(3-cycloalkyl-2, 3, 4, 5 - tetrahydro-1h-benzo [d] azepin-7-yloxy) derivatives, use thereof for inhibiting h3 receptors, pharmaceutical composition and preparation method

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

 

The present invention relates to new derivatives benzazepine having pharmacological activity, to processes for their preparation, to compositions containing these compounds and to their use for the treatment of neurological and psychiatric disorders.

In JP 2001226269 and WO 00/23437 (Takeda Chem. Ind. Ltd) describes a number of derivatives benzazepine, turning up as a means to treat obesity. In DE 2207430, US 4210749, FR 2171879 (Pennwalt Corp.) and GB 1268243 (Wallace and Tiernan Inc.) describes the number of derivatives benzazepine as antagonist drugs (such as morphine or codeine), as well as antihistamines and anticholinergics. In WO 02/14513 (Takeda Chem. Ind. Ltd) describes a number of derivatives benzazepine activity GPR12 as a means for treatment of the syndrome of impaired attention, narcolepsy or anxiety. In WO 02/02530 (Takeda Chem. Ind. Ltd) describes a number of derivatives benzazepine as GPR14 antagonist as a treatment for hypertension, atherosclerosis and myocardial infarction. In WO 01/03680 (Isis Innovation Ltd) describes a number of derivatives benzazepine, which is claimed as an effective means used to obtain cells for transplantation, as well as to suppress diseases such as diabetes. In WO 00/21951 (SmithKline Beecham pic) expands the number of derivatives tetrahydrobenzene as modulators of dopamine receptors D3 as antipsychotic drugs. In WO 01/87834 (Taeda Chem. Ind Ltd) describes a number of derivatives benzazepine as MCH antagonists, which are claimed as a treatment for obesity. In WO 02/15934 (Takeda Chem. Ind. Ltd) describes a number of derivatives benzazepine as antagonists of receptors urotensin II, which claimed as a treatment for neurodegenerative diseases.

The histamine receptor H3 is expressed predominantly in the Central nervous system of mammals (CNS), peripheral tissues it is expressed at a low level except for some sympathetic nerves (Leurs et al. (1998), Trends Pharmacol. Sci. 19, 177-183). Activation of H3 receptors under the action of selective agonists or histamine leads to inhibition of release of neurotransmitters from a number of different populations of nerve cells, including histaminergic and cholinergic neurons (Schlicker et al. (1994), Fundam. Clin. Pharmacol. 8, 128-137). Furthermore, studies in vitro and in vivo showed that H3 antagonists can facilitate the release of neurotransmitters from the areas of the brain as the cerebral cortex and hippocampus, which are related to cognitive abilities (Onodera et al. (1998), In: The Histamine H3 receptor, ed Leurs and Timmerman, pp. 255-267, Elsevier Science B. V.). In addition, several publications have demonstrated that H3 antagonists (for example, typename, closedprofit, ciproxifan and GT-2331) improve cognitive ability in the rabbit the models, including the following tests: task five-choice recognition object, the elevated cross maze, finding new challenges and passive avoidance (Giovanni et al. (1999), Behav. Brain Res. 104, 147-155). These data suggest that the new H3 antagonists and/or inverse agonists, such as certain compounds of the present invention can be used to treat the deterioration of cognitive abilities in such neurological diseases as Alzheimer's disease and related neurodegenerative disorders.

In the first aspect of the present invention provides a compound of formula (I) or its pharmaceutically acceptable salt:

where R1denotes-C3-7cycloalkyl, optionally substituted C1-3by alkyl;

R2denotes hydrogen, -C1-6alkyl, -X-C3-8cycloalkyl, -X-aryl, -X-heterocyclyl, -X-heteroaryl, -X-C3-8cycloalkyl-Y-C3-8cycloalkyl, -X-C3-8cycloalkyl-Y-aryl, -X-C3-8cycloalkyl-Y-heteroaryl, -X-C3-8cycloalkyl-Y-heterocyclyl, -X-aryl-Y-C3--8cycloalkyl, -X-aryl-Y-aryl, -X-aryl-Y-heteroaryl, -X-aryl-Y-heterocyclyl, -X-heteroaryl-Y-C3-8cycloalkyl, -X-heteroaryl-Y-aryl, -X-heteroaryl-Y-heteroaryl, -X-heteroaryl-Y-heterocyclyl, -X-heterocyclyl-Y-C3-8cycloalkyl, -X-heterocyclyl-Y-aryl, -X-heterocycle the-Y-heteroaryl, -X-heterocyclyl-Y-heterocyclyl;

X denotes a bond or C1-6alkyl;

Y represents a bond, C1-6alkyl, CO, COC2-6alkenyl, or SO2;

R3denotes halogen, C1-6alkyl, C1-6alkoxy, cyano, amino or trifluoromethyl;

n denotes 0, 1 or 2;

where these alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups, R2may be optionally substituted by one or more substituents (for example 1, 2 or 3), which may be the same or different and which may be selected from the group consisting of halogen, hydroxy, cyano, nitro, =O, trifloromethyl, triptoreline, formatosi, deformedarse, C1-6of alkyl, pentaborate, C1-6alkoxy, arils1-6alkoxy, C1-6alkylthio, C1-6alkoxyl1-6of alkyl, C3-7cycloalkyl1-6alkoxy, C1-6alkanoyl, C1-6alkoxycarbonyl, C1-6alkylsulfonyl, C1-6alkylsulfonyl, C1-6alkylsulfonate, C1-6alkylsulfonyl1-6of alkyl, sulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl1-6of alkyl, aryloxy, C1-6alkylsulfonamides, C1-6alkylamino, C1-6alkylamino, -R4, -CO2R4, -COR4C1-6alkylsulfonamides1-6of alkyl, C1-6alkylamides1-6of alkyl, arylsulfonamides, Arik is rocksmith, arylsulfonamides1-6of alkyl, arylcarboxamide1-6of alkyl, Arola, areils1-6of alkyl, aryls1-6alkanoyl or the group-NR5R6, -C1-6alkyl-NR5R6, -C3-8cycloalkyl-NR5R6, -CONR5R6, -NR5COR6, -NR5SO2R6, -OCONR5R6, -NR5CO2R6, -NR4CO2NR5R6or-SO2NR5R6(where R4, R5and R6independently represent hydrogen, C1-6alkyl, C3-8cycloalkyl, C1-6alkyl-C3-8cycloalkyl, aryl, heterocyclyl or heteroaryl, or-NR5R6can refer to a heterocyclic group containing a nitrogen atom, where the groups of R4, R5and R6may be optionally substituted by one or more substituents (for example 1, 2 or 3), which may be the same or different and which may be selected from the group consisting of halogen, hydroxy, C1-6of alkyl, C1-6alkoxy, cyano, amino, =O or trifloromethyl);

or their solvate.

In one particular embodiment of the present invention features a compound of formula (I)as defined above, where

R2denotes-C1-6alkyl, -X-C3-8cycloalkyl, -X-aryl, -X-heterocyclyl, -X-heteroaryl, -X-C3-8cycloalkyl-Y-C3-8cycloalkyl, -X-C3-8cycloalkyl-Y-aryl-X-C 3-8cycloalkyl-Y-heteroaryl, -X - C3-8cycloalkyl-Y-heterocyclyl, -X-aryl-Y-C3-8cycloalkyl, -X-aryl-Y-aryl, -X-aryl-Y-heteroaryl, -X-aryl-Y-heterocyclyl, -X-heteroaryl-Y-C3-8cycloalkyl, -X-heteroaryl-Y-aryl, -X-heteroaryl-Y-heteroaryl, -X-heteroaryl-Y-heterocyclyl, -X-heterocyclyl-Y-C3-8cycloalkyl, -X-heterocyclyl-Y-aryl, -X-heterocyclyl-Y-heteroaryl, -X-heterocyclyl-Y-heterocyclyl;

Y represents a bond, C1-6alkyl, CO, O or SO2; and

R4, R5and R6independently represent hydrogen, C1-6alkyl, -C3-8cycloalkyl, aryl, heterocyclyl or heteroaryl, or-NR5R6can refer to a heterocyclic group containing a nitrogen atom.

Especially may be mentioned the compounds of formula (I), where R2indicates an X-heterocyclyl, -X-heterocyclyl-Y-C3-8cycloalkyl, -X-heterocyclyl-Y-aryl, -X-heterocyclyl-Y-heteroaryl or-X-heterocyclyl-Y-heterocyclyl, and these heterocyclic groups connected to X via a carbon atom.

The alkyl groups present separately or as part of another group may be linear or branched, alkoxy group and alkanoyl interpret the same way. More preferably, the alkyl fragments are C1-4alkyl, for example methyl or ethyl. The term "halogen" is used in the description, unless otherwise specified, to define a group, select the authorized from fluorine, chlorine, bromine or iodine.

The term "aryl" includes monocyclic carbocyclic aromatic ring (e.g. phenyl) and bicyclic carbocyclic aromatic rings (e.g. naphthyl) or carbocyclic benzododecinium ring (for example, C3-8cycloalkyl condensed with the phenyl cycle, such as dihydroindeno or tetrahydronaphthalene).

It is implied that the term "heterocyclyl" denotes a 4-7-membered monocyclic saturated or partially unsaturated aliphatic cycle, or 4-7-membered saturated or partially unsaturated aliphatic cycle, condensed with the benzene ring cycle containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur. Suitable examples of such monocyclic rings include pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, tetrahydrofuranyl, tetrahydropyranyl, diazepan, azepane, imidazolidinyl, isothiazolinones, oxazolidinyl, pyrrolidine and tetrahydroazepine. Suitable examples benzododecinium heterocyclic rings include indolinyl, isoindolyl, benzodioxolyl, dihydroindol, dihydrobenzofuranyl, dihydrobenzofuranyl and dihydroisoquinolines.

It is implied that the term "heterocyclyl containing a nitrogen atom" refers to any heterocyclic group, it is to defined above, which contains a nitrogen atom.

It is implied that the term "heteroaryl" means a 5-7 membered monocyclic aromatic or condensed 8-11 membered bicyclic aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur. Suitable examples of such monocyclic aromatic cycles include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolin, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl and tetrahydropyranyl.

Suitable examples of such condensed aromatic cycles include benzododecinium aromatic cycles, such as chinoline, ethenolysis, hintline, honokalani, cinnoline, naphthyridine, indolyl, indazoles, properidine, pyrrolopyridine, benzofuranyl, benzothiazol, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, benzoxadiazole, benzothiadiazole etc.

Preferably R1denotes unsubstituted-C3-7cycloalkyl (for example, cyclobutyl, cyclopentyl or cyclohexyl). Also preferably, if R1denotes-C3-7cycloalkyl (for example, cyclopentyl), substituted C1-3alkyl (e.g. methyl) group.

Most preferably, R1indicates nezame the military cyclobutyl or cyclopentyl, especially the unsubstituted cyclobutyl.

Preferably R2means

hydrogen;

-C1-6alkyl (e.g. methyl or propyl), optionally substituted by a group-CO2R4or-CONR5R6;

-X-C3-8cycloalkyl-Y-heterocyclyl (for example, -X-cyclohexyl-Y-morpholinyl);

-X-aryl (for example, -X-phenyl), optionally substituted by one or two halogen atoms (e.g. fluorine, iodine or chlorine), groups C1-6alkyl (e.g. methyl), C1-6alkoxy (e.g. methoxy), -CO2R4,-CONR5R6, -NR5COR6, -SO2NR5R6or cyano;

-X-aryl-Y-heterocyclyl (for example, -X-phenyl-Y-piperazinil, -X-phenyl-Y-pyrrolidinyl or-X-phenyl-Y-morpholinyl), optionally substituted with one or two =O, halogen atoms (e.g. fluorine) or groups of R4;

-X-heteroaryl (for example, -X-pyridinyl, -X-pyrazinyl, -X-pyrimidinyl, -X-pyridazinyl, -X-chinoline, -X-pyrrolopyridine, -X-properidine, -X-naphthyridines, -X-thiazolyl or-X-thienyl), optionally substituted by one or two atoms of halogen (e.g. bromine or iodine), groups C1-6alkyl (e.g. methyl), C1-6alkoxy (e.g. methoxy or ethoxy), cyano, nitro, -OR4, -COR4, -CO2R4, -NR5R6, -NR5COR6, -CONR5R6or =O;

-X-heteroaryl-Y-aryl (for example, -X-pyrazinyl-Y-Fe is silt), optionally substituted C1-6alkylsulfonyl (for example, -SO2Me), or-NR5COR6;

-X-heteroaryl-Y-heteroaryl (for example, -X-pyridinyl-Y-pyrazolyl, -X-pyridinyl-Y-oxadiazolyl, -X-pyridinyl-Y-oxazolyl or-X-pyridinyl-Y-pyrazinyl), optionally substituted C1-6alkyl (e.g. methyl);

-X-heteroaryl-Y-heterocyclyl (for example, -X-pyridinyl-Y-morpholinyl, -X-pyridinyl-Y-pyrrolidinyl, -X-pyridinyl-Y-piperidinyl, -X-pyridinyl-Y-thiomorpholine, -X-pyridinyl-Y-tetrahydropyranyl, -X-pyridinyl-Y-imidazolidinyl, -X-pyridinyl-Y-tetrahydroazepine, -X-pyridinyl-Y-azetidinol, -X-pyridinyl-Y-oxazolidinyl, -X-pyridinyl-Y-isothiazolinones, -X-pyrazinyl-Y-morpholinyl, -X-pyrazinyl-Y-piperidinyl, -X-pyrazinyl-Y-pyrrolidinyl, -X-pyrazinyl-Y-thiomorpholine, -X-pyrazinyl-Y-oxazolidinyl, -X-pyrazinyl-Y-azetidinol, -X-pyrazinyl-Y-tetrahydropyranyl or-X-pyridazinyl-Y-morpholinyl), optionally substituted by one or two groups =O, C1-6alkyl (e.g. methyl), -OR4or halogen (e.g. chlorine or bromine);

-X-heterocyclyl (for example, -X-piperidinyl or-X-pyrrolidinyl), optionally substituted C1-6alkylsulfonyl (for example, -SO2Me), C1-6alkoxycarbonyl (for example, -CO-CH2CH2OMe), -CO2R4, -COR4or-COR5R6;

-X-heterocyclyl-Y-aryl (for example, -X-piperid the Nile-Y-phenyl or-X-pyrrolidinyl-Y-phenyl), optionally substituted by the group of halogen (e.g. fluorine), cyano, C1-6alkylsulfonyl (for example, -SO2Me), R4or-CONR5R6;

-X-heterocyclyl-Y-heterocyclyl (for example, -X-piperidinyl-Y-tetrahydropyranyl, -X-pyrrolidinyl-Y-tetrahydropyranyl, -X-piperidinyl-Y-dihydrobenzofuranyl, -X-pyrrolidinyl-Y-morpholinyl, -X-piperidinyl-Y-morpholinyl, -X-piperidinyl-Y-thiomorpholine, -X-piperidinyl-Y-dihydroindol, -X-piperidinyl-Y-piperazinil, -X-piperidinyl-Y-pyrrolidinyl, -X-piperidinyl-Y-piperidinyl or-X-piperidinyl-Y-dihydrobenzofuranyl), optionally substituted by one or two groups =O or R4;

-X-heterocyclyl-Y-C3-8cycloalkyl (for example, -X-piperidinyl-Y-cyclohexyl, -X-piperidinyl-Y-cyclopropyl, -X-piperidinyl-Y-cyclobutyl or-X-piperidinyl-Y-cyclopentyl) or

-X-heterocyclyl-Y-heteroaryl (for example, -X-piperidinyl-Y-ethenolysis, -X-piperidinyl-Y-chinoline, -X-piperidinyl-Y-isoxazolyl, -X-piperidinyl-Y-benzothiazolyl, -X-piperidinyl-Y-thiophenyl, -X-piperidinyl-Y-furanyl, -X-piperidinyl-Y-pyrazinyl, -X-piperidinyl-Y-pyridyl), optionally substituted by one or two groups of C1-6alkyl (e.g. methyl), =O, cyano, or-CONR5R6.

Preferably X denotes a bond or-CH2-, most preferably X denotes the connection.

Preferably Y represents a bond, CO, SO2the Li-CO-CH=CH-, most preferably Y represents a bond or CO, especially the connection.

Preferably R4denotes hydrogen, C1-6alkyl (e.g. methyl, ethyl or tert-butyl), -C1-6alkyl-C3-8cycloalkyl (for example, -CH2-cyclopropyl), aryl (e.g. phenyl, optionally substituted by halogen atom (e.g. fluorine)), heterocyclyl (for example, morpholinyl) or heteroaryl (e.g., pyridinyl or pyrazinyl), optionally substituted by a group halogen (e.g. fluorine) or C1-6alkoxy (e.g. methoxy).

Preferably R5and R6independently represent hydrogen, C1-6alkyl (e.g. methyl, ethyl, isopropyl or propyl), -C3-8cycloalkyl (for example, cyclobutyl or cyclopentyl), -C1-6alkyl-C3-8cycloalkyl (for example, -CH2-cyclopropyl), heterocyclyl (for example, pyrrolidinyl, piperidinyl, morpholinyl or tetrahydropyranyl) or aryl (e.g. phenyl), optionally substituted by a group halogen (e.g. fluorine), cyano or C1-6alkoxy (e.g. methoxy), or-NR5R6denotes a heterocyclic group containing nitrogen (for example, azetidine, morpholine, pyrrolidine or piperidine), optionally substituted by one or two groups =O.

More preferably R5and R6independently represent hydrogen, C1-6alkyl (e.g. methyl or ethyl), -C cycloalkyl (for example, cyclobutyl or cyclopentyl) or-C1-6alkyl-C3-8cycloalkyl (for example, -CH2-cyclopropyl).

Particularly preferably, R2means

hydrogen;

-C1-6alkyl (e.g. methyl or propyl), optionally substituted by a group-CO2R4(for example, -CO2Et or - CO2H) or-CONR5R6(for example, -CON(Me)2, -CON(H)(Me) -,- CON(H)(cyclopentyl), -CON(H)(phenyl), -CO-pyrrolidinyl, -CO-piperidinyl or-CO-morpholinyl);

-X-C3-8cycloalkyl-Y-heterocyclyl (for example, -cyclohexyl-CO-morpholinyl);

-X-aryl (e.g. phenyl or-CH2-phenyl), optionally substituted by one or two halogen groups (for example, fluorine, iodine or chlorine), C1-6alkyl (e.g. methyl), C1-6alkoxy (e.g. methoxy), -CO2R4(for example, -CO2H or-CO2Me), -CONR5R6(for example, -CON(H)(Me) -,- CON(Et)2(optionally substituted by a methoxy group), -CON(Me)(Pr) substituted by cyano), or-CON(H)(-CH2-cyclopropyl), -NR5COR6(for example, -NHCOMe), -SO2NR5R6(for example, -SO2N(Et)2or cyano;

-X-aryl-Y-heterocyclyl (for example, -phenylpyrrolidine, -phenyl-CO-pyrrolidinyl, -phenyl-CO-morpholinyl, -phenyl-SO2-morpholinyl, -CH2-phenyl-CO-pyrrolidinyl, -CH2-phenyl-CO-morpholinyl or-CH2-phenyl-CO-piperazinil), optionally substituted on the Noi or two groups =O, halogen (e.g. fluorine) or R4(for example, phenyl (optionally substituted by a fluorine atom) or pyridyl);

-X-heteroaryl (for example, pyridinyl, -CH2-pyridinyl, -pyrazinyl-pyrimidinyl-pyridazinyl-chinoline, -CH2-chinoline-pyrrolopyridine-propylidene-naphthyridines, -thiazolyl or thienyl), optionally substituted by one or two halogen groups (for example, bromine or iodine), C1-6alkyl (e.g. methyl), C1-6alkoxy (e.g. methoxy or ethoxy), cyano, nitro, -OR4(for example, hydroxy), -CO2R4(for example, CO2H or CO2Me), -COR4(for example, COMe), -NR5R6(for example, -NH2or-N(H)(Me)), -NR5COR6(for example, NHCOMe, NHCO-i-Pr, -NHCO-pyrrolidinyl, -NHCO-piperidinyl, -NHCO-morpholinyl or-NHCO-tetrahydropyranyl), -CONR5R6(for example, -CONH2, -CON(Me)2, -CON(Me)(Et), -CON(H)(Me) -,- CON(H)(i-Pr), -CON(Et)2(optionally substituted by a methoxy group), -CON(H)(Et) (optionally substituted by a methoxy group), -CON(H)(-CH2cyclopropyl), -CON(H)(cyclobutyl), -CON(H)(cyclopentyl), -CON(H)(cyclopropyl) or-CON(H)(tetrahydropyranyl)) or =O;

-X-heteroaryl-Y-aryl (for example-personifer), optionally substituted C1-6alkylsulfonyl (for example, -SO2Me), or-NR5COR6(for example, -NHCOMe);

-X-heteroaryl-Y-heteroaryl (for example, -pyridinylmethyl, peridiniaceae is alil, -pyridineacetic or pyridinylmethyl), optionally substituted C1-6alkyl (e.g. methyl);

-X-heteroaryl-Y-heterocyclyl (e.g., pyridinyl-CO-morpholinyl-pyridinyl-CO-pyrrolidinyl-pyridinyl-CO-piperidinyl-pyridinyl-CO-thiomorpholine-pyridiniomethyl-pyridinyl-CO-tetrahydroazepine-pyridinyl-CO-azetidine-pyridineacetonitrile-pyridineacetonitrile-personnelbargain-pyrazinyl-CO-morpholinyl-pyrazinyl-CO-piperidinyl-pyrazinyl-CO-pyrrolidinyl-personaltoolbarfolder-personlocation-pyrazinyl-CO-azetidinol, -personalberater-personalpersonal-pyridiniomethyl-pyridinylmethyl-pyridinyl-SO2-morpholinyl or pyridinyl-CO-morpholinyl), optionally substituted by one or two groups =O, C1-6alkyl (e.g. methyl), -OR4(for example, hydroxy) or halogen (e.g. chlorine or bromine);

-X-heterocyclyl (for example, -piperidinyl, -CH2-piperidinyl-pyrrolidinyl or-CH2-pyrrolidinyl), optionally substituted C1-6alkylsulfonyl (for example, -SO2Me), C1-6alkoxycarbonyl (for example, -CO-CH2CH2OMe), -CO2R4(for example, -CO2-t-Bu)-COR4(for example, -COCH2-cyclopropyl) or-COR5R6(for example, -CON(i-Pr)2, -CON(Et)2, -CON(i-Pr)(Et) (substituted IU auxillou group), -CON(H)(i-Pr), or-CON(H)(4-forfinal);

-X-heterocyclyl-Y-aryl (for example-piperidinyl-CO-phenyl, -pyrrolidinyl-CO-phenyl, -piperidinyl-CO-CH=CH-phenyl, -piperidinyl-SO2-phenyl, pyrrolidinyl-SO2-phenyl, -CH2-piperidinyl-CO-phenyl, -CH2-pyrrolidinyl-CO-phenyl, -CH2-piperidinyl-SO2-phenyl or-CH2-pyrrolidinyl-SO2-phenyl), optionally substituted by a group halogen (e.g. fluorine), cyano, C1-6alkylsulfonyl (for example, -SO2Me), R4(for example, phenyl or morpholinyl) or-CONR5R6(for example, -CO-pyrrolidinyl substituted by a group =O);

-X-heterocyclyl-Y-heterocyclyl (for example, -piperidinyl-CO-tetrahydropyranyl, -CH2-piperidinyl-CO-tetrahydropyranyl, pyrrolidinyl-CO-tetrahydropyranyl, CH2-pyrrolidinyl-CO-tetrahydropyranyl, piperidinyl-CO-dihydrobenzofuranyl, pyrrolidinyl-CO-morpholinyl,-CH2-pyrrolidinyl-CO-morpholinyl-piperidinyl-CO-morpholinyl, CH2-piperidinyl-CO-morpholinyl, piperidinyl-CO-thiomorpholine, piperidinyl-CO-dihydroindol, piperidinyl-CO-piperazinil, piperidinyl-CO-pyrrolidinyl, piperidinyl-CO-piperidinyl or piperidinyl-CO-dihydrobenzofuranyl), optionally substituted by one or two groups =O, or R4(for example, pyrazinyl);

-X-heterocyclyl-Y-C3-8cycloalkyl (for example, -piperidinyl-CO-cyclohexyl, -piperidinyl-CO-cyclopropyl, -PI is original-CO-cyclobutyl or piperidinyl-CO-cyclopentyl);

or-X-heterocyclyl-Y-heteroaryl (for example, -piperidinyl-CO-ethenolysis-piperidinyl-CO-chinoline-piperidinyl-CO-isoxazolyl-piperidinyl-SO2-isoxazolyl-piperidinyl-CO-benzothiazolyl-piperidinyl-CO-thiophenyl-piperidinyl-CO-furanyl-piperidinyl-CO-pyrazinyl-piperidinylmethyl-piperidinyl-CO-pyridinyl or-piperidinylidene), optionally substituted by one or two groups of C1-6alkyl (e.g. methyl), =O, cyano, or-CONR5R6(for example, -CON(H)(Me) -,- CON(H)(-CH2cyclopropyl), -CO-azetidinol or-CO-morpholinyl).

