CN1326838C

CN1326838C - Benzo[d]azepine derivatives for the treatment of neurological disorders

Info

Publication number: CN1326838C
Application number: CNB2003801063648A
Authority: CN
Inventors: 马克·J·班福德; 戴维·K·迪安; 桑吉特·S·塞米; 戴维·M·威尔逊; 贾森·威瑟林顿
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2002-12-20
Filing date: 2003-12-18
Publication date: 2007-07-18
Anticipated expiration: 2023-12-18
Also published as: GB0229820D0; CN1726042A; ZA200504270B

Abstract

The present invention relates to benzazepine derivatives of formula ( I ) wherein: R<1> represents -C3-7 cycloalkyl optionally substituted by C1-3 alkyl; having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.

Description

The benzazepine derivatives that is used for the treatment of sacred disease

The present invention relates to have new benzazepine derivatives, its preparation method of pharmacologically active, the composition that contains them and their application in treatment nervosa and psychosis.

JP 2001226269 and WO 00/23437 (Takeda Chem Ind Ltd) have described a series of benzazepine derivatives that can be used for treatment of obesity that it is believed that.DE 2207430, US 4,210,749 and FR2171879 (Pennwalt Corp) and GB 1268243 (Wallace and Tiernan Inc) all described and it is believed that can be used as narcotic (for example morphine or morphine monomethyl ether) antagonist also is a series of benzazepine derivatives of antihistaminic agent and cholilytic drug simultaneously.WO 02/14513 (Takeda Chem Ind Ltd) has described the active benzazepine derivatives of a series of GPR12 of having, and it is believed that it can be used for treating attention deficit, narcolepsy or anxiety.WO 02/02530 (Takeda Chem Ind Ltd) has described a series of benzazepine derivatives as the GPR14 antagonist, it is believed that it can be used for treating hypertension, atherosclerosis and cardiac infarction.WO 01/03680 (Isis Innovation Ltd) has described a series of benzazepine derivatives, it is believed that its except in suppressing the disease of diabetes for example as beneficial agents, can also be as preparation for transplanting with the beneficial agents in the cell.WO 00/21951 (SmithKline Beechamplc) discloses the tetrahydro benzo azepine  derivative of a series of conditioning agents as dopamine D 3 receptor, it is believed that it can be used as antipsychotic drug.WO 01/87834 (Takeda Chem Ind Ltd) has described a series of benzazepine derivatives as the MCH antagonist, it is believed that it can be used for treatment of obesity.WO02/15934 (Takeda Chem Ind Ltd) has described a series of benzazepine derivatives as urotensin II receptor antagonist, it is believed that it can be used for treating neurodegenerative disease.

Histamine H 3 receptor mainly is expressed in the mammiferous central nervous system (CNS), except some sympathetic nerve, also be expressed on a small quantity in the peripheral tissues (people such as Leurs, (1998), Trends Pharmacol.Sci.19,177-183).Can suppress neurotransmitter by selective agonist or histamine activation H3 acceptor and comprise the neurone of histaminergic and the cholinergic neuron and discharging (people such as Schlicker from various neuroplexus, (1994), Fundam.Clin.Pharmacol.8,128-137).In addition, studies show that in the external and body, the H3 antagonist can promote neurotransmitter the brain region relevant with the cognition release (people such as Onodera in pallium and the hippocampus for example, (1998), In:The Histamine H3 receptor, ed Leurs and Timmerman, pp 255-267, Elsevier Science B.V.).In addition, many reports in the existing document have confirmed that H3 antagonist (for example Thioperamide, clobenpropit, ciproxifan and GT-2331) is comprising five kinds of selections: task, Target Recognition, overhead cross labyrinth (elevated plusmaze), obtain to have in the rodent model of new task and passive avoidance and improve cognitive characteristic (people such as Giovanni, (1999), Behav.Brain Res.104,147-155).These data show, for example the new H3 antagonist of series of the present invention and/or inverse agonists can be used for the treatment of cognitive impairment for example Alzheimer's and the relevant neurodegenerative disease in the neuropathy.

First aspect present invention provides the compound or pharmaceutically acceptable salt thereof of formula (I) or their solvate:

Wherein:

R ¹Expression is optional by C _1-3Alkyl replaces-C _3-7Cycloalkyl;

R ²Expression hydrogen ,-C _1-6Alkyl ,-X-C _3-8Cycloalkyl ,-the X-aryl ,-the X-heterocyclic radical ,-the X-heteroaryl ,-X-C _3-8Cycloalkyl-Y-C _3-8Cycloalkyl ,-X-C _3-8Cycloalkyl-Y-aryl ,-X-C _3-8Cycloalkyl-Y-heteroaryl ,-X-C _3-8Cycloalkyl-Y-heterocyclic radical ,-X-aryl-Y-C _3-8Cycloalkyl ,-X-aryl-Y-aryl ,-X-aryl-Y-heteroaryl ,-X-aryl-Y-heterocyclic radical ,-X-heteroaryl-Y-C _3-8Cycloalkyl ,-X-heteroaryl-Y-aryl ,-X-heteroaryl-Y-heteroaryl ,-X-heteroaryl-Y-heterocyclic radical ,-X-heterocyclic radical-Y-C _3-8Cycloalkyl ,-X-heterocyclic radical-Y-aryl ,-X-heterocyclic radical-Y-heteroaryl ,-X-heterocyclic radical-Y-heterocyclic radical;

X represents chemical bond or C _1-6Alkyl;

Y represents chemical bond, C _1-6Alkyl, CO, COC _2-6Alkenyl, O or SO ₂

R ³Expression halogen, C _1-6Alkyl, C _1-6Alkoxyl group, cyano group, amino or trifluoromethyl;

N is 0,1 or 2;

R wherein ²In described alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical can choose wantonly by one or more (for example 1,2 or 3) identical or different following substituting group of being selected from and replace: halogen, hydroxyl, cyano group, nitro ,=O, trifluoromethyl, trifluoromethoxy, fluoro methoxyl group, difluoro-methoxy, C _1-6Alkyl, pentafluoroethyl group, C _1-6Alkoxyl group, aryl C _1-6Alkoxyl group, C _1-6Alkylthio, C _1-6Alkoxy C _1-6Alkyl, C _3-7Cycloalkyl C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl, C _1-6Alkyl sulphinyl, C _1-6Alkylsulfonyloxy, C _1-6Alkyl sulphonyl C _1-6Alkyl, alkylsulfonyl, aryl sulfonyl, aryl-sulfonyl oxygen, aryl sulfonyl C _1-6Alkyl, aryloxy, C _1-6Alkyl sulfonyl amino (sulfonamido), C _1-6Alkylamino, C _1-6Alkyl amido (alkylamido) ,-R ⁴,-CO ₂R ⁴,-COR ⁴, C _1-6The amino C of alkyl sulfonyl _1-6Alkyl, C _1-6Alkyl amido C _1-6Alkyl, Arenesulfonyl amino, aryl formamido group (arylcarboxamido), Arenesulfonyl amino C _1-6Alkyl, aryl formamido group C _1-6Alkyl, aroyl, aroyl C _1-6Alkyl, aryl C _1-6Alkyloyl or group-NR ⁵R ⁶,-C _1-6Alkyl-NR ⁵R ⁶,-C _3-8Cycloalkyl-NR ⁵R ⁶,-CONR ⁵R ⁶,-NR ⁵COR ⁶,-NR ⁵SO ₂R ⁶,-OCONR ⁵R ⁶,-NR ⁵CO ₂R ⁶,-NR ₄CONR ⁵R ⁶Or-SO ₂NR ⁵R ⁶(R wherein ⁴, R ⁵And R ⁶Represent hydrogen, C independently _1-6Alkyl ,-C _3-8Cycloalkyl ,-C _1-6Alkyl-C _3-8Cycloalkyl, aryl, heterocyclic radical or heteroaryl, perhaps NR ⁵R ⁶Can represent the nitrogen heterocyclic ring group, wherein said R ⁴, R ⁵And R ⁶Group can be chosen wantonly by one or more (for example 1,2 or 3) identical or different following substituting group that is selected from and replace: halogen, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, cyano group, amino ,=O or trifluoromethyl).

Definition formula (I) compound as above is provided in aspect one of the present invention is concrete, wherein:

R ²Expression-C _1-6Alkyl ,-X-C _3-8Cycloalkyl ,-the X-aryl ,-the X-heterocyclic radical ,-the X-heteroaryl ,-X-C _3-8Cycloalkyl-Y-C _3-8Cycloalkyl ,-X-C _3-8Cycloalkyl-Y-aryl ,-X-C _3-8Cycloalkyl-Y-heteroaryl ,-X-C _3-8Cycloalkyl-Y-heterocyclic radical ,-X-aryl-Y-C _3-8Cycloalkyl ,-X-aryl-Y-aryl ,-X-aryl-Y-heteroaryl ,-X-aryl-Y-heterocyclic radical ,-X-heteroaryl-Y-C _3-8Cycloalkyl ,-X-heteroaryl-Y-aryl ,-X-heteroaryl-Y-heteroaryl ,-X-heteroaryl-Y-heterocyclic radical ,-X-heterocyclic radical-Y-C _3-8Cycloalkyl ,-X-heterocyclic radical-Y-aryl ,-X-heterocyclic radical-Y-heteroaryl ,-X-heterocyclic radical-Y-heterocyclic radical; And

Y represents chemical bond, C _1-6Alkyl, CO, O or SO ₂And

R ⁴, R ⁵And R ⁶Represent hydrogen, C independently _1-6Alkyl ,-C _3-8Cycloalkyl, aryl, heterocyclic radical or heteroaryl, perhaps NR ⁵R ⁶Can represent nitrogen heterocycle.

Concrete class formula (I) compound that can mention is such compound, wherein: R ²Expression-X-heterocyclic radical ,-X-heterocyclic radical-Y-C _3-8Cycloalkyl ,-X-heterocyclic radical-Y-aryl ,-X-heterocyclic radical-Y-heteroaryl or-X-heterocyclic radical-Y-heterocyclic radical, described heterocyclic radical links to each other with X by carbon atom.

No matter be independent alkyl, still as the alkyl of another group part, it can be a straight or branched, and group alkoxyl group and alkyloyl also should similar understandings.Alkyl group is C more preferably _1-4Alkyl, for example methyl or ethyl.Unless otherwise defined, term as used herein ' halogen ' is meant the group that is selected from fluorine, chlorine, bromine or iodine.

' aryl ' comprises monocycle carbocyclic ring aromatic nucleus (as phenyl) and bicyclic carbocyclic aromatic nucleus (as naphthyl) or carbocyclic ring benzo ring (C for example _3-8Cycloalkyl and phenyl ring condense, as dihydro indenyl or tetralyl).

Term ' heterocyclic radical ' be meant the saturated or undersaturated aliphatics ring of part of 4-7 unit monocycle or contain 1-3 heteroatoms that is selected from oxygen, nitrogen or sulphur and with the saturated or undersaturated aliphatics ring of part of phenyl ring condensed 4-7 unit.The monocyclic suitable example of this class comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, tetrahydrofuran base, THP trtrahydropyranyl, Diazesuberane base, azepan base, imidazolidyl, isothiazole alkyl,  oxazolidinyl, pyrrolidone and tetrahydrochysene-oxygen azepine  base.The suitable example of benzo-fused heterocycle comprises indolinyl, iso-dihydro-indole-group, benzo dioxolyl, xylylenimine, dihydro benzo furyl, thiochroman base and dihydro-isoquinoline base.

Term ' nitrogen heterocycle ' expression contains any one definition heterocyclic group as above of nitrogen-atoms.

Term ' heteroaryl ' is meant 5-7 unit's monocycle aromatic nucleus or contains 1-3 the first condensed-bicyclic aromatic nucleus of heteroatomic 8-11 that is selected from oxygen, nitrogen and sulphur.The suitable example of this class monocycle aromatic nucleus comprises thienyl, furyl, pyrryl, triazolyl, imidazolyl,  azoles base, thiazolyl,  di azoly, isothiazolyl, different  azoles base, thiadiazolyl group, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl and THP trtrahydropyranyl.The suitable example that this class condenses aromatic nucleus comprises benzo-fused aromatic nucleus, for example quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indyl, indazolyl, furo pyridyl, pyrrolopyridinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzoxazol base, benzisoxa  azoles base, benzothiazolyl, benzisothiazole base, benzo  di azoly, diazosulfide base etc.

R ¹Unsubstituted-the C of preferred expression _3-7Cycloalkyl (as cyclobutyl, cyclopentyl or cyclohexyl).R ¹Also preferably represent by C _1-3Alkyl (as methyl) group replaces-C _3-7Cycloalkyl (as cyclopentyl).

R ¹Most preferably represent unsubstituted cyclobutyl or cyclopentyl, especially unsubstituted cyclobutyl.

