Quinoline and quinazoline derivatives with affinity to 5ht1-receptors

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline or quinazoline derivatives of general formula

Ib, where R1 is C1-6-alkyl or C1-6-alkoxy; X is N or CH; R3 and R4 independently denote hydrogen, C1-6-alkyl, C1-6-alkylsulphonyl or a group of formula (IIa), where A is oxygen or sulphur; D is -(CH2)t, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur, (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or a group of formula (IIb), where A is oxygen or sulphur; D is -(CH2)t-, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or R3 and R4 together with the nitrogen atom with which they are bonded form a 3-7-member ring or a 6-10-member bicyclic ring which can be saturated, partially saturated or unsaturated and contain 1, 2 or 3 heteroatoms selected from nitrogen, sulphur and oxygen, where each group is optionally substituted with 1 or 2 substitutes selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where aryl and aryl-C1-6-alkyl are also optionally substituted with 1 or 2 with C1-6-alkyls or C1-6-alkoxy). The invention also relates to use of formula Ib compounds in preparing a medicinal agent, to a pharmaceutical composition based on formula Ib compound and preparation method thereof.

EFFECT: obtaining novel quinoline and quinazoline derivatives having high affinity to 5-HT1-receptors.

12 cl, 171 ex

 

Description

The present invention relates to new compounds, to processes for their preparation, to contain their pharmaceutical compositions and to their use as drugs for treatment of disorders of the Central nervous system and other disorders.

Discovered a new class of compounds with high affinity to 5-HT1receptors and/or which are inhibitors of the reuptake of 5-HT. Therefore, in the first aspect, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salt:

in which:

R1represents halogen, cyano, C1-6-alkyl, C1-6-alkoxy, halogen-(C1-6-alkoxy or halogen-(C1-6-alkyl;

m is 0, 1, 2, 3 or 4;

X represents N or CH;

R2represents halogen, cyano, C1-6-alkyl, C1-6-alkoxy, halogen-(C1-6-alkoxy or halogen-(C1-6-alkyl;

n is 0, 1 or 2;

W represents-CH2-, -CH(C1-6-alkyl)- or-C(C1-6-alkyl)(C1-6-alkyl)-;

p is 0, 1, 2 or 3;

Y and Z together form C3-7-cycloalkenyl group, or Y represents-CH2-, -CH(C1-6-alkyl)- or-C(C1-6-alkyl)(C1-6-alkyl), and Z represents-CH2-, -CHOH-, -CHR6or CR6R7-(where R6and R7independently represent a ha shall ogen, cyano, C1-6-alkyl or C1-6-alkoxy);

R3and R4independently represent hydrogen, C1-6-alkyl, C1-6-alkylsulfonyl or a group of formula (II):

in which

r is 0, 1, 2, 3 or 4;

A represents oxygen or sulfur;

B represents a single bond or-NR8- (where R8represents hydrogen, C1-6is alkyl or aryl, where aryl optionally substituted by one or more substituents, independently selected from halogen, oxo, C1-6-alkyl, CF3, cyano, hydroxy, C1-6alkanoyl and C1-6-alkoxy);

D represents -(CH2)t-, -(CH2)tO - or-O(CH2)t-where t is 0, 1, 2, 3 or 4; and

E represents a C1-6-alkyl, halogen-(C1-6-alkyl, C3-7-cycloalkyl (optionally substituted by one or more substituents, independently selected from halogen, hydroxy, oxo, C1-6-alkyl, cyano, CF3, OCF3C1-6-alkoxy and C1-6alkanoyl), aryl (optionally substituted by one or more substituents, independently selected from halogen, oxo, C1-6-alkyl, CF3, cyano, hydroxy, C1-6alkanoyl and C1-6-alkoxy), or E is-NR9R10where R9and R10independently selected from hydrogen, C1-6and the Qila and aryl (optionally substituted by one or more substituents, independently selected from halogen, oxo, C1-6-alkyl, CF3, cyano, hydroxy, C1-6alkanoyl and C1-6-alkoxy);

or R3and R4form together with the nitrogen atom to which they are attached, 3-7-membered monocyclic heterocyclic group, or 8-11 membered bicyclic heterocyclic group, where each group is optionally substituted by one or more substituents selected from halogen, oxo, C1-6-alkyl, cyano, CF3C1-6-alkoxy, C1-6alkanoyl, aryl and aryl-C1-6-alkyl (where the aryl and aryl-C1-6-alkyl optionally additionally substituted by one or more halogen, oxo, C1-6-alkilani, cyano, CF3C1-6-alkoxy, C1-6-alkanoyl); and

R5independently represents halogen, cyano, C1-6-alkyl or C1-6-alkoxy; and

q is 0, 1, 2, 3, or 4.

The term "halogen" and its abbreviation "halo" refers to fluorine, chlorine, bromine or iodine.

The term "C1-6-alkyl" refers to containing from one to four carbon atoms, the alkyl group in any isomeric form, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.

The terms "halogen-C1-6-alkoxy or halogen-(C1-6-alkyl" are used for the description is of C 1-6-alkoxygroup or C1-6is an alkyl group, respectively, substituted by one or more Halogens. Examples include-CHCl2, -CF3, -OCF3and so on.

The term "C1-6-alkylsulfonyl" refers to the group (C1-6-alkyl)-SO2-. Examples include methylsulphonyl, ethylsulfonyl and propylsulfonyl.

The term "C3-7-cycloalkyl" refers to containing 3 to 7 carbon atoms cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "C1-6-alkoxy" refers to containing from 1 to 6 carbon atoms, linear or branched alkoxygroup (or "alkyloxy"), such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, neopentane, sec-pentox, n-pentox, isobutoxy, tert-pentox, hexose.

The term "C1-6-alkanoyl" refers to containing from 1 to 6 carbon atoms alkanoyloxy group, such as methanol (or "formyl"), ethanol (or "acetyl"), propanol, isopropanol, butanol, Isobutanol, second-butanol, pentanol, neopentyl, second-pentanol, isopentanol, tert-pentanol and hexanol.

The term "aryl", alone or as part of another group, is intended, unless otherwise specified, to refer to 3-7-membered monocyclic aromatic to LCA or 6-10-membered bicyclic aromatic ring, where one or more carbon atoms in the ring (or rings) is optionally replaced with a heteroatom independently selected from nitrogen, oxygen or sulfur. Examples of monocyclic aryl groups include phenyl, pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyrazolyl, isothiazolin, thiazolyl, isoxazolyl, furutani, furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, azepines and pyranyl. Used in this document, the term "bicyclic aromatic ring" includes bicyclic ring system, in which both rings are aromatic, and also bicyclic ring system in which one of the rings is partially or fully saturated. Examples of bicyclic aryl groups include naphthyl, indenyl, indolyl, isoindolyl, indazoles, benzimidazoles, benzoxazoles, benzothiazyl, benzofuranyl, dihydrobenzofuranyl, tetrahydrofuranyl, hinely, honokalani, hintline, ethanolic, indaily, indanyl, tetrahydronaphtyl, indolinyl, isoindolyl, tetrahydroisoquinoline, tetrahydroquinoline, benzoxazines, benzoxazines and benzodazepines. Used in this document, the term "aryl" refers to all of these groups. These groups can be attached to the remaining part of the molecule in any suitable position. For example used in this document, the term "naphthyl is, individually or as part of another group, is intended, unless otherwise specified, to refer to and 1-naftilos, and 2-naftilos group.

The term "oxo" refers to a group "=O".

The term "3-7-membered monocyclic heterocyclic group" refers to a 3-7-membered saturated, partially saturated or unsaturated ring containing 1, 2 or 3 heteroatoms selected from nitrogen, sulfur and oxygen. The term "8-11 membered bicyclic heterocyclic group" refers to an optionally substituted 8 to 11-membered bicyclic ring containing a 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, sulfur and oxygen, where each ring may be saturated, partially saturated or unsaturated. These groups can be attached to the remaining part of the molecule in any suitable position.

Implies that if R3and R4form together with the nitrogen atom to which they are attached, optionally substituted 3-7-membered monocyclic heterocyclic group or optionally substituted 8 to 11-membered bicyclic heterocyclic group, the heterocyclic group represents a N-linked heterocyclic group. Examples of N-linked 3 to 7 membered heterocyclic group include aziridinyl, azetidin, pyrrolidinyl, imidazolidinyl, pyrazolidine, isothiazolinones, t is atomidine, pyrrolyl, pyrrolidyl, pyrazolines, imidazoles, pyrazoles, triazoles, tetrazoles, piperidyl, piperazinil, morpholinyl, tiziani, azepines and azepane. Examples of N-linked 8-11-membered heterocyclic groups include 6H-thieno[2,3-b]pyrrolyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[5,1-b][1,3]thiazolyl, indolyl, isoindolyl, indazoles, benzimidazoles, decahydroquinoline, octahydro-2H-1,4-benzoxazine, octahydro-1H-cyclopent[b]pyridinyl, indolinyl, isoindolyl, tetrahydroisoquinoline, tetrahydroquinoline, benzoxazolyl, 2,3-dihydro-1,4-benzoxazines and benzodazepines.

All the above heterocyclic groups formed by R3and R4can be substituted by one or more (e.g., 1-4) substituents, which may be the same or different and which are selected from halogen, oxo, C1-6-alkyl, cyano, CF3C1-6-alkoxy, C1-6alkanoyl, aryl and aryl-C1-6-alkyl (where the aryl and aryl-C1-6-alkyl optionally additionally substituted by halogen, oxo, C1-6-alkyl, cyano, CF3C1-6-alkoxy or C1-6-alkanoyl). Optional Deputy (deputies) may be attached in any suitable position, including the atom (atoms) nitrogen, if available.

It should be understood that in formula (I) R1can be attached to the quinoline or khinazolinov GRU is ne in any convenient position. For example, it can be attached to X, if X represents CH.

In one embodiment of the invention m is 1, and R1attached in the following situation:

In one embodiment of the invention n is 0. In another example embodiment of the invention n is 1, and R2represents a C1-6-alkyl, such as methyl.

In one embodiment of the invention p is 0.

In one embodiment of the invention Y and Z form C3-7-cycloalkyl obtaining compounds, such as:

where G represents a C3-7-cycloalkenyl group, such as, for example, cyclopropyl.

In another example embodiment of the invention Y and Z independently represent-CH2-, -CH(CH3)- or-CH(OH)-.

Each R3and R4can independently be a higher group of the formula (II):

In one embodiment, of the invention of formula (II) may consist of:

where A represents oxygen or sulphur, D represents -(CH2)t-, -(CH2)tO - or-O(CH2)t-where t is 0, 1, 2, 3 or 4, and E represents C1-6-alkyl, C3-7-cycloalkyl (optionally substituted by one or more what their deputies, independently selected from halogen, hydroxy, oxo, C1-6-alkyl, cyano, CF3, OCF3C1-6-alkoxy and C1-6alkanoyl) or aryl (optionally substituted by one or more substituents, independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy, C1-6alkanoyl and C1-6-alkoxy);

or

where A represents oxygen or sulphur, D represents -(CH2)t-, -(CH2)tO - or-O(CH2)t-where t is 0, 1, 2, 3 or 4, and E represents C1-6-alkyl, C3-7-cycloalkyl (optionally substituted by one or more substituents, independently selected from halogen, hydroxy, oxo, C1-6-alkyl, cyano, CF3, OCF3C1-6-alkoxy and C1-6alkanoyl) or aryl (optionally substituted by one or more substituents, independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy, C1-6alkanoyl and C1-6-alkoxy).

In the case when E is optionally substituted aryl, he may represent, for example, a 5-7-membered monocyclic aromatic ring in which one or more carbon atoms in the ring (for example, 1-4 atom) optionally replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur (such as the to, for example, phenyl or pyridyl), where the ring is optionally substituted by one or more substituents independently selected from oxo, halogen, C1-6-alkyl, CF3, cyano, hydroxy, C1-6alkanoyl and C1-6-alkoxy; or E may represent, for example, 9-10-membered bicyclic aromatic ring in which one or more carbon atoms in the ring (for example, 1-4 atom) optionally replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur (such as, for example, tetrahydrofuranyl, benzoxazolyl, benzisoxazole or indolinyl), where the ring is optionally substituted by one or more substituents independently selected from oxo, halogen, C1-6-alkyl, CF3, cyano, hydroxy, C1-6alkanoyl and C1-6-alkoxy.

Examples of E include:

- C1-6-alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl;

- C3-7-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

is phenyl (optionally substituted by 1, 2 or 3 substituents, independently selected from CF3, cyano, C1-6-alkoxy, C1-6-alkyl and halogen);

- 3-7-membered monocyclic aromatic ring, such as:

where w is 0, 1, 2, 3 or 4, and R represents oxo, halogen, C1-6-alkyl, CF31-6-alkanoyl or C1-6-alkoxy, where R can be attached to any available atom, including any available nitrogen atoms; and

- 6-10-membered bicyclic aromatic ring, such as:

where w is 0, 1, 2, 3 or 4, and R independently represents oxo, halogen, C1-6-alkyl, CF3, cyano, hydroxy, C1-6-alkanoyl or C1-6-alkoxy, where R can be attached to any available atom, including any available nitrogen atoms.

In the case when E is-NR9R10(where R9and R10independently selected from hydrogen, C1-6the alkyl and aryl), examples of E include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamine, neopentylene, sec-pentylamine, n-pentylamine, isopentylamine, tert-pentylamine, hexylamine; dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamine, di-sec-butylamino, di-tert-butylamino, diphenhydamine, dineopentyl, digoxigenin, butylmethylamine, isopropylethylene, ethylisopropylamine, ethylmethylamino; monoarylamino, such as aniline; and mono-C1-6-ankylosauridae, such as-N(CH3)phenyl.

In the case when R3and R4form together with economista, to which they are attached, optionally substituted 3-7-membered monocyclic heterocyclic group, it can represent, for example, a 4 to 6 membered monocyclic heterocyclic group, optionally substituted by one or more (e.g. 1, 2, 3, or 4) substituents selected from oxo, halogen, C1-6-alkyl, cyano, CF3C1-6-alkoxy, C1-6alkanoyl, aryl and aryl-C1-6-alkyl (where the aryl and aryl-C1-6-alkyl optionally additionally substituted by one or more halogen, oxo, C1-6-alkilani, cyano, CF3C1-6-alkoxy or C1-6-alkanoyl). Examples include:

where w is 0, 1, 2, 3 or 4, and R independently represents halogen, oxo, C1-6-alkyl, cyano, CF3C1-6-alkoxy, C1-6-alkanoyl, aryl or aryl-C1-6-alkyl, where aryl and aryl-C1-6-alkyl optionally additionally substituted by one or more (e.g., 1-3) substituents selected from halogen, oxo, C1-6-alkyl, cyano, CF3C1-6-alkoxy and C1-6alkanoyl. Examples of R include halogen, such as fluorine or chlorine; C1-6-alkyl, such as methyl, ethyl, propyl and/or isopropyl; C1-6-alkoxy, such as methoxy or ethoxy; aryl, such as phenyl or pyridi is, each of which is optionally substituted by one or two C1-6-alkyl groups such as methyl, ethyl, propyl or isopropyl; and aryl-C1-6-alkyl, such as pyridylmethyl, optionally substituted by one or two C1-6-alkyl groups such as methyl, ethyl, propyl or isopropyl. R can be attached to any available atom in the above groups, including any available nitrogen atoms.

In the case when R3and R4form together with the nitrogen atom to which they are attached, optionally substituted 8 to 11-membered bicyclic heterocyclic group, it can represent, for example, 8-10-membered bicyclic heterocyclic group, optionally substituted by one or more (e.g. 1, 2, 3, 4, or 5) substituents selected from oxo, halogen, C1-6-alkyl, cyano, CF3C1-6-alkoxy, C1-6alkanoyl, aryl and aryl-C1-6-alkyl (where the aryl and aryl-C1-6-alkyl optionally additionally substituted by one or more halogen, oxo, C1-6-alkilani, cyano, CF3C1-6-alkoxy or C1-6-alkanoyl). Examples include:

where w is 0, 1, 2, 3 or 4, and R independently represents halogen, oxo, C1-6-alkyl, cyano, CF3C1-6-alkoxy, C1-6-alkanoyl, aryl or aryl-C1-6/sub> -alkyl, where aryl and aryl-C1-6-alkyl optionally additionally substituted by one or more halogen, oxo, C1-6-alkilani, cyano, CF3C1-6-alkoxy or C1-6-alkanolamine. Examples of R include halogen, such as fluorine or chlorine; C1-6-alkyl, such as methyl, ethyl, propyl and/or isopropyl; C1-6-alkoxy, such as methoxy or ethoxy; aryl, such as phenyl or pyridyl, each of which is optionally substituted by one or two C1-6-alkyl groups such as methyl, ethyl, propyl or isopropyl; and aryl-C1-6-alkyl, such as pyridylmethyl, optionally substituted by one or two C1-6-alkyl groups such as methyl, ethyl, propyl or isopropyl. It should be noted that R can be attached to any available atom in the above groups, including any available nitrogen atoms.

In one embodiment of the invention q may be 0. In another example embodiment of the invention q is 1, and R5is a halogen, such as fluorine attached to the phenyl group in the formula (I) in the para-position relative to the group-NR3R4.

In one example of the invention, the compounds of the present invention can have the General formula (Ia):

in which:

R1represents halogen, tzia is about, C1-6-alkyl, C1-6-alkoxy, halogen-(C1-6-alkoxy or halogen-(C1-6-alkyl;

m is 0, 1, 2, 3 or 4;

X represents N or CH;

p is 1, 2, 3 or 4;

Y represents-CH2-, -CH(C1-6-alkyl)- or-C(C1-6-alkyl)(C1-6-alkyl)-;

Z represents-CH2-, -CHOH-, -CHR6or CR6R7-, where R6and R7independently represent halogen, cyano, C1-6-alkyl or C1-6-alkoxy;

R3and R4independently represent hydrogen, C1-6-alkyl, C1-6-alkylsulfonyl or a group of formula (II):

in which:

r is 0, 1, 2, 3 or 4;

A represents oxygen or sulfur;

B represents a single bond or-NR8-, where R8represents hydrogen, C1-6is alkyl or aryl, optionally substituted by one or more substituents, independently selected from halogen, oxo, C1-6-alkyl, CF3, cyano, hydroxy, C1-6alkanoyl and C1-6-alkoxy;

D represents -(CH2)t-, -(CH2)tO - or-O(CH2)t-where t is 0, 1, 2, 3 or 4; and

E represents a C1-6-alkyl, halogen-(C1-6-alkyl, C3-7-cycloalkyl (optionally substituted by one or more halogen, hydroxy, oxo, C1-6-alkilani, cyano, CF3, OCF 3C1-6-alkoxy or C1-6-alkanoyl) or aryl (optionally substituted by one or more substituents, independently selected from halogen, oxo, C1-6-alkyl, CF3, cyano, hydroxy, C1-6alkanoyl and C1-6-alkoxy); or E is-NR9R10(where R9and R10independently selected from hydrogen, C1-6of alkyl and aryl, optionally substituted by one or more substituents, independently selected from halogen, oxo, C1-6-alkyl, CF3, cyano, hydroxy, C1-6alkanoyl and C1-6-alkoxy);

or R3and R4form together with the nitrogen atom to which they are attached, 3-7-membered monocyclic heterocyclic group (optionally substituted by 1-4 substituents, which may be the same or different and are selected from halogen, oxo, C1-6-alkyl, cyano, CF3C1-6-alkoxy and C1-6alkanoyl);

R5independently represents halogen, cyano, C1-6-alkyl or C1-6-alkoxy; and

q is 0, 1, 2, 3, or 4.

In another example embodiment of the invention the compounds of the present invention can have the General formula (Ib):

in which X, R1, R3and R4defined for formula (I).

All the characteristic features and options construction f is rmula (I) apply to formulae (Ia) and (Ib), with the necessary changes.

Specific compounds of the present invention include presented hereinafter in the examples No. 1-170 (E1-E170). For example, the present invention relates to the following compounds:

3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-ONU;

N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N'-phenylacetone;

N-[2-(metiloksi)phenyl]-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea;

1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone;

2,4-dimethyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-thiazole-5-carboxamide;

N-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;

2-fluoro-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide;

3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-1,3-oxazolidin-2-ONU;

3-(3-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-ONU;

1-methyl-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone;

1-(4-fluoro-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone;

3-(4-fluoro-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-ONU;

1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl)phenyl)-2,4-imidazolidinedione;

1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}is enyl)-1,3-dihydro-2H-imidazol-2-ONU;

1-methyl-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-ONU;

4,4-dimethyl-1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone;

and their pharmaceutically acceptable salts.

The compounds of formula (I) can form salts accession acids. Note that for use in medicine, the salts of the compounds of formula (I) must be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts are obvious to those skilled in the art and include salts presented in J. Pharm. Sci., 1977, 66, 1-19, such as salt accession acids, formed with inorganic acids, for example hydrochloric, Hydrobromic, sulfuric, nitric, itestosterone, metaphosphoric or phosphoric acid; and formed with organic acids such as succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, triperoxonane, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfonate, satynowej, mucus, hentaimovi, isonicotinic, sugar, glucuronic, frankenboob, glutamic, ascorbic, Anthranilic, salicylic, phenylacetic, almond, monowai (pambou), econsultancy, Pantothenic, stearic, sulfinilbis, alginic and the galacturonic acid; and educated with arylsulfonic the diversified acid, for example, benzosulfimide, para-toluensulfonate, methanesulfonate or naphtalenesulfonic acid; salts of attaching the base formed with alkali metals and alkaline earth metals, and organic bases such as N,N-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and an internal salt. Some compounds of formula (I) can form salts accession acid is less than one, with one or more equivalents of an acid, for example, with the formation of the dihydrochloride. In the scope of the present invention includes a stoichiometric or non-stoichiometric form. Salts containing a physiologically acceptable anion or cation included in the scope of the present invention as an intermediate product suitable for obtaining physiologically acceptable salts and/or for non-use, for example, in vitro.

The compounds of formula (I) can be obtained in crystalline and non-crystalline form, and in crystalline form may not necessarily form a hydrate or MES. In the scope of the present invention included a stoichiometric hydrate and a solvate, and also compounds containing various amounts of water and/or solvent.

Specific compounds of formula (I) can exist stereoisomeric forms (for example, in the form of geometric (or "CIS-TRANS) isomers, diastereomers and enantiomers), and the present invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated from each other by conventional methods, and any given isomer may be obtained by stereospecific or asymmetric synthesis. The present invention also extends to any and all tautomeric forms and mixtures thereof. Under the scope of the present invention is applicable to all such isomers, including mixtures.

The compounds of formula (I) can be obtained in accordance with the methodologies presented in this document or similar.

The scheme for obtaining compounds of formula (I)in which m is 1, R1represents methyl, p is 0, n is 0 and q is 0, is the following:

The above scheme can be adapted to obtain the compounds of formula (I)in which m is not equal to 1, R1is not the stands and is in a position other than the above, and p, n and q is not equal to 0.

The compounds of formula (I)in which Y and Z together form C3-7-cycloalkenyl group, can be obtained in accordance with the methodologies presented in this document or similar.

A typical scheme polycrystaline formula (I), in which Y and Z together form cyclopropylamino group, and in which m is 1, R1represents methyl, p is 0, n is 0 and q is 0, is the following:

where the values of X, R3and R4defined for the compounds of formula (I).

Thus, the processing of the above piperazine 2-arylacetamide results enamine, which can be processed under the reaction conditions known to a person skilled in the technical field, for example in the reaction of cyclopropylamine Simmons-Smith using diodata and diethylzinc, to obtain the compounds of formula (I)in which Y and Z together form C3-7-cycloalkenyl group. The above scheme can be adapted to obtain the compounds of formula (I)in which m is not equal to 1, R1is not the stands and is in any position other than above, p, n, and q is not equal to 0, and Y and Z form C3-7-cycloalkenyl a group other than cyclopropylamino.

Alternatively, the interaction of aromatic nucleophile such as a Grignard reagent (M=MgX) or argillite (M=Li), with cycloalkenyl the epoxide (where n=0, 1, 2) optionally in the presence of a catalyst, such as a halide of copper(I), can lead to the formation of an alcohol intermediate product as shown in the diagram above. The alcohol can in order to be properly converted to a ketone using a suitable oxidant, for example pyridinylamino. Then the ketone can be converted to the compound of formula (I) using methods presented in the previous diagram.

The schematic above illustrates the case when p is 0, but can be adapted for cases where p is not equal to 0.

Alternatively, the interaction of aromatic nucleophile such as a Grignard reagent (M=MgX) or argillite (M=Li), with α,β-unsaturated ketone (where n=1, 2) in the presence of a catalyst, such as a halide of copper(I), can lead to the formation of cycloalkylation product. Then the ketone can be converted to the compound of formula (I) using the above methods.

The schematic above illustrates the case when p is 0, but can be adapted for cases where p is not equal to 0.

Alternatively, the processing of substituted 2-phenylacetylide with diazomethane can lead to a mixture of regioisomers 1,2 - and 1,3-cyclobutadiene derivatives (Synthesis, 1977, (6), 411). Then the ketone regioisomers can be converted to the compound of formula (I) using the above methods.

The above scheme and lustrium case when p is 0, but can be adapted for cases where p is not equal to 0.

The compounds of formula (I) can also be obtained in accordance with the scheme below. The engagement of the substituted benzaldehyde with a reagent, such as ethoxymethylenemalononitrile, in the presence of a suitable base, for example potassium carbonate or sodium methoxide, yields a simple enol ether. Simple enol ether may be subjected to hydrolysis in acidic conditions, for example, using aqueous hydrochloric acid, optionally in a suitable co-solvent, such as tetrahydrofuran, to obtain the substituted 2-phenylacetaldehyde derived. The aldehyde can be connected with the restoration of 5-(1-piperazinil)quinoline or hinazolinam connection in conditions familiar to the person skilled in the technical field, for example, using triacetoxyborohydride sodium or laborgerate sodium. The product can be converted to the compound of formula (I) using the previously presented methods (if aromatic substituents do not always contain a group of the formula-NR3R4).

The schematic above illustrates the case when p is 0, but can be adapted for cases where p is not equal is 0.

Alternatively, the compounds of formula (I) can be obtained in accordance with the following scheme. Carrying out the esterification of the derived 3-aminophenylarsonic acid in acidic conditions in an alcohol solvent, e.g. methanol solution trimethylsilylpropyne, yields a hydrochloride acetate ester. The engagement hydrochloride acetate ester reagent, such as 2-halogenosilanes or its synthetic equivalent, for example the sequential addition of phosgene (or its equivalent, such as carbonyldiimidazole, disuccinimidyl) and 2-halogenation (Y=NH2or 2-halogenated (Y=OH), optionally in the presence of a base, results in an intermediate product, where X is defined above a leaving group. Processing the intermediate product of a strong base such as sodium hydride, yields cyklinowanie product. The reduction of the ester group with a suitable reagent, such as lithium borohydride, yields a derived 3-phenylethanol. Conversion of the alcohol group in stretching sulphonate group, for example, by performing interaction sulfonic anhydride or sulphonylchloride, such as methanesulfonamido, optionally in the presence of a suitable base, results in the receipt of the connection, which can be converted to the compound of formula (I) in accordance with the above methods.

Thus, in an additional aspect, the present invention relates to a method for obtaining compounds of formula (I) or its pharmaceutically acceptable salt, comprising the stage of:

(a) converting compounds of formula (III):

in which the values of R1, m, X, R2, n, W, p, Y, Z, R5and q defined for formula (I), or

(b) for compounds of formula (I)in which Y and Z form cyclopropylamino group, converting the compounds of formula (IV):

in which the values of R1, m, X, R2, n, W, p, R3, R4, R5and q defined for formula (I), or

(C) interaction of the compounds of formula (V):

in which the values of R1, m, X, R2, n, W, p, Y, Z, R5and q defined for formula (I), and L represents a leaving group, with a compound of formula (VI):

R3R4NH (VI)

in which the values of R3and R4defined for formula (I); or

(d) interaction of the compounds of formula (VII):

in which the values of R1, m, X, R2and n defined for formula(I), with the compound of the formula (VIII)

in which the values of W, p, Y, Z, R5, q, R3and R4defined for formula (I), and L represents a leaving group; or

(e) for compounds of formula (I)in which Z represents a-CH(OH), the interactions of a given stage (d) compounds of the formula (VII) with the compound of the formula (XIII):

in which the values of W, p, Y, Z, R5, q, R3and R4defined for formula (I); or

(f) for compounds of formula (I)in which Y and Z form C3-7-cycloalkenyl group interaction defined above of compounds of formula (VII) with the compound of the formula (XIV):

in which the values of R5, R2, R3and q defined for formula (I), a is 0, 1, 2, 3 or 4; or

(g) for compounds of formula (I), in which the group W, or Y, is attached to the nitrogen atom in piperazino group in the formula (I)represents CH2or CH(C1-6-alkyl), interactions defined above of compounds of formula (VII) with the compound of the formula (XV):

in which the values of R3, R4, R5, q, Z, Y and W are defined for formula (I), b is 0, 1 or 2, and Q represents hydrogen or C1-6-alkyl;

then optional for each of the stages (a)-(g):

remove any protective group and/or

conversion of compounds of formula (I) into another compound of formula (I) and/or

get pharmaceutically acceptable salt.

At the stage of (a) compound of formula (III) transform to obtain the compounds of formula (I) using standard well-known specialist reduction reactions, for example by interaction with iron and NH4OH obtaining the compounds of formula (I)in which R3and R4represent hydrogen. Then these compounds can be converted to other below the compounds of formula (I). The compounds of formula (III) can be obtained in accordance with the presented in this document, the methods according to the literature methods, or according to similar methods.

The compound of formula (I)in which Y and Z together form cyclopropylamino group, can be obtained at stage (b) by converting the compounds of formula (IV). As described above, the reaction conversion can represent, for example, the reaction of the Simmons-Smith. The compounds of formula (IV) can be obtained in accordance with the presented in this document, the methods according to the literature methods, or according to similar methods. For example, the compounds of formula (IV) can be obtained through the implementation of the EOI is to interact defined above of compounds of formula (VII) with the compound of the formula (XVI):

in which values of p, W, R3, R4, R5and q defined for formula (I).

At the stage (c) carry out the interaction of the compounds of formula (V) with the compound of the formula (VI). The interaction may be carried out under conditions known to the person skilled in the technical field, for example, optionally in the presence of a catalyst based on copper. The compounds of formula (V) can be obtained in accordance with the presented in this document, the methods according to the literature methods or in accordance with similar methods.

At stage (d) interact formula (VII) with the compound of the formula (VIII). Suitable conditions for the reaction in stage (d) include the use of a base, such as triethylamine or N, N-diisopropylethylamine, in a suitable solvent, such as dimethylformamide, acetonitrile, dimethylsulfoxide or N-methylpyrrolidinone, with optional heating of the reaction mixture to a temperature of 30-200°C, preferably up to 50-150°C.

Suitable leaving groups for conducting aliphatic nucleophilic substitution (J. March, Advanced Organic Chemistry, 4thEdition, John Wiley and Sons, 1992, pp.351-356) include, without limitation: halides such as chloro, bromo and iodide; sulfate; esters of sulfonic acids, such as toilet, brasilit, nosrat and mesilate; dialkyl the veil; hydronium ions; perchlorates, butylate (esters ammonioalkyl); activated esters of sulfonic acids, for example persulfonic, triftorbyenzola, nonflat and TResult; galogenovye ions; diethylamine and salts of 1-pyridinium.

Suitable leaving groups for conducting aromatic substitution (J. March, Advanced Organic Chemistry, 4thEdition, John Wiley and Sons, 1992, pp.652-653) include, without limitation: halides, such as fluorescent, chloro, bromo and iodide; trialkylamine; diazo; sulfate; esters of sulfonic acids, such as toilet, brasilit, nosrat and mesilate; phenylsulfanyl, phenylsulfonyl; activated esters of sulfonic acids, for example persulfonic, triftorbyenzola, nonflat and TResult; phosphate; dialkylphosphate; nitro; alkoxy; aryloxy; alkylsulfonyl and alkylsulfonyl.

The compounds of formula (VIII) can be obtained, for example, by converting compounds of the formula (XVII):

in which the values of W, p, Y, Z, R3, R4, R5and q defined for formula (I), for the introduction of the leaving group L, for example, by interaction with MeSO2Cl.

The present invention relates to a method for defined above of compounds of formula (Ia) or its pharmaceutically acceptable salts, including the implementation phase of the interaction of the compounds of formula (XVIII):

in which the values of R 1, m, X, Y, p, Z, R5and q are defined above for formula (Ia)with compound (compounds)containing a suitable functional group (s)who is (are) capable of interacting with the compound of the formula (XVIII) with a compound of formula (I). The compounds of formula (XVIII) can be obtained in accordance with the presented in this document, the methods according to the literature methods or in accordance with similar methods.

The compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques. For example, as an example, but not limitation, the following reactions are possible transformations include acylation with a suitable allermuir agent such as acetylchloride, alkylation using a suitable alkylating reagent, such as methyliodide, and the sulfonation using sulphurouses reagent, such as methanesulfonyl anhydride. For example, to obtain the compounds of formula (I)in which R3and R4independently represents a C1-6-alkylsulfonyl, can be carried out the interaction of the compounds of formula (I)in which R3and R4represent hydrogen, C1-6-alkylsulfonamides. To obtain the compounds of formula (I)in which R3and R4independently depict ablaut a compound of formula (II), can be made the interaction of the compounds of formula (I)in which R3and R4represent hydrogen, with a compound of formula (XIX):

in which r, A, B, D, and E are defined above for formula (II), and Q represents a suitable leaving group such as chlorine, or represents-OH, when r is 0. To obtain the compounds of formula (I)in which a represents a-NR8can be used suitable isocyanate or isothiocyanate. On the other hand, to obtain the compounds of formula (I)in which R3and R4form together with the nitrogen atom to which they are attached, 3-7-membered monocyclic heterocyclic group, for communicating with the compound of the formula (I)in which R3and R4represent hydrogen, may be used suitable chloroformate or isocyanate.

Specialist in the art will note that in the implementation of the above techniques may be required to protect specific reactive substituents. Can apply standard methods of introducing and removing the 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 is selected or triphenylethylene derivatives. The group of carboxylic acids can be protected in the form of esters. Aldehyde or ketone group may be protected as acetals, ketals, thioacetals or tionately. Removing protection from such groups achieve by conventional methods, well known in the art. For example, protective groups such as tert-butoxycarbonyl, can be removed using acid such as hydrochloric or triperoxonane acid, in a suitable solvent, such as dichloromethane, diethyl ether, isopropanol or mixtures thereof.

Pharmaceutically acceptable salts can be traditionally obtained through interaction with the appropriate acid or acid derivative.

The affinity of the compounds of the present invention to 5-HT1A-, 5-HT1Band 5-HT1Dreceptors can be determined using the following method of analysis. Expressing 5-HT1A-receptors in CHO cells (4×107cells/ml) homogenized in Tris buffer and stored in aliquot 1 ml of Expressing the 5-HT1B-receptors in CHO cells (4×107cells/ml) homogenized in Tris buffer and stored in aliquot 1.5 ml of Expressing the 5-HT1D-receptors in CHO cells (1×108cells/ml) homogenized in Tris buffer and stored in aliquot 1 ml of cell Suspension (0.4 ml) were incubated for 45 minutes PR is 37°C in Mg of Tris HCl buffer (pH=7,7) with test drug and [ 3H]-5-HT (4 nm) for 5-HT1B/1Dreceptors or with [3H]WAY100635 (1 nm) for 5-HT1A-receptors. Each test drug was tested at 10 concentrations (final concentration of 0.01 mm to 0.3 nm) measurement of nonspecific binding using 0.01 mm 5-HT. The total volume of the analyzed sample is 0.5 ml Incubation was stopped by conducting rapid filtration using a Packard Filtermate and measured the radioactivity on a Topcount scintillation counter. The pKi values were calculated based on the IC50obtained by using the processing program of the curves for the iterative version of the method of least squares.

Alternatively, the functional activity can be measured using the following Protocol assessment GTPγS binding. Used in the study cells were the cells of the Chinese hamster ovary (CHO) and embryonic stem cells human kidney (HEK293). The cells were transfusional DNA encoding the receptor of the person.

Cell line

HEK293_5-HT1A

CHO_5-HT1B

CHO_5-HT1D

Compounds were initially dissolved in 100% dimethylsulfoxide at a concentration of 10 mm. Serial dilution of drug in 100% dimethyl sulfoxide was performed using a Biomek FX. The maximum final concentration of compounds in the analyzed sample was 3 μm. In solid white 384-well analiticheskii the first tablet (Costar) was added compound in 1.0% of the total volume of the analyzed sample (TAV). Then 50% of TAV was added to the pretreated membrane for 90 minutes at room temperature; 5 µg/well), affine granules Wheatgerm Agglutinin Polystyrene Scintillation Proximity Assay (RPNQ0260 Amersham International; 0.25 mg/well) in 20 mm HEPES-buffer (pH=7,4), 100 mm NaCl, 3 mm MgCl2and 10 μm GDP. Then 20% of TAV was added to the buffer for agonist or EC80final concentration analysis (FAC) agonist for the 5 HT agonist in the buffer for analysis. The analysis was initiated by addition of GTPγS (0,38 nm FAC) in 29% of TAV. After all additions, the plates were incubated at room temperature for 2-3 hours. Counting the tablets was carried out on Viewlux (filter 613/55) for 5 minutes. Counting the tablets were carried out in the period of 2-6 hours after the final addition.