More preferably, R2means

-X-aryl (e.g. phenyl), optionally substituted by a group CONR5R6;

-X-aryl-Y-heterocyclyl (for example, -X-phenyl-Y-morpholinyl or-X-phenyl-Y-pyrrolidinyl);

-X-heteroaryl (for example, pyrazinyl or pyridinyl), optionally substituted by a group CONR5R6;

-X-heteroaryl-Y-heterocyclyl (for example, -X-pyridinyl-Y-morpholinyl, -X-pyridinyl-Y-pyrrolidinyl, -X-pyridinyl-Y-piperidinyl, -X-pyridinyl-Y-thiomorpholine, -X-pyrazinyl-Y-morpholinyl, -X-pyrazinyl-Y-piperidinyl or-X-pyrazinyl-Y-pyrrolidinyl), optionally substituted by one or two groups =O; or

-X-heterocyclyl-Y-heterocyclyl (for example, -X-piperidinyl-Y-tetrahydropyranyl, -X-piperidinyl-Y-morpholinyl or-X-pyrrolidinyl-Y-morpholinyl).

Further prepact the positive R 2means

-X-aryl (e.g. phenyl or-CH2-phenyl), optionally substituted by one or two halogen groups (for example, fluorine, iodine or chlorine), C1-6alkyl (e.g. methyl), C1-6alkoxy (e.g. methoxy), -CO2R4(for example, -CO2H or-CO2Me), -CONR5R6(for example, -CON(H)(Me) -,- CON(Et)2(optional substituted metaxylene group), -CON(Me)(Et), substituted by cyano), or-CON(H)(-CH2-cyclopropyl), -NR5COR6(for example, -NHCOMe), -SO2NR5R6(for example, -SO2N(Et)2or cyano;

-X-aryl-Y-heterocyclyl (for example, -phenylpyrrolidine, -phenyl-CO-pyrrolidinyl, -phenyl-CO-morpholinyl, -phenyl-SO2-morpholinyl, -CH2-phenyl-CO-pyrrolidinyl, -CH2-phenyl-CO-morpholinyl or-CH2-phenyl-CO-piperazinil), optionally substituted by one or two groups, =O, halogen (e.g. fluorine) or R4(for example, phenyl (optionally substituted by a fluorine atom) or pyridyl);

-X-heteroaryl (for example, pyridinyl, -CH2-pyridinyl, -pyrazinyl-pyrimidinyl-pyridazinyl-chinoline, -CH2-chinoline-pyrrolopyridine-propylidene-naphthyridines, -thiazolyl or thienyl), optionally substituted by one or two halogen groups (for example, bromine or iodine), C1-6alkyl (e.g. methyl), C1-6alkoxy (e.g. methoxy or ethoxy), cyano, nitro, -OR 4(for example, hydroxy), -CO2R4(for example, CO2H or CO2Me), -COR4(for example, COMe), -NR5R6(for example, -NH2or-N(H)(Me)), -NR5COR6(for example, NHCOMe, NHCO-i-Pr, -NHCO-pyrrolidinyl, -NHCO-piperidinyl, -NHCO-morpholinyl or-NHCO-tetrahydropyranyl), -CONR5R6(for example, -CONH2, -CON(Me)2, -CON(Me)(Et), -CON(H)(Me) -,- CON(H)(i-Pr), -CON(Et)2(optional substituted metaxylene group), -CON(H)(Et) (optionally substituted metaxylene group), -CON(H)(-CH2-cyclopropyl), -CON(H)(cyclobutyl), -CON(H)(cyclopentyl), -CON(H)(cyclopropyl) or-CON(H)(tetrahydropyranyl)) or =O;

-X-heteroaryl-Y-heterocyclyl (e.g., pyridinyl-CO-morpholinyl-pyridinyl-CO-pyrrolidinyl-pyridinyl-CO-piperidinyl-pyridinyl-CO-thiomorpholine-pyridiniomethyl-pyridinyl-CO-tetrahydroazepine-pyridinyl-CO-azetidine-pyridineacetonitrile-pyridineacetonitrile-personnelbargain-pyrazinyl-CO-morpholinyl-pyrazinyl-CO-piperidinyl-pyrazinyl-CO-pyrrolidinyl-personaltoolbarfolder-personlocation-pyrazinyl-CO-azetidinol, -personalberater-personalpersonal-pyridiniomethyl-pyridinylmethyl-pyridinyl-SO2-morpholinyl or pyridinyl-CO-morpholinyl), optionally substituted by one or two groups =O, C1-6alkyl (e.g. methyl), -OR4(for example, Ki is Roxie) or halogen (for example, chlorine or bromine); or

-X-heterocyclyl-Y-heterocyclyl (for example, -piperidinyl-CO-tetrahydropyranyl, -CH2-piperidinyl-CO-tetrahydropyranyl-pyrrolidinyl-CO-tetrahydropyranyl, -CH2-pyrrolidinyl-CO-tetrahydropyranyl-piperidinyl-CO-dihydrobenzofuranyl-pyrrolidinyl-CO-morpholinyl, -CH2-pyrrolidinyl-CO-morpholinyl-piperidinyl-CO-morpholinyl, -CH2-piperidinyl-CO-morpholinyl-piperidinyl-CO-thiomorpholine-piperidinyl-CO-dihydroindol-piperidinyl-CO-piperazinil-piperidinyl-CO-pyrrolidinyl-piperidinyl-CO-piperidinyl or piperidinyl-CO-dihydrobenzofuranyl), optionally substituted by one or two groups =O or R4(for example, pyrazinyl).

Most preferably, R2means

-X-aryl (e.g. phenyl), optionally substituted by one or two groups, halogen (e.g. fluorine), C1-6alkoxy (e.g. methoxy), -CONR5R6(for example, -CON(H)(Me)), -NR5COR6(for example, -NHCOMe), or cyano;

-X-aryl-Y-heterocyclyl (for example, -phenylpyrrolidine), optionally substituted by one or two groups =O or halogen (e.g. fluorine);

unsubstituted-X-heterocyclyl-Y-heterocyclyl (for example, -piperidinyl-CO-morpholinyl);

-X-heteroaryl (for example, -2-pyridinyl or 2-pyrazinyl), optionally substituted by a group-CONR5R6(for example, CON(H)(Me)); or

-X-heteroaryl the-Y-heterocyclyl (for example, -2-pyridinyl-N-pyrrolidinyl)where the specified heterocyclic group optionally substituted by a group =O (for example, -2-pyridinyl-N-pyrrolidine).

Particularly preferably, R2indicates an X-heteroaryl (for example, -2-pyridinyl)substituted by a group-CONR5R6(for example, 4-methylaminomethyluridine-2-yl).

Preferably, n represents 0 or 1, more preferably 0.

If n denotes 1, R3preferably denotes a halogen atom (for example, iodine or cyano.

Preferred compounds of this invention include examples E1-E288, as shown below, or their pharmaceutically acceptable salts.

More preferred compounds of this invention include

methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-carboxylic acid; and

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidone

or their pharmaceutically acceptable salts.

Especially preferred compound of this invention is 6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-nicotine amide or its pharmaceutically acceptable salt.

The compounds of formula (I) can form acid additive salts with conventional pharmaceutically acceptable acids, such as maleic, hydrochloric, bromatologia is, phosphoric, acetic, fumaric, salicylic, sulfuric, citric, lactic, almond, tartaric and methansulfonate. Thus, salt, solvate and hydrate compounds of formula (I) are aspect of the present invention.

Some compounds of formula (I) can exist in stereoisomeric forms. It should be understood that the invention encompasses all geometric and optical isomers of these compounds, and also mixtures thereof, including racemates. The tautomers are also aspect of the present invention.

The present invention also provides a method for obtaining compounds of formula (I) or its pharmaceutically acceptable salt, this method includes

(a) the interaction of the compounds of formula (II)

where R1, R3and n are such as defined above, with a compound of formula R2'-L1where R2'such as defined above for R2or represents a group capable of developing in R2and L1denotes a suitable leaving group such as halogen atom (e.g. bromine or iodine) or an optionally activated hydroxyl group;

(b) interaction of the compounds of formula (III)

where R2, R3and n are such as defined above, with a compound of formula R1'-L2where R1'such as defined above for R 1or represents a group capable of developing in R1and L2denotes a suitable leaving group such as halogen atom (e.g. bromine, iodine or toilet); or

(c) the interaction of the compounds of formula (III), as defined above, with a ketone of the formula R1'=O where R1'such as defined above for R1or represents a group capable of developing in R1; or

(d) removing the protective group of the protected compounds of formula (I) and

(e) vzaimoprevrascheny in other compounds of formula (I).

If the leaving group L1attached to the carbon atom in state sp3-hybridization, for example, if R2'-L1denotes alkylhalogenide, the process (a)typically comprises the use of a suitable base such as potassium carbonate, in a suitable solvent, such as 2-butanone, optionally in the presence of a catalyst such as potassium iodide, at a suitable temperature, such as the boiling temperature under reflux.

If the leaving group L1attached to the carbon atom in state sp2-hybridization, for example, if R2'-L1denotes aryl halides, the process (a)typically comprises the use of salts of copper (I), such as copper iodide (I), in the presence of such bases as sodium hydride, in a suitable the m solvent, such as pyridine, at a suitable temperature, such as the boiling temperature under reflux.

If the leaving group L1attached to an activated carbon atom in state sp2-hybridization, for example, if R2'-L1denotes heteroarylboronic, such as 2-chloropyridine or 2-chloropyrazine, the process (a)typically comprises the use of a suitable base such as sodium hydride, in a suitable solvent, such as dimethylformamide or dimethylsulfoxide, at a suitable temperature. Alternative you can use tert-piperonyl potassium tert-butanol at a suitable temperature.

If the leaving group L1attached to an activated carbon atom in state sp2-hybridization, for example, if R2'-L1denotes aryl halides, such as 3,4-diferential, the process (a)typically comprises the use of a suitable base, potassium carbonate, in a suitable solvent, such as dimethylsulfoxide, at a suitable temperature.

If L1denotes a hydroxyl group attached to the carbon atom in state sp3-hybridization, for example, if R2'-L1indicates an alcohol, the process (a)typically comprises the use of a phosphine, such as triphenylphosphine, in a suitable solvent, such to the to tetrahydrofuran, with the subsequent addition of azodicarboxylate, such as diethylazodicarboxylate, at a suitable temperature such as room temperature.

Process (b)typically comprises the use of a suitable base such as potassium carbonate, in a suitable solvent, such as 2-butanone, optionally in the presence of a catalyst such as potassium iodide, at a suitable temperature, such as the boiling temperature under reflux.

Process (c), typically involves the use of reducing conditions (such as treatment with borohydride, for example, triacetoxyborohydride sodium), optionally in the presence of acid, such as acetic acid, in a suitable solvent, such as dichloromethane, at a suitable temperature such as room temperature.

With regard to process (d), examples of protective groups and methods for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991). Suitable protective groups for amino include sulfonyl (for example, tosyl), acyl (e.g. acetyl, 2',2',2'-trichlorocyanuric, benzyloxycarbonyl or tert-butoxycarbonyl) and arylalkyl (e.g., benzyl), which can be removed by hydrolysis (e.g. using an acid such as hydrochloric in dioxane, or triperoxonane in dichloromethane), or recovery (for example, by hydrogenation of b is silnoi group, or, in the case of 2',2',2'-trichlorocarbanilide group, the recovery of zinc in acetic acid), respectively. Other suitable protective groups for amino groups include TRIFLUOROACETYL (-COCF3), which can be removed by hydrolysis, catalyzed by a base, or use as a solid phase resin with immobilized benzyl group, such as a Merrifield resin associated with 2,6-dimethoxybenzyl group (linker Ellman), which can be removed with acidic hydrolysis, for example using triperoxonane acid.

Process (e) can be performed using traditional methods of interconversion, such as epimerization, oxidation, reduction, alkylation, nucleophilic or electrophilic substitution in the aromatic nucleus, the hydrolysis of ester, amide bond formation or of combination reaction, mediated by transition metal. Examples of reactions combination catalyzed by transition metals and used as methods of interconversion include the following: catalyzed by palladium of combination reaction of electrophiles, such as aryl halides with ORGANOMETALLIC reagents, such as boric acid (reaction cross combination Suzuki (Suzuki)); catalyzed by palladium reaction, amination and amidation of organic electrophiles, such as aryl is halogenide, conducted with the use of nucleophiles such as amines and amides; catalyzed by copper the amidation reaction of organic electrophiles, such as aryl halides), conducted with the use of nucleophiles such as amides; and catalyzed by copper of combination reaction of phenols with boric acid.

Compounds of formulas (II) and (III) can be obtained according to the following scheme:

where R1, R2, R2', R3n and L1such as defined above, and P1represents a suitable protective group such as Boc.

Stage (i)typically comprises reaction of removing the protective group, for example, if P1represents Boc, the reaction of removing the protective group includes the interaction of the compounds of formula (IV) with an acid, for example hydrochloric acid in dioxane or triperoxonane acid in dichloromethane.

Stage (ii) can be performed in reducing conditions as described for process (c).

Stage (iii) can be performed according to the method described for process (a).

Stage (iv)typically comprises reaction of removing the protective group to obtain the compounds of formula (III) and may be conducted in accordance with method stage (i).

The compounds of formula (VI), where R2means-X-aryl, -X-heteroaryl, -X-aryl-Y-C3-8cycloalkyl, -X-aryl-Y-aryl, -X-aryl-Y-heteroaryl is, -X-aryl-Y-heterocyclyl, -X-heteroaryl-Y-C3-8cycloalkyl, -X-heteroaryl-Y-aryl, -X-heteroaryl-Y-heteroaryl or-X-heteroaryl-Y-heterocyclyl, and X denotes a bond, can be obtained according to the following scheme:

where R2, R2', R3and n are such as defined above, and P1represents a suitable protective group such as Boc.

Stage (i) can be carried out in the cross-combinations, catalyzed by palladium, for example, used as the catalytic system of the complex bis(diphenylphosphino)periodically(II) and

1,1'-bis(diphenylphosphino)ferrocene, in combination with a suitable base, such as potassium acetate, in a suitable solvent, such as dioxane, at a suitable temperature, for example at the boiling point under reflux.

Stage (ii) can be carried out in oxidizing conditions, for example, using periodate sodium in the presence of ammonium acetate, in a suitable solvent system such as acetone and water, at a suitable temperature, for example at room temperature.

Stage (iii) can be carried out in the presence of a copper salt such as copper acetate, in combination with a suitable base, such as triethylamine, using molecular sieves, in a suitable solvent, for example dichloromethane, at a suitable those is the temperature, for example, at room temperature.

The compounds of formula (IV) can be obtained according to the method described in description 3 WO 02/40471.

The compounds of formula (VII) can be obtained according to the method described in Bioorg. Med. Chem. Lett.; 10; 22; 2000; 2553-2556.

The compounds of formula (I) and their pharmaceutically acceptable salts have affinity to the histamine receptor H3, are antagonists and/or inverse agonists of the specified receptor and presumably can be used for the treatment of neurological diseases, including Alzheimer's disease, dementia, senile memory loss, a slight deterioration of cognitive abilities, impaired cognitive ability, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke and sleep disorders, including narcolepsy; psychiatric diseases, including schizophrenia (especially impaired cognitive abilities in schizophrenia, attention deficit disorder with hyperactivity, depression and addiction; and other diseases including obesity, asthma, allergic rhinitis, nasal congestion, chronic obstructive pulmonary disease and gastrointestinal disease.

Therefore, this invention also relates to the compound of formula (I) or its pharmaceutically acceptable salts for use as tera is eticeskaja tools for the treatment or prevention of the above diseases, especially violations cognitive abilities such diseases as Alzheimer's disease and related neurodegenerative disorders.

Further, this invention relates to a method of treatment or prophylaxis of the aforementioned diseases in mammals, including humans, which comprises administration to the patient a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

In another aspect this invention relates to the use of compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicine for the treatment of the above diseases.

For use in therapeutic purposes, the compounds of formula (I) are generally administered in a standard pharmaceutical composition. Such compositions can be obtained using standard methods.

Therefore, the present invention also relates to pharmaceutical compositions for the treatment of the above diseases, which contains a compound of the formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

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

The compounds of formula (I) can the be used in combination with other therapeutic means, for example, antagonists of histamine H1 or medicines, stated as a means to facilitate or symptomatic treatment of Alzheimer's disease. Suitable examples of the said other therapeutic agents can serve as the means, which are known to modify cholinergic transmission such as antagonists of 5-HT6, muscarinic M1 agonists, muscarinic M2 antagonists or inhibitors acetylcholinesterase. If compounds are used in combination with other therapeutic means, they can be administered sequentially or simultaneously by any suitable method.

Thus, in this aspect this invention relates to combinations of compounds of formula (I) or its pharmaceutically acceptable derivative with another therapeutic agent or other therapeutic means.

The above combination is convenient to use as pharmaceutical compositions, and, therefore, pharmaceutical compositions containing the above combination together with a pharmaceutically acceptable carrier or excipient, are another aspect of the present invention. The individual components of such combinations can be entered sequentially or simultaneously in different pharmaceutical compositions or in a single pharmaceutical composition.

If the compound of formula (I) and its pharmaceutically acceptable derivative is used in combination with another therapeutic agent, active against the same disease, the dose of each compound may differ from the dose used in the case of using a single connection. Specialists in this field can easily determine the right dose.

The pharmaceutical composition of the present invention that can be obtained by mixing, usually at ambient temperature and atmospheric pressure, as a rule, modify for oral, parenteral or rectal administration, and, as such, it may be in the form of tablets, capsules, liquid preparations for oral administration, powders, granules, pastilles, powders for dilution, solutions or suspensions for injection or infusion, or candles. Generally preferred are compositions for oral administration.

Tablets and capsules for oral administration may be in the form of standard dosage forms and may contain conventional excipients such as binders, fillers, lubricants, used to obtain tablets, dezintegriruetsja funds and acceptable moisturizer. Tablets may be coated according to methods well known in normal pharmaceutical practice.

Liquid preparations for oral administration may be in the form of, for example, aqueous or oil suspensions, Rast the Directors, emulsions, syrups or elixirs, or they can be in the form of a dry product for dilution with water or another suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspendresume tools, emulsifying means, non-aqueous environment (which can include edible oils), preservatives, and, if desired, conventional flavoring or coloring agents.

Liquid standard dosage forms for parenteral administration receive, using the compound of this invention or its pharmaceutically acceptable salt and sterile environment. Depending on the environment and the concentration of the compound can be either suspended or dissolved in the medium. Upon receipt of the solutions the compound can be dissolved to obtain a solution for injection, sterile with filter, then fill them suitable vial or ampoule and sealed them. Preferably dissolve in the environment tools such as local anesthetics, preservatives and tabularasa funds. To increase stability after filling vials and removal of water under vacuum, the composition can be frozen. Suspensions for parenteral administration receive essentially the same way, except that the compound does not dissolve, suspendered in the environment, and sterilization cannot be performed by filtration. The connection can be sterilized by exposure to ethylene oxide before suspendirovanie in a sterile environment. To ensure uniform distribution of the compound, preferably the composition is injected surfactant or moisturizer.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight of active substance, depending on the method of introduction. The dose of a compound used to treat the above diseases, as a rule, varies depending on the severity of the disease, weight of patient, and other factors. However, in General, a suitable single dose can range from 0.05 to 1000 mg, more preferably from 1.0 to 200 mg, with such occasional doses can be entered more than once a day, for example two or three times a day. This treatment may last for several weeks or months.

The following descriptions and examples illustrate the formation of compounds of the present invention.

Description 1

Tert-butyl ester of 7-benzyloxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (D1)

Tert-butyl ester of 7-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (PCT Int. Appl. (2002), WO 02/40471) (790 mg, 3 mmol), potassium carbonate (1.24 g, 9 mmol) and catalytic potassium iodide are suspended in 2-buta is none (20 ml). Add benzylbromide (536 μl, 4.5 mmol) and the mixture heated under reflux for 24 hours. Solids filtered and then washed with acetone. The filtrate was concentrated in vacuo and the crude oil purified column chromatography, elwira a mixture of ethyl acetate and hexane (1:4), getting mentioned in the title compound (D1) (1.06 g, 100%),1H NMR (CDCl3) 7,44 (5H, m), 7,03 (1H, d, J=8.1 Hz), 6,77 (1H, s), 6,74 (1H, DD, J=8.1 and 2.4 Hz), 3,49 (4H, m), 2,84 (4H, m)to 1.48 (9H, s).

Description 2

7-Benzyloxy-1,2,4,5-tetrahydrobenzo[d]azepin (D2)

Tert-butyl ester of 7-benzyloxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (D1) (1.06 g, 3 mmol) dissolved in dichloromethane (15 ml) and treated triperoxonane acid (15 ml). The solution is stirred at room temperature for 2 hours, concentrated in vacuo and then evaporated twice with dichloromethane. The residue is dissolved in methanol, applied to ion exchange SCX column (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture 0,880 ammonia/methanol. The combined basic fractions evaporated in vacuo and the residue purified column chromatography, elwira mixture 0,880 ammonia:ethanol:dichloromethane (1:9:90), getting mentioned in the title compound (D2) (702 mg, 93%), MS (ES+) m/e 254 [M+H]+.

Description 3

Tert-butyl ester 7-(4-methoxycarbonylbenzyl)-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (D3)

Tert-butyl ester of 7-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (WO 02/40471) (5,27 g, 20.0 mmol), potassium carbonate (8,30 g, 60,0 mmol) and catalytic potassium iodide are suspended in butanone (100 ml). Added dropwise methyl 4-(methyl bromide)benzoate (5.5 g, 24,0 mmol)dissolved in butanone (50 ml), after which the reaction mixture is stirred under reflux for 24 hours. The reaction mixture is cooled, the solids filtered and then washed with acetone. The filtrate was concentrated in vacuo and the crude mixture was purified column chromatography, elwira a mixture of ethyl acetate:hexane (1:4), and get mentioned in the title compound (D3). MS (ES+) m/e 344(M+H)-CO2tBu]+.

Description 4

Methyl ester of 4-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid (D4)

Tert-butyl ester 7-(4-methoxycarbonylbenzyl)-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (D3) (6,35 g) dissolved in dichloromethane (30 ml) and treated triperoxonane acid (30 ml). The solution is stirred at room temperature for 2 hours, concentrated in vacuo and then evaporated twice with dichloromethane. The residue is dissolved in dichloromethane and washed with 10% aqueous sodium hydroxide solution, water and saturated salt solution. The organic layer is tub over magnesium sulfate, filtered and concentrated in vacuo, obtaining mentioned in the title compound (D4).

Description 5

1-(6-Chloropyridin-3-yl)-1-morpholine-4-ylmethanol (D5)

Morpholine (0.2 ml, 2.2 mmol) is added to a stirred solution of 6-chloronicotinamide (250 mg, 1.4 mmol) in dichloromethane (10 ml). After 2 hours the reaction mixture is allowed to cool, the crude mixture is applied to the ion exchange SCX cartridge (Varian bond-elute, 10 g) and washed with methanol. The methanol fraction was concentrated in vacuo, obtaining mentioned in the title compound (D5).

Description 6-31

Connection descriptions 6-31 (D6-D31) are obtained according to the method of description 5 (D5) from the corresponding aryl halides and amines listed in the table, and use them without additional features:

DescriptionAryl halidesAmin
1-(6-Chloropyridin-3-yl)-1-pyrrolidin-1-ylmethanone (D6)6-ChloronicotinoylPyrrolidin
6-Chloronicotinamide (D7)6-ChloronicotinoylAmmonia
6-Chloro-N,N-diethylnicotinamide (D8) 6-ChloronicotinoylDimethylamine
6-Chloro-N-ethyl-N-nicotine amide (D9)6-ChloronicotinoylN-Ethylmethylamine
6-Chloro-N-nicotine amide (D10)6-ChloronicotinoylMethylamine
6-Chloro-N-cyclopentyl-nicotinamide (D11)6-ChloronicotinoylCyclopentylamine
1-(6-Chloropyridin-3-yl)-1-piperidine-1-yl-methanon (D12)6-ChloronicotinoylPiperidine
1-(2-Chloropyridin-4-yl)-1-piperidine-1-yl-methanon (D13)2-HorizontalanglePiperidine
1-(2-Chloropyridin-4-yl)-1-pyrrolidin-1-yl-methanon (D14)2-HorizontalanglePyrrolidin
1-(2-Chloropyridin-4-yl)-1-morpholine-4-yl-methanon (D15)2-HorizontalangleMorpholine
1-(6-Chloropyridin-2-yl)-1-piperidine-1-yl-methanon (D16) 6-Chloropyridin-2-carbonylchloridePiperidine
1-(6-Chloropyridin-2-yl)-1-(1,1-diocletianopolis-4-yl)-methanon (D17)6-Chloropyridin-2-carbonylchlorideThiomorpholine-1,1-dioxide
1-(6-Chloropyridin-2-yl)-1-pyrrolidin-1-yl-methanon (D18)6-Chloropyridin-2-carbonylchloridePyrrolidin
1-(6-Chloropyridin-2-yl)-1-morpholine-4-yl-methanon (D19)6-Chloropyridin-2-carbonylchlorideMorpholine
1-(2-Chloropyridin-3-yl)-1-morpholine-4-yl-methanon (D20)2-ChloronicotinoylMorpholine
1-(2-Chloropyridin-3-yl)-1-piperidine-1-ylmethanone (D21)2-ChloronicotinoylPiperidine
1-(4-Itfeel)-1-morpholine-4-ylmethanol (D22)4-IdentiliedMorpholine
4-Iodine-N-cyclopropylmethyl-benzamid (D23)4-IdentiliedCyclopropyl-
methylamine
1-4-Itfeel)-1-pyrrolidin-1-ylmethanone (D24) 4-IdentiliedPyrrolidin
4-Iodine-N-cyclobutylmethyl (D25)4-IdentiliedCyclobutylamine
4-Iodine-N,N-diethylbenzamide (D26)4-IdentiliedDiethylamin
4-Iodine-N-(2-cyanoethyl)-N-methylbenzamide (D27)4-Identilied3-Methylamino-propionitrile
1-(3-Itfeel)-1-morpholine-4-ylmethanol (D28)3-IdentiliedMorpholine
3-Iodine-N-cyclopropylmethyl-benzamid (D29)3-IdentiliedCyclopropylmethyl-Amin
4-(4-Iodobenzoyl-sulfonyl)morpholine (D30)4-IodobenzonitrileMorpholine
4-Iodine-N,N-diethylbenzene-sulfonamide (D31)4-IodobenzonitrileDiethylamin

Description 32

5-Bromo-2-(1-piperidinyl)pyrimidine (D32)

PI is Eridan (5,1 ml, 51.6 mmol) is added to a stirred solution of 5-bromo-2-chloropyrimidine (5 g, from 25.8 mmol) and triethylamine (9.0 ml, and 64.5 mmol) in toluene (30 ml). After stirring at room temperature for 24 hours, the reaction mixture was diluted with ethyl acetate and washed with 2N hydrochloric acid solution, saturated saline solution and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo, the obtained residue is purified column chromatography, elwira with ethyl acetate, and get mentioned in the title compound (D32).

