)

A mixture of ethyl-6-(2-oxoethyl)imidazo[1,5-a]quinoline-3-carboxylate (D91) (115 mg, 0.41 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (WO 2004/046124) (111 mg, 0.49 mmol) in 1,2-dichloroethane (5 ml) was stirred at room temperature for 30 minutes Then add triacetoxyborohydride sodium (104 mg, 0.49 mmol) and the resulting reaction mixture is stirred for 6 hours and then concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si elution with a mixture of 5% Meon in DCM, and receive free ground mentioned in the title compound as a white solid (105 mg, 52%). The free base (5 mg, 0.03 mmol) dissolved in dry Meon (0.5 ml) and treated with HCl (0,054 ml of a 1.25 M solution in Meon) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound (16 mg, 94%) as a pale yellow solid.1H-NMR (500 MHz, DMSO-d6) δ: 11,12 (users, 1H), to 9.32 (s, 1H), 8,86 (users, 1H), charged 8.52 (d, 1H), 8,1-8,0 (DD+users, 3H), 7,88 (osirm, 1H), 7,79 (t, 1H), 7,68 (osirm, 1H), to 7.61 (d, 1H), 7,60 (osirm, 1H), to 4.38 (q, 2H), 3,81 (m, 3H), 3,63 (m, 3H), 3.3V (m+water, 4H), and 2.8 (s, 3H), 2 28 (kV, 2H), and 2.14 (d, 2H), 1.39 in (t, 3H).

Example 87. The dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (E87)

A solution of trimethylaluminum (0,19 ml of 2.0 M solution in hexano, and 0.37 mmol) and methylamine (0,19 ml of 2.0 M solution in THF, and 0.37 mmol) in dry DCM (0.5 ml) was stirred at room temperature for 15 minutes Add ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (free base E85) (35 mg, 0,074 mmol) in dry DCM (1 ml) and continue stirring for another 6 hours at 56º. Upon completion of the reaction at 0 ° C is added dropwise water, and then 1 M NaOH solution up until the organic and aqueous phases are not separated. The mixture is extracted with DCM (3×10 ml)and the combined organic phases are dried (Na2SO4)and then evaporated in vacuum. The residue is treated with diethyl ether and receive free ground mentioned in the title compound as a white solid (29 mg, 76%). The free base (22,5 mg 0,047 mmol) dissolved in dry Meon (1 ml) and treated with HCl (0,083 ml of a 1.25 M solution in Meon) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound (22 mg, 85%) as a yellow solid.1H-NMR (500 MHz, DMSO-d6) δ: 11,19 (users, 1H), 9,26 (s, 1H), 8,7 (users, 1H), of 8.47 (d, 1H), 8,23 (kV, 1H), 8,13 (d, 1H), 7,87 (d, 1H), 7,9-7,6 (osirm, 3H), of 7.75 (t, 1H), 7,55 (d, 1H), 7,38 (users, 1H), 3,84 (userd, 2H), 3,7-3,2 (osirm+water, 10H), and 2.83 (s, 3H), 2,80 (s, 3H).

Example 88. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (E)

A mixture of ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (free base E85) (31 mg, 0,063 mmol) and potassium hydroxide (0.4 ml of 1 M solution in Meon) is stirred at 80 ° C for 2 hours. After purification by SPE-SCX extract 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxylate ammonium (0,063 mmol) and used without further purification to obtain the free base named in the title compound following the General procedure according to the teachings of amides, using hexamethyldisilazane (0,016 ml, 1.1 EQ.). Then the reaction mixture is evaporated in vacuo and the residue purified SCX. The free base (15 mg, to 0.032 mmol) dissolved in dry Meon (0.5 ml) and treated with HCl (0,071 ml of a 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound as a yellow solid (16 mg, total yield 47%). MS (ES) m/z: 465,2 [MH+]. C28H28N6O requires 464,6.1H-NMR (500 MHz, DMSO-d6) δ: 11,42 (users, 1H), 9,23 (s, 1H), 8,88 (users, 1H), 8,46 (d, 1H), 8,1 (userd, 1H), 7,93 (users, 2H), 7,87 (d, 1H), 7,8 (users, 1H), 7,73 (t, 1H), 7,58 (users, 1H), 7,54 (d, 1H), 7,45 (users, 1H), 7,25 (users, 1H), 3,82 (d, 2H)and 3.6 (DD, 2H), 3,54 (d, 2H), 3,5-3,2 (m+water, 6H), is 2.88 (s, 3H).

Example 89. The dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (E)

A solution of trimethylaluminum (0.1 ml, 2.0 M solution in hexano, 0.2 mmol) and methylamine (0.1 ml, 2.0 M solution in THF, 0.2 mmol) in dry DCM (0.5 ml) was stirred at room temperature for 15 minutes Add ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (free base E) (20 mg, 0.04 mmol) in dry DCM (1 ml) and continue stirring for 8 hours at 60'C. On the versenyi reaction at 0 ° C is added dropwise water, and then 1 M NaOH solution up until the organic and aqueous phases are not separated. The mixture is extracted with DCM (3×10 ml)and the combined organic phases are dried (Na2SO4) and then evaporated in vacuum. The residue is treated with diethyl ether and receive free ground mentioned in the title compound as a white solid (19 mg, 98%). The free base (18 mg, of 0.038 mmol) dissolved in dry Meon (0.5 ml) and treated with HCl (0,067 ml of a 1.25 M solution in Meon) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound (18 mg, 86%) as a pale yellow solid.1H-NMR (500 MHz, DMSO-d6) δ: of 10.93 (users, 1H), 9,23 (s, 1H), 8,69 (users, 1H), 8,44 (d, 1H), 8,21 (d, 1H)and 8.1 (d, 1H), 7,86 (d, 1H), 7,72 (t, 1H), 7,54 (d, 1H), 8.0 to 7,4 (osirm, 4H), 3,82 (d, 2H), 3,74 (t, 1H), to 3.58 (t, 2H), 3,5-3,2 (m+water, 4H), of 2.81 (d, 3H), 2,71 (s, 3H), of 2.23 (q, 2H), 2,11 (d, 2H).

Example 90. The dihydrochloride of N-(cyclopropylmethyl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (along the E90)

A solution of trimethylaluminum (0.15 ml of a 2.0 M solution in hexano, 0.3 mmol) and cyclopropanemethylamine (0,021 ml, 0.3 mmol) in dry DCM (0.5 ml) was stirred at room temperature for 15 minutes Add ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imides is[1,5-a]quinoline-3-carboxylate (free base E) (30 mg, 0.061 mmol) in dry DCM (1 ml) and continue stirring for 8 hours at 60'C. Upon completion of the reaction at 0 ° C is added dropwise water, and then 1 M aqueous NaOH solution up until the organic and aqueous phases are not separated. The aqueous mixture is extracted with DCM (3×10 ml)and the combined organic phases are dried (Na2SO4) and then evaporated in vacuum. The residue is treated with diethyl ether and receive free ground mentioned in the title compound as a white solid (31 mg, 100%). The free base (30 mg, 0.061 mmol) was dissolved in dry Meon (1 ml) and treated with HCl (0,107 ml of a 1.25 M solution in Meon) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound (30 mg, 83%) as a pale yellow solid.1H-NMR (500 MHz, DMSO-d6) δ: 11,04 (users, 1H), 9,25 (s, 1H), total of 8.74 (users, 1H), 8,46 (d, 1H), 8,25 (t, 1H)and 8.1 (d, 1H), 7,87 (d, 1H), 8.0 to 7,4 (osirm, 4H), 7,72 (t, 1H), 7,54 (d, 1H), 3,82 (d, 2H, in), 3.75 (t, 1H)and 3.59 (m, 2H), 3,5-3,1 (users+water, 4H), 3,17 (t, 2H), by 2.73 (s, 3H), of 2.25 (q, 2H), 2,11 (d, 2H), 1,08 (m, 1H), 0,42 (d, 2H), 0,26 (d, 2H).

Example 91. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (E)

A mixture of ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxy is ATA (free base E) (40 mg, of 0.081 mmol) and potassium hydroxide (0,49 ml of 1 M solution in Meon) is stirred at 80 ° C for 2 hours. After purification on SCX extract 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxylate ammonium and used without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (0,021 ml, 1.1 EQ.). Then the reaction mixture is evaporated in vacuo, and the residue purified SCX, and get named in the title compound as free base (20 mg, 0,043 mmol)which was dissolved in dry Meon (0.5 ml) and treated with HCl (0,076 ml of a 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound as a pale yellow solid (20 mg, total yield 46%). MS (ES) m/z: 464,2 [MH+]. C29H29N5O requires 463,6.1H-NMR (500 MHz, DMSO-d6) δ: 11,43 (users, 1H), 9,3 (users, 1H), which 9.22 (s, 1H), 8,45 (d, 1H), compared to 8.26 (userd, 1H), 8,08 (d, 2H), of 7.96 (userd, 1H), to $ 7.91 (d, 1H), 7,73 (m, 2H), 7,58 (users, 1H), 7,55 (d, 1H), 7,25 (users, 1H), 3,82 (d, 2H), 3,61 (DD, 2H), 3,6-3,2 (m+water, 5H), 2,96 (s, 3H), 2,32 (kV, 2H), 2,11 (d, 2H).

Example 92. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}tetrazolo[1,5-a]quinoline (E)

The mixture tetrazolo[1,5-a]quinoline-6-ylacetamide (D93) (50 mg, 0.24 mmol) and 2-methyl-5-piperazine-1-rhinolin (WO 2004/046124) (60 mg, 0.29 mmol) in 1,2-dichloroethane (3 ml) was stirred at room temperature for 30 minutes Then add triacetoxyborohydride sodium (61 mg, 0.29 mmol), the reaction mixture is stirred overnight and then concentrated in vacuo. The residue is purified on SPE cartridge-Si elution from DCM to a mixture of 4% Meon in DCM and receive free ground mentioned in the title compound as a white solid (83 mg, 81%). The free base (80 mg, 0,19 mmol) dissolved in dry Meon (1.5 ml) and treated with HCl (0.33 ml, 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 4 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound (82 mg, 87%) as a yellow solid. MS (ES) m/z: 424,0 [MH]+. C25H25N7requires 423,5.1H-NMR (500 MHz, DMSO-d6) δ: 11,88 (users, 1H), 8,92 (users, 1H), 8,71 (d, 1H), 8,63 (d, 1H), to 8.20 (d, 1H), 8.0 a (t, 1H), 8.0 a (m, 2H), and 7.8 (d, 1H), 7,8 (m, 1H), 7,47 (userd, 1H), 3,83 (d, 2H), of 3.77 (DD, 1H), 3,7-3,3 (osirm+water, 8H), 2.91 in (s, 3H).

Example 93. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}tetrazolo[1,5-a]quinoline (E)

The mixture tetrazolo[1,5-a]quinoline-6-ylacetamide (D93) (50 mg, 0.4 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (WO 2004/046124) (66 mg, 0.29 mmol) in 1,2-dichloroethane (3 ml) was stirred at room temperature for 30 minutes Then add triacetoxyborohydride sodium (61 mg, 0.29 mmol), the reaction mixture is stirred overnight and then concentrated in vacuo. The residue is purified on SPE cartridge-Si elution from DCM to a mixture of 4% Meon in DCM, and receive free ground mentioned in the title compound as a white solid (66 mg, 65%). The free base (60 mg, 0.14 mmol) dissolved in dry Meon (1.5 ml) and treated with HCl (0.25 ml of a 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 4 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound (62 mg, 89%) as a pale yellow solid. MS (ES) m/z: 423,0 [MH]+. C26H26N6requires 422,6.1H-NMR (500 MHz, DMSO-d6) δ: 11,14 (users, 1H), 8,84 (users, 1H), 8,68 (d, 1H), 8,63 (d, 1H), to 8.20 (d, 1H), 8.0 a (t, 1H), 8,1-7,8 (osirm, 2H), 7,82 (d, 1H), 7,69 (users, 1H), 7,56 (users, 1H), 3,83 (d, 2H), 3,74 (DD, 2H), 3,5-3,2 (osirm+water, 5H), 2,78 (s, 3H), and 2.26 (q, 2H), 2,12 (d, 2H).

Example 94. The dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}tetrazolo[1,5-a]quinoline (E)

The mixture tetrazolo[1,5-a]quinoline-6-ylacetamide (D93) (50 mg, 0.24 mmol) and 2-methyl-5-[(3R)-3-methyl-1-piperazinil]quinoline (WO 2004/046124) (70 mg, 0.29 to which mol) in 1,2-dichloroethane (3 ml) was stirred at room temperature for 30 minutes Then add triacetoxyborohydride sodium (61 mg, 0.29 mmol), the reaction mixture is stirred overnight and then concentrated in vacuo. The residue is purified on SPE cartridge-Si elution from DCM to a mixture of 4% Meon in DCM, and receive free ground mentioned in the title compound as a white solid (64 mg, 61%). The free base (60 mg, 0.14 mmol) dissolved in dry Meon (1.5 ml) and treated with HCl (in 0.24 ml of a 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 4 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound (64 mg, 90%) as a yellow solid. MS (ES) m/z: 438,0 [MH]+. C26H27N7requires 437,6.1H-NMR (500 MHz, DMSO-d6) δ: 11,70 (users, 1H), 8,8 (users, 1H), 8,69 (d, 1H), 8,63 (d, 1H), to 8.20 (d, 1H), 8.0 a (t, 1H), 7,9-7,8 (users, 2H), a 7.85 (d, 1H), 7,69 (users, 1H), 7,38 (users, 1H), 3.96 points (d, 2H), 3,9-3,1 (m+water, 8H), 3,82 (m, 1H), 2,82 (s, 3H), of 1.47 (d, 3H).

Example 95. The dihydrochloride 6-(2-{4-[2-(deformity)-5-chinoline]-1-piperazinil}ethyl)tetrazolo[1,5-a]quinoline (E95)

The mixture tetrazolo[1,5-a]quinoline-6-ylacetamide (D93) (50 mg, 0.24 mmol) and 2-(deformity)-5-(1-piperazinil]quinoline (D143) (76 mg, 0.29 mmol) in 1,2-dichloroethane (3 ml) was stirred at room temperature for 30 minutes Then add triacetoxyborohydride the reed sodium (61 mg, 0.29 mmol), the reaction mixture is stirred overnight and then concentrated in vacuo. The residue is purified on SPE cartridge-Si elution from DCM to a mixture of 4% Meon in DCM and receive free ground mentioned in the title compound as a white solid (48 mg, 44%). The free base (45 mg, 0,098 mmol) dissolved in dry Meon (1.5 ml) and treated with HCl (0,172 ml of a 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 4 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound (46 mg, 83%) as a white solid. MS (ES) m/z: 460,0 [MH]+. C25H23F2N7requires 459,5.1H-NMR (500 MHz, DMSO-d6) δ: 10,88 (users, 1H), up 8.75 (d, 1H), 8,64 (m, 2H), 8,24 (d, 1H), 8,01 (t, 1H), 7,9-to 7.6 (m, 4H), 7,43 (d, 1H), 7,13 (t, 1H), 3,84 (d, 2H), 3,71 (m, 2H), 3,55 (m, 6H), 3,3 (m+water, 2H).

Example 96. The dihydrochloride of 1-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}[1,2,4]triazolo[4,3-a]quinoline (E)

A mixture of (1-methyl)[1,2,4]triazolo[4,3-a]quinoline-6-yl)acetaldehyde and 1-(metiloksi)-2-(1-methyl[1,2,4]triazolo[4,3-a]quinoline-6-yl)ethanol (see D97) (30 mg, 0.13 mmol) and 2-methyl-5-piperazine-1-rhinolin (WO 2004/046124) (36 mg, 0.16 mmol) and a drop of glacial acetic acid in a mixture of 1,2-dichloroethane/acetonitrile (3:1, 4 ml) was stirred at room temperature in an atmosphere of AZ is that within 30 minutes Then add triacetoxyborohydride sodium (34 mg, 0.16 mmol), the reaction mixture is stirred for 6 hours, the reaction is quenched with saturated aqueous NaHCO3(10 ml) and the mixture extracted with DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified on SPE cartridge (silica gel) by elution with a mixture of 5% Meon in DCM and receive free ground mentioned in the title compound as a white solid (32 mg, 55%). The free base (30 mg, 0.07 mmol) dissolved in dry Meon (2 ml) and treated with HCl (0,123 ml of a 1.25 M solution in Meon, 0.15 mmol) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound (30 mg, 87%) as a yellow solid.1H-NMR (500 MHz, DMSO-d6) δ: 11,4 (users, 1H), 8,53 (users, 1H), at 8.36 (d, 1H), 8,11 (d, 1H), to 7.75 (m, 4H), to 7.59 (d, 1H), 7,54 (users, 1H), 7,29 (users, 1H), 3,82 (m, 2H), to 3.64 (m, 2H), 3,52 (m, 6H), 3,2 (m, 2H), to 3.09 (s, 3H), 2,72 (users, 3H).

Example 97. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (A)

A mixture of ethyl-6-(2-oxoethyl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D99) (36 mg, 0.13 mmol) and 2-methyl-5-piperazine-1-rhinolin (36 mg, 0.16 mmol who) in 1,2-dichloroethane (2 ml) was stirred at room temperature for 30 minutes Then add triacetoxyborohydride sodium (34 mg, 0.16 mmol)and the resulting reaction mixture is stirred overnight and then concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si elution with a mixture of 30% cyclohexane in ethyl acetate, and then with a mixture of 2% Meon in DCM and receive free ground named the title compound (60 mg, 93%). Part of the obtained material (15 mg) was dissolved in dry Meon (1 ml) and treated with HCl (to 0.055 ml of a 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound as a yellow solid.1H-NMR (500 MHz, DMSO-d6) δ: 11,64 (users, 1H), 8,92 (users, 1H), 8,77 (d, 1H), 8,58 (d, 1H), of 8.09 (d, 1H), 7,98 (t, 1H), 7,95 (users, 2H), 7,82 (d, 1H), 7,47 (users, 1H), 3,83 (d, 2H), 3,74 (DD, 1H), 3,7-3,5 (osirm+water, 6H), 3,39 (t, 2H), 2,90 (s, 3H), of 1.41 (t, 3H).

Example 98. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide (E)

A mixture of ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (free base E) (25 mg, of 0.081 mmol) and potassium hydroxide (0.3 ml of 1 M solution in Meon) is stirred at 80 ° C for 2 hours. After SCX purification extract 6-{2-[4-(2-methyl-5-chinoline)-1-Pipa is azinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate ammonium and used without further purification to obtain the free base named in the title compound, following the General procedure for obtaining amides, using hexamethyldisilazane (0,009 ml, 1.1 EQ.). Then the reaction mixture is evaporated in vacuo and the residue purified SCX, and then on the SPE-Si elution with a mixture of 2% Meon in DCM. The free base (9 mg, 0.019 mmol) was dissolved in dry Meon (0.5 ml) and treated with HCl (0,034 ml of a 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound as yellow solid (10 mg, total yield 23%).1H-NMR (500 MHz, DMSO-d6) δ: 11,76 (users, 1H), up 8.75 (d, 1H), 8,55 (users, 1H), at 8.36 (d, 1H), 8,21 (d, 1H), 8,2 (users, 2H), of 7.96 (t, 1H), to 7.77 (d, 1H), 7,74 (users, 2H), 7,69 (s, 1H), 7,56 (users, 1H), 7,31 (users, 1H), 3,84 (d, 2H), 3,68 (m, 2H), of 3.56 (m+water, 5H), 3,3 (m, 2H), by 2.73 (s, 3H).