The compounds specified in the examples below were tested and it was shown that the value of the pKi compounds in relation to 5-HT1Areceptors exceed 6.0, and many of the compounds have a significantly higher affinity (pKi values in the range of 8.0 to 10.0). Some compounds of the present invention have comparable affinity to 5-HT1Band 5-HT1D-receptors.

The internal activity of the compounds of the present invention may be determined in accordance with the following method of analysis. Cell membrane HEK293 stably expressing the 5-HT1Areceptors of the man, and the cell membrane is wound CHO, stably expressing the 5-HT1Breceptors person, homogenized in containing EDTA HEPES-buffer and stored in aliquot 1 ml, and performed studies of the binding of [35S]GTPγS essentially as described Lazareno et al, Life Sci., 1993, 52, 449) with a few minor changes. Membranes from 106cells pre-incubated at 30°C for 30 minutes in 20 mm HEPES-buffer (pH=7,4) in the presence of MgCl2(3 mm), NaCl (100 mm), GDP (10 μm) and ascorbate (0.2 mm), with or without added test compounds. The reaction was initiated by adding 50 μl of [35S]GTPγS (concentration in the analyzed sample of 100 PM)and then further incubated for 30 minutes at 30°C. Nonspecific binding was defined using previously added to the membranes of its radioactive isotope GTPγS (20 μm). The reaction was stopped by fast filtration through filters Whatman GF/B, and then washed with 5×1 ml ice-cold HEPES buffer (20 mm)containing MgCl2(3 mm). Radioactivity was measured by the method of liquid-scintillation spectrometry. This technique is hereafter in this document referred to as functional analysis of binding of [35S]GTPγS.

Using functional analysis of binding of [35S]GTPγS was shown that some compounds of formula (I) are antagonists of 5-HT1receptors, t is when others are inverse agonists, agonists or partial agonists.

The ability of the compounds of the present invention to inhibit the reuptake of serotonin can be measured using the method of analysis capture 5-HT by measuring the capture of [3H]5-HT LLCPK cells expressing the serotonin transporters humans or rats. Briefly, cells were grown and placed in 96-well plates (10,000 cells per well). After 24 h the cells were twice washed HBSSH (balanced salt Hanks solution with 20 mm HEPES). To each well was added 50 μl of test compound or solvent, and incubated for 10 minutes. Then add [3H]5-HT (final concentration 25 nm) and further incubated test the mixture for 7 minutes. The reaction was stopped by aspiration of the tested mixture, the cells are washed 6 times HBSSH, was added to the cells, 50 μl of scintillation cocktail account (Microscint-20, Packard) and hermetically closed top and bottom of the tablet. Reading on tablets spent 30 minutes on the Packard TopCount.

Alternatively, the ability of the compounds to contact the website serotonin reuptake can be assessed by analysis of binding of [3H]citalopram on recombinant epithelial cells of the kidney pig, stably transfected with SERT (hSERT/LLCPK) person. Cells were grown on Petri dishes with an area of 500 the m 2. When 80% of the closing of the monolayer of cells was transferred into a phosphate buffer solution (PBS)containing 5 mm EDTA, and centrifuged at 900 x g for 8 minutes at 4°C. the Precipitate after centrifugation of homogenized in 30-50 volumes of 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 minutes at 4°C. the Precipitate after centrifugation resuspendable in the same volume, incubated at 37°C for 20 minutes, centrifuged in the above-described conditions, and finally adjust the protein content to 0.2 mg/ml by the addition of cold buffer for analysis. For analysis of binding of [3H]citalopram mixture consisting of 100 μl of the test compounds, the buffer for analysis (to determine total binding) or paroxetine at a final concentration of 10 μm (for determination of nonspecific binding), 100 μl of [3H], resulting in a final concentration of 0.25 nm and 200 μl of membranes was diluted with buffer for analysis to protein concentration 2 μg/well. To initiate the reaction of the latter was added to the membrane and incubated for 2 h at room temperature. Then the reaction was stopped by rapid filtration through a 96-well filtration tablet GF/B, pre-soaked in 0.5% polyethylenimine (PEI) in the harvester cells Packard, washed three times 96-well filter Lancet cold 0.9% NaCl (1 ml/well) and radioactivity was counted on a Packard TopCount.

Using the analysis of capture was found that some of the examples of compounds able to contact the site of capture pIC50>6,0.

The compounds of formula (I) and their pharmaceutically acceptable salts are suitable for use in the treatment of certain CNS disorders such as depression (including bipolar depression; unipolar depression; one-time or recurring severe depression cases with symptoms of psychosis, symptoms of catatonia, signs of melancholia, atypical features or postpartum onset, or without them; seasonal depression and dysthymia; depressive disorder due to General health, including, without limitation, myocardial infarction, diabetes, miscarriage or abortion); anxiety disorders (which include General anxiety and anxiety caused by social circumstances), schizophrenia, panic disorder, agoraphobia, social phobia, a condition of compulsive neurosis, post-traumatic stress disorder, pain (particularly neuropathic pain), memory disorders (including dementia, amnestic disorders and age-related memory impairment), human behavior during meals (including the nervous and neurogenic anorexia bulimia), sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, the besso is an asylum, episodes of sleep apnea and narcolepsy), withdrawal syndrome when drug abuse (such as cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine phencyclidine and related compounds, opiates such as cannabis, heroin, morphine, sedative hypnotics, amphetamine or amphetamine related drugs such as dextroamphetamine, methylamphetamine or their combination), disorders of motor function, such as Parkinson's disease, dementia in Parkinson's disease, parkinsonism induced by neuroleptics, and late dyskinesia, as well as other mental disorders, and some disorders of the gastrointestinal tract, such as irritable bowel syndrome. The connection can also be suitable for treatment of tumors, such as tumors of the prostate gland.

It should be understood that as used in this document, the term "treatment" includes both prevention and alleviation of established symptoms.

Thus, the present invention also relates to the compound of formula (I) or its pharmaceutically acceptable salt for use as a therapeutic agent, in particular for the treatment of Central nervous system disorders, such as depression (including bipolar depression; unipolar depression; one-time or recurring severe depression cases, with the recognition of the AMI psychosis, signs of catatonia, signs of melancholia, atypical features or postpartum onset, or without them; seasonal depression and dysthymia; depressive disorder due to General health, including, without limitation, myocardial infarction, diabetes, miscarriage or abortion); anxiety disorders (which include General anxiety and anxiety caused by social conditions, schizophrenia, panic disorder, agoraphobia, social phobia, a condition of compulsive neurosis, post-traumatic stress disorder, pain (particularly neuropathic pain), memory disorders (including dementia, amnestic disorders and age-related memory impairment), human behavior in the food (including the nervous and neurogenic anorexia bulimia), sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, seizures, sleep apnea and narcolepsy), withdrawal syndrome when drug abuse (such as cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine phencyclidine and related compounds, opiates such as cannabis, heroin, morphine, sedative hypnotics, amphetamine or related amphetamine drugs, such as dextroamphetamine, methylamphetamine or their combination), disorders of motor function, such as Parkinson's disease, dementia etc the Parkinson's disease, parkinsonism induced by neuroleptics, and late dyskinesia, as well as other mental disorders, and some disorders of the gastrointestinal tract, such as irritable bowel syndrome, and tumors such as tumors of the prostate.

In particular the present invention relates to the use of compounds of formula (I) or its pharmaceutically acceptable salt as a therapeutic agent in the treatment of depression and/or anxiety.

Compounds of the present invention can be administered in combination with other active substances, such as 5HT3 antagonists, serotonin agonists, antagonists of NK-1, selective inhibitors of serotonin reuptake (SSRI), an inhibitor reuptake noradrenaline (SNRI), tricyclic antidepressants and/or dopaminergic antidepressants.

Suitable 5HT3 antagonists that can be used in combination with the compounds of the present invention, include, for example, ondansetron, granisetron, metoclopramide.

Suitable agonists of serotonin, which can be used in combination with the compounds of the present invention, include sumatriptan, rauwolscine, yohimbine, metoclopramide.

Suitable SSRI, which can be used in combination with the compounds of the present invention, include fluoxetine, citalopram, femoxetine, FL is voxamin, paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRI, which can be used in combination with the compounds of the present invention, include venlafaxine and reboxetine.

Suitable tricyclic antidepressants that can be used in combination with the compound of the present invention, include imipramine, amitriptyline, clomipramine and nortriptyline.

Suitable dopaminergic antidepressants, which can be used in combination with the compound of the present invention, include bupropion, amineptine.

It should be noted that the compounds of the combinations or compositions can be administered simultaneously (in the same or in different pharmaceutical compositions), separately or sequentially.

The present invention relates to a method of treating the above disorders in mammals, including humans, which includes an introduction to the patient a therapeutically safe and effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to the use of compounds of formula (I) or its pharmaceutically acceptable salt for a medicinal product for the treatment of the above disorders.

For use in therapy, the compounds of formula (I) is usually included in the composition of the pharmaceutical companies who stand in accordance with standard pharmaceutical practice.

The present invention also relates to a pharmaceutical composition which contains a compound of the formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient.

In an additional aspect, the present invention relates to a method for preparing a pharmaceutical composition, which comprises mixing the compounds of formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient.

The pharmaceutical composition may be prepared by mixing at a suitable temperature and a suitable atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, liquid preparations for oral administration, powders, granules, pastilles, resuspending powders, injectable or input by infusion solutions or suspensions, or suppositories. Generally preferred are oral input composition.

Tablets or capsules for oral administration may be in the form of a single dosage form and may contain conventional excipients such as binders (e.g., pre-gelatinizing corn starch, polyvinylpyrrolidone is whether hypromellose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants for tabletting (for example, magnesium stearate, talc or silica); disintegrating agents (e.g., potato starch or matrikamantra); and acceptable wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated according to well known in normal pharmaceutical practice methods.

Liquid preparations for oral administration can be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product intended for restoration of water or other suitable solvent before use. Such liquid preparations may contain conventional additives such as suspendresume agents (for example, morbity syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous solvents (which may include edible oils, for example almond oil, esters of natural oils, ethyl alcohol or separated into fractions of vegetable oils), preservatives (for example, methyl-para-hydroxybenzoate or propyl-para-hydroxybenzoate or sorbic acid) and, if necessary and as appropriate,traditional flavors and dyes, buffer salts and sweeteners. Preparations for oral administration can be formulated in such a suitable way to provide a controlled release of the active connection.

Liquid dosage forms for parenteral administration are prepared using the compounds of the present invention or its pharmaceutically acceptable salt and a sterile solvent. Injectable formulations can be presented in the form of a single dosage form, for example in ampoules or in a form for multiple dosed introduction of using the compounds of the present invention or its pharmaceutically acceptable salt and sterile solvent, optionally with the addition of preservative. The composition can be in such forms as suspensions, solutions or emulsions in oily or aqueous solvent, and may contain auxiliary agents, such as suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form to restore a suitable solvent, such as sterile pyrogen-free water, before use. Depending on the solvent and the applied concentration in the solvent, the compound may be dissolved or suspended. In preparing solutions the compound mo is et to be dissolved for injection and sterilized on the filter before filling a suitable vial or ampoule and sealing. Order of benefits, the solvent can be dissolved adjuvants such as local anesthetics actions, preservatives and tabularasa agents. To increase stability after filling the bottle, the composition can be frozen, and the water can be removed in vacuum. Suspensions for parenteral administration are prepared in essentially the same way, except that instead of dissolving the compound is suspended in the solvent, and sterilization is not followed by filtration. The connection can be sterilized by treatment with ethylene oxide before suspendirovanie in a sterile solvent. The purpose of benefits, to facilitate uniform distribution of the compounds in the composition include surface-active compound or a wetting agent.

Lotions can contain water or oil-based and, as a rule, can also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspendida agents, thickeners or dyes. Drops can contain an aqueous or nonaqueous basis, and one or more dispersing agents, stabilizing agents, solubilization or suspendida agents. They may also contain a preservative.

Compounds of the present invention can also be included inof the compositions for rectal administration, such as suppositories or retention enemas, e.g. containing conventional for the suppository base such as cocoa butter or other glycerides.

Compounds of the present invention may also be included in the composition of long-acting drugs. These long-acting drugs can be administered by implantation (for example, subcutaneous or intramuscular) or by intramuscular injection. So, for example, the compounds of the present invention can be included in the composition containing suitable polymeric or hydrophobic materials (for example, in the form of an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

Intranasal composition, containing the compounds of the present invention, may be in the form of solutions for injection by means of a suitable device for dosed or a single injection or, alternatively as a powder mix with a suitable carrier for administration using a suitable feeding device. Thus, the compounds of formula (I) can be included in the composition for oral, transbukkalno, parenteral, local (including ophthalmic and nasal), rectal injection or injection with prolonged action, or ahadiths in the form, suitable for administration by inhalation or insufflation (or through the nose or through the mouth).

Compounds of the present invention can be included in the composition for local application in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear drops or nose drops). In the composition of ointments or creams, for example, may include aqueous or oily base with the addition of suitable thickeners and/or gelling agents. Ointment for introduction into the eye can be performed in a sterile form using sterilized components.

Depending on the method of administration, the composition may contain from 0.1 wt.% up to 99 wt.%, preferably from 10 to 60 wt.%, the active substance. The dose of a compound used to treat the above disorders, varies in the usual manner according to the severity of the disorder, the patient's weight and other similar factors. However, as a General guide suitable single dose can range from 0.05 to 1000 mg, more convenient from 1.0 to 200 mg, and each single dose may be administered more than once a day, for example twice or three times a day. Such treatment can last up to several weeks or months.

All publications, including without limitation the patents and patent applications mentioned in the present description, included in or incorporated by reference, kakali would be specifically and expressly noted, each separate publication in its entirety is incorporated into this description by reference.

The following methods of preparation and examples illustrate the compounds of the present invention, and receipt of them.

Description 1

2-Methyl-5-chinainternational (D1)

A solution of 2-methylinosine-5-ol (2.5 g; 1 EQ.) in dichloromethane (25 ml) and pyridine (6.4 ml; 5 EQ.) was cooled to 0°C for 10 minutes was added dropwise to the anhydride triftormetilfullerenov acid (4,2 ml; 1.6 EQ.). The reaction mixture was stirred under inert atmosphere at room temperature for 1 h, then was poured into water (20 ml) and was extracted with ethyl acetate (3×15 ml). The organic layers were combined, dried over Na2SO4and concentrated under reduced pressure. The crude material was purified by the method of flash chromatography, elwira with ethyl acetate/cyclohexane (4/6), obtaining specified in the connection header with the release of 92% (4,2 g).

MS; (ES) m/z: 292,3 [MH+]. C11H8F3NO3S requires 291.

1H NMR (300 MHz, d6-DMSO) δ (ppm): with 8.05 (d, 1H), a 7.85 (d, 1H), to 7.64 (t, 1H), of 7.48 (d, 1H), 7,43 (d, 1H), 2,48 (c, 3H).

Description 2

1,1-Dimethylethyl-4-(2-methyl-5-chinoline)-1-piperidinecarboxylate (D2)

To a solution of 2-methyl-5-chinainternational (D1) in toluene (20 ml) under inert atmosphere was added tert-butyl-1-piperidinecarboxylate (,6 g; 1.2 equiv.) the cesium carbonate (1.7 g; 1.5 EQ.), the palladium acetate (0.33 g; 0,14 EQ.) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0,97 mg; of 0.15 EQ.). The reaction mixture was stirred while heating under reflux in nitrogen atmosphere for 8 hours. The reaction was extinguished at room temperature by addition of a saturated aqueous solution of ammonium chloride (15 ml) and was extracted with ethyl acetate (3×20 ml). The organic layers were combined, dried over Na2SO4and concentrated under reduced pressure. The crude material was purified by the method of flash chromatography, elwira with ethyl acetate/cyclohexane (3/7), obtaining specified in the connection header with the output 62% (1.4 g).

MS; (ES) m/z: 328,4 [MH]+. C19H25N3About2requires 327.

1H NMR (500 MHz, CDCl3) δ (ppm): to 8.40 (d, 1H), 7,76 (d, 1H), to 7.61 (t, 1H), 7,29 (d, 1H), 7,06 (d, 1H), 3,69 (users, 4H), 3,03 (users, 4H), 2,74 (c, 3H)and 1.51 (c, 9H).

Description 3

2-Methyl-5-(1-piperazinil)quinoline (D3)

1,1-Dimethylethyl-4-(2-methyl-5-chinoline)-1-piperidinecarboxylate (D2) (1.1 g) in 25% solution triperoxonane acid in dichloromethane (10 ml) was stirred at room temperature under inert atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure and absoluely using 20g cartridge SCX obtaining specified in the connection header with the release of 96% (0.74 g).

MS; (ES) m/z: 228,4 [MH]+. C14 H17N3requires 227.

1H NMR (300 MHz, d6-DMSO) δ (ppm): a 8.34 (d, 1H), EUR 7.57 (m, 2H), 7,35 (m, 1H), 7,06 (m, 1H), 2,93 (osirm, 8H), 2,62 (c, 3H).

Description 4

2-(3-Nitrophenyl)ethylmethanesulfonate (D4)

To a stirred solution of 2-(3-nitrophenyl)ethanol (0.5 g; 1 EQ.) in dichloromethane (3 ml) and triethylamine (0.5 ml; 1.2 EQ.) at 0°C under inert atmosphere was added dropwise methanesulfonanilide (0,28 ml). The solution was allowed to warm to room temperature and was stirred for 5 hours. The reaction mixture was diluted with water (3 ml) and was extracted with dichloromethane (3×3 ml). The organic layers were combined, dried over Na2SO4and concentrated under reduced pressure. The crude material was purified by the method of flash chromatography, elwira gradient from dichloromethane to dichloromethane/MeOH (98/2), to obtain specified in the connection header with the release of 84% (of 0.62 g).

1H NMR (300 MHz, CDCl3) δ (ppm): 8,15 (m, 2H), 7,53 (m, 2H), of 4.45 (t, 2H), 3.15 in (t, 2H), 2,92 (c, 3H).

Description 5

2-Methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinil}quinoline (D5)

To a solution of 2-methyl-5-(1-piperazinil)quinoline (D3) (0.2 g; 1 EQ.) and 2-(3-nitrophenyl)ethylmethanesulfonate (D4) (0,22; 1 EQ.) in dimethylformamide (1.5 ml) was added N,N-diisopropylethylamine (0.8 ml; 5 EQ.). The reaction mixture was heated to 100°C for 10 hours. The dark solution was concentrated under reduced pressure, diluted with water (3 ml) and brine (1 ml) and was extracted with ethyl acetate (3×3 ml). The organic layers were combined, dried over Na2SO4and concentrated under reduced pressure. The crude material was purified by the method of flash chromatography, elwira gradient from dichloromethane to dichloromethane/MeOH (98/2), to obtain specified in the connection header with the release of 64% (0.21 g).

MS; (ES) m/z: 228,4 [MH]+. C22H24N4About2requires 376.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), 8,11 (c, 1H), with 8.05 (d, 1H), of 7.70 (d, 1H), 7,55 (m, 2H), 7,45 (t, 1H), 7,25 (m, 1H), 7,05 (d, 1H), 3,10 (MT, 4H), 2.95 and (osirm, 2H), 2,75 (osirm, 6H), 2,70 (c, 3H).

Description 6

3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6)

To a suspension of iron powder (0.07 g; 3.2 EQ.) and ammonium chloride (0.1 g; 5.3 EQ.) in water (3 ml) was added dropwise a solution of 2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinil}quinoline (D5) (0.14 g; 1 EQ.) in methanol (3 ml). Participating in the reaction substance was heated under reflux for 8 hours, adding during the reaction with three portions of an additional quantity of iron powder (only 0.07 g; 3.2 EQ.) and ammonium chloride (0.1 g; 5,03 EQ.). The reaction mixture was filtered through Millipore filter. The filtrate was concentrated under reduced pressure, diluted with water (5 ml) and saturated aqueous sodium bicarbonate (2 ml)were extracted with ethyl acetate (3×5 ml), dried over Na2SO4and concentrated under reduced d is in relation with obtaining specified in the connection header with the release of 84% (0.11 g).

MS; (ES) m/z: 347,4 [MH]+. C22H26N4requires 346.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,55 (t, 1H), 7,25 (d, 1H), was 7.08 (m, 2H), 6,65 (MD, 1H), 6,55 (m, 2H), 3,65 (users, 2H), 3.15 in (t, 4H), 2,80 (m, 4H), 2,75 (c, 3H), 2,70 (m, 4H).

Description 7

N-Methyl-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D7)

The dihydrochloride propyl-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)carbamate (E47) (0,065 mmol) were applied to the cartridge for solid phase extraction (SCX) and suirable solution of ammonia in MeOH to obtain the corresponding free base (0,0618 mmol). Then, this base was dissolved in tetrahydrofuran (1 ml) and was treated with LiAlH4(3 EQ.). The resulting reaction mixture was heated to 70°C and was stirred for 3 h Then the reaction mixture was poured into an aqueous solution of NH4Cl at 0°C. the Aqueous phase was extracted with dichloromethane (20 ml). The organic phase was washed with water, dried over Na2SO4and concentrated under reduced pressure. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), using as eluent CH2Cl2/MeOH (98/2), to obtain specified in the connection header with the release of 43%.

MS: (ES/+) m/z: 361 [MH+]. C23H28N4requires 360.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (1H, d), of 7.70 (1H, d), the 7.65 (1H, t), 7,15-7,00 (2H, m), 6,55 (1H, d), 6,50-6,40 (2H, m), 3,15 (4H, is), 2,85-to 2.65 (8H, m), 2,80 (3H, c), 2,70 (3H, c).

Description 8

1-(3-AMINOPHENYL)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethanol (D8)

To a stirred solution of 2-methyl-5-(1-piperazinil)quinoline (D3) (1 EQ.) in tetrahydrofuran at room temperature under inert atmosphere was added sodium carbonate (1.5 EQ.) and 2-bromo-1-(3-nitrophenyl)alanon (1.5 EQ.) and leaving the reaction mixture was mixed for 1 h Then the solution was diluted with MeOH, was added NaBH4(2 EQ.) and leaving the reaction mixture was mixed for 1 h the Solvent was removed under reduced pressure. The crude material was purified on a cartridge for solid phase extraction (SCX), using as eluent a gradient from MeOH to MeOH/CH2Cl2(1/1), and then a 2M solution of NH3in MeOH, to obtain an intermediate product, which was recovered by the method similar to the one presented in the description D6, obtaining specified in the connection header with the release of 55%.

MS: (ES/+) m/z: 363 [MH+]. C22H26N4About 362 requires.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (1H, d), of 7.70 (1H, d), at 7.55 (1H, t), 7,25 (1H, d), 7,10 (1H, t), 7,05 (1H, d), 6,80-6,70 (2H, m), 6,60 (1H, DD), 4,70 (1H, DD), the 3.65 (2H, users), 3,15 (4H, users), of 3.00 (2H, osirm), 2,80-of 2.50 (7H, m).

A General method of obtaining the amides, ureas and carbamates using the approach formulated above as a starting compound:

The way A

To mix the solution and is avramidi (1 EQ.) in dioxane at room temperature in an inert atmosphere was added K 2CO3(1.5 equiv.) amide, urea or carbamate (2 equiv.) CuI (0.1 EQ.) and N,N'-dimethyl-1,2-amandemen (0.11 EQ.) and heated the reaction mixture at 90-100°C for 1-5 hours and Then the mixture was added to saturated aqueous solution of NH4Cl and extracted with dichloromethane. The organic phase is washed with saline, dried over Na2SO4and solvent was removed under reduced pressure. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), using as eluent cyclohexane/ethyl acetate (8/2), with end connections (outputs range from 18 to 99%).

Description 9

1-(3-Acetylphenyl)-2-pyrrolidinone (D9)

Specified in the title compound was obtained with the yield 98% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 1-(3-bromophenyl)Etalon and 2 pyrrolidinone.

MS: (ES) m/z: 204 [MH+]. C12H13NO2requires 203.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,15 (users, 1H), and 8.0 (DD, 1H), and 7.7 (DD, 1H), 7,45 (t, 1H), 3,95 (t, 2H), 2,65(m, 2H), 2,60 (c, 3H), 2,2 (m, 2H).

Description 10

1-(3-Acetylphenyl)-2-azetidinone (D10)

Specified in the title compound was obtained with the yield 97% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 1-(3-bromophenyl)this is it and 2 azetidinone.

MS: (ES) m/z: 190 [MH+]. C11H11NO2requires 189.

1H NMR (300 MHz, CDCl3) δ (ppm): 7,6 (d, 1H), 7,55 (DD, 1H), 7,45 (DD, 1H), 7,2 (t, 1H), 3,5 (t, 2H), 3,0 (t, 2H), 2,45 (c, 3H).

Description 11

3-(3-Acetylphenyl)-1,3-oxazolidin-2-he (D11)

Specified in the title compound was obtained with a quantitative yield according to the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 1-(3-bromophenyl)Etalon and 1,3-oxazolidin-2-it.

MS: (ES) m/z: 206 [MH+]. C11H11NO3requires 205.

1H NMR (300 MHz, CDCl3) δ (ppm): to 7.95 (m, 2H), and 7.7 (DD, 1H), 7,45 (t, 1H), and 4.5 (t, 2H), 4,2 (t, 2H), 2,6 (c, 3H).

Description 12

1-(3-Acetylphenyl)-2-imidazolidinone (D12)

Specified in the title compound was obtained with the yield of 18% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 1-(3-bromophenyl)Etalon and 2 imidazolidinone.

MS: (ES) m/z: 205 [MH+]. C11H12N2About2requires 204.

1H NMR (300 MHz, CDCl3) δ (ppm): 7,8 (m, 2H), 7,54 (DD, 1H), 7,25 (m, 1H), 5,0 (users, 1H), and 3.8 (t, 2H), 3,4 (t, 2H), 2,45 (c, 3H).

Description 13

2-(3-Bromophenyl)ethylmethanesulfonate (D13)

Specified in the title compound was obtained with the yield of 77% using techniques similar to those presented in the description D4, using as the source of a connection is to be placed 2-(3-bromophenyl)ethanol.

MS: (ES/+) m/z: 278 and 280 [MH+]. C9H11BrO3S requires 277 and 279.

1H NMR (200 MHz, CDCl3) δ (ppm): 7,40 (2H, m), and 7.5 (2H, m), and 4.40 (2H, t)of 3.00 (2H, t), 2,85 (3H, c).

Description 14

5-{4-[2-(3-Bromophenyl)ethyl]-1-piperazinil}-2-methylinosine (D14)

Specified in the title compound was obtained with the yield of 56% using techniques similar to those presented in the description D5, using as starting compounds 2-methyl-5-(1-piperazinil)quinoline (D3) and 2-(3-bromophenyl)ethylmethanesulfonate (D13).

MS: (ES/+) m/z: 412 and 410 [MH+]. C22H14BrN3requires 409 and 411.

1H NMR (400 MHz, CDCl3) δ (ppm): 8,29 (1H, d), 7,54 (2H, m), 7,35 (1H, osirm), 7,34 (1H, d), 7.23 percent (2H, m), 7,06 (1H, DD), 2,98 (4H, users), was 2.76 (2H, ushort), 2,68 (5H, users), 2,59 (2H, osirm), 2,58 (3H, c).

Description 15

2-(3-Nitrophenyl)ethyl-4-nitrobenzenesulfonate (D15)

Specified in the title compound was obtained with the yield 68% using techniques similar to those presented in the description D4, using as starting compounds 2-(3-nitrophenyl)ethanol and 4-nitrobenzenesulfonamide.

MS: (ES) m/z: 351 [MH+]. C14H12N2About7S requires 352.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,3 (m, 2H), with 8.05 (d, 1H), 8.0 to 7.9 in (m, 3H), 7.5 (m, 2H), 4,4 (t, 2H), 3,1 (t, 2H).

Description 16

7-Chloro-2-methyl-5-(1-piperazinil)quinoline (D16)

Specified in the title compound was obtained from 7-chloro-5-hydroxy-2-methylinosine the (WO/0234754) using techniques similar to the one presented in the descriptions D1, D2 and D3.

MS: (ES) m/z: 262,1 [MH]+. C14H16ClN3requires 261.

1H NMR (300 MHz, d6-DMSO) δ (ppm): at 8.36 (d, 1H), to 7.61 (d, 1H), 7,40 (d, 1H), 6,92 (d, 1H), 3,32 (m, 4H), of 2.93 (m, 4H), 2,62 (c, 3H).

Description 17

7-Chloro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinil}quinoline (D17)

Specified in the title compound was obtained with the yield of 92% using techniques similar to those presented in the description D5, using as starting compounds 7-chloro-2-methyl-5-(1-piperazinil)quinoline (D16) and 2-(3-nitrophenyl)ethyl-4-nitrobenzenesulfonate (D15).

MS: (ES) m/z: 411 [MH+]. C22H23ClN4About2requires 410.

1H NMR (300 MHz, CDCl3) δ (ppm): 8.3 (l, 1H), 8,2 (userd, 1H), 8,05 (userd, 1H), 7,7 (c, 1H), 7,55 (d, 1H), and 7.4 (t, 1H), 7,2 (d, 1H), 6,95 (c, 1H), 3,1 (osirm, 4H), 2.95 and (t, 2H), 2,8-2,6 (osirm, 6H), 2,6 (c, 3H).

Description 18

3-{2-[4-(7-Chloro-2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D18)

Specified in the title compound was obtained with the yield of 92% using techniques similar to those presented in the description D6, using as starting compound 7-chloro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinil}quinoline (D17).

MS: (ES) m/z: 381 [MH+]. C22H25ClN4requires 380.

1H NMR (300 MHz, CDCl3) δ (ppm): of 8.25 (d, 1H), 7,65 (c, 1H), 7,2 (d, 1H), 7,05 (t, 1H), 6,95 (c, 1H), and 6.6 (d, 1H), 6,5 (m, 2H), 3,6 (users, 2H), 2,8-2,5 (m, 12H), 2,65 (c, 3H).

Description 1

[3-(1H-Pyrazole-1-yl)phenyl]acetic acid (D19)

To a stirred solution of 3-bromoferrocene acid (1 EQ.) in dioxane at room temperature in an inert atmosphere was added pyrazole (1.2 equiv.) Cs2CO3(2.5 equiv.) CuI (0.5 equiv.) TRANS-1,2-cyclohexanediamine (0.6 EQ.) and dodecane (1 EQ.). The mixture was irradiated in a microwave reactor (PersonalChemistry Emrys™ Optimiser, 300 W, 160°C, 20 min), then was added to 1N. aqueous solution of NaOH and was extracted with Et2O. the Aqueous phase was acidified to pH=3 by addition of 2n. HCl, then was extracted with ethyl acetate, washed this phase brine, dried over Na2SO4and solvent was removed under reduced pressure. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), elwira gradient from cyclohexane/ethyl acetate (8/2) to cyclohexane/ethyl acetate (1/1), to obtain specified in the connection header with the release of 65%.

MS: (ES) m/z: 203 [MH+]. C11H10N2About2requires 202.

1H NMR (300 MHz, CDCl3) δ (ppm): 7.9 in (m, 1H), to 7.75 (m, 1H), 7,65 (m, 1H), 7,55 (d, 1H), 7,35 (m, 1H), and 7.3, and 7.1 (m, 2H), 6,55 (m, 1H), 3,7 (c, 2H).

Examples

A General method of obtaining amides, using as starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6):

Method B

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D) (1 EQ.) in dichloromethane at room temperature under inert atmosphere was added dropwise a triethylamine or diisopropylethylamine (1.7 equiv.) and then the acid chloride (1.5 EQ.). The reaction mixture was left to mix for 16 hours the mixture is Then washed with a saturated aqueous solution of NH4Cl, saturated aqueous NaHCO3, brine, dried over Na2SO4and solvent was removed under reduced pressure. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), using as eluent a gradient from dichloromethane/MeOH (99/1) to dichloromethane/MeOH (98/2), to obtain the final compounds (outputs range from 30 to 80%).

A General method of obtaining the amides and the corresponding dihydrochloride, using as starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6):

The method C

To a stirred solution of carboxylic acid (1.5 EQ.) in dichloromethane/dimethylformamide (1/1) at room temperature was sequentially added EDC·HCl (1.5 EQ.) and HOBt (1.5 EQ.). The reaction mixture was left to mix for 30 min and then was added dropwise 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) (1 EQ.), dissolved in dichloromethane/dimethylformamide (1/1). The solution was stirred for 16 h, then was diluted with dichloromethane and washed with saturated aqueous NaHCO3and brine, and then dried over Na2SO4. The solution was concentrated under reduced d is the pressure and removing the remaining solvent by SCX cartridges. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), elwira gradient from dichloromethane/MeOH (99/1) to dichloromethane/MeOH (98/2), to obtain the final compounds (outputs range from 20 to 96%).

The free base can be converted into the dihydrochloride by dissolving the compound in dichloromethane and added dropwise 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure to get the crude material, which was triturated with Et2O. Then by filtering the extracted target substance (quantitative yield).

Example 1

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E1)

Specified in the title compound was obtained with the yield 52% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and acetylchloride.

MS: (ES) m/z: 389 [MH]+. C24H28N4About 388 requires.

1H NMR (500 MHz, d6-DMSO) δ (ppm): 9,84 (c, 1H), with 8.33 (d, 1H), 7,58 (m, 2H), 7,46 (c, 1H), 7,39 (m, 2H), 7,19 (t, 1H), 7,10 (DD, 1H), 6,92 (d, 1H), 3,03 (osirm, 4H), 2,73 (osirm, 6H), 2,62 (c + users, 5H), 2,02 (c, 3H).

Example 2

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)propanamide (E2)

Specify the OU in the title compound was obtained with the yield 73% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and propanolol.

MS: (ES/+) m/z: 403 [MH+]. C25H30N4About 402 requires.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,55 (t, 1H), 7,50 (users, 1H), 7,25 (m, 3H), 7,12 (user, 1H), 7,07 (d, 1H), 6,98 (userd, 1H), 3,20 (osirm, 4H), 3.00 and-2,75 (osirm, 8H), 2,73 (c, 3H), is 2.37 (q, 2H), of 1.23 (t, 3H).

Example 3

2-Methyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)propanamide (E3)

Specified in the title compound was obtained with the yield 81% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-methylpropanoate.

MS: (ES/+) m/z: 417 [MH+]. C26H32N4About 416 requires.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,55 (m, 2H), 7,25 (m, 3H), 7,13 (users, 1H), was 7.08 (d, 1H), 6,98 (userd, 1H), 3,20 (osirm, 4H), 3.00 and-2,75 (osirm, 8H), 2,73 (c, 3H), 2,48 (m, 1H), 1,25 (d, 6H).

Example 4

3-Methyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)butanamide (E4)

Specified in the title compound was obtained with the yield of 64% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 3-methylbutanoate.

MS: (ES/+) m/z: 431 [MH+]. C27H34N4Will trebuet 430.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,60 is 7.50 (m, 2H), 7,30-7,20 (m, 3H), 7,10 (d, 2H), 7,00 (d, 1H), 3,20 (users, 4H), 3.00 and-2,80 (osirm, 8H), 2,70 (c, 3H), of 2.20 (m, 3H), and 1.00 (d, 6H).

Example 5

2,2-Dimethyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)propanamide (E5)

Specified in the title compound was obtained with the yield 66% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2,2-dimethylpropanoate.

MS: (ES/+) m/z: 431 [MH+]. C27H34N4About 430 requires.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,55 (t, 2H), 7,30-7,20 (m, 4H), 7,10 (d, 1H), 7,00 (m, 1H), 3,20 (users, 4H), 2,85 (users, 8H), 2,70 (c, 3H), 1,30 (c, 9H).

Example 6

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E6)

Specified in the title compound was obtained with the yield 60% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and benzoyl chloride.

MS: (ES/+) m/z: 451 [MH+]. C29H30N4About requires 450.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), 7,87 (m, 2H), 7,80 (users, 1H), 7,72 (d, 1H), 7,65 (users, 1H), 7,6 to 7.4 (m, 5H), 7,30 (m, 1H), 7,27 (m, 1H), was 7.08 (d, 1H), 7,05 (d, 1H), 3,18 (users, 4H), 3.00 and-2,75 (osirm, 8H), 2,72 (c, 3H).

Example 7

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperaz the Nile]ethyl}phenyl)- 2-phenylacetamide (E7)

Specified in the title compound was obtained with the yield of 64% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and phenylacetylene.