Description 33-35

Connection descriptions 33-35 (D33-D35) get in the way of description 32 (D32), replacing piperidine by the appropriate amine indicated in the table below:

DescriptionAmin
5-Bromo-2-(1-pyrrolidinyl)pyrimidine (D33)Pyrrolidin
4-(5-Bromo-2-pyrimidinyl)thiomorpholine-1,1-dioxide (D34)Thiomorpholine-1,1-dioxide
5-Bromo-N-methyl-2-pyrimidinamine (D35)Methylamine

Description 36-37

Connection descriptions 36-37 (D36-D37) are obtained according to the method of description 5 (D5), replacing the morpholine by the appropriate amine indicated in the table below:

DescriptionAmin6-Chloro-N-(cyclopropylmethyl)-3-pyridinecarboxamide (D36)Cyclopropanemethylamine5-(1-Azetidinone)-2-chloropyridin (D37)Azetidin

Description 38

5-Bromo-2-pyrimidinecarbonitrile (D38)

Sodium cyanide (2.30 g, with 46.6 mmol) dissolved in dimethylformamide (60 ml) and treated with 5-bromo-2-chloropyrimidine (6.0 g; and 31.1 mmol). The resulting mixture was stirred at room temperature for 18 hours, diluted with water and extracted with dichloromethane. The dichloromethane extracts are combined, washed with water, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product is purified column chromatography, elwira a mixture of ethyl acetate:hexane (1:4), and get mentioned in the title compound (D38).

Description 39

1,1-Dimethylethyl 7-({5-[(methylamino)carbonyl]-2-pyridinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D39)

Tert-butyl ester of 7-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (PCT Int. Appl. (2002), WO 02/40471) (8.7 g, 33 mmol) was dissolved in tert-butanol and treated with tert-piperonyl potassium (4 g, 36 mmol). After stirring for 30 the minutes at room temperature add 6-chloro-N-nicotine amide (D10) (5,1 g, 30 mmol) and the reaction mixture is stirred at the boiling temperature under reflux for 20 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. To the crude residue add ice water, which leads to the deposition of sludge, which is collected by filtration. The solid residue is dissolved in ethyl acetate, washed with saturated salt solution and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo, the obtained residue is purified column chromatography, elwira a mixture of ethyl acetate:hexane (1:1), and receive specified in the header connection (D39).1H NMR (CDCl3) charged 8.52 (1H, d, J=2,4), to 8.12 (1H, DD, J=8,8), 7,16 (1H, m), 6,95-for 6.81 (3H, m), of 6.02 (1H, usher.), of 3.57 (4H, usher.), to 3.02 (3H, d, J=2,4), 2,89 (4H, usher.), for 1.49 (9H, s).

Description 40

N-Methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40)

1,1-Dimethylethyl 7-({5-[(methylamino)carbonyl]-2-pyridinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D39) (3.98 g, 10 mmol) dissolved in dioxane (40 ml) and treated with 4M solution of hydrogen chloride in dioxane (35 ml). The reaction mixture was allowed to mix at room temperature for 6 hours and then concentrated in vacuo, obtaining specified in the header connection (D40); MS (ES+) m/e 298 [M+H]+.

Description 41

1,1-Dimethylethyl 7-hydroxy-8-the od-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D41)

A solution of tert-butyl methyl ether 7-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-carboxylic acid (PCT Int. Appl. (2002), WO 02/40471) (5.2 g, 20 mmol) in 33% methylamine in ethanol (30 ml) stirred at 0°C. a Solution of sodium iodide (4.6 g, 30 mmol) and iodine (5.2 g, 20 mmol) in water (30 ml) is added below the surface of the reaction mixture. After stirring at 0°C for 1 hour the mixture was concentrated in vacuo. The residue is diluted with ethyl acetate and water. The organic layer was separated, washed with water and saturated salt solution. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo, obtaining specified in the header connection (D41); (7.0 g, 90%),1H NMR (d6-DMSO) 10,0 (1H, users), 7,41 (1H, s), of 6.65 (1H, s), 3,40 (4H, m), 2,70 (4H, m)of 1.40 (9H, s).

Description 42

1,1-Dimethylethyl 7-iodine-8-({5-[(methylamino)carbonyl]-2-pyridinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D42)

Sodium hydride (60% dispersion in mineral oil, 240 mg, 6 mmol) is added to a stirred solution of 1,1-dimethylethyl 7-hydroxy-8-iodine-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D41) (1,94 g, 5 mmol) in dimethyl sulfoxide (10 ml). After 10 minutes add 6-chloro-N-nicotine amide (D10) (850 mg, 5 mmol) and the reaction mixture is heated to 100°C for 20 hours. After cooling to room temperature the reaction is mesh diluted with water and dichloromethane. The organic layer was separated, washed with water and saturated saline solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified column chromatography (1:1 ethyl acetate:hexane), getting listed in title product (D42).

Description 43

N-Methyl-6-(8-iodine-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D43)

Connection description 43 (D43) is obtained from 1,1-dimethylethyl 7-iodine-8-({5-[(methylamino)carbonyl]-2-pyridinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D42) according to the method of description 2 (D2); MS (ES+) m/e 424[M+H]+.

Description 44

1,1-Dimethylethyl 7-iodine-8-[(phenylmethyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D44)

Sodium hydride (60% dispersion in mineral oil, 576 mg, 14.4 mmol) is added to a stirred solution of 1,1-dimethylethyl 7-hydroxy-8-iodine-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D41) (4,67 g, 12 mmol) in dimethylformamide (30 ml). After 15 minutes add benzylbromide (2,04 g, 1.4 ml, 12 mmol) and the mixture is stirred for 2 hours. The mixture is diluted with water and ethyl acetate, the organic layer separated, washed with water and saturated saline solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified column chromatography, elwira a mixture of ethyl acetate:hexane (1:10), and which are square-specified in the header of the product (D44).

Description 45

7-Iodine-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (D45)

Connection description D45 (D45) is obtained from 1,1-dimethylethyl 7-iodine-8-[(phenylmethyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D44) according to the method of description 2 (D2); MS (ES+) m/e 380 [M+H]+.

Description 46

1-(3-Chloro-2-pyrazinyl)-2-pyrrolidinone (D46)

Stage 1: 3-Chloropyridine 1-oxide

A mixture of chloropyrazine (9.6 g, and 83.3 mmol) and hydrogen peroxide solution (30%, 16 ml) in glacial acetic acid (26 ml) is heated at 70°C for 18 hours. The mixture is allowed to cool to room temperature, poured into water (250 ml) and extracted with dichloromethane (3×100 ml). The dichloromethane extracts are combined, washed with saturated sodium bicarbonate solution (2×70 ml), water (3×100 ml) and saturated salt solution (100 ml). The organic fraction is dried over sodium sulfate and evaporated in vacuum, obtaining white solid, which is recrystallized from absolute ethanol, getting mentioned in the title compound (0.45 g).1H NMR (CDCl3) 8,27 compared to 8.26 (1H, d), of 8.15 (1H, s), 8,03-8,02 (1H, DD).

Stage 2: 2,3-Dichloropyrazine

3-Chloropyridine 1-oxide (D46, stage 1) (2.2 g, to 16.9 mmol) is slowly added to phosphorus oxychloride (10 ml) at 60°C. After complete addition, the mixture is heated under reflux during 60 minutes. The mixture is left to cool and poured into solid sodium acetate with ice (5 g). Mix until the ice melts, and then extracted with dichloromethane. The dichloromethane extracts are combined, washed with saturated sodium bicarbonate solution, water and saturated salt solution. The organic fraction is dried over sodium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography, elwira a mixture of ethyl acetate:hexane (1:20), and get mentioned in the title compound (0,86 g).1H NMR (CDCl3) 8,32 (2H, s).

Stage 3: 1-(3-Chloro-2-pyrazinyl)-2-pyrrolidinone

Sodium hydride (60% in mineral oil, 67 mg of 1.62 mmol) are added to a solution of pyrrolidinone (0,12 ml, 1.54 mmol) in dry dimethylformamide (5 ml) in an argon atmosphere at 0°C. the Mixture is left to warm to room temperature for 1.5 hours. Add a solution of 2,3-dichloropyrazine (D46, stage 2) (250 mg, was 1.69 mmol) in dry dimethylformamide (2 ml) and the mixture is stirred at room temperature in an argon atmosphere for 2 hours. The mixture was poured into water (30 ml) and extracted with ethyl acetate (×3). An ethyl acetate extracts are combined, washed with saturated salt solution, dried over magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography, elwira a mixture of ethyl acetate:pentane (1:1), obtaining specified in the header soy is inania (0.10 g); MS (ES+) m/e 198 [M+H]+.

Description 47

2.5-Dichloropyrazine (D47)

Stage 1: 5-Chloro-2-pyrazinamid

Aminopyrazine (10 g, 10.5 mmol) dissolved in dry dimethylformamide (60 ml) and treated with N-chlorosuccinimide (15,36 g, 11.5 mmol) in an argon atmosphere at 0°C. the Mixture is stirred for 30 minutes and then allowed to warm to room temperature. The mixture was poured into water and extracted with diethyl ether. Diethyl layers are combined and evaporated in vacuum. The resulting residue is purified column chromatography, elwira a mixture of ethyl acetate:pentane (1:9), and get mentioned in the title compound (1.40 g);1H NMR (CDCl3) 8,02 (1H, s), 7,76 (1H, s), br4.61 (2H, s).

Stage 2: 2.5-Dichloropyrazine

5-Chloro-2-pyrazinamid (D47, stage 1) (2,41 g of 18.6 mmol) was dissolved in concentrated hydrochloric acid (24 ml), cooled in a bath with a mixture of ice-acetone and treated dropwise with a solution of sodium nitrite (2,63 g of 38.1 mmol) in water (18 ml) for 1 hour. The mixture is cooled in a bath with a mixture of ice-water and allowed to mix for 1 hour. The mixture is left to warm to room temperature for 1 hour, neutralized by adding a solution (2M) of sodium hydroxide and extracted with dichloromethane. Dichloromethane layers are combined, dried over magnesium sulfate and evaporated in vacuum. The resulting residue is purified to lodochnoy chromatography, elwira a mixture of ethyl acetate:pentane (1:9), and get mentioned in the title compound (0.33 g);1H NMR (CDCl3) to 8.40 (2H, s).

Description 48

2.5-Dibromopyrazine (D48)

Stage 1: 5-Bromo-2-pyrazinamid

Aminopyrazine (5.0 g, for 52.6 mmol) dissolved in chloroform (150 ml) and add pyridine (5,11 ml, 63.2 mmol). Within 1 hour is added dropwise a solution of bromine (3,24 ml, 63.2 mmol) in chloroform (50 ml). The mixture is left to mix for 30 minutes, diluted with water (50 ml) and stirred for another 10 minutes. The organic layer was separated, washed with water (50 ml), dried over magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography, elwira a mixture of ethyl acetate:pentane (1:4), and get mentioned in the title compound (0.32 g); MS (ES+) m/e 175 [M+H]+.

Stage 2: 2.5-Dibromopyrazine

5-Bromo-2-pyrazinamid (D48, stage 1) (317 mg, 1.82 mmol) are added to a chilled (in the bath with a mixture of ice-acetone) solution of Hydrobromic acid (aqueous 48% solution) (2 ml). After stirring for 5 minutes add bromine (of 0.28 ml, 5.46 mmol) and then a solution of sodium nitrite (314 mg, 4,55 mmol) in water dropwise within 15 minutes. The mixture is stirred for 30 minutes and allowed to warm to room temperature for 30 minutes. Add a solution of sodium hydroxide (2.6 g) in water (7 ml) and the mixture paramashiva the t 1 hour. The mixture is extracted with dichloromethane. Dichloromethane layers are combined and evaporated in vacuum, obtaining mentioned in the title compound (60 mg).1H NMR(CDCl3) 8,49 (2H, s).

Description 49

N-Methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide (D49)

Step 1: 1,1-Dimethylethyl 7-({5-[(metiloksi)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

Sodium hydride (60% dispersion in mineral oil) (6.4 g, 0.16 mol) is added in portions to a solution of tert-butyl methyl ether 7-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (PCT Int. Appl. (2002), WO 02/40471) (40 g, 0.15 mol) in dry dimethylformamide (200 ml), cooled to 5°C within 15 minutes. After 15 minutes, the mixture is left to warm to room temperature while stirring for 60 minutes. The mixture is cooled in a bath with a mixture of ice-water and added in several portions of methyl 5-chloro-2-pyrazinecarboxamide (31,2 g, 0.18 mol). The mixture is left to warm to room temperature and stirred for 18 hours. The mixture was poured into water (500 ml) with ice (500 ml) and stirred until the ice melts. The obtained solid is collected by filtration, washed with water and dissolved in ethyl acetate (1500 ml). An ethyl acetate layer was washed with saturated saline (200 ml), dried over sodium sulfate and evaporated in vacuum. The crude product is CT purified column chromatography, elwira a mixture of ethyl acetate:hexane (1:2), and get mentioned in the title compound (35,07 g).

Stage 2: 5-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxamide acid

2M sodium hydroxide solution (110 ml) was added to a solution of 1,1-dimethylethyl 7-({5-[(metiloksi)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D49, stage 1) (29,38 g, 73,6 mmol) in acetone (480 ml) and the resulting mixture was stirred at room temperature for 25 minutes. The mixture was acidified with 2M hydrochloric acid and then poured into water (2 l). The obtained white solid is collected by filtration, washed with water and dissolved in ethyl acetate (1 liter). This solution is dried over sodium sulfate and evaporated in vacuum, obtaining specified in the header connection (27,3 g); MS (ES+) m/e 384 [M-H]+.

Stage 3: 1,1-Dimethylethyl 7-({5-[(methylamino)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

1,1'-Carbonyldiimidazole (16.6 g, 102 mmol) are added to a solution of 5-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxamide acid (D49, stage 2) (37,5 g, 97 mmol) in dry dichloromethane (400 ml) and the resulting mixture was stirred at room temperature for 18 hours. Added methylamine (2M solution in tetrahydrofuran (THF) (100 ml) and the mixture is stirred for 2 hours. The solvent is removed vacuume and the residue purified column chromatography, elwira a mixture of ethyl acetate:chloroform (1:1), and receive specified in the header connection (25,8 g); MS (ES+) m/e 399 [M+H]+.

Stage 4: N-Methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide

A solution of 1,1-dimethylethyl 7-({5-[(methylamino)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (D49, stage 3) (44,26 g, 0.11 mol) in dichloromethane (800 ml) is added dropwise to a stirred solution of 4M hydrogen chloride in dioxane (270 ml, 1.1 mol). The resulting mixture was stirred at room temperature for 60 minutes. Add a further quantity of 4M hydrogen chloride in dioxane (30 ml, 0.12 mol) and the mixture is stirred for 60 minutes. The obtained white solid is collected by filtration and washed with dichloromethane. The solid is dissolved in water (2 l) and alkalinized by addition of a saturated solution of sodium carbonate. The aqueous layer was extracted with dichloromethane and the extracts filtered through celite. Celite washed with methanol and the combined dichloromethane and methanol washings evaporated in vacuum, obtaining mentioned in the title compound (25.1 g); MS (ES+) m/e 299 [M+H]+.

Description 50-52

Connection descriptions 50-52 (D50-D52) are obtained according to the method of description 5 (D5) from the corresponding aryl halides and amines listed in the table, and use them without additional features:

DescriptionAryl halidesAmin
N-Ethyl-4-iodine-N-[2-(metiloksi)ethyl] benzamide (D50)4-Identilied2-Methoxyethylamine
4-iodine-N-methylbenzamide (D51)4-IdentiliedMethylamine
1-[(3-itfeel)carbonyl] pyrrolidin (D52)3-IdentiliedPyrrolidin

Description 53

(2E)-1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-3-(dimethylamino)-2-propen-1-he (D53)

A mixture of 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}of ethanone (E) (186 mg, 0.55 mmol), dimethylformamidine (0.25 ml) and xylene (4 ml) was heated under reflux for 8 hours. The residue is diluted with toluene and concentrated in vacuo, obtaining the compound (D53); MS (ES+) m/e 392 [M+H]+.

Description 54

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxamide (D54)

A mixture of thionyl chloride (2 ml) and 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridylcarbinol KIS is the notes (E196b) (200 mg, 0.59 mmol) is stirred at the boiling point under reflux for 1 hour. The reaction mixture was concentrated in vacuo, obtaining the crude residue. The residue is dissolved in tetrahydrofuran (5 ml), cooled to 0°C and added dropwise hydrazine hydrate (1.5 ml) in tetrahydrofuran (1.5 ml). The reaction mixture was left to warm to room temperature and stirred for 1 hour. Then the reaction mixture was diluted with ethyl acetate, washed with saturated sodium carbonate solution, water and saturated salt solution and dried (magnesium sulfate). The organic layer was filtered and concentrated in vacuo, obtaining specified in the header connection (D54); MS (ES+) m/e 361 [M+H]+.

Description 55

CIS-4-(4-Morpholinylcarbonyl)cyclohexanol (D55)

A solution of CIS-4-hydroxycyclohexanecarboxylate acid (720 mg, 0.5 mmol), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1,33 g, 6 mmol) and 1-hydroxy-7-isobenzofuranone (816 mg, 6 mmol) in dichloromethane (6 ml) is treated with morpholine (1.3 ml, 15 mmol). After stirring at room temperature for 18 hours, the crude reaction mixture was applied to ion exchange SCX cartridge (Varian bond-elute, 5 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). The combined basic fractions concentrated in vacuo, the obtained residue is cidaut column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (1:9:90)to give specified in the header connection (D55); MS (ES+) m/e 214 [M+H]+.

Description 56

2-Chloro-6-[4-(methylsulphonyl)phenyl]pyrazin (D56)

2,6-Dichloropyrazine (2,98 g, 20.0 mmol),

[4-(methylsulphonyl)phenyl]boronic acid (2 g, 10.0 mmol), tetrakis(triphenylphosphine)palladium (1,15 g, 1.0 mmol), potassium phosphate (10.2 g, 48 mmol) and dimethylformamide (90 ml) is heated at 80°C for 16 hours. The solvent is removed in vacuum, the product is dissolved in chloroform and filtered through celite. The filtrate is washed with water, and then share. The residue is purified column chromatography, elwira a mixture of ethyl acetate:hexane (4:6), and receive specified in the header connection. MS (ES+) m/e 270 [M+H]+.

Example 1

7-Benzyloxy-3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E1)

7-Benzyloxy-1,2,4,5-tetrahydrobenzo[d]azepin (D2) (25,3 g, 100 mmol) dissolved in 2.5% acetic acid solution in dichloromethane (400 ml) at 0°C and treated dropwise with cyclobutanone (11.2 ml, 150 mmol). The mixture is stirred for 30 minutes and then added in several portions of triacetoxyborohydride sodium (31.8 g, 150 mmol). The reaction mixture was stirred at room temperature for 4 hours, alkalinized with a saturated solution of sodium carbonate and extracted with dichloromethane. Obyedinennaya washed with water, saturated salt solution, dried over anhydrous sodium sulfate and concentrated in vacuo.

The crude residue fray with hexane and filtered, obtaining specified in the header of the product (E1).

MS (ES+) m/e 308 [M+H]+.

Example 2

7-Benzyloxy-3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E2)

Specified in the title compound (E2) obtained from 7-benzyloxy-1,2,4,5-tetrahydrobenzo[d]azepine (D2) and Cyclopentanone according to the method of example 1; MS (ES+) m/e 322 [M+H]+.

Example 3

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3)

7-Benzyloxy-3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E1) (which 9.22 g, 30 mmol) dissolved in ethanol (150 ml) and tetrahydrofuran (50 ml). Add palladium (1.5 g, 10% on coal paste) and the reaction mixture was stirred at room temperature in hydrogen atmosphere (1 ATM) for 5 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The crude residue fray with diethyl ether and filtered, getting listed in title product (E3); MS (ES+) m/e 218 [M+H]+.

Example 4

3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E4)

Specified in the title compound (E4) is obtained from 7-benzyloxy-3-cyclopentyl-2,3,4,5-tetrahedron-benzo[d]azepine (E2) according to the method of example 3 (E3); 1H NMR (DMSO-d6) the remaining 9.08 (1H, users), 6,70 (1H, d), 6,53-6,47 (2H, m), 3,31-2,50 (9H, m) of 1.88 was 1.43 (8H, m).

Example 5a

Tert-butyl ester 4-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-

carboxylic acid (E5a)

3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E4) (1.1 g, 4.8 mmol), tert-butyl ester 4-hydroxypiperidine-1-carboxylic acid (1,15 g, 5.7 mmol), di-tert-utilisationbased (1.31 g, 5.7 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) was stirred at room temperature for 16 hours in tetrahydrofuran (20 ml). The mixture is acidified with acetic acid and applied to ion exchange SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). The combined basic fractions concentrated in vacuo and the resulting residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (1:9:90), and get listed in title product (E5a); MS (ES+) m/e 415[M+H]+.

Example 5

3-Cyclopentyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E5)

Tert-butyl ester 4-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-

carboxylic acid (E5a) (593 mg, 1,43 mmol) dissolved in dichloromethane (5 ml) and treated triperoxonane acid (3 ml). The solution paramashiva the t at room temperature for 1 hour, concentrated in vacuo and applied to ion exchange SCX cartridge (Varian bond-elute, 5 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). The combined basic fractions concentrated in vacuo and the resulting residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (1:9:90), getting listed in title product (E5). MS (ES+) m/e 315 [M+H]+.

Examples 6-12

Compounds of examples 6-12 (E6-12) receive any of the 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3), or 3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E4) and the corresponding alcohols listed in the table, by way of example 5a (E5a) and then by the method of example 5 (E5).

329
ExampleThe original substanceAlcoholMAM/MS (M+N)+
3-Cyclobutyl-7-(piperidine-4-
yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)
E3Tert-butyl ether 4-hydroxypiperidine-1-carboxylic acid301
3-Cyclobutyl-7-(piperidine-4-
ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E7)
E3Tert-butyl ether 4-hydroxymethyl is peridin-1-carboxylic acid 315
3-Cyclobutyl-7-((R)-1-pyrrolidin-2-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E8)E3Tert-butyl ether (R)-2-hydroxyethylpyrrolidine-1-carboxylic acid301
3-Cyclobutyl-7-((R)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (e)E3Tert-butyl ether (R)-3-hydroxypyrrolidine-1-carboxylic acid287
3-Cyclobutyl-7-((S)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E10)E3Tert-butyl ether (S)-3-hydroxypyrrolidine-1-carboxylic acid287
3-Cyclobutyl-7-((S)-1-pyrrolidin-2-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E11)E3Tert-butyl ether (S)-2-hydroxyethylpyrrolidine-1-carboxylic acid301
3-Cyclopentyl-7-(piperidine-4-
ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E12)
E4Tert-butyl ether 4-hydroxyethylpiperazine-1-carboxylic acid

Example 13

4-{1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]methanol}benzonitrile (E13)

4-Cyanobenzoic acid (147 mg, 1 mmol), hydrate of 1-hydroxybenzotriazole (154 mg, 1 mmol) and N-cyclohexylcarbodiimide N'-metropolitical (1.8 mmol/g, 555 mg, 1 mmol) was stirred at room temperature in dichloromethane (5 ml) for 15 minutes. Add 3-cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) and stirring is continued for another 16 hours. The reaction mixture is applied on the ion exchange SCX cartridge (Varian bond-elute, 5 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). The combined basic fractions concentrated in vacuo and the resulting residue is purified column chromatography, elwira dichloromethane and then a mixture of .880 ammonia:ethanol:dichloromethane (1:9:90), and get listed in title product (E13). MS (ES+) m/e 430 [M+H]+.