Example 99. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (A)

A mixture of ethyl-6-(2-oxoethyl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D99) (41 mg, 0.14 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (WO 2004/046124) (39 mg, 0,17 mmol) in 1,2-dichloroethane (2 ml) was stirred at room temperature under nitrogen atmosphere for 30 minutes. Then add triacetoxyborohydride sodium (36 mg, 0,17 mmol), the reaction mixture is stirred for 6 hours and then concentrate the vacuum. The crude reaction product is purified on SPE cartridge-Si elution with a mixture of 20% cyclohexane in ethyl acetate and receive free ground named the title compound (65 mg, 94%). The free base (15 mg) was dissolved in dry Meon (0.5 ml) and treated with HCl (0,053 ml of a 1.25 M solution in methanol) at 0OC. The resulting suspension is stirred at room temperature for 2 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound (16 mg, 93%).1H-NMR (500 MHz, DMSO-d6) δ: of 10.58 (users, 1H), 8,76 (d, 1H), 8,58 (d, 1H), 8,49 (d, 1H), 8,10 (d, 1H), 7,97 (t, 1H), to 7.84 (d, 1H), 7,80 (d, 1H), 7,72 (t, 1H), 7,49 (d, 1H), 7,44 (d, 1H), 4,43 (kV, 2H), 3,84 (d, 2H), 3,71 (m, 3H), of 3.45 (m, 2H), 3.33 and (m, 2H), to 2.67 (s, 3H), 2,18 (m, 4H), of 1.41 (t, 3H).

Example 100. The dihydrochloride ethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (E100)

A mixture of ethyl-6-(2-oxoethyl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D99) (41 mg, 0.14 mmol) and 2-methyl-5-[(3R)-3-methyl-1-piperazinil]quinoline (WO 2004/046124) (41 mg, 0,17 mmol) in 1,2-dichloroethane (2 ml) was stirred at room temperature under nitrogen atmosphere for 30 minutes. Then add triacetoxyborohydride sodium (36 mg, 0,17 mmol)and the resulting reaction mixture is stirred for 6 hours and then concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si with what lirovanie a mixture of 20% cyclohexane in ethyl acetate, and receive free ground named the title compound (55 mg, 77%). The free base (15 mg) was dissolved in dry methanol (0.5 ml) and treated with HCl (0,052 ml of a 1.25 M solution in methanol) at 0OC. The resulting suspension is stirred at room temperature for 2 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound (15 mg, 90%).1H-NMR (500 MHz, DMSO-d6) δ: 10,94 (users, 1H), 8,77 (d, 1H), charged 8.52 (d, 1H), 8,45 (d, 1H), 8,12 (d, 1H), 7,98 (t, 1H), 7,83 (d, 1H), to 7.67 (m, 2H), 7,45 (d, 1H), 7.23 percent (users, 1H), of 4.45 (q, 2H), 3,83 (m, 1H), 3,69 (m, 4H), 3,49 (m, 3H), 3,30 (m, 2H), is 3.08 (m, 1H), 2,66 (s, 3H), of 1.46 (d, 3H), of 1.41 (t, 3H).

Example 101. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (E101)

A mixture of 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate ammonium (E) (20 mg) and 1,2-dichlorobenzene (1 ml) is exposed to in the microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 250º, 10 minutes). The solvent is removed on the cartridge SPE-SCX (elution with methanol, then 2 N solution of ammonia in methanol), and receive free ground mentioned in the title compound as a white solid (12.3 mg). The free base was dissolved in dry methanol (0.5 ml) and treated with HCl (0,073 ml of a 1.25 M solution in methanol) at 0OC. The resulting suspension peremeshivayte room temperature for 2 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound (14 mg, 96%).1H-NMR (500 MHz, DMSO-d6) δ: 10,52 (users, 1H), 8,69 (d, 1H), 8,6 (users, 1H), 8.34 per (s, 1H), 8,13 (d, 1H), 7,95 (d, 1H), 7,87 (m, 2H), 7,74 (m, 2H), 7,52 (users, 1H), 7,46 (d, 1H), 3,83 (d, 1H), 3,74 (d, 2H), to 3.64 (m, 2H), 3.43 points (m, 2H), to 3.35 (m, 2H), 2,69 (s, 3H), of 2.16 (m, 4H).

Example 102. Methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (E102)

Methyl-6-(2-oxoethyl)[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D104) (355 mg, 1,32 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (328 mg, 1,45 mmol) (WO 2004/046124) in 1,2-dichloroethane (15 ml) was stirred at room temperature under nitrogen atmosphere for 30 minutes. Then add triacetoxyborohydride sodium (306 mg, 1,45 mmol), the reaction mixture is stirred overnight, then the reaction quenched with a solution of NaHCO3(100 ml) and the mixture extracted with DCM (3×100 ml). The organic layers are combined, dried (Na2SO4) and concentrated in vacuo. The crude substance is purified on SPE cartridge-Si elution with a mixture of 2% Meon in DCM and get named in the title compound as a white solid (501 mg, 79%). MS (ES) m/z: 480,3 [MH+]. C29H29N5O2requires 479,6.

Example 103. The dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carbox the MFA (E)

A mixture of ethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (free base E100) (40 mg, 0,078 mmol) and KOH (1 M solution in Meon, 0.5 ml) is stirred while boiling under reflux for 2 hours. The solution is cooled to room temperature to dissolve precipitated precipitated substance, adding N2Oh, and then the solution is purified on SPE cartridge-SCX (elution with methanol, then 2 N solution of ammonia in methanol), and obtain 38 mg of 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate ammonium. Use of 20 mg (0.04 mmol) of the obtained intermediate compound without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (0.01 ml, 1.1 EQ.) (see example 14). Then the reaction mixture is evaporated in vacuo, and the residue purified SCX. The free base (18 mg, of 0.038 mmol) dissolved in dry Meon (0.5 ml) and treated with HCl (0,083 ml of a 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound as a yellow solid (20 mg, 90%).1H-NMR (500 MHz, DMSO- 6) δ: 10,56 (users, 1H), total of 8.74 (d, 1H), 8,48 (users, 1H), at 8.36 (m, 2H), and 8.2 (m, 2H), 7,95 (t, 1H), and 7.8 (d, 1H), 7,68 (m, 2H), of 7.48 (d, 1H), 7,25 (d, 1H), 3,86 (m, 1H), 3,61 (m, 9H), 3,06 (t, 1H), 2,68 (s, 3H), the 1.44 (d, 3H).

Example 104. The dihydrochloride of N-methyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (E104)

A solution of trimethylaluminum (0,113 ml of 2.0 M solution in hexano, 0,226 mmol) and methylamine (0, 113 ml of 2.0 M solution in THF, 0,226 mmol) in dry DCM (0.5 ml) was stirred at room temperature for 15 minutes Add ethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (free base E55) (20.7 mg, 0,041 mmol)and continue stirring for 8 hours at 56º. Upon completion of the reaction at 0 ° C is added dropwise water, and then 1 M NaOH solution up until the organic and aqueous phases are not separated. The mixture is extracted with DCM (3×10 ml)and the combined organic phases are dried (Na2SO4) and then evaporated in vacuum. The residue is purified by chromatography with elution with 0.25% NH3(2 M in Meon) in DCM, and receive free ground mentioned in the title compound as a white solid (13 mg, 64%). The resulting material dissolved in a mixture of Meon:DCM (1:1, 0.5 ml) and treated with HCl (0,047 ml of a 1.25 M solution in Meon) at 0OC. The resulting suspension is stirred at room temperature techenie hours. Evaporation of volatiles and processing diethyl ether to give named the title compound as a yellow solid (13 mg).1H-NMR (500 MHz, DMSO-d6) δ: 10,8 (users, 1H), 9,25 (s, 1H), 8,55 (m, 1H), 8,46 (d, 1H), they were 8.22 (d, 1H), 8,12 (d, 1H), 7,82 (d, 1H), 7,72 (osirm, 3H), 7,58 (d, 1H), 7,51 (users, 1H), 7,27 (users, 1H), 3,94 (d, 1H), 3,83 (m, 1H), to 3.73 (m, 1H), 3,42 (m, 7H), is 3.08 (m, 1H), 2,81 (s, 3H), and 2.7 (s, 3H), of 1.45 (d, 3H).

Example 105. The dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(3-methyl-1,2,4-oxadiazol-5-yl)imidazo[1,5-a]quinoline (E105)

To a suspension of sodium hydride (2.1 mg of 60% suspension in oil, 0,054 mmol) in dry THF (1 ml) add the oxime methylcarbamate (4 mg, 0,054 mmol), and then after 10 minutes, add ethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (free base E55) (25 mg, 0,049 mmol). After 30 minutes, add DMF (0.2 ml) and the reaction mixture was stirred at room temperature overnight. The conversion of the original substance is not completed, so add NaH (4.2 mg, to 0.108 mmol) and the reaction methylcarbamate (8 mg, to 0.108 mmol) and the reaction mixture is stirred for another 3 hours. The reaction is quenched with water (5 ml) and the mixture extracted with ethyl acetate (3×5 ml). After drying and evaporation of organic solvents the crude substance is purified by chromatography with elution with 0.25% NH3(2 M in IU Is N) in DCM and receive free ground mentioned in the title compound as a white solid (11 mg). The resulting material dissolved in a mixture of Meon:DCM (1:1, 0.5 ml) and treated with HCl (0,038 ml of a 1.25 M solution in Meon) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound as a yellow solid (11 mg).1H NMR (500 MHz, DMSO-d6) δ ppm of 1.44 (d, 3H), 2,69 (s, 3H), is 3.08 (t, 1H), 3,19-to 3.49 (m, 5H), 3,52 (d, 2H), 3,61 (s, 3H), 3,69-with 3.79 (m, 1H), 3,79-3,88 (m, 1H), 3,95 (d, 1H), 7,26 (users, 1H), 7,49 (users, 1H), to 7.64 (d, 1H), to 7.67-7,74 (m, 2H,), of 7.82 (t, 1H), 8,08 (d, 1H), 8,14 (d, 1H), 8,49 (users, 1H), 8,55 (d, 1H), 9,43-9,51 (m, 1H), 10,75 (users, 1H).

Example 106. The dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (E)

A mixture of ethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (free base E55) (28 mg, by 0.055 mmol) and potassium hydroxide (0.33 ml of 1 M solution in Meon) is stirred at 80 ° C for 3 hours. After purification on SCX extract 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}imidazo[1,5-a]quinoline-3-carboxylate ammonium and used without further purification to obtain the free base named in the title compound following the General procedure p is taking amides, using hexamethyldisilazane (of 0.014 ml, 1.1 EQ.) (see example 14). Then the reaction mixture is evaporated in vacuo and the residue purified on SCX, and then on the SPE-Si elution with a mixture of 2% Meon in DCM. The free base (10 mg, 0,021 mmol) dissolved in a mixture of dry Meon:DCM (1:1, 0.5 ml) and treated with HCl (0.037 ml, 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.44 (d, 3H), 2,77 (users, 3H), 3.00 and-and 3.16 (m, 2H), 3,19-3,66 (m, 6H), 3,69-of 3.80 (m, 1H), 3,80-3,91 (m, 1H), 3,91-4,00 (m, 1H), 7,26 (users, 1H), 7,33 (users, 1H), of 7.48-the 7.65 (m, 3H), 7,80 (users, 2H), 7,71-7,79 (m, 1H), of 7.82 (d, 1H), 8,12 (d, 1H), 8,64 (users, 1H), of 8.47 (d, 1H), 9,15 was 9.33 (m, 1H), 10,71 (users, 1H).

Example 107. The dihydrochloride ethyl-1-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (A)

A mixture of ethyl-1-methyl-6-(2-oxoethyl)imidazo[1,5-a]quinoline-3-carboxylate (D106) (85 mg, 0.29 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (77 mg, 0.34 mmol) (WO 2004/046124) in 1,2-dichloroethane (5 ml) was stirred at room temperature for 30 minutes. Then add triacetoxyborohydride sodium (34 mg, 0.16 mmol)and the resulting reaction mixture is stirred overnight and then concentrated in vacuo. Untreated the military reaction product is purified on SPE cartridge-Si elution with a mixture of 2% Meon in DCM and receive free ground named the title compound (70 mg, 48%). Part of the obtained substance (10 mg) dissolved in dry Meon (0.3 ml) and treated with HCl (or 0.035 ml of a 1.25 M solution in ethanole) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give the named header connection E in the form of a white solid (10 mg, 91%).1H NMR (500 MHz, DMSO-d6) δ ppm of 1.36 (t, 3H), 2.06 to 2,17 (m, 2H), 2,16 is 2.33 (m, 2H), of 2.81 (s, 3H), of 3.07 (s, 3H), 3,24-to 3.34 (m, 2H), 3,32-to 3.41 (m, 2H), 3,56-to 3.67 (m, 2H), of 3.73-to 3.89 (m, 3H), 4,27-4,39 (m, 2H), 7,54-7,63 (m, 2H), 7,73 (t, 1H), to 7.77-7,94 (m, 2H), 7,93-of 8.00 (m, 1H), 7,99-8,07 (m, 2H), 8,43 (d, 1H), 8,91 (users, 1H), of 10.93 (users, 1H).

Example 108. The dihydrochloride of 1-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (E)

A mixture of ethyl-1-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (free base E) (55 mg, to 0.108 mmol) and potassium hydroxide (0,65 ml of 1 M solution in Meon) is stirred at 80 ° C for 3 hours. After purification by SPE-SCX extract 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxylate ammonium and used without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (0,097 ml, 1.2 EQ.) Then the reaction mixture UPA is more in vacuum and the residue purified on SCX, and then on the SPE-Si elution with mixtures of 2% Meon in DCM to 5% Meon in DCM (20 mg, 39%). The resulting substance was dissolved in dry Meon (0.5 ml) and treated with HCl (0.075 ml, 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound as a white solid (18 mg, 82%).1H NMR (500 MHz, DMSO-d6) δ ppm 2,05-to 2.18 (m, 2H), 2,20 of-2.32 (m, 2H), 2,84 (s, 3H), 3,06 (s, 3H), 3,24-3,51 (m, 4H), 3,53-to 3.64 (m, 2H), 3,70-3,90 (m, 3H), 7,14-7,25 (m, 1H), 7,43-7,52 (m, 1H), 7,54 (d, 1H), EUR 7.57-7,66 (m, 1H), 7,69 (t, 1H), 7,72-7,86 (m, 2H), 7,84-of 8.00 (m, 1H), 8,00-to 8.12 (m, 1H), 8,15 (d, 1H), scored 8.38 (d, 1H), 8,63-a 9.35 (m, 1H), 11,07 (users, 1H).

Example 109. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide (E)

Methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (free base E102) (100 mg, 0.42 mmol) is treated with 2.5 ml of a 7 M solution of NH3in Meon and enter into cooperation in the microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W) at 145º for 1 hour. In order to improve the conversion of the educt, add another 7 M solution of NH3in the Meon (2 ml) and the reaction mixture reacts in the microwave reactor at 145º for 1 hour. The crude product is evaporated in vacuum and then the residue purified by chromatography on when likehere, and get a certain amount named in the header of the reaction product with a low output. The reaction is repeated on the same scale and under the same conditions. The crude substance obtained in this second interaction, together with a containing an impurity fractions from the first interaction and purified by chromatography on silica gel with elution with mixtures of 2% Meon in DCM to 4% Meon in DCM, and receive free ground named the title compound (80 mg, 41%). The free base (77 mg, 0,166 mmol) dissolved in dry Meon (3 ml) and treated with HCl (0,292 ml of a 1.25 M solution in ethanol) at 0OC. The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound as a yellow solid (79 mg, 88.5 percent).1H NMR (400 MHz, DMSO-d6) δ ppm 2,1-2,2 (m, 4H), to 2.67 (s, 3H), 3,32 is 3.40 (m, 2H), 3,42-to 3.52 (m, 2H), 3,61 at 3.69 (m, 2H), 3,69-of 3.77 (m, 1H), 3,85 (d, 2H), 7,4-8,0 (m, 7H), to 8.34 (d, 1H), 8,7 (users, 1H), up 8.75 (d, 1H), 10,4 (users, 1H).

Example 110. Ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (E110)

A mixture of ethyl-7-methyl-6-(2-oxoethyl)imidazo[1,5-a]quinoline-3-carboxylate (D112) (75 mg, 0.25 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (WO 2004/046124) (67 mg, 0.30 mmol) in 1,2-dichloroethane (2.5 ml) was stirred at room temperature for 1 the Asa. Then add triacetoxyborohydride sodium (63 mg, 0.30 mmol) and after stirring at room temperature for 18 hours the reaction is quenched with water (10 ml), the mixture is extracted with ethyl acetate (3×15 ml) and then extracts concentrated in vacuo. The crude reaction product is purified on SPE cartridge-Si elution with a mixture of 5% Meon in DCM and get named in the title compound as a white solid (60 mg, 47%). MS (ES/+) m/z: 507,3 [MH+]. C32H35N4O2requires 506,65.

Example 111. The dihydrochloride of 7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (e)

A mixture of ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxylate (E110) (60 mg, 0.12 mmol) and potassium hydroxide (4 ml of 1 M solution in Meon) is stirred at 80 ° C for 2 hours. After purification on SCX extract 7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxylate ammonium and used without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (0.002 ml, 1.1 EQ.). Precipitated precipitated from the reaction mixture, the white solid is collected by filtration and treated with a mixture of CH3HE/CH2Cl2, 9/1, and p is to obtain 16 mg of the free base as a white solid, which is dissolved in dry CH3HE (0.5 ml) and treated with HCl (0,059 ml of a 1.25 M solution in ethanol). The resulting suspension is stirred at room temperature for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound as a white solid (13 mg, total yield 27%).1H NMR (500 MHz, DMSO-d6) δ ppm 10,23 (users, 1H), 9,17 (s, 1H), 8,55 (d, 1H), at 8.36 (d, 1H), 8,08 (d, 1H), to 7.84 (d, 1H), 7,78 (d, 1H), 7,72 (t, 1H), 7.62mm (d, 1H), EUR 7.57 (s, 1H), 7,49 (d, 1H), 7,45 (d, 1H), 7,22 (s, 1H), 3,18-3,39 (m, 4H), 3,17-3,95 (m, 5H), to 2.66 (s, 3H), by 2.55 (s, 3H), 2.00 in of 2.26 (m, 4H).

Example 112. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (e)

A mixture of ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (free base E) (89 mg, 0.18 mmol) and potassium hydroxide (4 ml of 1 M solution in Meon) was stirred at 90ºC for 2 hours. After purification on SCX extract 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate ammonium and used without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (0,042 ml of 1.10 EQ.) (see example 14). Precipitated precipitated from the reaction mixture of the free base is named in the title compound was separated by filtration from the reaction mixture and treated with diethyl ether. Then the free base (38 mg, 0,082 mmol, yield 45%) are suspended in dry DCM (2 ml) and treated with HCl (0,165 ml of a 1.25 M solution in methanol) at 0OC. The resulting suspension was stirred at 0OC for 2 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound (40 mg, 0,074 mmol) as a white solid. MS (ES) m/z: 468,2 [MH+]. C28H29N5O2requires 467,57.1H NMR (500 MHz, DMSO-d6) δ ppm 2,05-of 2.15 (m, 2H), 2,19-of 2.34 (m, 2H), 2.95 and (s, 3H), 3,15-up 3.22 (m, 2H), 3,24-of 3.32 (m, 2H), 3,30-3,37 (m, 2H), 3,70-with 3.79 (m, 1H), 3,79-to 3.89 (m, 1H), to 5.58 (s, 2H), 7,16 (t, 1H), 7,26 (d, 1H), was 7.36 (users, 1H), 7,54 (users, 1H), 7,74 (d, 1H), to 7.84 (d, 1H), to 7.99 (d, 1H), 8,04-8,13 (m, 1H), 8,28 (d, 1H), to 8.57 (s, 1H), 9,31 (users, 1H), 10,89 (users, 1H).