MS: (ES/+) m/z: 465 [MH+]. C30H32N4About requires 464.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,55 (t, 1H), 7,45-to 7.15 (m, 9H), 7,10-to 6.95 (m, 3H), 3,70 (c, 2H), 3,10 (users, 4H), 2,90-2,70 (users, 8H), 2,70 (c, 3H).

Example 8

3,3-Dimethyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)butanamide (E8)

Specified in the title compound was obtained with the yield 62% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 3,3-dimethylbutanoate.

MS: (ES/+) m/z: 445 [MH+]. C28H36N4About requires 444.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,60 was 7.45 (m, 2H), 7,30-7,20 (m, 3H), 7,15-7,05 (m, 2H), 7,00 (d, 1H), 3,10 (t, 4H), 2,90-2,60 (m, 8H), 2,65 (c, 3H), 2,20 (c, 2H), 1,05 (c, 9H).

Example 9

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)cyclohexanecarboxylic (E9)

Specified in the title compound was obtained with the yield of 30% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazine is]ethyl}aniline (D6) and cyclohexanecarbonitrile.

MS: (ES/+) m/z: 457 [MH+]. C29H36N4About requires 456.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,60 is 7.50 (m, 2H), 7,30-7,20 (m, 3H), 7,15-7,05 (m, 2H), 7,00 (d, 1H), 3.15 in (users, 4H), 2.95 and is 2.75 (m, 8H), 2,70 (c, 3H), 2,20-of 1.40 (m, 7H), 1,40-1,10 (m, 4H).

Example 10

5-Methyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-3-isoxazolecarboxylic (E10)

Specified in the title compound was obtained with the yield of 40% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 5-methyl-3-isoxazolecarboxylic.

MS: (ES/+) m/z: 456 [MH+]. C27H29N5About2requires 455.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,50 (c, 1H), 8,35 (d, 1H), of 7.70 (d, 1H), 7,60 (m, 2H), 7,40 (d, 1H), 7,30-7,20 (m, 2H), 7,20-7,10 (t, 2H), 6,50 (c, 1H)and 3.15 (t, 4H), 2.95 and-2,70 (m, 8H), 2,70 (c, 3H), 2.50 each (c, 3H).

Example 11

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-(2-thienyl)ndimethylacetamide (E11)

Specified in the title compound was obtained with the yield of 42% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-trilateral.org.

MS: (ES/+) m/z: 471 [MH+]. C28H30N4OS requires 470.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,60 (t, 1H), 7,40 (c, 1H), 7,30 (DD, 1H), 7,25-to 7.15 (m, 3H), 7,10-of 6.90 (m, 5H), 3,9 (c, 2H), 3.15 in (users, 4H), 3.00 and-2,70 (m, 8H), 2,70 (c, 3H).

Example 12

2 Metiloksi-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E12)

Specified in the title compound was obtained with the yield 62% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and (metiloksi)acetylchloride.

MS: (ES/+) m/z: 419 [MH+]. C25H30N4About2requires 418.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), 8,20 (c, 1H), of 7.70 (d, 1H), 7,60 (t, 1H), 7,50 (c, 1H), 7,35 (d, 1H), 7,30-7,20 (m, 2H), 7,10-of 6.90 (DD, 2H), 4.00 points (c, 2H), 3,50 (c, 3H), 3,10 (t, 4H), 2,90-2,70 (m, 8H), 2,70 (c, 3H).

Example 13

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-(phenyloxy)ndimethylacetamide (E13)

Specified in the title compound was obtained with the yield 41% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and (phenyloxy)acetylchloride.

MS: (ES/+) m/z: 481 [MH+]. C30H32N4About2requires 480.

1H NMR (400 MHz, CDCl3) δ (ppm): 8,33 (d, 1H), 7,53 (m, 3H), 7,54 (users, 1H), 7,46 (userd, 1H), 7,37 (d, 1H), 7,30 (DD, 2H), 7.23 percent (t, 1H), to 7.09 (DD, 1H), 6,99 (m, 3H), of 6.96 (t, 1H), 4,67 (c, 2H), 3,02 (osirm, 4H), 2,80-2,60 (m, 8H), 2,62 (c, 3H).

Example 14

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)cyclopropanecarboxamide (E14)

The criminal code is mentioned in the title compound was obtained with the yield of 70% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and cyclopropanecarbonyl.

MS: (ES/+) m/z: 415 [MH+]. C26H30N4About 414 requires.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), 7,60 is 7.50 (m, 2H), 7,30 (users, 1H), 7,30-7,20 (m, 3H), 7,05 (d, 1H), 6,95 (userd, 1H), 3,10 (t, 4H), 2,90-2,70 (m, 8H), 2,70 (c, 3H), 1,20 (t, 1H), 1,10 (m, 2H), 0,85 (m, 2H).

Example 15

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-oxo-4-imidazolidinecarboxamide (E15)

Specified in the title compound was obtained in 51% yield according to the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-oxo-4-imidazolidinecarboxamide acid.

MS: (ES/+) m/z: 459 [MH+]. C26H30N6About2requires 458.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,40 (c, 1H), scored 8.38(d, 1H), of 7.70 (d, 1H), 7,55 (t, 1H), 7,50 (d, 1H), 7,40 (DD, 1H), 7,30-7,20 (m, 2H), 7,05 (m, 2H), 5,20 (d, 1H), 4.75 in (c, 1H), 4,45 (m, 1H), 4.00 points (t, 1H), 3,65 (DD, 1H), 3,10 (users, 4H), 2.95 and-2,70 (m, 8H), 2,70 (users, 3H).

Example 16

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-pyrazinecarboxamide (E16)

Specified in the title compound was obtained with the yield 89% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-pyrazino the oil acid.

MS: (ES/+) m/z: 453 [MH+]. C27H28N6About requires 452.

1H NMR (300 MHz, CDCl3) δ (ppm): 9,65 (c, 1H), 9,50 (m, 1H), 8,80 (d, 1H), at 8.60 (t, 1H) scored 8.38 (d, 1H), of 7.75 (d, 1H), of 7.70 (d, 1H), 7,58 (t, 1H), 7,55 (DD, 1H), 7,35 (m, 1H), 7,28 (d, 1H), was 7.08 (m, 2H), 3.15 in (users, 4H), 2.95 and-2,70 (m, 8H), 2,70 (users, 3H).

Example 17

5-(Metiloksi)-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazol-2-carboxamide (E17)

Specified in the title compound was obtained with the yield of 30% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 5-(metiloksi)-1,3-oxazol-2-carboxylic acid.

MS: (ES/+) m/z: 472 [MH+]. C27H29N5About2requires 471.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,58 (c, 1H), 8,39 (d, 1H), 7,71 (d, 1H), 7,58 (t, 1H) 7,60 (d, 1H), of 7.48 (DD, 1H), 7,30 (m, 1H), 7,26 (d, 1H), was 7.08 (DD, 1H),? 7.04 baby mortality (d, 1H), 6,28 (c, 1H), 4,03 (c, 3H), 3.15 in (t, 4H), 2.95 and-2,70 (m, 8H), 2,74 (users, 3H).

Example 18

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,2,3-thiadiazole-4-carboxamide (E18)

Specified in the title compound was obtained with a yield of 75% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1,2,3-thiadiazole-4-carboxylic acid.

MS: (ES/+) m/z: 459 [MH+]. C25H26N6OS requires 458.

1H NMR (300MHz, CDCl3) δ (ppm): of 9.30 (c, 1H), 9,25 (c, 1H), scored 8.38 (d, 1H), of 7.70 (d, 1H), 7,68 (d, 1H) 7,58 (t, 1H), 7,55 (DD, 1H), 7,35 (m, 1H), 7,28 (d, 1H), 7,10 (m, 2H), 3.15 in (users, 4H) 2,95-2,70 (m, 8H), 2,70 (c, 3H).

Example 19

2,4-Dimethyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-thiazole-5-carboxamide (E19)

Specified in the title compound was obtained with the yield 68% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid.

MS: (ES/+) m/z: 486 [MH+]. C28H31N5OS requires 485.

1H NMR (300 MHz, CDCl3) δ (ppm): scored 8.38 (d, 1H), of 7.70 (d, 1H), 7,58 (t, 1H) of 7.55 (d, 1H), 7,35-7,20 (DD, 1H), 7,30 (users, 1H), 7,10 (m, 2H), 3.15 in (t, 4H), 2.95 and-2,70 (m, 8H), 2,72 (c, 6H), 2,70 (c, 3H).

Example 20

1,5-Dimethyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1H-pyrazole-3-carboxamide (E20)

Specified in the title compound was obtained with the yield 35% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

MS: (ES/+) m/z: 469 [MH+]. C28H32N6About requires 468.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,60 (c, 1H), scored 8.38 (d, 1H), of 7.70 (d, 1H), 7,68 (d, 1H), 7,58 (t, 1H) 7,45 (d, 1H), 7,35-7,20 (DD, 2H), was 7.08 (d, 1H), 7,00 (d,1H), 6,60 (c, 1H), 3,80 (c, 3H), 3.15 in (t, 4H), 2.95 and-2,70 (m, 8H), 2,72 (c, 3H), 2,3 (c, 3H).

Example 21

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxamide (E21)

Specified in the title compound was obtained with a yield of 20% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carboxylic acid.

MS: (ES/+) m/z: 509 [MH+]. C31H32N4About3requires 508.

1H NMR (300 MHz, CDCl3) δ (ppm): 11,80 (c, 1H), 8,10 (c, 1H), scored 8.38 (d, 1H), 7,72 (d, 1H) of 7.70 (d, 1H), 7,65 (DD, 1H), 7,58 (t, 1H), 7,30-7,20 (m, 2H), was 7.08 (d, 1H), 7,00 (d, 1H), 3.15 in (t, 4H), 3.00 and-to 2.65 (m, 12H), 2,70 (c, 3H), of 2.25 (m, 2H).

Example 22

The dihydrochloride of 2-fluoro-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E22)

Specified in the title compound was obtained with the yield 96% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-fermenting acid.

MS: (ES/+) m/z: 469 [MH+]. C29H29FN4About requires 468.

1H NMR (500 MHz, d6-DMSO) δ (ppm): 11,00 (users, 1H), 10,46 (c, 1H), 8,80 (users, 1H), 8,00-7,72 (m, 4H), of 7.65 (t, 1H), 7,58 (kV, 1H), 7,52 (d, 1H), 7,73 (users, 1H), 7,37-to 7.32 (m, 3H), was 7.08 (d, 1H), 3,74 (d, 2H), 3,7-3,3 (m, 9H), 3.15 in (m, 2H), 2,88 (c, 3H).

Example 23

The dihydrochloride of 4-fluoro-N-(3-{2-[4-(2-methyl-5-chinoline is)-1-piperazinil]ethyl}phenyl)benzamide (E23)

Specified in the title compound was obtained with the yield 82% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 4-fermenting acid.

HPLC/MS: (ES/+): tR=6,45 min; sample >98.2% of a/a; m/z: 469 [MH+]. C29H29FN4About requires 468.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,29 (users, 1H), 10,36 (c, 1H), 8,96 (users, 1H), 8,08 (m, 2H), 7,99 (users, 1H), 7,86 (users, 1H), 7.62mm (d, 1H), 7,47 (userd, 1H), 7,40 (m, 3H), to 7.09 (d, 1H), 3,70-3,30 (m, 10H), 3,18 (DD, 2H), 2,93 (users, 3H).

Example 24

The dihydrochloride 2,4-debtor-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E24)

Specified in the title compound was obtained with the yield 78% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2,4-differentyou acid.

HPLC/MS: (ES/+): tR=6,51 min; sample >99% a/a; m/z: 487 [MH+]. C29H28F2N4About requires a 486.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,16 (users, 1H), 10,49 (c, 1H), 8,93 (users, 1H), 7,70 (users, 2H), 7,81 (users, 2H), to 7.75 (m, 1H), 7,53 (d, 1H), 7,47 (m, 2H), 7,39 (t, 1H), 7,25 (TD, 1H), 7,10 (d, 1H), 3,70-3,30 (m, 10H), 2,92 (c, 3H).

Example 25

The dihydrochloride of 3-fluoro-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E25)

Specified in sagola the COC connection was obtained with the yield 91% in accordance with the General method of obtaining the amides (method C), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 3-fermenting acid.

HPLC/MS: (ES/+): tR=6,45 min; sample >99% a/a; m/z: 469 [MH+]. C29H29FN4About requires 468.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,18 (users, 1H), 10,41 (c, 1H), 8,94 (users, 1H), 7,97 (users, 2H), 7,87 (users, 2H), 7,80 (m, 2H), 7.62mm (m, 2H), of 7.48 (m, 2H), 7,10 (d, 1H), 3,80-3,30 (m, 10H), 3,18 (m, 2H), 2,92 (users, 3H).

Example 26

The dihydrochloride 2.5-debtor-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E26)

Specified in the title compound was obtained with the yield 82% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2,5-differentyou acid.

HPLC/MS: (ES/+): tR=6,45 min; sample >99% a/a; m/z: 487 [MH+]. C29H28F2N4About requires a 486.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,20 (users, 1H), 10,54 (c, 1H), 8,91 (users, 1H), of 7.96 (osirm, 2H), 7,80 (osirm, 2H), 7,56-7,40 (m, 5H), was 7.36 (t, 1H), to 7.09 (d, 1H), 3,80-3,10 (m, 12H), 2,90 (c, 3H).

Example 27

The dihydrochloride 3.5-debtor-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E27)

Specified in the title compound was obtained with the yield of 74% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-hee is oliner)-1-piperazinil]ethyl}aniline (D6) and 3,5-differentyou acid.

HPLC/MS: (ES/+): tR=6,66 min; sample >98.6% of a/a; m/z: 487 [MH+]. C29H28F2N4About requires a 486.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,00 (users, 1H), 10,46 (c, 1H), 8,90 (users, 1H), 7,93 (c, 2H), of 7.90 (users, 1H), 7,72 (m, 2H), 7,86 (c, 1H), 7.62mm (d, 1H), 7,56 (m, 1H), 7,45 (users, 1H), 7,40 (t, 1H), 7,12 (d, 1H), 3,76 (d, 2H), 3,70-3,30 (m, 8H), 3,17 (m, 2H), 2,99 (users, 3H).

Example 28

The dihydrochloride 2,3-debtor-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E28)

Specified in the title compound was obtained with the yield of 86% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2,3-differentyou acid.

HPLC/MS: (ES/+): tR=6,41 min; sample >99% a/a; m/z: 486 [MH+]. C29H28F2N4About requires a 486.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,00 (users, 1H), to 10.62 (c, 1H), 8,95 (users, 1H), 7,94 (c, 2H), 7,82 (c, 1H), 7,80 (users, 1H), 7,65 (m, 1H), 7,53 (d, 1H), 7,50 (m, 1H), 7,45 (users, 1H), 7,39 (t, 1H), 7,38 (m, 1H), 7,12 (d, 1H), 3,76 (d, 2H), 3,70-3,30 (m, 8H), 3,17 (m, 2H), 2,96 (users, 3H).

Example 29

The dihydrochloride 2,6-debtor-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E29)

Specified in the title compound was obtained with the yield 68% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]et the l}aniline (D6) and 2,6-differentyou acid.

HPLC/MS: (ES/+): tR=6,24 min; sample >99% a/a; m/z: 486 [MH+]. C29H28F2N4About requires a 486.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,90 (users, 1H), 10,87 (c, 1H), 8,87 (users, 1H), 7,92 (c, 2H), 7,84 (c, 1H), 7,79 (users, 1H), 7.62mm (m, 1H), of 7.48 (d, 1H), 7,50 (m, 1H), 7,44 (users, 1H), 7,39 (t, 1H), 7,27 (m, 2H), 7,12 (d, 1H), 3,76 (d, 2H), 3,70-3,30 (m, 8H), 3,17 (m, 2H), 2,88 (users, 3H).

Example 30

The dihydrochloride 3,4-debtor-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E30)

Specified in the title compound was obtained with the yield 92% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 3,4-differentyou acid.

HPLC/MS: (ES/+): tR=6,66 min; sample >99% a/a; m/z: 486 [MH+]. C29H28F2N4About requires a 486.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,04 (users, 1H), 10,42 (c, 1H), 8,90 (users, 1H), 8,08 (m, 1H), 7,93 (c, 2H), of 7.90 (m, 1H), 7,85 (c, 1H), 7,81 (users, 1H), 7,65 (m, 1H), 7.62mm (d, 1H), 7,45 (users, 1H), 7,39 (t, 1H), 7,11 (d, 1H), 3,76 (d, 2H), 3,70-3,30 (m, 8H), 3,17 (m, 2H), 2,89 (users, 3H).

Example 31

The dihydrochloride of 3-(metiloksi)-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E31)

Specified in the title compound was obtained with the yield 83% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-Pipa is azinyl]ethyl}aniline (D6) and 3-(metiloksi)benzoic acid.

HPLC/MS: (ES/+): tR=6,39 min; sample >99% a/a; m/z: 481 [MH+]. C30H30N4About2requires 480.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,88 (users, 1H), 10.30 a.m. (c, 1H), 8,86 (users, 1H), to $ 7.91 (users, 2H), 7,87 (users, 1H), 7,78 (users, 2H), 7,63 (DD, 1H), 7,56 (d, 1H), 7,51 (m, 1H), 7,47 (t, 1H), 7,47 (users, 1H), 7,38 (m, 1H), 7,19 (DM, 1H), 7,09 (d, 1H), 3,86 (c, 3H), 3,76 (d, 2H), 3,70 is 3.25 (m, 8H), 3,17 (m, 2H), 2,88 (users, 3H).

Example 32

The dihydrochloride of 2-(metiloksi)-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E32)

Specified in the title compound was obtained with the yield of 85% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-(metiloksi)benzoic acid.

HPLC/MS: (ES/+): tRequals 6.54 min; sample >99% a/a; m/z: 481 [MH+]. C30H30N4About2requires 480.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,13 (users, 1H), 10,17 (c, 1H), 8,93 (users, 1H), 7,97 (c, 2H), 7,86-7,78 (users, 1H), to 7.64 (DD, 1H), 7,58 is 7.50 (m, 2H), 7,47 (users, 1H), was 7.36 (t, 1H), 7,21 (d, 1H), to 7.09 (dt, 1H), 7,07 (d, 1H), 3,92 (c, 3H), 3,76 (d, 2H), 3,70-3,30 (m, 8H), 3,17 (m, 2H), 2.91 in (users, 3H).

Example 33

The dihydrochloride 4-(metiloksi)-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E33)

Specified in the title compound was obtained with the yield 83% in accordance with the General method of obtaining the amides (method C), using as ishonishadimi 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 4-(metiloksi)benzoic acid.

HPLC/MS: (ES/+): tR=6,21 min; sample >99% a/a; m/z: 481 [MH+]. C30H30N4About2requires 480.

1H NMR (500 MHz, d6-DMSO) δ (ppm): 11,09 (users, 1H), 10,16 (c, 1H), 8,91 (users, 1H), of 7.97 (d, 2H), 7,94 (users, 2H), 7,84 (c, 1H), 7,81 (users, 1H), 7,60 (d, 1H), 7,44 (users, 1H), 7,34 (t, 1H), 7,05 (m, 3H), 3,83 (c, 3H), 3,74 (userd, 2H), 3,60 is 3.40 (m, 6H), 3.33 and (ushort, 2H), 3,14 (DD, 2H), 2,89 (users, 3H).

Example 34

The dihydrochloride of 4-cyano-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E34)

Specified in the title compound was obtained with the yield of 85% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 4-cyanobenzoic acid.

HPLC/MS: (ES/+): tR=6,15 min; sample >99% a/a; m/z: 481 [MH+]. C30H30N4About2requires 480.

1H NMR (500 MHz, d6-DMSO) δ (ppm): of 10.72 (users, 1H), 10,56 (c, 1H), 8,81 (users, 1H), 8,11 (d, 2H), 8,04 (d, 2H), 7,86 (users, 3H), 7,75 (users, 1H), to 7.59 (d, 1H), 7,39 (users, 1H), 7,38 (m, 1H), to 7.09 (d, 1H), 3,74 (userd, 2H), 3,70 is 3.40 (m, 6H), 3,28 (ushort, 2H), 3,14 (DD, 2H), 2,84 (users, 3H).

Example 35

3,5-Dimethyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-4-isoxazolecarboxylic (E35)

Specified in the title compound was obtained with the yield 56% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-x is nominal)-1-piperazinil]ethyl}aniline (D6) and 3,5-dimethyl-4-isoxazolidinone acid.

MS: (ES/+) m/z: 470 [MH+]. C28H31N5About2requires 469.

1H NMR (400 MHz, d6-DMSO) δ (ppm): scored 8.38 (d, 1H), 7,72 (d, 1H), 7,58 (t, 1H), 7,52 (users, 1H), 7,31 (m, 2H), 7,25 (d, 1H), 7,20 (users, 1H), was 7.08 (m, 2H), 3,14 (m, 4H), 2,90 (m, 2H), 2,81 (m, 4H), was 2.76 (m, 2H), 2,73 (c, 3H), 2,68 (c, 3H), 2,52 (c, 3H).

Example 36

The dihydrochloride of 2-methyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-4-trifluoromethyl-1,3-thiazole-5-carboxamide (E36)

Specified in the title compound was obtained with the yield of 33% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-methyl-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid.

MS: (ES/+) m/z: 540 [MH+]. C28H28F3N5OS requires 539.

1H NMR (400 MHz, d6-DMSO) δ (ppm): of 10.93 (users, 1H), 8,82 (users, 1H), 7,88 (users, 2H), 7,75 (users, 1H), 7,70 (users, 1H), 7,43 (d, 1H), 7,40 (users, 1H), was 7.36 (t, 1H), 7,10 (d, 1H), 3,8-3,2 (m, 10H), of 3.12 (m, 2H), 2,85 (c, 3H), 2,75 (c, 3H).

Example 37

The dihydrochloride of 2-methyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-thiazole-4-carboxamide (E37)

Specified in the title compound was obtained with the yield 52% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-methyl-1,3-thiazole-4-carboxylic acid.

MS: (ES/+) /z: 472 [MH +]. C27H29N5OS requires 471.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,70 (users, 1H), 10,15 (c, 1H), 8,77 (users, 1H), compared to 8.26 (c, 1H), 7,87 (users, 1H), 7,75-a 7.85 (m, 2H), 7,39 (users, 1H), 7,34 (t, 1H), 7,06 (d, 1H), 3,80-3,20 (m, 10H), of 3.12 (DD, 2H), 2,83 (users, 3H), was 2.76 (c, 3H).

Example 38

The dihydrochloride of 4-methyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-thiazole-5-carboxamide (E38)

Specified in the title compound was obtained with the yield 46% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 4-methyl-1,3-thiazole-5-carboxylic acid.

MS: (ES/+) m/z: 472 [MH+]. C27H29N5OS requires 471.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,83 (users, 1H), 10,28 (c, 1H), 9,13 (c, 1H), 8,86 (users, 1H), of 7.90 (users, 2H), 7,80-7,74 (users-c, 2H), 7,50 (d, 1H), 7,43 (users, 1H), 7,35 (m, 1H), was 7.08 (d, 1H), 3,9-3,2 (m, 10H), of 3.13 (DD, 2H), 2,87 (users, 3H), 2,61 (c, 3H).

Example 39

The dihydrochloride of 1-methyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1H-pyrazole-5-carboxamide (E39)

Specified in the title compound was obtained with the yield 60% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-methyl-1H-pyrazole-5-carboxylic acid.

MS: (ES/+) m/z: 455 [MH+]. C27H30N6About t is Eboue 454.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,96 (users, 1H), 10,27 (c, 1H), cent to 8.85 (users, 1H), 8,0 to 7.7 (m, 4H), and 7.6-7.5 (m, 2H), 7,42 (users, 1H), and 7.6 (t, 1H), 7,10-was 7.08 (m, 2H), 4.09 to (c, 3H), 3,74 (d, 2H), 3,51 be 3.29 (m, 8H), 3,14 (m, 2H), 2,87 (c, 3H).

Example 40

The dihydrochloride of N-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamide (E40)

Specified in the title compound was obtained with the yield 68% in accordance with the General method of obtaining the amides (method C), using as starting compounds 1-(3-AMINOPHENYL)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethanol (D8) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid.

MS: (ES/+) m/z: 502 [MH+]. C28H31N5About2S requires 501.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,18 (2H, users), cent to 8.85 (1H, users), 7,89 (3H, c), to 7.77 (1H, users), 7,53 (1H, d), 7,37 (2H, m), 7,18 (1H, d), 6,36 (1H, users), to 5.17 (1H, DD), 3,80-3,20 (10H, m), 2,85 (3H, c), of 2.64 (3H, c), of 2.53 (3H, c).

Example 41

The dihydrochloride of N-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-methyl-1,3-thiazole-4-carboxamide (E41)

Specified in the title compound was obtained with the yield 82% in accordance with the General method of obtaining the amides (method C), using as starting compounds 1-(3-AMINOPHENYL)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethanol (D8) and 2-methyl-1,3-thiazole-4-carboxylic acid.

MS: (ES/+) m/z: 488 [MH+]. C27H29N5About2S requires 487.

1 H NMR (400 MHz, d6-DMSO) δ (ppm): 10,38 (1H, users), 10,23 (1H, s), 8,88 (1H, users), 8,30 (1H, s), 8,08 (1H, users), 7,95 (2H, users), of 7.75 (1H, DD), 7,44 (1H, users), 7,41 (1H, t), 7,22 (1H, d), 6,40 (1H, users), with 5.22 (1H, userd), 3,81 (2H, userd), 3,70-3,30 (8H, osirm), 2,90 (3H, users), and 2.79 ppm (3H, s).

Example 42

The dihydrochloride of N-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide (E42)

Specified in the title compound was obtained with the yield of 95% in accordance with the General method of obtaining the amides (method C), using as starting compounds 1-(3-AMINOPHENYL)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethanol (D8) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

MS: (ES/+) m/z: 485 [MH+]. C28H32N6About2requires 484.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,30 (1H, users), becomes 9.97 (1H, c), 8,86 (1H, users), 8,08 (1H, c), 7,92 (2H, users), 7,79 (1H, users), of 7.69 (1H, d), the 7.43 (1H, users), 7,38 (1H, t), 7,17 (1H, d), to 6.58 (1H, c), 6,38 (1H, users), 5,19 (1H, userd), 3,86 (3H, c), of 3.80 (2H, osirm), 3,70-3,20 (8H, osirm), 2,89 (3H, users), 2,33 ppm (3H, c).

Example 43

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)methanesulfonamide (E43)

To a solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) (0.03 g; 1 EQ.) in pyridine (0.5 ml) was added dropwise methanesulfonanilide (8 μl; 1.2 EQ.). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrate who has demonstrated under reduced pressure, was diluted with water (1 ml) and saturated aqueous sodium hydrogen carbonate (1 ml), was extracted with dichloromethane (3×2 ml), dried over Na2SO4and concentrated under reduced pressure. The crude material was purified by the method of flash chromatography, elwira gradient from dichloromethane to dichloromethane/MeOH (98/2), to obtain specified in the connection header with the release of 44% (0,016 g).

MS: (ES) m/z: 425,4 [MH]+. C23H28N4About2S requires 424.

1H NMR (300 MHz, MeOD) δ (ppm): to 8.40 (d, 1H), 7,55 (m, 2H), 7,30 (d, 1H), 7,15 (t, 1H), 7,10 (m, 2H), 6.90 to ((ushort, 2H), 3,05 (ushort, 4H), 2,85 (c, 3H), and 2.83 2.63 in (osirm, 8H), 2,60 (c, 3H).

Example 44

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperidinyl]ethyl}phenyl)-1-propanesulfonate (E44)

Specified in the title compound was obtained with the yield of 62% with the use of a technique similar to the one presented in example E43, using as starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and propanesulfonate.

MS: (ES) m/z: 453,4 [MH]+. C25H32N4About2S requires 452.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,60 (t, 1H), 7,30 (m, 2H), and 7.1 (m, 2H), 7,01 (d, 1H), 3,30 (osirm, 6H), 2,80 (osirm, 6H), 2,60 (c, 3H), of 1.80 (m, 2H), 1,0 (t, 3H).

A General method of obtaining carbamates and related dihydrochloride, using as starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}EN the Lin (D6):

Method D

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) (1 EQ.) in dichloromethane at 0°C was sequentially added diisopropylethylamine (1.5 EQ.) and chloroformate (1.2 EQ.). The solution was stirred for 1 h at room temperature, then was diluted with dichloromethane, washed with saturated aqueous NH4Cl and brine, and then dried over Na2SO4. The solution was concentrated under reduced pressure. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), elwira gradient from dichloromethane/MeOH (99/1) to dichloromethane/MeOH (98/2), to obtain the final compounds (outputs range from 43%to 78%).

The free base can be converted into the dihydrochloride by dissolving the compound in dichloromethane and added dropwise 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure to get the crude material, which was triturated with Et2O. Then by filtering the extracted target substance (quantitative yield).

Example 45

Methyl-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)carbamate (E45)

Specified in the title compound was obtained with the yield 41% in accordance with the General method is coy obtain carbamates (method D), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and methylchloroform.

MS: (ES) m/z: 405,4 [MH]+. C24H28N4About2requires a 404.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,33 (d, 1H), of 7.70 (d, 1H), and 7.6 (t, 1H), 7,30 (users, 1H), 7,25 (m, 1H), 7,22 (DD, 1H), 7,20 (m, 1H), 7,10 (d, 1H), 6,95 (DD, 1H), 6,55 (users, 1H), 3,8 (c, 3H), 3,28 (osirm, 4H), of 3.28 (t, 2H), 2,85 (t, 2H), 2,75 (osirm, 4H), 2,66 (c, 3H).

Example 46

The dihydrochloride ethyl-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)carbamate (E46)

Specified in the title compound was obtained with the yield 79% in accordance with the General method of obtaining carbamates (method D), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and ethylchloride.

MS; (ES) m/z: 419 [MH+]. C25H30N4About2requires 418.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,00 (users, 1H), 9,74 (c, 1H), 8,95 (c, 1H), 8,00 (c, 2H), 7,87 (c, 1H), EUR 7.57 (c, 1H), 7,51 (users, 1H), was 7.36 (m, 2H), 7,02 (d, 1H), is 4.21 (q, 2H), 3,80 (d, 2H), 3,7-3,3 (m, 8H), 3,17 (m, 2H), 2,96 (users, 3H), of 1.33 (t, 3H).

Example 47

The dihydrochloride propyl-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)carbamate (E47)

Specified in the title compound was obtained with the yield 78% in accordance with the General method of obtaining carbamates (method D), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}Anil is n (D6) and propylchloride.

MS: (ES) m/z: 433 [MH+]. C28H32N4About2requires 432.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,88 (users, 1H), 9,65 (c, 1H), 8,84 (users, 1H), 7,89 (users, 2H), 7,76 (users, 1H), 7,47 (c, 1H), 7,40 (users, 1H), 7,27-6,92 (m-d, 3H), was 4.02 (t, 2H), 3,8-3,2 (osirm, 10H), of 3.07 (DD, 2H), 2,85 (users, 3H), 1,62 (m, 2H), of 0.91 (t, 3H).

Example 48

The dihydrochloride of 1-methylethyl-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)carbamate (E48)

Specified in the title compound was obtained with the yield 77% in accordance with the General method of obtaining carbamates (method D), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-methylethylenediamine.

MS: (ES) m/z: 433 [MH+]. C26H32N4About2requires 432.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,98 (users, 1H), 9,58 (c, 1H), 8,86 (users, 1H), to $ 7.91 (users, 2H), to 7.77 (users, 1H), of 7.48 (c, 1H), 7,42 (users, 1H), 7,25 (m, 2H), 6,91 (d, 1H), 4,87 (m, 1H), 3.75 to 3,2 (osirm, 10H), of 3.07 (DD, 2H), 2,87 (users, 3H), of 1.24 (d, 6H).

Example 49

The dihydrochloride of 2-methylpropyl-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)carbamate (E49)

Specified in the title compound was obtained with the yield of 70% in accordance with the General method of obtaining carbamates (method D), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-methylpropylamine.

MS: (ES) m/z: 447 [MH+]. C27 H34N4About2requires 446.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,94 (users, 1H), for 9.64 (c, 1H), 8,86 (c, 1H), to $ 7.91 (c, 2H), to 7.77 (c, 1H), of 7.48 (c, 1H), 7,41 (users, 1H), 7,28 (m, 2H), 6,93 (d, 1H), 3,85 (kV, 2H), 3,70 (d, 2H), 3,7-of 3.25 (m, 8H), of 3.07 (m, 2H), 2,86 (users, 3H), of 1.09 (m, 1H), to 0.92 (d, 6H).

Example 50

The dihydrochloride phenyl-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)carbamate (E50)

Specified in the title compound was obtained with the yield of 59% in accordance with the General method of obtaining carbamates (method D), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and familiarization.

MS: (ES) m/z: 467 [MH+]. C29H30N4About2requires 466.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,95 (users, 1H), 10,27 (c, 1H), 8,84 (c, 1H), of 7.90 (c, 2H), 7,75 (c, 1H), 7,52 (c, 1H), and 7.4 to 7.2 (m, 8H), of 7.00 (d, 1H), 3,71 (d, 2H), 3,7-3,3 (m, 8H), to 3.09 (m, 2H), 2,86 (users, 3H).

Example 51

The dihydrochloride of phenylmethyl-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)carbamate (E51)

Specified in the title compound was obtained with the yield 43% in accordance with the General method of obtaining carbamates (method D), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and phenylethylenediamine.

MS: (ES) m/z: 481 [MH+]. C30H32N4About2requires 480.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,8 (users, 1H), 9,8(s, 1H), 8,9 (users, 1H), 7,9 (users, 2H), 7,76 (users, 1H), 7,50 (users, 1H), and 7.4 to 7.2 (m, 8H), to 6.95 (d, 1H), 5,15 (c, 2H), 3.72 points userd, 2H), 3,6-3,2 (m, 8H), to 3.09 (m, 2H), 2,86 (users, 3H).

A General method of obtaining ureas or thioureas and related dihydrochloride, using as starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6):

Method E

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) (1 EQ.) in dichloromethane at room temperature under inert atmosphere was added isocyanate or isothiocyanate (1 EQ.) and leaving the reaction mixture was mixed for 16 hours Then the solution was poured into water and was extracted with dichloromethane, the organic phase was dried over Na2SO4and solvent was removed under reduced pressure. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), using as eluent a gradient from dichloromethane to dichloromethane/MeOH (95/5), to obtain the final compounds (outputs range from 30 to 80%).

The free base can be converted into the dihydrochloride by dissolving the compounds in Et2O and MeOH and added dropwise 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure to get crude Mat is the Rial, which is triturated with Et2O. Then by filtering the extracted target substance (quantitative yield).

A General method of obtaining ureas and related dihydrochloride, using as starting compound 3-(2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6):

Method F

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) (1 EQ.) in dichloromethane at 0°C under inert atmosphere was sequentially added triethylamine (6 EQ.) and solid triphosgene (0.5 EQ.). The reaction mixture was left to mix for 1 h, then was added dropwise dissolved in CH3CN diisopropylethylamine and amine (1.1 EQ.). The solution was stirred for 16 h, then was diluted with dichloromethane, washed with saturated aqueous NaHCO3and brine and dried over Na2SO4. The solution was concentrated under reduced pressure and the crude was purified material in the cartridge for solid phase extraction (silicon dioxide), elwira gradient from dichloromethane to dichloromethane/MeOH (98/2), to obtain the final compounds (outputs range from 20 to 50%).

The free base can be converted into the dihydrochloride by dissolving the compounds in Et2O and MeOH and added dropwise 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid, suspen the Oia was stirred for 15 minutes The solvent was removed under reduced pressure to get the crude material, which was triturated with Et2O. Then by filtering the extracted target substance (quantitative yield).

Example 52

The dihydrochloride of N-(3,5-differenl)-N'-(3-{2-[4-(2-methylinosine-5-yl)piperazine-1-yl]ethyl}phenyl)urea (E52)

Specified in the title compound was obtained with the yield of 40% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1,3-debtor-5-isocyanatobenzene.

MS: (ES/+) m/z: 502 [MH+]. C29H29F2N5About 501 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,8 (users, 1H), 9,71 (c, 1H), 9,29 (c, 1H), 8,9 (users, 1H), 7,94 (users, 2H), 7,82 (users, 1H), 7,53 (c, 1H), 7,45 (users, 1H), 7,31 (d, 2H), 7,20 (DD, 2H), 6,97 (t, 1H), 6,80 (TT, 1H), 3,70 (userd, 2H), 3,7-3,2 (m, 8H), of 3.13 (DD, 2H), 2,90 (users, 3H).

Example 53

The dihydrochloride of N-(2-chlorophenyl)-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E53)

Specified in the title compound was obtained with the yield 55% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-chloro-2-isocyanatobenzene.

MS: (ES/+) m/z: 500 [MH+]. C29H30ClN5About requires 499.