Examples 14-42

Connection examples 14-42 (E14-E42) receive by way of example 13 (E13) from the corresponding amines and acids, as indicated in the table below:

ExampleAminAcidMAM/MS (M+N)+
1-[4-(3-Cyclo is util-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-(tetrahydropyran-4-yl)methanon (E14) 3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)Tetrahydropyran-4-carboxylic acid413
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-cyclohexyl-methanon (E15 motorway)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)Cyclohexane-carboxylic acid411
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-isoquinoline-1-yl-methanon (e)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)Isoquinoline-1-carboxylic acid456
4-{(E)-3-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-3-oxopropyl}-benzonitrile (E17)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)(E)-3-(4-Cyanophenyl)-acrylic acid456
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-isoquinoline-6-yl-methanon (E18)Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) Isoquinoline-6-carboxylic acid456
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-(5-methyl-isoxazol-3-yl)methanon (E19)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)5-Methyl-isoxazol-3-carboxylic acid410
1-Benzothiazol-6-yl-1-[4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]metano (E20)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)Benzothiazole-6-carboxylic acid462
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-pyridin-4-yl-methanon (E21)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)Isonicotinoyl acid406
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-[4-(1-pyrrolidin-1-yl-methanol)phenyl]-
mechanon (E22)
3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) 4-(1-Pyrrolidin-1-yl-methanol)-benzoic acid (WO 03/04468)502
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-thiophene-3-yl-methanon (e)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)Thiophene-3-carboxylic acid411
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-furan-3-yl-methanon (e)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)Furan-3-carboxylic acid395
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)piperidine-1-yl]-1-(tetrahydropyran-4-yl)methanon (E25)3-Cyclobutyl-7-(piperidine-4-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E7)Tetrahydropyran-4-carboxylic acid427
1-[(R)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)-pyrrolidin-1-yl]-1-(tetrahydropyran-4-yl)methanon (E)3-Cyclobutyl-7-((R)-1-pyrrolidin-2-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E8) Tetrahydropyran-4-carboxylic acid413
1-[(R)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrrolidin-1-yl]-1-(tetrahydropyran-4-yl)methanon (E27)3-Cyclobutyl-7-((R)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (e)Tetrahydropyran-4-carboxylic acid399
1-[(S)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrrolidin-1-yl]-1-(tetrahydropyran-4-yl)methanon (E28)3-Cyclobutyl-7-((S)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E10)Tetrahydropyran-4-carboxylic acid399
1-[(S)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrrolidin-1-yl]-1-(tetrahydropyran-4-yl)methanon (E)3-Cyclobutyl-7-((S)-1-pyrrolidin-2-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E11)Tetrahydropyran-4-carboxylic acid413
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-(methanesulfonyl)-methanon (E30)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azep is n (E6) 4-Methanesulfonyl-benzoic acid483
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-pyrazin-2-yl-methanon (e)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)2-Pyrazin-carboxylic acid407
5-{1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-
methanol}-1H-pyridone (e)
3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)6-Hydroxy-nicotinic acid422
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-(2,3-dihydro-benzofuran-5-yl)-methanon (E)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)2,3-Dihydro-benzofuran-5-
carboxylic acid
447
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-3-methoxypropan-1-he (E34)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) 3-Methoxy-propionic acid387
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-(2,3-dihydro-benzofuran-7-yl)-methanon (E)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)2,3-Dihydro-benzofuran-7-
carboxylic acid
447
4-{1-[4-(3-Cyclopentyl-7-(piperidine-4-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylethoxy)piperidine-1-yl]-methanol}-
benzonitrile (E36)
3-Cyclopentyl-7-(piperidine-4-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E12)4-Cyanobenzoic acid458
1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)piperidine-1-yl]-1-[4-(1-pyrrolidin-1-yl-methanol)phenyl]-
mechanon (E)
3-Cyclopentyl-7-(piperidine-4-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E12)4-(1-Pyrrolidin-1-ylmethanol)-
benzoic acid (WO 03/04468A1)
530
4-{1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]methanol}-benzonitrile (E38)3-Cyclopentyl-7-(Piperi the Jn-4 yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E5) 4-Cyanobenzoic acid444
1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-pyridin-4-yl-methanon (E39)3-Cyclopentyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E5)Isonicotinoyl acid420
1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-quinoline-6-yl-methanon (E40)3-Cyclopentyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E5)The quinoline-6-carboxylic acid470
1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-[4-(1-pyrrolidin-1-yl-methanol)phenyl]-
mechanon (E)
3-Cyclopentyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E5)4-(1-Pyrrolidin-1-ylmethanol)-
benzoic acid (WO 03/04468A1)
516
1-Biphenyl-4-yl-1-[4-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]metano (E)3-Cyclopentyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E5) 4-Biphenyl-carboxylic acid495

Example 43

1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-cyclopentylamine (E43)

3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) is stirred in dichloromethane (5 ml) with diethylaminoethylcellulose (3.2 mmol/g, 625 mg, 2 mmol). Add cyclopentanecarbonitrile (80 μl, 0.6 mmol) and the mixture stirred at room temperature for 16 hours. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue is purified column chromatography, elwira dichloromethane, then with a mixture .880 ammonia:ethanol:dichloromethane (1:9:90), and get listed in title product (E43); MS (ES+) m/e 397 [M+H]+.

Examples 44-51

Connection examples 44-51 (E44-E51) receive by way of example 43 (E43) from the corresponding amines and carbonylchloride listed in the table below:

ExampleAminCarbonylchlorideMAM/MS (M+N)+
4-{1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]
azepin-7-intoximeter)piperidine-1-yl]-
methanol}benzonitrile (E)
3-Cyclobuta the l-7-(piperidine-4-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E7) 4-Cyanobenzoyl-chloride444
4-{1-[(R)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]
azepin-7-intoximeter)pyrrolidin-1-yl]-
methanol}benzonitrile (e)
3-Cyclobutyl-7-((R)-1-pyrrolidin-2-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E8)4-Cyanobenzoyl-chloride430
4-{1-[(R)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]
azepin-7-yloxy)pyrrolidin-1-yl]-methanol}
benzonitrile (E)
3-Cyclobutyl-7-((R)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (e)4-Cyanobenzoyl-chloride416
4-{1-[(S)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]
azepin-7-yloxy)pyrrolidin-1-yl]-methanol}
benzonitrile (E)
3-Cyclobutyl-7-((S)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E10)4-Cyanobenzoyl-chloride416
4-{1-[(S)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]
azepin-7-yloxy)pyrrolidin-1-yl]-methanol}-
benzonitrile (E)
3-Cyclobutyl-7-((S)-1-pyrrolidin-2-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E11)430
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]
azepin-7-yloxy)piperidine-1-yl]-2,2-DIMETHYLPROPANE-1-he (E)
3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)2,2-Dimethyl-propionate385
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]
azepin-7-yloxy)piperidine-1-yl]-1-cyclopropylethanol (E50)
3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)Cyclopropane-carbonylchloride369
1-Cyclobutyl-1-[4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]
azepin-7-yloxy)piperidine-1-yl]metano (e)
3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)CYCLOBUTANE-carbonylchloride383

Example 52

4-{1-{4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-morpholine-4-ylmethanol (E52)

3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) is stirred in dichloromethane (5 ml) with diethylaminoethylcellulose(3.2 mmol/g, 625 mg, 2 mmol). Add morpholinylcarbonyl (70 μl, 0.6 mmol) and the mixture stirred at room temperature for 16 hours. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue is purified column chromatography, elwira dichloromethane, then with a mixture .880 ammonia:ethanol:dichloromethane (1:9:90), and get listed in title product (E52). MS (ES+) m/e 414 [M+H]+.

Examples 53-60

Connection examples 53-60 (E53-E60) receive by way of example 52 (E52) from the corresponding amines and carbonylchloride listed in the table below:

td align="justify"> Morpholine-4-carbonylchloride
ExampleAminCarbonylchlorideMAM/MS
(M+N)+
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)piperidine-1-yl]-1-morpholine-4-ylmethanol (e)3-Cyclobutyl-7-(piperidine-4-
ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E7)
Morpholine-4-carbonylchloride428
1-[(R)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)pyrrolidin-1-yl]-1-morpholine-4-ylmethanol (E)3-Cyclobutyl-7-((R)-1-pyrrolidin-2-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepin (E8)
414
1-[(R)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrrolidin-1-yl]-1-morpholine-4-ylmethanol (E55)3-Cyclobutyl-7-((R)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepin (e)
Morpholine-4-carbonylchloride400
1-[(S)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrrolidin-1-yl]-1-morpholine-4-ylmethanol (E)3-Cyclobutyl-7-((S)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepin (E10)
Morpholine-4-carbonylchloride400
Diisopropylamide 4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-
carboxylic acid (E)
3-Cyclobutyl-7-(piperidine-4-
yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6)
Aminobutiramida-carbonylchloride428
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-
pyrrolidin-1-ylmethanone (e)
3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepine (E6)
Pyrrolidin-1-carbonylchloride/td> 398
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-piperidine-1-ylmethanone (E)3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepine (E6)
Piperidine-1-carbonylchloride412
1-[(S)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)pyrrolidin-1-yl]-1-morpholine-4-ylmethanol (E60)3-Cyclobutyl-7-((S)-1-pyrrolidin-2-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepin (E11)
Morpholine-4-carbonylchloride414

Example 61

Diethylamid 4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-carboxylic acid (E61)

3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (1.5 g, 5 mmol)dissolved in toluene (40 ml)is added slowly to a 20% solution of phosgene in toluene (12.5 ml, 25 mmol) at 0°C. the Mixture is stirred at room temperature for 3 hours and concentrated in vacuo, obtaining the crude residue (1,91 g). The crude product (300 mg, 0.75 mmol) is then added to the stirred suspension of diethylamine (207 μl, 2 mmol) and diethylaminoethylcellulose (3.2 mmol/g, 1,41 g, 4.5 mm is l) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 16 hours, filtered and concentrated in vacuo. The crude residue is purified column chromatography, elwira dichloromethane, then with a mixture .880 ammonia:ethanol:dichloromethane (1:9:90), and get listed in title product (E61). MS (ES+) m/e 400 [M+H]+.

Examples 62-65

Connection examples 62-65 (E62-E65) receive by way of example 61 (E61) of 3-cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) and the appropriate amine indicated in the table below:

ExampleAminMAM/MS (M+N)+
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-(1,3-dihydroindol-2-yl)methanon (E)2,3-Dihydro-1H-isoindole446
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-1-(2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)methanon (e)3,4,5,6-Tetrahydro-2H-[1,2']bipyridinyl491
Isopropyl-(2-methoxyethyl)amide 1-[4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine]-1-carboxylic acid (E)And propyl-2-methoxyethylamine 444
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-yl]-(1,1-diocletianopolis-4-yl)methanon (E65)Thiomorpholine 1,1-dioxide462

Example 66

Isopropylated 4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-carboxylic acid (E66)

A solution of 3-cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) and isopropylmalate (60 μl, 0.6 mmol) in dichloromethane (5 ml) was stirred at room temperature for 16 hours. The solution was concentrated in vacuo and the residue purified column chromatography, elwira dichloromethane, then with a mixture .880 ammonia:ethanol:dichloromethane (1:9:90), and get listed in title product (E66). MS (ES+) m/e 386 [M+H]+.

Example 67

(4-Forfinal)amide 4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-carboxylic acid (E67)

The compound of example 67 is obtained from 3-cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) and 4-perteneciente by way of example 66 (E66); MS (ES+) m/e 438 [M+H]+.

Example 68

2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N,N-dimethylacetamide (E68)

Sodium hydride (60% dispersion in mineral oil, 60 mg, 1.5 mmol) is added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, 0.9 mmol) in dimethyl sulfoxide (10 ml). After 0.5 hours add 2-chloro-N,N-dimethylacetamide (0.3 ml, 2.4 mmol) and the reaction mixture is heated at 120°C for 6 hours. The reaction mixture is allowed to cool, and then the crude mixture by ion exchange SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). The combined basic fractions evaporated in vacuum, obtaining specified in the header connection (E68). MS (ES+) m/e 303 [M+H]+.

Examples 69-71

Connection examples 69-71 (E69-E71) are obtained according to the method of example 68 (E68) of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and the corresponding chlorides listed in the table.

ExampleChlorideMAM/MS (M+N)+
2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-N-phenylacetamide (E)
2-Chloro-N-phenylacetamide351
2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-1-pyrrolidin-1-ylatason (E70)
2 is a PR-1-pyrrolidin-1-ylatason 329
2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-1-morpholine-4-ylatason (e)
2-Chloro-1-morpholine-4-ylatason345

Example 72

3-Cyclobutyl-7-(1-methanesulfonamido-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E72)

3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) is stirred in dichloromethane (5 ml) with diethylaminoethylcellulose (3.2 mmol/g, 625 mg, 2 mmol). Add methanesulfonanilide (43 μl, 0.55 mmol) and the mixture stirred at room temperature for 16 hours. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (1:9:90), and get listed in title product (E72); MS (ES+) m/e 379 [M+H]+.

Examples 73-78

Connection examples 73-78 (E73-E78) are obtained according to the method of example 72 (E72) from the corresponding amines and sulphonylchloride listed in the table below:

ExampleAminSulphonylchlorideMAM/MS (M+N)+
4-[4-(3-Cyclobuta the l-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)piperidine-1-sulfonyl]
benzonitrile (E)
3-Cyclobutyl-7-(piperidine-4-
yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepine (E6)
4-Cyanobenzoyl-sulphonylchloride466
3-Cyclobutyl-7-[1-(3,5-dimethylisoxazol-4-sulfonyl)
piperidine-4-yloxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E)
3-Cyclobutyl-7-(piperidine-4-
yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepine (E6)
3,5-Dimethylisoxazol-4-sulphonylchloride460
4-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)piperidine-1-
sulfonyl]benzonitrile (E75)
3-Cyclobutyl-7-(piperidine-4-
ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepin (E7)
4-Cyanobenzoyl-sulphonylchloride480
4-[(R)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)pyrrolidin-1-
sulfonyl]benzonitrile (E)
3-Cyclobutyl-7-((R)-1-pyrrolidin-2-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepin (E8)
4-Cyanobenzoyl-sulphonylchloride466
4-[(R)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrrolidin-sulfonyl]benzonitrile (E77) 3-Cyclobutyl-7-((R)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepin (e)
4-Cyanobenzoyl-sulphonylchloride452
4-[(S)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrrolidin-1-sulfonyl]benzonitrile (E)3-Cyclobutyl-7-((S)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]
azepin (E10)
4-Cyanobenzoyl-sulphonylchloride452

Example 79

3-Cyclobutyl-7-(2,4-deferasirox)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E79)

Potassium carbonate (778 mg, 5.6 mmol) is added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (868 mg, 4.0 mmol), 2,4-diferenciada (0.25 ml, 2.1 mmol) and potassium iodide (25 mg) in butanone (9 ml). The reaction mixture is stirred at the boiling temperature under reflux for 18 hours, cooled, filtered and concentrated in vacuo. The crude residue is dissolved in ethyl acetate and washed with water and saturated salt solution. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (0,25:2,25:97,5, then 19:10), and get listed in the title compound (E79); MS (ES+) m/e 344 [M+H]+.

Examples 80-87

Connection examples 80-87 (E80-E87) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and the corresponding halides listed in the table, according to the General method described in example 80 (E80):

ExampleThe halideMAM/MS (M+N)+
3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
intoximeter)benzonitrile (E80)
3-Bromomethylbiphenyl333
3-Cyclobutyl-7-(3-methoxy-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E)1-methyl bromide-3-methoxybenzoyl338
3-Cyclobutyl-7-(pyridine-2-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E)2-Bromomethylphenyl309
3-Cyclobutyl-7-(pyridine-3-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (e)3-Bromomethylphenyl309
3-Cyclobutyl-7-(pyridine-4-ylethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E) 4-Bromomethylphenyl309
2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
intoximeter)benzonitrile (E85)
2-Bromomethylbiphenyl333
4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
intoximeter)benzonitrile (E)
4-Bromomethylbiphenyl333
6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
intoximeter)-1-methyl-1H-quinoline-2-he (E87)
6-methyl bromide-1-methyl-1H-quinoline-2-he389

Example 88

Methyl ester of 4-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid (E88)

Methyl ester of 4-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter]benzoic acid (D4) (2.83 g, 9.1 mmol) and Cyclopentanone (1.6 ml, 18.2 mmol) dissolved in dichloromethane (30 ml) and acetic acid (0.5 ml). Add triacetoxyborohydride sodium (3,85 g, 18.2 mmol) and the solution stirred at room temperature for 4 hours. The reaction mixture was washed with a saturated solution of sodium carbonate, the organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified column x is omatography, elwira mixture .880 ammonia:ethanol:dichloromethane (1:9:90), and get mentioned in the title compound (E88); MS (ES+) m/e 380 [M+H]+.

Example 89

4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid (E89)

Methyl ester of 4-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid (E88) (3.1 g, 8.1 mmol) dissolved in a mixture of methanol (90 ml), 2N sodium hydroxide solution (12 ml) and water (30 ml). The resulting mixture was stirred at 60°C for 4 hours and then cooled to room temperature. The mixture was concentrated in vacuo to remove organic solvents, and then acidified to pH 6 (2N hydrochloric acid). The precipitate is filtered off, washed with water and dried in vacuum, obtaining specified in the header connection (E89); MS (ES+) m/e 366 [M+H]+.

Example 90

1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)phenyl]-1-pyrrolidineethanol (E90)

4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid (E89) (0,201 mg, 0.55 mmol), 1,3-diisopropylcarbodiimide (44 μl, 0.6 mmol) and the hydrate of 1-hydroxybenzotriazole (82 mg, 0.6 mmol) dissolved in a mixture of dichloromethane (2 ml) and dimethylformamide (1 ml). After stirring at room temperature for 0.5 h the sa add pyrrolidine (41 μl, 0.5 mmol) and the resulting mixture allowed to mix for 16 hours. The crude reaction mixture was applied to ion exchange SCX cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of .880 ammonia:methanol (1:9). The combined basic fractions concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (1:9:90), and get mentioned in the title compound (E90); MS (ES+) m/e 419 [M+H]+.

Examples 91-93

Connection examples 91-93 (E91-E93) are obtained according to the method of example 90 (E90) of 4-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid (E89) and the appropriate amine indicated in the table below:

ExampleAminMAM/MS (M+N)+
1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
intoximeter)phenyl]-1-morpholine-4-ylmethanol (E)
Morpholine435
1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
intoximeter)phenyl]-1-(4-pyridin-4-yl-piperazine-1-yl)methanon (E)
1-Pyridin-4-yl-piperazine511
1-[4-(3-Cyclopentyl-2,3,4,5-tetrahed the o-1H-benzo[d]azepin-7-
intoximeter)phenyl]-1-[4-(4-forfinal)piperazine-1-yl]metano (E)
1-(4-Forfinal)piperazine528

Example 94

Methyl ester 3-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid (E94)

The compound of example 94 (E94) receive by way of example 88 (E88) of tert-butyl methyl ether 7-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (WO 02/40471) and methyl ester 3-bromomethylphenyl acid using the methods described in description 3 (D3), 4 (D4) and example 88 (E88); MS (ES+), m/e 380 [M+H]+.

Example 95

3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid (E95)

The compound of example 95 (E95) is obtained from the methyl ester 3-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid of example 94 (E94) according to the method of example 89 (E89); MS (ES+), m/e 366 [M+H]+.

Example 96

1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)phenyl]-1-pyrrolidineethanol (E96)

The compound of example 96 (E96) obtained from pyrrolidine and 3-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid (E95) according to the method of example 90 (E90); MS (ES+), m/e 419 [M+H]+.

Examples 97-99

Connection examples 97-99 (E97-E99) is obtained from 3-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-intoximeter)benzoic acid (E95) and the appropriate amine indicated in the table, by way of example 96 (E96).

ExampleAminMAM/MS (M+N)+
1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
intoximeter)phenyl]-1-morpholine-4-ylmethanol (E)
Morpholine435
1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
intoximeter)phenyl]-1-(4-pyridin-4-yl-piperazine-1-yl)methanon (E)
1-Pyridin-4-yl-piperazine511
1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
intoximeter)phenyl]-1-[4-(4-forfinal)piperazine-1-yl)methanon (E)
1-(4-Forfinal)piperazine528

Example 100

6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)nicotinamide (E100)

Sodium hydride (60% dispersion in mineral oil, 60 mg, 1.5 mmol) is added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 m is, 0.9 mmol) in dimethyl sulfoxide (10 ml). After 0.5 hours add 6-chloronicotinamide (250 mg, 1.8 mmol) and the reaction mixture is heated at 120°C for 6 hours. After cooling, the crude reaction mixture was applied to ion exchange SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). The combined basic fractions evaporated in vacuum, obtaining specified in the header connection (E100); MS (ES+) m/e 320 [M+H]+.

Examples 101-120

Connection examples 101-120 (E101-E120) are obtained according to the method of example 100 (E100) of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and the appropriate aromatic chlorides listed in the table below:

ExampleChlorideMAM/MS (M+N)+
3-Cyclobutyl-7-(pyridine-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E101)2-Chloropyridin295
1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-3-yl]-1-morpholine-4-ylmethanol (E102)
1-(6-Chloropyridin-3-yl)-1-morpholine-4-ylmethanol (D5)408
1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)Piri is INF-3-yl]-1-pyrrolidin-1-ylmethanone (E)
1-(6-Chloropyridin-3-yl)-1-pyrrolidin-1-ylmethanone (D6)392
6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)nicotinamide (E104)
6-Chloronicotinamide (D7)338
6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-N,N-diethylnicotinamide (E105)
6-Chloro-N,N-diethylnicotinamide (D8)366
6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-N-ethyl-N-nicotine amide (E)
6-Chloro-N-ethyl-N-nicotine amide (D9)380
6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-N-cyclopentylamine (E)
6-Chloro-N-cyclopentyl-nicotinamide (D11)406
1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-3-yl]-1-piperidine-1-ylmethanone (E)
1-(6-Chloropyridin-3-yl)-1-piperidine-1-ylmethanone (D12)406
1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-4-yl]-1-piperidine-1-ylmethanone (E)
1-(2-Chloropyridin-4-yl)-1-piperidine-1-ylmethanone (D13)406
1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-4-yl]-1-pyrrolidin-1-ylmethanone (E110)
1-(2-Chloropyridin-4-yl)-1-pyrrolidin-1-ylmethanone (D14)392
1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-4-yl]-1-morpholine-4-ylmethanol (e)
1-(2-Chloropyridin-4-yl)-1-morpholine-4-ylmethanol (D15)408
1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-2-yl]-1-piperidine-1-ylmethanone (e)
1-(6-Chloropyridin-2-yl)-1-piperidine-1-ylmethanone (D16)406
1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-2-yl]-1-(1,1-diocletianopolis-4-yl)methanon (E)
1-(6-Chloropyridin-2-yl)-1-(1,1-diocletianopolis-4-yl)methanon (D17)466
1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-2-yl]-1-pyrrolidin-1-ylmethanone (E)
1-(6-Chloropyridin-2-yl)-1-pyrrolidin-1-ylmethanone (D18)392
yloxy)pyridine-2-yl]-1-morpholine-4-ylmethanol (E115)1-(6-Chloropyridin-2-yl)-1-morpholine-4-ylmethanol (D19)408
1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-3-yl]-1-morpholine-4-ylmethanol (E)
1-(2-Chloropyridin-3-yl)-1-morpholine-4-ylmethanol (D20)408
1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-3-yl]-1-piperidine-1-ylmethanone (E)
1-(2-Chloropyridin-3-yl)-1-piperidine-1-ylmethanone (D21)406
3-Cyclobutyl-7-(pyrazin-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E)2-Chloropyrazine296
3-Cyclobutyl-7-(pyrimidine-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E119)2-Chloropyrimidine296
7-(5-Bromopyrimidine-2-yloxy)-3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E120)5-Bromo-2-chloropyrimidine375

Example 121

6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-nicotine amide (E121)

Hidri the sodium (60% dispersion in mineral oil, 60 mg, 1.5 mmol) is added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, 0.9 mmol) in dimethyl sulfoxide (10 ml). After 0.5 hours add 6-chloro-N-nicotine amide (D10) (400 mg, 2.5 mmol) and the reaction mixture is heated at 120°C for 6 hours. The reaction mixture is allowed to cool, and then the crude mixture by ion exchange SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). The combined basic fractions evaporated in vacuum, obtaining specified in the header connection (E121).1H NMR (DMSO-d6) δ 8,56 (1H, DD, J=2,4, 0,4 Hz), 8,48 (1H, osirm), to 8.20 (1H, DD, J=8,4, 2.4 Hz), 7,16 (1H, d, J=8.0 Hz), 7,03 (1H, DD, J=8,4, 0,4 Hz)6,91 (1H, d, J=2.4 Hz), 6,86 (1H, DD, J=8.0 a, 2,4 Hz), 2,87-2,77 (8H, m), 2,36 (4H, m), from 2.00 (2H, m), of 1.78 (2H, m), 1,58 (2H, m); MS (ES+) m/e 352 [M+H]+.

Example 121 (Alternative 1)

6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-nicotine amide (E121)

Sodium hydride (0,331 g of 8.28 mmol, 60% dispersion in mineral oil) is added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.5 g, 6,9 mmol) in dimethyl sulfoxide (15 ml). After 0.5 hours add 6-chloro-N-nicotine amide (D10) (2,34 g of 13.8 mmol) and the reaction mixture is heated at 100°C for 18 hours. The reaction mixture is allowed to cool to room temperature the s and distributed between ethyl acetate and water. An ethyl acetate layer is separated and the aqueous layer washed with additional amount of ethyl acetate. Then the combined organic layers washed with water, saturated salt solution, dried (Na2SO4) and filtered. The mixture was concentrated in vacuo and the resulting residue is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (0.5 in:4,5:95, then 1:9:90), and get mentioned in the title compound (E121), which is then recrystallized from toluene.1H NMR (DMSO-d6) δ 8,56 (1H, DD, J=2,4, 0,4 Hz), 8,48 (1H, osirm), to 8.20 (1H, DD, J=8,4, 2.4 Hz), 7,16 (1H, d, J=8.0 Hz), 7,03 (1H, DD, J=8,4, 0,4 Hz)6,91 (1H, d, J=2.4 Hz), 6,86 (1H, DD, J=8.0 a, 2,4 Hz), 2,87-2,77 (8H, m), 2,36 (4H, m), from 2.00 (2H, m), of 1.78 (2H, m), 1,58 (2H, m); MS (ES+) m/e 352 [M+H]+.