Example 113. The dihydrochloride of 3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazine (E)

To a suspension of sodium hydride (ceiling of 5.60 mg of 60% suspension in oil, 0.14 mmol) in dry THF (3,50 ml) add the oxime methylcarbamate (10,6 mg, 0.14 mmol), and then after 10 minutes, add ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (free base E) (66 mg, 0.13 mmol). After 10 minutes, add DMF (0,50 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified on SCX, and then on the SPE-Si elution what MESU 3% Meon in DCM, and receive free ground mentioned in the title compound as a white foam (13,8 mg, or 0.027 mmol, yield 19%). Then the free base is suspended in dry DCM (2 ml) and treated with HCl (0,054 ml of a 1.25 M solution in methanol) at 0OC. The resulting suspension was stirred at 0OC for 2 hours. Evaporation of volatiles and processing diethyl ether to give named the title compound (13 mg, of 0.022 mmol) as a white solid. MS (ES) m/z: 507,3 [MH+]. C30H30N6O2requires 506,61.1H NMR (500 MHz, DMSO-d6) δ ppm 2,04 and 2.13 (m, 2H), 2,13-of 2.28 (m, 2H), 2.40 a (s, 3H), and 2.79 (s, 3H), 3,13-of 3.25 (m, 2H), 3,22-3,47 (m, 4H), 3,66-of 3.85 (m, 3H), of 5.68 (s, 2H), 7,20 (m, 1H), 7,31 (d, 1H), 7,47-to 7.61 (m, 1H), to 7.61 for 7.78 (m, 1H), 7,78-7,89 (m, 1H), to $ 7.91 (d, 1H), 7,93-8,08 (m, 1H), cent to 8.85 (users, 1H), 8,80 (s, 1H), 10,53 (users, 1H).

Example 114. The dihydrochloride of 1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-yl)ethanone (E)

To a solution of N-methyl-N-(metiloksi)-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (I) (0.39 g, from 0.76 mmol) in anhydrous THF (5 ml) under cooling with ice and stirring, methylanisole (0,30 ml of 3 M solution in diethyl ether, 0.90 mmol) and the resulting solution was stirred for 1 hour at 0 ° C. The reaction mixture is poured into holodnuju 1 N hydrochloric acid (5 ml), then treated with a solution of NaHCO3/sub> (15 ml) and extracted with EtOAc (3×15 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and the residue purified by SPE-Si elution with a mixture of 3% methanol in DCM, and receive free ground named the title compound (175 mg, 0.38 mmol, yield 50%) as a white solid. Then the free base (to 19.8 mg, 0,042 mmol) suspended in dry DCM (2 ml) and treated with HCl (0,085 ml of a 1.25 M solution in methanol) at 0OC. The resulting suspension was stirred at 0OC for 1 hour. Evaporation of volatiles and processing diethyl ether to give named the title compound (17.5 mg, to 0.032 mmol) as a white solid. MS (ES) m/z: 467,3 [MH+]. C29H30N4O2requires 466,58.1H NMR (500 MHz, DMSO-d6) δ ppm 2,08 (d, 2H), 2,16-2,31 (m, 2H), 2,48 (s, 3H), 2,85 (s, 3H), 3,11-3,24 (m, 2H), 3,24-to 3.50 (m, 2H), 3.27 to the 3.35 (m, 2H), 3,63-a 3.87 (m, 3H), 5,59 (s, 2H), 7,16 (t, 1H), 7,28 (d, 1H), 7,50-the 7.65 (m, 1H), 7,72-to 7.84 (m, 1H), 7,86 (d, 1H), 7,88-to 7.99 (m, 1H), 8,01-8,17 (m, 1H), 8,63 (s, 1H), 8,72-9,24 (m, 1H), 10,78 (users, 1H).

Example 115. The dihydrochloride of 3-(3-methyl-5-isoxazolyl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazine (E115)

A mixture of (2Z)-3-(dimethylamino)-1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-yl)-2-butene-1-it (D113) (57 mg, 0.16 mmol) and hydroxylamine hydrochloride (16,68 mg, 0.24 mmol) in EtOH (1.50 ml) is heated under lane is mesheanii at 150 º C under the influence of microwave radiation for 5 minutes Precipitated precipitated substance is filtered off from the reaction mixture and washed with diethyl ether, and get named in the title compound (54 mg, 0.10 mmol, yield 65%) as a white solid. MS (ES) m/z: 506,3 [MH+]. C31H31N5O2requires 505,62.1H NMR (300 MHz, DMSO-d6) δ ppm 2,02-of 2.20 (m, 2H), 2,18-to 2.40 (m, 2H), 2,31 (s, 3H), 2,99 (s, 3H), 3,13-3,51 (m, 4H), 3,41-to 3.89 (m, 5H), 5,63 (s, 2H), 6,62 (s, 1H), 7,20 (m, 1H), 7,31 (d, 1H), of 7.75 (d, 1H), of 7.90 (d, 1H), 8,00 (d, 1H), 8,10 (t, 1H), 8,28 (d, 1H), 8,73 (s, 1H), 9,31 (d, 1H), 10,87 (users, 1H).

Example 116. The dihydrochloride of 3-(3-methyl-1H-pyrazole-5-yl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazine (E)

A mixture of (2Z)-3-(dimethylamino)-1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-yl)-2-butene-1-it (D113) (33 mg, holding 0.062 mmol) and hydrazine monohydrate (0.003 ml 0,096 mmol) in EtOH (1.5 ml) is heated with stirring at 150 º C under the influence of microwave radiation within 5 minutes. Precipitated precipitated free base named in the title compound is filtered off from the reaction mixture and treated with diethyl ether. Then the free base (29 mg, 0,058 mmol, yield 60%) was suspended in dry DCM (2 ml) and treated with HCl (0,116 ml of a 1.25 M solution in methanol) at 0OC. The resulting suspension was stirred at 0OC for 1 hour. Evaporation of volatiles and processing diethyl EF the rum give named the title compound (28 mg, 0,048 mmol) as a pale yellow solid. MS (ES) m/z: 505,3 [MH+]. C31H32N6O requires 504,63.1H NMR (300 MHz, DMSO-d6) δ ppm 2,01-of 2.36 (m, 4H), of 2.30 (s, 3H), of 2.92 (s, 3H), 3,12-4,01 (m, 9H), 5,62 (s, 2H), to 6.43 (s, 1H), 7,20 (m, 1H), 7,33 (d, 1H), to 7.61-to 7.77 (m, 1H), 7,80-of 7.96 (m, 2H), of 7.96-8,08 (m, 1H), 8.07-a by 8.22 (m, 1H), 8,96 (s, 1H), 9,04-9,24 (m, 1H), 10,52 (users, 1H).

Example 117. Hydrochloride ethyl-6-(2-{4-[2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-4-yl]-1-piperazinil}ethyl)imidazo[1,5-a]quinoline-3-carboxylate (A)

Named the title compound is obtained in yield of 20%, following the General procedure described in example 1 from ethyl-6-(2-oxoethyl)imidazo[1,5-a]quinoline-3-carboxylate (D91) (44 mg, 0.15 mmol) and 1-[2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-4-yl]-1-piperazine (D116) (55 mg, 0,19 mmol). MS (ES) m/z: 551,2 [MH+]. C31H30N6O4requires 550,62.1H NMR (500 MHz, DMSO-d6) δ ppm 1,37 (t, J=6,83 Hz, 3H), 2.63 in (s, 3H), 3,24-to 3.52 (m, 6H), of 3.60 (DD, 2H), 3,80 (d, J=a 10.74 Hz, 2H), 3,86 (d, J=12,69 Hz, 2H), 4,36 (kV, 2H), 6,92 (d, J=7,81 Hz, 1H), 7,37-7,47 (m, 2H), 7,58 (d, J=6,83 Hz, 1H), 7,79 (t, 1H), 8,01-of 8.04 (m, 3H), charged 8.52 (d, J=7,81 Hz, 1H), to 9.32 (s, 1H), br11.01 (users, 1H).

Example 118. Ethyl-6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A)

A mixture of ethyl-6-(2-oxoethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (D6) (83 mg, 0.28 mmol) and 7-fluoro-2-methyl-5-[(3R)-3-methyl-1-piperazinyl]quinoline (90 mg, 0.35 mmol) (obtained by the procedure similar to the procedure described in WO 2004/046124) in dry 1,2-dichloroethane (10 ml) was stirred at room temperature under nitrogen atmosphere for 40 minutes. Then add triacetoxyborohydride sodium (74 mg, 0.35 mmol), the reaction mixture is stirred for 3 hours, the reaction is quenched with saturated aqueous NaHCO3(10 ml) and the mixture extracted with DCM (3×10 ml). The organic layers are combined, dried (Na2SO4) and concentrated in vacuo. The crude reaction product is purified column chromatography on silica with elution with a mixture of 1% methanol in DCM, and get named in the title compound as a white foam (63 mg, 34%). MS (ES) m/z: 530,1 [MH+]. C30H32FN5O3requires 529,61.1H-NMR (500 MHz, CDCl3) δ: a 8.34 (d, 1H), 8,03 (s, 1H), 7,76 (d, 1H), and 7.4 (d, 1H), and 7.3 (m, 1H), 7,2 (d, 1H), and 7.1 (m, 2H), 5,59 (s, 2H), 4,45 (quart, 2H), 3,-2,7 (osirm, 11H), 2,77 (s, 3H), of 1.46 (t, 3H), 1,2 (m, 3H).

Example 119. The dihydrochloride 6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E119)

Named the title compound is obtained in yield of 45% according to the General procedure for obtaining amides (see example 14), starting from 6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (A) (38 mg, 0.07 mmol) is hexamethyldisilazane (1.1 EQ.). MS (ES) m/z: 501,5 [MH+]. C28H29N6O2requires 500,58.1H-NMR (500 MHz, DMSO-d6) δ: 11,20 (users, 1H), and 9.1 (d, 1H), 8,58 (s, 1H), 8,16 (m, 1H), 8,11 (d, 1H), 7,92 (d, 1H), 78,4 (d, 1H), 7.5 (d, 1H), and 7.3 (d, 1H), 7,15 (t, 1H), 5,62 (s, 2H), 4,0 and 2.9 (m, 11N), to 2.99 (s, 3H), 2,74 (d, 3H).

Example 120. The dihydrochloride of 2-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-2,4-dihydro-1H-[1,2,4]triazolo[3,4-C][1,4]benzoxazin-1-it (E120)

Named the title compound is obtained in yield 61%, following the General procedure for the amination of example 1 from (2-methyl-1-oxo-2,4-dihydro-1H-[1,2,4]triazolo[3,4-C][1,4]benzoxazin-6-yl)acetaldehyde (D120) (64 mg, 0,261 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-2%), and receive free ground named the title compound (72 mg, 61%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 4 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 457,00 [MH+]. C26H28N6O2requires 456,55.1H NMR (500 MHz, DMSO-d6) δ ppm 2,69 (s, 3H), 3,11-3,17 (m, 2H), up 3.22 (t, 2H), 3,26-3,39 (m, 4H), 3,40 (s, 3H), 3,41 of 3.54 (m, 2H), 3,66 is 3.76 (m, 2H), 5,24 (s, 2H), 7,08-7,34 (m, 3H), 7,37-7,58 (m, 1H), 7,58-to 7.84 (m, 2H), of 8.06 (d, 1H), compared to 8.26-8,61 (m, 1H), 10,45 (users, 1H).

Example 121. The dihydrochloride of 1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-yl)ethanone (the 121)

Named in the title compound, receive, following the procedure of example 35, using methylacrylamide (of 0.081 ml of 3 M solution in diethyl ether, 0,243 mmol) and N-methyl-N-(metiloksi)-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (I) (105 mg, 0,206 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-5%), and receive free ground named the title compound (24 mg, 25%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 2 ml) at 0 ° C gives named the title compound as a white solid. MS (ES) m/z: 465,00 [MH+]. C30H32N4O requires 464,61.1H NMR (500 MHz, DMSO-d6) δ ppm 2,05-of 2.23 (m, 4H), to 2.46 (s, 3H), 2,77 (s, 3H), of 3.00 (t, 2H), 3,07-3,61 (m, 6H), of 3.28 (t, 2H), 3,66-a 3.83 (m, 3H), 7,29 (d, 1H), 7,41 (t, 1H), 7,47-to 7.59 (m, 1H), 7,60-7,76 (m, 1H), 7,80 (d, 1H), 7,82-of 7.90 (m, 1H), of 7.90-8,03 (m, 1H), 8,53 (s, 1H), 8,66-8,99 (m, 1H), accounted for 10.39 (users, 1H).

Example 122. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (e)

A mixture of free base ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A) (32 mg, 0,065 mmol) and potassium hydroxide (5 ml of 1 M solution in Meon) is stirred while boiling with skim milk is the first refrigerator for 2.5 hours. After purification on SCX extract 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylic acid (0,065 mmol) and used without further purification according to the General procedure for obtaining amides using hexamethyldisilazane (of 0.015 ml, 0,071 mmol) (see example 14). Precipitated precipitated free base is filtered off and treated with ethyl ether (12 mg, 40%) and then treated with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 2 ml) at 0OC, and get named in the title compound as a white solid. MS (ES) m/z: 466,00 [MH+]. C29H31N5O requires 465,60.1H NMR (500 MHz, DMSO-d6) δ ppm 2,08-of 2.24 (m, 4H), 2,75 (users, 3H), 2,99 (t, 2H), 3,18-to 3.49 (m, 8H), 3,71-of 3.77 (m, 1H), 3,78 (d, 2H), 7,15 (users, 1H), 7,27 (d, 1H), was 7.36 (users, 1H), 7,40 (t, 1H), 7,51 (users, 1H), 7.62mm (users, 1H), 7,78 (d, 1H), 7,81 (users, 1H), 7,93 (users, 1H), of 8.47 (s, 1H), 8,72 (users, 1H), 10,38 (users, 1H).

Example 123. The dihydrochloride ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A)

Named in the title compound, receive, following the procedure of example 80, from 7-methyl-8-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-she (D121) (173 mg, 0,417 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DC (1-3%), and receive free ground named the title compound (87 mg, 41%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 2 ml) at 0 ° C gives named the title compound as a white solid. MS (ES) m/z: 511,00 [MH+]. C31H34N4O3requires 510,63.1H NMR (400 MHz, DMSO-d6) δ ppm of 1.31 (t, 3H), 2,03-of 2.24 (m, 4H), 2.40 a (s, 3H), 2,69 (s, 3H), 3,03-of 3.25 (m, 4H), 3.25 to 3,51 (m, 2H), 3,64-of 3.77 (m, 1H), 3,80 (d, J=11,35 Hz, 2H), 4,27 (kV, 2H), to 5.57 (s, 2H), 7,06 (d, J=8,42 Hz, 1H), 7,49 (users, 1H), to 7.61 (users, 1H), 7,76 (d, J=of 8.06 Hz, 1H), 7,81 (users, 1H), of 7.90 (users, 1H), 8,58 (s, 1H), 8,80 (users, 1H), 10,17 (users, 1H).

Example 124. The dihydrochloride of N,7-dimethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E124)

Named in the title compound, receive, following the procedure of example 38, using trimethylaluminum (2.0 M solution in hexano, 392 μl, 0,784 mmol), methylamine (2.0 M solution in THF, 392 μl, 0,784 mmol) and the free base ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A) (40 mg, 0,078 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-3%), and receive free ground named the title compound (25 mg, 64%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (11, 2 ml) at 0 ° C gives named the title compound as a white solid. MS (ES) m/z: 496,00 [MH+]. C30H33N5O2requires 495,62.1H NMR (400 MHz, DMSO-d6) δ ppm 2,10-to 2.18 (m, 4H), 2.40 a (s, 3H), 2,71 (s, 3H), was 2.76 (d, 3H), 3,11-3,24 (m, 2H), 3,24-3,62 (m, 4H), 3,67 of 3.75 (m, 1H), 3,81 (d, 2H), ceiling of 5.60 (s, 2H), 7,05 (d, 1H), 7,47 (users, 1H), 7,58 (users, 1H), 7,72 (d, 1H), of 7.75-to 7.84 (m, 1H), 7,83-7,98 (m, 1H), 8,13 (kV, 1H), 8,55 (s, 1H), 8,68 (users, 1H), of 10.21 (users, 1H).

Example 125. The dihydrochloride of 7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E)

A mixture of free base ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxylate (A) (36 mg, 0,071 mmol) and potassium hydroxide (4 ml of 1 M solution in Meon) stirred at the boil under reflux for 2 hours. After purification on SCX extract 7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (24 mg, 0,050 mmol, 71%) and used without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (0,023 ml, to 0.108 mmol). Phase precipitates during the reaction of the free base named in the title compound is filtered off and treated with ethyl ether is m (10.3 mg, 26%). Then the free base is treated with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 2 ml) at 0OC, and get named in the title compound as a white solid. MS (ES) m/z: 482,00 [MH+]. C29H31N5O2requires 481,60.1H NMR (500 MHz, DMSO-d6) δ ppm 2,07-to 2.18 (m, 4H), of 2.38 (s, 3H), by 2.73 (s, 3H), 3,10-3,24 (m, 4H), 3,24-to 3.52 (m, 2H), 3,69-of 3.77 (m, 1H), 3,80 (d, 2H), to 5.57 (s, 2H), 7,03 (d, 1H), 7,31 (s, 1H), 7,45-7,56 (m, 2H), 7,60 (users, 1H), 7,73 (d, J=8,18 Hz, 1H), 7,79 (users, 1H), to $ 7.91 (users, 1H), charged 8.52 (s, 1H), 8,69 (users, 1H), there is a 10.03 (users, 1H).

Example 126. The dihydrochloride ethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A)

Named the title compound is obtained in yield 72%, following the General procedure of reductive amination of example 1 from ethyl-6-(2-oxoethyl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D86) (103 mg, 0,363 mmol) and 2-methyl-5[(3R)-3-methyl-1-piperazinil]quinoline (131 mg, 0,544 mmol) (WO 2004/046124). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-3%), and receive free ground named the title compound (134 mg, 72%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 2 ml) at 0 ° C gives named the title compound as a yellow solid. MS (ES) m/z: 510,10 [MH+]. C 31H35N5O2requires 509,65.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.30 (t, 3H), USD 1.43 (s, 3H), 2,74 (s, 3H), 3,03 (t, 2H), 3,17-3,91 (m, 6H), 3,20-3,37 (m, 2H), 3,26 (t, 2H), 3,40 of 3.56 (m, 2H), 3,85 (d, 1H), 4.26 deaths (kV, 2H), 7.23 percent-7,30 (m, 1H), 7,32 (d, 1H), 7,40 (t, 1H), 7,46-the 7.65 (m, 1H), 7,69 for 7.78 (m, 2H), 7,80 (d, 1H), charged 8.52 (s, 1H), 8,53-8,69 (m, 1H), 10,94 (users, 1H).

Example 127. The dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (E127)

A mixture of free base ethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (E) (122 mg, 0.24 mmol) and potassium hydroxide (5 ml of 1 M solution in Meon) is stirred while boiling under reflux for 4 hours. After purification on SCX extract 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylic acid (114 mg, 0.24 mmol, 100%) and used without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (by 0.055 ml, 0,261 mmol) (see example 14). Phase precipitates during the reaction of the free base named in the title compound is filtered off and treated with ethyl ether (89 mg, 78%). Then the free base is treated with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DM (1:1, 4 ml) at 0OC, and get named in the title compound as a yellow solid. MS (ES) m/z: 481,30 [MH+]. C29H32N6O requires 480,61.1H NMR (500 MHz, DMSO-d6), δ ppm was 1.43 (s, 3H), 2,70 (s, 3H), 2,99 (t, 2H), 3,16-3,82 (m, 6H), of 3.27 (t, 2H), 3,26-to 3.36 (m, 2H), 3.43 points-of 3.53 (m, 2H), 3,86 (d, 1H), 7,14 (s, 1H), 7,20-7,27 (m, 1H), 7,30 (d, 1H), 7,35 (s, 1H), 7,40 (t, 1H), 7,43-7,56 (m, 1H), the 7.65 to 7.75 (m, 2H), 7,78 (d, 1H), 8,46 (s, 1H), 8,46 at 8.60 (m, 1H), 10,41 (users, 1H).