Preferably, R ²Expression

Hydrogen;

Optional quilt-CO ₂R ⁴Or-CONR ⁵R ⁶Group replaces-C _1-6Alkyl (as methyl or propyl group);

-X-C _3-8Cycloalkyl-Y-heterocyclic radical (as-X-cyclohexyl-Y-morpholinyl);

Optional by one or two halogen (as fluorine, iodine or chlorine), C _1-6Alkyl (as methyl), C _1-6Alkoxyl group (as methoxyl group) ,-CO ₂R ⁴,-CONR ⁵R ⁶,-NR ⁵COR ⁶,-SO ₂NR ⁵R ⁶Or the cyano group replacement-the X-aryl (for example-the X-phenyl);

Optional by one or two=O, halogen (as fluorine) or R ⁴Group replaces-X-aryl-Y-heterocyclic radical (as-X-phenyl-Y-piperazinyl ,-X-phenyl-Y-pyrrolidyl or-X-phenyl-Y-morpholinyl);

Optional by one or two halogen (as bromine or iodine), C _1-6Alkyl (as methyl), C _1-6Alkoxyl group (as methoxy or ethoxy), cyano group, nitro ,-OR ⁴,-COR ⁴,-CO ₂R ⁴,-NR ⁵R ⁶,-NR ⁵COR ⁶,-CONR ⁵R ⁶Or=the O group replaces-the X-heteroaryl (as-X-pyridyl ,-the X-pyrazinyl ,-the X-pyrimidyl ,-the X-pyridazinyl ,-the X-quinolyl ,-the X-pyrrolopyridinyl ,-X-furo pyridyl ,-the X-naphthyridinyl ,-the X-thiazolyl or-the X-thienyl);

Optional by C _1-6Alkyl sulphonyl (as-SO ₂Me) or-NR ⁵COR ⁶The group replacement-X-heteroaryl-Y-aryl (as-X-pyrazinyl-Y-phenyl);

Optional by C _1-6Alkyl (as methyl) replaces-X-heteroaryl-Y-heteroaryl (as-X-pyridyl-Y-pyrazolyl ,-X-pyridyl-Y- di azoly ,-X-pyridyl-Y- azoles base or-X-pyridyl-Y-pyrazinyl);

Optional by one or two=O, C _1-6Alkyl (as methyl) ,-OR ⁴Or the replacement of halogen (as chlorine or bromine) group-X-heteroaryl-Y-heterocyclic radical (as-X-pyridyl-Y-morpholinyl,-X-pyridyl-Y-pyrrolidyl,-X-pyridyl-Y-piperidyl,-X-pyridyl-Y-thio-morpholinyl,-X-pyridyl-Y-THP trtrahydropyranyl,-X-pyridyl-Y-imidazolidyl,-X-pyridyl-Y-tetrahydrochysene-oxygen azepine  base,-X-pyridyl-Y-azelidinyl,-X-pyridyl-Y- oxazolidinyl,-X-pyridyl-Y-isothiazole alkyl,-X-pyrazinyl-Y-morpholinyl,-X-pyrazinyl-Y-piperidyl,-X-pyrazinyl-Y-pyrrolidyl,-X-pyrazinyl-Y-thio-morpholinyl,-X-pyrazinyl-Y- oxazolidinyl,-X-pyrazinyl-Y-azelidinyl,-X-pyrazinyl-Y-THP trtrahydropyranyl or-X-pyridazinyl-Y-morpholinyl);

Optional by C _1-6Alkyl sulphonyl (as-SO ₂Me), C _1-6Alkoxy carbonyl (as-CO-CH ₂CH ₂OMe) ,-CO ₂R ⁴,-COR ⁴Or-COR ⁵R ⁶Group replaces-the X-heterocyclic radical (as-X-piperidyl or-the X-pyrrolidyl);

Optional by halogen (as fluorine), cyano group, C _1-6Alkyl sulphonyl (as-SO ₂Me), R ⁴Or-CONR ⁵R ⁶Group replaces-X-heterocyclic radical-Y-aryl (as-X-piperidyl-Y-phenyl or-X-pyrrolidyl-Y-phenyl);

Optional by one or two=O or R ⁴Group replaces-X-heterocyclic radical-Y-heterocyclic radical (as-X-piperidyl-Y-THP trtrahydropyranyl ,-X-pyrrolidyl-Y-THP trtrahydropyranyl ,-X-piperidyl-Y-dihydro benzo furyl ,-X-pyrrolidyl-Y-morpholinyl ,-X-piperidyl-Y-morpholinyl ,-X-piperidyl-Y-thio-morpholinyl ,-X-piperidyl-Y-xylylenimine ,-X-piperidyl-Y-piperazinyl ,-X-piperidyl-Y-pyrrolidyl ,-X-piperidyl-Y-piperidyl or-X-piperidyl-Y-thiochroman base);

-X-heterocyclic radical-Y-C _3-8Cycloalkyl (as-X-piperidyl-Y-cyclohexyl ,-X-piperidyl-Y-cyclopropyl ,-X-piperidyl-Y-cyclobutyl or-X-piperidyl-Y-cyclopentyl); Perhaps

Optional by one or two C _1-6Alkyl (as methyl) ,=O, cyano group or-CONR ⁵R ⁶The group replacement-X-heterocyclic radical-Y-heteroaryl (as-X-piperidyl-Y-isoquinolyl ,-X-piperidyl-Y-quinolyl ,-the different  azoles of X-piperidyl-Y-base ,-X-piperidyl-Y-benzothiazolyl ,-X-piperidyl-Y-thienyl ,-X-piperidyl-Y-furyl ,-X-piperidyl-Y-pyrazinyl ,-X-piperidyl-Y-pyridyl).

X preferably represent chemical bond or-CH ₂-, X most preferably represents chemical bond.

Y preferably represents chemical bond, CO, SO ₂Or-CO-CH=CH-, Y most preferably represents chemical bond or CO, especially chemical bond.

Preferably, R ⁴Expression hydrogen, C _1-6Alkyl (as methyl, ethyl or the tertiary butyl) ,-C _1-6Alkyl-C _3-8Cycloalkyl (as-CH ₂Cyclopropyl), aryl (as the optional phenyl that is replaced by halogen atom (as fluorine)), heterocyclic radical (as morpholinyl) or heteroaryl (as pyridyl or pyrazinyl), it is optional by halogen (as fluorine) or C _1-6Alkoxyl group (as methoxyl group) group replaces.

Preferably, R ⁵And R ⁶Represent hydrogen, C independently _1-6Alkyl (as methyl, ethyl, sec.-propyl or propyl group) ,-C _3-8Cycloalkyl (as cyclobutyl or cyclopentyl) ,-C _1-6Alkyl-C _3-8Cycloalkyl (as-CH ₂-cyclopropyl), heterocyclic radical (as pyrrolidyl, piperidyl, morpholinyl or THP trtrahydropyranyl) or aryl (as phenyl), it is optional by halogen (as fluorine), cyano group or C _1-6Alkoxyl group (as methoxyl group) group replaces, perhaps-and NR ⁵R ⁶Expression optional by one or two=nitrogen heterocycle (as azelidinyl, morpholinyl, pyrrolidyl or piperidyl) that the O group replaces.

More preferably, R ⁵And R ⁶Represent hydrogen, C independently _1-6Alkyl (as methyl or ethyl) ,-C _3-8Cycloalkyl (as cyclobutyl or cyclopentyl) or-C _1-6Alkyl-C _3-8Cycloalkyl (as-CH ₂-cyclopropyl).

Particularly preferably, R ²Expression

Hydrogen;

Optional quilt-CO ₂R ⁴(as-CO ₂Et or-CO ₂H) or-CONR ⁵R ⁶(as-CON (Me) ₂,-CON (H) (Me) ,-CON (H) (cyclopentyl) ,-CON (H) (phenyl) ,-the CO-pyrrolidyl ,-the CO-piperidyl or-the CO-morpholinyl) group replaces-C _1-6Alkyl (as methyl or propyl group);

-X-C _3-8Cycloalkyl-Y-heterocyclic radical (as-cyclohexyl-CO-morpholinyl);

Optional by one or two halogen (as fluorine, iodine or chlorine), C _1-6Alkyl (as methyl), C _1-6Alkoxyl group (as methoxyl group) ,-CO ₂R ⁴(as-CO ₂H or-CO ₂Me) ,-CONR ⁵R ⁶(as-CON (H) (Me) ,-CON (Et) ₂(optional replaced) by methoxyl group ,-CON (Me) (Pr) (optional replaced) by cyano group or-CON (H) (CH ₂-cyclopropyl) ,-NR ⁵COR ⁶(as-NHCOMe) ,-SO ₂NR ⁵R ⁶(as-SO ₂N (Et) ₂) or cyano group replace-the X-aryl (as-phenyl or-CH ₂-phenyl);

Optional by one or two=O, halogen (as fluorine) or R ⁴(as phenyl (choose wantonly and replaced by fluorine atom) or pyridyl) group replacement-X-aryl-Y-heterocyclic radical (as-phenyl-pyrrolidyl ,-phenyl-CO-pyrrolidyl ,-phenyl-CO-morpholinyl ,-phenyl-SO ₂-morpholinyl ,-CH ₂-phenyl-CO-pyrrolidyl ,-CH ₂-phenyl-CO-morpholinyl or-CH ₂-phenyl-CO-piperazinyl);

Optional by one or two halogen (as bromine or iodine), C _1-6Alkyl (as methyl), C _1-6Alkoxyl group (as methoxy or ethoxy), cyano group, nitro ,-OR ⁴(as hydroxyl) ,-CO ₂R ⁴(as CO ₂H or CO ₂Me) ,-COR ⁴(as COMe) ,-NR ⁵R ⁶(as-NH ₂Or-N (H) (Me)) ,-NR ⁵COR ⁶(as NHCOMe, NHCO-sec.-propyl ,-the NHCO-pyrrolidyl ,-the NHCO-piperidyl ,-the NHCO-morpholinyl or-the NHCO-THP trtrahydropyranyl) ,-CONR ⁵R ⁶(as-CONH ₂,-CON (Me) ₂,-CON (Me) (Et) ,-CON (H) (Me) ,-CON (H) (sec.-propyl) ,-CON (Et) ₂(optional replaced) by methoxyl group ,-CON (H) (Et) (optional replaced) by methoxyl group ,-CON (H) (CH ₂Cyclopropyl) ,-CON (H) (cyclobutyl) ,-CON (H) (cyclopentyl) ,-CON (H) (cyclopropyl) or-CON (H) (THP trtrahydropyranyl)) or=the O group replaces-the X-heteroaryl (as-pyridyl ,-CH ₂-pyridyl ,-pyrazinyl ,-pyrimidyl ,-pyridazinyl ,-quinolyl ,-CH ₂-quinolyl ,-pyrrolopyridinyl ,-the furo pyridyl ,-naphthyridinyl ,-thiazolyl or-thienyl);

Optional by C _1-6Alkyl sulphonyl (as-SO ₂Me) or-NR ⁵COR ⁶(as-NHCOMe) group replaces-X-heteroaryl-Y-aryl (as-pyrazinyl-phenyl);

Optional by C _1-6Alkyl (as methyl) replaces-X-heteroaryl-Y-heteroaryl (for example-the pyridyl-pyrazol base ,-pyridyl- di azoly ,-pyridyl- azoles base or-pyridyl-pyrazinyl);

Optional by one or two=O, C _1-6Alkyl (as methyl) ,-OR ⁴The replacement of (as hydroxyl) or halogen (as chlorine or bromine) group-X-heteroaryl-Y-heterocyclic radical (as-pyridyl-CO-morpholinyl;-pyridyl-CO-pyrrolidyl;-pyridyl-CO-piperidyl;-pyridyl-CO-thio-morpholinyl;-pyridyl-imidazolidyl;-pyridyl-CO-tetrahydrochysene-oxygen azepine  base;-pyridyl-CO-azelidinyl;-pyridyl- oxazolidinyl;-pyridyl-isothiazole alkyl;-pyrazinyl-morpholinyl;-pyrazinyl-CO-morpholinyl;-pyrazinyl-CO-piperidyl;-pyrazinyl-CO-pyrrolidyl;-pyrazinyl-thio-morpholinyl;-pyrazinyl- oxazolidinyl;-pyrazinyl-CO-azelidinyl;-pyrazinyl-piperidyl;-pyrazinyl-pyrrolidyl;-pyridyl-pyrrolidyl;-pyridyl-piperidyl;-pyridyl-SO ₂-morpholinyl or-pyridazinyl-CO-morpholinyl);

Optional by C _1-6Alkyl sulphonyl (as-SO ₂Me), C _1-6Alkoxy carbonyl (as-CO-CH ₂CH ₂OMe) ,-CO ₂R ⁴(as-CO ₂-the tertiary butyl)-COR ⁴(as-COCH ₂Cyclopropyl) or-COR ⁵R ⁶(as-CON (sec.-propyl) ₂,-CON (Et) ₂,-CON (sec.-propyl) (Et) (optional replaced) by methoxyl group ,-CON (H) (sec.-propyl) or-CON (H) (4-fluorophenyl) group replaces-the X-heterocyclic radical (as-piperidyl ,-CH ₂-piperidyl ,-pyrrolidyl or-CH ₂-pyrrolidyl);