Example 121 (Alternative method 2)

6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-nicotine amide (E121)

A mixture of N-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) (1.04 g, 3.5 mmol) in dichloromethane (12 ml)containing acetic acid (240 ml) at 0°C, treated dropwise with cyclobutanone (400 μl, 5.3 mmol) and then stirred at room temperature for 1 hour. The mixture is then cooled to 0°C, portions add triacetoxyborohydride sodium (1,11 g, 5.3 mmol) and stirred at room temperature for 16 hours. The solution gently alkalinized 2N solution of hydro is sid sodium, stirred for 30 minutes and then extracted with dichloromethane. The combined extracts washed with saturated saline solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude substance is purified column chromatography, elwira first dichloromethane, then with a mixture .880 ammonia:methanol:dichloromethane (1:9:90), and get mentioned in the title compound (E121); MS (ES+) m/e 352[M+H]+.

Example 122

Methyl ester 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-carboxylic acid (E122)

Sodium hydride (60% dispersion in mineral oil, 332 mg, 8.3 mmol) is added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.64 g, 7.5 mmol) in dimethylformamide (4 ml). After 0.5 hours, add a solution of methyl ester 5-chloropyrazine-2-carboxylic acid (1,95 g, 11.3 mmol) in dimethylformamide (8 ml) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and the organic layer washed with water, saturated salt solution and dried over magnesium sulfate. The organic layer was filtered, concentrated in vacuo and the resulting residue is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (1:9:90), and get mentioned in the title compound (E122). MS (ES+) m/e 354 [M+H] +.

Example 123a

5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-carboxylic acid (E123a)

Methyl ester 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-carboxylic acid (E122) (880 mg, 2.5 mmol) dissolved in a mixture of ethanol (15 ml) and 2N sodium hydroxide solution (4 ml). The resulting mixture was stirred at room temperature for 0.5 hours and then concentrated in vacuo to remove organic solvents. Then the reaction mixture is acidified to pH 5 (2N hydrochloric acid) and the resulting precipitation was filtered, washed with water and dried in vacuum, obtaining specified in the header connection (E123a); MS (ES+) m/e 340 [M+H]+.

Example 123

1-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-yl]-1-morpholine-4-ylmethanol (E123)

Stage 1: 5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-

carbonylchloride

Thionyl chloride (5 ml) is slowly added to 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-carboxylic acid (E123a) (485 mg). The resulting reaction mixture was stirred at room temperature for 1 hour and then heated under reflux for another 1 hour. The reaction mixture is cooled, diluted with toluene and concentrated in vacuo, the floor is th specified in the title compound, which is used without additional features.

Stage 2: 1-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-yl]-1-morpholine-4-ylmethanol

Morpholine (0.17 ml, 2.0 mmol) is added to a stirred solution of the product of stage 1 (394 mg, 1 mmol) and diethylaminoethylcellulose (1.88 g, 3.2 mmol/g, 6 mmol) in dichloromethane (10 ml). The resulting mixture was allowed to mix at room temperature for 24 hours and filtered. The filtrate was concentrated in vacuo, the crude residue is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (1:9:90), and get mentioned in the title compound (E123). MS (ES+) m/e 409 [M+H]+.

Examples 124, 126-127

Connection examples 124, 126-127 (E124 and E126-E127) is obtained from the product of example 123, step 1, and the appropriate amine indicated in the table, by way of example 123, step 2:

ExampleAminMAM/MS (M+N)+
Ethylmethylamino 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)
pyrazin-2-carboxylic acid (E124)
N-Ethylmethylamine381
1-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)is irisin-2-yl]-1-piperidine-4-ylmethanol (E) Piperidine407
1-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-yl]-1-pyrrolidin-4-ylmethanol (E127)Pyrrolidin393

Example 125

Methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-carboxylic acid (E125)

The product of example 123, step 1 (1,59 mmol) in dry dichloromethane (10 ml) is treated with methylamine (5 ml, 10 mmol, 2M solution in THF) and stirred at room temperature for 18 hours. The mixture is evaporated in vacuo, the crude substance is applied on the ion exchange SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). Then the main fraction evaporated, the crude product is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (0,2:1,8:98 and then to 0.4:3,6:96), and get mentioned in the title compound (E125).1H NMR (CDCl3) δ 8,91 (1H, d, J=1.3 Hz), compared to 8.26 (1H, d, J=1.3 Hz), to 7.61 (1H, userra, J=4,8 Hz), to 7.15 (1H, m), 6,92 (2H, m), 3,03 (3H, d, J=5,1 Hz), with 2.93 (4H, m), and 2.79 (1H, m), 2,47 (4H, m), of 2.08 (2H, m), at 1.91 (2H, m), 1.70 to tariff-1.62 (2H, m).

Example 128

3-Cyclobutyl-7-phenoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E128)

Sodium hydride (60% dispersion in mineral is enom oil, 96 mg, 2.4 mmol) is added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (435 mg, 2.0 mmol) and copper bromide (I) (402 mg, 2.8 mmol) in pyridine (10 ml) at 0°C. After stirring for 0.5 hours at room temperature add iadanza (0.45 ml, 4.0 mmol) and the reaction mixture heated under reflux for 24 hours. The reaction mixture is allowed to cool, filtered and then the filtrate was concentrated in vacuo. The crude residue is dissolved in ethyl acetate and washed with water and saturated salt solution. The organic layer is dried over magnesium sulfate, filtered, concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (0.25:2,25:97,5 to 1:9:90), and get mentioned in the title compound (E128); MS (ES+) m/e 294 [M+H]+.

Examples 129-138

Connection examples 129-138 (E129-E138) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and the appropriate aromatic halides listed in the table, by way of example 128 (E128):

ExampleAromatic halideMAM/MS (M+N)+
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)phenyl]-1-morpho is in 4-ylmethanol (E129)
1-(4-Itfeel)-1-morpholine-4-ylmethanol (D22)407
4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-N-cyclopropylbenzene (E)
4-Iodine-N-cyclopropylmethyl-benzamid (D23)391
1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)phenyl]-1-pyrrolidin-1-ylmethanone (E131)
1-(4-Itfeel)-1-pyrrolidin-1-ylmethanone (D24)391
N-Cyclobutyl-4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)benzamide (e)
4-Iodine-N-cyclobutylmethyl (D25)391
4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-N,N-diethylbenzamide (E133)
4-Iodine-N,N-diethylbenzamide (D26)393
N-(2-Cyanoethyl)-4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-N-methylbenzamide (E)
4-Iodine-N-(2-cyanoethyl)-N-methylbenzamide (D27)404
1-[3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)phenyl]-1-morpholine-4-ylmethanol (E)
1-(3-what openil)-1-morpholine-4-ylmethanol (D28) 407
3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-N-cyclopropylbenzene (E)
3-Iodine-N-cyclopropylmethyl-benzamid (D29)391
3-Cyclobutyl-7-[4-(morpholine-4-sulfonyl)phenoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E)4-(4-Identicality)-morpholine (D30)443
4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-N,N-determinationand (E)
4-Iodine-N,N-determinationand (D31)429

Example 139

7-Benzyloxy-3-cyclohexyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E139)

The compound of example 139 (E139) is obtained from the compound of description 2 (D2) and cyclohexanone according to the method of example 1; MS (ES+) m/e 336 [M+H]+.

Example 140

3-Cyclobutyl-7-{[2-(1-piperidinyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E140)

Sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol) is added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, of 0.92 mmol) and copper bromide (I) (184 mg, 1.3 mmol) in pyridine (10 ml) at 0°C. After re is eshiwani for 0.5 hours at room temperature, add 5-bromo-2-(1-piperidinyl)pyrimidine (D32) (0,669 g, 2.8 mmol) and the reaction mixture heated under reflux for 2 hours. The reaction mixture is allowed to cool, filtered and the filtrate concentrated in vacuo. The crude residue is dissolved in ethyl acetate and washed with water and saturated salt solution. The organic layer is dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (0.25:2,25:97,5 to 1:9:90), and get mentioned in the title compound (E140). MS (ES+) m/e 379 [M+H]+.

Examples 141-143

Connection examples 141-143 (E141-E143) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and the corresponding bromides listed in the table, by way of example 140 (E140):

ExampleBromideMAM/MS (M+N)+
3-Cyclobutyl-7-{[2-(1-pyrrolidinyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E141)5-Bromo-2-(1-pyrrolidinyl)pyrimidine (D33)365
3-Cyclobutyl-7-{[2-(1,1-dioxido-4-thiomorpholine)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E142)1,1-dioxide, 4-(5-bromo-2-pyrimidinyl)-thiomorpholine (D34) 429
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)
oxy]-N-methyl-2-pyrimidinamine (E)
5-Bromo-N-methyl-2-pyrimidinamine (D35)325

Example 144

3-Cyclobutyl-7-{[2-(metiloksi)-5-pyrimidinyl]hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepin (E144)

The compound of example 144 (E144) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 5-bromo-2-(metiloksi)pyrimidine (PCT Int. Appl. PCT (2002), WO 02/62423) according to the method of example 140 (E140); MS (ES+) m/e 326 [M+H]+.

Examples 145-147

Connection examples 145-147 (E145-E147) is obtained from 3-cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) and the appropriate acids listed in the table, by way of example 13 (E13):

ExampleAcidMAM/MS (M+N)+
1-[4-({4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}carbonyl)phenyl]-2-pyrrolidinone) (E145)4-(2-Oxo-1-pyrrolidinyl)benzoic acid488
3-Cyclobutyl-7-[(1-{[3-(methylsulphonyl)phenyl]carbonyl}-4-piperidinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E146) 3-(Methylsulphonyl)benzoic acid483
3-Cyclobutyl-7-({1-[(1,1-dioxido-3,4-dihydro-2H-1-benzothiophen-6-yl)carbonyl]-4-piperidinyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepin (E147)1,1-Dioxide, 3,4-dihydro-2H-1-benzothiophen-6-carboxylic acid509

Examples 148-150

Connection examples 148-150 (E148-E150) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and the corresponding alcohols listed in the table, by way of example 5a (E5a) and then by the method of example 5 (E5).

ExampleAlcoholMAM/MS (M+N)+
3-Cyclobutyl-7-{[(3S)-3-pyrrolidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E148)1,1-Dimethylethyl (3S)-3-(hydroxymethyl)-1-pyrrolidinecarboxylic301
3-Cyclobutyl-7-{[(3S)-3-piperidinylmethyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E149)1,1-Dimethylethyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate315
3-Cyclobutyl-7-[(3S)-3-piperidinyloxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E150) 1,1-Dimethylethyl (3S)-3-hydroxy-1-piperidinecarboxylate301

Examples 151-153

Connection examples 151-153 (E151-E153) is obtained from the corresponding amines listed in the table, and morpholinylcarbonyl by way of example 52:

ExampleAminMAM/MS (M+N)+
3-Cyclobutyl-7-({[(3S)-1-(4-morpholinylcarbonyl)-3-piperidinyl]methyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepin (E151)3-Cyclobutyl-7-{[(3S)-3-piperidinylmethyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E149)428
3-Cyclobutyl-7-({[(3S)-1-(4-morpholinylcarbonyl)-3-pyrrolidinyl]methyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepin (E152)3-Cyclobutyl-7-{[(3S)-3-pyrrolidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E148)414
3-Cyclobutyl-7-{[(3S)-1-(4-morpholinylcarbonyl)-3-piperidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E153)3-Cyclobutyl-7-[(3S)-3-piperidinyloxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E150)414

Examples 154-156

Connection examples 154-156 (E154-E156) is obtained from the corresponding amines, azannyh in the table, and 4-cyanobenzaldehyde by way of example 43 (E43):

ExampleAminMAM/MS (M+N)+
4-[((3S)-3-{[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]methyl}-1-piperidinyl)carbonyl]benzonitrile (E154)3-Cyclobutyl-7-{[(3S)-3-piperidinylmethyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E149)444
4-[((3S)-3-{[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]methyl}-1-pyrrolidinyl)carbonyl]benzonitrile (E155)3-Cyclobutyl-7-{[(3S)-3-pyrrolidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E148)430
4-({(3S)-3-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl)carbonyl]benzonitrile (E156)3-Cyclobutyl-7-[(3S)-3-piperidinyloxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E150)430

Examples 157-159

Connection examples 157-159 (E157-E159) is obtained from the corresponding amines listed in the table, and tetrahydropyran-4-carboxylic acid according to the method of example 13 (E13):

ExampleAmin MAM/MS (M+N)+
3-Cyclobutyl-7-({[(3S)-1-(tetrahydro-2H-Piran-4-ylcarbonyl)-3-pyrrolidinyl]methyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepin (E157)3-Cyclobutyl-7-{[(3S)-3-pyrrolidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E148)413
3-Cyclobutyl-7-({[(3S)-1-(tetrahydro-2H-Piran-4-ylcarbonyl)-3-piperidinyl]methyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepin (E158)3-Cyclobutyl-7-{[(3S)-3-piperidinylmethyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E149)427
3-Cyclobutyl-7-{[(3S)-1-(tetrahydro-2H-Piran-4-ylcarbonyl)-3-piperidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E159)3-Cyclobutyl-7-[(3S)-3-piperidinyloxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E150)413

Example 160

6-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}-3-pyridylcarbonyl (E160)

3-Cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (60 mg, 0.2 mmol), 6-chloronicotinamide (31 mg, 0.22 mmol) and triethylamine (of 0.03 ml, 0.22 mmol) dissolved in acetonitrile (2 ml) and heated at 180°C. in a microwave reactor for 10 minutes. The reaction mixture was diluted with et is lacerata, washed with water, saturated salt solution and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (0.25:2,25:97,5 to 1:9:90), and get mentioned in the title compound (E); MS (ES+) m/e 403 [M+H]+.

Examples 161-166

Connection examples 161-166 (E161-E166) is obtained from 3-cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) and the corresponding chlorides listed in the table, by way of example 160 (E160):

ExampleChlorideMAM/MS (M+N)+
6-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)
oxy]-1-piperidinyl}-N-(cyclopropylmethyl)-3-pyridinecarboxamide (E)
6-Chloro-N-(cyclopropylmethyl)-3-pyridinecarboxamide (D36)475
7-({1-[5-(1-Azetidinone)-2-pyridinyl]-4-piperidinyl}oxy)-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin (E162)5-(1-Azetidinone)-2-chloropyridin (D37)461
3-Cyclobutyl-7-({1-[5-(4-morpholinylcarbonyl)-2-pyridinyl]-4-piperidinyl}oxy)-2,3,4,5-tetrahydro-1H-3-Ben is azepin (E163) 1-(6-Chloropyridin-3-yl)-1-morpholine-4-ylmethanol (D5)491
6-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}-N-methyl-3-pyridinecarboxamide (E164)6-Chloro-N-nicotine amide (D10)435
2-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}-4-pyridylcarbonyl (E165)2-Chloro-4-pyridylcarbonyl403
3-Cyclobutyl-7-{[1-(2-pyrazinyl)-4-piperidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E166)2-Chloropyrazine (D9)379

Example 167a

Ethyl 4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoate (E167a)

Ethyl 4-bromobutyrate (2 ml, of 13.8 mmol) is added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (2.00 g, 9.2 mmol) and potassium carbonate (3.8 g, 27.6 mmol) in 2-butanone (50 ml). After stirring at the boiling point under reflux for 24 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude substance is purified column chromatography, elwi the UYa mixture of methanol:dichloromethane (5:95), and get listed in the title compound (E167a). MS (ES+) m/e 332 [M+H]+.

Example 167b

4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy] butane acid (E167b)

Ethyl 4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoate (E167a) (1.5 g, 4.5 mmol) was diluted with ethanol (30 ml) and treated with 2N sodium hydroxide solution (7.9 ml). After stirring at the boiling point under reflux for 24 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude mixture is applied to the ion exchange SCX cartridge (Varian bond-elute) and washed with water, methanol and a mixture of .880 ammonia:methanol (1:9). The combined basic fractions evaporated in vacuum, obtaining specified in the header connection (E167b) in the form of ammonium salt. MS (ES+) m/e 303 [M+H]+.

Example 167

3-Cyclobutyl-7-{[4-oxo-4-(1-piperidinyl)butyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E167)

Stage 1: 3-Cyclobutyl-7-{[4-(1H-imidazol-1-yl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin

4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butane acid (E167b) (0,90 g, 2.8 mmol) dissolved in dimethylformamide (10 ml) and treated with 1,1'-carbonyl diimidazol (0,59 g, 3.6 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo. The crude residue is dissolved in dichloromethane, washed with saturated salt solution and dried (sodium sulfate). The organic layer was filtered, concentrated in vacuo and the crude residue used in the next stage without additional purification.

Stage 2: 3-Cyclobutyl-7-{[4-oxo-4-(1-piperidinyl)butyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E167)

Piperidine (0.1 ml, 1.1 mmol) is added to a stirred solution of 3-cyclobutyl-7-{[4-(1H-imidazol-1-yl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine (E167, stage 1) (150 mg, 0.42 mmol) in dichloromethane (5 ml). After stirring at room temperature for 5 days, the reaction mixture was concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:ethanol:dichloromethane (1:9:90), and get mentioned in the title compound (E167); MS (ES+) m/e 371 [M+H]+.

Examples 168-170

Connection examples 168-170 (E168-E170) is produced from compound of example 167, step 1, by way of example 167, step 2, substituting piperidine for the appropriate amine indicated in the table below:

ExampleAminMAM/MS (M+N)+
3-Cyclobutyl-7-{[4-oxo-4-(1-pyrrolidinyl)butyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E168) Pyrrolidin357
4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-cyclopentylamine (E169)Cyclopentylamine371
4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbutane (E170)Methylamine317

Examples 171-176

Connection examples 171-176 (E171-E176) is produced from compound of example 123, step 1, and the appropriate amine indicated in the table, by way of example 123, step 2 (E123):

ExampleAminMAM/MS (M+N)+
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(1-methylethyl)-2-pyrazinecarboxamide (E171)Isopropylamine381
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(tetrahydro-2H-Piran-4-yl)-2-pyrazinecarboxamide (E172)Tetrahydro-2H-Piran-4-amine423
7-{[5-(1-Azetidinone)-2-pyrazinyl]oxy}-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin (E173) Azetidin379
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,N-diethyl-2-pyrazinecarboxamide (E174)Diethylamin395
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-[2-(metiloksi)ethyl]-2-pyrazinecarboxamide (E175)2-(Metiloksi)ethylamine397
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-2-pyrazinecarboxamide (E176)Ethylamine367

Example 177a

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarbonitrile (E177a)

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) (1,81 g of 8.33 mmol) dissolved in pyridine (40 ml) and add sodium hydride (60% in mineral oil, 0.40 g, 10.0 mmol) with stirring in an argon atmosphere at 0°C. the Mixture is left to mix for 5 minutes. Add the copper bromide (I) (1.68 g, 11.7 mmol) and the mixture is left to warm to room temperature for 30 minutes. Add 5-bromo-2-pyrimidinecarbonitrile (D38) (2.30 g, 12.5 mmol) in pyridine (8 ml) and the mixture is heated at 100°C for 1 hour. The mixture is left to cool to room temperature the tours and the solvent is removed in vacuum. The crude product is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0,2:1,8:98), and get mentioned in the title compound (E177a); MS (ES+) m/e 321 [M+H]+.

Example 177b

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarbonitrile acid (E177b)

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarbonitrile (E177a) (1.22 g, 3,81 mmol) dissolved in ethanol (20 ml), treated with 10% sodium hydroxide solution (20 ml) and heated under reflux for 90 minutes. The mixture is cooled to room temperature and applied to ion exchange SCX column (Varian bond-elute, 10 g), elwira water, methanol and then a mixture of 0,880 ammonia:methanol (1:9). The main fractions are combined and concentrated in vacuo, obtaining specified in the header connection (E177b); MS (ES+) m/e 340 [M+H]+.

Example 177

3-Cyclobutyl-7-{[2-(4-morpholinylcarbonyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E177)

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarbonitrile acid (E177b) (130 mg, of 0.37 mmol) dissolved in dimethylformamide (4 ml), treated with 1,1'-carbonyl diimidazol (180 mg, 1.11 mmol) and allowed to mix in the atmosphere of argon at room temperature for 5 hours. The mixture is treated with mo is polinom (0,19 ml, 2.22 mmol) and allowed to mix at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture 0,880 ammonia:methanol:dichloromethane (0,5:1,5:95), and get mentioned in the title compound (E177). MS (ES+) m/e 409 [M+H]+.

Examples 178-186

Connection examples 178-186 (E178-E186) is produced from compound of example 177b (E177b) and the appropriate amine indicated in the table, by way of example 177 (E177):

ExampleAminMAM/MS (M+N)+
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(cyclopropylmethyl)-2-pyrimidinecarboxylic (E178)Cyclopropanemethylamine393
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-2-pyrimidinecarboxylic (E179)Ethylamine367
7-{[2-(1-Azetidinone)-5-pyrimidinyl]oxy)-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin (E180)Azetidin379
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy-N-ethyl-N-methyl-2-pyrimidinecarboxylic (E181) Ethyl(methyl)amine381
N-cyclobutyl-5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarboxylic (E182)Cyclobutylamine393
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(tetrahydro-2H-Piran-4-yl)-2-pyrimidinecarboxylic (E183)Tetrahydro-2H-Piran-4-amine423
3-Cyclobutyl-7-{[2-(1-pyrrolidinylcarbonyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E184)Pyrrolidin393
3-Cyclobutyl-7-{[2-(1-piperidinylcarbonyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E185)Piperidine407
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrimidinecarboxylic (E186)Methylamine353

Example 187a

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-piridinkarbonovaya acid (E187a)

Specified in the header connection (E187a) is obtained from 5-[(3-cyclobutyl-2,3,4,5-then it is carbonated the ro-1H-3-benzazepin-7-yl)oxy]-2-pyridinecarboxamide (E) according to the method of example 177b (E177b); MS (ES+) m/e 339 [M+H]+.

Examples 188-195

Connection examples 188-195 (E188-E195) is obtained from 5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyridineboronic acid (E187a) and the appropriate amine indicated in the table, by way of example 177 (E177):

Ethyl-[2-(metiloksi)ethyl]amine
ExampleAminMAM/MS (M+N)+
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyridinecarboxamide (E187)Methylamine352
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-2-pyridinecarboxamide (E188)Ethylamine366
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-N-methyl-2-pyridinecarboxamide (E189)Ethyl(methyl)amine380
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,N-diethyl-2-pyridinecarboxamide (E190)Diethylamin394
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-N-[2-(metiloksi)ethyl]-2-pyridinecarboxamide (E191)424
3-Cyclobutyl-7-{[6-(1-pyrrolidinylcarbonyl)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E192)Pyrrolidin392
3-Cyclobutyl-7-{[6-(4-morpholinylcarbonyl)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E193)Morpholine408
3-Cyclobutyl-7-{[6-(tetrahydro-1,4-oxazepine-4(5H)-ylcarbonyl)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E194)Hexahydro-1,4-oxazepine422
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-cyclopentyl-2-pyridinecarboxamide (E195)Cyclopentylamine406

Example 196a

Methyl ester of 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridineboronic acid

Specified in the title compound is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and methyl 6-chloro-3-pyridinecarboxylic according to the method described for compound E122; MS

(ES+) m/e 353 [M+H]+.

Example 196b

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)about the si]-3-piridinkarbonovaya acid (E196b)

Specified in the title compound is obtained from the compound of example 196a (E126a) according to the method of example 123a (E123a); MS (ES+) m/e 339 [M+H]+.

Example 196

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-cyclopropyl-3-pyridinecarboxamide (E196)

Carbonyldiimidazole (142 mg, 0.88 mmol) is added to a stirred solution of 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridineboronic acid (E196b) (150 mg, 0.44 mmol) in dichloromethane (5 ml). After stirring at room temperature for 3 hours add cyclopropylamine (0.15 ml, 2.2 mmol) and the mixture allowed to mix for another 18 hours. The reaction mixture is applied on the ion exchange SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). The combined basic fractions concentrated in vacuo, obtaining specified in the header connection (E196). MS (ES+) m/e 378 [M+H]+.

Examples 197-202

Connection examples 197-202 (E197-E202) is obtained from 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridineboronic acid (E196b) and the appropriate amine indicated in the table, by way of example 196 (E196):

ExampleAminMAM/MS (M+N)+
6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(1-methylethyl)-3-pyridinecarboxamide (E197)Isopropylamine380
6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-3-pyridinecarboxamide (E198)Ethylamine366
N-cyclobutyl-6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxamide (E199)Cyclobutylamine392
6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(tetrahydro-2H-Piran-4-yl)-3-pyridinecarboxamide (E200)Tetrahydro-2H-Piran-4-amine422
6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,N-diethyl-3-pyridinecarboxamide (E201)Diethylamin394
6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-[2-(metiloksi)ethyl]-3-pyridinecarboxamide (E202)[2-(Metiloksi)ethyl]amine396

Examples 203-205

Connection examples 203-205 (E203-205) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-what Enzo[d]azepin-7-ol (E3) and the appropriate aromatic iodides, listed in the table, by way of example 128 (E128):

ExampleIodideMAM/MS (M+N)+
4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-N-[2-(metiloksi)ethyl]benzamide (E203)4-Iodine-N-ethyl-N-[2-(metiloksi)ethyl]benzamide (D50)423
4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide (E204)4-Iodine-N-methylbenzamide (D51)351
3-Cyclobutyl-7-(3-pyridyloxy)-2,3,4,5-tetrahydro-1H-3-benzazepin (E205)3-Iodopyridine294

Example 206

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyridylcarbonyl (E206)

Specified in the header connection (E206) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) and 5-iodine-2-pyridylcarbonyl (Biochemical Journal, 1973, 131 (4), 625) according to the method described for compound E177a; MS (ES+) m/e 320 [M+H]+.