1H NMR (400 MHz, d6 -DMSO) δ (ppm): 10,89 (users, 1H), 9,66 (c, 1H), 8,86 (users, 1H), to 8.41 (c, 1H), 8,14 (DD, 1H), of 7.90 (users, 2H), 7,78 (users, 1H), 7,54 (d, 1H), 7,40 (users, 1H), 7,43 (DD, 1H), 7,27 (m, 3H), 7,02 (dt, 1H), 6,93 (m, 1H), 3,71 (d, 2H), 3,6-3,2 (m, 8H), 3,10 (m, 2H), 2,86 (users, 3H).

Example 54

The dihydrochloride of N-(3-chlorophenyl)-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E54)

Specified in the title compound was obtained with the yield 52% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-chloro-3-isocyanatobenzene.

MS: (ES/+) m/z: 500 [MH+]. C29H30ClN5About requires 499.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,53 (users, 1H), 9,34 (c, 1H), 9.15, with (c, 1H), 8,81 (users, 1H), 7,88 (users, 2H), 7,76 (t, 1H), 7,74 (users, 1H), EUR 7.57 (c, 1H), 7,41 (users, 1H), 7,30 (m, 4H), 7,03 (dt, 1H), of 6.96 (userd, 1H), 3,76 (userd, 2H), 3,6-3,2 (m, 8H), 3,11 (DD, 2H), 2,85 (users, 3H).

Example 55

The dihydrochloride of N-(3-forfinal)-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E55)

Specified in the title compound was obtained with the yield 48% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-fluoro-3-isocyanatobenzene.

MS: (ES/+) m/z: 484 [MH+]. C29H30FN5About requires 483.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,7 users, 1H), for 9.47 (c, 1H), 9,24 (c, 1H), 8,75 (users, 1H), 7,81 (users, 2H), 7,68 (users, 1H), 7,50 (d + users, 2H), 7,44 (users, 1H), 7,31 (m, 1H), and 7.3-7,24 (m, 2H), to 7.09 (d, 1H), 6.89 in (d, 1H), 6,74 (TD, 1H), 3,7-3,2 (m, 10H), of 3.07 (m, 2H), 2,8 (users, 3H).

Example 56

The dihydrochloride of N-(4-forfinal)-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E56)

Specified in the title compound was obtained with the yield of 64% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-fluoro-4-isocyanatobenzene.

MS: (ES/+) m/z: 484 [MH+]. C29H30FN5About requires 483.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,49 (users, 1H), 9,40 (c, 1H), 8,96 (c, 1H), 8,77 (users, 1H), 7,83 (users, 2H), 7,71 (users, 1H), 7,51 (users, 1H), 7,45 (DD, 2H), 7,37 (users, 1H), 7,25 (userd, 2H), 7,10 (t, 2H), 6.90 to (ushort, 1H), 3,8-3,2 (m, 10H), a 3.06 (DD, 2H), 2,81 (users, 3H).

Example 57

The dihydrochloride of N-(2-forfinal)-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E57)

Specified in the title compound was obtained with a yield of 75% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-fluoro-2-isocyanatobenzene.

MS: (ES/+) m/z: 484 [MH+]. C29H30FN5About requires 483.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,9 (users, 1H), 9,36 (c, 1H), 8,8 (users,1H), 8,67 (c, 1H), 8,11 (t, 1H), 7,86 (users, 2H), 7,71 (users, 1H), 7,49 (d, 1H), 7,37 (users, 1H), 7,26 (m, 2H), 7,20 (DD, 1H), 7,07 (DD, 1H), 6,98 (m, 1H), 6.90 to (m, 1H), 3,69 (d, 2H), 3,5-3,2 (m, 8H), to 3.09 (m, 2H), 2,82 (users, 3H).

Example 58

The dihydrochloride of N-[4-(metiloksi)phenyl]-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E58)

Specified in the title compound was obtained with the yield of 54% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-isocyanato-4-(metiloksi)benzene.

MS: (ES/+) m/z: 496 [MH+]. C30H33N5About2requires 495.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,66 (users, 1H), 8,92 (c, 1H), 8,82 (users, 1H), 8,80 (c, 1H), 7,88 (users, 2H), 7,76 (users, 1H), 7,50 (users, 1H), 7,39 (users, 1H), 7,24 (m, 2H), to 6.88 (m, 1H), 7,34 (d, 2H), at 6.84 (d, 2H), and 3.72 (m, 2H), 3,69 (c, 3H), 3,6-3,0 (m, 10H), 2,81 (users, 3H).

Example 59

The dihydrochloride of N-[3-(metiloksi)phenyl]-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E59)

Specified in the title compound was obtained with the yield 58% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-isocyanato-3-(metiloksi)benzene.

MS: (ES/+) m/z: 496 [MH+]. C30H33N5About2requires 495.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,54 (users 1H), 9,00 (c, 1H), 8,99 (c, 1H), 8,80 (users, 1H), to $ 7.91 (t, 1H), 7,85 (users, 2H), 7,73 (users, 1H), 7,52 (users, 1H), 7,39 (users, 1H), 7,25 (m, 2H), 7,15 (t, 1H), 6.90 to (m, 1H), and 3.72(m, 2H), 3,69 (c, 3H), 3,6-3,0 (m, 10H), 2,81 (users, 3H).

Example 60

The dihydrochloride of N-[2-(metiloksi)phenyl]-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E60)

Specified in the title compound was obtained with the yield of 42% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-isocyanato-2-(metiloksi)benzene.

MS: (ES/+) m/z: 496 [MH+]. C30H33N5About2requires 495.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,77 (users, 1H), 9,43 (c, 1H), 8,83 (users, 1H), compared to 8.26 (c, 1H), 8,10 (DD, 1H), 7,88 (users, 2H), 7,75 (users, 1H), 7,56 (c, 1H), 7,40 (users, 1H), 7,24 (m, 2H), 7,0 to 6.8 (m, 4H), 3,86 (c, 3H), and 3.72 (d, 2H), 3,6-3,2 (m, 8H), is 3.08 (m, 2H), 2,84 (users, 3H).

Example 61

The dihydrochloride of N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N'-[2-(trifluoromethyl)phenyl]urea (E61)

Specified in the title compound was obtained with the yield of 63% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-isocyanato-2-(trifluoromethyl)benzene.

MS: (ES/+) m/z: 534 [MH+]. C30H30F3N5About 533 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm) 10,83 (users, 1H), 9,54 (c, 1H), 8,83 (users, 1H), 8,15 (c, 1H), 8,14 (DD, 1H), 7,88 (users, 2H), 7,73 (users, 1H), to 7.64 (d, 1H), to 7.59 (t, 1H), 7,50 (c, 1H), 7,38 (users, 1H), 7,25 (m, 3H), 6,91 (m, 1H), 3,69 (m, 2H), 3,6-3,2 (m, 8H), of 3.07 (m, 2H), 2,83 (users, 3H).

Example 62

The dihydrochloride of N-(3-{2-[4-(6-methyl-1-naphthalenyl)-1-piperazinil]ethyl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea (E62)

Specified in the title compound was obtained with the yield of 23% in accordance with the General method of obtaining ureas (method E), using as starting compounds 3-(2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-isocyanato-3-(trifluoromethyl)benzene.

MS: (ES/+) m/z: 534 [MH+]. C31H31F3N4About 533 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,41 (users, 1H), for 9.47 (c, 1H), 9,16 (c, 1H), 8,81 (users, 1H), 8,08 (c, 1H), 7,86 (users, 2H), 7,72 (users, 1H), to 7.61 (c, 1H), and 7.6-7.5 (m, 2H), 7,41 (users, 1H), 7,35-7,25 (m, 3H), 6,97 (d, 1H), 3,76 (osirm, 2H), 3,7-3,3 (osirm, 6H), 3.27 to (osirm, 2H), 3,11 (m, 2H), 2,85 (users, 3H).

Example 63

The dihydrochloride of N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N'-[4-(trifluoromethyl)phenyl]urea (E63)

Specified in the title compound was obtained with the yield 45% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-isocyanato-4-(trifluoromethyl)benzene.

MS: (ES/+) m/z: 534 [MH+]. C30H30F3N5About 533 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,34 (users, 1H), 9,45 (c, 1H), 9,12 (c, 1H), 8,71 (users, 1H), 7,81 (t, 1H), 7,63 (m, 5H), 7,54 (c, 1H), 7,53 (users, 1H), 7,27 (users, 2H), 6,93 (userd, 1H), 3,8-3,1 (osirm, 10H), of 3.07 (DD, 2H), 2,79 (users, 3H).

Example 64

The dihydrochloride of N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N'-propylacetic (E64)

Specified in the title compound was obtained with the yield of 53% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-isocyanatopropyl.

MS: (ES/+) m/z: 432 [MH+]. C26H33N5About 431 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,5 (users, 1H), 8,75 (users, 1H), 8,54 (c, 1H), 7,83 (users, 2H), 7,7 (users, 1H), 7,45 (c, 1H), 7,38 (users, 1H), 7,18 (m, 2H), for 6.81 (d, 1H), 6,23 (ushort, 1H), 3,7-3,25 (userd, ushort, 4H), 3,6-3,3 (m, 4H), 3,4-to 3.02 (m, m, 6H), 2,81 (users, 3H), of 1.41 (m, 2H), of 0.85 (t, 3H).

Example 65

The dihydrochloride of N-(1,1-dimethylethyl)-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E65)

Specified in the title compound was obtained with the yield 79% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-isocyanato-2-methylpropan.

MS: (ES/+) m/z: 446 [MH+]. C27H35N5About requires 445.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,48 (IRS, 1H), 8,75 (users, 1H), of 8.37 (c, 1H), 7,83 (users, 2H), 7,7 (users, 1H), 7,51 (c, 1H), 7,38 (users, 1H), 7,17 (t, 1H),? 7.04 baby mortality (DD, 1H), 6,79 (d, 1H), between 6.08 (c, 1H), 3,71-3,24 (userd, ushort, 4H), 3,6-3,3 (m, 4H), 3,40 (m, 2H), to 3.02 (m, 2H), 2,81 (users, 3H), 1.27mm (c, 9H).

Example 66

The dihydrochloride of N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N'-(phenylmethyl)urea (E66)

Specified in the title compound was obtained with the yield 68% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and (isocyanatomethyl)benzene.

MS: (ES/+) m/z: 480 [MH+]. C30H33N5About requires 479.

1H NMR (400 MHz, d6-DMSO) δ (ppm): a 10.74 (users, 1H), 8,84 (users, 1H), 8,76 (c, 1H), 7,88 (users, 2H), 7,75 (users, 1H), of 7.48 (c, 1H), 7,40 (users, 1H), 7,32 (m, 4H), 7,20 (m, 3H), to 6.80 (m, 1H), 6,77 (t, 1H), 4,28 (d, 2H), 3,70 (d, 2H), 3,71 (d, 2H), 3,6-3,2 (m, 8H), 3.04 from (m, 2H), 2,85 (users, 3H).

Example 67

The dihydrochloride of N-methyl-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N-phenylacetone (E67)

Specified in the title compound was obtained with the yield 47% in accordance with the General method of obtaining ureas (method F), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and N-methylaniline.

MS: (ES/+) m/z: 480 [MH+]. C30H33N5About requires 479.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,9 (users, 1H), cent to 8.85 (users, 1H), 8,14 (c, 1H, 7,9 (users, 2H), 7,75 (users, 1H), 7,44 and 7.36 (m, 4H), 7,32-7,25 (m, 3H), 7,24 (d, 1H), 7,20 (m, 1H), to 6.88 (d, 1H), 3,69 (userd, 2H), 3,6-3,2 (m, 8H), 3,26 (c, 3H), 3,05 (m, 2H), 2,85 (users, 3H).

Example 68

The dihydrochloride of N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N'-phenylacetone (E68)

Specified in the title compound was obtained with the yield 73% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and isocyanatobenzene.

MS: (ES/+) m/z: 466 [MH+]. C29H31N5About 465 requires.

1H NMR (500 MHz, d6-DMSO) δ (ppm): 10,4 (users, 1H), 8,95 (userd, 2H), 8,75 (users, 1H), 7,83 (users, 2H), 7,7 (users, 1H), 7,54 (c, 1H), 7,45 (DD, 2H), 7,38 (users, 1H), 7,27 (m, 4H), of 6.96 (m, 1H), 6,91 (m, 1H), of 3.73 (userd, 2H), 3,6-3,3(m, 6H), 3,24 (t, 2H), is 3.08 (DD, 2H), 2,81 (users, 3H).

Example 69

The dihydrochloride of N-cyclohexyl-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E69)

Specified in the title compound was obtained with the yield of 64% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and socialecological.

MS: (ES/+) m/z: 472 [MH+]. C29H37N5About 471 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 8,84 (users, 1H), 8,5 (userd, 1H), 7,9 (users, 2H), 7,78 (users, 1H), and 7.4 (users, 2H), 7,26 (m, 2H), 6,8 (d, 1H) 6,2 (userd, 1H), 3,7-3,2 (m, 11N), 3,03 (DD, 2H), 2,85 (users, 3H), 1.8 m (m, 2H), 1,65 (m, 2H), 1,5 (m, 1H), 1,25 (m, 3H)and 1.15 (m, 2H).

Example 70

The dihydrochloride of N-ethyl-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)thiourea (E70)

Specified in the title compound was obtained with the yield of 74% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and isothiocyanoethane.

MS: (ES/+) m/z: 434 [MH+]. C25H31N5S requires 433.

1H NMR (400 MHz, d6-DMSO) δ (ppm): to 11.11 (users, 1H), 9,73 (users, 1H), 8,93 (users, 1H), 7,99 (m, 3H), 7,82 (userd, 1H), 7,44 (c, 2H), 7,30 (m, 2H), 7,03 (DD, 1H), 3,8-3,2 (m, 12H), 3,1 (m, 2H), 2,9 (users, 3H), 1,10 (t, 3H).

Example 71

The dihydrochloride of N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N'-[2-(2-thienyl)ethyl]urea (E71)

Specified in the title compound was obtained with the yield 46% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-(2-isocyanatomethyl)thiophene.

MS: (ES/+) m/z: 500 [MH+]. C29H33N5OS requires 499.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,48 (users, 1H), 8,75 (users, 1H), 8,64 (c, 1H), 7,83 (m, 3H), 7,68 (users, 1H), of 7.48 (users, 1H), was 7.36 (users, 1H), 7,33 (DD, 1H), 7,19 (t, 1H), 7,15 (dt, 1H), 6,95 (DD, 1H), 6.89 in (m, 1H), PC 6.82 (dt, 1H), 6,3 (t, 1H), 3,71 (userd, 2H), 3,6-3,2 (m, 12H, to 3.02 (m, 2H), 2.95 and (users, 2H), 2,81 (users, 3H).

Example 72

The dihydrochloride of N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N'-phenyltoloxamine (E72)

Specified in the title compound was obtained with the yield of 59% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and isothiocyanatobenzene.

MS: (ES/+) m/z: 482 [MH+]. C29H31N5S requires 481.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,55 (users, 1H), to 10.09 (c, 1H), 10,07 (c, 1H), 8,75 (users, 1H), 7,83 (users, 2H), 7,68 (users, 1H), 7,51 (c, 1H), 7,49 (d, 2H), between 7.4 and 7.3 (m, 2H), 7,35 (users, 1H), 7,31 (m, 2H), 7,10 (t, 1H), 7,06 (d, 1H), 3,71 (d, 2H), 3,5-3,2 (m, 8H), to 3.09 (m, 2H), 2,80 (users, 3H).

Example 73

The dihydrochloride of N-cyclopentyl-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E73)

Specified in the title compound was obtained with the yield 96% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and isocyanatoacetate.

MS: (ES/+) m/z: 458 [MH+]. C28H35N5O requires 457.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,94 (users, 1H), 8,89 (users, 1H), 8,51 (c, 1H), 7,93 (users, 2H), 7,80 (userd, 1H), 7,43 (users, 2H), 7,17 (m, 2H), for 6.81 (m, 1H), 6.35mm (userd, 1H), 3,90 (m, 1H), 3,8-3,2 (osirm, 10H), totaling 3.04 (DD, 2H), 2,88 (users, 3H), of 1.80 (m, 2H), 1,62 (m, 2H), 1,5 (m, 2H), of 1.34 (m, 2H).

Example 74

The dihydrochloride of N-(1-methylpropyl)-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E74)

Specified in the title compound was obtained with the yield 60% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-isocyanatomethyl.

MS: (ES/+) m/z: 446 [MH+]. C27H35N5O requires 445.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,07 (users, 1H), 8,91 (users, 1H), 8,57 (c, 1H), 7,95 (osirm, 2H), 7,81 (userd, 1H), 7,43 (users, 2H), 7,17 (m, 2H), to 6.80 (m, 1H), 6,17 (userd, 1H), 3,8-3,2 (osirm, 11H), 3,06 (DD, 1H), 2,89 (users, 3H), 1.39 in (kV, 1H)that was 1.04 (d, 3H), of 0.85 (t, 3H).

Example 75

The dihydrochloride of N-ethyl-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E75)

Specified in the title compound was obtained with the yield of 95% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and isocyanates.

MS: (ES/+) m/z: 418 [MH+]. C25H31N5O requires 417.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,89 (users, 1H), 8,60 (users, 1H), 8,90 (c, 1H), 7,92 (users, 2H), 7,80 (users, 1H), 7,44 (c, 2H), 7,19 (m, 2H), for 6.81 (m, 1H), 3,71 (d, 2H), 3,6-3,2 (m, 10H), of 3.07 (m, 2H), 2,87 (users, 3H), of 1.02 (t, 3H).

Example 76

The dihydrochloride of N-(2-were)-N'-(3-{2-[4-(2-methyl-5-hinai who yl)-1-piperazinil]ethyl}phenyl)urea (E76)

Specified in the title compound was obtained with the yield 60% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-isocyanato-2-methylbenzo.

MS: (ES/+) m/z: 480 [MH+]. C30H33N5O requires 479.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,65 (users, 1H), 9,37 (c, 1H), 8,80 (d, 1H), 8,13 (c, 1H), a 7.85 (m, 2H), 7,79 (d, 1H), 7,72 (users, 1H), 7,52 (c, 1H), 7,37 (users, 1H), 7,25 (m, 1H), to 7.09 (m, 2H), to 6.88 (m, 2H), 3,69 (d, 2H), 3,6-3,2 (m, 6H), 3,06 (m, 2H), 2,81 (users, 3H), 2,22 (c, 3H).

Example 77

The dihydrochloride of N-[3,5-bis(trifluoromethyl)phenyl]-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E77)

Specified in the title compound was obtained with the yield 60% in accordance with the General method of obtaining ureas (method E), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 1-isocyanato-3,5-bis(trifluoromethyl)benzene.

MS: (ES/+) m/z: 602 [MH+]. C31H29F6N5O requires 601.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,6 (user, 1H), 10,06 (c, 1H), 9,41 (c, 1H), cent to 8.85 (users, 1H), 8,15 (c, 2H), 7,9 (users, 2H), 7,78 (users, 1H), 7,66 (c, 1H), 7,6 (c, 1H), 7,43 (users, 1H), 7,32 (d, 2H), 6,99 (t, 1H), 3,76 (userd, 2H), 3,4-3,7 (osirm, 6H), 3,29 (t, 2H), 3,13 (DD, 2H), 2,87 (users, 3H).

Example 78

The dihydrochloride of N-methyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N'-phenylace the us (E78)

Specified in the title compound was obtained with the yield of 85% in accordance with the General method of obtaining ureas (method E), using as starting compounds N-methyl-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D7) and isocyanatobenzene.

MS: (ES) m/z: 480 [MH+]. C30H35Cl2N5About requires 479.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,90 (1H, users), 8,80 (1H, users), 8,18 (1H, c), 7,88 (2H, users), of 7.75 (1H, users), the 7.43 (2H, d), 7,37 (1H, d), the 7.43 (1H, d), 7,30 (1H, users), 7,25-to 7.15 (2H, m), 7,19 (2H, dt), 6,92 (1H, TT), of 3.69 (4H, userd), 3,60-3,20 (6H, m), or 3.28 (3H, c), of 3.12 (2H, m), 2,85 (2H, c).

Example 79

The dihydrochloride of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-3-phenyl-2-imidazolidinone (E79)

Specified in the title compound was obtained with the yield of 50% in accordance with the General method of obtaining ureas of the approach formulated above (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinil}-2-methylinosine (D14) and 1-phenyl-2-imidazolidinone, using a 3.0 EQ. CuI and N,N'-dimethylethylenediamine.

MS: (ES/+) m/z: 492 [MH+]. C31H33N5About requires 491.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,0 (1H, users), of 8.90 (1H, users), 7,94 (2H, users), 7,80 (1H, users), 7,71 (1H, users), 7,66 (2H, d), 7,51 (1H, userd), 7,39 (1H, m), to 7.09 (1H, m), 7,05 (1H, d), to 4.01 (4H, c), 3,80-3,20 (10H, m), 3,17 (2H, DD), 2,90 (2H, users).

Example 80

The dihydrochloride of 1-[4-(metiloksi)phenyl]-3-(3-{2-[4-(2-methyl-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E80)

Specified in the title compound was obtained with the yield of 16% in accordance with the General method of obtaining ureas of the approach formulated above (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinil}-2-methylinosine (D14) and 1-[4-(metiloksi)phenyl]-2-imidazolidinone using 6,0 EQ. CuI and N,N'-dimethylethylenediamine, which was added in two portions at 3.0 equiv.

MS: (ES) m/z: 522 [MH+]. C23H35N5About2requires 521.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,57 (1H, users), 8,76 (2H, users), to 7.84 (2H, users), of 7.69 (1H, users), to 7.68 (1H, c), 7,52 (d, 2H), 7,46 (d, 1H), 7,37 (users, 1H), was 7.36 (t, 1H), 7,01 (1H, d), 6,94 (2H, d), of 3.95 (4H, c), 3,74 (3H, c), and 3.72-3,13 (12H, m), 2,82 (3H, users).

Example 81

The dihydrochloride of 1-[2-(metiloksi)phenyl]-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E81)

Specified in the title compound was obtained with the yield 65% in accordance with the General method of obtaining ureas of the approach formulated above (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinil}-2-methylinosine (D14) and 1-[2-(metiloksi)phenyl]-2-imidazolidinone using 6,0 EQ. CuI and N,N'-dimethylethylenediamine, which was added in two portions at 3.0 equiv.

MS: (ES/+) m/z: 522 [MH+]. C23H35N5About2requires 521.

1H NMR (400 MHz, d6-DMSO) δ (ppm): of 10.93 (1H, users), 8,88 (1H, users), to 7.93 (2H, users), 7,79 (1H,users), to 7.67 (1H, users), of 7.48 (1H, DD), 7,44 (1H, users), 7,37 (1H, t), 7,32 (2H, m), 7,14 (1H, userd), 7,01 (2H, m)4,00 (2H, DD), 3,86 (2H, m), of 3.84 (3H, c in), 3.75 (2H, userd), 3,70-3,20 (8H, m)and 3.15 (2H, DD), 2,89 (3H, users).

Example 82

The dihydrochloride of 1-(2-were)-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E82)

Specified in the title compound was obtained with the yield 65% in accordance with the General method of obtaining ureas of the approach formulated above (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinil}-2-methylinosine (D14) and 1-(2-were)-2-imidazolidinone, using a 3.0 EQ. CuI and N,N'-dimethylethylenediamine.

MS: (ES/+) m/z: 506 [MH+]. C32H35N5About 505 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,90 (1H, users), of 8.90 (1H, users), to 7.93 (users, 2H), 7,80 (1H, users), to 7.67 (1H, c), 7,49 (DD, 1H), 7,44 (1H, users), 7,40-7,20 (m, 5H), 7,02 (1H, DD), a 4.03 (2H, t), 3,88 (2H, t), 3,74 (2H, userd), 3,70-3,20 (8H, m)and 3.15 (2H, DD), 2,89 (3H, users), and 2.26 (3H, c).

Example 83

The dihydrochloride of 1-(3-were)-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E83)

Specified in the title compound was obtained with the yield 55% in accordance with the General method of obtaining ureas of the approach formulated above (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinil}-2-methylinosine (D14) and 1-(3-were)-2-imidazolidinone, using 10 mol.% CuI and N,N'-dim is telerilevamento.

MS: (ES/+) m/z: 506 [MH+]. C32H35N5About 505 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,80 (1H, users), cent to 8.85 (1H, users), 7,89 (2H, users), 7,76 (1H, users), of 7.70 (1H, c), of 7.48 (1H, c), was 7.45 (1H, d), 7,42 (2H, osirm), 7,37 (1H, t), from 7.24 (1H, t), 7,02 (1H, d), 6.89 in (1H, d), 3,98 (4H, c), 3,74 (2H, userd), 3,60-3,30 (8H, m), 3,14 (2H, DD), of 2.86 (3H, users), 2,32 (3H, c).

Example 84

The dihydrochloride of 1-(4-were)-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E84)

Specified in the title compound was obtained with the yield 65% in accordance with the General method of obtaining ureas of the approach formulated above (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinil}-2-methylinosine (D14) and 1-(4-were)-2-imidazolidinone, using a 3.0 EQ. CuI and N,N'-dimethylethylenediamine.

MS: (ES/+) m/z: 506 [MH+]. C32H35N5About 505 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,94 (1H, users), of 8.90 (1H, users), 7,94 (2H, users), 7,80 (1H, users), 7,71 (1H, users), 7,53 (2H, d), 7,49 (22H, m), 7,45 (1H, users), 7,38 (1H, t), 7,19 (2H, d),? 7.04 baby mortality (1H, d), 3,99 (4H, c in), 3.75 (2H, userd), 3,70-3,30 (8H, m), and 3.16 (2H, DD), 2,90 (3H, users), from 2.00 (3H, c).

General methods of synthesis of cyclic ureas and carbamates and related dihydrochloride, using as starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D3):

Method G

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-piperazinyl]ethyl}aniline (1 equiv.) in dichloromethane at 0°C was sequentially added diisopropylethylamine (1.5 EQ.) and chloroformate or isocyanate (1.2 EQ.). The solution was stirred for 1 h at room temperature, then was diluted with dichloromethane and washed with saturated aqueous NH4Cl and brine, and then dried over Na2SO4. The solution was concentrated under reduced pressure. The crude material was dissolved in dimethylformamide, cooled to 0°C in an inert atmosphere portions was added NaH (1.1 EQ.). The mixture was stirred for 2 h at room temperature, and then solvent was removed using an SCX cartridge. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), elwira gradient from dichloromethane/MeOH (99/1) to dichloromethane/MeOH (98/2), to obtain the final compounds (outputs ranged from 22 to 87%).

The free base can be converted into the dihydrochloride by dissolving the compounds in Et2O and MeOH and added dropwise 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure to get the crude material, which was triturated with Et2O. Then by filtering the extracted target substance (quantitative yield).

Example 85

The dihydrochloride of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E85)

Specified in the title compound floor is Ali with the release of 22% in accordance with the General method of synthesis of cyclic ureas and carbamates (method G) using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D3) and 1-chloro-2-isocyanatomethyl, through the stage of obtaining the free base 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone.

MS: (ES) m/z: 416 [MH+]. C25H29N5About requires 415.

1H NMR (400 MHz, d6-DMSO) δ (ppm): or 10.60 (users, 1H), 8,77 (c, 1H), 7,85 (c, 2H), 7,71 (c, 1H), to 7.59 (c, 1H), 7,38 (DD, 1H), 7,28 (m, 1H), of 6.96 (users, 1H), 6,92 (d, 1H), 3,83 (m, 2H), 13,71 (d, 2H), 3,7-3,2 (m, 10H), is 3.08 (m, 2H), 2,82 (users, 3H).

Alternative obtain 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone

Hydrochloride methyl-(3-AMINOPHENYL)acetate

One weight part 3-aminophenylarsonic acid suspended in 5 volumes of methanol in a nitrogen atmosphere at 20°C. for 60 minutes at 20°C was added 1.26 volume of chlorotrimethylsilane. The reaction mixture was stirred at 20°C for 1 hour and then concentrated under reduced pressure to 3 volumes. Added 4 volumes of methyl tert-butyl ether and stirred the resulting suspension at room temperature for 18 hours. The solid is collected by filtration and washed with methyl tert-butyl ether (4×1 volume). The resulting material was dried in a drying oven at 40°C for 5 hours to obtain specified in the connection header.

MS: (ES) m/z: 166 [MH+]. C9H1 NO2requires 165.

1H NMR (300 MHz, d6-DMSO) δ (ppm): 7,40 (m, 1H), 7,19 (m, 3H), 3,74 (c, 2H), to 3.58 (c, 3H).

Methyl-[3-(2-oxo-1-imidazolidinyl)phenyl]acetate

Hydrochloride methyl-(3-AMINOPHENYL)acetate suspended in 7 volumes of dichloromethane in a nitrogen atmosphere. At 20°C for 30 minutes was added 1.04 volume diisopropylethylamine and stirred the reaction mixture for 30 minutes at 20°C. At 20°C for 100 minutes was added dropwise 0.44 volume 2-chlorotriazine. The reaction mixture was stirred at 20°C for 3 hours. Within 10 min was added dropwise to 5 volumes of a saturated solution of ammonium chloride and stirred the mixture for 10 minutes. The organic phase was separated and washed with 5 volumes of water. Added tetrahydrofuran (2×3 volumes) and concentrated mixture of 2 volumes. Added 5 volumes of anhydrous tetrahydrofuran and concentrated mixture of 2 volumes. At 20°C in nitrogen atmosphere was added 3 volumes of anhydrous THF. The reaction mixture was cooled to 0°C and five servings of added weight of 0.56 part of tert-butoxide potassium with an interval of 20 minutes between two successive additions. The reaction mixture was stirred at 20°C for 1 hour. Within 20 minutes was added dropwise 2 volume 0,5h. of hydrochloric acid. Added 10 volumes of ethyl acetate and the separated organic phase. The organic layer was washed 2 about what hemami 4% aqueous sodium hydrogen carbonate solution and 2 volumes of salt solution, and then was evaporated organic layer to dryness in vacuo to obtain specified in the title compound (total yield: 90 wt.%).

1H NMR (300 MHz, CDCl3) δ (ppm): 7,50 was 7.45 (m, 2H), 7,30 (m, 1H), 7,00 (d, 1H), 4,98 (users, 1H), 4.95 points (t, 2H), 3,68 (c, 3H), 3,62 (c, 2H), 3,54 (t, 2H).

1-[3-(2-Hydroxyethyl)phenyl]-2-imidazolidinone

Methyl-[3-(2-oxo-1-imidazolidinyl)phenyl]acetate was dissolved in 10 volumes of anhydrous dichloromethane. At 20°C for 1 hour was added dropwise 4.3 volume of lithium borohydride (2M solution in THF). The resulting suspension was stirred at 20°C for 2.5 hours. At 20°C for 60 minutes was added dropwise to 2 volumes of water. The resulting suspension was concentrated to 2 volumes and added 3 amount of 7% aqueous solution of ammonium chloride (pH adjusted to pH=3 by adding 10% hydrochloric acid). The suspension was stirred at 20°C for 2 hours and then filtered. The filter cake thoroughly washed with 2 volumes of 7% aqueous solution of ammonium chloride (pH adjusted to pH=3 by adding 10% hydrochloric acid) and 2 volumes of water to obtain a filtrate pH=7. The filter cake was dried at 80°C with obtaining specified in the title compound (75%yield).

1H NMR (300 MHz, d6-DMSO) δ (ppm): of 7.36-7,27 (m, 2H), 7,19 (t, 1H), 7,86 (m, 1H), 7,81 (d, 1H), 4,58 (users, 1H), 3,60 (t, 2H), 3,52 (m, 2H), 3,35 (t, 2H), 2,64 (t, 2H).

2-[3-(2-Oxo-1-imidazolidinyl)fenilatilmalonamid

1-[3-(2-Hydroxyethyl)phenyl]-2-imidazolidinone suspended in 4 volumes of DMF and heated to 35°C to obtain a clear solution. At 30°C for 15 minutes was added dropwise 1 volume of triethylamine. The mixture was cooled to 20°C and for 30 min was added 0,46 volume methanesulfonanilide. The resulting suspension was stirred at 20°C for 15 minutes. Added 10 volumes of dichloromethane and washed the organic layer with 5 volumes of saline/water (1/1)and then water (3×5 volumes). The organic phase was concentrated to 1 volume) was added to 4 volumes of methanol, and in the absence of complete dissolution of the mixture was heated to 35°C to dissolve the solid. Added 10 volumes of methyl tert-butyl ether and leaving the suspension to stand for 18 hours at room temperature. The suspension was filtered and washed precipitate on the filter with 2 volumes of methyl tert-butyl ether. The solid was dried at 40°C for 18 hours to obtain specified in the title compound (yield 70%).

1H NMR (300 MHz, CDCl3) δ (ppm): 7,54 (c, 1H), 7,40-7,25 (m, 2H), 6,92 (d, 1H), 4.72 in (users, 1H), to 4.41 (t, 2H), 3,92 (t, 2H), 3,60 (t, 2H), to 3.09 (t, 2H), 2,87 (c, 3H).

Alternatively, 1-[3-(2-hydroxyethyl)phenyl]-2-imidazolidinone suspended in 5 volumes of acetonitrile at room temperature in a nitrogen atmosphere. Within 15 minutes, was added dropwise 1 volume of triethylamine. The mixture which was gladly to 0°C for 30 minutes was added 0.73 volume methanesulfonanilide. The reaction mixture was stirred at room temperature for 2 hours and then diluted with 10 volumes of ethyl acetate. The mixture was washed with a saturated solution of ammonium chloride (2×3 volumes), and then with water/brine (1/1, 2×3 volumes). The organic phase was concentrated to 5 volumes) was added 5 volumes of ethyl acetate and the solution was evaporated to dryness to obtain specified in the title compound as a cream solid (yield 90%).

2-Methyl-5-chinainternational

The hydrobromide 5-hydroxy-2-methylinosine (WO/2002034754, Chem. Abstr. 136:355241, 1 weight part, 1 EQ.) suspended in 20 volumes of ethyl acetate and added 7 volumes of a saturated solution of sodium bicarbonate. The organic layer was washed with 7 volumes of a saturated solution of sodium bicarbonate and separated the two layers. The organic layer was concentrated to 2 volumes, then added ethyl acetate (2×3 volumes), each time concentrating the mixture to 2 volumes. Was added toluene (2×10 volumes), each time concentrating the mixture to 2 volumes, obtaining a suspension of 5-hydroxy-2-methylinosine. In the atmosphere of nitrogen at room temperature was added to 9 volumes of toluene and pyridine (0.68 volume of 1.33 EQ.). The mixture was cooled to 0°C and was added dropwise to the anhydride triftormetilfullerenov acid (1.27 volume, 1.2 EQ.), maintaining the temperature of 0°C and then heated to 25°C in those who tell 3 hours. Added 7 volumes of a saturated aqueous solution of ammonium chloride and the mixture was stirred for 10 minutes. Two layers were separated, the organic layer was washed with 7 volumes of water, 7 volumes of 4% solution of sodium bicarbonate, 7 volumes of water, and then concentrated to 3 volumes. Was added toluene (2×7 volumes) and concentrated mixture of 3 volumes of obtaining the crude brown solution specified in the title compound (yield 70%)which was used without further purification.

1,1-Dimethylethyl-4-(2-methyl-5-chinoline)-1-piperidinecarboxylate

A solution of 2-methyl-5-chinainternational (1 weight part, 1 EQ.) 7 volumes of toluene was degirolami under reduced pressure and then purged with nitrogen. To the mixture was added N-Boc-piperazine (of 1.05 equiv.) powdered cesium carbonate (1.5 EQ.), (+/-)-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, of 0.15 EQ.) and palladium acetate (of 0.05 EQ.). The resulting mixture was stirred at 95°C for 16 hours. The solution was cooled, concentrated to approximately 4 volumes and added to 10 volumes of cyclohexane to obtain a suspension. The suspension was stirred for 30 minutes and filtered through a layer of silica gel (approximately 2.5 volume). The filtrate was washed with 10 volumes of water and concentrated under reduced pressure to obtain specified in the title compound as a brown solid which was directly used in the next stage.

2-Methyl-5-(1-piperazinil)quinoline

To a solution of 1,1-dimethylethyl-4-(2-methyl-5-chinoline)-1-piperidinecarboxylate in 3 volumes of 2-propanol was added dropwise 3 of 37% hydrochloric acid. The mixture was stirred at 40°C for 1.5 hours and then concentrated. Added 30 volumes of water and was extracted with ethyl acetate solution (3×20 volumes). The aqueous layer was podslushivaet the addition of an aqueous sodium carbonate solution and then was extracted with dichloromethane (5×40 volumes). The combined organic extracts were dried and evaporated to obtain specified in the connection header in the form of not-quite-white solid (yield 80%in stage 2).

1-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E85)

2-[3-(2-Oxo-1-imidazolidinyl)phenyl]ethylmethanesulfonate (1,32 weight parts) and 2-methyl-5-(1-piperazinil)quinoline (1 weight part) suspended in 5 volumes of acetonitrile at room temperature in a nitrogen atmosphere. Within 30 minutes was added dropwise 1.53 volume diisopropylethylamine, and then stirred the mixture at 75°C for 4 hours. The reaction mixture was cooled to room temperature, concentrated to 2 volume and diluted with 7 volumes of ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride (2×3 volumes), and then water (1×3 volumes). The organic layer was evaporated DOS is ha obtaining specified in the title compound as a brown foam (yield 70%).