Optional by halogen (as fluorine), cyano group, C _1-6Alkyl sulphonyl (as-SO ₂Me), R ⁴(as phenyl or morpholinyl) or-CONR ⁵R ⁶(as quilt=O group replace-the CO-pyrrolidyl) group replaces-X-heterocyclic radical-Y-aryl (as-piperidyl-CO-phenyl ,-pyrrolidyl-CO-phenyl ,-piperidyl-CO-CH=CH-phenyl ,-piperidyl-SO ₂-phenyl, pyrrolidyl-SO ₂-phenyl ,-CH ₂-piperidyl-CO-phenyl ,-CH ₂-pyrrolidyl-CO-phenyl ,-CH ₂-piperidyl-SO ₂-phenyl or-CH ₂-pyrrolidyl-SO ₂-phenyl);

Optional by one or two=O or R ⁴The replacement of (as pyrazinyl) group-X-heterocyclic radical-Y-heterocyclic radical (as-piperidyl-CO-THP trtrahydropyranyl ,-CH ₂-piperidyl-CO-THP trtrahydropyranyl ,-pyrrolidyl-CO-THP trtrahydropyranyl ,-CH ₂-pyrrolidyl-CO-THP trtrahydropyranyl ,-piperidyl-CO-dihydro benzo furyl ,-pyrrolidyl-CO-morpholinyl ,-CH ₂-pyrrolidyl-CO-morpholinyl ,-piperidyl-CO-morpholinyl ,-CH ₂-piperidyl-CO-morpholinyl ,-piperidyl-CO-thio-morpholinyl ,-piperidyl-CO-xylylenimine ,-piperidyl-CO-piperazinyl ,-piperidyl-CO-pyrrolidyl ,-piperidyl-CO-piperidyl or-piperidyl-CO-thiochroman base);

-X-heterocyclic radical-Y-C _3-8Cycloalkyl (as-piperidyl-CO-cyclohexyl ,-piperidyl-CO-cyclopropyl ,-piperidyl-CO-cyclobutyl or-piperidyl-CO-cyclopentyl); Perhaps

Optional by one or two C _1-6Alkyl (as methyl) ,=O, cyano group or-CONR ⁵R ⁶(as-CON (H) (Me) ,-CON (H) (CH ₂Cyclopropyl) ,-the CO-azelidinyl or-the CO-morpholinyl) group replaces-X-heterocyclic radical-Y-heteroaryl (as-piperidyl-CO-isoquinolyl ,-piperidyl-CO-quinolyl ,-the different  azoles of piperidyl-CO-base ,-piperidyl-SO ₂-different  azoles base ,-piperidyl-CO-benzothiazolyl ,-piperidyl-CO-thienyl ,-piperidyl-CO-furyl ,-piperidyl-CO-pyrazinyl ,-piperidyl-pyrazinyl ,-piperidyl-CO-pyridyl or-piperidyl-pyridyl).

More preferably, R ²Expression

Optional by CONR ⁵R ⁶Group replaces-X-aryl (as phenyl);

-X-aryl-Y-heterocyclic radical (as-X-phenyl-Y-morpholinyl or-X-phenyl-Y-pyrrolidyl);

Optional by CONR ⁵R ⁶Group replaces-X-heteroaryl (as pyrazinyl or pyridyl);

Optional by one or two=the O group replaces-X-heteroaryl-Y-heterocyclic radical (as-X-pyridyl-Y-morpholinyl ,-X-pyridyl-Y-pyrrolidyl ,-X-pyridyl-Y-piperidyl ,-X-pyridyl-Y-thio-morpholinyl ,-X-pyrazinyl-Y-morpholinyl ,-X-pyrazinyl-Y-piperidyl or-X-pyrazinyl-Y-pyrrolidyl);

-X-heterocyclic radical-Y-heterocyclic radical (as-X-piperidyl-Y-THP trtrahydropyranyl ,-X-piperidyl-Y-morpholinyl or-X-pyrrolidyl-Y-morpholinyl).

Further more preferably, R ²Expression

Optional by one or two halogen (as fluorine, iodine or chlorine), C _1-6Alkyl (as methyl), C _1-6Alkoxyl group (as methoxyl group) ,-CO ₂R ⁴(as-CO ₂H or-CO ₂Me) ,-CONR ⁵R ⁶(as-CON (H) (Me) ,-CON (Et) ₂(optional replaced) by methoxyl group ,-CON (Me) (Et) (optional replaced) by cyano group or-CON (H) (CH ₂-cyclopropyl) ,-NR ⁵COR ⁶(as-NHCOMe) ,-SO ₂NR ⁵R ⁶(as-SO ₂N (Et) ₂) or cyano group replace-the X-aryl (as-phenyl or-CH ₂-phenyl);

Optional by one or two=O or R ⁴The replacement of (as pyrazinyl) group-X-heterocyclic radical-Y-heterocyclic radical (as-piperidyl-CO-THP trtrahydropyranyl ,-CH ₂-piperidyl-CO-THP trtrahydropyranyl ,-pyrrolidyl-CO-THP trtrahydropyranyl ,-CH ₂-pyrrolidyl-CO-THP trtrahydropyranyl ,-piperidyl-CO-dihydro benzo furyl ,-pyrrolidyl-CO-morpholinyl ,-CH ₂-pyrrolidyl-CO-morpholinyl ,-piperidyl-CO-morpholinyl ,-CH ₂-piperidyl-CO-morpholinyl ,-piperidyl-CO-thio-morpholinyl ,-piperidyl-CO-xylylenimine ,-piperidyl-CO-piperazinyl ,-piperidyl-CO-pyrrolidyl ,-piperidyl-CO-piperidyl or-piperidyl-CO-thiochroman base).

Most preferably, R ²Expression

Optional by one or two halogen (as fluorine), C _1-6Alkoxyl group (as methoxyl group) ,-CONR ⁵R ⁶((Me)) as-CON (H) ,-NR ⁵COR ⁶(as-NHCOMe) or cyano group replace-X-aryl (as-phenyl);

Optional by one or two=O or halogen (as fluorine) group replace-X-aryl-Y-heterocyclic radical (as-phenyl-pyrrolidyl);

Unsubstituted-X-heterocyclic radical-Y-heterocyclic radical (as-piperidyl-CO-morpholinyl);

Optional quilt-CONR ⁵R ⁶(as CON (H) (Me)) group replaces-the X-heteroaryl (as-2-pyridyl or-the 2-pyrazinyl); Perhaps

-X-heteroaryl-Y-heterocyclic radical (as-2-pyridyl-N-pyrrolidyl), the optional quilt=O group replacement of wherein said heterocyclic radical (as-2-pyridyl-N-pyrrolidone).

Particularly preferably, R ²Expression quilt-CONR ⁵R ⁶The group replacement-the X-heteroaryl (as-the 2-pyridyl) (as 4-methylamino carbonyl pyridine-2-yl).

N preferably represents 0 or 1, more preferably represents 0.

When n represents 1, R ³Be preferably halogen (as iodine) atom or cyano group.

Preferred compound comprises embodiment E 1-E288 as follows or its pharmacologically acceptable salt according to the present invention.

Preferred compound comprises according to the present invention:

5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carboxylic acid methane amide; With

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-2-Pyrrolidone;

Or its pharmacologically acceptable salt.

Particularly preferred compound is 6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-methyl-niacinamide or its pharmacologically acceptable salt according to the present invention.

Formula (I) compound can for example pharmaceutically acceptable acid such as toxilic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, acetate, fumaric acid, Whitfield's ointment, sulfuric acid, citric acid, lactic acid, amygdalic acid, tartrate and the methylsulphonic acid of routine form acid addition salt with acid.Therefore salt, solvate and the hydrate of formula (I) compound have constituted an aspect of of the present present invention.

Some formula (I) compound can exist with stereoisomeric forms in any ratio.It should be understood that the present invention includes these compounds all how much and optical isomer and composition thereof comprise racemoid.Tautomer has also constituted an aspect of of the present present invention.

The present invention also provides the method for a kind of preparation formula (I) compound or pharmaceutically acceptable salt thereof, and described method comprises:

(a) with formula (II) compound

R wherein ¹, R ³The same with the n definition, with formula R ²'-L ¹Compound reaction, wherein R ²' as above in the face of R ²Definition or can be converted into R ²Group, L ¹The suitable leavings group of expression is the hydroxyl of halogen atom (as bromine or iodine) or optional activation for example;

(b) with formula (III) compound

R wherein ², R ³The same with the n definition, with formula R ¹'-L ²Compound reaction, wherein R ¹' as above in the face of R ¹Definition or can be converted into R ¹Group, L ²The leavings group that expression suits is halogen atom (as bromine, iodine or tosylate) for example; Perhaps

(c) will define as above formula (III) compound and formula R ¹The reactive ketone of '=O, wherein R ¹' as above in the face of R ¹Definition or can be converted into R ¹Group; Perhaps

(d) with protected formula (I) compound deprotection; And

(e) change becomes other formula (I) compound.

As leavings group L ¹Be connected in sp ³In the time of on the hydridization carbon, R for example ²'-L ¹During for alkyl halide, step (a) generally include choose wantonly catalyzer for example potassiumiodide in the presence of, optimal temperature for example use under the reflux temperature suitable alkali for example salt of wormwood at the suitable solvent solution in the 2-butanone for example.

As leavings group L ¹Be connected in sp ²In the time of on the hydridization carbon, R for example ²'-L ¹During for aryl halide, step (a) is usually included in alkali for example under the existence of sodium hydride, optimal temperature for example use under the reflux temperature copper (I) salt for example cupric iodide (I) at the suitable solvent solution in the pyridine for example.

As leavings group L ¹Be connected in activation sp ²In the time of on the hydridization carbon, R for example ²'-L ¹During for heteroaryl halogenide such as 2-chloropyridine or 2-chloropyrazine, step (a) be usually included under the optimal temperature use suitable alkali for example sodium hydride at the suitable solvent solution in dimethyl formamide or the dimethyl sulfoxide (DMSO) for example.Perhaps, also can under optimal temperature, use the t-butanol solution of potassium tert.-butoxide.

When leaving group because of L ¹Be connected in activation sp ²In the time of on the hydridization carbon, R for example ²'-L ¹For aryl halide as 3, during 4-two fluoro-benzonitriles, step (a) is usually included under the optimal temperature uses for example solution of salt of wormwood in suitable solvent of suitable alkali.

Work as L ¹For being connected in sp ³During hydroxyl on the hydridization carbon, R for example ²'-L ¹During for alcohol, step (a) be usually included in optimal temperature for example use under the room temperature phosphine for example triphenylphosphine then add for example azoethane dicarboxylic ester of azodicarboxylate again at the suitable solvent solution in the tetrahydrofuran (THF) for example.

Step (b) is usually included in catalyzer for example under the existence of potassiumiodide, optimal temperature for example use under the reflux temperature suitable alkali for example salt of wormwood at the suitable solvent solution in the 2-butanone for example.

Step (c) generally include choose wantonly acid for example acetate in the presence of, for example for example use reductive condition (for example using hydroborate such as sodium triacetoxy borohydride to handle) under the room temperature in optimal temperature in the methylene dichloride in suitable solvent.

In step (d), the example of blocking group and the method for removing thereof can be referring to T.W.Greene ' Protective Groups in Organic Synthesis ' (J.Wiley and Sons, 1991).Suitable amine protecting group group comprise alkylsulfonyl (as tosyl group), acyl group (as ethanoyl, 2 '; 2 '; 2 '-trichloro-ethoxycarbonyl, carbobenzoxy-(Cbz) or tertbutyloxycarbonyl) and aralkyl (as benzyl); they can according to suitable mode by hydrolysis (for example using the two  alkane solution of sour example hydrochloric acid or the dichloromethane solution of trifluoroacetic acid) or reduction (for example use the acetic acid solution hydrogenolysis benzyl of zinc or reduction remove 2 '; 2 ', 2 '-trichloro-ethoxycarbonyl) remove.Other suitable amine protecting group group comprises trifluoroacetyl group (COCF ₃), it can be by alkali catalyzed hydrolysis or solid-phase resin bonding benzyl Merrifield resin-bonded 2 for example, and 6-dimethoxy-benzyl (Ellman linker) is removed, and described resin can for example be removed with the trifluoroacetic acid catalytic hydrolysis by acid.

Step (e) can adopt conventional change step to carry out, the linked reaction of for example epimerization reaction, oxidizing reaction, reduction reaction, alkylated reaction, nucleophilic or electrophilic aromatic substitution reaction, ester hydrolysis reaction, acid amides binding reaction or transition metal mediation.The linked reaction example that can be used for the transition metal mediation of change step comprises: the palladium catalyzed coupling reaction between organic electrophilic reagent such as aryl halide and organometallic reagent such as the boric acid (Suzuki cross-coupling reaction); Palladium catalytic aminoization between organic electrophilic reagent such as aryl halide and nucleophilic reagent such as amine and the acid amides and amidate action; Copper catalysis amidate action between organic electrophilic reagent (as aryl halide) and nucleophilic reagent such as the acid amides; And the linked reaction of the mediation of the copper between phenols and the boric acid.

Formula (II) and (III) compound can be according to the preparation of following schema,

R wherein ¹, R ², R ²', R ³, n and L ¹Define the same, P ¹Blocking group such as Boc that expression is suitable.

Step (i) generally includes deprotection reaction, for example works as P ¹During expression Boc, deprotection reaction comprises the dichloromethane solution reaction with two  alkane solution of formula (IV) compound and sour example hydrochloric acid or trifluoroacetic acid.