Example 128. The dihydrochloride ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A)

Named the title compound is obtained in yield 62%, following the General procedure of reductive amination of example 1 from ethyl-7-methyl-6-(2-oxoethyl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D125) (110 mg, 0,369 mmol) and 2-methyl-5-(1-piperazinil)quinoline (101 mg, 0,443 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of methanol in DCM (2%) and receive free ground named the title compound (117 mg, 62%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol (1 ml) at 0 ° C gives named the title compound as a yellow solid. MS (ES) m/z: 510,10 [MH+]. C31H35N5O2requires 509,65.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.31 (t, 3H), 2,41 is 2.46 (m, 3H), 2,78 (users, 3H), 2,99-to 3.09 (m, 2H), 3,21-of 3.43 (m, 8H), 3,44-3,61 (m, 4H), of 3.80 (d, 2H), 4,25 (kV, 2H), 7,28 (d, 1H), 7,35 (users, 1H), 7,58 (users, 1H), of 7.70 (d, 1H), 7,84 (users, 2H), of 8.47 are 8.53 (m, 1H), 8,68 (users, 1H), 10,89 (users, 1H).

Example 129. The dihydrochloride ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (E129)

Named the title compound is obtained in yield of 88%, following the General procedure of reductive amination of example 1 from ethyl-7-methyl-6-(2-oxoethyl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D125) (110 mg, 0,369 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (100 mg, 0,443 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of methanol in DCM (2%) and receive free ground named the title compound (166 mg, 88%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol (1 ml) at 0 ° C gives named the title compound as a white solid. MS (ES) m/z: 509,10 [MH+]. C32H36N4O2requires 508,66.1H NMR (500 MHz, DMSO-d6), δ ppm of 1.30 (t, 3H), 2,03-to 2.29 (m, 4H), 2,39 is 2.46 (m, 3H), 2,81 (users, 3H), 2,97-to 3.09 (m, 2H), 3,11-of 3.54 (m, 8H), 3,69-of 3.78 (m, 1H), 3,80-to 3.92 (m, 2H), 4.26 deaths (kV, 2H), 7,27 (d, 1H), 7,46-8,10 (m, 4H), of 7.70 (d, 1H), of 8.47-8,54 (m, 1H), 8,95 (users, 1H), 10,65 (users, 1H).

Example 130. The dihydrochloride ethyl-7-methyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A)

Named the title compound is obtained in yield 89%, following the General procedure of reductive amination of example 1 from ethyl-7-methyl-6-(2-oxoethyl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D125) (110 mg, 0,369 mmol) and 2-methyl-5-[(3R)-3-methyl-1-piperazinil]quinoline (107 mg, 0,443 mmol) (WO 2004/046124). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%), and receive free ground named the title compound (172 mg, 89%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol (1 ml) at 0 ° C gives named the title compound as a yellow solid. MS (ES) m/z: 524,10 [MH+]. C32H37N5O2requires 523,68.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.31 (t, 3H), of 1.45 (d, 3H), 2,41 is 2.46 (m, 3H), 2,80 (users, 3H), 2,97-of 3.12 (m, 2H), 3,19-3,44 (m, 8H), 3,47-of 3.60 (m, 2H), 3,68-of 3.85 (m, 2H), a 3.87-to 3.99 (m, 1H), 4,25 (kV, 2H), 7,26-7,30 (m, 1H), was 7.36 (users, 1H), to 7.61 (users, 1H), 7.68 per-7,73 (m, 1H), 7,86 (users, 2H), 8,46-8,54 (m, 1H), 8,76 (users, 1H), 10,99 (users, 1H).

Example 131. The dihydrochloride of N,7-dimethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (E131)

Named in the title compound, receive, following the procedure of example 38, using free base ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-CT is oxylate (E) (50 mg, 0,098 mmol). The crude reaction product is purified on a SCX cartridge and receive free ground named the title compound (30 mg, 61%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) at 0 ° C gives named the title compound as a yellow solid. MS (ES) m/z: 495,10 [MH+]. C30H34N6O requires 494,64.1H NMR (400 MHz, DMSO-d6) δ ppm of 2.44 (s, 3H), of 2.72 (s, 3H), was 2.76 (d, 3H), to 3.02 (t, 2H), 3,17-3,44 (m, 8H), 3,45-3,63 (m, 4H), 3,74-3,90 (m, 2H), 7,21-7,33 (m, 2H), 7,54 (users, 1H), 7,68 (d, 1H), 7,71-7,80 (m, 2H), 7,93-8,02 (m, 1H), 8,45 (s, 1H), 8,53 (users, 1H), 11,12 (users, 1H).

Example 132. The dihydrochloride of N,7-dimethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (e)

Named in the title compound, receive, following the procedure of example 38, using free base ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (E129) (60 mg, 0.118 the mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-2%), and receive free ground named the title compound (40 mg, 69%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) at 0 ° C gives named the title compound as a white solid. MS (ES) m/z: 494,10 [MH+]. C31 H35N5O requires 493,65.1H NMR (400 MHz, DMSO-d6) δ ppm 2,07-of 2.20 (m, 2H), 2,18-of 2.36 (m, 2H), 2,43 (s, 3H), was 2.76 (d, 3H), was 2.76 (s, 3H), to 3.02 (t, 2H), 3,11-to 3.52 (m, 8H), 3,66-with 3.79 (m, 1H), of 3.77-3,91 (m, 2H), 7,25 (d, 1H), 7,45-to 7.59 (m, 1H), to 7.59-7,74 (m, 2H), 7,76-7,89 (m, 1H), 7,92-with 8.05 (m, 2H), 8,39-8,49 (m, 1H), 8,78 (users, 1H), 11,02 (users, 1H).

Example 133. The dihydrochloride of N,7-dimethyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (E133)

Named in the title compound, receive, following the procedure of example 38, using free base ethyl-7-methyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A) (70 mg, 0,134 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (1-2%) and receive free ground named the title compound (55 mg, 79%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) at 0 ° C gives named the title compound as a yellow solid. MS (ES) m/z: 509,10 [MH+]. C31H36N6O requires 508,67.1H NMR (400 MHz, DMSO-d6) δ ppm for 1.49 (d, 3H), of 2.45 (s, 3H), was 2.76 (s, 3H), and 2.79 (s, 3H), 2,96-3,10 (m, 2H), 3,13 is 3.57 (m, 12H), 3,67-3,86 (m, 1H), 7,26 (d, 1H), 7,29-7,38 (m, 1H), EUR 7.57-7,66 (m, 1H), 7,69 (d, 1H), 7,75-7,89 (m, 2H), 7,92-8,02 (m, 1H), 8,45 (s, 1H), 8,70 (users, 1H), 11,64 (users,1H).

Example 134. The dihydrochloride of 7-methyl-6-{2[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (E)

A mixture of free base ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A) (57 mg, 0,112 mmol) and potassium hydroxide (4 ml of 1 M solution in Meon) is stirred while boiling under reflux for 4 hours. After purification on SCX extract 7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylic acid (54 mg, 0,112 mmol, 100%) and used without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (0,031 ml, 0,146 mmol). Precipitated precipitated free base is filtered off and treated with ethyl ether (24 mg, 50%). Then the free base is treated with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) at 0OC and get named in the title compound as a yellow solid. MS (ES) m/z: 481,30 [MH+]. C29H32N6O requires 480,61.1H NMR (300 MHz, DMSO-d6) δ ppm to 2.42 (s, 3H), 2,71 (s, 3H), 2,99 (t, 2H), 3,10-of 3.60 (m, 12H), 3,74-3,90 (m, 2H), 7,01 (s, 1H), 7,24 (d, 1H), 7.24 to 7,33 (m, 2H), 7,54 (users, 1H), 7,66 (d, 1H), 7,71-7,80 (osirm, 2H), to 8.41 (s, 1H), 8,53 (users, 1H), 10,71 (users, 1H).

Example 135. The dihydrochloride of 7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (Prov. 135)

A mixture of free base ethyl-7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (E129) (96 mg, 0,189 mmol) and potassium hydroxide (4 ml of 1 M solution in Meon) is stirred while boiling under reflux for 4 hours. After purification on SCX extract 7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylic acid (91 mg, 0,189 mmol, 100%) and used without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (0,052 ml, 0,246 mmol). Precipitated precipitated free base named in the title compound is filtered off and treated with diethyl ether (46 mg, 50%). Then the free base is treated with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) at 0OC, and get named in the title compound as a white solid. MS (ES) m/z: 480,30 [MH+]. C30H33N5O requires 479,62.1H NMR (400 MHz, DMSO-d6) δ ppm 2,10-to 2.29 (m, 4H), of 2.44 (s, 3H), was 2.76 (s, 3H), 3,01 (t, 2H), 3,13-to 3.52 (m, 8H), 3,68-with 3.79 (m, 1H), 3,80-3,90 (m, 2H), 7,14 (s, 1H), 7,28 (d, 1H), 7,35 (s, 1H), 7,54 (osirm, 1H), to 7.59-7.68 per (osirm, 1H), 7,69 (d, 1H), 7,84 (osirm, 1H), 7,98 (osirm, 1H), 8,44 (s, 1H), 8,75 (users, 1H), 10,59 (users, 1H).

Example 136. The dihydrochloride of 7-methyl-6-{2-[(2R)-2-ethyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (E)

A mixture of ethyl-7-methyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (free base E) (92 mg, 0,176 mmol) and potassium hydroxide (4 ml of 1 M solution in Meon) is stirred while boiling under reflux for 4 hours. After purification on SCX extract 7-methyl-6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylic acid (87 mg, 0,176 mmol, 100%) and used without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (0,048 ml, 0,228 mmol) (see example 14). Precipitated precipitated free base named in the title compound is filtered off and treated with ethyl ether (26 mg, 30%). Then the free base is treated with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) at 0OC and get named in the title compound as a yellow solid. MS (ES) m/z: 495,30 [MH+]. C30H34N6O requires 494,64.1H NMR (400 MHz, DMSO-d6) δ ppm of 1.47 (d, 3H), of 2.45 (s, 3H), of 2.75 (s, 3H), 3,03 (t, 2H), 3,13 is 3.57 (m, 12H), 3,67-3,86 (m, 1H), 7,14 (s, 1H), 7,26 and 7.36 (m, 3H), EUR 7.57 (osirm, 1H), of 7.70 (d, 1H), to 7.77 (s, 1H), 8,45 (s, 1H), 8,62 (users, 1H), 10,89 (users, 1H).

Example 137. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazine is]ethyl}-4H-tetrazolo[5,1-C][1,4]benzoxazine (E)

Named the title compound is obtained in yield of 77%, following the General procedure of reductive amination of example 1, based on 4H-tetrazolo[5,1-C][1,4]benzoxazin-6-ylacetamide (D129) (47 mg, 0,218 mmol) and 2-methyl-5-(1-piperazinil)quinoline (74 mg, 0,326 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of methanol in DCM (2%) and receive free ground named the title compound (72 mg, 77%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) at 0 ° C gives named the title compound as a yellow solid. MS (ES) m/z: 428,00 [MH+]. C24H25N7O requires 427,51.1H NMR (500 MHz, DMSO-d6) δ ppm of 2.72 (s, 3H), 3,18 of 3.56 (m, 10H), 3,66-of 3.78 (m, 2H), of 5.84-5,97 (m, 2H), 7,22-to 7.32 (m, 2H), 7,43 (d, 1H), 7,47-7,63 (m, 1H), to 7.67-7,83 (m, 2H), 7,89 (DD, 1H), at 8.36 is 8.75 (m, 1H), 11,24 (users, 1H).

Example 138. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-tetrazolo[5,1-C][1,4]benzoxazine (E)

Named the title compound is obtained in yield 86%, following the General procedure of reductive amination of example 1, based on 4H-tetrazolo[5,1-C][1,4]benzoxazin-6-ylacetamide (D129) (50 mg, 0,231 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (78 mg, 0,347 mmol). The crude reaction product is purified flash chromatography on silica gel what elution with a gradient of methanol in DCM (2-3%) and receive free ground named the title compound (86 mg, 86%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (3:1, 4 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 427,10 [MH+]. C25H26N6O requires 426,52.1H NMR (500 MHz, DMSO-d6) δ ppm 2,02-of 2.24 (m, 4H), 2,71 (s, 3H), 3.15 and is 3.25 (m, 2H), 3,23-to 3.41 (m, 4H), 3,65-3,82 (m, 3H), 5,91 (s, 2H), 7,27 (t, 1H), 7,37-7,49 (m, 2H), 7,49-7,63 (m, 1H), 7.68 per-of 7.82 (m, 1H), 7,83-to 7.95 (m, 2H), 8,44-8,83 (m, 1H), 10,32 (users, 1H).

Example 139. The dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-tetrazolo[5,1-C][1,4]benzoxazine (E)

Named the title compound is obtained in yield of 77%, following the General procedure of reductive amination of example 1, based on 4H-tetrazolo[5,1-C][1,4]benzoxazin-6-ylacetamide (D129) (47 mg, 0,217 mmol) and 2-methyl-5-[(3R)-3-methyl-1-piperazinil]quinoline (79 mg, 0,326 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of methanol in DCM (2%) and receive free ground named the title compound (74 mg, 77%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) at 0 ° C gives named the title compound as a yellow solid. MS (ES) m/z: 442,00 [MH+]. C25H27N7O requires 441,54.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.45 (d, 3H), 2,70 (s, 3H), is 3.08-3,86 (m, 11H), 5,91 (s, 2H), 7,17-to 7.32 (m, 2H), 7,39-7,58 (m, 2H), 7,63-7,81 (m, 2H), 7,88 (d, 1H), 8,2-8,71 (m, 1H), 11,47 (users, 1H).

Example 140. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydrotetrazolo[1,5-a]quinoline (E)

Named the title compound is obtained in yield 82%, following the General procedure of reductive amination of example 1, based on 4,5-dihydrotetrazolo[1,5-a]quinoline-6-ylacetamide (D130) (41 mg, 0,192 mmol) and 2-methyl-5-(1-piperazinil)quinoline (65 mg, 0,287 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%) and receive free ground named the title compound (67 mg, 82%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) at 0 ° C gives named the title compound as a yellow solid. MS (ES) m/z: 426,10 [MH+]. C25H27N7requires 425,54.1H NMR (500 MHz, DMSO-d6) δ ppm of 2.72 (s, 3H), 3,19-of 3.43 (m, 10H), 3,42-to 3.58 (m, 4H), 3,67-3,82 (m, 2H), 7,21-7,31 (m, 1H), 7,41 (d, 1H), 7,45-to 7.59 (m, 1H), 7,51 (t, 1H), to 7.67-of 7.82 (m, 2H), 7,88 (d, 1H), of 8.37-to 8.70 (m, 1H), of 11.69 (users, 1H).

Example 141. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydrotetrazolo[1,5-a]quinoline (e)

Named the title compound is obtained in yield 86%, following the General procedure of reductive amination of example 1, based on 4,5-dihydrotetrazolo[1,5-a]quinoline-6-ylacetamide the guide (D130) (50 mg, 0,234 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (79 mg, 0,350 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%), and receive free ground named the title compound (86 mg, 86%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (3:1, 4 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 425,10 [MH+]. C26H28N6requires 424,55.1H NMR (500 MHz, DMSO-d6) δ ppm 2,02-of 2.27 (m, 4H), of 2.72 (s, 3H), 3,17-of 3.46 (m, 10H), 3,64-of 3.85 (m, 3H), 7,43 (d, 1H), 7,44-7,49 (m, 1H), 7,51 (t, 1H), 7,53-7,63 (m, 1H), 7,71-to 7.84 (m, 1H), 7,84-7,94 (m, 2H), 8,31-8,91 (m, 1H), 10,56 (users, 1H).

Example 142. The dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydrotetrazolo[1,5-a]quinoline (E)

Named in the title compound are obtained from the output 90%, following the General procedure of reductive amination of example 1, based on 4,5-dihydrotetrazolo[1,5-a]quinoline-6-ylacetamide (D130) (41 mg, 0,192 mmol) and 2-methyl-5-[(3R)-3-methyl-1-piperazinil)quinoline (69 mg, 0,287 mmol) (WO 2004/046124). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%), and receive free ground named the title compound (76 mg, 90%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) 0º network named the title compound as a yellow solid. MS (ES) m/z: 440,10 [MH+]. C26H29N7requires 439,56.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.46 (d, 3H), 2,71 (s, 3H), 3,10-of 3.60 (m, 12H), 3,60-to 3.73 (m, 1H), of 3.73-3,81 (m, 1H), 3,81-to 3.89 (m, 1H), 7,20-7,35 (m, 1H), 7,46 (d, 1H), 7,51 (t, 1H), 7,53 to 7.62 (m, 1H), 7.68 per-7,83 (m, 2H), of 7.90 (d, 1H), to 8.41-8,77 (m, 1H), 11,53 (users, 1H).

Example 143. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-[1,2,3]triazolo[5,1-C][1,4]benzoxazin-3-carboxylate (A)

Named the title compound is obtained in yield of 88%, following the General procedure of reductive amination of example 1 from ethyl-6-(2-oxoethyl)-4H-[1,2,3]triazolo[5,1-C][1,4]benzoxazin-3-carboxylate (D136) (96 mg, 0.33 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (113 mg, 0.50 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%), and receive free ground named the title compound (144 mg, 88%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 2 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 498,30 [MH+]. C29H31N5O3requires 497,60.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.34 (t, 3H), 2,03 and 2.13 (m, 2H), 2,12-of 2.28 (m, 2H), 2,75 (s, 3H), 3,16 is 3.23 (m, 2H), 3,23-of 3.48 (m, 4H), 3,66-3,82 (m, 3H), 4,35 (kV, 2H), 5,78 (s, 2H), 7,24 (t, 1H), 7,42 (d, 1H), 7,45-of 7.55 (m, 1H), 7,54-7,72 (m, 1H), 7,73-7,87 (m, 1H), 7,87-of 7.97 (m, 1H), to 7.99 (DD, 1H), 8,43-remaining 9.08 (m, 1H), 10,49 (users, 1H).

Example 144. The dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-[1,2,3]triazolo[5,1-C][1,4]benzoxazin-3-carboxamide (E)

Named in the title compound, receive, following the procedure of example 38, using free base ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-[1,2,3]triazolo[5,1-C][1,4]benzoxazin-3-carboxylate (A) (44 mg, 0,089 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%) and receive free ground named the title compound (34 mg, 79%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (2:1, 3 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 509,10 [MH+]. C28H30N6O2requires 482,58.1H NMR (400 MHz, DMSO-d6) δ ppm 1,98-of 2.15 (m, 4H), to 2.67 (s, 3H), was 2.76 (d, 3H), is 3.08-3,18 (m, 2H), 3,18-to 3.38 (m, 4H), to 3.58-of 3.78 (m, 3H), 5,74 (s, 2H), 7,20 (m, 1H), 7,35 (d, 1H), 7,39-7,46 (m, 1H), 7,45 to 7.62 (m, 1H), 7,66 for 7.78 (m, 1H), 7,78-7,89 (m, 1H), to 7.93 (d, 1H), 8,51-8,67 (m, 1H), 8,71 (d, 1H), of 10.05 (users, 1H).