Sulfate compounds E85: 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone

1-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (300 mg, 1 weight part) suspended in 20 volumes of methanol (6.0 ml) at room temperature under nitrogen atmosphere. Solution was added sulfuric acid (71 mg, 1 EQ.) in methanol. A transparent solution was made of the seed and watched the crystallization of solids. The suspension was stirred for 16 h at room temperature. The solid was filtered and dried at room temperature in vacuum to obtain the desired salt.

1-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone can exist in two different physical forms, form 1 or form 2.

1-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone, form 1

The free base was completely dissolved in 10 volumes of DCM at reflux. The mixture was concentrated in vacuo (rotary evaporator at 40°C (ambient temperature) prior to the beginning of crystallization (the mixture was reduced to 2-3 volumes). The suspension was cooled to 25°C. then, while stirring, was added 10 volumes of methyl tert-butyl ether. The suspension was stirred at 25°C for 18 hours. The precipitate was filtered off, washed with 1 volume of methyl tert-butyl ether which was dried at 40°C for 18 hours to obtain specified in the connection header with TPL=170°C.

1-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone, form 2

The free base was completely dissolved in 10 volumes of DCM at reflux. The solution was cooled to 25°C. then, while stirring, was added 10 volumes of methyl tert-butyl ether. The suspension was stirred at 25°C during the night. Thus obtained precipitate was filtered, washed with methyl tert-butyl ether/DCM (1/1, 2×1 by volume) and dried at 40°C for 18 hours to obtain specified in the connection header with TPL=164°C.

Example 86

The dihydrochloride of 3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-it (E86)

Specified in the title compound was obtained with the yield 81% in accordance with the General method of synthesis of cyclic ureas and carbamates (method G), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D3) and the acid chloride (2-bromacil)carbamino acid.

MS: (ES) m/z: 417 [MH+]. C25H28N4About2requires 416.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,99 (users, 1H), 8,87 (osirm, 1H), to $ 7.91 (osirm, 2H), 7,79 (osirm, 1H), EUR 7.57 (c, 1H), 7,40 (m, 3H), was 7.08 (d, 1H), 4,43 (t, 2H), 4,07 (t, 2H), 3.72 points to 3.3 (m, 10H), 3.15 in (m, 2H), 2,87 (users, 3H).

Example 87

The dihydrochloride of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)tetrahydro-2(1H)-pyrimidinone (E87)

Indicated the data in the title compound was obtained with the yield of 87% in accordance with the General method of synthesis of cyclic ureas and carbamates (method G) using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D3) and 1-chloro-3-isocyanatopropyl.

MS: (ES) m/z: 430 [MH+]. C26H31N5About requires 429.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,05 (users, 1H), 8,94 (c, 1H), 7,97 (c, 2H), to 7.84 (d, 1H), 7,46 (users, 1H), 7,30 (m, 2H), 7,19 (DD, 1H), was 7.08 (d, 1H), 6,58 (c, 1H), 3,70 (osirm, 4H), 3,63 (t, 2H), 3,6-3,3 (osirm, 6H), 3,24 (t, 2H), of 3.12 (m, 2H), 2.91 in (c, 3H), 1,95 (t, 2H).

Example 88

The dihydrochloride of 3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)tetrahydro-2H-1,3-oxazin-2-it (E88)

Specified in the title compound was obtained with a yield of 75% in accordance with the General method of synthesis of cyclic ureas and carbamates (method G), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D3) and the acid chloride (3-chlorpropyl)carbamino acid.

MS: (ES) m/z: 431 [MH+]. C26H30N4About2requires 430.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,89 (users, 1H), 8,84 (osirm), 7,89 (osirm, 2H), 7,76 (osirm, 1H), 7,40 (m, 4H), 7,31 (c, 1H), 4,32 (t, 2H), 3.72 points to 3.3 (m, 10H), 3,66 (t, 2H), 3,13 (m, 2H), 2,85 (users, 3H), 2,10 (m, 2H).

General methods of synthesis of cyclic amide, urea and urethane derivatives of 1-(3-AMINOPHENYL)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethanol (D8) and related dihydrochloride, using as starting compounds 1-(3-acetylphenyl)-2-cyclic amides, machev the us and carbamates.

Method H

To a stirred solution of 1-(3-acetylphenyl)-2-cyclic amide, urea and carbamate (1 EQ.) in Et2O or dichloromethane at 0°C was added dropwise AlCl3(1 wt.%), and then bromine (1 EQ.). The solution was stirred for 1 h at room temperature, then was diluted with dichloromethane, washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl and brine, and then dried over Na2SO4. The solution was concentrated under reduced pressure. The crude material was dissolved in dimethylformamide was added 2-methyl-5-(1-piperazinil)quinoline (D3) (1 EQ.) and Na2CO3(1.5 EQ.). The solution was stirred for 2-4 h at room temperature. Then was added MeOH in volume equal to the volume of dimethylformamide, and then NaBH4(2 EQ.) and stirred the solution for 15 minutes at room temperature. The solvent was removed using an SCX cartridge. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), elwira gradient from dichloromethane/MeOH (99/1) to dichloromethane/MeOH (98/2), to obtain the final compounds (outputs range from 39%to 71%).

The free base can be converted into the dihydrochloride by dissolving the compounds in Et2O and MeOH and added dropwise 1M ethereal HCl solution (2.1 EQ.). Drawn in yellow precipitate TV is Joe substance and the suspension was stirred for 15 minutes The solvent was removed under reduced pressure to get the crude material, which was triturated with Et2O. Then by filtering the extracted target substance (quantitative yield).

Example 89

The dihydrochloride of 1-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-pyrrolidinone (E89)

Specified in the title compound was obtained with the yield of 25% in accordance with the General method of synthesis of cyclic amide, urea and urethane derivatives of 1-(3-AMINOPHENYL)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethanol (method H), using as starting compounds 1-(3-acetylphenyl)-2-pyrrolidinone (D9) and 2-methyl-5-(1-piperazinil)quinoline (D3).

MS: (ES) m/z: 431 [MH+]. C26H30N4About2requires 430.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,2 (users, 1H), 8,8 (users, 1H), 7,86 (users, 2H), 7,81 (c, 1H), 7,73 (users, 1H), 7,54 (DD, 1H), 7,40 (t, 1H), 7,38 (users, 1H), 7,20 (m, 1H), 6,36 (users, 1H), 5,18 (DD, 1H), 3,83 (t, 2H), 3,76 (ushort, 2H), 3,7-3,2 (m, 8H), 2,83 (users, 3H), 2,5 (m, 2H), 2,07 (kV, 2H).

Example 90

The dihydrochloride of 1-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-azetidinone (E90)

Specified in the title compound was obtained with the yield of 39% in accordance with the General method of synthesis of cyclic amide, urea and urethane derivatives of 1-(3-AMINOPHENYL)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethanol (method H), ISOE is isua as a source of compounds 1-(3-acetylphenyl)-2-azetidinone (D10) and 2-methyl-5-(1-piperazinil)quinoline (D3).

MS: (ES) m/z: 417 [MH+]. C25H28N4About2requires 416.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,35 (users, 1H), 8,84 (users, 1H), to $ 7.91 (users, 2H), to 7.77 (users, 1H), 7,51 (c, 1H), 7,40 (t + users, 2H), 7.23 percent (d, 1H), 7,15 (d, 1H), 6,38 (users, 1H), 5,19 (d, 1H), 3,8-3,2 (m, 12H), to 3.09 (t, 2H), 2,86 (users, 3H).

Example 91

The dihydrochloride of 3-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-it (E91)

Specified in the title compound was obtained with the yield 34% in accordance with the General method of synthesis of cyclic amide, urea and urethane derivatives of 1-(3-AMINOPHENYL)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethanol (method H), using as starting compounds 1-(3-acetylphenyl)-1,3-oxazolidin-2-he (D11) and 2-methyl-5-(1-piperazinil)quinoline (D3).

MS: (ES) m/z: 433 [MH+]. C25H28N4About3requires 432.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,3 (users, 1H), 8,8 (users, 1H), 7,89 (users, 2H), 7,76 (users, 2H), 7,44 (m, 3H), 7,20 (m, 1H), 6,4 (users, 1H), total of 5.21 (DD, 1H), 4,45 (t, 2H), 4,06 (t, 2H), 3,76 (ushort, 2H), 3,7-3,2 (m, 8H), 2,85 (users, 3H).

Example 92

The dihydrochloride of 1-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E92)

Specified in the title compound was obtained with the yield of 26% in accordance with the General method of synthesis of cyclic amide, urea and urethane derivatives of 1-(3-AMINOPHENYL)-2-[4-(2-methyl-5-China the Nile)-1-piperazinil]ethanol (method H), using as starting compounds 1-(3-acetylphenyl)-2-imidazolidinone (D12) and 2-methyl-5-(1-piperazinil)quinoline (D3).

MS: (ES) m/z: 432 [MH+]. C25H29N5About2requires 431.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,2 (users, 1H), 8,8 (users, 1H), 7,87 (users, 2H), 7,74 (users, 2H), 7,43 (DD, 1H), 7,40 (users, 1H), 7,33 (t, 1H), 7,06 (d, 1H), 6,98 (users, 1H), 6,3 (users, 1H), 5,14 (DD, 1H), 3,84 (t, 2H), 3,78 (ushort, 2H), 3,7 to 3.0 (m, 10H), 2,84 (users, 3H).

Example 93

1-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,5-pyrrolidinedione (E93)

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) (1 EQ.) in toluene/pyridine (3/2) at room temperature under inert atmosphere was added dihydro-2,5-furandione (2 EQ.). The solution was stirred for 30 min at room temperature, and then was irradiated in a microwave reactor (PersonalChemistry Emrys™ Optimiser, 300 W, 170°C, 20 min, 4 cycles), was diluted with dichloromethane, washed with saturated aqueous NH4Cl and brine, and then dried over Na2SO4. The solution was concentrated under reduced pressure. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), elwira gradient from dichloromethane/MeOH (99/1) to dichloromethane/MeOH (98/2), with the final connection to the output 76%.

The free base can be converted into the dihydrochloride PU is eat dissolving compounds in Et 2O and MeOH and added dropwise 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure to get the crude material, which was triturated with Et2O obtaining specified in the connection header.

MS: (ES) m/z: 429 [MH+]. C26H28N4About2requires 428.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,1 (users, 1H), 8,91 (users, 1H), 7,94 (users, 2H), 7,81 (users, 1H), 7,49 (t, 1H), 7,44 (users, 1H), 7,37 (d, 1H), 7,22 (c, 1H), 7,18 (d, 1H), of 3.73 (osirm, 2H), 3,59 (osirm, 2H), 3,48 (osirm, 4H), to 3.33 (m, 2H), 3,19 (m, 2H), 2,89 (users, 3H), 2,80 (users, 4H).

Example 94

The dihydrochloride of N-(3-{2-[4-(7-chloro-2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E94)

Specified in the title compound was obtained with the yield 65% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(7-chloro-2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D18) and acetylchloride.

MS: (ES) m/z: 423 [MH+]. C24H27ClN4About 422 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): is 10.68 (users, 1H), 9,99 (c, 1H), 8,53 (users, 1H), 7,80 (c, 1H), 7,65 (c, 1H), 7,58 (d, 1H), 7,37 (d, 1H), 7,28 (m, 2H), 6,97 (d, 1H), 4-3,2 (osirm, 10H), of 3.07 (DD, 1H), 2,74 (c, 3H), 2,04 (c, 3H).

Example 95

The dihydrochloride of N-(3-{2-[4-(7-chloro-2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)methanesulfonamide (E95)

Specified in the title compound was obtained with the yield of 65% using a technique similar to the one presented in example E43, using as starting compound 3-{2-[4-(7-chloro-2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D18) and methanesulfonamide.

MS: (ES) m/z: 459 [MH+]. C23H27ClN4About2S·2HCl requires 458.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,69 (users, 1H), 9,80 (c, 1H), 8,53 (d, 1H), 7,79 (c, 1H), 7,58 (d, 1H), 7,33 (t, 1H), 7,27 (c, 1H), 7,15 (d, 1H), 7,11 (d, 1H), 7,05 (d, 1H), 3,7-3,2 (osirm, 10H), to 3.09 (DD, 2H), 3,01 (c, 3H), 2,73 (c, 3H).

Example 96

The dihydrochloride N1N1-dimethyl-N2-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)glycinamide (E96)

To a stirred solution of 3-{2-[4-(7-chloro-2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (1 equiv.) in dimethylformamide at room temperature in an inert atmosphere successively added diisopropylethylamine (2 equiv.) NaI (2 EQ.) and 2-chloro-N,N-dimethylacetamide (1.1 EQ.). The solution was stirred for 2 h at 60°C, then the solvent was removed using an SCX cartridge. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), elwira gradient from dichloromethane/MeOH (99/1) to dichloromethane/MeOH (98/2), to obtain the final compounds with 38%.

The free base can be converted into the dihydrochloride by dissolving the compounds in Etsub> 2O and MeOH and added dropwise 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure to get the crude material, which was triturated with Et2O obtaining specified in the connection header.

MS: (ES) m/z: 466 [MH+]. C26H32ClN5About 465 requires.

1H NMR (500 MHz, CD3OD) δ (ppm): 9,19 (d, 1H), 7,95 (d, 1H), of 7.90 (d, 1H), 7.62mm (d, 1H), 7,45 (t, 1H), 7,32 (users, 1H), 7,25 (userd, 1H), 7,19 (userd, 1H), 4,37 (users, 2H), 3,85 (userd, 2H), 3,65 (osirm, 4H), of 3.60 (DD, 2H), 3.45 points (ushort, 2H), 3,25 (DD, 2H), 3,06 (c, 3H), 3,02 (c, 3H), 3,01 (c, 3H).

Example 97

2-Methyl-5-(4-{[3-(1H-pyrazole-1-yl)phenyl]acetyl}-1-piperazinil)quinoline (E97)

To a stirred solution of [3-(1H-pyrazole-1-yl)phenyl]acetic acid (D19) (1.1 EQ.) in dimethylformamide at room temperature in an inert atmosphere successively added EDC·HCl (1.5 EQ.), HOBt (2 EQ.) and 2-methyl-5-(1-piperazinil)quinoline (D3) (1 EQ.). The solvent was removed using an SCX cartridge. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), elwira gradient from dichloromethane/MeOH (99/1) to dichloromethane/MeOH (98/2), to obtain specified in the connection header with the yield 74%.

MS: (ES) m/z: 412 [MH+]. C25H25N5About 411 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): at 8.36 (d, 1H), to 7.93(d, 1H), of 7.75 (d, 1H), 7,71 (c, 1H), 7,69 (c, 1H), 7,58 (d, 1H), 7,55 (t, 1H), 7,42 (t, 1H), 7,25 (m, 2H), 7,00 (d, 1H), 6,46 (c, 1H), a 3.87 (c, 2H), of 4.0 to 3.7 (m, 4H), of 3.1 and 2.9 (m, 4H), 2,72 (c, 3H).

Example 98

2-Methyl-5-(4-{2-[3-(1H-pyrazole-1-yl)phenyl]ethyl}-1-piperazinil)quinoline (E98)

To a stirred solution of 2-methyl-5-(4-{[3-(1H-pyrazole-1-yl)phenyl]acetyl}-1-piperazinil)quinoline (E97) (1 EQ.) in tetrahydrofuran at room temperature under inert atmosphere was added a 1M solution of a complex of borane/tetrahydrofuran (3 EQ.) in tetrahydrofuran. The solution was heated to 60°C for 3 hours was Added 3n. an aqueous solution of HCl and was stirred solution at room temperature for 12 h the Solvent was removed under reduced pressure. The crude material was purified by SCX cartridge with obtaining specified in the connection header with the release of 52%.

MS: (ES) m/z: 398 [MH+]. C25H27N5requires 397.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.90 (d, 1H), of 7.70 (d, 1H), 7,70 (c, 1H), 7,65 (t, 1H), 7,60 (t, 1H), 7,50 (DD, 1H), 7,35 (m, 1H), 7,25 (d, 1H), 7,15 (d, 1H), 7,05 (d, 1H), 6,45 (t, 1H), 3,20 (m, 4H), 3,0-2,7 (m, 8), 2,70 (c, 3H).

Example 99

N-(3-{2-[4-(6-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E99)

1,1-Dimethylethyl-4-(6-fluoro-2-methyl-5-chinoline)-1-piperidinecarboxylate

In a sealed tube at 120°C for 20 h was stirred mixture of 5-bromo-6-fluoro-2-methylinosine (0,285 g; Chem. Pharm. Bull., 1989, 37(8), 2103-8), 1,1-dimethylethyl-1 piperidinecarboxylate (0,265 g, 1.2 EQ), Pd(OA)2(15 mol.%, 0.04 g), bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 30 mol.%, 0,221 g), cesium carbonate (1.5 EQ, 0,580 g) and toluene (3.5 ml). The mixture was cooled to room temperature and distributed between ethyl acetate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by the method of flash chromatography (SiO2; elwira gradient DCM/MeOH from 99/1 to 90/10), obtaining specified in the title compound as a colourless solid (0,270 g, yield 65%).

MS: (ES/+) m/z: 346 [MH+]. C19H24FN3About2requires 345.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,55 (d, 1H), 7,80 (DD, 1H), 7,40 to 7.2 (m, 2H), 3,5-2,9 (m, 8H), 2,65 (c, 3H), 1.5 a (c, 9H).

6-fluoro-2-methyl-5-(1-piperazinil)quinoline

To a solution of 1,1-dimethylethyl-4-(6-fluoro-2-methyl-5-chinoline)-1-piperidinecarboxylate (0,178 g) in dioxane (4 ml) at 0°C was added a solution of hydrogen chloride in dioxane (4M, 4 ml). The resulting mixture was heated to room temperature and was stirred for 15 hours the Mixture was concentrated in vacuum and distributed between aqueous sodium hydroxide solution and DCM. The combined organic phases are washed with saline, dried over sodium sulfate and concentrated to obtain specified in the title compound (198 mg, yield 100%).

MS: (ES/+) m/z: 246 [MH+]. C14H16FN3requires 245.

<> 1H NMR (300 MHz, CDCl3) δ (ppm): 8,55 (d, 1H), 7,80 (DD, 1H), 7,40 to 7.2 (m, 2H), 3,5-2,9 (m, 8H), 2,65 (c, 3H).

6-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinil}quinoline

To a solution of 2-methyl-5-(1-piperazinil)-6-ftorhinolona (0.075 g; 1 EQ.) and 2-(3-nitrophenyl)ethylmethanesulfonate (D4) (0.08 g; 1.1 EQ.) in dimethylformamide (3.0 ml) was added N,N-diisopropylethylamine (0.15 ml; 3 EQ.). The reaction mixture was heated to 100°C for 10 hours. The dark solution was concentrated under reduced pressure, diluted with water (3 ml) and brine (1 ml) and was extracted with ethyl acetate (3×3 ml). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by the method of flash chromatography on silica gel, elwira gradient from dichloromethane to dichloromethane/methanol (98/2), to obtain specified in the connection header with the release of 42% (0.05 g).

MS: (ES) m/z: 395,2 [MH]+. C22H23FN4About2requires 394.

3-{2-[4-(6-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline

To a suspension of iron powder (0.05 g; 7 EQ.) and ammonium chloride (0.05 g; 7 EQ.) in water (3 ml) was added dropwise a solution of 6-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinil}quinoline (0.05 g; 1 EQ.) in methanol (3 ml). Participating in the reaction substance was heated under reflux for 8 hours, adding during the reaction the three portions of the additional quantity of iron powder (0.05 g; 7 EQ.) and ammonium chloride (0.05 g; 7 EQ.). The reaction mixture was cooled to room temperature and filtered using a Millipore filter. The filtrate was concentrated under reduced pressure, diluted with water (5 ml) and saturated aqueous sodium bicarbonate (2 ml) and was extracted with ethyl acetate (3×5 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain specified in the connection header with the release of 91% (0.04 g).

MS: (ES) m/z: 365 [MH]+. C22H26N4requires 346.

1H NMR (300 MHz, d6-DMSO) δ (ppm): 8,50 (d, 1H), 7,80 (m, 1H), to 7.75 (m, 1H), 7,60 (d, 1H), 6,80 (t, 1H), 6,65 (users, 1H), 6,60 (m, 2H), 3,3-2,8 (osirm, 12H), 3.15 in (t, 4H), 2,75 (c, 3H).

N-(3-{2-[4-(6-fluoro-2-methyl-5-chinoline)-1 piperazinil]ethyl}phenyl)ndimethylacetamide (E99)

Specified in the title compound was obtained with the yield 78% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(6-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline and acetylchloride.

MS: (ES) m/z: of 407.5 [MH+]. C24H27FN4O requires 406.

1H NMR (300 MHz, d6-DMSO) δ (ppm): 9,67 (users, 1H), and 8.50 (d, 1H), 7,73 (DD, 1H), 7,53 (DD, 1H), 7,44 (d, 1H), 7,46 (users, 1H), 7,39 (d, 1H), 7,19 (t, 1H), 6,93 (d, 1H), 3,17 (users, 4H), 2,8-2,5 (osirm, 8H), 2,64 (c, 3H), 2,03 (c, 3H).

Example 100

N-(3-{2-[4-(8-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl)Hairdryer is l)ndimethylacetamide(E100)

8-fluoro-2-methyl-5-chinainternational

A solution of 8-fluoro-2-methyl-quinoline-5-ol (WO/2002034754) (103 mg, of 0.58 mmol) and pyridine (1 ml) in dichloromethane (4 ml) was cooled to 0°C and added anhydride triftormetilfullerenov acid (144 ml). The reaction mixture was stirred under inert atmosphere at room temperature for 1 h, then was poured into water and was extracted with ethyl acetate. The organic layers were combined, dried (sodium sulfate) and concentrated under reduced pressure. The crude product was purified by the method of flash chromatography on silica gel, elwira with ethyl acetate/cyclohexane (4/6) to obtain the specified title compound (134 mg, yield 74%).

1H NMR (300 MHz, d6-DMSO) δ (ppm): 8,31 (m, 1H), a 7.85 (m, 1H), 7,60 (m, 2H), 2,82 (c, 3H).

Tert-butyl ester 4-(8-fluoro-2-methyl-5-quinoline-5-yl)piperazine-1-carboxylic acid

To a solution of 8-fluoro-2-methyl-5-chinainternational (134 mg, 0.43 mmol) in toluene (1.5 ml) under inert atmosphere was added 1,1-dimethylethyl-1-piperidinecarboxylate (96 mg, 0.52 mmol), cesium carbonate (211 mg, of 0.65 mmol), palladium acetate (14 mg, 0.06 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (80 mg, 0.13 mmol). The reaction mixture was stirred under reflux for 6 hours. Then the reaction mixture was cooled to room temperature, was extinguished by the addition of saturated aqueous solution of chloride Ammon who I am and were extracted with ethyl acetate. The organic layers were combined, dried (sodium sulfate) and concentrated under reduced pressure. The crude product was purified by the method of flash chromatography on silica gel, elwira with ethyl acetate/cyclohexane (1/9), with specified title compound (50 mg, yield 34%). MS: (ES) m/z: 346 [MH+]. C19H14FN3About2requires 345.

8-fluoro-2-methyl-5-piperazine-1-rhinolin

Tert-butyl ester 4-(8-fluoro-2-methyl-5-quinoline-5-yl)piperazine-1-carboxylic acid (50 mg, 0.14 mmol) was dissolved in 1,4-dioxane (0.5 ml) was added under stirring HCl (2.5 ml 4n. solution in dioxane). After stirring for 4 hours the solvent is evaporated to obtain a white solid, which was dissolved in water, podslushivaet addition of solid sodium hydroxide (pH>10) and was extracted with dichloromethane. The organic layer was dried (sodium sulphate)then evaporated under reduced pressure to obtain specified in the title compound (50 mg, yield 70%).

MS: (ES) m/z: 246 [MH+]. C14H16FN3requires 245.

8-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinil}quinoline

To a solution of 2-methyl-5-(1-piperazinil)-8-ftorhinolona (0,170 g; 1 EQ.) and 2-(3-nitrophenyl)ethylmethanesulfonate (D4) (0.17 g; 1 EQ.) in dimethylformamide (4.0 ml) was added N,N-diisopropylethylamine (0.25 ml; 3 EQ.). The reaction mixture was heated to 100°C at the tip is of 10 hours. The dark solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (3 ml) and brine (1 ml) and was extracted with ethyl acetate (3×3 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by the method of flash chromatography on silica gel, elwira gradient from dichloromethane to dichloromethane/methanol (98/2), to obtain specified in the connection header with the outlet 46% (0.126 g).

MS: (ES) m/z: 395,5 [MH]+. C22H23FN4O2requires 394.

1H NMR (300 MHz, CDCl3) δ (ppm): scored 8.38 (d, 1H), 8,10 (c, 1H), with 8.05 (m, 1H), 7,56 (m, 1H), 7,50 (t, 1H), 7,35 (m, 2H), 6,95 (m, 1H), 3.15 in (m, 4H), 2.95 and (m, 2H), 2,80-2,70 (m, 7H), 2,75 (c, 3H).

3-{2-[4-(8-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline

To a suspension of iron powder (0.125 g; 7 EQ.) and ammonium chloride (0,119 g; 7 EQ.) in water (4 ml) was added dropwise a solution of 8-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinil}quinoline (0.126 g; 1 EQ.) in methanol (4 ml). Participating in the reaction substance was heated under reflux for 8 hours, adding during the reaction with three portions of an additional quantity of iron powder (only 0.125 g; 7 EQ.) and ammonium chloride (just 0,119 g; 7 EQ.). The reaction mixture was cooled to room temperature and filtered using a Millipore filter. The filtrate is the end of what was tarawali under reduced pressure, was diluted with water (5 ml) and saturated aqueous sodium bicarbonate (2 ml) and was extracted with ethyl acetate (3×5 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain specified in the connection header with the release of 77% (0,090 g).

MS: (ES) m/z: 365,3 [MH]+. C22H25FN4requires 364.

1H NMR (300 MHz, CDCl3) δ (ppm): at 8.36 (d, 1H), 7,31 (m, 1H), 7,05 (t, 1H), 7,00 (m, 1H), 6,70 (m, 1H), 6,55 (m, 2H), 3,70 (users, 2H), 3.15 in (osirm, 4H), 2,80-2,70 (m, 7H), 2,75 (c, 3H).

N-(3-{2-[4-(8-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E100)

Specified in the title compound was obtained with the yield of 26% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(8-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline and acetylchloride.

MS: (ES) m/z: of 407.5 [MH+]. C24H27FN4O requires 406.

1H NMR (300 MHz, d6-DMSO) δ (ppm): a 10.74 (users, 1H), 10,00 (c, 1H), 8,46 (DD, 1H), 7,63 (users, 1H), 7,55 (d, 1H), 7,49 (DD, 1H), 7,39 (d, 1H), 7.23 percent (t, 1H), 7,18 (DD, 1H), 6,97 (d, 1H), 3,69 (userd, 2H), 3,44 (m, 2H), 3,83 (m, 2H), 3,21 (m, 2H), 3,32 (m, 2H), is 3.08 (m, 2H), 2,69 (c, 3H), 2,04 (c, 3H).

Example 101

The dihydrochloride O-methyl-(2-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)THIOCARBAMATE (E101)

Specified in the title compound was obtained with the yield 55% in accordance with the General method of obtaining carbamates (the manual (D), using as a starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and fenilalaninemia. The crude material is hydrolyzed by addition of 1N. aqueous NaOH in THF/MeOH (4/1) and was purified in accordance with the above General method.

MS: (ES/+) m/z: 421 [MH+]. C25H30N4About2requires 420.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11 (2H, c), of 8.90 (1H, users), 7,94 (2H, users), 7,81 (1H, users), the 7.43 (1H, m), 7,33 (2H, t), 7,19 (1H, d), of 4.0 to 3.2 (15H, m), 2,96 (3H, c).

Example 102

N-(3-{1-Hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E102)

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]acetyl}phenyl)ndimethylacetamide

To a stirred solution of 2-methyl-5-(1-piperazinil)quinoline (D6, 0.14 g, 1 EQ.) in anhydrous DMF (5 ml) under inert atmosphere was added potassium carbonate (0.11 g, 1.2 EQ.) and a solution of N-[3-(2-chloroacetyl)phenyl]ndimethylacetamide (J. Chem. Soc., 1949, 552-553, 0.17 g, 1.2 EQ.) in DMF (3 ml). The reaction mixture was stirred for 1.5 hours the Mixture was diluted with water (8 ml) and was extracted with DCM (3×15 ml). The organic phase is washed with brine (25 ml), dried over sodium sulfate and solvent was removed under reduced pressure. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), using as eluent DCM/methanol (95/5), to obtain specified in the header connection : the om 42% (0.104 g g).

MS: (ES) m/z: 403,2 [MH+]. C24H26N4O2requires 402.

1H NMR (500 MHz, CDCl3) δ (ppm): to 8.40 (d, 1H), 8,13 (c, 1H), to 7.84 (d, 1H), 7,79 (d, 1H), 7,73 (d, 1H), to 7.59 (t, 2H), 7,45 (t, 1H), 7,39 (users, 1H), 7,27 (d, 1H), to 7.09 (d, 1H), 3,95 (c, 2H), 3,18 (t, 4H), 2.91 in (users, 4H), 2,74 (c, 3H), 2.23 to (c, 3H).

N-(3-{1-Hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E102)

To a stirred solution of N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]acetyl}phenyl)ndimethylacetamide (is 0.102 g, 1 EQ.) in anhydrous DCM (2 ml), cooled to 0°C in an inert atmosphere was added sodium borohydride (0.015 g, 1.6 EQ.). The reaction mixture was heated to room temperature and was stirred for 18 hours. The mixture was diluted with DCM (10 ml) and washed with water (2×10 ml). The organic phase was dried over sodium sulfate and solvent was removed under reduced pressure. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), using as eluent DCM/methanol (97/3), obtaining specified in the connection header with the release of 42% (0.104 g g).

MS: (ES) m/z: 405,3 [MH+]. C24H28N4O2requires a 404.

1H NMR (500 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,60 (c+d, 2H), 7,40 (d, 1H), 7,30 (m, 1H), 7,30 to 7.2 (d+c, 2H), 7,20-7,10 (t, 1H), 7,05 (d, 1H), 4,8 (DD, 1H), 3,10 (users, 4H), 3.0 a (users, 2H), and 2.7 (m, 4H), 2,7 (c, 3H), 2,1 (c, 3H).

Example 103

N-(5-Chloro-1,3-benzoxazol-2-yl)-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}is enyl)urea (E103)

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) (1 EQ.) in dichloromethane at 0°C in an inert atmosphere portions was added triethylamine (6 EQ.), and then triphosgene (0.5 EQ.). The reaction mixture was stirred for 1 hour To the mixture was added acetonitrile, diisopropylethylamine (2 EQ.) and 5-chloro-1,3-benzoxazol-2-amine (1.1 EQ.). The reaction mixture was stirred for 16 hours

The mixture was extracted with dichloromethane, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and solvent was removed under reduced pressure. The crude material was purified according to the method of chromatography on a cartridge for solid phase extraction (silicon dioxide), using as eluent a gradient from dichloromethane/MeOH (99:1) to dichloromethane/MeOH (98:2), with specified title compound (yield 47%).

1H NMR (400 MHz, CDCl3) δ (ppm): 8,35 (1H, d), and 7.8 (1H, d), and 7.6 (1H, t), of 7.55 (2H, m), 7,45 (1H, d), 7,35-7,20 (4H, m), to 7.15 (1H, d), 7,05 (1H, d), the 3.35 (4H, m), and 3.2 (4H, m), 3,1 (4H, c), a 2.75 (3H, c).

Example 104

The dihydrochloride (R or S)-N-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamide (E104)

The racemate of N-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamide (E40) divided by the method of preparative chiral HPLC on a column of Daiel Chiralcel OJ, using a mixture of n-hexane/ethanol (75/25) as eluent, to obtain specified in the connection header in the form aliremove the first enantiomer.

MS: (ES/+) m/z: 502 [MH+]. C28H31N5About2S requires 501,65.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,18 (2H, users), cent to 8.85 (1H, users), 7,89 (3H, c), to 7.77 (1H, users), 7,53 (1H, d), 7,37 (2H, m), 7,18 (1H, d), 6,36 (1H, users), to 5.17 (1H, DD), 3,80-3,20 (10H, m), 2,85 (3H, c), of 2.64 (3H, c), of 2.53 (3H, c).

Example 105

The dihydrochloride (S or R)-N-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamide (E105)

The racemate of N-(3-{1-hydroxy-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamide was divided by the method of preparative chiral HPLC on a column (Daicel Chiralcel OJ, using a mixture of n-hexane/ethanol (75/25) as eluent, to obtain specified in the connection header in the form aliremove second enantiomer.

MS: (ES/+) m/z: 502 [MH+]. C28H31N5About2S requires 501,65.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,18 (2H, users), cent to 8.85 (1H, users), 7,89 (3H, c), to 7.77 (1H, users), 7,53 (1H, d), 7,37 (2H, m), 7,18 (1H, d), 6,36 (1H, users), to 5.17 (1H, DD), 3,80-3,20 (10H, m), 2,85 (3H, c), of 2.64 (3H, c), of 2.53 (3H, c).

A General method of obtaining imides, using as starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6): the Way I

A solution of 3-{2-[4-(2-methyl-5-chinoline)-1-PIP is retinyl]ethyl}aniline (D6), phthalic anhydride (2 EQ.) in anhydrous pyridine and anhydrous toluene (ratio 2/3) was heated in a microwave apparatus at 160°C for 20 minutes in an inert atmosphere. Then the mixture was cooled to room temperature, diluted with DCM, washed with saturated aqueous ammonium chloride, dried over sodium sulfate and solvent was removed under reduced pressure. The crude material was purified according to the method of chromatography on a cartridge for solid phase extraction (silicon dioxide), elwira gradient from dichloromethane/MeOH (99:1) to dichloromethane/MeOH (95:5), to obtain the final compounds (outputs ranging from 55 to 94%).

Example 106

2-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1H-isoindole-1,3(2H)-dione (E106)

Was obtained from 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 2-benzofuran-1,3-dione in accordance with method I.

MS: (ES) m/z: 477,3 [MH]+. C30H28N4About2requires 476.

1H NMR (300 MHz, CDCl3) δ (ppm): of 8.37 (d, 1H), 7,94 (m, 2H), 7,79 (m, 2H), of 7.70 (d, 1H), 7,56 (t, 1H), 7,43 (t, 1H), 7,31-7,22 (m, 4H), 7,06 (d, 1H), 3,10 (m, 4H), 2,90 (m, 2H), 2,80 (m, 6H), 2,70 (c, 3H).

Example 107

2-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,3-dihydro-1H-isoindole-1-he (E107)

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6, 1 EQ.) in dichloromethane (0,1M) at 0°C was slowly added a solution of trimethyl uminia (2,0M in hexane, 1 EQ.). The reaction mixture was stirred for 15 min, then was added dropwise a solution of phthalide (1 EQ.) in dichloromethane. The solution was stirred for 2 h at 0°C, then was distributed between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was dried over sodium sulfate and concentrating the solution under reduced pressure. The crude 2-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide was dissolved in dichloromethane, then sequentially added N,N-diisopropylethylamine (1 EQ.) and methanesulfonyl chloride (1 EQ.). The reaction mixture was stirred for 2 hours at room temperature, then was distributed between saturated aqueous ammonium chloride and dichloromethane. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography method on the cartridge for solid phase extraction (silicon dioxide), elwira gradient dichloromethane/methanol from (100/2) to (98/2), to obtain the specified title compound (yield 45%).

MS: (ES) m/z: 463,3 [MH]+. C30H30N4About requires 462.

1H NMR (400 MHz, CDCl3) δ (ppm): to 8.41 (d, 1H), 8,01 (d, 1H), 7,73 (d, 1H), 7,62-of 7.48 (m, 3H), 7,44 (d, 1H), 7,34-7,22 (m, 2H), 7,17 (m, 2H), to 7.09 (d, 1H), 7,02 (d, 1H), 5,42 (c, 2H), 3,17 (t, 4H), 2,94-to 2.74 (m, 8H), 2,74 (c, 3H).

Example 108

4-Fluorine-2-(3-{2-[4-(2-methyl-5-chinoline)-1-PI is arsenil]ethyl}phenyl)-1H-isoindole-1,3(2H)-dione (E108)

Was obtained from 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 4-fluoro-2-benzofuran-1,3-dione in accordance with method I.

MS: (ES) m/z: 495,3 [MH]+. C30H27FN4About2requires 494.