Step (ii) can be carried out under reductive condition according to being similar to the described method of step (c).

Step (iii) can be carried out according to being similar to the described method of step (a).

Step (iv) generally includes deprotection reaction to obtain formula (III) compound, and it can carry out according to the method for describing in the step (i).

R wherein ²Expression-X-aryl ,-the X-heteroaryl ,-X-aryl-Y-C _3-8Cycloalkyl ,-X-aryl-Y-aryl ,-X-aryl-Y-heteroaryl ,-X-aryl-Y-heterocyclic radical ,-X-heteroaryl-Y-C _3-8Cycloalkyl ,-X-heteroaryl-Y-aryl ,-X-heteroaryl-Y-heteroaryl or-X-heteroaryl-Y-heterocyclic radical, X represents that formula (VI) compound of chemical bond can also be according to the preparation of following schema,

R wherein ², R ²', R ³The same with the n definition, P ¹Blocking group such as Boc that expression is suitable.

Step (i) can be carried out under the catalytic cross-coupling condition of palladium, for example use two (diphenylphosphino) ferrocene palladium chloride (II) complex compounds and 1,1 '-two (diphenylphosphino) ferrocene is as catalyst system, simultaneously optimal temperature for example use under the reflux temperature suitable alkali for example Potassium ethanoate at the suitable solvent solution in the two  alkane for example.

Step (ii) can be carried out under oxidizing condition, for example in the presence of ammonium acetate, for example uses under the room temperature sodium periodate at the suitable solvent system solution in acetone and the water for example in optimal temperature.

Step (iii) can mantoquita for example neutralized verdigris in the presence of, in optimal temperature for example under the room temperature, for example triethylamine and molecular sieve for example carry out in the methylene dichloride in suitable solvent to use suitable alkali simultaneously.

Formula (IV) compound can prepare according to the method described in the description example 3 of similar WO 02/40471.

Formula (VII) compound can be according to being summarized in Bioorg.Med.Chem.Lett.; 10; 22; 2000; Method preparation among the 2553-2556.

Formula (I) compound and pharmacologically acceptable salt thereof have affinity to histamine H 3 receptor, be the antagonist and/or the inverse agonists of histamine H 3 receptor, thereby it is believed that can potentially be used for the treatment of the treatment neuropathy comprises that Alzheimer's, dementia, memory dysfunction, mild cognitive damage, cognitive defect, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, apoplexy and the dyssomnias relevant with the age comprise narcolepsy; Psychosis comprises schizophrenia (the particularly cognitive defect in the schizophrenia), attention deficit, the disease of being overexcited, dysthymia disorders and habit-forming; And other disease comprises obesity, asthma, rhinallergosis, nasal congestion, chronic retardancy tuberculosis and gastrointestinal tract disease.

Therefore, the present invention also provides a kind of formula (I) compound or pharmaceutically acceptable salt thereof, and it is used as therapeutant in the treatment of the above-mentioned disease especially cognitive impairment in for example Alzheimer's and related neural degenerative disease or prevention.

The present invention further also provides a kind of treatment or prevention Mammals to comprise the method for people's above-mentioned disease, and described method comprises to the formula of patient's administering therapeutic significant quantity (I) compound or pharmaceutically acceptable salt thereof.

On the other hand, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof and be used for the treatment of purposes in the medicine of above-mentioned disease in preparation.

When in treatment, using, usually formula (I) compound is mixed with the form of conventional medicine composition.This based composition can adopt the conventional steps preparation.

Therefore, the present invention further also provides a kind of pharmaceutical composition that is used for the treatment of above-mentioned disease, and it comprises formula (I) compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.

The present invention further also provides a kind of pharmaceutical composition, and it contains formula (I) compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.

Formula (I) compound can with other therapeutical agent, for example histamine H 1 antagonist or the declare disease that can be used for Alzheimer's alleviates or the medicine of symptom treatment merges and uses.The example of this other therapeutical agent of class can be to alleviate the known pharmaceutical agents that cholinergic transmits, for example 5-HT ₆Antagonist, M1 muscarinic agonist, M2 muscarine antagonist or acetylcholinesterase depressant.When these compounds and other therapeutical agent merge when using, these compounds can be according to the conventional route successive administration, or according to conventional route administration simultaneously.

Therefore on the other hand, the invention provides a kind of and use medicine, it contains formula (I) compound or its pharmaceutically acceptable derivative and other therapeutical agent or medicament.

Above-mentioned and can be easily use with the form of pharmaceutical preparation with medicine, therefore contain simultaneously definition as above and constituted another aspect of the present invention with the pharmaceutical preparation of medicine and pharmaceutically acceptable carrier or vehicle.This class also can be used with the pharmaceutical dosage forms that separates or unite continuously or simultaneously with each the independent component in the medicine.

When formula (I) compound or its pharmaceutically acceptable derivative with above-mentioned identical disease is had active second therapeutical agent of antagonism and unites when using, the dosage of each compound can be different with the dosage when this compound uses separately.Those skilled in the art can determine appropriate dosage easily.

Be generally suitable for per os, parenteral, rectal administration by the suitably mixed pharmaceutical composition of the present invention for preparing under envrionment temperature and barometric point, for example can be, can dilute (reconstitutable) powder, injectable or infusion solution agent or the suspensoid or the suppository of preparation for tablet, capsule, oral liquid, powder, granule, lozenge.Common preferred peroral administration composition.

Peroral administration tablet and capsule can be the forms of dosage unit, can contain conventional vehicle, for example tackiness agent, weighting agent, compressing tablet lubricant, disintegrating agent and acceptable wetting agent.Tablet can carry out dressing according to well-known method in the standard pharmacy practice.

Oral liquid can be the form of water-based or oiliness suspensoid, solution, emulsion, syrup or elixir for example, also can be for before use with the drying products form of water or other appropriate medium dilution preparation.This class I liquid I preparation can contain conventional additive for example suspending agent, emulsifying agent, non-aqueous media (can comprise edible oil), sanitas and can also contain conventional seasonings or tinting material if necessary.

For administered parenterally, utilize compound or pharmaceutically acceptable salt thereof of the present invention and sterile media to prepare the liquid unit dosage form.According to used medium and concentration, compound can suspend or be dissolved in the medium.In the preparation process of solution, can charge in suitable bottle or the ampoule then and sealing with compound dissolution for injecting and sterile filtration.With assistant agent for example local anesthetic, sanitas and buffer reagent to be dissolved in the medium be favourable.In order to improve solvability, composition can be carried out freezingly after charging into bottle, under vacuum, remove moisture.The suppository of administered parenterally is according to the preparation of substantially the same method, except compound being suspended in rather than being dissolved in the medium and sterilization can not undertaken by filtration.Compound can be sterilized by being exposed under the oxyethane before being suspended in sterile media.In order to promote the uniform distribution of compound, adding tensio-active agent or wetting agent are favourable in composition.

Composition can contain 0.1 weight % to 99 weight %, be preferably the active substance of 10-60 weight %, and this depends on medication.Be used for the compound dosage of the treatment of aforementioned diseases can be by convention along with the different and difference to some extent of severity, weight in patients and other similar factor of disease.Yet as total principle, suitable dosage unit can be 0.05-1000mg, be preferably 1.0-200mg that described dosage unit can repeatedly be taken every day, for example one day twice or three times.Such treatment can continue several weeks or several months.

Following description example and embodiment for example understand the preparation of The compounds of this invention.

Example 1 is described

7-benzyloxy-1,2,4,5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (D1)

With 7-hydroxyl-1,2,4,5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (PCT international application (2002), WO 02/40471) (790mg, 3mmol), salt of wormwood (1.24g, 9mmol) and the potassiumiodide of catalytic amount be suspended in the 2-butanone (20ml).(536 μ L, 4.5mmol), mixture heating up refluxed 24 hours to add bromotoluene.Cross filter solid, use washing with acetone then.Vacuum concentrated filtrate, thick oil be by the column chromatography purifying, obtains title compound (D1) (1.06g, 100%) with the mixture wash-out of ethyl acetate and hexane (1: 4), ¹H NMR (CDCl ₃) 7.44 (5H, m), 7.03 (1H, d, J 8.1Hz), 6.77 (1H, s), 6.74 (1H, dd, J 8.1﹠amp; 2.4Hz), 3.49 (4H, m), 2.84 (4H, m), 1.48 (9H, s).

Example 2 is described

7-benzyloxy-1,2,4,5-tetrahydrochysene-benzo [d] azepine  (D2)

With 7-benzyloxy-1,2,4, (1.06g 3mmol) is dissolved in the methylene dichloride (15ml) 5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (D1), handles with trifluoroacetic acid (15ml).Solution at room temperature stirred 2 hours, and vacuum concentration is then with twice of methylene dichloride coevaporation (co-evaporating).Resistates is dissolved in the methyl alcohol, and (Varian bond-elute 10g), uses 0.880 ammoniacal liquor (.880 ammonia)/carbinol mixture washing with methyl alcohol earlier again to be filled to the SCX ion exchange column.Concentrate the basic moiety (basic fractions) that merges under the vacuum, resistates is by the column chromatography purifying, and use 0.880 ammoniacal liquor: ethanol: the mixture wash-out of methylene dichloride (1: 9: 90) obtains title compound (D2) (702mg, 93%) MS (ES+) m/e254[M+H ,] ⁺

Example 3 is described

7-(4-methoxycarbonyl-benzyloxy)-1,2,4,5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (D3)

With 7-hydroxyl-1,2,4,5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (WO 02/40471) (5.27g, 20.0mmol), salt of wormwood (8.30g, 60.0mmol) and the potassiumiodide of catalytic amount be suspended in the butanone (100ml).(5.5g 24.0mmol) is dissolved in solution in the butanone (50ml), and the reaction mixture stirring and refluxing is 24 hours then dropwise to add 4-(brooethyl) methyl benzoate.Reaction mixture is crossed filter solid and is used washing with acetone then.Vacuum concentrated filtrate, crude mixture is by the column chromatography purifying, and use ethyl acetate: the mixture wash-out of hexane (1: 4) obtains title compound (D3).MS (ES+) m/e 344[(M+H)-CO ₂The tertiary butyl] ⁺

Example 4 is described

4-(2,3,4,5-four ammonia-1H-benzo [d] azepine -7-base oxygen ylmethyl)-methyl benzoate (D4)

With 7-(4-methoxycarbonyl-benzyloxy)-1,2,4,5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (D3) (6.35 g) is dissolved in the methylene dichloride (30ml), handles with trifluoroacetic acid (30ml).Solution at room temperature stirred 2 hours, and vacuum concentration is then with twice of methylene dichloride co-evaporated.Resistates is dissolved in the methylene dichloride, with 10% aqueous sodium hydroxide solution, water and salt water washing.The organic layer dried over mgso is filtered and vacuum concentration obtains title compound (D4).

Example 5 is described

1-(6-chloro-pyridin-3-yl)-1-morpholine-4-base-ketone (D5)

(0.2ml, (250mg is in methylene dichloride 1.4mmol) (10ml) solution 2.2mmol) to be added to 6-chloronicotinoyl chloride after the stirring with morpholine.After 2 hours, make the reaction cooling, crude mixture is filled to SCX ion-exchange tube, and (Varian bond-elute 10g), uses methanol wash.Vacuum concentration methyl alcohol part obtains title compound (D5).

Routine 6-31 is described

Utilize the method for describing in the example 5 (D5) of describing, prepared by suitable aryl halide shown in the following table and amine and describe routine 6-31 (D6-D31), it directly uses no longer further and handles.