Example 145. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-[1,2,3]triazolo[5,1-C][1,4]benzoxazin-3-carboxamide (E)

A mixture of ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-[1,2,3]triazolo[5,1-C][1,4]benzoxazin-3-carboxylate (free base E) (90 mg, 0,181 mmol) and guide the oxide lithium (30 mg, 0,724 mmol) in a mixture of THF/N2On (3/1, 8 ml) was stirred at room temperature for 2 hours. After purification on SCX extract 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-[1,2,3]triazolo[5,1-C][1,4]benzoxazin-3-carboxylic acid (80 mg, 0,171 mmol, 94%) and used without further purification to obtain the free base named in the title compound following the General procedure for obtaining amides, using hexamethyldisilazane (0,040 ml, 0,188 mmol). Precipitated precipitated free base is filtered off and treated with ethyl ether (31 mg, 39%) and then treated with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 4 ml) at 0OC, and get named in the title compound as a white solid. MS (ES) m/z: 469,00 [MH+]. C27H28N6O2requires 468,56.1H NMR (500 MHz, DMSO-d6) δ ppm 2,03-of 2.15 (m, 2H), 2,14-2,31 (m, 2H), 2,78 (s, 3H), 3,03-3,59 (m, 6H), 3,65-3,86 (m, 3H), 5,77 (s, 2H), 7,21 (t, 1H), 7,40 (d, 1H), 7,47-7,58 (m, 1H), 7,58-7,72 (m, 1H), 7,74 (s, 1H), 7,78-to $ 7.91 (m, 1H), to $ 7.91-8,07 (m, 1H), of 7.96 (d, 1H), 8,15 (s, 1H), 8,56-remaining 9.08 (m, 1H), at 10.64 (users, 1H).

Example 146. The dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (A)

Named the title compound is obtained in yield 92%, following the General procedure of reductive amination of example 1 from ethyl-6-(2-octoate is)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D137) (71 mg, 0,249 mmol) and 2-methyl-5-(4-piperidinyl)quinoline (84 mg, 0,374 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%) and receive free ground named the title compound (113 mg, 92%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 2 ml) at 0 ° C gives named in the title compound in the form of solids. MS (ES) m/z: 496,10 [MH+]. C30H33N5O2requires 495,62.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.35 (t, 3H), 2,04-to 2.29 (m, 4H), to 2.75 (s, 3H), 3,14 (t, 2H), 3,21-to 3.49 (m, 8H), 3,68-a-3.84 (m, 3H), 4,36 (kV, 2H), 7,42 (d, 1H), 7,45-of 7.55 (m, 1H), 7,49 (t, 1H), 7,55-of 7.69 (m, 1H), 7,74-7,87 (m, 1H), 7,87-to 7.99 (m, 1H), 8,01 (d, 1H), 8,45-9,05 (m, 1H), 10,55 (users, 1H).

Example 147. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide (E)

A mixture of ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (free base E) (103 mg, 0,208 mmol) and lithium hydroxide (35 mg, 0,832 mmol) in a mixture of THF/N2On (3/1, 8 ml) was stirred at room temperature for 5 hours. After purification on SCX extract 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylic acid (88 mg, 0,188 mmol, 91%) and used without further purification to obtain the free bases of the deposits mentioned in the title compound, following the General procedure for obtaining amides, using hexamethyldisilazane (0,044 ml, 0,207 mmol) (see example 14). Precipitated precipitated free base is filtered off and treated with ethyl ether and methanol (30.9 mg, 35%) and then treated with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 2 ml) at 0OC, and get named in the title compound as a white solid. MS (ES) m/z: 467,30 [MH+]. C28H30N6O requires 466,59.1H NMR (500 MHz, DMSO-d6) δ ppm 2,04-of 2.24 (m, 4H), 2,71 (s, 3H), 3,10 (t, 2H), 3,20-3,47 (m, 8H), 3,64-a 3.87 (m, 3H), 7,40 (d, 1H), 7,43-7,51 (m, 2H), 7,52-to 7.59 (m, 2H), 7.68 per-of 7.82 (m, 1H), 7,82-to 7.93 (m, 1H), 7,94 (s, 1H), 8,00 (d, 1H), 8,45-8,80 (m, 1H), 10,34 (users, 1H).

Example 148. The dihydrochloride cyclopropyl(6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-yl)methanone (E)

To a solution of N-methyl-N-(metiloksi)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E25) (150 mg, 0,292 mmol) in THF (2.5 ml) under cooling with ice and stirring, cyclopropylmagnesium (0,72 ml of 0.5 M solution in THF, 0.351 mmol) and the resulting solution is stirred first for 1 hour at 0 ° C and then 2 days at room temperature. The reaction mixture was poured into cold hydrochloric acid (4 ml of a 2.5m solution), then treated with saturated solution of NaHCO3(15 ml) and DCM (3×15 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and the crude brown oil is purified on a SPE cartridge-Si (2 g) with elution with diethyl ether, and receive free ground named the title compound (22 mg, 60%) as a white solid. The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 494,4 [MH+]. C30H31N5O2requires 493,61.1H-NMR (500 MHz, DMSO-d6) δ: 11,05 (users, 1H), 9,02 (userd, 1H), to 8.70 (s, 1H), 8,02 (m, 2H), 7,9 (m, 2H), 7,51 (m, 1H), and 7.3 (d, 1H), 7,2 (t, 1H), 5,62 (s, 2H), 3,8-3,2 (m, 12H), to 3.09 (m, 1H), 2,96 (s, 3H), 1.00 m (m, 4H).

Example 149 (mixture of E/Z isomers). The dihydrochloride O-methyloxime 1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-yl)ethanone (E)

A solution of 1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-yl)ethanone (free base E) (75 mg, 0,160 mmol), pyridine (4 ml) and the hydrochloride methoxylamine (27 mg, 0.32 mmol) in 95% ethanol (4 ml) stirred at the boil under reflux for 2 hours. The solvent is evaporated in vacuum, the residue is dissolved in water and the solution extracted with DCM (3 the 15 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, the obtained brown oil is purified on a SPE cartridge-Si (2 g) with elution with a mixture of 4% methanol in DCM, and receive free ground mentioned in the title compound as a white solid (80 mg, 100%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid (mixture of E/Z isomers in a ratio of 85/15). MS (ES) m/z: 497.4 m [MH+]. C29H32N6O2requires 496,61.1H-NMR (500 MHz, DMSO-d6) δ: 11,29 (users, 1H), 8,95 (userd, 1H), 8,58 (s, 1H), 7,99 (m, 2H), to 7.84 (m, 2H), 7,46 (userd, 1H), and 7.3, and 7.1 (m, 2H), 5,48 (s, 2H), with 3.89 (s, 3H), 3,8-3,1 (m, 12H), of 2.92 (s, 3H), 2,2 (s, 3H).

Example 150 (mixture of E/Z isomers). The dihydrochloride O-methyloxime cyclopropyl(6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-yl)methanone (E150)

The solution cyclopropyl(6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-yl)methanone (free base E) (80 mg, rate £ 0.162 mmol), pyridine (4 ml) and the hydrochloride methoxylamine (27 mg, 0.32 mmol) in 95% ethanol (4 ml) stirred at the boil under reflux for 2 hours. The solvent is evaporated in vacuum, the OST is OK is dissolved in water and the solution extracted with DCM (3×15 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, the obtained brown oil is purified on a SPE cartridge-Si (2 g) with elution with a mixture of 4% methanol in DCM, and receive free ground mentioned in the title compound E150 in the form of a white solid (44 mg, 52%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid (mixture of E/Z isomers in the ratio 65/15). MS (ES) m/z: of 523.4 [MH+]. C31H34N6O2requires is 522.6.1H-NMR (500 MHz, DMSO-d6), (given only for the prevailing isomer), δ: 11,58 (users, 1H), 9,10 (d, 1H), 8,58 (s, 1H), 8,14 (d, 1H), with 8.05 (t, 1H), 7,94 (d, 1H), 7,83 (DD, 1H), 7,53 (d, 1H), 7,26 (m, 1H), 7,17 (m, 1H), 5,41 (s, 2H), 3,90 (s, 3H), of 3.77 (d, 2H), 3,6-3,4 (m, 8H), 3,23 (m, 2H), 3,01 (s, 3H), 2,41 (m, 1H), 1,42 (m, 2H), 0,89 (m, 2H).

Example 151. The dihydrochloride 2,2,2-triptorelin-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A)

To a mixture of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (E2) (50 mg, 0,106 mmol) and DMF (1 ml) is added DIPEA (0,018 ml, 0,116 mmol), and the suspension gradually turns into a clear solution. To the solution was added TBTU (38 mg, 0,116 mmol), and react the mixture was stirred at room temperature for 1 hour. Add 2,2,2-Cryptor-1-ethanol (0.05 ml) and the resulting reaction mixture is stirred over night at room temperature. The crude solution was purified on SPE cartridge-SCX (elution with methanol, then 2 N solution of ammonia in methanol) and then on the cartridge SPE-Si (2 g) with elution with a mixture of 3% methanol in DCM and receive free ground mentioned in the title compound as a white solid (15 mg, 26%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 552,2 [MH+]. C29H28F3N5O3requires 551,57.1H-NMR (500 MHz, DMSO-d6) δ: 11,35 (users, 1H), 9,05 (d, 1H), 8,72 (s, 1H), of 8.06 (d, 1H), 8,01 (t, 1H), to $ 7.91 (d, 1H), 7,89 (d, 1H), 7.5 (d, 1H), 7,29 (d, 1H), 7,19 (t, 1H), 5,6 (s, 2H), equal to 4.97 (q, 2H), of 3.73 (userd, 2H), 3,5 (osirm, 4H), 3,39 (osirm, 4H), 3,21 (Ust, 2H), 2,97 (s, 3H).

Example 152. The dihydrochloride 2,2,2-Cryptor-1-methylethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E152)

To a mixture of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (E2) (40 mg, 0,0852 mmol) and DMF (1 ml) is added DIPEA (0,017 ml, 0,0938 mmol), and the suspension gradually becomes transparent RA is creative. To the solution was added TBTU (30 mg, 0,0938 mmol) and the reaction mixture was stirred at room temperature for 1 hour, then add 1,1,1-Cryptor-2-propanol (0.05 ml) and the resulting reaction mixture is stirred over night at room temperature. The crude solution was purified on SPE cartridge-SCX (elution with methanol, then 2 N solution of ammonia in methanol) and then on the cartridge SPE-Si (2 g) with elution with a mixture of 3% methanol in DCM, and receive free ground mentioned in the title compound as a white solid (40 mg, 83%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 566,7 [MH+]. C30H30F3N5O3requires 565,59.1H NMR (500 MHz, DMSO-d6), δ ppm for 1.49 (d, 3H), of 2.97 (s, 3H), up 3.22 (DD, 2H), 3,35-3,47 (m, 4H), 3,47 is 3.57 (m, 4H), of 3.75 (d, 2H), 5,61 (s, 2H), 5,66-5,74 (m, 1H), 7,20 (m, 1H), 7,30 (d, 1H), 7,51 (d, 1H), 7,87-to 7.95 (m, 2H), 7,98-8,11 (m, 2H), 8,72 (s, 1H), 9,06 (d, 1H), 11,34 (users, 1H).

Example 153. The dihydrochloride cyclopropylmethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E153)

To a mixture of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (who 2) (40 mg, 0,0852 mmol) and DMF (1 ml) is added DIPEA (0,017 ml, 0,0938 mmol), and the suspension gradually turns into a clear solution. To the solution was added TBTU (30 mg, 0,0938 mmol)and the reaction mixture stirred at room temperature for 1 hour, then add cyclopropylmethanol (0.06 ml)and the resulting reaction mixture is stirred over night at room temperature. The crude solution was purified on SPE cartridge-SCX (elution with methanol, and then 2 N solution of ammonia in methanol) and then on the cartridge SPE-Si (2 g) with elution with a mixture of 3% methanol in DCM, and receive free ground mentioned in the title compound as a white solid (40 mg, 83%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 524,3 [MH+]. C31H33N5O3requires 523,63.1H NMR (500 MHz, DMSO-d6) δ ppm 0,35 (kV, J=5,86 Hz, 2H), 0,57 (kV, J=7,81 Hz, 2H), 1,15-of 1.27 (m, 1H), 2,99 (s, 3H), up 3.22 (DD, J=7,81 Hz, 2H), 3,41-3,44 (m, J=a 10.74 Hz, 4H), 3,49-of 3.54 (m, J=a 10.74 Hz, 4H), 3,74 (d, J=a 10.74 Hz, 2H), 4.09 to (l, J=7,81 Hz, 2H), 5,62 (s, 2H), 7,18 (t, J=7,81 Hz, 1H), 7,29 (d, J=6,83 Hz, 1H), 7,52 (d, J=7,81 Hz, 1H), 7,88 (d, J=7,81 Hz, 1H), to 7.93 (d, J=8,79 Hz, 1H), 8,03 (t, J=8,30 Hz, 1H), 8,10 (d, 1H), 8,67 (s, 1H), the remaining 9.08 (d, J=8,79 Hz, 1H), 11,48 (users, 1H).

Example 154. The dihydrochloride of 1-methylethyl-6-{2-[4(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A)

To a mixture of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (E2) (40 mg, 0,0852 mmol) and DMF (1 ml) is added DIPEA (0,017 ml, 0,0938 mmol), and the suspension gradually turns into a clear solution. To the solution was added TBTU (30 mg, 0,0938 mmol)and the reaction mixture stirred at room temperature for 1 hour, then add isopropanol (0.10 ml)and the resulting reaction mixture is stirred over night at room temperature. The crude solution was purified on SPE cartridge-SCX (elution with methanol, then 2 N solution of ammonia in methanol) and then on the cartridge SPE-Si (2 g) with elution with a mixture of 3% methanol in DCM, and receive free ground mentioned in the title compound as a white solid (40 mg, 92%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 512,3 [MH+]. C30H33N5O3requires 511,62.1H NMR (500 MHz, DMSO-d6) δ ppm 1,31 (d, J=6,83 Hz, 6H), to 2.99 (s, 3H), up 3.22 (t, 2H), 3,42-3,44 (m, 4H), 3,51-of 3.54 (m, J=9,76 Hz, 4H), 3,74 (d, J=9,76 Hz, 2H), 5,06-5,19 (m, 1H), ceiling of 5.60 (s, 2H), 7,17 (t, J=7,81 Hz, 1H), 7,28 (d, J=7,81 Hz, 1H), 7,52 (d, 1H), 7,87 (d, J=8,79 Hz, 1H), to 7.93 (d, J=8,79 Hz, 1H), 8,03 (t, J=8,30 Hz, 1H), of 8.09 (d, 1H), 8,65 with, 1H), 9,07 (d, J=8,79 Hz, 1H), 11,48 (users, 1H).

Example 155. The dihydrochloride cyclopentyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A)

To a mixture of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylic acid (E2) (40 mg, 0,0852 mmol) and DMF (1 ml) is added DIPEA (0,017 ml, 0,0938 mmol), and the suspension gradually turns into a clear solution. To the solution was added TBTU (30 mg, 0,0938 mmol)and the reaction mixture stirred at room temperature for 1 hour, then add Cyclopentanol (0.10 ml)and the resulting reaction mixture is stirred over night at room temperature. The crude solution was purified on SPE cartridge-SCX (elution with methanol, then 2 N solution of ammonia in methanol) and then on the cartridge SPE-Si (2 g) with elution with a mixture of 3% methanol in DCM, and receive free ground mentioned in the title compound as a white solid (40 mg, 87%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 538,3 [MH+]. C32H35N5O3requires 537,66.1H-NMR (500 MHz, DMSO-d6) δ: 11,41 (users, 1H), 9,07 (d, 1H), 865 (s, 1H), 8,08 (d, 1H), 8,02 (t, 1H), 7,92 (d, 1H), 7,87 (d, 1H), 7.5 (d, 1H), 7,27 (d, 1H), 7,16 (t, 1H), to 5.58 (s, 2H), 5,28 (m, 1H), 3,74 (userd, 2H), 3,47 (m, 4H), to 3.38 (m, 4H), 3,19 (m, 2H), 2,97 (s, 3H), at 1.91 (m, 2H), 1,74 (m, 4H), 1,61 (osirm, 2H).

Example 156. The dihydrochloride of N'-acetyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carbohydrazide (E)

To a solution of trimethylaluminum (0.9 ml of 2 M solution in hexane, 1.8 mmol) in dry DCM (1.5 ml) at 0 ° C add acetohydrazide (134 mg, 1.8 mmol)and the resulting mixture was stirred at room temperature for 30 minutes. Add dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E1) (150 mg, 0.3 mmol) in dry DCM (1.5 ml)and the resulting solution was stirred at 54º for 4 hours. The reaction is quenched with water (be careful, the reaction is highly exothermic), then add 1 M NaOH solution (15 ml)and the reaction mixture extracted with DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and get a pale yellow solid, which was treated with ethyl ether, and receive free ground named the title compound (116 mg, 74%) as a white solid. The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and treatment of diethyl EPE is ω give named the title compound as a yellow solid. MS (ES) m/z: 527,2 [MH+]. C29H33N7O3requires 526,6.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.88 (s, 3H), equal to 2.94 (s, 3H), 3,16-of 3.25 (m, 2H), 3,32 is 3.40 (m, 2H), 3,40-3,47 (m, 2H), 3.46 in of 3.56 (m, 4H), to 3.73 (d, 2H), to 5.58 (s, 2H), 7,17 (t, 1H), 7,27 (d, 1H), 7,49 (d, 1H), 7,80-7,94 (m, 2H), 7,93-8,08 (m, 2H), to 8.62 (s, 1H), 9,02 (users, 1H), made up 9.77 (s, 1H), of 9.89 (s, 1H), 11.11 is (users, 1H).

Example 157. The dihydrochloride of 3-(5-methyl-1,3,4-oxadiazol-2-yl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazine (E)

To a suspension of N'-acetyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carbohydrazide (free base E) and dry pyridine (0.015 g ml to 0.19 mmol) in dry DCM under stirring at 0OC add triperoxonane (triflic) anhydride (0,029 ml, 1,71 mmol)and the resulting mixture is stirred for 1 hour at 0 ° C and overnight at room temperature. The reaction mixture is alkalinized to pH 8-9 NaHCO3and then extrait DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, the crude oil is purified on a SPE cartridge-Si (2 g) with elution with a mixture of 4% methanol in DCM, and receive free ground mentioned in the title compound as a white solid (24 mg, 50%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation dissolve the El and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 508,2 [MH+]. C29H29N7O2requires 507,6.1H NMR (500 MHz, DMSO-d6) δ ppm of 2.58 (s, 3H), of 2.92 (s, 3H), up 3.22 (t, 2H), 3,32-to 3.41 (m, 2H), 3,41-of 3.48 (m, 2H), 3,48-to 3.58 (m, 2H), to 3.58-a 3.83 (m, 4H), to 5.66 (s, 2H), 7,20 (m, 1H), 7,30 (d, 1H), 7,47 (d, 1H), 7,81-7,87 (m, 1H), to $ 7.91 (d, 1H), 7,99 (users, 2H), 8,77 (s, 1H), 8,97 (users, 1H), 11,13 (users, 1H).