1H NMR (400 MHz, CDCl3) δ (ppm): 8,42 (d, 1H), 7,84-of 7.82 (m, 2H), of 7.75 (d, 1H), 7.62mm (t, 1H), 7,51-7,47 (m, 2H), 7,35-7,28 (m, 4H), 7,12 (d, 1H), 3,19 (users, 4H), 3,10-2,70 (m, 8H), was 2.76 (c, 3H).

Example 109

5,6-Dichloro-2-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1H-isoindole-1,3(2H)-dione (E109)

Was obtained from 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 5,6-dichloro-2-benzofuran-1,3-dione in accordance with method I.

MS: (ES) m/z: 545,2 [MH]+. C30H26Cl2N4About2requires 544.

1H NMR (400 MHz, CDCl3) δ (ppm): 8,42 (d, 1H), 8,07 (c, 2H), of 7.75 (d, 1H), 7.62mm (t, 1H), 7,49 (t, 1H), was 7.36-7,28 (m, 4H), 7,11 (d, 1H), 3,18 (users, 4H), 3,10-2,70 (m, 6H), to 2.99 (t, 2H), was 2.76 (c, 3H).

Example 110

5-Methyl-2-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1H-isoindole-1,3(2H)-dione (E110)

Was obtained from 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) and 5-methyl-2-benzofuran-1,3-dione in accordance with method I.

MS: (ES) m/z: 491,3 [MH]+. C31H30N4About2requires 490.

1H NMR (400 MHz, CDCl3) δ (ppm): 8,42 (d, 1H), 7,87 (d, 1H), 7,79 (c, 1H), 7,76 (d, 1H), of 7.64-of 7.60 (m, 2H), of 7.48 (t, 1H), 7,35-7,29 (m, 4H), 7,13 (d, 1H), 3,21 (users, 4H), 3,10-2,80 (m, 8H), 2,77 (c, 3H), 2,59 (c, 3H).

Example 111

4-(Methoxy)-N-(3-{2-[4(2-methyl-5-chinoline)-1-piperazinil]propyl}phenyl)benzamide (E111)

5-{4-[2-(3-Bromophenyl)propyl]-1-piperazinil}-2-methylinosine (D20)

To a stirred solution of 1-(3-bromophenyl)-2-propanone (50 mg) and 2-methyl-5-(1-piperazinil)quinoline (D3) (2.0 EQ., 107 mg) in methanol (1 ml) was added a solution of zinc chloride(II) (0,5M in THF, 0.5 EQ., 234 μl). The mixture was stirred for 10 minutes, then the solution was added laborgerate sodium (1M in THF, 1.0 equiv., 234 μl). The obtained white mixture was stirred at room temperature until complete disappearance of starting material, as determined by the method of HPLC. The mixture was concentrated under reduced pressure, diluted with an aqueous solution of sodium hydroxide (1M) and extracted with DCM. The combined organic phases are washed with saline, dried over sodium sulfate and concentrated. The crude material was purified according to the method of chromatography on a cartridge for solid phase extraction (SiO2using DCM/methanol (98/2) as eluent, to obtain the specified title compound (50 mg, yield 50%).

MS: (ES/+) m/z: 424, 426 [MH+]. C23H26BrN3requires 423, 425.

1H NMR (300 MHz, CDCl3) δ (ppm): 8.30 to (d, 1H), 7,80 (d, 1H), of 7.70 (t, 1H), 7,50-7,30 (m, 6H), 3.25 to 2,95 (m, 10H), 2,80 (c, 3H), by 2.55 (m, 1H)and 1.15 (d, 3H).

4-(Methoxy)-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]propyl}phenyl)benzamide (E111)

Specified in the title compound was obtained with the yield of 21% in accordance with the General methodological who obtain amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)propyl]-1-piperazinil}-2-methylinosine (D20) and 4-methoxybenzamide.

MS: (ES/+) m/z: 495 [MH+]. C31H34N4About2requires 494.

1H NMR (400 MHz, DMSO) δ (ppm): 10,63 (users, 1H), 10,16 (c, 1H), 8,91 (users, 1H), to 7.99 (d, 2H), 7,86 (m, 3H), 7,74 (users, 1H), to 7.61 (d, 1H), 7,41 (users, 1H), 7,37 (t, 1H), was 7.08 (d, 3H), 3,86 (c, 3H), 3,66 (users, 4H), 3,80-2,70 (m, 10H), of 1.28 (d, 3H).

Example 112

2-Fluoro-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]propyl}phenyl)benzamide (E112)

Specified in the title compound was obtained with the yield of 40% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)propyl]-1-piperazinil}-2-methylinosine (D20) and 2-perbenzoic.

MS: (ES/+) m/z: 483 [MH+]. C30H31FN4About 482 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,85 (users, 1H), 10,48 (c, 1H), 8,97 (users, 1H), 7,92 (users, 2H), 7,83 (c, 1H), 7,78 (users, 1H), 7,68 (TD, 1H), to 7.61 (arcs, 1H), 7,55 (d, 1H), 7,43 (users, 1H), 7,40-7,34 (m, 3H), 7,11 (d, 1H), 4,0 is 2.7 (m, 11H), 2,88 (c, 3H), of 1.28 (d, 3H).

Example 113

3-Fluoro-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]propyl}phenyl)benzamide (E113)

Specified in the title compound was obtained with the yield 55% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-4-[2-(3-bromophenyl)propyl]-1-piperazinil}-2-methylinosine (D20) and 3-perbenzoic.

MS: (ES/+) m/z: 483 [MH+]. C30H31FN4About 482 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): accounted for 10.39 (c, 1H), 10.30 a.m. (users, 1H), 8,77 (users, 1H), of 7.90-of 7.82 (m, 5H), 7,70-7,52 (m, 3H), of 7.48 (TD, 1H), 7,40-7,35 (m, 2H), 7,12 (d, 1H), 3,8-2,7 (m, 14H), of 1.28 (d, 3H).

Example 114

3-(Methoxy)-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]propyl}phenyl)benzamide (E114)

Specified in the title compound was obtained with the yield 35% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)propyl]-1-piperazinil}-2-methylinosine (D20) and 3-methoxybenzamide.

MS: (ES/+) m/z: 495 [MH+]. C31H34N4About2requires 494.

1H NMR (400 MHz, d6-DMSO) δ (ppm): to 10.7 (users, 1H), 10,29 (c, 1H), 8,90 (users, 1H), 7,89 (users, 2H), 7,86 (c, 1H), 7,75 (users, 1H), 7.62mm (d, 1H), EUR 7.57 (d, 1H), 7,51 (t, 1H), 7,45 (users, (1H), 7,38 (m, 1H), 7,19 (DD, 1H), 7,11 (DD, 1H), 3,86 (c, 3H), of 3.75 (m, 1H), 3,66-of 2.86 (m, 14H), 2,78 (t, 1H), 1.28 (in d, 3H).

Example 115

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]propyl}phenyl)ndimethylacetamide (E115)

Specified in the title compound was obtained with the yield of 64% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)propyl]-1-piperazinil}-2-methylinosine (D20) and ndimethylacetamide.

MS: (ES/+) m/z: 403 [MH+]. C25H30N4About 402 requires.

1H NMR (400 MHz,d 6-DMSO) δ (ppm): a 10.74 (users, 1H), 10,01 (c, 1H), 8,93 (users, 1H), of 7.90 (users, 2H), 7,76 (users, 1H), 7,65 (c, 1H), 7,41 (userd, 2H), 7,31 (m, 1H), 7,02 (d, 1H), 3,80-by 2.73 (m, 11H), 2,87 (c, 3H), 2.06 to (c, 3H), of 1.24 (d, 3H).

Example 116

1-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-3-phenyl-2-imidazolidinone (E116)

Specified in the title compound was obtained with the yield 55% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)propyl]-1-piperazinil}-2-methylinosine (D20) and 1-phenyl-2-imidazolidinone.

MS: (ES/+) m/z: 506 [MH+]. C32H35N5About 505 requires.

1H NMR (400 MHz, DMSO) δ (ppm): 10,4 (users, 1H), 8,80 (users, 11-1), 7,83 (users, 2H), 7,71 (c, 1H), 7,66 (d, 1H), 7,70-of 7.60 (m, 1H), 7,51 (userd, 1H), 7,40 (m, 4H), 7,10-7,05 (m, 2H), 4,01 (users, 4H), 3,78 (osirm, 1H), 3,66 (osirm, 4H), 3,5 (osirm, 5H), 2,87 (osirm, 4H), of 1.24 (d, 3H).

Example 117

3-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-1,3-oxazolidin-2-he (E117)

Specified in the title compound was obtained with the yield 73% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)propyl]-1-piperazinil}-2-methylinosine (D20) and 2-oxazolidone.

(ES/+) m/z: 431 [MH+]. C26H30N4About2requires 430.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,6 (users, 1H), 8,90 (users, 1H), 7,87 (OSiR.the, 2H), 7,73 (c, 1H), to 7.61 (c, 1H), 7,46 (d, 1H), 7,42 (t, 1H), 7,40 (users, 1H), 7,12 (d, 1H), 4,47 (t, 2H), 4,10 (2H), of 3.77 (osirm, 1H), 3,65 (users, 4H), 3,50-3,40 (osirm, 5H), 2,84 (users, 4H), 2,80 (m, 1H), 1,25 (d, 3H).

Example 118

N-(3-{1-Methyl-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E118)

Methyl(3-nitrophenyl)acetate

To a stirred solution of 3-(nitrophenyl)acetic acid (4.0 g) in methanol (60 ml) was added trimethylsilane (5.6 ml, 2.0 EQ.). The resulting solution was stirred at room temperature for 18 hours, then concentrated under reduced pressure and distributed between DCM and aqueous sodium hydrogen carbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuum to obtain specified in the title compound as a colourless liquid (4,2 g, 100%).

1H NMR (300 MHz, CDCl3) δ (ppm): 8,15 (c, 1H), 8,07 (d, 1H), 7,60 (d, 1H), 7,47 (t, 1H), 3,85 (c, 2H), 3,80 (c, 3H).

Methyl-2-(3-nitrophenyl)propanoate

To a stirred solution of methyl(3-nitrophenyl)acetate (4,2 g) in THF (30 ml) at -30°C was added dropwise a solution of hexamethyldisilazide lithium (1M in hexane, 1.0 EQ., a 21.5 ml). The mixture was heated to 0°C and then re-cooled to -30°C, then added iodomethane (1.0 EQ., 3.0 g). The solution was heated to room temperature, poured into aqueous ammonium chloride and was extracted with ethyl acetate. The combined organic phases are washed with the salt solution, was dried over sodium sulfate and concentrated. The crude material was purified according to the method of chromatography (SiO2solid phase extraction using cyclohexane/ethyl acetate (80/20) as eluent, to obtain specified in the title compound as a yellow liquid (1.50 g, yield 30%).

1H NMR (300 MHz, CDCl3) δ (ppm): 8,15 (c, 1H), 8,10 (d, 1H), 7,60 (d, 1H), 7,45 (t, 1H), 3,85 (kV, 1H), 3,65 (c, 3H), of 1.50 (d, 3H).

2-(3-Nitrophenyl)-1-propanol

To a solution of methyl 2-(3-nitrophenyl)propanoate (0.7 g) in THF solution was added lithium borohydride (2M in THF, 2.0 EQ, 3.4 ml). The resulting mixture was stirred for 18 hours, then concentrated and poured into hydrochloric acid (10%) at 0°C. the Mixture was extracted with ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated to obtain specified in the title compound as a yellow oil (0,610 g, yield 100%).

1H NMR (300 MHz, CDCl3) δ (ppm): 8,10 (c, 1H), with 8.05 (d, 1H), 7,60 (d, 1H), 7,45 (t, 1H, in), 3.75 (d, 2H), 3,05 (c, 1H), of 1.30 (d, 3H).

2-(3-Nitrophenyl)propanal

To a stirred suspension of 1,1,1-Tris(atomic charges)-1,1-dihydro-1,2-benzodioxol-3(1H)-she (periodinane dessa-Martin, 1.1 EQ., 1.52 g) in DCM (4 ml) was added 2-(3-nitrophenyl)-1-propanol (0,610 g). The resulting solution was stirred for 1 h, then was poured into water and was extracted with DCM. The combined organic phases were washed with an aqueous solution of hydrocarb the Nata sodium and salt solution, was dried over sodium sulfate, and then concentrated to obtain a brown solid (1.4 g). This solid was dissolved in ether and filtered. The filtrate was concentrated in vacuum to obtain specified in the title compound as a yellow liquid (or 0.57 g, yield 94%).

1H NMR (300 MHz, CDCl3) δ (ppm): 9,70 (c, 1H), 8,15 (d, 2H), 8,10 (c, 1H), 7,6 (m, 2H, in), 3.75 (q, 1H), 1,50 (d, 3H).

2-Methyl-5-{4-[2-(3-nitrophenyl)propyl]-1-piperazinil}quinoline

A mixture of 2-(3-nitrophenyl)propanal (1.2 equiv, 50 mg), 2-methyl-5-(1-piperazinil)quinoline (D3) (52 mg) and DCM (2 ml) was stirred for 1 h was Added triacetoxyborohydride sodium (1.2 EQ, 58 mg) and stirred the mixture for 18 hours the Reaction mixture was concentrated in vacuum and purified by the method of ion exchange chromatography (SCX-2), elwira methanol, and then 1M ammonia in methanol. The basic fractions were concentrated in vacuum and purified by chromatography method (solid-phase extraction, SiO2using DCM/methanol (98/2) as eluent, to obtain specified in the title compound as a yellow liquid (78 mg, yield 78%).

MS: (ES) m/z: 391 [MH]+. C23H26N4About2requires 390.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), 8,15 (users, 1H), with 8.05 (d, 1H), 7,68 (d, 1H), 7,55 (m, 2H), 7,45 (t, 1H), 7,22 (d, 1H), 7,05 (d, 1H), 3.25 to about 3.00 (m, 5H), of 2,75 2,50 (m, 9H), of 1.30 (d, 3H).

3-{1-Methyl-2-[4-(2-methyl-5-chinoline)-1-piperazine is l]ethyl}aniline (D21)

To a stirred suspension of iron powder (3.0 EQ., 30 mg) and ammonium chloride (5.0 EQ., 48 mg) in water (1 ml) was added dropwise a solution of 2-methyl-5-{4-[2-(3-nitrophenyl)propyl]-1-piperazinil}quinoline (70 mg) in methanol (1 ml). Participating in the reaction substance was heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, and then filtered using a Millipore filter. The filtrate was concentrated under reduced pressure and was purified by chromatography method (solid-phase extraction, SiO2), elwira DCM/methanol (95/5), to obtain the specified title compound (40 mg, yield 60%).

MS: (ES) m/z: 361 [MH]+. C23H28N4requires 360.

1H NMR (300 MHz, CDCl3) δ (ppm): 8.30 to (d, 1H), 87,70 (d, 1H), 7,55 (t, 1H), 7,68 (d, 1H), 7,25-7,00 (m, 2H), 6,60-6,50 (m, 3H), 3,10-of 2.50 (m, 14H), of 1.30 (d, 3H).

N-(3-{1-Methyl-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E118)

Specified in the title compound was obtained with a yield of 75% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{1-methyl-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D21), and acetic acid.

MS: (ES/+) m/z: 403 [MH+]. C26H30N6About2requires 402.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,18 (users, 1H), 10,02 (users, 1H), 8,78 (users, 1H), 7,88 (users, 2H), 7,74 (users, 1H), to 7.67 (c, 1H), 7,44 (d, 1H),7,38 (users, 1H), 7,32 (m, 1H), to 7.09 (d, 1H), 3,70-3,20 (m, 1H), 2,85 (users, 3H), 2.06 to (c, 3H), of 1.35 (d, 3H).

Example 119

2-Fluoro-N-(3-{1-methyl-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide (E119)

Specified in the title compound was obtained with the yield of 64% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{1-methyl-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D21) and 2-fermenting acid.

MS: (ES/+) m/z: 483 [MH+]. C30H31FN4About 482 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,48 (c, 1H), 10,08 (users, 1H), 8,76 (users, 1H), 7,87 (users, 3H), 7,72 (users, 1H), 7,70-to 7.50 (m, 3H), 7,40-7,20 (m, 5H), 3,70-3,20 (osirm, 10H)2,84 (users, 3H), of 1.39 (d, 3H).

Example 120

2,4-Dimethyl-N-(3-{1-methyl-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-thiazole-5-carboxamide (E120)

Specified in the title compound was obtained with the yield of 87% in accordance with the General method of obtaining the amides (method C)using as a starting compound 3-{1-methyl-2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D21) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid.

MS: (ES/+) m/z: 501 [MH+]. C29H33N5OS requires 500.

1H NMR (400 MHz, DMSO) δ (ppm): 10,63 (users, 1H), 10,16 (s, 1H), 8,97 (userd, 1H), 8,01 (m, 2H), 7,87 (d, 1H), to 7.77 (c, 1H), 7,54 (d, 1H), 7,46 (d, 1H), 7,37 (t, 1H), 7,18 (d, 1H), 3,5 (m, 11H), 2,95 (c, 3H), 2,68 (c, 3H), 2,56 (c, 3H), of 1.39 (d, 3H).

Example 121

7-fluoro-2-(3-{2-[4-(2-METI the-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,3-dihydro-1H-isoindole-1-he (E121)

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6) (1 EQ.) in dichloromethane (0.1 M) at 0°C was slowly added a solution of trimethylaluminum (2,0M in hexane, 1 EQ.). The reaction mixture was stirred for 15 min and then was added dropwise a solution of 7-fluoro-2-benzofuran-1(3H)-it (1 EQ., Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM. The solution was stirred for 2 h at 0°C, then was distributed between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide was dissolved in DCM and cooled to 0°C. To the stirred solution was added dropwise thionyl chloride (1 EQ.). The reaction mixture was heated to room temperature, was stirred for 1 hour, and then was distributed between saturated aqueous sodium bicarbonate and DCM. The organic phase was dried over sodium sulfate, filtered and solvent was removed under reduced pressure. Thus obtained crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide was dissolved in methanol and cooled to 0°C. To the mixed solution portions were added sodium methoxide (1.2 EQ.). The solution was heated to room temperature and stirred is within 18 hours. The solution was concentrated and distributed between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography method on the cartridge for solid phase extraction (silicon dioxide), elwira DCM/methanol (96/4), with specified title compound (yield 24%).

The free base can be converted into the dihydrochloride by dissolving the compound in dichloromethane and added dropwise 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure to get the crude material, which was triturated with ether. Then by filtering the extracted target substance (quantitative yield).

MS: (ES) m/z: 481,3 [MH]+. C30H29FN4About requires 480.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,4 (ocessors, 1H), 8,60 (ocessors, 1H), 7,95 (c, 1H), 7,79-7,72 (m, 4H), 7,60 (ocessors, 1H), 7,53-7,46 (d+t, 2H), 7,34 (t+ocessors, 2H), 7,18 (d, 1H), 5,08 (c, 2H), 3,80-3,10 (m, 12H), 2,77 (c, 3H).

Example 122

(R or S)-3-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-1,3-oxazolidin-2-he (E122)

3-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-1,3-oxazolidin-2-he (E118) divided by the method of preparative chiral HPLC [column, Daicel Chiralcel OD; elwira the-hexane/ethanol (55/45)] to obtain specified in the connection header in the form aliremove the first enantiomer.

(ES/+) m/z: 431 [MH+]. C26H30N4About2requires 430.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,6 (users, 1H), 8,90 (users, 1H), 7,87 (users, 2H), 7,73 (c, 1H), to 7.61 (c, 1H), 7,46 (d, 1H), 7,42 (t, 1H), 7,40 (users, 1H), 7,12 (d, 1H), 4,47 (t, 2H), 4,10 (2H), of 3.77 (osirm, 1H), 3,65 (users, 4H), 3,50-3,40 (osirm, 5H), 2,84 (users, 4H), 2,80 (m, 1H), 1,25 (d, 3H).

Example 123

(S or R)-3-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-1,3-oxazolidin-2-he (E123)

3-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-1,3-oxazolidin-2-he (E118) divided by the method of preparative chiral HPLC [column, Daicel Chiralcel OD; elwira n-hexane/ethanol (55/45)] to obtain specified in the connection header in the form aliremove second enantiomer.

(ES/+) m/z: 431 [MH+]. C26H30N4About2requires 430.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,6 (users, 1H), 8,90 (users, 1H), 7,87 (users, 2H), 7,73 (c, 1H), to 7.61 (c, 1H), 7,46 (d, 1H), 7,42 (t, 1H), 7,40 (users,1H), 7,12 (d, 1H), 4,47 (t, 2H), 4,10 (2H), of 3.77 (osirm, 1H), 3,65 (users, 4H), 3,50-3,40 (osirm, 5H), 2,84 (users, 4H), 2,80 (m, 1H), 1,25 (d, 3H).

Example 124

The dihydrochloride of 1-(3-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E124)

2-Methyl-5-[(3R)-3-methyl-1-piperazinil]quinoline

To a solution of 2-methyl-5-chinainternational (D1) (0.8 g; 1 EQ.) in toluene (30 ml) under inert atmosphere was added (2R)-2-methylpiperazin (0,550 g; 2 EQ.), carbonate CAS is I (1.78 g; 2 equiv.) the palladium acetate (0,123 g; 0.2 EQ.) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0,513 g; 0.3 EQ.). The reaction mixture was stirred under reflux in nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, was extinguished by saturated aqueous ammonium chloride (15 ml) and was extracted with ethyl acetate (3×20 ml). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by the method of flash chromatography on silica gel, elwira dichloromethane/methanol (95/5), to obtain specified in the connection header with the release of 58% (0,383 g).

MS: (ES) m/z: 242,3 [MH]+. C15H19N3requires 241.

1H NMR (300 MHz, CDCl3) δ (ppm): to 8.40 (d, 1H), 7,76 (d, 1H), to 7.61 (t, 1H), 7,29 (d, 1H), 7,06 (d, 1H), 3,2 (m, 5H), 2,85 (t, 1H), 2,74 (c, 3H), 2,5 (t, 1H) of 1.25 (d, 3H).

The dihydrochloride of 1-(3-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E124)

A mixture of N,N-diisopropylethylamine (0,072 ml, 2 equiv.) 2-methyl-5-[(3R)-3-methyl-1-piperazinil]quinoline (0.05 g; 1 EQ.), 2-[3-(2-oxo-1-imidazolidinyl)phenyl]ethylmethanesulfonate (0.07 g; 1.2 EQ.) and acetonitrile (0.5 ml) was irradiated in a microwave reactor (PersonalChemistry Emrys™ Optimiser, 300 watts, 180°C, 15 min). The dark solution was applied to the ion exchange SCX cartridge (5 g) and suirable methanol, and then a 1M solution of ammonia in methanol. The main fraction conc the Wali under reduced pressure and optionally purified by the method of flash chromatography on silica gel, elwira gradient from dichloromethane to dichloromethane/methanol (98/2)to obtain the free base of the desired intermediate product with a yield of 67%. Related dihydrochloride was obtained in accordance with the description presented for a General method for obtaining the amides and the corresponding dihydrochloride, using as starting compound 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6), obtaining specified in the connection header with the release of 57% (0.03 g).

MS: (ES) m/z: 430,4 [MH]+. C26H31N5About requires 429.

1H NMR (500 MHz, DMSO) δ (ppm): 10,8-10,66 (2 users, 1H), 8,54 (users, 1H), 7,72 (users, 1H), to 7.61 (c, 1H), 7,49 (m, 2H), 7,41 (t, 1H), 7,26 (m, 1H), 7,14 (m, 1H), 3,8 (t, 3H), 3,2 (m, 5H), 3.15 in/2,65 (userd-m, 7H), 2,5 (c, 3H)and 1.3 (d, 3H).

Example 125

3-(3-{2-[(2R)-2-Methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-he (E125)

3-[3-(2-Hydroxyethyl)phenyl]-1,3-oxazolidin-2-he

Specified in the title compound was obtained with the yield 48% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 2-(3-bromophenyl)ethanol and 1,3-oxazolidin-2-it.

MS: (ES) m/z: 208 [MH+]. C11H13NO3requires 207.

1H NMR (300 MHz, CDCl3) δ (ppm): 7,45 (c, 1H), 7,32 (m, 2H), 7,03 (d, 1H), 4,48 (t, 2H), of 4.05 (t, 2H), 3,85 (osirm, 2H), 2,87 (t, 2H), 1,58 (c, 1H).

2-[3-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]atile sulfonate

Specified in the title compound was obtained with the yield of 93% in accordance with the General method of obtaining the amides (method B), using as starting compounds 3-[3-(2-hydroxyethyl)phenyl]-1,3-oxazolidin-2-he and methanesulfonanilide. The crude material was purified on a cartridge for solid phase extraction (silicon dioxide), using as eluent a gradient from cyclohexane (100%) to cyclohexane/ethyl acetate (8/2), with the final connection.

MS: (ES) m/z: 286 [MH+]. C12H15NO5S requires 285.

1H NMR (300 MHz, CDCl3) δ (ppm): 7,5 (c, 1H), and 7.3 (m, 2H), 6,95 (d, 1H), 4,3 (m, 4H), 4 (t, 2H), 3 (t, 2H), 2,8 (c, 3H).

3-(3-{2-[(2R)-2-Methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-he (E125)

Specified in the title compound was obtained with the yield of 33% with the use of a technique similar to the one presented for example E124, using as starting compounds 2-methyl-5-[(3R)-3-methyl-1-piperazinil]quinoline and 2-[3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethylmethanesulfonate.

MS: (ES) m/z: 431,4 [MH]+. C26H30N4About2requires 430.

1H NMR (500 MHz, d6-DMSO) δ (ppm): 10,8-10,66 (2 users, 1H), 8,54 (users, 1H), 7,72 (users, 1H), to 7.61 (c, 1H), 7,49 (m, 2H), 7,41 (t, 1H), 7,26 (m, 1H), 7,14 (m, 1H), and 3.8 (t, 2H), 3,4 (m, 3H), 3,2-2,8 (userd-m, 9H), 2,71 (osirm, 2H), 2,5 (c, 3H), of 1.41 (d, 3H).

Example 126

The dihydrochloride of 1-(3-{2-[(2S)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazine is]ethyl}phenyl)-2-imidazolidinone (E126)

2-Methyl-5-[(3S)-3-methyl-1-piperazinil]quinoline

Specified in the title compound was obtained with the yield of 27% with the use of a technique similar to the one presented in example 127, using as starting compounds (2S)-2-methylpiperazine and 2-methyl-5-chinainternational (D1).

MS: (ES) m/z: 242,3 [MH]+. C15H19N3requires 241.

1H NMR (300 MHz, CDCl3) δ (ppm): to 8.40 (d, 1H), 7,76 (d, 1H), to 7.61 (t, 1H), 7,29 (d, 1H), 7,06 (d, 1H), 3,2 (m, 5H), 2,85 (t, 1H), 2,74 (s, 3H), 2,5 (t, 1H), 1,1 (d, 3H).

The dihydrochloride of 1-(3-{2-[(2S)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E126)

Specified in the title compound was obtained with the yield of 47% with the use of a technique similar to the one presented in example 127, using as starting compounds 2-methyl-5-[(3S)-3-methyl-1-piperazinil]quinoline and 2-[3-(2-oxo-1-imidazolidinyl)phenyl]ethylmethanesulfonate.

MS: (ES) m/z: 430,4 [MH]+. C26H31N5About requires 429.

1H NMR (500 MHz, d6-DMSO) δ (ppm): 10,8-10,66 (2 users, 1H), 8,54 (users, 1H), 7,72 (users, 1H), to 7.61 (s, 1H), 7,49 (m, 2H), 7,41 (t, 1H), 7,26 (m, 1H), 7,14 (m, 1H), 3,8 (t, 3H), 3,2 (m, 5H), 3.15 in/2,65 (userd-m, 7H), and 2.5 (s, 3H), 1,3 (d, 3H).

Example 127

3-(3-{2-[(2S)-2-Methyl-4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-he (E127)

Specified in the title compound was obtained with the yield of 33% using techniques similar to those presented deprimere E124, using as starting compounds 2-methyl-5-[(3S)-3-methyl-1-piperazinil]quinoline (D2) and 2-[3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethylmethanesulfonate (Etc.).

MS: (ES) m/z: 431,4 [MH]+. C26H30N4About2requires 430.

1H NMR (500 MHz, d6-DMSO) δ (ppm): 10,8-10,66 (2 users, 1H), 8,54 (users, 1H), 7,72 (users, 1H), to 7.61 (s, 1H), 7,49 (m, 2H), 7,41 (t, 1H), 7,26 (m, 1H), 7,14 (m, 1H), 4,48 (t, 3H), 4,1 (t, 2H), 3,8/3,7-3 (userd-m, 11N), 2,71 (osirm, 2H), of 1.41 (d, 3H).

Example 128

The dihydrochloride of 3-(3-{(1R,2S)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]cyclopropyl}phenyl)-1,3-oxazolidin-2-it dihydrochloride and 3-(3-{(1S,2R)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]cyclopropyl}phenyl)-1,3-oxazolidin-2-it (E128)

3-[3-(2-Hydroxyethyl)phenyl]-1,3-oxazolidin-2-he

A solution of 2-(3-bromophenyl)ethanol (1,00 g, 5.00 mmol), 2-oxazolidin-2-it (874 mg, 10,04 mmol), copper iodide(I) (96 mg, 0.50 mmol), N,N'-dimethyl-1,2-academia (60 μl, 49 mg of 0.56 mmol) and potassium carbonate (1.04 g, 7,50 mmol) suspended in dioxane (6 ml). The mixture was stirred in nitrogen atmosphere for 2.5 h at 100°C. After the addition of copper iodide(I) (96 mg, 0.50 mmol) and N,N'-dimethyl-1,2-academia (60 μl, 49 mg of 0.56 mmol) stirring was continued for additional 2 h at 100°C. After cooling to room temperature the mixture was poured into a saturated aqueous solution of ammonium chloride and was extracted with dichloromethane. The organic layer was dried over sulfate MAGN what I was concentrated under reduced pressure. The crude compound was purified by the method of flash chromatography on silica gel, elwira with ethyl acetate/cyclohexane (1/1 to 1/0), obtaining specified in the connection header with the release of 64% (664 mg).

1H NMR (300 MHz, CDCl3) δ (ppm): 7.4 in (c, 1H), 7,0-to 7.3 (m, 2H), a 7.85 (m, 1H), 4,25 (t, 2H), 3,85 (t, 2H), the 3.65 (t, 2H), 2,65 (t, 2H), 1.50 in (c, 1H).

[3-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]acetaldehyde

1,1,1-Tris(atomic charges)-1,1-dihydro-1,2-benzodioxol-3(1H)-he (periodinane dessa-Martin, 709 mg, 1,67 mmol) was added to a solution of 3-[3-(2-hydroxyethyl)phenyl]-1,3-oxazolidin-2-she (315 mg, of 1.52 mmol) in dichloromethane (10 ml). The mixture was stirred at room temperature for 30 min, then washed with an aqueous solution of sodium hydroxide (1M, 10 ml). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain specified in the connection header with the release of 89% (278 mg). The connection used in the next stage without additional purification.

1H NMR (300 MHz, CDCl3) δ (ppm): 9,73 (c, 1H), 7,49 (c, 1H), 7.3 to 7.4 (m, 2H), of 6.96 (m, 1H), 4,47 (t, 2H), of 4.05 (t, 2H), 3,70 (c, 2H).

The dihydrochloride of 3-(3-{(1R,2S)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]cyclopropyl}phenyl)-1,3-oxazolidin-2-it dihydrochloride and 3-(3-{(1S,2R)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]cyclopropyl}phenyl)-1,3-oxazolidin-2-it (E128)

[3-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]acetaldehyde (275 mg, of 1.34 mmol), hydrate pair-toloo the sulfonic acid (13 mg, 0.07 mmol) and 2-methyl-5-(1-piperazinil)quinoline (304 mg, 1,340 mmol) was dissolved in toluene (30 ml) and was heated for 2 h in the apparatus of the Dean-stark until completion of education imine (determined on Al2O3-TLC-plates). After cooling to room temperature and evaporation of the solvent under reduced pressure the crude Imin used without further purification.

To a solution of diethylzinc (1M in hexano, 2.0 ml, 2.00 mmol) in anhydrous dichloromethane (5 ml) at 0°C under nitrogen atmosphere was added diiodomethane (0,22 ml, 718 mg, 2.68 mmol) and was stirred for 10 minutes. Untreated Imin was dissolved in anhydrous dichloromethane (5 ml) and at 0°C was added dropwise to the reaction mixture. The reaction mixture was heated to room temperature and continued stirring for additional 2 hours, the Mixture was put out by adding methanol, and then were applied to the ion exchange cartridge (SCX-2) and suirable methanol, and then 1M ammonia in methanol. The basic fractions were concentrated in vacuum and purified by the method of flash chromatography on silica gel, elwira cyclohexane/ethyl acetate (1/1 to 1/2), and finally was isolated by HPLC with distribution by mass (Fraction LYNX) obtaining specified in the connection header with the release of 2% (10 mg). The free base can be converted into the dihydrochloride by dissolving the compounds in dichlor is Tanya and added dropwise 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure to get the crude material, which was triturated with ether. Then by filtering the extracted specified in the title compound (quantitative yield).

MC; (ES) m/z: 429 [MH+]. C26H28N4About2requires 428.

1H NMR (500 MHz, d6-DMSO) δ (ppm): is 11.39 (users, 1H), 8,84 (users, 1H), 7,89 (users, 2H), to 7.77 (users, 1H), 7,45 (d, 1H), 7,44 (c, 1H), 7,39 (users, 1H), 7,34 (t, 1H), of 6.96 (d, 1H), of 4.44 (t, 2H), 4,07 (t, 2H), 3,8-3,0 (osirm, 9H), 2,86 (users, 3H), 1,87 (users, 1H), 1,42 (users, 1H).

Example 129

The dihydrochloride of 2,4-dimethyl-N-(4-{(1R,2S)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]cyclopropyl}phenyl)-1,3-thiazole-5-carboxamide dihydrochloride and 2,4-dimethyl-N-(4-{(1R,2S)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]cyclopropyl}phenyl)-1,3-thiazole-5-carboxamide (E129)

2-(3-AMINOPHENYL)ethanol

2-(3-Nitrophenyl)ethanol (836 mg, 5.00 mmol) and Pd (10% on charcoal, 200 mg) is suspended in anhydrous methanol (10 ml). After adding moravcikova ammonium (1,450 g, 23 mmol) observed a slightly exothermic reaction with evolution of gas. After stirring for 1 h at room temperature the reaction mixture was filtered through brownmillerite. The filtrate was evaporated and the residue was dissolved in ethyl acetate. After washing with a saturated aqueous solution of hydrocar is onata sodium, water and brine the organic layer was dried (magnesium sulfate) and the solvent was removed under reduced pressure to obtain specified in the connection header with the release of 54% (373 mg) as a white solid.

MC; (ES) m/z: 138 [MH+]. C8H11NR requires 137.

1H NMR (300 MHz, d6-DMSO) δ (ppm): to 6.80 (t, 1H), from 6.25 to 6.35 (m, 3H), 4,85 (c, 2H), 4,50 (t, 1H), of 3.45 (dt, 2H), of 2.45 (t, 2H).

N-[3-(2-Hydroxyethyl)phenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide

To a solution of 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (1,652 g, 10,51 mmol), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2,015 g, 10,51 mmol) and 1-hydroxybenzotriazole (1,420 g, 10,51 mmol) in anhydrous DMF (20 ml) was added 2-(3-AMINOPHENYL)ethanol (1,202 g, 8,76 mmol). The mixture was stirred for 14 h, then under reduced pressure to remove DMF and distributed the residue between DCM and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude compound was purified by the method of flash chromatography on silica gel, elwira with ethyl acetate/cyclohexane (1/1 to 1/0), obtaining specified in the connection header with the release of 73% (1,772 g).

MC; (ES) m/z: 277 [MH+]. C14H16N2About2S requires 276.

1H NMR (300 MHz, d6-DMSO) δ (ppm): 9,95 (c, 1H), 7,40-to 7.50 (m, 2H), 7,19 (t, 1H), 6,92 (d,1H), 4,60 (t, 1H), 5,57 (DD, 2H), 2,66 (t,2H), 2,61 (c, 3H), 2.49 USD (c, 3H).

2,4-Dimethyl-N-[3-(2-oxoethyl)phenyl]-1,3-thiazole-5-carboxamide

Specified in the title compound was synthesized in accordance with methods described, for example, E128, using N-[3-(2-hydroxyethyl)phenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide (800 mg, 2,895 mmol)and was purified by the method of flash chromatography on silica gel, elwira DCM/methanol (95/5), with 519 mg (65%).

MC; (ES) m/z: 275 [MH+]. C14H14N2About2S requires 274.

1H NMR (300 MHz, CDCl3) δ (ppm): 9,85 (c, 1H), 7,60 (m, 1H), and 7.3-7.5 (m, 3H), of 7.00 (d, 1H), 3,70 (c, 2H), 3,65 (c, 6H).