Example is described	Aryl halide	Amine
Example is described	Aryl halide	Amine	1-(6-chloro-pyridin-3-yl)-1-tetramethyleneimine-1-base-ketone (D6)	The 6-chloronicotinoyl chloride	Tetramethyleneimine
6-chloro-niacinamide (D7)	The 6-chloronicotinoyl chloride	Ammonia		The 6-chloronicotinoyl chloride	Tetramethyleneimine
6-chloro-niacinamide (D7)	The 6-chloronicotinoyl chloride	Ammonia	6-chloro-N, N-dimethyl-niacinamide (D8)	The 6-chloronicotinoyl chloride	Dimethylamine
6-chloro-N-ethyl-N-methyl-niacinamide (D9)	The 6-chloronicotinoyl chloride	N-ethyl-methyl-amine	6-chloro-N, N-dimethyl-niacinamide (D8)	The 6-chloronicotinoyl chloride	Dimethylamine
6-chloro-N-ethyl-N-methyl-niacinamide (D9)	The 6-chloronicotinoyl chloride	N-ethyl-methyl-amine	6-chloro-N-methyl-niacinamide (D10)	The 6-chloronicotinoyl chloride	Methylamine
6-chloro-N-cyclopentyl-niacinamide (D11)	The 6-chloronicotinoyl chloride	Cyclopentyl amine	6-chloro-N-methyl-niacinamide (D10)	The 6-chloronicotinoyl chloride	Methylamine
6-chloro-N-cyclopentyl-niacinamide (D11)	The 6-chloronicotinoyl chloride	Cyclopentyl amine	1-(6-chloro-pyridin-3-yl)-1-piperidines-1-base-ketone (D12)	The 6-chloronicotinoyl chloride	Piperidines
1-(2-chloro-pyridin-4-yl)-1-piperidines-1-base-ketone (D13)	The different nicotinoyl chlorine of 2-chloro-	Piperidines	1-(6-chloro-pyridin-3-yl)-1-piperidines-1-base-ketone (D12)	The 6-chloronicotinoyl chloride	Piperidines
1-(2-chloro-pyridin-4-yl)-1-piperidines-1-base-ketone (D13)	The different nicotinoyl chlorine of 2-chloro-	Piperidines	1-(2-chloro-pyridin-4-yl)-1-tetramethyleneimine-1-base-ketone (D14)	The different nicotinoyl chlorine of 2-chloro-	Tetramethyleneimine
1-(2-chloro-pyridin-4-yl)-1-morpholine-4-base-ketone (D15)	The different nicotinoyl chlorine of 2-chloro-	Morpholine		The different nicotinoyl chlorine of 2-chloro-	Tetramethyleneimine
1-(2-chloro-pyridin-4-yl)-1-morpholine-4-base-ketone (D15)	The different nicotinoyl chlorine of 2-chloro-	Morpholine	1-(6-chloro-pyridine-2-yl)-1-piperidines-1-base-ketone (D16)	6-chloro-pyridine-2-carbonyl chloride	Piperidines
1-(6-chloro-pyridine-2-yl)-1-(1,1-dioxy thiomorpholine-4-yl)-ketone (D17)	6-chloro-pyridine-2-carbonyl chloride	Thiomorpholine 1, the 1-dioxide		6-chloro-pyridine-2-carbonyl chloride	Piperidines
	6-chloro-pyridine-2-carbonyl chloride	Thiomorpholine 1, the 1-dioxide	1-(6-chloro-pyridine-2-yl)-1-tetramethyleneimine-1-base-ketone (D18)	6-chloro-pyridine-2-carbonyl chloride	Tetramethyleneimine
1-(6-chloro-pyridine-2-yl)-1-morpholine-4-base-ketone (D19)	6-chloro-pyridine-2-carbonyl chloride	Morpholine		6-chloro-pyridine-2-carbonyl chloride	Tetramethyleneimine
1-(6-chloro-pyridine-2-yl)-1-morpholine-4-base-ketone (D19)	6-chloro-pyridine-2-carbonyl chloride	Morpholine	1-(2-chloro-pyridin-3-yl)-1-morpholine-4-base-ketone (D20)	2-chloro-nicotinoyl chlorine	Morpholine
1-(2-chloro-pyridin-3-yl)-1-piperidines-1-base-ketone (D21)	2-chloro-nicotinoyl chlorine	Piperidines	1-(2-chloro-pyridin-3-yl)-1-morpholine-4-base-ketone (D20)	2-chloro-nicotinoyl chlorine	Morpholine
1-(2-chloro-pyridin-3-yl)-1-piperidines-1-base-ketone (D21)	2-chloro-nicotinoyl chlorine	Piperidines	1-(4-iodo-phenyl)-1-morpholine-4-base-ketone (D22)	4-iodo-Benzoyl chloride	Morpholine
4-iodo-N-cyclopropyl methyl-4-benzamide (D23)	4-iodo-Benzoyl chloride	Cyclopropyl methyl-amine	1-(4-iodo-phenyl)-1-morpholine-4-base-ketone (D22)	4-iodo-Benzoyl chloride	Morpholine
4-iodo-N-cyclopropyl methyl-4-benzamide (D23)	4-iodo-Benzoyl chloride	Cyclopropyl methyl-amine	1-(4-iodo-phenyl)-1-tetramethyleneimine-1-base-ketone (D24)	4-iodo-Benzoyl chloride	Tetramethyleneimine
4-iodo-N-cyclobutyl-benzamide (D25)	4-iodo-Benzoyl chloride	Cyclobutyl amine	1-(4-iodo-phenyl)-1-tetramethyleneimine-1-base-ketone (D24)	4-iodo-Benzoyl chloride	Tetramethyleneimine
4-iodo-N-cyclobutyl-benzamide (D25)	4-iodo-Benzoyl chloride	Cyclobutyl amine	4-iodo-N, N-diethyl-benzamide (D26)	4-iodo-Benzoyl chloride	Diethylamine
4-iodo-N-(2-cyano group-ethyl)-N-methyl-benzamide (D27)	4-iodo-Benzoyl chloride	3-methylamino-propionitrile	4-iodo-N, N-diethyl-benzamide (D26)	4-iodo-Benzoyl chloride	Diethylamine
4-iodo-N-(2-cyano group-ethyl)-N-methyl-benzamide (D27)	4-iodo-Benzoyl chloride	3-methylamino-propionitrile	1-(3-iodo-phenyl)-1-morpholine-4-base-ketone (D28)	3-iodo-Benzoyl chloride	Morpholine
3-iodo-N-cyclopropyl methyl-benzamide (D29)	3-iodo-Benzoyl chloride	Cyclopropyl methyl-amine	1-(3-iodo-phenyl)-1-morpholine-4-base-ketone (D28)	3-iodo-Benzoyl chloride	Morpholine
3-iodo-N-cyclopropyl methyl-benzamide (D29)	3-iodo-Benzoyl chloride	Cyclopropyl methyl-amine	4-(4-iodo-benzenesulfonyl)-morpholine (D30)	4-iodo-benzene sulfonyl chloride	Morpholine
4-iodo-N, N-diethyl-benzsulfamide (D31)	4-iodo-benzene sulfonyl chloride	Diethylamine	4-(4-iodo-benzenesulfonyl)-morpholine (D30)	4-iodo-benzene sulfonyl chloride	Morpholine

Example 32 is described

5-bromo-2-(piperidino) pyrimidine (D32)

With piperidines (5.1ml, 51.6mmol) be added to 5-bromo-2-chloropyrimide after the stirring (5g, 25.8mmol) and triethylamine (9.0ml is in toluene 64.5mmol) (30ml) solution.After at room temperature stirring 24 hours, reaction mixture is diluted with ethyl acetate, with 2N hydrochloric acid, salt water washing and dry (sal epsom).Filter organic layer, vacuum concentration by the column chromatography purifying, is used eluent ethyl acetate with resulting resistates, obtains title compound (D32).

Routine 33-35 is described

Utilization is similar to the method for describing in the example 32 (D32) of describing, and the piperidines that substitutes wherein with the suitable amine shown in the following table prepares description routine 33-35 (D33-D35).

Example is described	Amine
Example is described	Amine	5-bromo-2-(1-pyrrolidyl) pyrimidine (D33)	Tetramethyleneimine
4-(5-bromo-2-pyrimidyl) thiomorpholine 1,1-dioxide (D34)	Thiomorpholine 1, the 1-dioxide	5-bromo-2-(1-pyrrolidyl) pyrimidine (D33)	Tetramethyleneimine
4-(5-bromo-2-pyrimidyl) thiomorpholine 1,1-dioxide (D34)	Thiomorpholine 1, the 1-dioxide	5-bromo-N-methyl-2-PYRIMITHAMINE (D35)	Methylamine

Routine 36-37 is described

Utilization is similar to the method for describing in the example 5 (D5) of describing, and the morpholine that substitutes wherein with the suitable amine shown in the following table prepares description routine 36-37 (D36-37).

Example is described	Amine
Example is described	Amine	6-chloro-N-(cyclopropyl methyl)-3-picolinamide (D36)	The cyclopropyl methylamine
5-(1-azelidinyl carbonyl)-2-chloropyridine (D37)	Azetidine	6-chloro-N-(cyclopropyl methyl)-3-picolinamide (D36)	The cyclopropyl methylamine

Example 38 is described

5-bromo-2-pyrimidine nitrile (D38)

(2.30g 46.6mmol) is dissolved in the dimethyl formamide (60ml), and (6.0g 31.1mmol) handles with 5-bromo-2-chloropyrimide with sodium cyanide.Resulting mixture at room temperature stirred 18 hours, dilute with water, and use dichloromethane extraction.The combined dichloromethane extraction liquid washes with water, and dry (sal epsom) filters and vacuum concentration.Crude product is by the column chromatography purifying, and use ethyl acetate: the mixture wash-out of hexane (1: 4) obtains title compound (D38).

Example 39 is described

7-(the 5-[(methylamino) carbonyl]-the 2-pyridyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (D39)

With 7-hydroxyl-1,2,4, (8.7g 33mmol) is dissolved in the trimethyl carbinol 5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (PCT international application (2002), WO 02/40471), and (4g 36mmol) handles with potassium tert.-butoxide.After at room temperature stirring 30 minutes, add 6-chloro-N-methyl-niacinamide (D10) (5.1g, 30mmol), with reaction mixture stirring and refluxing 20 hours.Reaction mixture is cooled to room temperature, vacuum concentration.In thick resistates, add ice/water, separate out precipitation, filter and collect.Solid sediment is dissolved in the ethyl acetate, with salt water washing and dry (sal epsom).Filter organic layer, vacuum concentration, by the column chromatography purifying, use ethyl acetate: the mixture wash-out of hexane (1: 1) obtains title compound (D39) with resulting resistates.NMR(CDCl ₃)8.52(1H，d，J＝2.4)，8.12(1H，dd，J＝8.8)，7.16(1H，m)，6.95-6.81(3H，m)，6.02(1H，br)，3.57(4H，br)，3.02(3H，d，J＝2.4)，2.89(4H，br)，1.49(9H，s)。

Example 40 is described

N-methyl-6-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-3-picolinamide (D40)

With 7-({ 5-[(methylamino) carbonyl]-the 2-pyridyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1, (3.98g 10mmol) is dissolved in the two  alkane (40ml) 1-dimethyl ethyl ester (D39), with two  alkane (35ml) solution-treated of 4M hydrogenchloride.Reaction mixture places under the room temperature and stirred 6 hours, and vacuum concentration obtains title compound (D40) then; MS (ES+) m/e 298[M+H] ⁺

Example 41 is described

7-hydroxyl-8-iodo-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (D41)

With 7-hydroxyl-1,2,4, (5.2g, 33% methylamine solution 20mmol) stir down in 0 ℃ in ethanol (30ml) 5-tetrahydrochysene-3H-benzo [d] azepine -3-carboxylic acid tert-butyl ester (PCT international application (2002), WO 02/40471).Below the liquid level of reaction mixture, add sodium iodide (4.6g, 30mmol) and iodine (5.2g, water 20mmol) (30ml) solution.After stirring 1 hour under 0 ℃, vacuum concentrated mixture.Resistates dilutes with ethyl acetate and water.Separate organic layer, water and salt water washing.The organic layer dried over mgso is filtered and vacuum concentration obtains title compound (D41); (7.0g, 90%), ¹H NMR (d ₆-DMSO) 10.0 (1H, br s), 7.41 (1H, s), 6.65 (1H, s), 3.40 (4H, m), 2.70 (4H, m), 1.40 (9H, s).

Example 42 is described

7-iodo-8-(the 5-[(methylamino) carbonyl]-the 2-pyridyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (D42)

(60% mineral oil dispersion, 240mg 6mmol) are added to 7-hydroxyl-8-iodo-1 after the stirring with sodium hydride, 2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1, (1.94g is in methyl-sulphoxide 5mmol) (10ml) solution for 1-dimethyl ethyl ester (D41).After 10 minutes, (850mg, 5mmol), reaction mixture is heated to 100 ℃, continues 20 hours to add 6-chloro-N-methylnicotinamide (D10).After being cooled to room temperature, reaction mixture water and methylene dichloride dilution.Separate organic layer, water and salt water washing, dried over mgso is filtered and vacuum concentration.(1: 1 ethyl acetate: purifying hexane) obtains title product (D42) to resistates by column chromatography.

Example 43 is described

N-methyl-6-(8-iodo-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-3-picolinamide (D43)

Utilization is similar to the described method of example 2 (D2) of describing, by 7-iodo-8-({ 5-[(methylamino) carbonyl]-the 2-pyridyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (D42) prepares and describes example 43 (D43); MS (ES+) m/e 424[M+H] ⁺

Example 44 is described

7-iodo-8-[(phenmethyl) oxygen base]-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (D44)

(60% mineral oil dispersion, 576mg 14.4mmol) are added to 7-hydroxyl-8-iodo-1 after the stirring with sodium hydride, 2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1, (4.67g is in dimethyl formamide 12mmol) (30ml) solution for 1-dimethyl ethyl ester (D41).After 15 minutes, (12mmol), mixture stirred 2 hours for 2.04g, 1.4ml to add bromotoluene.Mixture water and ethyl acetate dilution separate organic layer, water and salt water washing, and dried over mgso is filtered and vacuum concentration.Resistates is passed through to use ethyl acetate: the column chromatography purifying of hexane (1: 10) mixture wash-out obtains title product (D44).