Examples 207-208

Connection examples 207-208 (E207-208) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and the appropriate aromatic PI is the reeds, listed in the table, according to the method of example 100 (E100):

ExampleChlorideMAM/MS (M+N)+
3-Cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207)2-Chloro-5-iodopyridine421
3-Cyclobutyl-7-[(5-nitro-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E208)2-Chloro-5-nitropyridine340

Example 209

N-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}ndimethylacetamide (E209)

Iron filings (451 mg, 8,07 mmol) is added to a stirred solution of 3-cyclobutyl-7-[(5-nitro-2-pyridinyl)oxy)]-2,3,4,5-tetrahydro-1H-3-benzazepine (E208) (550 mg, of 1.62 mmol) in a mixture of acetic acid: a solution of acetic anhydride (1:1, 10 ml) and heated at 80°C for 16 hours. The reaction mixture is cooled, poured on ice and adjusted to pH8 with sodium bicarbonate. The product is extracted in ethyl acetate, then the organic extract was washed with saturated saline solution and dried over sodium sulfate. The residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:95), and get listed in the agolove connection (E209). MS (ES+) m/e 352 [M+H]+.

Example 210a

3-Cyclobutyl-7-[(5-nitro-1,3-thiazol-2-yl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E210a)

Sodium hydride (60% dispersion in mineral oil, 150 mg, 3,66 mmol) is added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (530 mg, 2,43 mmol) in dimethylformamide (10 ml) at 5°C. After 0.5 hours, add a solution of 2-bromo-5-nitro-1,3-thiazole (1.0 g, 4,78 mmol) in dimethylformamide (5 ml) and the reaction mixture left to warm to room temperature while stirring for 2 hours. The reaction mixture was diluted with ethyl acetate, the organic layer washed with water, saturated salt solution, dried (sodium sulfate) and concentrated in vacuo. Clear column chromatography, elwira mixture 0,880 ammonia:methanol:dichloromethane (0,25:2,25:97,5), and get mentioned in the title compound (E210a); MS (ES+) m/e 346 [M+H]+.

Example 210

N-{2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1,3-thiazol-5-yl}ndimethylacetamide (E210)

Iron powder (162 mg, 2.9 mmol) is added to a stirred solution of 3-cyclobutyl-7-[(5-nitro-1,3-thiazol-2-yl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E210a) (162 mg, 0.47 mmol) in acetic acid (1 ml) and acetic anhydride (1 ml). The reaction mixture was stirred at 80°C for 16 hours, then Oh adut and poured on ice. The solution is alkalinized to pH 8 (sodium bicarbonate) and the resulting mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried (sodium sulfate). Concentration in vacuo followed by purification of the obtained residue column chromatography (elute with a mixture of .880 ammonia:methanol:dichloromethane (0,3:2,7:97) gives specified in the header connection (E210). MS (ES+) m/e 358 [M+H]+.

Example 211

3-Cyclobutyl-7-[(5-nitro-2-thienyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E211)

A mixture of 2-bromo-5-nitrothiophene (478 mg, 2.3 mmol), 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (500 mg, 2.3 mmol) and potassium carbonate (765 mg, 5.5 mmol) in dimethylformamide (10 ml) was stirred at 80°C for 16 hours. The reaction mixture is cooled, diluted with ethyl acetate and washed with water, saturated salt solution and dried (sodium sulfate). Concentration in vacuo and purification of the obtained residue column chromatography (elute with a mixture of .880 ammonia:methanol:dichloromethane (1:8:300) gives specified in the header connection (E211); MS (ES+) m/e 345 [M+H]+.

Example 212

N-{5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-thienyl}ndimethylacetamide (E212)

The compound of example 212 (E212) is obtained from 3-cyclobutyl-7-[(5-nitro-2-thienyl)oxy]-2,3,4,5-tetrahydro-1H-3-be zotepine (E211) according to the method of example 210 (E210); MS (ES+) m/e 357 [M+H]+.

Example 213a

3-Cyclobutyl-7-{[6-(metiloksi)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E213a)

Specified in the title compound is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 5-bromo-2-methoxypyridine by way of example 128 (E128); MS (ES+) m/e 325 [M+H]+.

Example 213

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2(1H)-pyridinone (E213)

3-Cyclobutyl-7-{[6-(metiloksi)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E213a) (69 mg, 0.21 mmol) was dissolved in a saturated solution of hydrogen chloride in ethanol (5 ml). The reaction mixture is stirred under reflux for 18 hours, cooled and concentrated in vacuo. The resulting residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (1:9:90), and get mentioned in the title compound (E213). MS (ES+) m/e 311 [M+H]+.

Example 214

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}Etalon (E214)

The compound of example 214 (E214) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 1-(6-chloropyridin-3-yl)ethanone according to the method of example 100 (E100); MS (ES+) m/e 337 [M+H]+.

Example 215

3-Cyclobutyl-7-{[5-(1H-pyrazole-5-yl)-2-pyridinyl]oxy}-2,3,4,5-then it is carbonated the ro-1H-3-benzazepin (E215)

A mixture of (2E)-1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-3-(dimethylamino)-2-propen-1-it (D53) (195 mg, 0.5 mmol) and hydrazine hydrate (0.4 ml) in methanol (3 ml) is heated under reflux for 24 hours. The reaction mixture is cooled, causing the ion exchange SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia/methanol (1:9). The combined basic fractions concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (1:9:90), and get mentioned in the title compound (E215). MS (ES+) m/e 361 [M+H]+.

Example 216

3-Cyclobutyl-7-{[5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E216)

A mixture of triethylorthoformate (3 ml) and 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxamide (D54) (185 mg, 0.52 mmol) is heated under reflux for 16 hours. The reaction mixture was concentrated, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0,1:5:95), and get mentioned in the title compound (E216). MS (ES+) m/e 377 [M+H]+.

Example 217

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidone (E217)

A mixture of 3-cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (252 mg, 0.6 mmol), 2-pyrrolidinone (153 mg, 1.8 mmol), potassium carbonate (83 mg, 0.6 mmol) and copper powder (126 mg, 1.2 mmol) is heated in a microwave reactor at 150°C for 1 minute. The reaction mixture was diluted with 2-pyrrolidinone (1 g, 12 mmol) and heated for another 20 minutes at 200°C. the Reaction mixture is cooled, causing the ion exchange SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia/methanol. The combined basic fractions concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (1:9:90), and get mentioned in the title compound (E217). MS (ES+) m/e 378 [M+H]+.

Example 218

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-piperidine (E218)

The compound of example 218 (E218) is obtained from 3-cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and 2-piperazinone by way of example 217 (E217); MS (ES+) m/e 392 [M+H]+.

Example 219

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-azetidinone (E219)

The cesium carbonate (678 mg, 1.04 mmol) are added to a solution of 2-azetidinone (308 mg, 4.3 mmol) in dioxane (1 ml). The mixture is heated in mi is Romanova reactor at 150°C for 1 minute, then add a mixture of 3-cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (294 mg, 0.7 mmol), TRANS-1,2-diaminocyclohexane (0,02 ml) and copper iodide (I) (126 mg, 1.2 mmol) and the resulting mixture heated in a microwave reactor at 180°C for 1 hour. The reaction mixture is cooled, put on a SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia/methanol (1:9). The combined basic fractions concentrated in vacuo, the obtained residue is purified column chromatography (0,5:2,5:97,5), receiving specified in the header connection (E219). MS (ES+) m/e 364 [M+H]+.

Example 220

3-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-1,3-oxazolidin-2-he (E220)

The compound of example 220 (E220) is obtained from 3-cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and 1,3-oxazolidin-2-it is by way of example 219 (E219); MS (ES+) m/e 380 [M+H]+.

Example 221

3-Cyclobutyl-7-{[5-(1H-pyrazole-1-yl)-2-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E221)

A mixture of 3-cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (294 mg, 0.7 mmol), pyrazole (58 mg, 0.84 mmol), cesium carbonate (479 mg, 1.5 mmol), copper iodide (I) (7 mg, 0.04 mmol) and 1,10 phenanthroline (13 mg, 0.07 mmol) in dioxane (2 ml) is heated in a microwave re store at 180°C for 20 minutes. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of ammonium chloride, water, saturated salt solution and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:95), and get mentioned in the title compound (E221); MS (ES+) m/e 361 [M+H]+.

Example 222

3-Cyclobutyl-7-{[5-(3,5-dimethyl-4-isoxazolyl)-2-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E222)

A mixture of 3-cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (252 mg, 0.6 mmol), 3,5 dimethyl-4-isoxazolidine acid (168 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium (0) in 2M sodium carbonate solution (5 ml) and dimethyl ether of ethylene glycol (10 ml) is stirred under reflux for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water, saturated salt solution and dried (sodium sulfate). The organic layer was filtered, concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:95), and get mentioned in the title compound (E222); MS (ES+) m/e 390 [M+H]+.

Example 223

6-[(3-Cyclopentyl-2,3,4,5-tetr the hydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide (E223)

N-Methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) (150 mg, 0.5 mmol) is dissolved in 2.5% acetic acid solution in methanol (5 ml) and treated dropwise with Cyclopentanone (and 0.09 ml, 1 mmol). The mixture is stirred for 30 minutes and then add cyanoborohydride (polystability)trimethylammonium (2.04 mmol/g, 490 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 14 hours, applied to a SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia/methanol. The combined basic fractions concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0,25:2,25:97,5), and get mentioned in the title compound (E223). MS (ES+) m/e 366 [M+H]+.

Example 224

N-Methyl-6-{[3-(2-methylcyclopentene)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]oxy}-3-pyridinecarboxamide (E224)

The compound of example 224 (E224) is obtained from N-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) and 2-methylcyclopentanone by way of example 223; MS (ES+) m/e 380 [M+H]+.

Example 225

6-[(3-Cyclobutyl-8-iodine-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide (E225)

N-Methyl-6-(8-iodine-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylox is)-3-pyridinecarboxamide (D43) (423 mg, 1.0 mmol) dissolved in 2.5% acetic acid solution in methanol (5 ml) and treated dropwise with cyclobutanone (of 0.11 ml, 1.5 mmol). The mixture is stirred for 30 minutes and then add cyanoborohydride (polystability)trimethylammonium (2.0 mmol/g, 1 g, 2 mmol). The reaction mixture was stirred at room temperature for 18 hours, applied to ion exchange SCX cartridge (Varian bond-elute, 10 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). The combined basic fractions concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:2,25:97,5), and get mentioned in the title compound (E225). MS (ES+) m/e 478 [M+H]+.

Example 226

3-Cyclobutyl-7-iodine-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E226)

The compound of example 226 (E226) obtained from 7-iodine-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (D45) and cyclobutanone by way of example 225 (E225); MS (ES+) m/e 434 [M+H]+.

Example 227

3-Cyclobutyl-7-{[6-methyl-4-(metiloksi)-2-chinoline]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E227)

A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (58 mg, 0,267 mmol), 2-chloro-6-methyl-4-(metiloksi)quinoline (WO 99/55677) (56 mg, or 0.027 mmol) and cesium carbonate (260 mg, 0,801 mmol) in dry DMF (3 ml) is heated at 150°C in t the value of 2×30 minutes (300W) in a microwave reactor. The cooled reaction mixture is distributed between ethyl acetate (3×20 ml) and water (30 ml). The combined organic layers washed with saturated saline (2×30 ml), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is purified column chromatography on silica gel, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:95), and get mentioned in the title compound (E227); MS (ES+) m/e 389 [M+H]+.

Examples 228-230

Connection examples 228-230 (E228-E230) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and the appropriate aromatic halides listed in the table, by way of example 227:

ExampleAromatic chlorideMAM/MS (M+N)+
3-Cyclobutyl-7-{[4-(metiloksi)-1,7-naphthiridine-2-yl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E228)2-Chloro-4-(metiloksi)-1,7-naphthiridine376
3-Cyclobutyl-7-(1,5-naphthiridine-2-yloxy)-2,3,4,5-tetrahydro-1H-3-benzazepin (E229)2-Bromo-1,5-naphthiridine (J. W. Henk, J. Org. Chem., 1982, 47(9), 1673-1677)346
N-{7-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy-6-methyl-1,8-naphthiridine-2-yl}ndimethylacetamide (E230) N-(7-Chloro-6-methyl-1,8-naphthiridine-2-yl}
the ndimethylacetamide (S. Carboni, Gazz. Chim. Ital., 1966, 96(11), 1456-1469)
417

Example 231

Dimethyl 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate (E231)

A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.5 g), dimethyl 6-chloro-2,3-pyridinedicarboxylate (1,58 g; Kenji Niiyama et al. Bioorg. Med. Chem. Lett. 12, 21, 2002, 3041-3054) and cesium carbonate (4.4 g) in dry DMF (30 ml) is heated at 80°C for 3 hours, the Cooled mixture was partitioned between water (20 ml) and ethyl acetate (3×100 ml), the combined organic extracts washed with saturated brine solution (2×100 ml) and dried (Na2SO4). The solvent is evaporated, receiving the oil, which is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:95), and get mentioned in the title compound (E231); MS (ES+) m/e 411 [M+H]+.

Example 232

Disodium 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate (E232)

A solution of sodium hydroxide (0.66 g) in water (3 ml) was added to a solution of dimethyl 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate (E231) (1,69 g of 4.12 mmol) in ethanol (20 ml) at room temperature. The mixture is vigorously stirred for p and room temperature for 4 h and the resulting precipitate is filtered off, getting listed in the title compound as a colourless solid (E232); MS (ES+) m/e 383 [M+H]+.

Example 233

2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-5H-pyrrolo[3,4b]pyridine-5,7(6N)-dione (E233)

A suspension of disodium 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate (E232) (0.2 g, 0.52 mmol) in acetic anhydride (2 ml) is stirred and heated at 120°C for 20 minutes the Cooled mixture was concentrated in vacuo, to the residue add ndimethylacetamide (0.1 g) and the mixture is heated at 160°C for 0.5 h Then cooled mixture was purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 to:4,5:95). The obtained pale-yellow solid fray with ether (5 ml) and filtered, obtaining specified in the header connection (E233); MS (ES+) m/e 364[M+H]+.

Example 234

2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-he (E234)

Perchlorate magnesium (0,89 g) are added to a solution of 2-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (E233) (0,72 g of 1.98 mmol) in a mixture of chloroform:methanol (1:1; 20 ml) at 0°C in an argon atmosphere. Add sodium borohydride (113 mg) and the mixture is stirred for 0.5 hours the pH of the mixture was adjusted to 2 with HC (2M), stirred for further 0.5 h, then brought to pH 11 with sodium hydroxide (2N). The mixture is then extracted with dichloromethane, the combined organic extracts dried (Na2SO4) and evaporated. The residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (1:9:90), and get mentioned in the title compound (E234); MS (ES+) m/e 366 [M+H]+.

Example 235

2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-he (E235)

A mixture of 2-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-it (E234) (90 mg, 0.25 mmol) and triethylsilane (0.1 ml) in triperoxonane acid (0.1 ml) is vigorously stirred at room temperature for 1 h the Mixture was concentrated in vacuo and the residue purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (1:9:90); MS (ES+) m/e 350 [M+H]+.

Example 236

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridylamine (E236)

3-Cyclobutyl-7-[(5-nitro-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E208) (100 mg, 0.29 mmol) dissolved in ethanol (10 ml). Add palladium (20 mg, 10% on coal paste) and the reaction mixture was stirred at room temperature in hydrogen atmosphere (1 ATM) for 12 hours. P is a promotional mixture is filtered through celite and the filtrate was concentrated in vacuo, getting listed in the title compound (E236); MS (ES+) m/e 310 [M+H]+.

Example 237

Morpholine-4-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyridine-3-yl]amide (E237)

Morpholine-4-carbonylchloride (0.15 ml, 1.38 mmol) is added to a stirred solution of 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridylamine (E236) (77 mg, 0.25 mmol) and triethylamine (0.04 ml, 0.30 mmol) in dichloromethane (5 ml) at 0°C. the Reaction mixture is heated to room temperature and left to mix for 24 hours. The reaction mixture is applied on the ion exchange SCX cartridge (Varian bond-elute, 5 g) and washed first with methanol, then with a mixture .880 ammonia:methanol (1:9). The combined basic fractions concentrated in vacuo and the resulting residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:95), and get mentioned in the title compound; MS (ES+) m/e 423 [M+H]+.

Examples 238-240

Connection examples 238-240 obtained from 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridylamine (E236) and related carbonylchloride or acid chlorides listed in the table, by way of example 237 (E237):

ExampleCarbonylchloride/
loranger is d
MAM/MS (M+N)+
Piperidine-1-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-3-yl]amide (E238)
Piperidine-1-carbonylchloride421
Pyrrolidin-1-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-3-yl]amide (E239)
Pyrrolidin-1-carbonylchloride407
N-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyridine-3-yl]isobutyramide (E240)
Isobutylene380

Example 241

Tetrahydropyran-4-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyridine-3-yl]amide (E241)

Tetrahydropyran-4-carboxylic acid (252 mg, 1.94 mmol), 1-hydroxybenzotriazole (262 mg, 1.94 mmol) and N-cyclohexylcarbodiimide N'-metropolitical (1.7 mmol/g, 2.3 g, 3.88 mmol) was stirred at room temperature in dichloromethane (10 ml) for 15 minutes. Add 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridylamine (E236) (300 mg, 0.97 mmol) and stirring is continued for 16 hours. The reaction mixture is applied to jonoob the military SCX cartridge (Varian bond-elute, 5 g) and washed first with methanol, then with a mixture .880 ammonia/methanol. The combined basic fractions concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:95), and get listed in title product (E241); MS (ES+) m/e 422 [M+H]+.

Example 242

3-Cyclobutyl-7-[5-(4,6-dimethoxypyrimidine-2-yl)pyridine-2-yloxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E242)

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (125 mg, of 0.58 mmol), 2-(6-chloropyridin-3-yl)-4,6-dimethoxypyrimidine (145 mg, of 0.58 mmol), calcium carbonate (720 mg, 2.2 mmol) and dimethylformamide (4 ml) is heated in a microwave reactor at 180°C for 900 seconds at 300 watts. The mixture is diluted with ethyl acetate, washed with water, then with saturated salt solution and dried over sodium sulfate. The residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0,2:1,8:98), and receive specified in the header of the product. MS (ES+)m/e 433 [M+H]+.

Examples 243-249

Connection examples 243-249 (E243-E249) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and arylhalides listed in the table, by way of example 242 (E242).

ExampleAreshared MAM/MS (M+N)+
3-Cyclobutyl-7-[5-(4-methanesulfonyl)pyrazin-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E243)2-(6-Chloropyridin-3-yl)-5-methysulfonylmethane450
N-{4-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)pyrazin-2-yl]phenyl}ndimethylacetamide (E244)
N-[4-(5-Chloropyrazine-2-yl)phenyl]ndimethylacetamide429
3-Cyclobutyl-7-(3,5-dimethylpyridin-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E245)2-Chloro-3,5-dimethylpyridin323
3-Cyclobutyl-7-[5-(morpholine-4-sulfonyl)pyridine-2-yloxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E246)4-(6-Chloropyridin-3-sulfonyl)morpholine444
3-Cyclobutyl-7-(2-methyl-furo[2,3-c]pyridine-7-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin (E247)7-Chloro-2-methyl-furo[2,3-c]pyridine349
2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-4-detoxination (E)
2-Chloro-4-detoxination364
6-(3-C is clopotel-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
yloxy)-2-methylnicotinamide (E)
6-Chloro-2-methylnicotinamide334

Example 250

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-5-methyl-2-pyrrolidinone (E250)

3-Cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (294 mg, 0.7 mmol), 1,10 phenanthroline (38 mg, 0.2 mmol) and 5-methyl-2-pyrrolidone (139 mg, 1.4 mmol) dissolved in dioxane (2 ml). Add iodide copper (I) - (39 mg, 0.2 mmol) and cesium carbonate (479 mg, 1.5 mmol) and the mixture is heated in a microwave reactor at 175°C for 15 minutes. The mixture is cooled and filtered through celite, washing with dichloromethane. The filtrate was concentrated in vacuo and the crude substance is purified column chromatography, elwira dichloromethane and then a mixture of .880 ammonia:methanol:dichloromethane (1:9:90), and get mentioned in the title compound (137 mg); MS (ES+) m/e 392 [M+H]+.

Example 251

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-3-methyl-2-imidazolidin (E251)

3-Cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (294 mg, 0.7 mmol), 1-methyl-2-imidazolidinone (90 mg, 0.9 mmol), cesium carbonate (364 mg, 1.1 mmol) and Xanthos (12 mg, 0.02 mmol) suspended in toluene (10 ml). Add Tris(dibenzylidene Eton)diplegia (0) (6 mg, to 0.007 mmol) and the mixture heated under reflux overnight. Then the reaction mixture is immediately applied to the ion exchange SCX cartridge (Varian, 5 g) and washed with methanol and then a mixture of .880 ammonia:methanol (1:9). The main fraction evaporated and the crude substance is purified by automated chromatography on reversed phase, getting listed in title product (104 mg); MS (ES+) m/e 393 [M+H]+.

Example 252

(4R)-1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-4-hydroxy-2-pyrrolidinone (E252)

The compound of example 252 (E252) is obtained from 3-cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and (4R)-4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-pyrrolidinone (Tetrahedron, 2000, 56 (39), 7705-7713) according to the method described for E251; MS (ES+) m/e 394 [M+H]+.

Example 253

N-Methyl-6-{[3-(3-methylcyclopentene)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]oxy}-3-pyridinecarboxamide (E253)

The compound of example 253 (E253) is obtained from N-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) and 3-methylcyclopentanone by way of example 223; MS (ES+) m/e 380 [M+H]+.

Example 254

5-[(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide (E254)

The compound of example 254 (E254) receive the jut of N-methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide (D49) and Cyclopentanone according to the method of example 223; MS (ES+) m/e 367 [M+H]+.

Example 255

N-Methyl-5-{[3-(3-methylcyclopentene)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]oxy}-2-pyrazinecarboxamide (E255)

The compound of example 255 (E255) is obtained from N-methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide (D49) and 3-methylcyclopentanone by way of example 223; MS (ES+) m/e 381 [M+H]+.

Example 256

1-{3-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinyl}-2-pyrrolidinone (E256)

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (103 mg, 0.47 mmol) dissolved in dry dimethylformamide (3 ml), cooled to 0°C and treated with sodium hydride (60% in mineral oil, 20 mg, 0.49 mmol). The mixture is left to warm to room temperature over 40 minutes. Add a solution of 1-(3-chloro-2-pyrazinyl)-2-pyrrolidinone (D46) (103 mg, 0.52 mmol) in dry dimethylformamide (1 ml), the mixture is stirred at room temperature for 2 hours and heated at 80°C for 2.5 hours. The mixture is allowed to cool to room temperature, applied to SCX column and washed with methanol and then a mixture of .880 ammonia/methanol (1:9). The main factions unite, concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0,2:1,8:98), and receive specified in the header of the giving (86 mg); MS (ES+) m/e 379 [M+H]+.

Example 257

7-[(5-Chloro-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin (E257)

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (184 mg, 0.85 mmol) was dissolved in dry dimethylformamide (3 ml), cooled to 0°C and treated with sodium hydride (60% in mineral oil, 36 mg, 0.89 mmol). The mixture is left to warm to room temperature for 30 minutes. Add a solution of 2,5-dichloropyrazine (D47) (139 mg, of 0.94 mmol) in dry dimethylformamide (1 ml) and the mixture is stirred at room temperature for 5 hours. The mixture is applied on a SCX column and washed with methanol and then a mixture of .880 ammonia/methanol (1:9). The main fractions are combined and concentrated in vacuo, obtaining mentioned in the title compound (268 mg); MS (ES+) m/e 330 [M+H]+.

Example 258

1-{5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinyl}-2-pyrrolidinone (E258)

A mixture of 7-[(5-Chloro-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine (E257) (132 mg, 0.40 mmol), pyrrolidinone (0.06 ml, 0.80 mmol), potassium carbonate (200 mg, 1,45 mmol), copper iodide (I) (23 mg, 0.12 mmol) and N,N'-dimethylethylenediamine (0.01 ml, 0.12 mmol) in dry dioxane (3 ml) is heated in a microwave reactor at 175°C within 30 minutes. The mixture is diluted with methanol, applied to SCX column and washed the t methanol and then a mixture of .880 ammonia/methanol (1:9). The main factions unite, concentrated in vacuo, the obtained residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0,2:1,8:98), and get mentioned in the title compound (64 mg); MS (ES+) m/e 379 [M+H]+.

Example 259

7-[(5-Bromo-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin (E259)

Specified in the title compound is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 2,5-dibromopyrazine (D48) according to the method of example 257 (E257); MS (ES+) m/e 375 [M+H]+.

Example 260

3-{5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinyl}-1,3-oxazolidin-2-he (E260)

Specified in the title compound is obtained from 7-[(5-bromo-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine (E259) and oxazolidinone by way of example 258 (E258); MS (ES+) m/e 381 [M+H]+.