Example 129

The dihydrochloride of 2,4-dimethyl-N-(4-{(1R,2S)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]cyclopropyl}phenyl)-1,3-thiazole-5-carboxamide dihydrochloride and 2,4-dimethyl-N-(4-{(1R,2S)-2-[4-(2-methyl-5-chinoline)-1-piperazinil]cyclopropyl}phenyl)-1,3-thiazole-5-carboxamide

Specified in the title compound was synthesized in accordance with methods described, for example, E128, using 2,4-dimethyl-N-[3-(2-oxoethyl)phenyl]-1,3-thiazole-5-carboxamide (D6, 85 mg, 0.30 mmol), to obtain the enantiomeric mixture (5 mg, 3%).

MC; (ES) m/z: 498 [MH+]. C29H31N5OS requires 497.

1H NMR (500 MHz, d6-DMSO) δ (ppm): to 11.11 (users, 1H), to 10.09 (c, 1H), 8,78 (users, 1H), 7,85 (users, 2H), 7,73 (users, 1H), 7,6 (c, 1H), 7,47 (d, 1H), 7,38 (users, 1H), 7,29 (m, 1H), 6,97 (d, 1H), 3,8-3,0 (osirm, 9H), 2,7-2,9 (users, 4H), 2,65 (c, 3H), 2,53 (c, 3H), 1,85 (users, 1H), 1,4 (users, H).

Example 130

1-Methyl-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E130)

To a stirred solution of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E85) in THF was added methyliodide (1 EQ.), and then sodium hydride (1.2 EQ.) and stirred the reaction mixture for 60 minutes. The mixture was applied to the ion exchange cartridge (SCX-2) and suirable methanol, and then 1M ammonia in methanol. The basic fractions were concentrated in vacuum and purified by the method of column chromatography (cartridge for solid phase extraction, silicon dioxide), using as eluent a gradient from DCM/methanol (99/1) to DCM/methanol (98/2), to obtain the end compound (yield 45%).

MS: (ES/+) m/z: 430 [MH+]. C26H31N5About2requires 429.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,19 (1H, users), to 8.94 (1H, users), to 7.99 (2H, users), to 7.84 (1H, userd), and 7.6 (1H, users), of 7.48 (1H, users), was 7.45 (1H, d), 7,32 (1H, t), of 6.96 (1H, d), 3,81 (2H, t), of 3.73 (2H, userd), which is 3.7 to 3.2 (10H, m), of 3.13 (2H, m), with 2.93 (3H, c), and 2.79 (3H, c).

Example 131

The dihydrochloride of N-(2-methoxy-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E131)

2-(Methoxy)-3-nitrobenzaldehyde

To a solution of 2-hydroxy-3-nitrobenzaldehyde in DMF portions was added cesium carbonate (3 EQ.), and then iodomethane (1.2 EQ.). The solution was heated to 60°C for 2 hours, then was cooled to on the th temperature and filtered. The filtrate was concentrated in vacuum and purified by the method of column chromatography on a cartridge for solid phase extraction (silicon dioxide), using as eluent cyclohexane/ethyl acetate (8/2), to obtain the product with a yield of 72%.

1H NMR (300 MHz, CDCl3) δ (ppm): 10,28 (1H, c), 7,95 (2H, m), 7.23 percent (1H, m), of 3.97 (3H, s).

[2-(Methoxy)-3-nitrophenyl]acetaldehyde

To a stirred solution of 2-(methoxy)-3-nitrobenzaldehyde in THF was added 18-crown-6 (0.2 equiv.) (methoxymethyl)triphenylphosphonium (2 EQ.) and potassium carbonate (6.5 EQ.). The resulting suspension was heated to 60°C for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuum and purified by the method of chromatography on a cartridge of silica (elwira cyclohexane/ethyl acetate 9/1) to give a mixture of 2-(methoxy)-1-[(E)-2-methoxyethyl]-3-nitrobenzene and 2-metiloksi-1-[(Z)-2-(metiloksi)ethynyl]-3-nitrobenzene. A mixture of alkenes was dissolved in THF and 6N. hydrochloric acid (1/1) and stirred for 1 hour. The solution was podslushivaet adding an aqueous solution of sodium carbonate and was extracted with DCM. The organic layer was washed (water, brine), dried (sodium sulfate) and concentrated in vacuum to obtain specified in the title compound (total yield 54%).

1H NMR (300 MHz, CDCl3) δ (ppm): of 9.75 (1H, s), and 7.8 (1H, d), and 7.4 (1H, d), 7,2 (1H,m), of 3.85 (3H, s), 3,8 (2H, s).

2-(Methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline

To a stirred solution of [2-(methoxy)-3-nitrophenyl]acetaldehyde in acetonitrile was added 2-methyl-5-(1-piperazinil)quinoline and stirred the solution at room temperature for 15 minutes. Added triacetoxyborohydride sodium and stirred suspension within 75 minutes. The intermediate product, 2-methyl-5-(4-{2-[2-(methoxy)-3-nitrophenyl]ethyl}-1-piperazinil)quinoline was extracted by the method of ion-exchange chromatography [SCX cartridge-2; elwira gradient of 1M ammonia in methanol/methanol, (1/0) to (0/1)]. Specified in the title compound was obtained from 2-methyl-5-(4-{2-[2-methoxy-3-nitrophenyl]ethyl}-1-piperazinil)quinoline in accordance with the methodology contained in the description 6 (D6), with a total yield of 71%.

MS: (ES/+) m/z: 377 [MH+]. C23H28N4About 376 requires.

1H NMR (300 MHz, CDCl3) δ (ppm): of 8.37 (1H, d), to 7.68 (1H, d), EUR 7.57 (1H, t), 7,22 (1H, d), 7,07 (1H, d), to 6.88 (1H, t), 6,63 (2H, d), 3,76 (4H, users), of 3.13 (4H, users), 2,95 of 2.6 (10H, ocsi).

The dihydrochloride of N-(2-(methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E131)

Specified in the title compound was obtained with the yield of 42% in accordance with the General method of obtaining the amides (method B), using as starting compounds 2-(methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline and acetylchloride.

+]. C25H30N4About2requires 418.

1H NMR (400 MHz, d6-DMSO) δ (ppm): at 10.64 (1H, user), 9,38 (1H, c), 8,77 (1H, users), to 7.84 (3H, m), 7,72 (1H, users), 7,39 (1H, c), to 7.09 (2H, m), of 3.77 (3H, c), 3,52 (2H, m), 3,6-3,3 (8H, m)and 3.15 (2H, m), and 2.83 (3H, c), and 2.14 (3H, c).

Example 132

The dihydrochloride of N-(2-(methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)methanesulfonamide (E132)

Specified in the title compound was obtained with the yield of 72% in accordance with the General method of obtaining the amides (method B), using as starting compounds 2-(methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline and methanesulfonanilide.

MS: (ES/+) m/z: 455 [MH+]. C25H30N4About2requires 454.

1H NMR (400 MHz, d6-DMSO) δ (ppm): is 10.68 (1H, user), 9,19 (1H, c), and 8.8 (1H, users), 7,87 (2H, users), 7,72 (1H, users), 7,39 (1H, c), 7,33 (1H, m), 7,16 (2H, m), 3,82 (3H, c), of 3.77 (2H, m), 3,6-3,3 (8H, m)and 3.15 (2H, m), 3,11 (3H, c), and 2.83 (3H, c).

Example 133

The dihydrochloride of 3-(2-(methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-it (E133)

Specified in the title compound was obtained with the yield of 63% in accordance with the General method of synthesis of cyclic ureas and carbamates (method G), using as starting compounds 2-(methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline and acid chloride of 2-(bromacil)carbamino acid.

MS: (ES/+) m/z: 447 [MH+]. C26H30N4 About3requires 446.

1H NMR (400 MHz, d6-DMSO) δ (ppm): of 10.73 (1H, user), 8,82 (1H, users), 7,88 (2H, users), of 7.75 (1H, users), 7,42 (1H, c), 7,38 (1H, DD), 7,31 (1H, DD), 7,21 (1H, t), 4,51 (2H, t), of 3.97 (2H, t), 3,81 (3H, c), of 3.77 (2H, m), 3,6-3,3 (8H, m), 3,17 (2H, m), 2,85 (3H, c).

Example 134

The dihydrochloride of 1-(2-(methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E134)

Specified in the title compound was obtained with the yield of 38% in accordance with the General method of synthesis of cyclic ureas and carbamates (method G), using as starting compounds 2-(methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline and 1-chloro-2-isocyanatomethyl.

MS: (ES/+) m/z: 446 [MH+]. C26H31N5About2requires 445.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,78 (1H, user), cent to 8.85 (1H, users), and 7.9 (2H, users), 7,76 (1H, users), 7,42 (1H, c), and 7.3 (1H, DD), 7,21 (1H, DD), 7,13 (1H, t), 6,79 (1H, users), with 3.79 (3H, c), of 3.78 (2H, t), of 3.6 and 3.3 (12H, m)and 3.15 (2H, m), 2,87 (3H, c).

Example 135

The dihydrochloride of 1-methyl-3-(2-(methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E135)

Specified in the title compound was obtained with 20% yield in accordance with methods described for example 130, using as starting compounds 1-(2-(methoxy)-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone and iodomethane.

MS: (ES/+) m/z: 460 [MH+]. C26H31N5About2t is Eboue 459.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,95 (1H, user), 10,7-10,5 (1H, user), 8,88 (1H, users), to 7.93 (2H, users), and 7.8 (1H, users), 7,44 (1H, c), 7,27 (1H, DD), 7,21 (1H, DD), 7,14 (1H, t), of 3.77 (2H, m), 3,76 (3H, c), and 3.7 (2H, t), of 3.6 and 3.3 (8H, m), 3,17 (2H, m), 2,9 (5H, m), 2,87 (3H, c).

Example 136

N-(4-Fluoro-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E136)

Specified in the title compound was obtained with the yield 66% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(5-bromo-2-forfinal)ethyl]-1-piperazinil}-2-methylinosine and ndimethylacetamide.

MS: (ES/+) m/z: 407 [MH+]. C24H27FN4About 406 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,69 (users, 1H), 10,08 (c, 1H), 8,82 (users, 1H), 7,88 (users, 2H), 7,75 (users, 1H), 7,74 (DD, 1H), 7,41 (m, 1H), 7,19 (t, 1H), of 3.77 (DD, 2H), 3,61-3,30 (m, 8H), 3,14 (m, 2H), 2,85 (c, 3H), 2.06 to (c, 6H).

5-{4-[2-(5-Bromo-2-forfinal)ethyl]-1-piperazinil}-2-methylinosine

Specified in the title compound was obtained with the yield of 95% of (5-bromo-2-forfinal)acetaldehyde (0,98 g), 2-methyl-5-(1-piperazinil)quinoline (0.51 g) and triacetoxyborohydride sodium (0.95 g) in accordance with methods described for example 131.

MS: (ES/+) m/z: 428, 430 [MH+]. C22H23BrFN4requires 427, 429.

1H NMR (300 MHz, CDCl3) δ (ppm): of 8.37 (d, 1H), 7,69 (d, 1H), 7,52 (t, 1H), 7,40 (DD, 1H), 7,26-to 7.18 (t, 2H), 7,07 (DD, 1H), to 6.88 (t, 1H), 3,11 (t, 4H), 2,90 is 2.75 (t, 6H), 2,69 (c, 3H) and $ 2.68 (t, 2H).

<> (5-Bromo-2-forfinal)acetaldehyde

Specified in the title compound was obtained from (E/Z)-2-(5-bromo-2-forfinal)etinilestradiolo ether in accordance with the methods described for example 131, and used without further purification and without defining additional parameters.

(E/Z)-2-(5-Bromo-2-forfinal)etinilestradiol ether

Specified in the title compound was obtained with the yield of 48% of 5-bromo-2-forventelige (2.00 g) and chloride (methoxymethyl)triphenylphosphine (of 4.05 g) in accordance with methods described for example 131.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,07 (d, 0,5H), 7,30-7,00 (m, 2H), 6,72 (m, 1H), 6,17 (d, 0,5H), the 5.65 (d, 0,5H), 5,32 (d, 0,5H), 3,68 (c, 1,5H) and 3,59 (c, 1,5H).

Example 137

N-(4-Fluoro-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,2-dimethylpropanamide (E137)

Specified in the title compound was obtained with the yield 52% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(5-bromo-2-forfinal)ethyl]-1-piperazinil}-2-methylinosine and 2,2-dimethylpropanamide.

MS: (ES/+) m/z: 449 [MH+]. C27H33FN4About requires 448.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,56 (users, 1H), was 9.33 (c, 1H), 8,77 (users, 1H), 7,84 (users, 2H), and 7.8 (DD, 1H), 7,71 (users, 1H), 7,51 (m, 1H), 7,39 (users, 1H), 7,19 (t, 1H), of 3.77 (DD, 2H), 3,61-3,30 (m, 8H), 3,14 (m, 2H), 2,83 (c, 3H), 1,24 (c, 9H).

Example 138

N-(4-FPO is-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)methanesulfonamide (E138)

Specified in the title compound was obtained with the yield of 69% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(5-bromo-2-forfinal)ethyl]-1-piperazinil}-2-methylinosine and methanesulfonamide.

MS: (ES/+) m/z: 434 [MH+]. C25H28FN5About 433 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,92 (users, 1H), 9,78 (c, 1H), 8,77 (users, 1H), 7,92 (users, 2H), 7,78 (users, 1H), 7,43 (users, 1H), 7.3 to to 7.15 (m, 3H), 3,76 (DD, 2H), 3,6-3,3 (m, 8H), 3,17 (m, 2H), 3,01 (c, 3H), 2,85 (c, 3H).

Example 139

1-(4-Fluoro-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E139)

Specified in the title compound was obtained with the yield 35% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(5-bromo-2-forfinal)ethyl]-1-piperazinil}-2-methylinosine and 2-imidazolidone.

MS: (ES/+) m/z: 434 [MH+]. C23H27FN4OS requires 433.

1H NMR (400 MHz, d6-DMSO) δ (ppm): at 10.64 (users, 1H), 8,33 (users, 1H), 7,88 (users, 2H), 7,74 (users, 1H), to 7.67 (DD, 1H), 7,45 (DD, 1H), and 7.4 (users, 1H), 7,21 (t, 1H), 7,02 (c, 1H), 3,86 (t, 2H), of 3.77 (DD, 2H), 3,6-3,3 (m, 10H), and 3.16 (m, 2H), 2,85 (c, 3H).

Example 140

3-(4-Fluoro-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-he (E140)

Specified in the title compound was obtained with the yield of 95% in accordance with the General IU odili obtain amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(5-bromo-2-forfinal)ethyl]-1-piperazinil}-2-methylinosine and 2-imidazolidone.

MS: (ES/+) m/z: 435 [MH+]. C25H28FN5About 434 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): of 10.73 (users, 1H), cent to 8.85 (users, 1H), 7,89 (users, 2H), to 7.77 (users, 1H), 7,68 (DD, 1H), and 7.5 (DD, 1H), 7,43 (users, 1H), 7,39 (t, 1H), 4,47 (DD, 2H), 4.09 to (DD, 2H), of 3.77 (DD, 2H), 3,6-3,3 (m, 8H), 3,19 (m, 2H), 2,87 (c, 3H).

Example 141

The dihydrochloride of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,4-imidazolidinedione (E141)

5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinil}-2-methylinosine (46 mg, 0,100 mmol), as (44,8 mg, 0,444 mmol), potassium carbonate (23.1 mg, 0,167 mmol), copper iodide(I) (107 mg, 0,561 mmol) and N,N'-dimethyl-1,2-amandemen (60 μl, 50 mg, 0,563 mmol) was dissolved in dioxane (2 ml) and was heated at 150°C for 75 min by microwave radiation. The mixture was cooled to room temperature and distributed between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude compound was purified by the method of flash chromatography on silica gel, elwira dichloromethane/methanol (97/3 to 95/5), to obtain specified in the connection header with the release of 23% (10 mg) in the form aliremove first regioisomer as.

MS: (ES/+) m/z: 430 [MH+]. C25H27N5About2tre is the duty to regulate 429.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,12 (1H, users), and 8.3 (1H, d), 7,55 (2H, m), of 7.48 (1H, users), and 7.4 (1H, userd), 7,35 (1H, d), from 7.24 (1H, t), 7,06 (1H, DD), 6,97 (1H, userd), 4,4 (2H, c), 3 (4H, users), 2,8-2,5 (8H, osirm), at 2.59 (3H, c).

Example 142

The dihydrochloride of 3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,4-imidazolidinedione (E142)

Specified in the title compound was obtained in accordance with the method, are presented for example 144, and extracted with a yield of 18% (8 mg) in the form aliremove second regioisomer as.

MS: (ES/+) m/z: 430 [MH+]. C25H27N5About2requires 429.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 8,23 (1H, userd), 8,24 (1H, users), 7,55 (2H, users), 7,34 (1H, userd), between 7.4 to 7.0 (5H, m), was 4.02 (2H, c), 3 (4H, users), 2,81-2,59 (8H, osirm), at 2.59 (3H, c).

Example 143

The dihydrochloride (R or S)-3-(3-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-1,3-oxazolidin-2-it (E143)

A mixture of 3-[3-(2-oxopropyl)phenyl]-1,3-oxazolidin-2-it 2-methyl-5-[(3R)-3-methyl-1-piperazinil]quinoline (1.2 EQ.) suspended in isopropoxide titanium(IV) (2 EQ.) and was stirred for 12 hours. The solution was carefully heated to 60°C and was stirred for 1 hour, was added methanol, and then was added sodium borohydride (9 EQ.) and additionally mixture was stirred for 4 hours. The solution was poured into an aqueous solution of ammonium chloride and was extracted with DCM. The organic phase koncentrirane and in vacuum and purified by chromatography method (cartridge for solid phase extraction, silicon dioxide), using as eluent a gradient dichloromethane/methanol from 99/1 to 98/2, with a mixture of diastereoisomers (yield 34%). After separation by the method of preparative HPLC (column Chiralpak AD 10 μm, 250×20 mm; mobile phase: A: n-hexane, B: isopropanol + 0.1% of 2-propanol; gradient: isocratic elution with 20% B; volumetric flow rate: 7 ml/min; UV wavelength: 220 nm; analysis time: 60 min) was obtained the free base is specified in the header connection in the form of aliremove first diastereoisomer. The free base was dissolved in dichloromethane and treated with 1M ethereal solution of hydrogen chloride (2.1 EQ.). Precipitated precipitated solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure to obtain solid, which is triturated with ether. Then by filtering the extracted specified in the title compound (quantitative yield).

MS: (ES/+) m/z: 445 [MH+]. C27H32N4About2requires 444.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,96 (1H, users), 8,96 (1H, users), and 7.9 (2H, users), 7,76 (1H, users), a 7.62 (1H, c), and 7.4 (3H, m), to 7.15 (1H, d), 4,47 (2H, t), 4,1 (2H, m), 4-3,2 (10H, osirm), 2,87 (3H, users), of 1.42 (3H, d), of 1.24 (3H, d).

Example 144

The dihydrochloride (S or R)-3-(3-{2-[(2R)-2-methyl-4-(2-methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-1,3-oxazolidin-2-it (E144)

The method presented is Oh to example 143, allocated specified in the title compound in the form of aliremove second diastereoisomer.

MS: (ES/+) m/z: 445 [MH+]. C27H32N4About2requires 444.

1H NMR (400 MHz, d6-DMSO) δ (ppm): was 10.82 (1H, ocessors), 8,97 (1H, ocessors), 7,92 (2H, users), 7,78 (1H, users), to 7.64 (1H, c), and 7.4 (3H, m), 7,14 (1H, d), 4,47 (2H, t), 4,11 (2H, m), 4-2,7 (10H, osirm), 2,89 (3H, users), 1,5 (3H, d), of 1.32 (3H, d).

Example 145

The dihydrochloride of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-it (E145)

A mixture of 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinil}-2-methylinosine (117 mg, 0,256 mmol), 1,3-dihydro-2H-imidazol-2-she (84 mg, 1,023 mmol, R.A. Whitney, Tet. Lett. 1981, 22, 2063-2066), potassium carbonate (53 mg, 0.384 mmol), copper iodide(I) (244 mg, 1.28 mmol), N,N'-dimethyl-1,2-academia (163 μl, 135 mg, 1,536 mmol) and dioxane (2.5 ml) was heated at 150°C for 90 min by microwave radiation. The mixture was cooled to room temperature and distributed between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude compound was purified by the method of flash chromatography on silica gel, elwira dichloromethane/methanol (97/3), obtaining specified in the connection header with a yield of 20% (23 mg). The free base was converted into the corresponding dihydrochloride by dissolving the compound in dichloromethane and add a drop of the 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure, the residue triturated with ether. Then by filtering the extracted specified in the title compound (quantitative yield).

MS: (ES/+) m/z: 414 [MH+]. C25H27N5About 413 requires.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 10,75 (1H, users), 10,28 (c, 1H), 8,78 (users, 1H), 7,84 (users, 2H), 7,7 (users, 1H), 7,69 (t, 1H), 7,56 (DD, 1H), 7,38 (m, 1H), was 7.36 (users, 1H), 7,13 (d, 1H), 6,92 (DD, 1H), return of 6.58 (DD, 1H), 3,69 (userd, 2H), 3,5 to 3.2 (8H), of 3.12 (m, 2H), 2,81 (users, 3H).

Example 146

The dihydrochloride of 1-methyl-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-it (E146)

To a solution of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-it (free base E145, 23 mg, 0,056 mmol) in anhydrous DMF (1 ml) at 0°C was added sodium hydride (3.5 mg, 0,084 mmol, 60% suspension in mineral oil). After stirring for 30 min was added methyliodide (4 μl, 9.5 mg, 0,067 mmol) and continued stirring for 6 hours was Added to methanol, the mixture was applied to the ion exchange cartridge (SCX-2) and obtained the crude product, elwira 1H. solution of ammonia in methanol. The crude compound was purified by the method of flash chromatography on silica gel, elwira dichloromethane/methanol (99/1 to 97/3), obtaining specified in sialometaplasia with the release of 23% (5.5 mg). The free base was converted into the corresponding dihydrochloride by dissolving the compound in dichloromethane and added dropwise 1M ethereal HCl solution (2.1 EQ.). Precipitated precipitated yellow solid and the suspension was stirred for 15 minutes the Solvent was removed under reduced pressure, the residue triturated with ether. Then by filtering the extracted specified in the title compound (quantitative yield).

MS: (ES/+) m/z: 428 [MH+]. C26H29N5About requires 427.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 11,5 (2 ocessors, 1H), 8,79 (ocessors, 1H), 7,87 (users, 2H), 7,74 (users, 2H), 7,63 (d, 1H), 7,46 (t, 1H), and 7.4 (users, 1H), 7,21 (d, 1H),? 7.04 baby mortality (d, 1H), 6,78 (d, 1H), 3,8-2,9 (ocsi, 12H), 3,21 (c, 3H), 2,85 (users, 3H).

Example 147

N-(3-{2-[4-(2-methyl-5-hintline)-1-piperazinil]ethyl}phenyl)methanesulfonamide (E147)

A mixture of 2-methyl-5-(1-piperazinil)hintline (50 mg), 2-{3-[(methylsulphonyl)amino]phenyl}ethylmethanesulfonate (65 mg), diisopropylethylamine (192 μl) and DMF (0.5 ml) was heated to 100°C in a sealed tube and stirred for 24 hours. The mixture was cooled to room temperature and distributed between an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was washed (water, brine), dried (sodium sulfate) and concentrated in vacuum. The residue was purified by the method of column chromatography [SiO2; elwira gradient DCM/Meant 100/0 to 95/5] obtaining specified in the title compound as a beige foam (35 mg).

MC; (ES) m/z: 426 [MH+]. C22H27N5About2S requires 425.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 9,65 (c, 1H), 9,48 (c, 1H), 7,82 (t, 1H), 7,50 (d, 1H), 7,24 (t, 1H), 7,15 (d, 1H), 7,11 (c, 1H),? 7.04 baby mortality (d, 1H), 7,01 (d, 1H), 3,12 (m, 4H), 2,97 (c, 3H), of 2.75 (m, 6H), 2,73 (c, 3H) and 2,63 (m, 2H).

2-{3-[Methylsulfonylamino]phenyl}ethylmethanesulfonate

Specified in the title compound was obtained from 3-aminophenethyl alcohol (U.S. patent No. 2641602) and methanesulfonamide (2 EQ.) in accordance with the methodology contained in the description 4. The product was used immediately without further purification and without defining additional parameters.

2-Methyl-5-(1-piperazinil)hinzelin

To a stirred solution of 2-methyl-5-ftorhinolona (WO 2003068772, Chem. Abstr. 139:197493, 2 g; 12.3 mmol) in anhydrous dimethylformamide (10 ml) was added triethylamine (3.4 ml, 2 EQ.) and piperazine (11 g; 10 EQ.). The reaction mixture was stirred in nitrogen atmosphere at 120°C for 4 h, then cooled to room temperature, poured into water (10 ml) and was extracted with ethyl acetate (5×15 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuum. The crude product was purified by the method of ion exchange chromatography (SCX-2; elwira gradient MeOH-(1M NH3/MeOH) from 1/0 to 0/1) to obtain specified in the title compound as a yellow solid (1.8 g; yield 64%).

MS: (ES) m/z: 229 [MH+]. C11 H8F3NO3S requires 228.

1H NMR (300 MHz, CDCl3) δ (ppm): 9,58 (c, 1H), 7,89 (t, 1H), 7.62mm (d, 1H), 7,27 (d, 1H), 3,25 (m, 8H), 2.91 in (c, 3H).

Example 148

N-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N-(methylsulphonyl)methanesulfonamide (E148)

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (370 mg) and triethylamine (178 μl) in DCM (3 ml) was added methanesulfonamide (33 μl). The mixture was stirred for 18 h, and then was distributed between saturated aqueous sodium bicarbonate and DCM. The organic layer was washed with water, dried and concentrated in vacuum. The residue was purified by the method of column chromatography (SiO2; elwira gradient DCM/MeOH from 20/1 to 20/0) obtaining specified in the title compound (342 mg).

MS: (ES) m/z: 503 [MH+]. C24H30N4O4S2requires 502.

1H NMR (400 MHz, d6-DMSO) δ (ppm): 8,33 (d, 1H), and 7.6-7.5 (m, 2H), 7,42-7,30 (m, 5H), to 7.09 (DD, 1H), 3,52 (c, 6H), to 3.02 (osirm, 4H), of 2.86 (t, 2H), 2,8-2,6 (m, 6H) and 2,62 (c, 3H).

Example 149

N-Methyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E149)

A solution of N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (50 mg) was dissolved in THF (2.5 ml) and at 0°C was added sodium hydride (60 wt.% dispersion in oil, 0.005 g, 1 EQ.). After 5 minutes was added iodomethane (5 μl, 1.0 EQ.) and the mixture was heated to room so the temperature. After 10 h, the solution was distributed between water (3 ml) and ethyl acetate (3×5 ml). The combined organic extracts were washed with saline, dried over sodium sulfate and concentrated in vacuum. The crude product was purified by the method of flash chromatography on silica gel, elwira gradient from dichloromethane to dichloromethane/methanol (98/2), to obtain specified in the connection header with the release of 61% (0.02 g).

MS: (ES) m/z: 403,4 [MH+]. C25H31ClN4requires 402.

1H NMR (300 MHz, d6-DMSO) δ (ppm): 10,85 (users, 1H), 8,79 (users, 1H), 8,7 (osirm, 16H), 3,8-3,0 (osirm, 15H), 2,84 (users, 3H), 1,79 (users, 3H).

Example 150

N-(1-Methylethyl)-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)urea (E150)

Specified in the title compound was obtained from 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6, 30 mg) and isopropylmalate (10,2 mm)using toluene (1 ml) as solvent, in accordance with method E (yield 23 mg).

MS: (ES) m/z: 432 [MH+]. C26H33N5About 431 requires.

1H NMR (400 MHz, CDCl3) δ (ppm): to 8.40 (d, 1H), 7,73 (d, 1H), 7,60 (t, 1H), and 7.3 to 7.2 (m, 3H), to 7.09 (d, 2H), 6,99 (d, 1H), 6,15 (c, 1H), 4,49 (d, 1H), was 4.02 (m, 1H), 3,16-and 2.83 (m, 12H) and 1.2 (d, 6H).

Example 151

N-Methyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)methanesulfonamide (E151)

A sample of the hydrochloride of N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)is metansulfonate (E43, 25 mg) was distributed between saturated aqueous sodium bicarbonate and DCM. The organic phase was dried over sodium sulfate and concentrated in vacuo to obtain the free base (18.5 mg)which was dissolved in THF (1.5 ml) and cooled to 0°C. To the stirred solution was added sodium hydride (60%, 5 mg). The mixture was stirred for 30 minutes and then added iodomethane (5 ál). The mixture was heated to room temperature and was stirred for 18 hours the Mixture was cooled to 0°C and added an additional portion of sodium hydride (60%, 5 mg) and iodomethane (5 ál). The mixture was heated to room temperature and was stirred for 24 h, and then distributed between the aqueous solution of ammonium chloride and DCM. The organic layer was washed (water), dried (sodium sulfate) and concentrated in vacuum. The residue was purified by the method of column chromatography (SiO2; elwira DCM/MeOH 97/3), with specified title compound (5 mg).

MC; (ES) m/z: 439 [MH+]. C24H30N4About2S requires 438.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,32 (d, 1H), of 7.70 (d, 1H), 7,58 (t, 1H), 7,30-7,20 (m, 3H), 7,17 (c, 1H), 7,10-7,00 (m, 3H), of 3.78 (t, 2H), 3,37 (t, 2H), 3,12 (m, 4H), 2,87 (m, 2H), 2,80 (m, 4H), of 2.72 (m, 2H), 2,71 (c, 3H) and 2.52 (q, 2H).

Example 152

1-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-pyrrolidinone (E152)

1-[3-(2-Hydroxyethyl)phenyl]-2-pyrrolidinone

Specified in the header is VCE compound was obtained with the yield of 15% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 2-(3-bromophenyl)ethanol and 2-pyrrolidinone. Purification was performed by the method of flash chromatography on silica gel, elwira with ethyl acetate.

1H NMR (300 MHz, CDCl3) δ (ppm): 7,60 (c, 1H), 7,40 (d, 1H), 7,30 (m, 1H), 7,00 (d, 1H), and 4.40 (t, 2H), 3,85 (m, 4H), 2,85 (t, 2H), 2,60 (t, 2H), 2,10 (kV, 2H).

2-[3-(2-Oxo-1-pyrrolidinyl)phenyl]ethylmethanesulfonate

To a stirred solution of 1-[3-(2-hydroxyethyl)phenyl]-2-pyrrolidinone (0,30 g) and triethylamine (0,42 ml) in dichloromethane (10 ml) at room temperature under inert atmosphere was added dropwise methanesulfonanilide (0,124 ml). The solution was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml), aqueous hydrochloric acid (1N., 2×50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and brine (50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by the method of flash chromatography on silica gel, elwira with ethyl acetate/cyclohexane (50/50), obtaining specified in the connection header with the release of 93% (0,384 g).

1H NMR (300 MHz, CDCl3) δ (ppm): 7,60 (c, 1H), 7,40 (d, 1H), 7,30 (m, 1H), 7,00 (d, 1H), and 4.40 (t, 2H), 3,85 (t, 2H), 3,05 (t, 2H), 2,85 (c, 3H), 2,60 (t, 2H), 2,15 (kV, 2H).

1-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-pyrrolidinone (E152)

To a solution of methyl-5-(1-piperazinil)quinoline (D3) (0.05 g) and 2-[3-(2-oxo-1-pyrrolidinyl)phenyl]ethylmethanesulfonate (0,071 g) in dimethylformamide (1 ml) was added N,N-diisopropylethylamine (0,23 ml), heated the mixture to 100°C for 18 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml), the mixture of water and salt solution (1/1, 2×50 ml) and brine (50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by the method of flash chromatography on silica gel, elwira methanol/ethyl acetate (90/10), obtaining specified in the connection header with the release of 77% (0.07 g).

MC; (ES) m/z: of 415.3 [MH]+, 208,4 [M+2H]2+. C26H30N4About 414 requires.

1H NMR (300 MHz, CDCl3) δ (ppm): of 8.37 (d, 1H), of 7.70 (d, 1H), EUR 7.57 (m, 2H), 7,37 (m, 1H), 7,25 (m, 2H), 7,07 (d, 1H), 7,03 (userd, 1H), 3,85 (t, 2H), 3,13 (osirm, 2H), 2,9-2,75 (osirm, 8H), 2,70 (c, 3H), 2,60 (t, 2H), 2,15 (kV, 2H).

Example 153

5-(4-{2-[3-(1,1-Dioxido-2-isothiazolinone)phenyl]ethyl}-1-piperazinil)-2-methylinosine (E153)

To a stirred solution of 3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6, 30 mg) in pyridine (0.5 ml) was added 2-Kharatishvili (13 μl). The mixture was stirred for 1 h, then concentrated in vacuo and was distributed between saturated aqueous sodium bicarbonate and DCM. The organic layer was washed (water), dried (sodium sulfate) and concentrated in vacuum. The residue was dissolved in THF (1 ml) and cooled to 0°C under stirring. To peremeshivaemogo the solution was added sodium hydride (60%, 20 mg). The mixture was heated to room temperature and left to stand for 4 days. The reaction mixture was diluted with water and concentrated in vacuum. The residue was distributed between DCM and water. The organic layer was washed (water), dried (sodium sulfate) and concentrated in vacuum. The residue was purified by the method of column chromatography (SiO2; elwira EtOAc) to obtain the specified title compound (4.4 mg).

1H NMR (400 MHz, CDCl3) δ (ppm): scored 8.38 (d, 1H), 7,72 (d, 1H), 7,58 (t, 1H), 7,35-7,07 (m, 6H), 3,34 (c, 3H), 2,86 (c, 3H), 2,73 (c, 3H) and 3.3 and 2.7 (m, 12H).

Example 154

N-(3-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E154)

2-Methyl-5-(1-piperazinil)-7-ftorhinolon

Stir a mixture of piperazine (20 g), potassium carbonate (32 g), hydrochloride 5,7-debtor-2-methylinosine (WO/2002034754, 20 g) and dimethyl sulfoxide (390 ml) was heated to 120°C for 15 hours. The mixture was cooled to room temperature, diluted with water (600 ml) and was extracted with 6×500 ml of a mixture of DCM/diethyl ether (15/85). The combined organic extracts were washed with water (200 ml) and brine (200 ml), dried (sodium sulfate) and partially the solvent evaporated in vacuum. Obtained during the solvent is evaporated, the precipitate was filtered off, washed with diethyl ether (50 ml) and dried in vacuum to obtain specified in the title compound (4.7 g, 21%).

1 H NMR (300 MHz, CDCl3) δ (ppm): of 8.27 (d, 1H), 7,27 (DD, 1H), 7,17 (DD, 1H), 6,78 (DD, 2H), 3,10 (m, 4H), 3,01 (m, 4H), 2,67 (c, 3H).

7-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinil}quinoline

To a solution of 2-methyl-5-(1-piperazinil)-7-ftorhinolona (0.03 g; 1 EQ.) and 2-(3-nitrophenyl)ethylmethanesulfonate (D4) (0,033 g; 1.1 EQ.) in dimethylformamide (1.0 ml) was added N,N-diisopropylethylamine (0,07 ml; 3 EQ.). The reaction mixture was heated to 90°C for 10 hours. The dark solution was cooled to room temperature and concentrated under reduced pressure, diluted with water (3 ml) and brine (1 ml) and was extracted with ethyl acetate (3×3 ml). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by the method of flash chromatography on silica gel, elwira gradient from dichloromethane to dichloromethane/MeOH (98/2), to obtain specified in the connection header with the release of 88% (0.04 g).

MC; (ES) m/z: 395,4 [MH]+. C22H23FN4About2requires 394.

3-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline

To a suspension of iron powder (0.04 g; 7 EQ.) and ammonium chloride (0.04 g; 7 EQ.) in water (3 ml) was added dropwise a solution of 7-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinil}quinoline (0,046 g; 1 EQ.) in methanol (3 ml). Participating in the reaction substance was heated under reflux for 8 hours, until the of avlee during the reaction with three portions of an additional quantity of iron powder (only 0.04 g; 7 EQ.) and ammonium chloride (a total of 0.04 g; 7 EQ.). The reaction mixture was cooled to room temperature and filtered using a Millipore filter. The filtrate was concentrated under reduced pressure, diluted with water (5 ml) and saturated aqueous sodium bicarbonate (2 ml) and was extracted with ethyl acetate (3×5 ml). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to obtain specified in the connection header with the release of 32% (0,012 g).

MS: (ES) m/z: 365,4 [MH]+. C22H25FN4requires 364.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), 7,35 (d, 1H), 7,20 (m, 1H), 6,85 (m, 2H), 7,55 (m, 2H), 6,45 (m, 2H), 3,05 (osirm, 4H), 2,8-2,7 (osirm, 7H), 2,70 (c, 3H).