Example 45 is described

7-iodo-8-[(phenmethyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (D45)

Utilization is similar to describes the described method of example 2 (D2), by 7-iodo-8-[(phenmethyl) the oxygen base]-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (D44) prepare describes routine D45 (D45); MS (ES+) m/e 380[M+H] ⁺

Example 46 is described

1-(3-chloro-2-pyrazinyl)-2-Pyrrolidone (D46)

Step 1:3-chloropyrazine 1-oxide compound

With chloropyrazine (9.6g, 83.3mmol) and superoxol (30%, mixture 16ml) in Glacial acetic acid (26ml) in 70 ℃ of down heating 18 hours.Mixture is cooled to room temperature, and impouring water (250ml) is with methylene dichloride (3 * 100ml) extractions.The combined dichloromethane extraction liquid, with saturated sodium bicarbonate solution (2 * 70ml), water (3 * 100ml) and salt solution (100ml) wash.The organic moiety dried over sodium sulfate, vacuum-evaporation obtains white solid, and it is obtained title compound (0.45g) with the dehydrated alcohol recrystallization. ¹H NMR(CDCl ₃)8.27-8.26(1H，d)，8.15(1H，s)，8.03-8.02(1H，dd)。

Step 2:2, the 3-dichloropyrazine

Under 60 ℃, (D46, (2.2g 16.9mmol) slowly is added in the phosphorus oxychloride (10ml) step 1) with 3-chloropyrazine 1-oxide compound.After reinforced the finishing, mixture reflux 60 minutes.Mixture is placed cooling, impouring ice and solid sodium-acetate (5g).It is stirred up to ice-out, use dichloromethane extraction then.The combined dichloromethane extraction liquid is with saturated sodium bicarbonate solution, water and salt water washing.The organic moiety dried over sodium sulfate, vacuum-evaporation.Resulting resistates is passed through to use ethyl acetate: the column chromatography purifying of hexane (1: 20) mixture wash-out obtains title compound (0.86 g). ¹H NMR(CDCl ₃)8.32(2H，s)。

Step 3:1-(3-chloro-2-pyrazinyl)-2-Pyrrolidone

Under argon shield, ((0.12ml is in anhydrous dimethyl formamide 1.54mmol) (5ml) solution 1.62mmol) to be added to pyrrolidone for 60% mineral oil dispersion, 67mg with sodium hydride in 0 ℃.Mixture was warmed to room temperature in 1.5 hours.Add 2,3-dichloropyrazine (D46, step 2) (250mg, anhydrous dimethyl formamide 1.69mmol) (2ml) solution, mixture under argon shield in stirring at room 2 hours.In the mixture impouring water (30ml), with ethyl acetate (x3) extraction.The combined ethyl acetate extraction liquid is used the salt water washing, dried over mgso and vacuum-evaporation.Resulting resistates is passed through to use ethyl acetate: the column chromatography purifying of pentane (1: 1) mixture wash-out obtains title compound (0.10g); MS (ES+) m/e 198[M+H] ⁺

Example 47 is described

2,5-dichloropyrazine (D47)

Step 1:5-chloro-2-pyrazine amine

Under argon shield, (10g 10.5mmol) is dissolved in the anhydrous dimethyl formamide (60ml), and (15.36g 11.5mmol) handles with N-chloro-succinimide with amino pyrazine in 0 ℃.Mixture stirred 30 minutes, was warmed to room temperature then.In the mixture impouring water, use extracted with diethyl ether.Combined ether layer and vacuum-evaporation.Resulting resistates is passed through to use ethyl acetate: the column chromatography purifying of pentane (1: 9) wash-out obtains title compound (1.40g); ¹H NMR (CDCl ₃) 8.02 (1H, s), 7.76 (1H, s), 4.61 (2H, s).

Step 2:2, the 5-dichloropyrazine

(D47, (2.41g 18.6mmol) is dissolved in the concentrated hydrochloric acid (24ml) step 1), cools off in ice-acetone bath, and (2.63g, water 38.1mmol) (18ml) solution is handled by dropwise added Sodium Nitrite in 1 hour with 5-chloro-2-pyrazine amine.Mixture cools off in ice-water-bath, places and stirs 1 hour.Mixture is warmed to room temperature, continues 1 hour,, use dichloromethane extraction by adding sodium hydroxide solution (2M) neutralization.The combined dichloromethane layer is with dried over mgso and vacuum-evaporation.Resulting resistates is passed through to use ethyl acetate: the column chromatography purifying of pentane (1: 9) mixture wash-out obtains title compound (0.33g); ¹H NMR (CDCl ₃) 8.40 (2H, s).

Example 48 is described

2,5-two bromo-pyrazines (D48)

Step 1:5-bromo-2-pyrazine amine

With amino pyrazine (5.0g 52.6mmol) is dissolved in the chloroform (150ml), add pyridine (5.11ml, 63.2mmol).In 1 hour, dropwise add bromine (3.24ml, chloroform 63.2mmol) (50ml) solution.Mixture stirred 30 minutes, and water (50ml) dilution was stirred 10 minutes.Separate organic layer, water (50ml) washing is with dried over mgso and vacuum-evaporation.Resulting resistates is passed through to use ethyl acetate: the column chromatography purifying of pentane (1: 4) mixture wash-out obtains title compound (0.32g); MS (ES+) m/e175[M+H] ⁺

Step 2:2,5-two bromo-pyrazines

With 5-bromo-2-pyrazine amine (D48, step 1) (317mg, 1.82mmol) be added to after the cooling (ice-acetone bath) hydrobromic acid solution (48% aqueous solution) (2ml) in.Stir after 5 minutes, in 15 minutes, successively dropwise add bromine (0.28ml, 5.46mmol) and Sodium Nitrite (314mg, aqueous solution 4.55mmol).Mixture stirred 30 minutes, was warmed to room temperature in 30 minutes.Water (7ml) solution that adds sodium hydroxide (2.6g), mixture stirred 1 hour.The mixture dichloromethane extraction.Combined dichloromethane layer, vacuum-evaporation obtain title compound (60mg). ¹H NMR(CDCl ₃)8.49(2H，s)。

Example 49 is described

N-methyl-5-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-2-pyrazinoic acid amide (D49)

Step 1:7-(the 5-[(methoxyl group) carbonyl]-the 2-pyrazinyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

In 15 minutes, with sodium hydride (60% mineral oil dispersion) (6.4g, 0.16mol) be added to the 7-hydroxyl-1 that is cooled to 5 ℃ in batches, 2,4, (40g is in anhydrous dimethyl formamide 0.15mol) (200ml) solution for 5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (PCT international application (2002), WO 02/40471).After 15 minutes, mixture is warmed to room temperature, stirs 60 minutes.Mixture cools off in ice-water-bath, add in batches 5-chloro-2-pyrazine carboxylate methyl ester (31.2g, 0.18mol).Mixture is warmed to room temperature, stirs 18 hours.To stir up to ice-out in mixture impouring water (500ml) and the ice (500ml).Collect resulting solid by filtering, wash with water and be dissolved in the ethyl acetate (1500ml).Ethyl acetate layer washs with salt solution (200ml), dried over sodium sulfate and vacuum-evaporation.Crude product is passed through to use ethyl acetate: the column chromatography purifying of hexane (1: 2) mixture wash-out obtains title compound (35.07g).

Step 2:5-[(3-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-pyrazine carboxylic acid

2M sodium hydroxide solution (110ml) is added to 7-({ 5-[(methoxyl group) carbonyl]-the 2-pyrazinyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (D49, (29.38g, in acetone 73.6mmol) (480ml) solution, resulting mixture at room temperature stirred 25 minutes step 1).Mixture 2M hcl acidifying is then in the impouring water (2L).Collect resultant white solid by filtering, wash with water and be dissolved in the ethyl acetate (1L).Solution obtains title compound (27.3g) with dried over sodium sulfate and vacuum-evaporation; MS (ES+) m/e 384[M-H] ⁺

Step 3:7-(the 5-[(methylamino) carbonyl]-the 2-pyrazinyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

With 1,1 '-carbonyl dimidazoles (16.6g, 102mmol) be added to 5-[(3-{[(1, the 1-dimethyl ethyl) oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-2-pyrazine carboxylic acid (D49, step 2) (37.5g, in anhydrous methylene chloride 97mmol) (400ml) solution, resulting mixture at room temperature stirred 18 hours.Add methylamine (tetrahydrofuran solution of 2M) (100ml), mixture stirred 2 hours.Solvent removed in vacuo, resistates is passed through to use ethyl acetate: the column chromatography purifying of chloroform (1: 1) wash-out obtains title compound (25.8g); MS (ES+) m/e 399[M+H] ⁺

Step 4:N-methyl-5-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-2-pyrazinoic acid amide

With 7-({ 5-[(methylamino) carbonyl]-the 2-pyrazinyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (D49, (44.26g, methylene dichloride 0.11mol) (800ml) solution dropwise are added to two  alkane of 4 M hydrogenchloride after the stirring, and (270ml is 1.1mol) in the solution for step 3).Resulting mixture at room temperature stirred 60 minutes.Add more two  alkane of volume 4 M hydrogenchloride (30ml, 0.12mol) solution, mixture stirring 60 minutes.Collect resulting white solid and use washed with dichloromethane by filtering.Solid is dissolved in the water (2L), by adding the saturated sodium carbonate solution alkalization.The water layer dichloromethane extraction, extraction liquid passes through diatomite filtration.The diatomite methanol wash, methylene dichloride and methyl alcohol washing lotion that vacuum-evaporation merges obtain title compound (25.1g); MS (ES+) m/e 299[M+H] ⁺

Routine 50-52 is described

Utilize the method for describing in the example 5 (D5) of describing, prepared by suitable aryl halide shown in the following table and amine and describe routine 50-52 (D50-D52), it directly uses no longer further and handles.

Example is described	Aryl halide	Amine
Example is described	Aryl halide	Amine	N-ethyl-4-iodo-N-[2-(methoxyl group) ethyl] benzamide (D50)	4-iodobenzene formyl chloride	2-methoxy ethyl ethamine
4-iodo-N-methyl-benzamide (D51)	4-iodobenzene formyl chloride	Methylamine	N-ethyl-4-iodo-N-[2-(methoxyl group) ethyl] benzamide (D50)	4-iodobenzene formyl chloride	2-methoxy ethyl ethamine
4-iodo-N-methyl-benzamide (D51)	4-iodobenzene formyl chloride	Methylamine	The 1-[(3-iodophenyl) carbonyl] tetramethyleneimine (D52)	3-iodobenzene formyl chloride	Tetramethyleneimine

Example 53 is described

(2E)-and 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-3-(dimethylamino)-2-propylene-1-ketone (D53)

With 1-{6-[(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-the 3-pyridyl } and ethyl ketone (E214) (186mg, 0.55mmol), the mixture heating up of dimethyl formamide dimethyl ethanoyl (0.25ml) and dimethylbenzene (4ml) refluxed 8 hours.Resistates dilution with toluene, vacuum concentration obtain title compound (D53); MS (ES+) m/e 392[M+H] ⁺

Example 54 is described

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-pyridine carbohydrazide (D54)

With thionyl chloride (2ml) and 6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-(200mg, 0.59mmol) stirring and refluxing is 1 hour for 3-pyridine carboxylic acid (E196b).The vacuum concentration reaction mixture obtains thick resistates.Resistates is dissolved in the tetrahydrofuran (THF) (5ml), is cooled to 0 ℃, dropwise add tetrahydrofuran (THF) (1.5ml) solution of hydrazine hydrate (1.5ml).Reaction mixture is warmed to room temperature, stirs 1 hour.Then reaction mixture is diluted with ethyl acetate, with saturated sodium carbonate solution, water, salt water washing and drying (sal epsom).Filter organic layer and vacuum concentration and obtain title compound (D54); MS (ES+) m/e 361[M+H] ⁺

Example 55 is described

Cis-4-(4-morpholinyl carbonyl) hexalin (D55)

With cis-4-hydroxyl hexahydrobenzoic acid (720mg, 0.5mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.33g, 6mmol) with 1-hydroxyl-7-azepine benzotriazole (816mg, (1.3ml 15mmol) handles methylene dichloride 6mmol) (6ml) solution with morpholine.After at room temperature stirring 18 hours, with the crude reaction thing be filled to SCX ion-exchange tube (Varian bond-elute, 5g) in, earlier use 0.880 ammoniacal liquor again: the washing of methyl alcohol (1: 9) mixture with methyl alcohol.The basic moiety that vacuum concentration merges, resulting resistates is passed through to use 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (D55); MS (ES+) m/e 214[M+H] ⁺

Example 56 is described

2-chloro-6-[4-(methylsulfonyl) phenyl] pyrazine (D56)

With 2, and the 6-dichloropyrazine (2.98g, 20.0mmol), [4-(methylsulfonyl) phenyl] boric acid (2g; 10.0mmol), tetrakis triphenylphosphine palladium (1.15g; 1.0mmol), potassiumphosphate (10.2g, 48mmol) and dimethyl formamide (90ml) be heated to 80 ℃, continue 16 hours.Solvent removed in vacuo, product are dissolved in the chloroform, pass through diatomite filtration.The filtrate water washing separates then.Resistates is passed through to use ethyl acetate: the column chromatography purifying of hexane (4: 6) mixture wash-out obtains title compound.MS(ES+)m/e 270[M+H] ⁺。

Embodiment 1

7-benzyloxy-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E1)