Example 158. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(1,3-oxazol-5-yl)-4H-imidazo[5,1-C][1,4]benzoxazine (E)

A mixture of 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carbaldehyde (D138) (50 mg, 0.11 mmol), K2CO3(31 mg, 0.22 mmol) and p-toluensulfonate (21 mg, 0.11 mmol) in Meon (1 ml) is stirred overnight at room temperature. The crude solution was purified on SPE cartridge-SCX (elution with methanol, then 2 N solution of ammonia in methanol) and then treated with diethyl ether, and obtain the corresponding free base named in the title compound as a solid (51 mg, 100%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 493,4 [MH+]. C29H28N6O2requires 492,58.1H NMR (500 MHz, DMSO-d6) δ MD,99 (s, 3H), 3,19 of 3.28 (m, 2H), 3,37-of 3.48 (m, 4H), 3,47-of 3.60 (m, 4H), 3,74 (d, 2H), to 5.56 (s, 2H), 7,17 (t, 1H), 7,27 (d, 1H), 7,42 (s, 1H), 7,51 (d, 1H), 7,86 (d, 1H), to 7.93 (d, 1H), 8,03 (t, 1H), 8,13 (d, 1H), 8,44 (s, 1H), 8,73 (s, 1H), remaining 9.08 (d, 1H), of 11.61 (users, 1H).

Example 159. The dihydrochloride of 3-(3-methyl-5-isoxazolyl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazine (E)

(2Z)-3-(Dimethylamino)-1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-yl)-2-butene-1-he (D139) (33 mg, 0,0614 mmol) dissolved in ethanol (2 ml) and added hydroxylamine hydrochloride (6.5 mg, 0,0922 mmol). The reaction mixture is exposed to microwave radiation in the microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 150 º C, 5 minutes). The solvent is evaporated, then add saturated aqueous solution of NH4Cl (10 ml) and the mixture extracted with ethyl acetate (3×10 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and receive free ground mentioned in the title compound as a cream solid (15 mg, 48%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 507,3 [MH+]. C30H30N6O2requires 506,61.1H NMR (500 MHz, DMSO-d6) δ ppm of 2.28 (s, 3), 2,98 (s, 3H), 3,18-of 3.27 (m, 2H), 3,36-3,47 (m, 4H), 3,47 is 3.57 (m, 4H), 3,74 (d, 2H), 5,61 (s, 2H), 6,60 (s, 1H), 7,18 (t, 1H), 7,27 (d, 1H), 7,51 (d, 1H), 7,87 (d, 1H), to 7.93 (d, 1H), 8,02 (t, 1H), 8,10 (d, 1H), 8,72 (s, 1H), 9,07 (d, 1H), 11,48 (users, 1H).

Example 160. The dihydrochloride of 3-(3-methyl-1H-pyrazole-5-yl)-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazine (E)

(2Z)-3-(Dimethylamino)-1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-yl)-2-butene-1-he (D139) (33 mg, 0,0614 mmol) dissolved in ethanol (2 ml) and add hydrazinehydrate (0.003 mg, 0,0922 mmol). The reaction mixture is exposed to microwave radiation in the microwave reactor (PersonalChemistry EmrysTM Optimiser, 300 W, 150 º C, 5 min). The solvent is evaporated, then add saturated aqueous solution of NH4Cl (5 ml) and the mixture extracted with ethyl acetate (3×10 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and receive free ground mentioned in the title compound as a cream solid (16 mg, 48%). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 506,4 [MH+]. C30H31N7O requires 505,62.

Example 161. The dihydrochloride ethyl-6-{2-[4-fluoro-4-(5-chinoline)-1-piperidin the yl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A)

A solution of 5-(4-fluoro-4-piperidinyl)quinoline (D142) (90 mg, 0,391 mmol) and ethyl-6-(2-oxoethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (D6) (100 mg, 0,365 mmol) in 1,2 DCE (2 ml) was stirred at room temperature for 30 minutes, then add triacetoxyborohydride sodium (75 mg, 0,355 mmol) and the resulting mixture was stirred at the same temperature throughout the night. The reaction is quenched with water (10 ml) and the mixture extracted with DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo, the mixture was purified on SPE cartridge-Si (2 g) with elution with a mixture of 50% ethylacetate in cyclohexane and receive free ground mentioned in the title compound as a white foam (122 mg, 62%). MS (ES) m/z: 501,3 [MH+]. C29H29FN4O3requires 500,57.1H-NMR (400 MHz, CDCl3-d6) δ: 9,07 (userd, 2H), 8,15 (d, 1H), with 8.05 (s, 1H), and 7.7 (t, 1H), 75 (userd, 1H), and 7.4 (userd, 2H), 7,27 (userd, 1H), 7,16 (t, 1H), to 5.58 (s, 2H), 4,4 (kV, 2H), 3,3-2,0 (osirm, 12H), 1,4 (t, 3H). The free base is treated with HCl (2.1 EQ. 1 M solution in diethyl ether) in dry methanol at 0OC. Evaporation of the solvent and processing diethyl ether to give named the title compound as a yellow solid. MS (ES) m/z: 501,3 [MH+]. C29H29FN4O3requires 500,57.

Example 162. Ethyl-6-(2-{4-[2-(permitil)-5-chinoline]-1-piperazinil}ethyl) - 4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E162)

Named the title compound (118 mg, 54%) receive the procedure described to obtain the compound of example 56, using 2-(permitil)-5-(1-piperazinil)quinoline (D146) (104 mg, 0,424 mmol). MS (ES; m/z): 516 [MH+]. C29H30FN5O3requires 515,59. NMR (1H, 300 MHz, CDCl3) δ: 8,56 (d, 1H), of 7.97 (s, 1H), 7.7 (d, 1H), 7,56 (m, 2H), 7,34 (d, 1H), 7,14 (m, 2H), 7,11 (t, 1H), 5,62 (d, 2H), of 5.53 (s, 2H), to 4.38 (q, 2H), 3,1 (m, 4H), to 2.94 (m, 2H), 2,82 (m, 4H), of 2.72 (m, 2H), of 1.40 (t, 3H).

Example 163. Ethyl-6-(2-{4-[2-(deformity)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E163)

Named the title compound (211 mg, 95%) receive the procedure of example 56 using 2-(deformity)-5-(1-piperazinil)quinoline (D143) (109 mg, 0,414 mmol). MS (ES; m/z): 534 [MH+]. C29H29F2N5O3requires 533,58. NMR (1H, 300 MHz, CDCl3) δ: 8,64 (d, 1H), 7,98 (s, 1H), 7,82 (d, 1H), to 7.67 (m, 2H), 7,34 (m, 1H), 7,18 (m, 2H), 7,14 (t, 1H), 6.75 in (t, 1H), of 5.53 (s, 2H), 4,39 (kV, 2H), 3.15 in (m, 4H), 2.95 and (m, 2H), 2,83 (osirm, 4H), of 2.72 (m, 2H), of 1.41 (t, 3H).

Example 164. Ethyl-6-[2-(4-{2-[(dimethylamino)carbonyl]-5-chinoline}-1-piperazinil)ethyl]-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A)

Named the title compound (152 mg, 76%) are obtained by the procedure of example 56 using N,N-dimethyl-5-(1-piperazinil)-2-chinainternational (D150) (10 mg, 0,359 mmol). MS (ES; m/z): 555 [MH+]. C31H34N6O4requires 554,66. NMR (1H, 300 MHz, CDCl3) δ: 8,58 (s, 1H), of 7.97 (s, 1H), 7,76 (d, 1H), to 7.64 (m, 2H), 7,34 (d, 1H), 7,15 (m, 2H), 7,05 (t, 1H), of 5.53 (s, 2H), 4,39 (kV, 2H), 3,1 (m, 10H), 2.95 and (m, 2H), 2,83 (users, 4H), 2,70 (m, 2H), 1,40 (t, 3H).

Example 165. Ethyl-6-[2-(4-{2-[(methylamino)carbonyl]-5-chinoline}-1-piperazinil)ethyl]-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A)

Named the title compound (133 mg, 69%) receive the procedure of example 56 using N-methyl-5-(1-piperazinil)-2-chinainternational (D151) (96 mg, 0,355 mmol). MS (ES; m/z): 541 [MH+]. C30H32N6O4requires 540,62. NMR (1H, 300 MHz, CDCl3) δ: to 8.62 (d, 1H), of 8.25 (d, 1H), and 8.2 (d, 1H), of 7.97 (s, 1H), 7,74 (d, 1H), to 7.67 (t, 1H), 7,34 (d, 1H), 7,15 (m, 2H),? 7.04 baby mortality (t, 1H), of 5.53 (s, 2H), 4,39 (kV, 2H), 3,1 (m, 7H), 2.95 and (m, 2H), 2,90 (m, 4H), of 2.72 (m, 2H), 1,40 (t, 3H).

Example 166. 6-(2-{4-[2-(Permitil)-5-chinoline]-1-piperazinil}ethyl)-N-methyl-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E)

Named the title compound (21 mg, 74%) are obtained by the procedure of example 57 using ethyl-6-(2-{4-[2-(permitil)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E162) (29 mg, 0,057 mmol). Stirring is carried out at room temperature over night. MS (ES; m/z: 501 [MH+]. C28H29FN6O2requires 500,58. NMR (1H, 40 MHz, DMSO-d6) δ: 8,58 (d, 1H), 8,55 (s, 1H), 8,14 (kV, 1H), 7,76 (DD, 1H), and 7.7 (m, 2H), to 7.64 (d, 1H), 7,22 (m, 2H), 7,10 (t, 1H), 5,66 (d, 2H), of 5.55 (s, 2H), 3,07 (users, 4H), 2,89 (t, 2H), 2,8 (users, 4H), 2,77 (d, 3H), to 2.65 (t, 2H).

Example 167. 6-(2-{4-[2-(Permitil)-5-chinoline]-1-piperazinil}ethyl)-N,N-dimethyl-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E)

Named the title compound (24 mg, 82%) are obtained by the procedure of example 58 using ethyl-6-(2-{4-[2-(permitil)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E162) (29 mg, 0,057 mmol) and dimethylamine (2.0 M/THF). Stirring is carried out at room temperature over night. MS (ES; m/z: 515 [MH+]. C29H31FN6O2requires 514,61. NMR (1H, 400 MHz, DMSO-d6) δ: 8,58 (d, 1H), 8,58 (s, 1H), 7,76 (DD, 1H), and 7.7 (m, 2H), to 7.64 (d, 1H), 7,22 (m, 2H), 7,10 (t, 1H), 5,66 (d, 2H), 5,48 (s, 2H), 3,49 (users, 3H), 3,07 (users, 4H), 2,98 (users, 3H), 2,89 (t, 2H), 2,78 (users, 4H), to 2.66 (t, 2H).

Example 168. 6-(2-{4-[2-(Permitil)-5-chinoline]-1-piperazinil}ethyl)-3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-C][1,4]benzoxazin (E)

Named the title compound (25 mg, 80%) receive the procedure of example 59 using ethyl-6-(2-{4-[2-(permitil)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E162) (29 mg, 0,057 mmol). Stirring is carried out at room temperature overnight, and the ZAT is 4 hours at 50'C. MS (ES; m/z: 557 [MH+]. C31H33FN6O3requires 556,65. NMR (1H, 400 MHz, DMSO-d6) δ: 8,58 (d, 1H), 8,56 (s, 1H), to 7.77 (DD, 1H), and 7.7 (m, 2H), to 7.64 (d, 1H), 7,22 (m, 2H), 7,11 (t, 1H), 5,66 (d, 2H), 5,51 (s, 2H), 4,3 (users, 2H), 3,66 (m, 6H), is 3.08 (users, 4H), 2,89 (ushort, 2H), 2,78 (users, 4H), 2,66 (ushort, 2H).

Example 169. 6-(2-{4-[2-(Deformity)-5-chinoline]-1-piperazinil}ethyl)-N-methyl-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E)

Named the title compound (40 mg, 78%) are obtained by the procedure of example 57 using ethyl-6-(2-{4-[2-(deformity)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E163) (53 mg, 0,099 mmol). Stirring is carried out at room temperature over night. MS (ES; m/z): 519 [MH+]. C28H28F2N6O2requires 518,57. NMR (1H, 400 MHz, DMSO-d6) δ: 8,71 (d, 1H), 8,55 (s, 1H), 8,13 (kV, 1H), 7,78 (m, 4H), 7,30 (DD, 1H), 7,24 (DD, 1H), and 7.1 (t, 1H), 7,12 (t, 1H), of 5.55 (s, 2H), 3,09 (users, 4H), 2,89 (t, 2H), 2,8 (users, 4H), 2,77 (d, 3H), of 2.66 (t, 2H).

Example 170. 6-(2-{4-[2-(Deformity)-5-chinoline]-1-piperazinil}ethyl)-N,N-dimethyl-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E)

Named the title compound (47 mg, 90%) receive the procedure of example 58 using ethyl-6-(2-{4-[2-(deformity)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E163) (53 mg, 0,099 mmol) dimethylamine (2.0 M/THF). Stirring is carried out at room temperature over night. MS (ES; m/z): 533 [MH+]. C29H30F2N6O2requires 532,60. NMR (1H, 400 MHz, DMSO-d6) δ: 8,71 (d, 1H), 8,55 (s, 1H), 7,78 (m, 4H), 7,30 (DD, 1H), 7,25 (DD, 1H), and 7.1 (t, 1H), and 7.1 (t, 1H), 5,48 (s, 2H), 3,49 (users, 3H), 3,09 (users, 4H), 2,98 (users, 3H), 2,89 (t, 2H), 2,78 (users, 4H), to 2.66 (t, 2H).

Example 171. 6-(2-{4-[2-(Deformity)-5-chinoline]-1-piperazinil}ethyl)-3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-C][1,4]benzoxazin (E171)

Named the title compound (39 mg, 68%) receive the procedure of example 59 using ethyl-6-(2-{4-[2-(deformity)-5-chinoline]-1-piperazinil}ethyl)-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (E163) (29 mg, 0,057 mmol). Stirring is carried out at room temperature overnight, and then 4 hours at 50'C. MS (ES; m/z): 575 [MH+]. C31H32F2N6O3requires 574,64. NMR (1H, 400 MHz, DMSO-d6) δ: 8,71 (d, 1H), 8,56 (s, 1H), and 7.8 (m, 4H), 7,31 (Quint, 1H), 7,24 (d, 1H), and 7.1 (m, 2H), 5,51 (s, 2H), 4,3 (acsis, 2H), and 3.7 (m, 6H), 3,09 (users, 4H), 2,89 (t, 2H), 2,78 (users, 4H), to 2.66 (m, 2H).

Example 172. N-Methyl-6-[2-(4-{2-[(methylamino)carbonyl]-5-chinoline}-1-piperazinil)ethyl]-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E172)

Named the title compound (14 mg, 43%) receive the procedure of example 57 using ethyl-6-[2-(4-{2-[(methylamino)ka is bonyl]-5-chinoline}-1-piperazinil)ethyl]-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A) (33 mg, 0.061 mmol). Stirring is carried out at room temperature over night. MS (ES; m/z): 526 [MH+]. C29H31N7O3requires 525,62. NMR (1H, 400 MHz, DMSO-d6) δ: 8,88 (kV, 1H), 8,66 (d, 1H), 8,55 (s, 1H), 8,13 (DD, 1H), 8,13 (kV, 1H), 7,78 (m, 3H), 7,29 (DD, 1H), 7,25 (DD, 1H), and 7.1 (t, 1H), of 5.55 (s, 2H), 3,09 (users, 4H), 2,9 (d, 3H), 2,88 (t, 2H), 2,8 (users, 4H), 2,77 (d, 3H), of 2.66 (t, 2H).

Example 173. N,N-Dimethyl-6-[2-(4-{2-[(methylamino)carbonyl]-5-chinoline}-1-piperazinil)ethyl]-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E173)

Named the title compound (29 mg, 88%) are obtained by the procedure of example 58 using ethyl-6-[2-(4-{2-[(methylamino)carbonyl]-5-chinoline}-1-piperazinil)ethyl]-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A) (33 mg, 0.061 mmol) and dimethylamine (2.0 M/THF). Stirring is carried out at room temperature over night. MS (ES; m/z): 540 [MH+]. C30H33N7O3requires 539,64. NMR (1H, 400 MHz, DMSO-d6) δ: 8,88 (kV, 1H), 8,66 (d, 1H), 8,55 (s, 1H), 8,13 (d, 1H), 7,78 (m, 3H), 7,28 (DD, 1H), 7,24 (DD, 1H), and 7.1 (t, 1H), 5,48 (s, 2H), 3,49 (users, 3H), 3,09 (users, 4H), 2,98 (users, 3H), of 2.86 (t, 2H), 2,9 (d, 3H), 2,78 (users, 4H), to 2.66 (t, 2H).

Example 174. N-Methyl-5-(4-{2-[3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-C][1,4]benzoxazin-6-yl]ethyl}-1-piperazinil)-2 - chinainternational (E)

Named the title compound (24 mg, 70%) obtained by procedure p is of emer 59 using ethyl-6-[2-(4-{2-[(methylamino)carbonyl]-5-chinoline}-1-piperazinil)ethyl]-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A) (33 mg, 0.061 mmol). Stirring is carried out at room temperature overnight, and then 4 h at 50'C. MS (ES; m/z: 582 [MH+]. C32H35N7O4requires 581,68. NMR (1H, 400 MHz, DMSO-d6) δ: 8,88 (quart, 1H), 8,66 (DD, 1H), 8,56 (s, 1H), 8,13 (d, 1H), and 7.8 (m, 3H), 7,28 (DD, 1H), 7,24 (DD, 1H), 7,11 (t, 1H), 5,51 (s, 2H), 4,3 (users, 2H), and 3.7 (m, 6H), 3,09 (users, 4H), 2,9 (d, 3H), 2,9 (m, 2H), 2,78 (users, 4H), to 2.66 (m, 2H).

Example 175. 6-[2-(4-{2-[(dimethylamino)carbonyl]-5-chinoline}-1-piperazinil)ethyl]-N,N-dimethyl-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (E)

Named the title compound (35 mg, 92%) are obtained by the procedure of example 58 using ethyl-6-[2-(4-{2-[(dimethylamino)carbonyl]-5-chinoline}-1-piperazinil)ethyl]-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A) (38 mg, 0,068 mmol) and dimethylamine (2.0 M/THF). Stirring is carried out at room temperature over night. MS (ES; m/z): 554 [MH+]. C31H35N7O3requires 553,67. NMR (1H, 400 MHz, DMSO-d6) δ: 8,58 (d, 1H), 8,55 (s, 1H), 7,76 (DD, 1H), 7,73 (m, 2H), 7,63 (d, 1H), 7,25 (m, 2H), and 7.1 (t, 1H), 5,48 (s, 2H), 3,49 (users, 3H), 3,09 (users, 4H), is 3.08 (s, 3H), 3.0 a (s, 3H), 2,98 (users, 3H), of 2.86 (t, 2H), 2,69 (users, 4H), to 2.66 (t, 2H).

Example 176. N,N-Dimethyl-5-(4-{2-[3-(4-marilynwilkerson)-4H-imidazo[5,1-C][1,4]benzoxazin-6-yl]ethyl}-1-piperazinil)-2 - chinainternational (E)

Named in the header link is (37 mg, 92%) are obtained by the procedure of example 59 using ethyl-6-[2-(4-{2-[(dimethylamino)carbonyl]-5-chinoline}-1-piperazinil)ethyl]-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxylate (A) (38 mg, 0,068 mmol). Stirring is carried out at room temperature overnight, and then 4 hours at 50'C. MS (ES; m/z): 596 [MH+]. C33H37N7O4requires 595,71. NMR (1H, 400 MHz, DMSO-d6) δ: 8,59 (d, 1H), 8,56 (s, 1H), to 7.77 (DD, 1H), and 7.7 (m, 2H), 7,63 (d, 1H), 7,25 (m, 2H), 7,11 (t, 1H), 5,51 (s, 2H), 4,3 (users, 2H), and 3.7 (m, 6H), is 3.08 (users, 4H), is 3.08 (s, 3H), 3.0 a (s, 3H), 2,89 (t, 2H), 2,77 (users, 4H), to 2.66 (m, 2H).