Example 261

3-Cyclobutyl-7-[5-(1,1-dioxo-2-isothiazolin-2-yl)pyridine-2-yloxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E261)

A mixture of 3-cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (200 mg, 0.48 mmol), isothiazolinone 1,1-dioxide (116 mg, 0.96 mmol), (Evans, Brian J.; Takahashi Doi, Joyce; Musker, Kenneth W.; J. Org. Chem.; 55; 9; 1990; 2580-2586), potassium carbonate (238 mg, at 1.73 mmol), copper iodide (I) (27 mg, 0.14 mmol) and N,N-dimethylethylene the amine (0,02 ml, 0.14 mmol) in dry dioxane (3 ml) is heated in a microwave reactor at 140°C for 20 minutes. The mixture is diluted with methanol and applied to SCX column, elwira with methanol and then a mixture of .880 ammonia/methanol (1:9). The main fractions are combined and concentrated in vacuo. The resulting residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:95), and get mentioned in the title compound (145 mg); MS (ES+) m/e 414 [M+H]+.

Example 262

1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-imidazolidinone (E262)

Specified in the title compound is obtained from 3-cyclobutyl-7-[(5-iodine-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and 2-imidazolidinone according to the method of example 261; MS (ES+) m/e 379 [M+H]+.

Example 263

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxamide (E263)

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxamide acid (E123a) (168 mg, 0.47 mmol) dissolved in dry dimethylformamide (5 ml), treated with 1,1'-carbonyl diimidazol (230 mg, of 1.42 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. The mixture is treated .880 ammonia (0,14 ml, 2,84 mmol) and stirred for 4 hours. The reaction mixture was concentrated in HAC the mind, the resulting residue is purified column chromatography, elwira a mixture of 0.5:4,5:95), and get mentioned in the title compound; MS (ES+) m/e 339 [M+H]+.

Example 264

4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-(metiloksi)benzamide (E264)

Step 1: 1,1-Dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

A mixture of 1,1-dimethylethyl 7-{[(trifluoromethyl)sulfonyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (2.0 g, of 5.06 mmol) (Bioorg. Med. Chem. Lett.; 10; 22; 2000; 2553-2556), bis(pinacolato)Debora (1,41 g, to 5.57 mmol), the complex of 1,1'-bis(diphenylphosphino)periodically (II) (0,22 g, 0.30 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.17 g, 0.30 mmol) and potassium acetate (1,49 g of 15.2 mmol) in dry dioxane is heated at 80°C for 3 hours. The mixture is allowed to cool to room temperature, diluted with ethyl acetate and washed with water and saturated salt solution. The organic fraction is dried over magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography, elwira a mixture of ethyl acetate:pentane (1:9), and get mentioned in the title compound (1.60 g); MS (ES+) m/e 274(M+H)-CO2tBu]+.

Stage 2: (3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid

1,1-Dimethylethyl 7-(4,4,5,5-t is trimethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E264, stage 1) (1.60 g, the 4.29 mmol) dissolved in acetone (25 ml), treated with periodate sodium (2,75 g, 12.9 mmol), ammonium acetate (0.73 g, 9,44 mmol) and water (25 ml) and the resulting mixture stirred for 18 hours at room temperature. The acetone is removed by evaporation in vacuo and the remaining aqueous layer was extracted with ethyl acetate and dichloromethane. The organic layers are combined, dried over magnesium sulfate and evaporated in vacuum, obtaining mentioned in the title compound (1.06 g); MS (ES+) m/e 192(M+H)-CO2tBu]+.

Stage 3: 1,1-Dimethylethyl 7-({2-(metiloksi)-4-[(metiloksi)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, step 2) (500 mg, 1,72 mmol) dissolved in dry dichloromethane (15 ml) and successively treated with metilfenidato (313 mg, 1,72 mmol), molecular sieves (4, 1.0 g), copper acetate (467 mg, 2.58 mmol) and triethylamine (1.20 ml, 8.60 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The mixture is diluted with dichloromethane, filtered through celite and evaporated in vacuum. The residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic fraction is dried over magnesium sulfate and evaporated in vacuum. The resulting residue is purified column chromatography, elwira mixture (0,1:9,9), and we shall have specified in the title compound (240 mg). MS (ES+) m/e 328(M+H)-CO2tBu]+.

Stage 4: 4-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-(metiloksi)benzoic acid

1,1-Dimethylethyl 7-({2-(metiloksi)-4-[(metiloksi)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E264, stage 3) (240 mg, 0,56 mmol) dissolved in ethanol (2 ml), treated with 2M solution of sodium hydroxide (1 ml) and the resulting mixture stirred for 1.5 hours. The mixture was acidified with 2M-hydrochloric acid and extracted with ethyl acetate. An ethyl acetate layers are combined, dried over magnesium sulfate and evaporated in vacuum, obtaining mentioned in the title compound (0.15 g); MS (ES+) m/e 314(M+H)-CO2tBu]+.

Stage 5: 1,1-Dimethylethyl 7-{[4-[(methylamino)carbonyl]-2-(metiloksi)phenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

4-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-(metiloksi)benzoic acid (E264, stage 4) (145 mg, 0.35 mmol) dissolved in dry dimethylformamide (5 ml), treated with 1,1'-carbonyl diimidazol (85 mg, of 0.53 mmol) and the resulting mixture was stirred at room temperature for 3 hours. The mixture is treated with methylamine (of 0.53 ml, 1.05 mmol, 2M solution in THF) and stirred for 4 hours. The reaction mixture was concentrated in vacuo and the resulting residue is purified column chromatography (1:1 ethyl acetate:pentane) receiving specified in the title compound (0.10 g); MS (ES+) m/e 327(M+H)-CO2tBu]+.

Stage 6: N-Methyl-3-(metiloksi)-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide

1,1-Dimethylethyl 7-{[4-[(methylamino)carbonyl]-2-(metiloksi)phenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E264, stage 5) (100 mg, 0.23 mmol) dissolved in dry dichloromethane (2 ml), treated triperoxonane acid (1 ml) and the resulting mixture was stirred at room temperature for 2 hours. The solvent is removed in vacuum, the residue is dissolved in methanol and applied to SCX column, elwira with methanol and then a mixture of .880 ammonia:methanol (1:9). The main fractions are combined and concentrated in vacuo, obtaining mentioned in the title compound (78 mg); MS (ES+) m/e 327 [M+H]+.

Stage 7: 4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-(metiloksi)benzamid

N-Methyl-3-(metiloksi)-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide (E264, stage 6) (78 mg, 0.24 mmol) dissolved in dry dichloromethane (5 ml), treated with cyclobutanone (0.04 ml, 0.48 mmol) and acetic acid (1 drop) and the resulting mixture is stirred for 15 minutes. Add triacetoxyborohydride sodium (102 mg, 0.48 mmol) and the mixture is stirred for 30 minutes. The mixture is diluted with methanol and applied to SCX column, elwira with methanol and then a mixture of .880 ammonia/methanol (1:9). The main fractions are combined and concentrated in vacuo. The obtained residue cleaned the Ute column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:95), and get mentioned in the title compound (20 mg); MS (ES+) m/e 381 [M+H]+.

Example 265

2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]benzonitrile (E265)

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (300 mg, 1.38 mmol) was dissolved in pyridine (10 ml), cooled in an ice bath and treated with sodium hydride (60% in mineral oil) (66 mg, of 1.66 mmol) in argon atmosphere. The resulting mixture was stirred for 5 minutes, treated with copper bromide (I) (277 mg, of 1.93 mmol) and left to warm to room temperature for 30 minutes. Add a solution of 2-iodobenzonitrile (948 mg, 4.14 mmol) in pyridine (2 ml) and the mixture heated under reflux for 2.5 hours. The mixture is allowed to cool to room temperature and the solvent is removed in vacuum. The resulting residue is purified column chromatography, elwira a mixture of ammonia:methanol:dichloromethane (0,2:1,8:98), and get mentioned in the title compound (180 mg); MS (ES+) m/e 319 [M+H]+.

Example 266

3-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-4-(metiloksi)benzamide (E266)

Step 1: 1,1-Dimethylethyl 7-({2-(metiloksi)-5-[(metiloksi)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

Specified in is the head of the compound obtained from (3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, stage 2) and methyl-3-hydroxy-4-methoxybenzoate according to the method of example 264, step 3; MS (ES+) m/e 328(M+H)-CO2tBu]+.

Stage 2: 3-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-4-(metiloksi)benzoic acid

Specified in the title compound is obtained from 1,1-dimethylethyl 7-({2-(metiloksi)-5-[(metiloksi)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E266, stage 1) by the method of example 264, step 4; MS (ES+) m/e 314(M+H)-CO2tBu]+.

Stage 3: 1,1-Dimethylethyl 7-{[5-[(methylamino)carbonyl]-2-(metiloksi)phenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

Specified in the title compound is obtained from 3-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-4-(metiloksi)benzoic acid (E266, stage 2) and methylamine according to the method of example 264, step 5; MS (ES+) m/e 327(M+H)-CO2tBu]+.

Stage 4: N-Methyl-4-(metiloksi)-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide

Specified in the title compound is obtained from 1,1-dimethylethyl 7-{[5-[(methylamino)carbonyl]-2-(metiloksi)phenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E266, stage 3) according to the method of example 264, step 6; MS (ES+) m/e 327 [M+H]+.

Stage 5: 3-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-4-(metiloksi)benzamid

Specified in the header of the link is obtained from N-methyl-4-(metiloksi)-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide (E266, stage 4), by way of example 264, step 7; MS (ES+) m/e 381 [M+H]+.

Example 267

3-Chloro-4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide (E267)

Step 1: 1,1-Dimethylethyl 7-({2-chloro-4-[(metiloksi)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

Specified in the title compound is obtained from methyl 3-chloro-4-hydroxybenzoate (320 mg, 1,72 mmol) and (3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, stage 2) by the method described in example 264, step 3 (211 mg, 29%); NMR (CDCl3) δ for 1.49 (9H, s), is 2.88 (4H, m), of 3.56 (4H, m), 3,91 (3H, s), is 6.78-6.89 in (3H, m), 7,12 (H, m), 7,84 (H, m), 8,14 (H, C).

Stage 2: 3-Chloro-4-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]benzoic acid

Specified in the title compound is obtained from 1,1-dimethylethylene ester 7-({2-chloro-4-[(metiloksi)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylic acid (E267, stage 1) by the method described in example 264, step 4; MS (ES-)m/e 416 and 418 [M-H].

Stage 3: 1,1-Dimethylethyl 7-({2-chloro-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

Specified in the title compound is obtained from 3-chloro-4-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]benzoic acid (E267, stage 2) and methylamine by the way is, described in example 264, step 5 (82 mg, 52%); MS (ES+), m/e 431 and 433 [M+H]+.

Stage 4: 3-Chloro-N-methyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide

Specified in the title compound is obtained from 1,1-dimethylethyl 7-({2-chloro-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E267, stage 3) according to the method described in example 264, step 6 (54 mg, 94%); MS (ES+), m/e 331 and 333 [M+H]+.

Stage 5: 3-Chloro-4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide

Specified in the title compound is obtained from 3-chloro-N-methyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide (E267, stage 4) and cyclobutanone according to the method described in example 264, step 7 (36 mg, 57%); MS (ES+), m/e 385 and 387 [M+H]+.

Example 268

4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,3-dimethylbenzamide (E268)

Step 1: 1,1-Dimethylethyl 7-({2-methyl-4-[(metiloksi)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

Specified in the title compound is obtained from tert-butyl methyl ether 7-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (PCT Int. Appl. (2002), WO 02/40471) and methyl 4-bromo-3-methylbenzoate according to the method described in example 128 (211 mg, 29%); NMR (CDCl3) δ for 1.49 (9H, s), 2,32 (3H, m), of 2.86 (4H, m), 3,55 (4H, m)to 3.89 (3H, s)of 6.71-for 6.81 (3H, m), 7,08 (H, m), 7,80 (H, m), 7,94 (H, C).

Stage 2: 4-[(3-{[(1,1-Dimethy is ethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-methylbenzoic acid

Specified in the title compound is obtained from 1,1-dimethylethyl 7-({2-methyl-4-[(metiloksi)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E268, stage 1) by the method described in example 264, step 4; (247 mg, 94%); MS (ES-)m/e 396 [M-H].

Stage 3: 1,1-Dimethylethyl 7-({2-methyl-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

Specified in the title compound is obtained from 4-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-methylbenzoic acid (E268, stage 2) and methylamine according to the method described in example 264, step 5 (136 mg, 53%); MS (ES+), m/e 411 [M+H]+.

Stage 4: N,3-Dimethyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide

Specified in the title compound is obtained from 1,1-dimethylethyl 7-({2-methyl-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E268, stage 3) according to the method described in example 264, step 6 (90 mg, 88%); MS (ES+), m/e 311 [M+H]+.

Stage 5: 4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,3-dimethylbenzamide

Specified in the title compound is obtained from N,3-dimethyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide (E268, stage 4) (90 mg, 0.29 mmol) and cyclobutanone (50 μl, of 0.58 mmol) by the method described in example 264, step 7 (71 mg, 67%); MS (ES+), m/e 365 [M+H]+.

Example 269

3-Cyclobutyl-8-[(phenylmethyl)on the si]-2,3,4,5-tetrahydro-1H-3-benzazepin-7-carbonitrile (E269)

A mixture of 3-cyclobutyl-7-iodine-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E226) (250 mg, of 0.58 mmol), tetrakis(triphenylphosphine)palladium(0) (33 mg, 0,029 mol), copper iodide (I) (11 mg, 0,058 mmol) and sodium cyanide (56 mg, 1.15 mmol) in tetrahydrofuran (5 ml) was heated under reflux for 16 hours. The mixture is cooled and diluted with ethyl acetate, filtered through celite, washed with water, then with saturated salt solution and dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified HPLC on reversed phase, getting mentioned in the title compound; MS (ES+) m/e 333 [M+H]+.

Example 270

3-Cyclobutyl-7-[(2-forfinal)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E270)

The compound of example 270 (E270) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 2-periodental by way of example 128; MS (ES+) m/e 312 [M+H]+.

Example 271

4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-perbenzoate (E271)

A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) (100 mg, 0.46 mmol), 3,4-difterential (70 mg, 0.51 mmol) and potassium carbonate (159 mg, 1.15 mmol) in dimethyl sulfoxide (2 ml) is heated at 85°C for 2 hours. The reaction mixture is cooled, causing the ion exchange SCX cartridge (Varian bond-elute, 10 g) and raybaut first with methanol, then the mixture .880 ammonia/methanol (1:9). The combined basic fractions concentrated in vacuo, obtaining specified in the header connection (E271). MS (ES+) m/e 337 [M+H]+.

Example 272

4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-Formentera acid (E272)

4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-perbenzoate (E271) (150 mg, 0.45 mmol) dissolved in a mixture of ethanol (1 ml) and water (1.5 ml), treated with sodium hydroxide (150 mg, 4.5 mmol) and heated under reflux for 2 hours. Then the reaction mixture is treated with acetic acid (0,39 ml of 6.75 mmol) and concentrated in vacuo. The resulting residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (2:18:80), and receive specified in the header connection. MS (ES+) m/e 356 [M+H]+.

Example 273

4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluoro-N-methylbenzamide (E273)

A solution of 4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fermenting acid (E272) (164 mg, 0.36 mmol) and O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea of hexaflurophosphate (438 mg, 1.15 mmol) in dimethylformamide (2 ml) is treated with diisopropylethylamine (and 0.40 ml, 2.3 mmol), then 2M solution of methylamine in tetrahydrofuran (2 ml). The reaction mixture was paramesh what happens at room temperature for 4 hours, put on ion exchange SCX column (Varian bond-elute, 10 g), washed first with methanol, then with a mixture .880 ammonia/methanol, and the basic fraction was concentrated in vacuo. The resulting residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:95), and receive specified in the header connection. MS (ES+) m/e 369 [M+H]+.

Example 274

3-Cyclobutyl-7-[(2-fluoro-4-itfeel)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E274)

Step 1: 1,1-Dimethylethyl 7-[(2-fluoro-4-nitrophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

3,4-diplomarbeit (664 mg, 4,18 mmol) are added to a mixture of tert-butyl methyl ether 7-hydroxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-carboxylic acid (WO 02/40471) (1 g, 3.8 mmol) and potassium carbonate (1.3 g, 9,49 mmol) in dimethylformamide (10 ml) and the reaction mixture is heated at 130°C for 3 hours. The reaction mixture is cooled, diluted with ethyl acetate, washed with water, then with a mixture of water:saturated salt solution (1:1), dried over sodium sulfate and concentrated in vacuo. The resulting residue is purified column chromatography, elwira a mixture of ethyl acetate:pentane (1:10), receiving specified in the header connection. MS (ES+) m/e 303 [M-COOtBu]+.

Stage 2: 1,1-Dimethylethyl 7-[(4-amino-2-forfinal)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

To a solution of 1,1-dimethylethyl 7[(2-fluoro-4-nitrophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E274, stage 1) (1,37 g, 3,40 mmol) in ethanol (25 ml) is added palladium-on-coal (10 wt.% palladium) (300 mg) and the reaction mixture was stirred at room temperature in hydrogen atmosphere (1 ATM) for 3 hours. The reaction mixture was filtered through celite and concentrated in vacuo, obtaining specified in the header connection. MS (ES+) m/e 273 [M-M-COOtBu]+.

Stage 3: 1,1-Dimethylethyl 7-[(2-fluoro-4-itfeel)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

To a solution of 1,1-dimethylethyl 7-[(4-amino-2-forfinal)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E274, stage 2) (0.5 g, of 1.34 mmol) and iodoform (1 g, 2,69 mmol) in tetrahydrofuran (10 ml) is added dropwise tert-butylnitrite (0,32 ml, 2,69 mol). Then the reaction mixture is heated under reflux for 1 hour, cooled, concentrated in vacuo, the obtained residue is purified column chromatography, elwira a mixture of ethyl acetate:pentane (1:10), and receive specified in the header connection. MS (ES+) m/e 384 [M-COOtBu]+.

Stage 4: 7-[(2-Fluoro-4-itfeel)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin

Specified in the title compound is obtained from 1,1-dimethylethyl 7-[(2-fluoro-4-itfeel)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E274, stage 3) according to the method of description 2 (D2). MS (ES+) m/e 384 [M+H]+.

Stage 5: 3-Cyclobutyl-7-[(2-fluoro-4-itfeel)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin

Specified in the header of the link is obtained from 7-[(2-fluoro-4-itfeel)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E274, stage 4) by the method of example 1 (E1). MS (ES+) m/e 438 [M+H]+.

Example 275

1-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-forfinal}-2-pyrrolidone (E275)

Specified in the header of the product obtained from 3-cyclobutyl-7-[(2-fluoro-4-itfeel)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E274) according to the method of example 258 (E258). MS (ES+) m/e 395 [M+H]+.

Example 276

N-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-forfinal}ndimethylacetamide (E276)

Step 1: 1,1-Dimethylethyl 7-{[4-(acetylamino)-2-forfinal]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

To a solution of 1,1-dimethylethyl 7-[(4-amino-2-forfinal)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E274, stage 2) (250 mg, 0.67 mmol) in dichloromethane (10 ml), add triethylamine (0,19 ml of 1.34 mmol) and acetylchloride (50 μl, of 0.74 ml) and the reaction mixture stirred at room temperature for 16 hours. Then the reaction mixture was diluted with dichloromethane, washed with 3N aqueous citric acid solution, saturated sodium bicarbonate solution, water and dichloromethane, dried over sodium sulfate and concentrated in vacuo. The resulting residue is purified column chromatography, elwira a mixture of ethyl acetate:pentane (1:1), and receive specified in the header connection. MS (ES+) m/e 413 [M-H]-.

Stage 2: N-{4-[(3-Cyclobutyl-23,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-forfinal}ndimethylacetamide

Specified in the title compound is obtained from 1,1-dimethylethyl 7-([4-(acetylamino)-2-forfinal]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E276, stage 1), using 2-stage method described in example 274, stage 4-5. MS (ES+) m/e 369 [M+H]+.

Example 277

The compound of example 277 (E277) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and the appropriate aromatic iodide indicated in the table, by way of example 128 (E128):

ExampleAromatic iodideMAM/MS [M+H]+
1-[3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]
azepin-7-yloxy)phenyl]-1-pyrrolidin-1-ylmethanone (E)
1-[(3-Itfeel)carbonyl]pyrrolidin (D52)391

Example 278

The compound of example 278 (E278) is obtained from 5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyridineboronic acid (E187a) and the appropriate amine indicated in the table, by way of example 177 (E177):

ExampleAminMAM/MS [M+H]+
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy]-N-(tetrahydro-2H-Piran-4-yl)-2-pyridinecarboxamide (E) Tetrahydro-2H-Piran-4-amine422

Example 279

3-Cyano-4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide (E279)

Stage 1: 3-Cyano-4-(metiloksi)benzoic acid

Specified in the title compound is obtained from methyl 3-cyano-4-(metiloksi)benzoate by the method of example 264, step 4;1H NMR (CDCl3) 8,32 (1H, d), 8,29-of 8.27 (1H, DD), 7,06? 7.04 baby mortality (1H, d), a 4.03 (3H, s).

Stage 2: 3-Cyano-N-methyl-4-(metiloksi)benzamid

Specified in the title compound is obtained from 3-cyano-4-(metiloksi)benzoic acid (E279, stage 1) by the method of example 264, step 5; MS (ES+) m/e 191 [M+H]+.

Stage 3: 3-Cyano-4-hydroxy-N-methylbenzamide

3-Cyano-N-methyl-4-(metiloksi)benzamide (E279, stage 2) (346 mg, 1.82 mmol) dissolved in dry dichloromethane (10 ml), cooled to 0°C and treated with boron bromide (1 M solution in dichloromethane) (9,11 ml, 9,11 mmol). The mixture is stirred for 30 minutes, allowed to warm to room temperature and stirred for 18 hours. The mixture is cooled in an ice bath, treated with added dropwise with water and then left to warm to room temperature. The mixture is then poured into 2M hydrochloric acid solution (10 ml) and extracted with ethyl acetate. An ethyl acetate layers are combined, dried over magnesium sulfate iprivate in vacuum. The resulting residue is purified column chromatography, elwira a mixture of ethyl acetate:dichloromethane (1:1), and get mentioned in the title compound (86 mg); MS (ES+) m/e 177 [M+H]+.

Stage 4: 1,1-Dimethylethyl 7-({2-cyano-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate

Specified in the title compound is obtained from 3-cyano-4-hydroxy-N-methylbenzamide (E279, stage 3) and (3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, stage 2) by the method of example 264, step 3; MS (ES+) m/e 322(M+H)-CO2tBu]+.

Stage 5: 3-Cyano-N-methyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide

Specified in the title compound is obtained from 1,1-dimethylethyl 7-({2-cyano-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-carboxylate (E279, stage 4) by the method of example 264, step 6; MS (ES+) m/e 322 [M+H]+.

Step 6: 3-Cyano-4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide

Specified in the title compound is obtained from 3-cyano-N-methyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide (E279, stage 5), by way of example 264, step 7; MS (ES+) m/e 376 [M+H]+.

Example 280

3-Cyclobutyl-7-{[6-(4-morpholinylcarbonyl)-3-pyridazinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E280)

Stage 1: 4-[(6-Chloro-3-p is ridazine)carbonyl]morpholine

A mixture of 6-oxo-1,6-dihydro-3-pyridineboronic acid (A.E. Mourad et al. J. Het. Chem. 1992; 29 (6), 1583-1592; 0.5 g) and phosphorus oxychloride (2 ml) was heated under reflux for 2 hours, the Excess phosphorus oxychloride evaporated and to the residue add THF (5 ml). Then the solution is cooled to 0°C, add triethylamine (1.1 ml) and then morpholine (1,87 ml). The mixture is left to warm to room temperature, stirred for 16 h, then diluted with ethyl acetate (10 ml) and filtered. The filtrate is evaporated and purified by chromatography on silica gel, elwira with ethyl acetate, and get mentioned in the title compound; MS (ES+) m/e 228 [M+H]+.

Stage 2: 3-Cyclobutyl-7-{[6-(4-morpholinylcarbonyl)-3-pyridazinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin

A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) (84 mg, 0,385 mmol), 4-[(6-chloro-3-pyridazinyl)carbonyl]the research (E280, stage 1) (70 mg, 0,308 mmol) and potassium carbonate (85 mg, 0,616 mmol) in dry acetone (3 ml) is heated at 140°C for 2×15 min (300 W) in a microwave reactor. The cooled reaction mixture is filtered, concentrated in vacuo and purified column chromatography on silica gel, elwira mixture .880 ammonia:methanol:dichloromethane (0.5 in:4,5:190), and get mentioned in the title compound; MS (ES+) m/e 409 [M+H]+.

Examples 281-282

Connection examples 281-282 (E281-282) is obtained from 3-cyclobutyl-2,3,4,5-tetrahedron-3-benzazepin-7-ol (E3) and 6-oxo-1,6-dihydro-3-pyridineboronic acid, using the appropriate amine indicated in the table, the two-stage method described in example 280:

ExampleAminMAM/MS (M+N)+
6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide (E281)Methylamine353
6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-N-methyl-3-pyridinecarboxamide (E282)Ethyl(methyl)amine381

Example 283

3-Cyclobutyl-7-{[4-(4-morpholinyl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E283)

Stage 1: 4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butane acid

Ethyl 4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoate (E167a) (2.2 g, 6.6 mmol) dissolved in methanol (40 ml) and treated with 2N sodium hydroxide solution (10.0 ml). After stirring at reflux for 1 hour, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude mixture is applied to the ion exchange SCX cartridge (Varian bond-elute) and washed with water and is eaten with methanol. The organic fraction is evaporated in vacuum, obtaining specified in the header connection (E283); MS (ES+) m/e 304 [M+H]+.