Under 0 ℃, with 7-benzyloxy-1,2,4, (25.3g 100mmol) is dissolved in methylene dichloride (400ml) solution of 2.5% acetate 5-tetrahydrochysene-benzo [d] azepine  (D2), and (11.2ml 150mmol) handles dropwise to add cyclobutanone.Mixture stirred 30 minutes, add then in batches sodium triacetoxy borohydride (31.8g, 150mmol).Reaction mixture at room temperature stirred 4 hours, with the saturated sodium carbonate solution alkalization, used dichloromethane extraction.The extraction liquid water, the salt water washing that merge, anhydrous sodium sulfate drying, and vacuum concentration.Thick resistates grinds with hexane, filters, and obtains title product (E1).MS(ES+)m/e 308[M+H] ⁺。

Embodiment 2

7-benzyloxy-3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E2)

Utilize the method for describing among the embodiment 1, by 7-benzyloxy-1,2,4,5-tetrahydrochysene-benzo [d] azepine  (D2) and cyclopentanone prepare title compound (E2); MS (ES+) m/e 322[M+H] ⁺

Embodiment 3

3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3)

With 7-benzyloxy-3-cyclobutyl-2,3,4, (9.22g 30mmol) is dissolved in ethanol (150ml) and the tetrahydrofuran (THF) (50ml) 5-tetrahydrochysene-1H-benzo [d] azepine  (E1).Add palladium (1.5g, 10% is carried on charcoal sticks with paste on (charcoal paste)), reaction mixture was at room temperature stirred 5 hours down in nitrogen atmosphere (1 normal atmosphere).By diatomite filtration reaction mixture, vacuum concentrated filtrate.Thick resistates is ground with ether, filter, obtain title product (E3); MS (ES+) m/e 218[M+H] ⁺

Embodiment 4

3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E4)

Utilize the method for describing among the embodiment 3 (E3), by 7-benzyloxy-3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E2) prepares title compound (E4); ¹H NMR (DMSO, d ₆) 9.08 (1H, brs), 6.70 (1H, d), 6.53-6.47 (2H, m), 3.31-2.50 (9H, m), 1.88-1.43 (8H, m).

Embodiment 5a

4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid tert-butyl ester (E5a)

With 3-cyclopentyl-2,3,4, and 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E4) (1.1g, 4.8mmol).4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester (1.15g, 5.7mmol), azo-2-carboxylic acid's di tert butyl carbonate (1.31g, 5.7mmol) and triphenylphosphine (1.5g 5.7mmol) at room temperature stirred in tetrahydrofuran (THF) (20ml) 16 hours.Mixture is with after the acetate acidifying, be filled to SCX ion-exchange tube (Varian bond-elute, 10g) in, use 0.880 ammoniacal liquor again with methyl alcohol earlier: the washing of methyl alcohol (1: 9) mixture.The basic moiety that vacuum concentration merges, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title product (E5a); MS (ES+) m/e 415[M+H] ⁺

Embodiment 5

3-cyclopentyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E5)

(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-(593mg 1.43mmol) is dissolved in the methylene dichloride (5ml) piperidines-1-carboxylic acid tert-butyl ester (E5a), handles with trifluoroacetic acid (3ml) with 4-.Solution at room temperature stirred 1 hour, vacuum concentration, be filled to then SCX ion-exchange tube (Varianbondelute, 5g) in, earlier use 0.880 ammoniacal liquor again: the washing of methyl alcohol (1: 9) mixture with methyl alcohol.The basic moiety that vacuum concentration merges, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title product (E5).MS(ES+)m/e 315[M+H] ⁺。

Embodiment 6-12

Utilization is similar to the method for describing among the embodiment 5a (E5a), follow the method for describing in the preparation by embodiment 5 (E5) again, by 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H benzo [d] azepine -7-alcohol (E3) or 3-cyclopentyl-2,3,4, the suitable alcohol shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E4) and the following table prepares embodiment 6-12 (E6-12).

Embodiment	Starting raw material	Alcohol	LC/MS (M+H ⁺)
Embodiment	Starting raw material	Alcohol	LC/MS (M+H ⁺)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	E3	4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester	301
3-cyclobutyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E7)	E3	4-methylol-piperidines-1-carboxylic acid tert-butyl ester	315		E3	4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester	301
	E3	4-methylol-piperidines-1-carboxylic acid tert-butyl ester	315	3-cyclobutyl-7-((R)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E8)	E3	(R)-2-methylol-tetramethyleneimine-1-carboxylic acid tert-butyl ester	301
3-cyclobutyl-7-((R)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E9)	E3	(R)-3-hydroxyl-tetramethyleneimine-1-carboxylic acid tert-butyl ester	287		E3		301
	E3		287	3-cyclobutyl-7 ((S)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E10)	E3	(S)-3-hydroxyl-tetramethyleneimine-1-carboxylic acid tert-butyl ester	287
3-cyclobutyl-7-((S)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E11)	E3	(S)-2-methylol-tetramethyleneimine-1-carboxylic acid tert-butyl ester	301		E3		287
	E3		301	3-cyclopentyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E7)	E4	4-methylol-piperidines-1-carboxylic acid tert-butyl ester	329

Embodiment 13

4-{1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-formyl radical }-benzonitrile (E13)

With 4-cyanobenzoic acid (147mg, 1mmol), I-hydroxybenzotriazole hydrate (154mg, 1mmol) (1.8mmol/g, 555mg 1mmol) at room temperature stirred 15 minutes in methylene dichloride (5ml) with N-carbodicyclo hexylimide N '-methylated polystyrene.Add 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4, (150mg 0.5mmol), continues to stir 16 hours 5-tetrahydrochysene-1H-benzo [d] azepine  (E6).Reaction mixture is filled to SCX ion-exchange tube, and (Varian bond-elute 5g), uses 0.880 ammoniacal liquor with methyl alcohol earlier: methyl alcohol (1: 9) washing again.The basic moiety that vacuum concentration merges, resulting resistates is used 0.880 ammoniacal liquor by elder generation again with methylene dichloride: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title product (E13).MS(ES+)m/e 430[M+H] ⁺。

Embodiment 14-42

Utilization is similar to the method for describing among the embodiment 13 (E13), prepares embodiment 14-42 (E14-E42) by suitable amine shown in the following table and acid

Embodiment	Amine	Acid	LC/MS (M+H ⁺)
Embodiment	Amine	Acid	LC/MS (M+H ⁺)	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(tetrahydrochysene-pyrans-4-yl)-ketone (E14)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Tetrahydrochysene-pyrans-4-carboxylic acid	413
1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base) piperidines-1-yl]-1-cyclohexyl-ketone (E15)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Hexahydrobenzoic acid	411			Tetrahydrochysene-pyrans-4-carboxylic acid	413
		Hexahydrobenzoic acid	411	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-isoquinoline 99.9-1-base-ketone (E16)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Isoquinoline 99.9-1-carboxylic acid	456
4-{ (E)-3-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-3-oxo-propenyl)-benzonitrile (E17)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	(E)-3-(4-cyano group-phenyl)-vinylformic acid	456			Isoquinoline 99.9-1-carboxylic acid	456
		(E)-3-(4-cyano group-phenyl)-vinylformic acid	456	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-isoquinoline 99.9-6-base-ketone (E18)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Isoquinoline 99.9-6-carboxylic acid	456
1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(5-methyl-different  azoles-3-yl)-ketone (E19)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] cyanogen  (E6) that mixes	5-methyl-different  azoles-3-carboxylic acid	410			Isoquinoline 99.9-6-carboxylic acid	456
		5-methyl-different  azoles-3-carboxylic acid	410	1-benzothiazole-6-base-1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-ketone (E20)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Benzothiazole-6-carboxylic acid	462

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-[yl]-1-pyridin-4-yl-ketone (E21)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Yi Yansuan	406
		Yi Yansuan	406	1-[4-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-[4-(1-tetramethyleneimine-1-base-formyl radical)-phenyl]-ketone (E22)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	4-(1-tetramethyleneimine-1-base-formyl radical)-phenylformic acid (WO03/04468)	502
1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-thiene-3-yl--ketone (E23)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Thiophene-3-carboxylic acid	411				502
		Thiophene-3-carboxylic acid	411	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-furans-3-base-ketone (E24)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Furans-3-carboxylic acid	395
1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-piperidines-1-yl]-1-tetrahydrochysene-pyrans-4-yl)-ketone (E25)	3-cyclobutyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E7)	Tetrahydrochysene-pyrans-4-carboxylic acid	427			Furans-3-carboxylic acid	395
		Tetrahydrochysene-pyrans-4-carboxylic acid	427	1-[(R)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-tetramethyleneimine-1-yl]-1-(tetrahydrochysene-pyrans-4-yl)-ketone (E26)	3-cyclobutyl-7-((R)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E8)	Tetrahydrochysene-pyrans-4-carboxylic acid	413
1-[(R)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-1-(tetrahydrochysene-pyrans 4-yl)-ketone (E27)	3-cyclobutyl-7-((R)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E9)	Tetrahydrochysene-pyrans-4-carboxylic acid	399			Tetrahydrochysene-pyrans-4-carboxylic acid	413
		Tetrahydrochysene-pyrans-4-carboxylic acid	399	1-[(S)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-(tetrahydrochysene-pyrans-4-yl)-ketone (E28)	3-cyclobutyl-7-((S)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E10)	Tetrahydrochysene-pyrans-4-carboxylic acid	399
1-[(s)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-1-(tetrahydrochysene-pyrans-4-yl)-ketone (E29)	3-cyclobutyl-7-((S)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E11)	Tetrahydrochysene-pyrans-4-carboxylic acid	413			Tetrahydrochysene-pyrans-4-carboxylic acid	399
		Tetrahydrochysene-pyrans-4-carboxylic acid	413	1-[4-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(methylsulfonyl-phenyl)-ketone (E30)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	4-methylsulfonyl-phenylformic acid	483

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-pyrazine-2-base-ketone (E31)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	2-pyrazine carboxylic acid	407
		2-pyrazine carboxylic acid	407	5-{1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-formyl radical }-1H-pyridone (E32)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	The 6-hydroxy niacin	422
1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(2,3-dihydro-cumarone-5-yl)-ketone (E33)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	2,3-dihydro-cumarone-5-carboxylic acid	447			The 6-hydroxy niacin	422
		2,3-dihydro-cumarone-5-carboxylic acid	447	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-3-methoxyl group-third-1-ketone (E34)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	3-methoxyl group-propionic acid	387
1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1 H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-(2,3-dihydro-cumarone-7-yl)-ketone (E35)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	2,3-dihydro-cumarone-7-carboxylic acid	447			3-methoxyl group-propionic acid	387
		2,3-dihydro-cumarone-7-carboxylic acid	447	4-{1-{4-(3-cyclopentyl-7-(piperidin-4-yl methoxyl group)-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl) piperidines-1-yl }-formyl radical }-benzonitrile (E36)	3-cyclopentyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E12)	4-cyano group-phenylformic acid	458
1-[4-(3-cyclopentyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-piperidines-1-yl]-1-[4-(1-tetramethyleneimine-1-base-formyl radical)-phenyl]-ketone (E37)	3-cyclopentyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E12)	4-(1-tetramethyleneimine-1-base-formyl radical)-phenylformic acid (WO 03/04468A1)	530			4-cyano group-phenylformic acid	458
			530	4-{1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-formyl radical }-benzonitrile (E38)	3-cyclopentyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E5)	4-cyano group-phenylformic acid	444
1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-pyridin-4-yl-ketone (E39)	3-cyclopentyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E5)	Yi Yansuan	420			4-cyano group-phenylformic acid	444
		Yi Yansuan	420	1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-quinoline 6-base-ketone (E40)	3-cyclopentyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E5)	QUINOLINE-6-CARBOXYLIC ACID	470

1-[4-(3-cyclopentyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-[4-(1-tetramethyleneimine-1-base-formyl radical)-phenyl] ketone (E41)	3-cyclopentyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E5)	4-(1-tetramethyleneimine-1-base-formyl radical)-phenylformic acid (WO 03/04468A1)	516
			516	1-biphenyl-4-base-1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-ketone (E42)	3-cyclopentyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E5)	The 4-biphenyl carboxylic acids	495

Embodiment 43

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-cyclopentyl-ketone (E43)

With 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4, (150mg, 0.5mmol) (3.2mmol/g, 625mg 2mmol) stir in methylene dichloride (5ml) 5-tetrahydrochysene-1H-benzo [d] azepine  (E6) with the diethylamino methylated polystyrene.(80 μ l, 0.6mmol), mixture at room temperature stirred 16 hours to add the pentamethylene carbonyl chloride.Filter resin and use washed with dichloromethane, vacuum concentrated filtrate.Resistates is used 0.880 ammoniacal liquor by elder generation again with methylene dichloride: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title product (E43); MS (ES+) m/e 397[M+H] ⁺

Embodiment 44-51

Utilization is similar to the method for describing among the embodiment 43 (E43), prepares embodiment 44-51 (E44-E51) by suitable amine shown in the following table and carbonyl chloride.