Examples 177-179 (pure enantiomers). Ethyl-6-{2-[2-methyl-4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A-179)

A solution of 2-methyl-5-(2-methyl-4-piperidinyl)quinoline (D163) (212 mg, 0,883 mmol) and ethyl-6-(2-oxoethyl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D86) (228 mg, 0,803 mmol) in 1,2 DCE (2 ml) was stirred at room temperature for 30 minutes. Add triacetoxyborohydride sodium (170 mg, 0,803 mmol) and the resulting mixture was stirred at the same temperature throughout the night. The reaction is quenched with water (10 ml) and the mixture extracted with DCM (3×10 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo. The residue is purified on a column of Horizon (25M) with elution with a mixture of 3% methanol in DCM, and receive a racemic mixture named for the head of the compounds in the form of a white foam (340 mg, 77%). MS (ES) m/z: 509,3 [MH+]. C32H36N4O2requires 508,66.

The racemic mixture was separated prepreparation chromatography on a SFC (Gilson) [CHIRALCEL AD-H, 25×2.1 cm; modifier 27% (ethanol + 0.1% Isopropylamine); flow rate = 22 ml/min; pressure 195 bar; T = 36º; wavelength UV 220 nm; loop = 1 ml] and get enantiomer 1 (E) (21 mg), enantiomer 4 (A) (13 mg); enantiomer 2+3 (E) (110 mg). The enantiomeric excess of the enantiomer 1 and 4 confirm the conditions of the analysis by SFC (Berger): chiral column CHIRALPAK AD-H, 25×0,46 cm; modifier 27% (ethanol + 0.1% Isopropylamine); flow rate = 2.5 ml/min; pressure 180 bar; T = 35; wavelength UV 220 nm; loop = 10 ál.

Enantiomer 1 E (as/and UV 100%, retention time min, EE = 100%).

Enantiomer 4 E (as/and UV 100%, retention time min, EE = 100%).

Enantiomer 2+3 E.

Example 180. 6-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A)

To ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (free base E) (138 mg, 0,379 mmol) is added KOH (1 M solution in Meon, 10 ml) and the mixture is stirred while boiling under reflux. After 3 hours the solution is cooled to room temperature, the solvent is removed in vacuum and the crude reaction product is purified on a SCX cartridge. Named in the title is Obedinenie receive in the form of ammonium salts with exit 94% (122 mg). MS (ES) m/z: 468,20 [MH+]. C28H29N5O2requires 467,57.1H-NMR (300 MHz, DMSO-d6) δ: of 8.40 (s, 1H), with 8.33 (d, 1H), 7,66 (d, 1H), EUR 7.57 (m, 2H), was 7.36 (d, 1H), 7,29 (m, 1H), 7,20 (m, 1H), 7,09 (kV, 1H), 3,22 (ushort, 2H), 3,03 (acsim, 4H), 2.91 in (osirm, 4H), was 2.76 (acsim, 4H), 2,62 (s, 3H), 2,62 at 2.45 (m, 2H).

Example 181. 6-{2-[4-(2-Methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate ammonium (E)

To ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (free base E) (50 mg, 0.1 mmol) is added KOH (1 M solution in Meon, 0.6 ml) and the mixture is stirred while boiling under reflux. After 2 hours the solution is cooled to room temperature, precipitated precipitated substance is completely dissolved, adding N2Oh, and then the solution is purified on SPE cartridge-SCX (elution with methanol, then 2 N solution of ammonia in methanol), and get called in the header connection. MS (ES) m/z: 466,2 [MH+]. C28H27N5O2requires 465,5.

Example 182. N-Methyl-N-(metiloksi)-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C]benzoxazin-3-carboxamide (E)

A solution of trimethylaluminum (2.0 M solution in hexano, 2,60 ml, 5,20 mmol) and hydrochloride of N,O-dimethylhydroxylamine (0.51 g, 5,20 mmol) in dry DCM (20 ml) was stirred at room temperature in ECENA 30 minutes. Then gradually add ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C]benzoxazin-3-carboxylate (free base E) (0,43 g, 0.87 mmol) and the resulting reaction mixture was stirred at 40 ºC for 2 hours. Upon completion of the reaction is added dropwise 1 M aqueous NaOH solution (20 ml)until there is no further gas evolution. The aqueous solution is extracted with DCM (3×20 ml). The combined organic phases are dried (Na2SO4) and evaporated in vacuo. The crude reaction product is treated with diethyl ether and get named in the title compound (0.39 g, from 0.76 mmol, yield 87%) as a pale yellow solid. MS (ES; m/z): 512,3 [MH+]. C30H33N5O3requires 511,62.1H NMR (400 MHz, CDCl3) δ ppm 1,95-2,05 (osirm, 4H), 2,34-2,42 (osirm, 2H), 2,63-2,70 (osirm, 1H), 2,75 (s, 3H), 2.95 and-is 3.08 (osirm, 2H), 3,30-3,37 (osirm, 4H), 3,61 (users, 3H), with 3.89 (s, 3H), to 5.58 (s, 2H), to 7.09 (t, 1H), 7,21 (d, 1H), 7,40-to 7.32 (m, 2H), of 7.48 (d, 1H), to 7.64 (t, 1H), 7,92 (d, 1H), 8,04 (s, 1H), 8,31 (d, 1H).

Example 183. 6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4H-imidazo[5,1-C]benzoxazin-3-carboxylic acid (E)

To a solution of ethyl-6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4H-imidazo[5,1-C]benzoxazin-3-carboxylate (A) (58 mg, 0.1 mmol) in Meon (3 ml) is added NaOH (1 ml of 10% aqueous solution) and the resulting white suspension is heated within 2 hours at 80ºC. The mixture is evaporated and the crude reaction product is purified on a SCX column with elution with a solution of ammonia in methanol, removing 0,038 g named in the title compound A in the form of a pale yellow foam. MS (ES) m/z: 502,5 [MH+]. C28H28FN5O3requires 501,56.

Example 184. N-Methyl-N-(metiloksi)-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (E)

Named in the title compound, receive, following the procedure of example 41, using hydrochloride methoxylamine (118 mg, to 1.21 mmol) and the free base ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A) (100 mg, 0,202 mmol). MS (ES) m/z: 510,1 [MH+]. C31H35N5O2requires 509,65.1H NMR (300 MHz, CDCl3) δ ppm 2.06 to (osirm, 3H), 2.40 a (osirm, 2H), 2,60-2,85 (osirm, 2H), 2,77 (s, 3H), 2,90-of 3.60 (m, 13H), with 3.89 (s, 3H), 7,20-7,40 (m, 4H), 7,47 (d, 1H), 7,68 (t, 1H), to 7.93 (d, 1H), to 7.99 (s, 1H), 8,32 (d, 1H).

Example 185. Ethyl-6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate

Named the title compound is obtained in yield 49%, following the General procedure of reductive amination of example 1 from ethyl-6-(2-oxoethyl)-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (D86) (91 mg, 0.32 mmol) and 7-fluoro-2-m is Tyl-5-[(3R)-3-methyl-1-piperazinil]quinoline (obtained by the procedure similar to the procedure described in WO 2004/046124) (100 mg, 0,39 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of methanol in DCM (1%) and receive free ground named in the connection header. MS (ES) m/z: consists 528.3 [MH+]. C31H34FN5O2requires 527,64.1H-NMR (400 MHz, CDCl3) δ: 8,39 (d, 1H), 8,00 (s, 1H), 7,37-7,56 (m, 4H), and 7.3 (m, 1H), 6,9 (d, 1H), 4,45 (quart, 2H), 3,-2,7 (osirm, 11H), 2,77 (s, 3H), of 1.46 (t, 3H), 1,25 (m, 3H).

Example 186. 6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylic acid (E)

A mixture of free base ethyl-6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A) (100 mg, 0,19 mmol) and KOH (1 M solution in Meon, 1.2 ml) was stirred at the boil under reflux for 2 hours. The yellow solid is filtered off, collected and suspended in water (5 ml). Add acetic acid to pH 7, and the resulting pale yellow solid is filtered off, washed with diethyl ether and dried in vacuum. Named the title compound (80 mg, 0.14 mmol, 84%) are recovered in the form of a pale yellow foam. MS (ES) m/z: 500,3 [MH+]. C29H30FN5O2requires 501,5.

Example 187. Ethyl-6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperaz the Nile]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (A)

Named the title compound is obtained in yield 92%, following the General procedure of reductive amination of example 1 from ethyl-6-(2-oxoethyl)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (D137) (50 mg, 0,175 mmol) and 7-fluoro-2-methyl-5-[(3R)-3-methyl-1-piperazinil]quinoline (50 mg, rate of 0.193 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of methanol in DCM (2%) and receive free ground named the title compound (85 mg, 92%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol (1 ml) at 0 ° C gives named the title compound as a yellow solid. MS (ES) m/z: 529,10 [MH+]. C30H33FN6O2requires 528,63.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.34 (t, 3H), of 1.45 (d, 3H), 2,70 (s, 3H), 2,97-to 3.67 (m, 4H), 3.15 in (t, 2H), 3,20-of 3.54 (m, 4H), 3,39 (t, 2H), 3,48-of 3.94 (m, 3H), 4.26 deaths is 4.45 (m, 2H), 7,20 (m, 1H), 7,37-7,56 (m, 4H), 8,02 (d, 1H), 8,39-8,62 (m, 1H), 10,96 (users, 1H).

Example 188. 6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylic acid (E)

A mixture of ethyl-6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (free base E) (75 mg, 0,142 mmol) and KOH (1 M solution in Meon, 2 ml) is stirred while boiling under reflux for is of 45 minutes. The mixture was purified by SCX column with elution with a solution of NH3in methanol and receive named the title compound (70 mg, 0.14 mmol, 99%) as a pale yellow foam. MS (ES) m/z: 501,3 [MH+]. C28H28FN6O2requires 500,5.

Example 189. The dihydrochloride 6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide (E)

Named in the title compound, receive, following the General procedure for obtaining amides (see example 14), starting from 6-{2-[(2R)-4-(7-fluoro-2-methyl-5-chinoline)-2-methyl-1-piperazinil]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylic acid (A) (70 mg, 0.14 mmol), using hexamethyldisilazane (0,033 ml, 0,154 mmol). The crude reaction product is purified on a SCX cartridge and flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%) and receive free ground named in the connection header. Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:2, 3 ml) at 0 ° C gives named the title compound as a yellow solid. MS (ES) m/z: 500,10 [MH+]. C28H30FN7O requires 499,59.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.45 (d, 3H), 2,71 (s, 3H), 3,05-is 3.21 (m, 2H), 3,19-to 3.52 (m, 4H), 3,22-to 3.33 (m, 2H), 3,23-3,63 (m, 6H), to 3.58-a-3.84 (m, 1H), 7,22 (d, 1H), 7,43 (d, 1H), 7,47 (t, 1H), 7,45-rate of 7.54 (m, 1H), 7,45-7,53 (m, 1H), EUR 7.57 (s, 1H), of 7.96 (s, 1H), 8,00 (d, 1H), at 8.36-8,69 m, 1H), 11,19 (users, 1H).

Example 190. N-Methyl-N-(metiloksi)-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide (E)

Named in the title compound, receive, following the procedure of example 184, using the hydrochloride of N,O-dimethylhydroxylamine (178 mg, 1.82 mmol) and ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (free base E) (150 mg, 0,303 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%) and get named in the title compound (106 mg, 69%). MS (ES) m/z: 511,3 [MH+]. C30H34N6O2requires 510,64.1H NMR (300 MHz, CDCl3) δ ppm 2,03 (osirm, 3H), 2.40 a (osirm, 2H), 2,61-2,82 (osirm, 2H), 2,75 (s, 3H), 2.95 and-the 3.65 (m, 13H), of 3.95 (s, 3H), 7,22-of 7.48 (m, 4H), of 7.65 (t, 1H), of 7.90 (d, 1H), of 8.06 (d, 1H), 8,28 (d, 1H).

Example 191. The dihydrochloride of 1-(6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydro[1,2,3]triazolo[1,5-a]quinoline-3-yl)ethanone (E)

Named in the title compound, receive, following the procedure of example 121 using methylacrylamide (0,082 ml of 3 M solution in diethyl ether, 0,245 mmol) and E (106 mg, 0,208 mmol). The crude reaction product is purified flash chromatography on silica gel with elution with a mixture of methanol is in DCM (2%) and receive free ground named the title compound (44 mg, 45%). Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:1, 2 ml) at 0 ° C gives named the title compound as white solids). MS (ES) m/z: 466,00 [MH+]. C29H31N5O requires 465,60.1H NMR (500 MHz, DMSO-d6) δ ppm 2,03-of 2.15 (m, 2H), 2,13-of 2.34 (m, 2H), 2.63 in (s, 3H), 2,77 (s, 3H), of 3.12 (t, 2H), 3,14-to 3.49 (m, 6H), 3,19-3,47 (m, 2H), 3,64-3,88 (m, 3H), 7,42 (d, 1H), 7,49 (t, 1H), of 7.48-7,58 (m, 1H), EUR 7.57-7,76 (m, 1H), 7,76-of 7.90 (m, 1H), of 7.90 shed 8.01 (m, 1H), 8,01 (d, 1H), 8,35-9,27 (m, 1H), 10,87 (users, 1H).

Example 192. 6-{2-[2-Methyl-4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylic acid (E)

Ethyl-6-{2-[2-methyl-4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A, enantiomer 1) (45 mg, 0.08 mmol) and KOH (1 M solution in Meon, 1.5 ml) is stirred while boiling under reflux for 1 hour. The mixture is then loaded into a SCX column with elution with a solution of NH3in methanol and receive named the title compound (43 mg, 0,089 mmol, 100%). MS (ES) m/z: 481,3 [MH+]. C30H32N4O2requires 480,61.

Example 193. 6-{2-[2-Methyl-4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide

Named in the title compound, receive, following the General procedure for obtaining amides (see example 14), starting from 6-{2-[2-methyl-4-(2-methyl-5-China the Nile)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylic acid (A) (43 mg, 0,089 mmol), using hexamethyldisilazane (0,02 ml, 0,098 mmol). The crude reaction product is purified on a SCX cartridge and flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%) and receive free ground named in the connection header. Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:2, 3 ml) at 0 ° C gives named the title compound as a white solid (39 mg, 79%). MS (ES) m/z: 480,1 [MH+]. C30H33N5O requires 479,62.1H NMR (400 MHz, DMSO-d6) δ ppm: 11,19 (users, 1H), was 9.33 (users, 1H), 8,64 (users, 1H), 8,27 (users, 1H), 8,09 (t, 1H), 7,9 (d, 1H), and 7.8 (d, 1H), of 7.75 (d, 1H), 7,46-7,41 (m, 2H), 7,37 (d, 1H), 7,26 (users, 1H), 3,93-3,24 (osirm, 8H), 3,02-of 2.97 (m, 7H), 2,3 (m, 1H), 2,1 (osirm, 3H), of 1.45 (d, 3H).

Example 194. 6-{2-[2-Methyl-4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylic acid (E)

Ethyl-6-{2-[2-methyl-4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylate (A, enantiomer 4) (20 mg, 0,039 mmol) and KOH (1 M solution in Meon, 1.5 ml) is stirred while boiling under reflux for 1 hour. The mixture is then loaded into a SCX column with elution with a solution of NH3in methanol, and get named in the title compound (20 mg, 100%). MS (ES) m/z: 481,3 [MH+]. C30H32N4O2requires 480,61.

Example 195. 6-{2-[-methyl-4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (E)

Named in the title compound, receive, following the General procedure for obtaining amides (see example 14), starting from 6-{2-[2-methyl-4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxylic acid (I) (20 mg, 0,039 mmol), using hexamethyldisilazane (of 0.015 ml, 0,068 mmol). The crude reaction product is purified on a SCX cartridge and flash chromatography on silica gel with elution with a gradient of methanol in DCM (2-3%) and receive free ground named in the connection header. Treatment with HCl (2.2 EQ. 1.25 M solution in Meon) in methanol/DCM (1:2, 3 ml) at 0 ° C gives named the title compound as a white solid (22 mg, 100%). MS (ES) m/z: 480,1 [MH+]. C30H33N5O requires 479,62.1H NMR (400 MHz, DMSO-d6) δ ppm: 11,51 (users, 1H), 9,41 (d, 1H), 8,82 (users, 1H), 8.3 (l, 1H), 8,1 (t, 1H), 8.0 a (d, 1H), and 7.7 (t, 2H), 7.5 (d, 1H), and 7.4 (m, 2H), 7,37 (d, 1H), 4,0 (m, 3H), to 3.58 (userd, 1H), 3,4 (userd, 1H), 3,2 (osirm, 3H), 3,07-3,00 (m, 6H), to 2.75 (t, 1H, in), 2.25 (m, 1H), 1,98 (t, 2H), 1,74 (d, 1H), 1.55V (d, 3H).

Biological tests

a) the Functional capacity of the primary screening

Functional capacity can be determined using the following Protocol GTPγS binding. The cells used in the study are cells of SSC and primary human kidney (NEC). Cells transferout DNA that encodes a human recipe is ture, as follows: NEC-HT1A; SNO-HT1Band SNO-HT1D. The test compounds are first dissolved in 100% dimethyl sulfoxide to a concentration of 10 mm. Serial dilution of the test compounds in 100% dimethyl sulfoxide carried out using a Biomek FX in 384-well analytical tablets so that the final top concentration of test compounds in the analysis is 3 μm. Add the test compound in the amount of 1.0% of the total analysis (TAV) in solid white 384-well analytical tablet (Costar). Add 50% TAV membranes (5 μg/well), pre-connected (within 90 min at RT) with pellets for analysis Wheatgerm Agglutinin Polystirole Scintillation Proximity Assay (RPNQ0260 Amersham International) (0.25 mg/well) in 20 mm HEPES, pH 7.4, 100 mm NaCl, 3 mm MgCl2and 10 μm GDP. The third addition is adding 20% TAV or buffer format agonist or EU80final concentration in the assay (FAC) agonist, antagonist format NT received in the buffer for analysis. The analysis begins by adding 29% TAV GTPγS 0,38 nm FAC. After all additions analytical tablets incubated at RT for 2-3 hours. Counting on analytical tablets is performed on the filter Viewlux 613/55 within 5 min. Analytical tablets read between 2-6 hours after the last addition.

Using the analysis of (a) compounds of examples tipin the show fpKi against 5-HT 1Amore than 6,0. Using analysis and connection examples 14, 15, 24, 83, 89, 91, 94, 97, 105, 109, 122, 124 and 125 show the value of fpKi more 8,0 when the receptor 5-HT1A. Some of these compounds show the value of fpKi receptors for 5-HT1Band 5-HT1Dsimilar values for receptor 5-HT1A. Using analysis a) compound of example 24 shows fpKi 9,7.

b) Affinity to receptors

The affinity of compounds of the invention to the receptor 5-HT1A, 5-HT1Band 5-HT1Dcan be determined using the following analysis.

Homogenize the cells of the Chinese hamster ovary (Cho)expressing the receptors 5-HT1A(4×107cells/ml) in Tris buffer and stored in aliquot 1 ml of Homogenized cells SNO expressing the receptors 5-HT1B(4×107cells/ml) in Tris buffer and stored in aliquot of 1.5 ml of Homogenized cells SNO expressing the receptors 5-HT1D(1×108cells/ml) in Tris buffer and stored in aliquot 1 ml Analyses linking is carried out in a total volume of 500 ál. For everybody experiencing connection receive seven solutions with concentrations ranging from 0.3 mm to 0.3 nm (100×final concentration). Distribute the solution containing the test compound, 5 μl per well, and add 100 ál of radioligand at a concentration of 5× the final desired for analysis conc the tion, i.e. [3H]5-HT 15 nm (final concentration for analysis 3 nm)in a buffer of Tris-Mg-HCl (pH 7,7) receptors for 5-HT1B/1Dand [3H]-WAY100635 2.5 nm (final concentration for analysis 0.5 nm)in buffer Tris-Mg-HCl (pH of 7.7)containing 150 μm GPP(NH)p (final concentration in the analysis of 30 μm) for receptors 5-HT1A. Add 400 µl/well of a suspension of cell membranes in a buffer of Tris-Mg-HCl (pH 7,7) and receive a total of 505 mm. Incubated at 37º within 45 minutes. Determine the nonspecific binding using 0.01 mm 5-HT receptors for 5-HT1B/1Dand 0.01 mm WAY100635 receptors for 5-HT1A. Cut incubation rapid filtration using a Packard Filtermate. Radioactivity was measured using a Topcount scintillation counter. The pKi values calculated from the IC50received the iterative approximation of the curve by points area of least squares.