Stage 2: 3-Cyclobutyl-7-{[4-(4-morpholinyl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin

4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butane acid (E283, stage 1) (0.15 g, 0.50 mmol) dissolved in dry dichloromethane (5 ml) and dry dimethylformamide (2 ml), treated with hydrate of 1-hydroxybenzotriazole (0.14 g, 1.0 mmol), N-cyclohexylcarbodiimide and N'-metropolitian HL (of 0.53 g, 1.0 mmol, 1.7 mmol/g) and stirred for 45 minutes. Add morpholine (0,056 ml of 0.65 mmol) and the mixture is stirred for 3 hours at ambient temperature. The crude reaction mixture was applied to ion exchange SCX cartridge (Varian bond-elute) and washed with water, methanol and then a mixture of .880 ammonia:methanol (1:9). The combined basic fractions evaporated in vacuum. The resulting residue is purified column chromatography, elwira mixture .880 ammonia:methanol:dichloromethane (0.5:4.5 to:95 to 1:9:90), and get mentioned in the title compound (E283); MS (ES+) m/e 373 [M+H]+.

Examples 284-285

Connection examples 284-285 (E284-285) is obtained from 3-cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) and the appropriate acid indicated in the table, by way of example 13 (E13):

When the er AcidMAM/MS (M+N)+
3-Cyclobutyl-7-[(1-{[4-(4-morpholinyl)phenyl]carbonyl}-4-piperidinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E284)4-(4-Morpholinyl)benzoic acid490
3-Cyclobutyl-7-{[1-(cyclopropylmethyl)-4-piperidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E285)Cyclopropylalanine acid383

Example 286

3-Cyclobutyl-7-[(1-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl}-4-piperidinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepin (E)

The compound of example 286 (E) is obtained from 3-cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) and CIS-2,6-dimethylmorpholine by way of example 61 (E61). MS (ES+) m/e 442 [M+H]+.

Example 287

3-Cyclobutyl-7-{[TRANS-4-(4-morpholinylcarbonyl)cyclohexyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E)

The compound of example 287 (E) is obtained from 3-cyclobutyl-7-(piperidine-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) and CIS-4-(4-morpholinylcarbonyl)cyclohexanol (D55) according to the method of example 5A (E5a). MS (ES+) m/e 413 [M+H]+.

All listed in this document publications, which include the e limited to, patents and patent applications included in this description by reference as if each individual publication, it was stated that it is fully incorporated into this description by reference.

Example 288

3-Cyclobutyl-7-{[6-(4-morpholinyl)-2-pyrazinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepin (E)

The compound of example 288 (E) is obtained from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 4-(6-chloro-2-pyrazinyl)of the research [Zagulyaeva, O.A. J. Org. Chem. USSR, EN, 14; 1978; 377-380] according to the method of example 242 (E242); MS (ES+) m/e 381 [M+H]+.

Biological data

Membrane preparation containing receptors for histamine H3 can be obtained as follows.

(i) obtaining a cell line containing histamine H3

DNA containing the gene of the human histamine H3 (Huvar, A. et al. (1999) Mol. Pharmacol. 55(6), 1101-1107), clone in support vector pCDNA3.1 TOPO (InVitrogen), cDNA isolated from this vector by restriction cleavage of plasmid DNA with enzymes BamH1 and Not-1 and are ligated in the induced expression vector pGene (InVitrogen), cleaved with the same enzymes. With the GeneSwitch systemTM(the system where the transgene expression ceases in the absence of the inducing factor and is run in the presence of the inducing factor) operate according to the method described in patent No.: 5364791; 5874534 and 5935934. Legirovannoi DNA p is rinoseat into competent bacterial host cell DH5α E. coli and put them on the agar broth, Luria (Luria Broth (LB)containing ZeocinTM(antibiotic, which allows selection of cells expressing the gene of the sh ble, which is present in pGene and pSwitch) at a concentration of 50 μg/ml Colonies containing re legirovannoi plasmid, identified using restriction analysis. DNA for transfection into mammalian cells is obtained from a 250 ml culture of bacterial host containing plasmid pGeneH3, and produce with the help of a set of DNA (Qiagen Midi-Prep), following the manufacturer's instructions (Qiagen). Cells CHO K1, advance transfetsirovannyh regulatory plasmid pSwitch (InVitrogen)for 24 hours before using seeded at a concentration of 2×106cells per T75 flask in complete medium containing environment HamsF12 (GIBCOBRL, Life Technologies), supplemented with 10% vol./about. detalizirovannoi fetal bovine serum, L-glutamine and gidrolizina (100 g/ml). Plasmid DNA transferout in cells using lipofectamine, in accordance with the manufacturer's instructions (InVitrogen). 48 hours after transfection, the cells are placed in complete medium supplemented with 500 μg/ml ZeocinTM.

To induce receptor expression, 10-14 days after breeding to culture medium, add 10 nm mifepristone (InVitrogen). 18 hours after induction the cells detach from the flask, using ethylenediaminetetraacetic acid (DTA; 1:5000; InVitrogen), and then washed several times with phosphate buffered saline pH 7.4 and re-suspended in the medium for sorting, containing a minimum maintenance medium (MEM) without phenol red, supplemented with salts Earl and 3% Foetal Clone II (Hyclone). Approximately 1×107cells analyzed for receptor expression by staining rabbit polyclonal antibody, 4a, against the N-terminal domain of the histamine receptor H3, then incubated on ice for 60 minutes and washed twice with medium for sorting. Antibodies associated with the receptor, detected by incubation of the cells for 60 minutes on ice with goat antibodies against rabbit antibodies conjugated with a fluorescent marker Alexa 488 (Molecular Probes). After two additional washes for sorting cells filtered through a 50 μm FilconTM(BD Biosciences) and then analyzed on a flow cytometer FACS Vantage SE with automatic console for the preparation of cellular products. As a control use neindutsirovannom cells treated in this way. Stained cells are placed in separate cells in 96-well plates, to which is added a complete medium containing 500 μg/ml ZeocinTMand leave to rise before re-analysis of the expression of the receptor binding antibodies and ligands. CL is h 3H3 selected to obtain membranes.

(ii) Obtaining membranes from cultured cells

All stages of a method carried out at 4°C using pre-cooled reagents. Cellular precipitate resuspended in 10 volumes of buffer A2, containing 50 mm N-2-hydroxyethylpiperazine-N'-2-econsultancy acid (HEPES) (pH 7,40), supplemented with 10-4M leupeptin (acetyl-leucyl-leucyl-arginyl; Sigma L2884), 25 μg/ml bacitracin (Sigma B0125), 1 mm ethylenediaminetetraacetic acid (EDTA), 1 mm phenylmethylsulfonyl (PMSF) and 2×10-6M pepstatin A (Sigma). The cells are then homogenized pulses 2×15 seconds in 1-liter glass Waring mixer and centrifuged for 20 minutes at 500g. Then the supernatant centrifuged for 30 minutes at 48000g. The precipitate is again suspended in 4 volumes of buffer A2 by intensive mixing for 5 seconds, then homogenized in a Dounce homogenizer (10-15 strokes). At this point, take an aliquot of the preparation, put them in polypropylene tubes and stored at -70°C.

The biological activity of the compounds of this invention can be analyzed in vitro by the following methods.

(I) analysis of the binding of histamine H3

For each of the analyzed compounds in 96-well plate, the wells of which are transparent bottom and white walls, add:

(a) 10 ál of the test compounds (or 10 μl of jodieproffit (known antagonist of histamine H) with a final concentration of 10 mm), diluted to the desired concentration of 10% DMSO;

(b) 10 µl125I 4-[3-(4-impenitency)propyl]-1H-imidazole (impression) (Amersham; of 1.85 MBq/ml or 50 µci/ml; specific activity of ~2000 CI/mmol) diluted to 200 PM buffer for analysis (50 mm Tris(hydroxymethyl)aminobutanoic buffer (TRIS) pH of 7.4, 0.5 mm ethylenediaminetetraacetic acid (EDTA)), obtaining a final concentration of 20 PM; and

(c) 80 μl of the mixture balls/diaphragms obtained in the following way: beads for scintillation proximal analysis (SPA) type WGA-PVT suspended in the buffer for analysis at a concentration of 100 mg/ml, then mixed with membranes (obtained by the above method) and diluted in buffer for analysis, receiving the final volume of 80 μl, which contains 7,5 mg protein and 0.25 mg of beads per well - a mixture of pre-mixed at room temperature for 60 minutes on the roller. The tablet is shaken for 5 minutes and then allowed to stand at room temperature for 3-4 hours before reading the counter Wallac Microbeta using normalized within 1 minute to account for tritium. Data analyzed using a 4-parameter logistic equation.

(II) Functional antagonistic analysis of histamine H3

For each of the analyzed compounds in 96-well plate, the wells of which are transparent bottom and white walls, add:

(a) 10 m the l of the analyzed compounds (or 10 ál guanosin-5'-triphosphate (GTP) (Sigma) as a control for nonspecific binding), diluted to the desired concentration buffer for analysis (20 mm N-2-hydroxyethylpiperazine-N'-2-econsultancy acid (HEPES) + 100 mm NaCl +10 mm MgCl2, a pH of 7.4 with NaOH);

(b) 60 ál of the mixture into balls/membrane/GDF obtained as follows: the balls for scintillation proximal analysis (SPA) agglutinin wheat germ-polyvinyltoluene (WGA-PVT) suspended in buffer for analysis at a concentration of 100 mg/ml, then mixed with membranes (obtained by the above method) and diluted with buffer for analysis, receiving the final volume of 60 μl, containing 10 μg of protein and 0.5 mg of beads per well - a mixture of pre-mixed at 4°C for 30 minutes on the roller and immediately before entering into the tablet add guanosine 5'-diphosphate (GDF) (Sigma; diluted analytical buffer) to obtain a final concentration of 10 μm. To balance the antagonist and the receptor/balls, tablet incubated at room temperature with shaking for 30 minutes, then add:

(c) 10 μl of histamine (Tocris) with a final concentration of 0.3 μm; and

(d) 20 ál salt of triethylamine and guanosine 5'[γ35-S]citrifolia (Amersham; radioactivity concentrations = 37 CVR/µl or 1 MCI/ml; specific activity 1160 CI/mmol)diluted with buffer for analysis to a concentration of 1.9 nm, final concentration of 0.38 nm.

The tablet then incubated nasaker at room temperature for 30 minutes, then centrifuged for 5 minutes at 1500 rpm in 3-6 hours after centrifugation tablet read on the counter Wallac Microbeta using normalized within 1 minute to account for tritium. Data analyzed using a 4-parameter logistic equation. Basal activity when in the wells do not add histamine, used as a minimum.

Results

The compounds of examples E1-3, E5-149, E151-230, E233-235, E237-256, E258, E260-270, E273 and E275-288 test using functional antagonistic analysis of histamine H3 and find that they exhibit antagonism in the following interval: 6,5-10,5 pKb. More specifically, the compounds of examples 1, 52, 121, 125, and 217 exhibit antagonism in the following interval: 9,0-10,5 pKb. More specifically, the compound of example 121 is antagonism > 9,5 pKb.

1. The compound of General formula (I)

where R1represents an unsubstituted cyclobutyl;
R2is a 2-pyrazinyl, substituted CON(H)(Me), or 2-pyridinyl-M-pyrrolidinyl where the specified pyrrolidinyl group substituted by a group =O; which is:
methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-carboxylic acid
; or
1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy] - pyridinyl}-2-pyrrolidinone
;
or their pharmaceutically acceptable salt.

2. The compound of formula (I) according to claim 1, which is 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

or its pharmaceutically acceptable salt.

3. The compound of formula (I) according to claim 1, which is 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone
.

4. Pharmaceutically acceptable salt according to claim 2, which is an acid additive salt formed 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone and acid.

5. Pharmaceutically acceptable salt according to claim 4, where the acid is a maleic, hydrochloric, Hydrobromic, phosphoric, acetic, fumaric, salicylic, sulfuric, citric, lactic, almond, tartaric and methansulfonate acid.

6. Pharmaceutical composition having affinity to the histamine receptor H3, which contains a therapeutically effective amount of 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone
or
its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier or excipient.

7. 1-{6-[(3-cyclobuta the l-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone or its pharmaceutically acceptable salt, used as a therapeutic substance having affinity to the histamine receptor H3.

8. The method of obtaining the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt
,
where R1represents an unsubstituted cyclobutyl;
R2is a 2-pyrazinyl, substituted CON(H)(Me), 2-pyridinyl-N-pyrrolidinyl where the specified pyrrolidinyl group substituted by a group =O;
where the connection accordingly is methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[C1]azepin-7-yl hydroxy)pyrazin-2-carboxylic acid
; or
1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

or their pharmaceutically acceptable salt, which comprises the interaction of the compounds of formula (II)

where R1defined above,
with the compound of the formula R2'-L1where R2'such as defined above for R2,
and L1denotes a suitable leaving group such as halogen atom or an optionally activated hydroxyl group.

9. The method of obtaining the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt

where R1represents an unsubstituted cyclobutyl;
R2 represents a 2-pyrazinyl, substituted CON(H)(Me), 2-pyridinyl-N-pyrrolidinyl where the specified pyrrolidinyl group substituted by a group =O;
where the connection accordingly is methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl hydroxy)pyrazin-2-carboxylic acid

or
1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

or their pharmaceutically acceptable salt, which comprises the interaction of the compounds of formula (III)

where R2as defined above, with a compound of formula R1'-L2where R1'such as defined above for R1and L2denotes a suitable leaving group such as halogen atom.

10. The method of obtaining the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt
,
where R1represents an unsubstituted cyclobutyl;
R2is a 2-pyrazinyl, substituted CON(H)(Me), 2-pyridinyl-N-pyrrolidinyl where the specified pyrrolidinyl group substituted by a group =O;
where the connection accordingly is methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[C1]azepin-7-yl hydroxy)pyrazin-2-carboxylic acid

or
1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridi the yl}-2-pyrrolidinone

or their pharmaceutically acceptable salt, which comprises the interaction of the compounds of formula (III)

where R2such as defined above, with a ketone of the formula R1'-O, where R1'the same as defined for R1.

11. The method of obtaining the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt
,
where R1represents an unsubstituted cyclobutyl;
R2is a 2-pyrazinyl, substituted CON(H)(Me), 2-pyridinyl-N-pyrrolidinyl where the specified pyrrolidinyl group substituted by a group =O;
where the connection accordingly is methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)pyrazin-2-carboxylic acid

or
1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

or their pharmaceutically acceptable salt,
which includes the removal of the protective group of the protected compounds of formula (I).



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described are spirocyclic derivatives of cyclohexane of general formula . Values of radicals are given in the formula of invention. The compounds have affinity to the ORL1 receptor and can be used for treating abstinence syndrome (withdrawal syndrome) and pain. Also described is a medicinal agent and use of formula (I) compounds for preparing respective medicinal agents.

EFFECT: increased effectiveness of using the compounds.

13 cl, 17 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) , where R1 is hydrogen, C1-C7 alkyl; R2 is C1-C7 alkyl, aryl, C1-C7 haloalkyl or C3-C8 cycloalkyl; R3, R4 each independently represents hydrogen, halogen, C1-C7 alkoxy, C1-C7 alkylsuphonyl; R5 is hydrogen, halogen, C1-C7 alkyl, C1-C7 haloalkoxy, or aryloxy, or is -NR7R8, where R7 and R8 represent C1-C7 alkyls, or R7 and R8 together with the nitrogen atom to which they are bonded can form a 4-7-member heterocycloalkyl group, which can be substituted with one or more substitutes selected from a group consisting of halogen, C1-C7 alkyl, C1-C7 alkoxy, hydroxyl, phenyl and di(C1-C7)alkylamino; R6 is hydrogen or together with R5 can form a 5- or 6-member heterocycloalkyl group which can be substituted with one or more halogens; and their pharmaceutically acceptable salts of acid compound, except the range of compounds given in paragraph 1 of the formula of invention. The invention also relates to medicine based on said compounds, with activity of allosteric enhancer of GABA-B receptors and use of compounds of the formula to prepare medicines used in treating central nervous system disorders, including anxiety and depression.

EFFECT: novel compounds are obtained and described, which can be used for preparing medicines used in treating central nervous system disorders, including anxiety and depression.

14 cl, 58 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: chemistry.

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9 cl, 1 dwg, 7 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula IId and their pharmacologically acceptable salts. In formula IId M represents -CH- or -N-; R2c bonded with carbon atom of 5-member ring and is selected from hydrogen and methyl; R2d is bonded with carbon atom from 6-member ring and selected from hydrogen and fluorine; one of R2a and R2b represents methoxy, and other is Q1X1, where X1 represents -O-, and values of other radicals are given in formula IId, to pharmaceutical composition, inhibiting antiogenesis and/or reducing vessel permeability, which contains as active component compound of formula IId, to application of invention compounds for preparation of medication and to compounds of 7-benzyloxy-4(4-fluorine-2-methylindol-5-iloxy)-6-methoxyquinazoline and 4-(4-fluorine-2- methylindol -5-yloxy)-7-hydroxy-6-methoxyquinazo-line.

EFFECT: development of effective method of obtaining quinazoline compounds.

12 cl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) , where R1 and R2 are independently chosen from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5; X and Y are independently chosen from O and (CR6R7)n; R3 represents hydrogen, alkyl or M; M represents an ion, chosen from aluminium, calcium, lithium, magnesium, potassium, sodium, zinc or their mixture; Z represents CR4; R4 is chosen from hydrogen, halogen, alkyl, alkylaryl and XYR5; R5 is chosen from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently chosen from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R1 and R2 represents XYR5, and at least one of X and Y represents (CR6R7)n. The invention also pertains to the method of increasing concentration of D-serine and/or reducing concentration of toxic products of D-serine oxidation under the effect of DAAO in mammals, involving introduction into a subject of a therapeutically effective amount of a formula I compound, to the method of treating schizophrenia, treating or preventing loss of memory and/or cognitive ability, to the method of improving learning ability, method of treating neuropathic pain, as well as to a pharmaceutical composition, with DAAO inhibitory activity, based on these compounds.

EFFECT: obtained are new compounds and a pharmaceutical composition based on these compounds.

27 cl, 4 tbl, 72 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to new quinazoline derivative or its pharmaceutically acceptable acid-additive salt. Quinazoline derivative is described with general formula (I): , where Z is NH; m is 2; the first R1 group located in 5th position is chosen from isopropoxy and tetrahydropyran-4-yloxy; the second R1 group located in 7th position is chosen from ethoxy or propoxy substituted with chlorine or certain substituted or unsubstituted heterocycles containing at least one or two N atoms and at least one O atom together with N atom; n is 0 or 1; R3 group located in 5th or 6th position of 2,3-methylenedioxypyridine-4-yl group, is chosen from Cl or Br. Besides, there is disclosed pharmaceutical composition used as antiinvasive agent to control distribution and/or treat solid cancer, containing this quinazoline derivatives combined with pharmaceutically acceptable diluent or carrier. Declared quinazoline derivatives possess considerable antineoplastic action ensured with effective inhibition of one or more nonreceptor protein kinases, specific to tyrosine, referring to Src linase family.

EFFECT: treatment of cancer in homoiotherms and human.

11 cl, 2 tbl, 22 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.

EFFECT: increased effectiveness of using the compounds.

24 cl, 20 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from compounds of formulae Ia, lb and Ic, which have protein kinase activity on kinase selected from CDKs, Aurora, Jak2. Rock, CAMKI, FLT3, Tie2, TrkB, FGFR3 and KDR, abnormal activity of which is observed in pathological conditions such as nonmalignant and malignant proliferative diseases. In compounds of formulae , and : n equals 0 or 1, R1 is selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted CpC6alkyl and halogen-substituted C1-C6alkoxy, R2 is selected from a group comprising phenyl, 6-member heteroaryl containing 1-2 nitrogen atoms in the heteroaryl ring as heteroatoms, and phenyl(C0-C4)alkyl, where the said phenyl and heteroaryl in R2 are optionally substituted with 1-3 radicals independently selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy, -S(O)0-2R5, -COOR5 and -NR5C(O)R6, where R5 is selected from C1-C6alkyl, and R6 is selected from phenyl, where the said phenyl in R6 is optionally substituted with 1-3 radicals independently selected from a group comprising C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy, X is selected from CR7 and N, where R7 is selected from hydrogen or C1-C6alkyl.

EFFECT: increased effectiveness of using the compounds.

7 cl, 3 dwg, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydropyridoindole derivatives of general formula , where R1, R2, R3 and R4 independently represent hydrogen; C1-C5alkyl, which can be optionally substituted and represents trifluoromethyl if C1-C5alkyl is substituted; C1-C3alkoxy or halogen, and R5 is C1-C6alkylcarbonyl, C1-C5alkylcarbamoyl, C1-C5alkoxycarbonyl, C2-C5alkenylcarbonyl, C3-C6cycloalkylcarbonyl, C3-C6cycloalkyl(C1-C3)alkylcarbonyl, C3-C6cycloalkylcarbamoyl, C3-C6cycloalkylthiocarbamoyl, phenylcarbonyl or phenyl(C1-C3)alkylcarbonyl, where the phenyl residue in these two groups contains one, two, three or four substitutes, independently selected from a group comprising C1-C4alkyl, C1-C3alkoxy, halogen, trifluoromethyl and trifluoromethoxy, monosubstituted with a C3-C6cycloalkyl group, or monosubstituted with a phenyl group which in turn is substituted with a C1-C3alkyl group; phenyl(C1-C3)alkoxycarbonyl, phenylcarbamoyl or phenylthiocarbamoyl (where these two groups are optionally independently monosubstituted with a C1-C5alkyl group or halogen atoms); phenyl(C1-C3)alkylcarbamoyl, phenyl(C1-C3)alkylthiocarbamoyl, biphenylcarbamoyl, naphthylcarbonyl, naphthyl(C1-C3)alkylcarbonyl or naphthylcarbamoyl (where the naphthyl residues in these three groups are optionally monosubstituted with substitutes independently selected from a group comprising C1-C3alkyl, C1-C3alkoxy and halogen); fluorenylcarbonyl, optionally substituted with an oxo group, fluorenyl(C1-C3)alkoxycarbonyl; or 5-9-member heteroarylcarbonyl groups containing one or two heteroatoms, independently selected from a group comprising oxygen, nitrogen and sulphur, where the said groups can be substituted with one or two groups independently selected from C1-C3alkyl and halogen, provided that if R1, R2, R3, R4 are hydrogen, R5 is not ethoxycarbonyl or tert-butoxycarbonyl, or salt thereof. The invention also relates to a pharmaceutical composition based on the compound of formula I and to use of the compound in preparing a medicinal agent.

EFFECT: obtaining novel tetrahydropyridoindole derivatives which have CRTH2 receptor antagonistic activity.

14 cl, 14 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel therapeutically suitable derivatives of pyridazin-3(2H)-one of formula and pharmaceutical compositions containing the said derivatives. These compounds are used for treating, preventing or inhibiting corresponding pathological conditions, diseases or disorders, mainly asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable colon syndrome.

EFFECT: obtaining compounds which are active and selective phosphodiesterase 4 (PDE4) inhibitors.

11 cl, 1 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable additive salts and stereochemically isomeric forms as 11-HSD1 inhibitors, to their use, a pharmaceutical composition based on the said compounds and method of obtaining the said compounds. In general formula (I) , X is C or N; Y is C or N; L is methyl or a single bond; Z1 is a single bond, C1-2alkyl or a radical of formula -CH=; Z2 is a single bond, C1-2alkyl; R1 is hydrogen, halogen, hydroxy; R2 is hydrogen, halogen or C1-4alkyloxy; A is phenyl or a monocyclic heterocycle selected from a group consisting of thiophenyl or pyrridinyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by 11-HSD1.

9 cl, 7 dwg, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidine and pyrrolopyridine of general formula (I), substituted with a cyclic amino group (II), or their pharmaceutically acceptable salts having CRF antagonist properties. In general formula the cyclic amino group has formula , in which the cyclic amino group is a 6-member saturated cyclic amine, the said cyclic amine is substituted with a group of formula -(CH2)mX; in which X is -CO2H, -CONH2,-P(=O)(OH)2 or -S(=O)2OH; Y is N or CH; m is an integer selected from 1, 2 and 3; R4 is hydrogen; R5 is hydrogen; R6 is C1-5alkyl; R7 and R8 are identical or different and independently represent hydrogen, C1-5alkyl, Ar is phenyl which is unsubstituted or substituted with one or more substitutes which are identical or different and are selected from a group consisting of halogen, C1-5alkyl, C1-5alkoxy, C1-5alkylthio, trifluoromethyl and trifluoromethoxy.

EFFECT: compounds can be used for therapeutic or preventive treatment of diseases where CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension etc.

12 cl, 6 dwg, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention provides novel pyrrolo[2,3-c]pyridine derivatives of formula (I), where radicals R1, R2, R3, R4 and R5 are as indicated in paragraph 1 of the formula of invention, or their pharmaceutically acceptable salts, as well as methods of producing the said compounds and a pharmaceutical composition having proton pump inhibiting effect.

EFFECT: novel compounds which exhibit excellent proton pump inhibiting effect and can have reversible proton pump inhibiting effect are obtained and described.

6 cl, 927 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

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