N-(3-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)ndimethylacetamide (E154)

Specified in the title compound was obtained with the yield 46% in accordance with the General method of obtaining the amides (method B), using as a starting compound 3-{2-[4-(7-fluoro-2-methyl-5-chinoline)-1-piperazinil]ethyl}aniline and acetylchloride.

MS: (ES) m/z: 407,3 [MH+]. C24H28N4O requires 437.

1H NMR (300 MHz, d6-DMSO) δ (ppm): 10,48 (users, 1H), 9,98 (c, 1H), charged 8.52 (users, 1H), 7,65 (c, 1H), 7,53 (users, 1H), 7,45 (userd, 1H), was 7.36 (d, 1H), 7,28 (m, 1H), 7.23 percent (d, 1H), 6,97 (d, 1H), 3,8-3,2 (osirm, 10H), 3,06 (DD, 2H), 2,72 (c, 3H), 2,04 (c, 3H).

Example 155

2,2'-[(3-{2-[4-(7-Chloro-2-methyl-5-chinoline)-1-piperazinil]the Teal}phenyl)imino]bis(N,N-dimethylacetamide) (E155)

According to methods described for example 96 was allocated specified in the title compound with yield of 16%.

MS: (ES) m/z: 552 [MH+]. C30H39ClN6O2requires 551.

1H NMR (500 MHz, CD3OD) δ (ppm): 9,17 (d, 1H), 7,95 (d, 1H), of 7.90 (c, 1H), to 7.61 (c, 1H), 7,20 (m, 1H), 6,74 (d, 1H), 6,59 (c, 1H), 6,53 (d, 1H), 4,39 (c, 4H), 3,81-3,62-3,41 (d-t-t, 2-4-2), 3,55 (t, 2H), 3,16-3,03 (t, 2H), 3,01 (c, 3H).

Example 156

Hydrochloride of 1-ethyl-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E156)

To a stirred solution of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (example 85, 50 mg) in DMF (1 ml) was added sodium hydride (60%, 10 mg). The mixture was stirred for 15 minutes and then added Iodate (11 μl). The mixture was stirred for 90 minutes, then diluted with methanol (5 ml) and was purified by the method of ion exchange chromatography (SCX-2; elwira gradient MeOH-(1M NH3/MeOH from 100/0 to 0/100). The basic washings were concentrated in vacuo, purified by the method of column chromatography (SiO2; elwira gradient of cyclohexane/EtOAc/MeOH from 1/1/0 to 0/10/1) and was converted into the hydrochloride as described in the description of the General methods (D6) to obtain the specified title compound (49 mg).

MS: (ES) m/z: 444 [MH+]. C27H33N5O requires 443.

1H NMR (300 MHz, d6-DMSO) δ (ppm): 11.4 in (m, 1H) 9,0 (d, 1H), 7,9 (m, 2H), and 7.8 (d, 2H), 7.5 (d, 1H), and 7.4 (m, 2H), 7,2 (who, 2H)and 6.9 (d, 1H), 3,6 (m, 4H), 3,6-3,3 (m, 10H), 3,2-3,1 (m, 4H), 3.0 a (c, 3H) and 1.2 (c, 3H).

Example 157

The dihydrochloride of 1-(1-methylethyl)-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E157)

Specified in the title compound was obtained in accordance with methods described for example 156 using 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (example 85, 50 mg), DMF (1 ml), sodium hydride (60%, 10 mg) and 2-jumprope (13 ml) (yield 17 mg).

MS: (ES) m/z: 458 [MH+]. C28H35N5O requires 457.

1H NMR (300 MHz, d6-DMSO) δ (ppm): 9,00 (d, 1H), 8,05-to 7.95 (m, 2H), a 7.85 (d, 1H), 7,55 (c, 1H), 7,40 (DD, 1H), 7,32 (DD, 1H), 7,27 (t, 1H), 6.90 to (d, 1H), 4,05 (Sextus., 1H), 4,85-4,70 (m, 4H), 3,55-of 3.25 (m, 10H), 3.15 in (t, 2H), 2.95 and (c, 3H) and 1.12 (d, 6H).

Example 158

The dihydrochloride of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-3-(4-pyridinylmethyl)-2-imidazolidinone (E158)

Specified in the title compound was obtained in accordance with methods described for example 156 using 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (example 85, 50 mg), DMF (1 ml), sodium hydride (60%, 14 mg) and the hydrochloride of 4-chloromethylpyridine (20 mg) (yield 19 mg).

MS: (ES) m/z: 507 [MH+]. C31H34N6O requires 506.

1H NMR (300 MHz, d6-DMSO) δ (ppm): 9,00 (d, 1H), 8,82 (d, 2H), 8,02-to 7.95 (m, 2H), 7,92-a 7.85 (m, 3H), 7,60 (c, 1H), 7,52 (d, 2H), 7,35 (m, 1H), 7,00 (d, 1H), 5,67 (c, 2H), 3,92 (t, 2H), to 3.67 (t, 2H), to 3.58-3,30 (m, 10H, 3,17 (m, 2H) and 2,92 (c, 3H).

Example 159

The dihydrochloride of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-3-(3-pyridinylmethyl)-2-imidazolidinone (E159)

Specified in the title compound was obtained in accordance with methods described for example 156 using 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (example 85, 50 mg), DMF (1 ml), sodium hydride (60%, 14 mg) and the hydrochloride of 3-chloromethylpyridine (20 mg) (yield 20 mg).

MS: (ES) m/z: 507 [MH+]. C31H34N6O requires 506.

1H NMR (300 MHz, d6-DMSO) δ (ppm): 8,98 (d, 1H), 8,78 (c, 1H), up 8.75 (m, 1H), 8,27 (d, 1H), 8,05-to 7.95 (m, 2H), of 7.90-of 7.82 (m, 2H), 7.62mm (c, 1H), 7,50 (m, 2H), 7,35 (m, 1H), 6,98 (d, 1H), 4,57 (c, 2H), a 3.87 (t, 2H), 3,71 (m, 2H), 3,57-3,30 (m, 10H), 3,20 (t, 2H) and 2.95 (c, 3H).

Example 160

1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)octahydro-2H-benzimidazole-2-he (E160)

Specified in the title compound was obtained with the yield of 100% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-itfinal)ethyl]-1-piperazinil}-2-methylinosine, octahydro-2H-benzimidazole-2-it.

MS: (ES/+) m/z: 470 [MH+]. C29H35N5O requires 469.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,55 (t, 1H), 7,35-7,00 (m, 6H), 3,5-3,0 (m, 6H), 2.95 and-to 2.65 (m, 11H), 2,25-of 1.30 (m, 8H).

Example 161

(S)-2-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)g is kagero-3H-pyrrolo[1,2-c]imidazol-3-one (E161)

(S)-Hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one

(S)-2-(Aminomethyl)pyrrolidine (250 mg) and carbonyldiimidazole (400 mg, 1.0 EQ.) was dissolved in DCM (50 ml). The resulting mixture was stirred at room temperature for 18 hours and then concentrated in vacuum. The residue was purified by the method column flash chromatography (cartridge for solid phase extraction, SiO2using DCM/methanol (95/5) as eluent, to obtain specified in the title compound as a colourless solid (150 mg, yield 50%).

MS: (ES/+) m/z: 127 [MH+]. C6H10N2O requires 126.

1H NMR (300 MHz, CDCl3) δ (ppm): 4,3 (users, 1H), of 3.7-3.8 (m, 1H), 3,65-3,55 (m, 2H), 3,25 (DD, 1H), 3,05 (m, 1H), 2.00 in to 1.70 (m, 3H), of 1.40 (m, 1H).

2-(3-Itfinal)ethanol

To a stirred solution of 3-IOpenRowset acid (4.0 g) in THF (100 ml), cooled to 0°C was added dropwise a solution of borane (1M in THF, 2.5 equiv, 38,2 ml). The resulting mixture was stirred at 0°C for 1 h, then was heated to room temperature and was further stirred for 3 hours the Mixture was poured into aqueous ammonium chloride and was extracted with ethyl acetate. The combined organic phases are washed with saline, dried (sodium sulfate) and concentrated. The crude material was purified according to the method of column chromatography (cartridge for solid phase extraction, SiO2using the cycle is hexane/ethyl acetate (70/30) as eluent, obtaining specified in the title compound (3.5 g, yield 92%).

1H NMR (400 MHz, CDCl3) δ (ppm): 7.5 to 7 (m, 5H), 4,0 (m, 2H), 2,9 (m, 2H).

2-(3-Itfinal)ethylmethanesulfonate

To a stirred solution of 2-(3-itfinal)ethanol (3.6 g) in dichloromethane (100 ml) and diisopropylethylamine (3.8 ml, 1.5 EQ.) at 0°C was added dropwise methanesulfonamide (1.5 ml, 1.2 EQ.). The solution was heated to room temperature and was stirred for 18 hours, the Reaction mixture was diluted with an aqueous solution of ammonium chloride and was extracted with dichloromethane. The organic layers were combined, washed with an aqueous solution of sodium bicarbonate, saline, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified according to the method of column chromatography (cartridge for solid phase extraction, SiO2), elwira DCM/cyclohexane (70/30), with specified title compound (3.2 g, yield 45%).

1H NMR (400 MHz, CDCl3) δ (ppm): 7,58 (m, 2H), 7,25-7,0 (m, 2H), 4,48 (t, 2H), 3,0 (t, 3H).

5-{4-[2-(3-Itfinal)ethyl]-1-piperazinil}-2-methylinosine

To a solution of 2-methyl-5-(1-piperazinil)quinoline (D3) (1.31 g; 0.9 EQ.) and 2-(3-iodophenyl)ethylmethanesulfonate (2.1 g) in dimethylformamide (20 ml) was added N,N-diisopropylethylamine (1.7 ml; 1.5 EQ.). The reaction mixture was heated to 90°C for 5 hours. The dark solution was concentrated under reduced is the making and was purified by the method of ion exchange chromatography (SCX-2), elwira gradient MeOH-(1M NH3/MeOH) from 1/0 to 0/1. The combined basic fractions were concentrated in vacuum and purified by the method of column chromatography (cartridge for solid phase extraction, SiO2), elwira dichloromethane/methanol (95/5), to obtain the specified title compound (1.5 g, yield 60%).

MS: (ES) m/z: 457, 459 [MH]+. C22H24IN3requires 457.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), 7.5 (d, 1H), and 7.6-7.5 (m, 3H), 7.3 to a 7.0 (m, 4H), 3,1 (m, 4H), 2,85-to 2.65 (m, 11H).

(S)-2-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one (E161)

Specified in the title compound was obtained with the yield 60% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-itfinal)ethyl]-1-piperazinil}-2-methylinosine and (S)-hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one.

MS: (ES/+) m/z: 456 [MH+]. C28H33N5O requires 455.

1H NMR (400 MHz, CDCl3) δ (ppm): is 10.68 (ocessors, 1H), 8,82 (ocessors, 1H), 7,88 (users, 2H), 7,76 (users, 1H), 7,66 (c, 1H), 7,47 (d, 1H), 7,40 (users, 1H), 7,34 (t, 3H), of 7.00 (d, 1H), 4,10-3,0 (ocsi, 17H), 2,86 (users, 3H), 2,1 to 1.37 (m, 4H).

Example 162

(R)-2-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one (E162)

(R)-(1,1-Dimethylethyl-2-{[(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)amino]methyl}-1-Pierre is licensability

3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}aniline (D6, 115 mg) and N-(tert-butoxycarbonyl)-L-prolinal (1.2 EQ., 79 mg) was stirred in methanol (2 ml) until until the mixture becomes transparent. Then add triacetoxyborohydride sodium (1.2 EQ., 85 mg). After 24 h the reaction mixture was applied to the ion exchange cartridge (SCX-2) and suirable with methanol and then 1 m ammonia/methanol. The combined basic fractions were concentrated in vacuum and purified by the method of column chromatography (cartridge for solid phase extraction, silicon dioxide), using DCM/methanol (95/5) as eluent, to obtain the specified title compound (70 mg, yield 40%).

MS: (ES/+) m/z: 530 [MH+]. C32H43N5O2requires 529.

1H NMR (300 MHz, CDCl3) δ (ppm): 8,35 (d, 1H), of 7.70 (d, 1H), 7,2 (d, 1H), 7,15-7,00 (m, 2H), 6,5 (osirm, 3H), 4,00-2,90 (ocsi, 20H) (m, 4H), 2,00-1,50 (ocsi, 13H).

(R)-2-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one (E162)

A solution of (R)-(1,1-dimethylethyl-2-{[(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)amino]methyl}-1-pyrrolidinecarboxylic in methanol was treated with 1M solution of hydrogen chloride in diethyl ether. The resulting mixture was stirred 30 minutes, then concentrated in vacuo, and then was applied to the ion exchange cartridge (SCX-2) and suirable with methanol and then 1 m ammonia/methanol. the joint basic fractions were concentrated in vacuum. Then the remainder (10 mg) was dissolved in DCM (1 ml) and treated with triphosgene (23 mg, 0.3 equiv.) Diisopropylamine (4 μl, 3 EQ.). The mixture was stirred for 1 h, then was concentrated in vacuum and purified by the method of preparative HPLC with the distribution of mass with obtaining specified in the title compound (3.1 mg).

MS: (ES/+) m/z: 456 [MH+]. C28H33N5O requires 455.

1H NMR (300 MHz, DMSO) δ (ppm): 8,35 (d, 1H), of 7.75 (d, 1H), 7,65 (c, 1H), 7,60 (d, 1H), 7,20-7,35 (m, 3H), 7,30 (d, 1H), 6,95 (d, 1H), 6,5 (osirm, 3H), 4,00-2,90 (ocsi, 12H) 2,85 (c, 3H), 2.00 in a 1.50 (m, 4H).

Example 163

5,5-Dimethyl-1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E163)

4,4-Dimethyl-2-imidazolidinone

A solution of (2-amino-1,1-dimethylethyl)amine (1.0 g) and 1,1'-carbonyldiimidazole (1,9 g, 1.0 EQ.) in DCM (50 ml) was stirred for 18 hours, then concentrated and purified according to the method of column chromatography (cartridge for solid phase extraction, SiO2using DCM/methanol (95/5) as eluent, to obtain specified in the title compound as a colourless solid (1.0 g, yield 83%).

MS: (ES/+) m/z: 115 [MH+]. C5H10N2O requires 114.

1H NMR (300 MHz, CDCl3) δ (ppm): 4,5 (users, 1H), 3,25 (c, 2H), 1,25 (c, 6H).

5,5-Dimethyl-1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone (E163)

Specified in the header of the connection is received and output from 87% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-itfinal)ethyl]-1-piperazinil}-2-methylinosine and 4,4-dimethyl-2-imidazolidinone.

MS: (ES/+) m/z: 444 [MH+]. C27H33N5O requires 443.

1H NMR (400 MHz, CDCl3) δ (ppm): 10,89 (users, 1H), 8,87 (users, 1H), 7,92 (users, 2H), 7,58 (DD, 1H), and 7.4 (users, 1H), 7,44 (DD, 1H), and 7.3 (t, 1H), 7,21 (c, 1H), 6,95 (d, 1H), 3,74 (DD, 2H), 3,61 (c, 2H), 3,60-3,30 (m, 8H), 2,87 (c, 3H), 1,3 (c, 6H).

Example 164

(R or S)-1-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-2-imidazolidinone (E164)

The racemate of 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]propyl}phenyl)-2-imidazolidinone was obtained with the yield 41% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-bromophenyl)propyl]-1-piperazinil}-2-methylinosine (D20) and 2-imidazolidinone.

The racemate was separated by the method of preparative chiral HPLC (column Daicel Chiralcel OD), elwira n-hexane/ethanol (60/40), with the specified header connection in the form of aliremove the first enantiomer.

MS: (ES/+) m/z: 430 [MH+]. C26H31N5O requires 429.

1H NMR (500 MHz, d6-DMSO) δ (ppm): to 10.62 (users, 1H), 8,94 (users, 1H), 7,88 (users, 2H), 7,75 (users, 1H), 7,58 (c, 1H), 7,50-of 6.90 (m, 4H), between 6.08 (users, 1H), 3,90-2,70 (osirm, 15H), 2,85 (users, 3H), 1,22 (d, 3H).

Example 165

(S or R)-1-(3-{2-[4-(2-Methyl-5-chinoline)-1-Pipa is azinyl]propyl}phenyl)-2-imidazolidinone (E165)

Specified in the title compound was obtained in accordance with the method, are presented for example 164, and extracted in the form of aliremove second enantiomer.

MS: (ES/+) m/z: 430 [MH+]. C26H31N5O requires 429.

1H NMR (500 MHz, d6-DMSO) δ (ppm): to 10.62 (users, 1H), 8,94 (users, 1H), 7,88 (users, 2H), 7,75 (users, 1H), 7,58 (c, 1H), 7,50-of 6.90 (m, 4H), between 6.08 (users, 1H), 3,90-2,70 (osirm, 15H), 2,85 (users, 3H), 1,22 (d, 3H).

Example 166

N-(3-{3-[4-(2-Methylinosine-5-yl)-piperazine-1-yl]propyl}phenyl)methanesulfonamide (E166)

N-3-Idfenumeration

To a stirred solution of 3-joanina (1,99 g, 9.1 mmol) in anhydrous pyridine (20 ml) at 0°C in small portions was added anhydride methanesulfonic acid (1.92 g, 11 mmol). The resulting mixture was stirred with heating from 0°C to room temperature, while the aniline will not be spent. The pyridine was removed in vacuum. The residue was distributed between dichloromethane (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The organic layer was dried (sodium sulfate) and evaporated in vacuo. The crude product was purified by the method of chromatography on silica gel (elwira gradient of ethyl acetate in hexane from 10% to 30%) to obtain the specified title compound as a yellow solid (2.38 g, 89%).

MS (API-): Found: 296 ([M-H]-). With7H8INO2's required is 297.

1H NMR (CDCl3) δ (ppm): 3.04 from (3H, c), 6.42 per (1H, user, c), was 7.08 (1H, m), 7,22 (1H, m), 7,53 (1H, m), 7,56 (1H, c).

N-[3-(3-Oxopropyl)phenyl]methanesulfonamide

A mixture of N-3-idfenumeration (2.4 g, 8 mmol), chloride, Tetra-n-butylamine (2,22 g, 8 mmol), allyl alcohol (0.7 g, 12 mmol), sodium bicarbonate (1.6 g, 19 mmol) and palladium(II) chloride (0.36 g, 1.8 mmol) in anhydrous dimethylformamide (30 ml) was stirred at room temperature for 48 h in an argon atmosphere. The mixture is then diluted with 5% aqueous hydrochloric acid (100 ml) and was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried (sodium sulfate) and evaporated in vacuo. The crude product was purified by the method of chromatography on silica gel (elwira gradient of ethyl acetate in hexane from 30% to 50%) to produce specified in the title compound as an amber oil (1.1 g, 60%).

MS (API-): Found: 226 ([M-H]-). With10H13NO3S requires 227.

1H NMR (CDCl3) δ (ppm): 2,80 (2H, m), 2,96 (2H, t, J=8 Hz), 3,01 (3H, c), 6,46 (1H, users), 7,00-7,10 (3H, m), 7,28 (1H, t, J=8 Hz), 9,82 (1H, c).

N-(3-{3-[4-(2-Methylinosine-5-yl)-piperazine-1-yl]-propyl}phenyl)methanesulfonamide (E166)

Specified in the title compound was obtained from N-[3-(3-oxo-propyl)phenyl]methanesulfonamide and 2-methyl-5-(1-piperazinil)quinoline (D3) in accordance with the methods presented in the description of 4 and 5.

MS (API-): Found: 437 ([MN] -). With24H30N4O2S requires 438.

1H NMR (CDCl3) δ (ppm): 1,91 (2H, m)of 2.50 (2H, m), 2,71 (6H, m), 2,73 (3H, c), to 3.02 (3H, c), of 3.12 (4H, m), 6,30 (1H, user, c), 7,00-7,10 (4H, m), 7,26 (2H, m), 7,58 (1H, t, J=8 Hz), 7,72 (1H, d, J=8 Hz), of 8.28 (1H, d, J=8 Hz).

Example 167

4-(3-{2-[4-(2-Methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,4-dihydro-3H-1,2,4-triazole-3-one (E167)

Specified in the title compound was obtained as a mixture (85/15) with regioisomer 2-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,2-dihydro-3H-1,2,4-triazole-3-in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-itfinal)ethyl]-1-piperazinil}-2-methylinosine and 1,2-dihydro-3H-1,2,4-triazole-3-one.

MS: (ES/+) m/z: 415 [MH+]. C24H26N6About 414 requires.

1H NMR (300 MHz, CDCl3) δ (ppm): 11,92 (users, 1H), 8,32 (d, 1H), 8.30 to (d, 1H), 7,55 (users, 1H), 7,53 (m, 2H), of 7.48 (DD, 1H), 7,37 (t, 1H), 7,34 (d, 1H), 7,22 (d, 1H), 7,05 (DD, 1H), 7,05 (DD, 1H), 2,99 (users, 4H), 2,85 of 2.6 (m, 10H), 2,58 (c, 4H).

Example 168

5-Methyl-2-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2,4-dihydro-3H-pyrazole-3-one (E168)

Specified in the title compound was obtained with the yield 58% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-itfinal)ethyl]-1-piperazinil}-2-methylinosine and 5-methyl-2,4-dihydro-3H-pyrazole-3-one.

+]. C26H29N5About requires 427.

1H NMR (300 MHz, CDCl3) δ (ppm): 8.30 to (d, 1H), 7,65 (m, 2H), 7,50 (t, 1H), 7,27-7,16 (m, 3H), 7,01-6,98 (m, 2H), is 3.08 (m, 4H), 2,90-2,60 (m, 14H), and 2.14 (c, 2H).

Example 169

2-(4-Fluoro-3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-5-methyl-2,4-dihydro-3H-pyrazole-3-one (E169)

Specified in the title compound was obtained with the yield 92% in accordance with the General method of obtaining amides, ureas and carbamates (method A), using as starting compounds 5-{4-[2-(3-itfinal)ethyl]-1-piperazinil}-2-methylinosine and 5-methyl-2,4-dihydro-3H-pyrazole-3-one.

MS: (ES/+) m/z: 446 [MH+]. C26H28FN5About requires 445.

1H NMR (300 MHz, CDCl3) δ (ppm): 8.30 to (d, 1H), 7,71-to 7.59 (m, 3H), 7,50 (t, 1H), 7,17 (d, 1H), 7.0 and 6.4 (m, 2H), 3,35 (c, 2H), 3,05 (m, 4H), 2,88-of 2.64 (m, 11H), 2,13 (c, 2H).

Example 170

5-(4-{2-[3-(5,6-Dihydro-7H-imidazo[2,1-c][1,2,4]triazole-7-yl)phenyl]ethyl}-1-piperazinil)-2-methylinosine (E170)

5,6-Dihydro-1H-imidazo[2,1-c][1,2,4]triazole

The hydrobromide of 2-hydrazino-2-imidazoline (200 mg) suspended in utilitiarian (2 ml) and stirred at 150°C under microwave irradiation for 10 minutes, the Reaction mixture was cooled to room temperature, then was diluted with methanol and applied to ion exchange column (SCX-2), which was suirable with methanol and then 1 m ammonia/methanol. The combined basic fractions were concentrated in vacuum and purified by IU the ode column chromatography [SiO 2; elwira DCM/MeOH (90/10)] to obtain specified in the title compound as a colourless solid (60 mg, yield 60%).

MS: (ES/+) m/z: 112 [MH+]. C4H6N4requires 111.

1H NMR (300 MHz, CDCl3) δ (ppm): 7.95 is (c, 1H), 6,25 (c, 1H), 3,95 (m, 4H).

5-(4-{2-[3-(5,6-Dihydro-7H-imidazo[2,1-c][1,2,4]triazole-7-yl)phenyl]ethyl}-1-piperazinil)-2-methylinosine (E170)

5-{4-[2-(3-Itfinal)ethyl]-1-piperazinil}-2-methylinosine (59 mg), 5,6-dihydro-1H-imidazo[2,1-c][1,2,4]triazole (50 mg, 3.5 EQ.), the palladium(II) acetate (9 mg, 0.3 EQ.) 2-(dicyclohexylphosphino)-2'-methylbiphenyl (42 mg, 0.9 EQ.) and potassium phosphate (97 mg, 3.5 EQ.) suspended in DME and stirred at 150°C under microwave irradiation for 2 h the Mixture was cooled to room temperature, diluted with methanol and applied to an ion-exchange cartridge (SCX-2), which was suirable with methanol and then 1 m ammonia/methanol. The combined basic fractions were concentrated in vacuum and purified by the method of column chromatography [SiO2; elwira DCM/MeOH (90/10)] to obtain specified in the title compound as a colourless solid (13 mg, yield 26%).

MS: (ES/+) m/z: 440 [MH+]. C26H29N7requires 439.

1H NMR (300 MHz, CDCl3) δ (ppm): to 8.40 (d, 1H), of 7.90 (c, 1H), of 7.70 (d, 1H), and 7.6-7.5 (m, 2H), 7,35-7,20 (m, 3H), and 7.1 (d, 1H), 6,9 (d, 1H), 4,55 (t, 2H), 4,28 (t, 2H), 3.15 in (m, 4H), 3,0-2,7 (m, 11H).

1. The compound of formula (Ib) or its pharmaceutically p is Jemima salt:

where R1represents a C1-6-alkyl or C1-6-alkoxy;
X represents N or CH;
R3and R4independently represent hydrogen, C1-6-alkyl, C1-6-alkylsulfonyl or a group of formula (IIa):

where a represents oxygen or sulfur;
D represents -(CH2)t-, -(CH2)tO - or-O(CH2)t-where t is 0, 1, 2, 3 or 4; and
E represents a C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-membered monocyclic aromatic ring, or 6-10-membered bicyclic aromatic ring, in which 1-3 carbon atoms in the ring(s) optionally replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur (optionally substituted by 1 or 2 substituents, independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy);
or a group of formula (IIb):

where a represents oxygen or sulfur;
D represents -(CH2)t-, -(CH2)tO - or-O(CH2)t-where t is 0, 1, 2, 3 or 4; and
E represents a C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-membered monocyclic aromatic ring, or 6-10-membered bicyclic aromatic ring, in which 1-3 carbon atoms in Kohl is e(s) optionally substituted by a heteroatom, independently selected from nitrogen, oxygen and sulfur (optionally substituted by 1 or 2 substituents, independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy);
or R3and R4form together with the nitrogen atom to which they are attached, 3-7-membered ring, or 6-10-membered bicyclic ring which can be saturated, partially saturated or unsaturated and can contain 1, 2 or 3 heteroatoms selected from nitrogen, sulfur and oxygen, where each group is optionally substituted by 1 or 2 substituents selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where the aryl and aryl-C1-6-alkyl optionally additionally substituted by 1 or 2 C1-6-alkilani or1-6-alkoxy).

2. The compound according to claim 1, in which E represents a 5-7-membered monocyclic aromatic ring system, in which 1-3 carbon atoms in the ring is optionally replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur, where the ring is optionally substituted by 1 or 2 substituents, independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy; or E is a 9-10 membered bicyclic aromatic ring system, in which 1-3 carbon atoms in the ring is optionally replaced by a heteroatom independently selected from nitrogen, to the of Sloboda and sulfur, where the ring is optionally substituted by 1 or 2 substituents, independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy.

3. The compound according to claim 1, in which R3and R4form together with the nitrogen atom to which they are attached, a 4 to 6 membered monocyclic heterocyclic group optionally substituted by 1 or 2 substituents selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where the aryl and aryl-C1-6-alkyl optionally additionally substituted by 1 or 2 C1-6-alkilani or1-6-alkoxy; or R3and R4form together with the nitrogen atom to which they are attached, 8-10-membered bicyclic heterocyclic group, optionally substituted by 1 or 2 substituents selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where the aryl and aryl-C1-6-alkyl optionally additionally substituted by 1 or 2 C1-6-alkilani or1-6-alkoxy).

4. The compound according to claim 1, which is:
3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-oxazolidin-2-he;
N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-N'-prilocaine;
N-[2-(metiloksi)phenyl]-N'-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl} phenyl)urea;
2,4-dimethyl-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-eazol-5-carboxamide;
2-fluoro-N-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)benzamide;
1-methyl-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone;
1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl)phenyl)-2,4-imidazolidinedione;
1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-he;
1-methyl-3-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-he;
5,5-dimethyl-1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl}phenyl)-2-imidazolidinone;
1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl)phenyl)-2-imidazolidinone;
or its pharmaceutically acceptable salt.

5. The compound according to claim 1, which is 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl)phenyl)-2-imidazolidinone or its pharmaceutically acceptable salt.

6. The compound according to claim 5, which is 1-(3-{2-[4-(2-methyl-5-chinoline)-1-piperazinil]ethyl)phenyl)-2-imidazolidinone.

7. The compound according to any one of claims 1 to 6 for use in the treatment of disorders of the Central nervous system.

8. The connection according to claim 7, where the disorder is a depression or anxiety.

9. The use of compounds according to any one of claims 1 to 6 to obtain drugs for use in the treatment of disorders of the Central nervous system.

10. The use according to claim 9, where the disorder is a depression or anxiety.

11. Pharmaceutical composition for use in the treatment of RAS is trojstva CNS, containing an effective amount of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or excipient.

12. The method of preparation of the pharmaceutical composition according to claim 11, comprising mixing the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or excipient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to N-(2-thiazolyl)amide of 2-(2-oxo-3-indolinylidene)hydrazine-4-oxo-4-phenyl-2-butenoic acid of formula: .

EFFECT: obtaining a compound having antibacterial and analgesic activity.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein dashed lines present single or double bonds, and the values of radicals R1, R2, R3, R4 are described in cl. 1 of the patent claim. Besides the invention refers to application and a based pharmaceutical composition for prevention and treatment of neurodegenerative diseases and other diseases wherein cell dystrophy and/or cell loss (apoptosis) caused by free radicals act the main part.

EFFECT: production of new compounds and the based pharmaceutical composition which can find application in medicine for prevention and treatment of neurodegenerative diseases.

6 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts and esters. The disclosed compounds have inhibitory effect on cyclin-dependant kinase. In formula I R1 denotes , R3 is selected from a group consisting of H, CO2R6, C(O)R6, SO2R6 and SO2NR5R6, R5 and R6 are each independently selected from a group which includes H and (lower)alkyl, R2 is phenyl which contains one, two or three substitutes independently selected from a group which includes halogen or -O-(lower)alkyl.

EFFECT: preparation of a pharmaceutical composition which contains an effective amount of a formula I compound as an active ingredient.

6 cl, 1 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention describes a phenothiazine derivative, specifically 2-(1-(2-(2-chloro-10H-phenothiazin-10-yl)-2-oxoethyl)-5-methyl-1H-1,2,4-triazol-3-yl)phenol of formula I: .

EFFECT: obtaining compounds with hypotensive and antiarrhythmic activity during intraperitoneal administration.

3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to methods for producing 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzotiazin-3-carboxamides-1,1-dioxide (meloxicam) of formula of a high degree purity. In one of the ways potassium salt monohydrate of meloxicam of formula is dissolved, which is produced by interaction of meloxicam formula (II) with potassium hydroxide or potassium carbonate dissolved in water or in a mixture of water and organic solvent and, if desired, crystallisation of this monohydrate potassium salt of meloxicam of formula (I) in water or in a mixture of water and organic solvent, insoluble impurities are removed and the resulting solution is processed with organic or inorganic acid and crystallise meloxicam. The invention also refers to potassium salt monohydrate of meloxicam of formula (I) and method of its production, as well as to anti-inflammatory pharmaceutical composition based on it.

EFFECT: improvement of composition efficacy.

18 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication, reducing desire for alcohol, which represents substituted 1H-benzimidazoles of general formula 1 or their pharmaceutically acceptable salts and/or hydrates, pharmaceutical composition, and medication on their basis. Compounds can be applied in treatment of alcohol abuse with application of ethanol-containing products, if necessary, together with antidepressants. In compounds of general formula 1 , where: W represents sulfur atom or group S=O; R1 represents one or more substituents, selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkyloxy, optionally substituted 5-6-member azaheterocyclyl with 1-2 atoms of nitrogen and/or oxygen in cycle; R2 represents atom of hydrogen or optionally substituted C1-C4alkyl; R3 and R4 independently on each other represent optionally similar substituents, selected from hydrogen, optionally substituted C1-C4alkyl, C3-C6cycloalkyl; R5 represents alkyl substituent, selected from hydrogen or optionally substituted C1-C7alkyl, C1-C7alkenyl, C1-C4alkynyl, optionally substituted phenyl, optionally substituted 5-6-member heterocyclyl with 1-3 heteroatoms, selected from nitrogen, oxygen and sulfur, possibly condensed with benzene ring; C1-C4-alkoxycarbonyl, optionally substituted amino carbonyl, or group CR3R4R together stands for group , where Alk stands for C1-C4alkyl.

EFFECT: medication allows to reduce symptoms of alcohol abuse considerably as compared with earlier known compounds and does not produce unfavorable effect on liver function.

12 cl, 3 tbl, 2 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives having FAK inhibitory activity of formula (I), where R0 is hydrogen; R1 is a 5- or 6-member heterocycle containing 1 or 2 nitrogen atoms substituted with (C1-C7)alkyl, hydroxyl group, dialkylamino group or a 6-member heterocycle containing one nitrogen atom; R2 is hydrogen; R3 is carbamoyl substituted once or twice with (C1-C7)alkyl; a 5-member heterocycle containing 4 nitrogen atoms; SO2N(R12)R13, where R12 is hydrogen or (lower)alkyl, and R13 is hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy(C1-C7)alkyl, di(C1-C7)alkylamino(C1-C7)alkyl, hydroxy(C1-C7)alkyl, or R12 and R13 together a nitrogen atom with which they are bonded form a 6-member heterocycle containing two nitrogen atoms, where the said heterocycle is not substituted or substituted with (C1-C7)alkyl; R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; (C1-C7)alkoxy; carbamoyl which is not substituted or substituted with (lower)alkyl; a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with di(C1-C7)alkylamino, (C1-C7)alkyl, hydroxy, 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms, unsubstituted or substituted with (C1-C7)alkyl; 6-member heterocycle-oxy containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms which is not substituted or substituted with (C1-C7)alkyl; R8 is hydrogen; halide; (C1-C7)alkoxy, carbamoyl unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5-member heterocycle containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with one or two substitutes independently selected from hydroxy, (C1-C7)alkyl, aminocarbonyl and (C1-C7)alkylamino; 6-member heterocycle-oxy, containing 1 nitrogen ring atom, unsubstituted or substituted 1-5 times with (C1-C7)alkyl or di(C1-C7)alkylamino; or R7 and R8 together with atoms with which they are bonded form a 6-member heterocycle containing two nitrogen or oxygen atoms, unsubstituted or substituted once or twice with (C1-C7)alkyl or oxo group; R9 is hydrogen; R10 is (C1-C7)alkoxy, as well as to their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and synthesis method.

EFFECT: novel compounds have useful biological activity.

4 cl, 167 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I) and pharmaceutically acceptable salts, where R1-R7 mean the same as provided in the invention description and claim. Compounds of the formula (I) are specific inhibitors of 11b-HSD1. They can be applied in treatment and/or prevention of diseases caused by dysfunctions related to 11b-HSD1 enzyme, particularly in treatment and/or prevention of metabolic diseases, obesity, dyslipidemia, hypertension and/or diabetes, especially diabetes type "П". Additionally subject matter includes pharmaceutical composition for treatment and/or prevention of the said diseases.

EFFECT: improved efficiency of derivatives.

21 cl, 1 tbl, 146 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication, reducing desire for alcohol, which represents substituted 1H-benzimidazoles of general formula 1 or their pharmaceutically acceptable salts and/or hydrates, pharmaceutical composition, and medication on their basis. Compounds can be applied in treatment of alcohol abuse with application of ethanol-containing products, if necessary, together with antidepressants. In compounds of general formula 1 , where: W represents sulfur atom or group S=O; R1 represents one or more substituents, selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkyloxy, optionally substituted 5-6-member azaheterocyclyl with 1-2 atoms of nitrogen and/or oxygen in cycle; R2 represents atom of hydrogen or optionally substituted C1-C4alkyl; R3 and R4 independently on each other represent optionally similar substituents, selected from hydrogen, optionally substituted C1-C4alkyl, C3-C6cycloalkyl; R5 represents alkyl substituent, selected from hydrogen or optionally substituted C1-C7alkyl, C1-C7alkenyl, C1-C4alkynyl, optionally substituted phenyl, optionally substituted 5-6-member heterocyclyl with 1-3 heteroatoms, selected from nitrogen, oxygen and sulfur, possibly condensed with benzene ring; C1-C4-alkoxycarbonyl, optionally substituted amino carbonyl, or group CR3R4R together stands for group , where Alk stands for C1-C4alkyl.

EFFECT: medication allows to reduce symptoms of alcohol abuse considerably as compared with earlier known compounds and does not produce unfavorable effect on liver function.

12 cl, 3 tbl, 2 ex, 1 dwg

Up!