(C) Analysis of binding [3H]-citalopram for SERT person

The affinity of compounds to the binding site of re-absorption of the carrier serotonin (SERT) can be estimated using analysis of binding of [3H]is citalopram made in recombinant epithelial cells of the kidney pig, stably transfected with SERT person (hSERT/LLCPK). Grow cells in Petri dishes, 500 cm2, and is used to produce membranes at 80% confluence. To etki collected in phosphate buffered saline (PBS), containing 5 mm etc, and centrifuged at 900 g for 8 min at 4ºC. Homogenized sediment in about 30-50. buffer for analysis (50 mm Tris, 120 mm NaCl, 5 mm KCl, 10 μm of pargyline, 0.1% ascorbate (pH 7,7)) and centrifuged at 48000 g for 20 min at 4ºC. Resuspending cellular precipitate in the same volume, and after incubation at 37º for 20 min, centrifuged as described earlier, and get the ultimate aliquots at ~0.2 mg protein/ml in cold buffer for analysis. For analysis on the binding of [3H]-citalopram add 4 μl solution of the test compounds (100-fold in pure DMSO) (for definition of full binding) or fluoxetine at a final concentration of 10 μm in DMSO (to determine non-specific binding), 200 μl of a solution of [3H] -, resulting in a final concentration of 0.25 nm in the buffer for analysis, and 200 μl of membranes diluted in buffer for analysis at a concentration of 1 μg/ml protein a (finite volume analysis 400 µl). Add membrane to initiate the reaction and incubated the mixture at room temperature for 2 hours. Stop the reaction by rapid filtration through filter tablet GF/96, pre-soaked in 0.5% polyethylenimine (PEI)using a harvester cells Packard. Washed with 96-well filter tablet 3 times 1 ml/well of cold 0.9% NaCl solution and count the radioactivity in the counter Packard TopCount.

1. With the Association of the formula (I)

its pharmaceutically acceptable salt,
where the ---- is independently single or double bond;
a loop Q is an imidazole, triazole (e.g., 1,2,3-triazole or 1,3;4-triazole) tetrazol or oxadiazole;
Represents a C(R7)(R8) or C(R7), where in the case when the bond connecting b and Y represents a simple bond, A represents C(R7)(R8), and when the bond connecting b and Y is a double bond, A is a C(R7);
Y is C(R7), C(R7)(R8) or, in the case where, when the bond connecting b and Y represents a simple bond, Y is C(R7)(R8or Oh, and when the bond connecting b and Y is a double bond, A is a C(R7);
Z1represents-CH2-, -(CH2)2-, -CH2CH-CH3-where the left link Z1attached to the nitrogen atom, or -(CH2)3-;
X represents C(R1or N;
But chenail, hintline or benzofuranyl, any of which is optionally substituted by 1-4 substituents, which may be the same or different and selected from the group consisting of halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, -C(O)N(R3)(R4), 5-membered heterocyclics the ring, including 1-3 heteroatoms selected from N or O; and a heterocyclic ring optionally substituted C1-6-alkyl;
when R is present, each represents independently halogen, C1-6-alkyl;
each R1represents hydrogen or methyl;
each R2represents cyano, C1-6-alkyl,
C1-6-alkoxy, halogen-(C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5R6, -C(O)R6,
-C(O)OR7, -C(O)NHNHC(O)R6A 5-membered heterocyclic ring comprising 1-3 heteroatoms selected from N or O; and a heterocyclic ring optionally substituted C1-6-alkyl;
R3and R4are independently hydrogen, C1-6-alkyl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3and R4connected to the same nitrogen atom, together with the nitrogen atom form a 4-, 5 - or 6-membered cycle, optionally containing one additional atom Of loop;
R5represents a C1-4-alkyl;
R6represents a C3-7-cycloalkyl or1-6-alkyl;
R7and R8are independently hydrogen or C1-6-alkyl;
p is 0, 1 or 2;
r is 0, 1, 2 or 3;
s is 0, 1, 2, or 3.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, the de loop Q is an imidazole or a triazole (e.g., 1,2,3-triazole or 1,3,4-triazole).

3. The compound according to claim 1 or 2, or its pharmaceutically acceptable salt, where Q is an imidazole.

4. The compound according to claim 1 or its pharmaceutically acceptable salt, where Z1represents -(CH2)2-.

5. The compound according to claim 1 or its pharmaceutically acceptable salt, where each R2represents a C1-6-alkyl, -C(O)N(R3)(R4or-C(O)R6.

6. The compound according to claim 1 or its pharmaceutically acceptable salt, where X represents C(R1or N.

7. The compound according to claim 1 or its pharmaceutically acceptable salt, where X represents CH or N.

8. The compound according to claim 1 or its pharmaceutically acceptable salt, where the substituents a are selected from the group consisting of halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, and-C(O)N(R3)(R4).

9. The compound according to claim 1 or its pharmaceutically acceptable salt, where R, when present, is selected from the group consisting of fluorine, chlorine, methyl or ethyl.

10. The compound according to claim 1 or its pharmaceutically acceptable salt, where s is equal to 1 or 2.

11. The compound according to claim 1 or its pharmaceutically acceptable salt, selected from
dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (example 14);
dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (example 15);
dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(4-morpholinylcarbonyl)-4H-imidazo[5,1-C][1,4]benzoxazine (example 24);
dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (example 83);
dihydrochloride of N-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (example 89);
dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo[1,5-a]quinoline-3-carboxamide (example 91);
dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}tetrazolo[1,5-a]quinoline (example 94);
dihydrochloride ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxylate (example 97);
dihydrochloride 6-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-3-(3-methyl-1,2,4-oxadiazol-5-yl)imidazo[1,5-a]quinoline (example 105);
dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide (example 109);
dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (example 122);
dihydrochloride of N,7-dimethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (example 124);
dihydrochloride of 7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (example 125); and
7-ethyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (example 134)
or their other pharmaceutically acceptable salts or free bases.

12. 6-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}-4H-imidazo[5,1-C][1,4]benzoxazin-3-carboxamide (free base, example 14).

13. The dihydrochloride 6-{2-[4-(2-Methyl-5-chinoline)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide (example 91).

14. The dihydrochloride 6-{2-[4-(2-methyl-5-chinoline)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide (example 109).

15. The dihydrochloride of 7-methyl-6-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide (example 134).

16. The compound or its pharmaceutically acceptable salt according to any one of the preceding paragraphs, is suitable as a drug.

17. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 16, is suitable in the treatment or prevention of a disease or condition mediated by modulation of the receptor 5-HT1and/or receptor reuptake of serotonin.

18. The compound or its pharmaceutically acceptable salt 17, where the disease or condition is anxiety or depression.

19. The compound or its pharmaceutically acceptable salt 17, where the disease or condition is premature ejaculation.

20. The use of compound or its pharmaceutically acceptable salt according to any one of claims 1 to 16 when receive the Institute of drugs for treating or preventing the disease or condition mediated by modulation of the receptor 5-HT1and/or receptor reuptake of serotonin.

21. The application of claim 20, where the disease or condition is a state of anxiety or depression.

22. The application of claim 20, where the disease or condition is premature ejaculation.

23. Pharmaceutical composition having activity mediated by modulation of the receptor 5-HT1containing the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 16 in combination with one or more pharmaceutically acceptable carriers, diluents and/or excipients.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of a compound of formula , where R1 is an alkyl or aryl group, or a pharmaceutically acceptable salt or solvate thereof, including hydrate, involving reaction of a compound of formula with a Grignard reagent of formula , where X is a halogen selected from Cl, Br and I, and R1 is an alkyl or aryl group; and optional conversion of the obtained free base compound of formula (I) to a pharmaceutically acceptable salt. The invention also relates to a compound of formula II; a compound of formula , where X is a halogen selected from O, Br and I and to use of formula II and IIIA compounds in synthesis of delmopinol and a derivative of the formula I compound.

EFFECT: novel method for synthesis of a compound of formula I using novel intermediate compounds of formulae II and IIIA.

18 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are derivatives of 5H-pyrazolo[1,5-c][1,3]benzoxasin-5-yl)phenylmethanon of formula , possessing ability to inhibit HIV replication, where values of R1, R2, R3 substitutes are given in invention formula. Also describes is pharmaceutical preparation and application of compound for obtaining medication applied for treatment of conditions associated with HIV infection.

EFFECT: claimed compounds are applicable for prevention or treatment of HIV-produced infection and for AIDS treatment.

15 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I with anti-HIV activity , where R1 represents C1-6(Ar1)alkyl or C1-6(Ar1)oxyalkyl; R2 represents hydrogen or OR14; R3 represents hydrogen, halogen, hydroxyl, cyano, C1-6alkyl, C5-7cycloalkenyl, C1-6halogenalkyl, C1-6alkoxy, C1-6alkylthio, N(R8)(R9), NHAr2, N(R6)COR7, OCON(R8)(R9), OCH2CON(R9)(R9), CO2R6, CON(R8)(R9), SOR7, S(=N)R7, SO2R7, SO2N(R6)(R6), PO(OR6)2, C2-4(R12)alkynyl, R13, Ar2 or Ar3; R4 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R5 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R6 represents hydrogen or C1-6alkyl; R7 represents C1-7alkyl; R8 represents hydrogen or C1-6alkyl; R9 represents hydrogen, C1-6alkyl, C1-6hydroxyalkyl or C1-6(C1-6dialkylamino)alkyl; or N(R8)(R9) taken together represent azetidinyl, pyrrolydinyl, (R10)-piperidinyl, N-(R11)-piperazinyl, morpholinyl or dioxothiazinyl; R10 represents hydrogen; R11 represents hydrogen, C1-6alkyl, COR6 or CO2R6 ; R12 represents hydrogen, hydroxyl, N(R6)(R6), OSO2R7 or dioxothiazinyl; R13 represents dioxothiazinyl; R4 represents hydrogen or C1-6alkyl; Ar1 represents ,,,,,,,,; or Ar2 represents tetrazolyl, triazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl or indolyl, and is substituted with 0-2 substitutes selected from a group consisting of halogen, benzyl, C1-6alkyl, C1-6alkoxy, N((R8)(R9), CON(R8)(R9) and CO2R8; Ar3 represents phenyl substituted with 0-2 substitutes selected from a group consisting of halogen, cyano, hydroxy, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)methyl, C1-6halogenalkoxy, N(R8)(R9), CON(R6)(R6) and CH2N(R8)(R9), or represents dioxolanylphenyl; and X-Y-Z represents C(R14)2OC(R14)2C(R14)2, C(R14)2OC(R14)2C(R14)2C(R14)2; or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition.

EFFECT: bicyclic heterocycles are disclosed, as well as their use HIV integrase inhibitors.

21 cl, 38 dwg, 8 tbl, 282 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R1 and R2 independently represent a hydrogen atom or a C1-6alkyl group, R3 is a hydroxyl group, R4 is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR7R8 or NR9, R5 is a hydrogen atom, R6 is a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group, C3-8cycloalkenyl group, amino group, C1-6alkylamino group, C6-14aryl group, C2-9heteroaryl group or C2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 2,3-dihydro-6-nitroimidazo[2,1-b]oxazol of general formula (1), as well as to their optically active forms and pharmacologically acceptable salts: where values of R1, R2 and n are given in i.1 of invention formula.

EFFECT: development of compounds, which have bactericidal action against Mycobacterium tuberculosis, polyresistant Mycobacterium tuberculosis and can be applied as antituberculosis medication.

3 cl, 16 ex, 183 tbl, 1515 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention describes dibenzo[b,f]pyrido[1,2-d][1,4]diazepinyl derivatives of general formula I: or pharmaceutically acceptable salts thereof (values of radicals are listed in the claim), which are glucocorticoid receptor modulators.

EFFECT: derivatives can be used in treating immunological and inflammatory diseases.

11 cl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to systems containing an imidazole ring, which correspond to a substance of formula (I-1): , in which: X denotes alkylene which is facultatively interrupted with one or more -O- groups; Z denotes -C(O)-; R1-1 is selected from a group comprising: hydrogen, alkyl, phenyl, -N(CH3)(OCH3), and phenyl which is substituted with one or more halogens; R2 denotes hydrogen; alkyl; hydroxyalkyl; or alkoxyalkyl; RA and RB taken together form an open phenyl ring, or to pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions for inducing biosynthesis of cytokine, which contains such substances.

EFFECT: substances can be used in medicine as immunomodulators for inducing or inhibiting biosynthesis of cytokines in animals and when treating diseases, including viral and malignant diseases.

18 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to imidazo[1,2-a]pyridine derivatives of formula in which radicals R1, R2, R3 and R4 independently denote a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a (C1-C12)alkyl radical which can be substituted with one or more halogen atoms or OH, and a O-(C1-C12)alkyl radicalwhich is substituted with phenyl, or two of radicals R1, R2, R3 and R4 can denote part of a phenyl ring; R5 denotes a (C1-C12)alkyl radical which can be substituted with one or more OH, methanesulphanyl, COOH or a halogen atom, (C2-C12)alkenyl radical, (C2-C12)alkynyl radical, (C6-C10)aryl radical, heteroaryl radical, which is an aromatic groupcontaining 5-10 ring members and 1-2 nitrogen or oxygen ring atoms, (C3-C10)cycloalkyl radical, (C1-C12)alkyl(C3-C10)cycloalkyl radical, (C6-C10)aryl(C1-C12)alkyl radical; radicals R6 and R7 independently denote a hydrogen atom or a (C1-C12)alkyl radical, which can be substituted with COOH, (C6-C10)aryl radical; and X denotes a group of formula - CO-NHOH or formula where U denotes a bond, CH2, V denotes O, S, W denotes NH, and Y denotes OH, or pharmaceutically acceptable salts thereof, solvates, hydrates. The invention also relates to the pharmaceutical composition based on the formula I compound and use of the formula I compound.

EFFECT: novel derivatives have peptide deformylase inhibiting activity.

16 cl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel ligands, including novel compounds of general formula 1, a wide range of biological activity which simultaneously includes alpha-adrenoceptors, dopamine receptors, histamine receptors, imidazoline receptors and serotonin receptors, including serotonin 5-HT7 receptors, in form of free bases, geometric isomers, racemic mixtures or separate optical isomers, as well as in form of pharmaceutically acceptable salts and/or hydrates. In formula 1

R1 denotes hydrogen; C1-C4alkyl optionally substituted with C1-C4alkoxycarbonyl, aromatic or saturated optionally annelated or optionally substituted with a five- or six-member heterocycle containing 1-2 N heteroatoms; C1-C3acyl; saturated optionally substituted six-member N-heterocycle; C1-C4alkoxycarbonyl; optionally substituted arylsulphonyl, R2 denotes a substitute of a cyclic system, including hydrogen; halogen; optionally substituted C1-C4alkyl;CF3, CN, C1-C4alkoxy; C1-C4alkoxycarbonyl; carboxyl; unsaturated six-member N-containing heterocyclyl or optionally substituted arylsulphonyl, Ar denotes phenyl, optionally substituted with C1-C4alkyl, dimethylamino group, one or more C1-C4alkoxy groups, one or more halides, CF3 group, nitro group, carboxyl, C1-C4alkoxycarbonyl, C1-C4acylamino group, CN, optionally annelated with a saturated heterocycle; optionally annelated and optionally substituted unsaturated five- or six-member heterocycle containing one or two heteroatoms selected from nitrogen, oxygen or sulphur; W denotes an optionally substituted (CH2)m group, optionally substituted CH=CH group, optionally substituted CH2-CH=CH group, C≡C group, SO2 group; n = 1 or 2; m=1, 2 or 3, the solid line accompanied by a dotted line (---) denotes a single or double bond.

EFFECT: compounds can be used to treat and/or prevent diseases or pathological conditions of the central nervous system, whose pathogenesis is associated with hyper- or hypo-activation of said receptors, for example anxiety or cognitive disorders, neurodegenerative and psychotic diseases.

42 cl, 26 dwg, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 3,11b-cis-dihydrotetrabenazine or its pharmaceutically acceptable salts to prepare a medicinal agent for preventing or treating schizophrenia. The invention also relates to compounds for use in preventing or treating psychosis, methods of preventing or treating psychosis, as well as methods of preventing or alleviating a psychotic episode.

EFFECT: use of 3,11b-cis-dihydrotetrabenazine to prepare a medicinal agent for preventing or treating schizophrenia.

34 cl, 7 ex, 6 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound under the invention is represented by formula (I) or its pharmaceutically acceptable salt where R1 and R2 represent H or optionally substituted alkyl where substitutes are specified from -N(CH3)2, -OH, -OCH3; B represents N; Z represents N; each of W, X and Y independently represents C-H, C-J; Ar represents an optionally substituted phenyl ring where substitutes are specified from halogen, -NH-CH3; each J independently represents NR1R2; and n is equal to 0; provided the compound is not 4-[2-(5-chloro-2-fluorophenyl)pteridine-4-ylamino]nicotinamide. The compounds of formula (I) can find application in treating HCV related conditions.

EFFECT: preparation of the new compounds for making a drug for treating HCV infection.

15 cl, 2 tbl, 9 ex

Chemical compounds // 2405780

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I): , in which: R1 and R2 are independently specified from hydrogen, C1-6alkyl, C1-6alkoxy and cyclopropyl; X1, X2 and X3 independently represent =N- or =CR10; R3 and R10 are independently specified from hydrogen, halogen, nitro, cyano, amino, carboxy, carbamoyl, C1-6alkyl, N-(C1-6alkyl)amino, N,N(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkoxycarbonyl; R4 represents hydrogen; R5 and R6 are independently specified from hydrogen, hydroxy and C1-6alkyl where R5 and R6 independently can be optionally substituted in carbon atom with one or more R16 where R16 represents hydroxy; A represents a single link or C1-2alkylene; where specified C1-2alkylene can be optionally substituted with one or more R18; the ring C represents a saturated, partially saturated or unsaturated mono- or bicyclic ring containing 5 or 6 atoms in which at least one atom can be specified from nitrogen, sulphur or oxygen which can be linked with carbon or nitrogen atom where the -CH2- group can be optionally substituted with -C(O)- and ring sulphur atom can be optionally oxidised to produce S-oxide; R7 is specified from halogen and C1-6alkyl where R7 can be optionally substituted in carbon atom with halogen; n is equal to 0.1 or 2; where R7 values can be equal or different; and R18 is independently specified from halogen and hydroxy; or its pharmaceutically acceptable salt. Also the invention refers to their pharmaceutical compositions and methods for preparation and application thereof for cancer treatment.

EFFECT: preparation of new compounds which can find application for cancer treatment.

23 cl, 96 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel chemical compound - 1-(2-isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo [3,2-d]pyrimidin-4-one and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds and use thereof. Disclosed compound has myeloperoxidase enzyme inhibiting properties.

EFFECT: compounds are especially useful in treating and preventing neuroinflammatory disorders such as Parkinson's disease, cardiovascular disorders and respiratory disorders.

3 cl, 1 tbl, 33 ex

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