Embodiment	Amine	Carbonyl chloride	LC/MS (M+H ⁺)
Embodiment	Amine	Carbonyl chloride	LC/MS (M+H ⁺)	4-{1-[4-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-piperidines-1-yl]-formyl radical }-benzonitrile (E44)	3-cyclobutyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine (E7)	The 4-cyano-benzoyl chloride	444
4-{1-[(R)-2-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-tetramethyleneimine-1-yl]-formyl radical }-benzonitrile (E45)	3-cyclobutyl-7-((R)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E8)	The 4-cyano-benzoyl chloride	430			The 4-cyano-benzoyl chloride	444

4-{1-[(R)-3-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-formyl radical }-benzonitrile (E46)	3-cyclobutyl-7-((R)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E9)	4-cyano group-Benzoyl chloride	416
		4-cyano group-Benzoyl chloride	416	4-{1-[(S)-3-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-formyl radical }-benzonitrile (E47)	3-cyclobutyl-7-((S)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E10)	4-cyano group-Benzoyl chloride	416
4-{1-[(S)-2-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-formyl radical }-benzonitrile (E48)	3-cyclobutyl-7-((S)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E11)	4-cyano group-Benzoyl chloride	430			4-cyano group-Benzoyl chloride	416
		4-cyano group-Benzoyl chloride	430	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-2,2-dimethyl-third-1-ketone (E49)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	2,2-dimethyl-propionyl chloride	385
1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-cyclopropyl-ketone (E50)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Cyclopropane carbonyl chlorine	369			2,2-dimethyl-propionyl chloride	385
		Cyclopropane carbonyl chlorine	369	1-cyclobutyl-1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-ketone (E51)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Tetramethylene carbonyl chlorine	383

Embodiment 52

4-{1-{4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-morpholine-4-base-ketone (E52)

With 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4, (150mg, 0.5mol) (3.2mmol/g, 625mg 2mol) stir in methylene dichloride (5ml) 5-tetrahydrochysene-1H-benzo [d] azepine  (E6) with the diethylamino methylated polystyrene.(70 μ L, 0.6mmol), mixture at room temperature stirred 16 hours to add the morpholine urea chloride.Filter resin and use washed with dichloromethane, vacuum concentrated filtrate.Resistates is used 0.880 ammoniacal liquor by elder generation again with methylene dichloride: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title product (E52).MS(ES+)m/e 414[M+H] ⁺。

Embodiment 53-60

Utilization is similar to the method for describing among the embodiment 52 (E52), prepares embodiment 53-60 (E53-E60) by amine shown in the following table and carbonyl chloride.

Embodiment	Amine	Acid	LC/MS (M+H ⁺)
Embodiment	Amine	Acid	LC/MS (M+H ⁺)	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-piperidines-1-yl]-1-morpholine-4-base-ketone (E53)	3-cyclobutyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E7)	Morpholine-4-carbonyl chlorine	428
1-[(R)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-tetramethyleneimine-1-yl]-1-morpholine-4-base-ketone (E54)	3-cyclobutyl-7-((R)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E8)	Morpholine-4-carbonyl chlorine	414			Morpholine-4-carbonyl chlorine	428
		Morpholine-4-carbonyl chlorine	414	1-[(R)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-1-morpholine-4-base-ketone (E55)	3-cyclobutyl-7-((R)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E9)	Morpholine-4-carbonyl chlorine	400
1-[(S)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-1-morpholine-4-base-ketone (E56)	3-cyclobutyl-7-((S)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E10)	Morpholine-4-carbonyl chlorine	400			Morpholine-4-carbonyl chlorine	400
		Morpholine-4-carbonyl chlorine	400	4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid diisopropylamide (E57)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Di-isopropyl-carbonyl chlorine	428
1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-tetramethyleneimine-1-base-ketone (E58)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Tetramethyleneimine-1-carbonyl chlorine	398			Di-isopropyl-carbonyl chlorine	428
		Tetramethyleneimine-1-carbonyl chlorine	398	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-piperidines-1-base-ketone (E59)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	Piperidines-1-carbonyl chlorine	412
1-[(S)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-tetramethyleneimine-1-yl]-1-morpholine-4-base-ketone (E60)	3-cyclobutyl-7-((S)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E11)	Morpholine-4-carbonyl chlorine	414			Piperidines-1-carbonyl chlorine	412

Embodiment 61

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid diethylamide (E61)

Under 0 ℃, will be dissolved in the 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4 in the toluene (40ml), 5-tetrahydrochysene-1H-benzo [d] azepine  (E6) (1.5g, 5mmol) slowly be added to 20% carbonyl chloride toluene solution (12.5ml, 25mmol) in.Mixture was at room temperature stirred 3 hours, and vacuum concentration obtains thick resistates (1.91g).(300mg, (207 μ L, 2mmol) (3.2mmol/g, 1.41g is in methylene dichloride 4.5mmol) (10ml) soup compound with the diethylamino methylated polystyrene 0.75mmol) to be added to diethylamine after the stirring with this crude product then.Reaction mixture at room temperature stirred 16 hours, filtered and vacuum concentration.Thick resistates is by using 0.880 ammoniacal liquor again with methylene dichloride earlier: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title product (E61).MS(ES+)m/e 400[M+H] ⁺。

Embodiment 62-65

Utilization is similar to the method for describing among the embodiment 61 (E61), and by 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4, the suitable amine shown in 5-tetrahydrochysene-1H-benzo [d] azepine  (E6) and the following table prepares embodiment 62-65 (E62-E65).

Embodiment	Amine	LC/MS (M+H ⁺)
Embodiment	Amine	LC/MS (M+H ⁺)	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(1,3-dihydro-isoindole-2-yl)-ketone (E62)	2,3-dihydro-1H-isoindole	446
1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(2,3,5,6-tetrahydrochysene-[1,2 '] connection pyrazine-4-yl)-ketone (E63)	3,4,5,6-tetrahydrochysene-2H-[1,2 '] the connection pyrazine	491		2,3-dihydro-1H-isoindole	446
		491	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid sec.-propyl-(2-methoxyl group-ethyl) acid amides (E64)	Sec.-propyl-(2-methoxyl group-ethyl-amine	444
1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-(1,1-dioxo-thiomorpholine-4-yl)-ketone (E65)	Thiomorpholine 1, the 1-dioxide	462		Sec.-propyl-(2-methoxyl group-ethyl-amine	444

Embodiment 66

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid sec.-propyl acid amides (E66)

With 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4, (150mg, 0.5mmol) (60 μ L, methylene dichloride 0.6mmol) (5ml) solution at room temperature stirred 16 hours 5-tetrahydrochysene-1H-benzo [d] azepine  (E6) with the isocyanic acid isopropyl esters.Vacuum concentrated solution, resistates is used 0.880 ammoniacal liquor by elder generation again with methylene dichloride: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title product (E66).MS(ES+)m/e 386[M+H] ⁺。

Embodiment 67

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid (4-fluoro-phenyl)-acid amides (E67)

Utilize the method for describing among the embodiment 66 (E66), by 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6) and 4-fluorophenyl-isocyanic ester prepare embodiment 67; MS (ES+) m/e 438[M+H] ⁺

Embodiment 68

2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N, N-dimethyl-ethanamide (E68)

(60% mineral oil dispersion, 60mg 1.5mmol) are added to 3-cyclobutyl-2,3,4 after the stirring, and (200mg is in methyl-sulphoxide 0.9mmol) (10ml) solution for 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) with sodium hydride.0.5 after hour, (0.3ml, 2.4mmol), reaction mixture is heated to 120 ℃, continues 6 hours to add 2-chloro-N,N-dimethylacetamide.Make reaction cooling, with crude mixture be filled to SCX ion-exchange tube (Varian bond-elute, 10g) in, use 0.880 ammoniacal liquor again with methyl alcohol earlier: the washing of methyl alcohol (1: 9) mixture.The basic moiety that vacuum concentration merges obtains title compound (E68).MS(ES+)m/e303[M+H] ⁺。

Embodiment 69-71

Utilize the method for describing among the embodiment 68 (E68), by 3-cyclobutyl-2,3,4, the suitable muriate shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepares embodiment 69-71 (E69-E71).

Embodiment	Muriate	LC/MS(M+H ⁺)
Embodiment	Muriate	LC/MS(M+H ⁺)	2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-phenyl-ethanamide (E69)	2-chloro-N-phenyl-ethanamide	351
2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-1-tetramethyleneimine-1-base-ethyl ketone (E70)	2-chloro-1-tetramethyleneimine-1-base-ethyl ketone	329		2-chloro-N-phenyl-ethanamide	351
	2-chloro-1-tetramethyleneimine-1-base-ethyl ketone	329	2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-1-morpholine-4-base-ethyl ketone (E71)	2-chloro-1-morpholinyl-4-base-ethyl ketone	345

Embodiment 72

3-cyclobutyl-7-(1-methylsulfonyl-piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E72)

With 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4, (150mg, 0.5mmol) (3.2mmol/g, 625mg 2mmol) stir in methylene dichloride (5ml) 5-tetrahydrochysene-1H-benzo [d] azepine  (E6) with the diethylamino methylated polystyrene.(43 μ L 0.55mmol), and at room temperature stirred mixture 16 hours to add methylsulfonyl chloride.Filter resin and use washed with dichloromethane, vacuum concentrated filtrate.Resistates is passed through to use 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title product (E72); MS (ES+) m/e 379[M+H] ⁺

Embodiment 73-78

Utilization is similar to the method for describing among the embodiment 72 (E72), prepares embodiment 73-78 (E73-E78) by suitable amine shown in the following table and SULPHURYL CHLORIDE.

Embodiment	Amine	SULPHURYL CHLORIDE	LC/MS (M+H ⁺)
Embodiment	Amine	SULPHURYL CHLORIDE	LC/MS (M+H ⁺)	4-[4-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-alkylsulfonyl]-benzonitrile (E73)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	4-cyano group-benzene sulfonyl chloride	466
3-cyclobutyl-7-[1-(35-dimethyl-different  azoles-4-alkylsulfonyl)-piperidin-4-yl oxygen base]-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine  (E74)	3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6)	3,5-dimethyl-different  azoles-4-SULPHURYL CHLORIDE	460			4-cyano group-benzene sulfonyl chloride	466
		3,5-dimethyl-different  azoles-4-SULPHURYL CHLORIDE	460	4-[4-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-piperidines-1-alkylsulfonyl]-benzonitrile (E75)	3-cyclobutyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E7)	4-cyano group-benzene sulfonyl chloride	480
4-[(R)-2-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-tetramethyleneimine-1-alkylsulfonyl]-benzonitrile (E76)	3-cyclobutyl-7-((R)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E8)	4-cyano group-benzene sulfonyl chloride	466			4-cyano group-benzene sulfonyl chloride	480
		4-cyano group-benzene sulfonyl chloride	466	4-[(R)-3-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-alkylsulfonyl]-benzonitrile (E77)	3-cyclobutyl-7-((R)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E9)	4-cyano group-benzene sulfonyl chloride	452
4-[(S)-3-(3-cyclobutyl-2; 3; 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-alkylsulfonyl]-benzonitrile (E78)	3-cyclobutyl-7-((S)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E10)	4-cyano group-benzene sulfonyl chloride	452			4-cyano group-benzene sulfonyl chloride	452

Embodiment 79

3-cyclobutyl-7-(2,4-two fluoro-benzyloxies)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E79)

(778mg 5.6mmol) is added to 3-cyclobutyl-2,3 after the stirring with salt of wormwood, 4, and 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) (868mg, 4.0mmol), 2, (0.25ml is 2.1mmol) and in butanone (9ml) solution of potassiumiodide (25mg) for the 4-difluoro benzyl bromide.With reaction mixture stirring and refluxing 18 hours, cooling was filtered and vacuum concentration.Thick resistates is dissolved in the ethyl acetate water and salt water washing.The organic layer dried over mgso is filtered and vacuum concentration.Resulting resistates is by using 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (0.25: 2.25: 97.5 1: 9: 10 then) mixture wash-out obtains title compound (E79); MS (ES+) m/e 344[M+H] ⁺

Embodiment 80-87

Utilize the usual method of describing among the embodiment 80 (E80), by 3-cyclobutyl-2,3,4, the suitable halogenide shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepares embodiment 80-87 (E80-E87).

Embodiment	Halogenide	LC/MS(M+H ⁺)
Embodiment	Halogenide	LC/MS(M+H ⁺)	3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-benzonitrile (E80)	3-brooethyl-benzonitrile	333
3-cyclobutyl-7-(3-methoxyl group-benzyloxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E81)	1-brooethyl-3-anisole	338		3-brooethyl-benzonitrile	333
	1-brooethyl-3-anisole	338	3-cyclobutyl-7-(pyridine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E82)	2-brooethyl-pyridine	309
3-cyclobutyl-7-(pyridin-3-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E83)	3-brooethyl-pyridine	309		2-brooethyl-pyridine	309
	3-brooethyl-pyridine	309	3-cyclobutyl-7-(pyridin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E84)	4-brooethyl-pyridine	309
2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-benzonitrile (E85)	2-brooethyl-benzonitrile	333		4-brooethyl-pyridine	309
	2-brooethyl-benzonitrile	333	4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-benzonitrile (E86)	4-brooethyl-benzonitrile	333
6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-1-methyl isophthalic acid H-quinoline-2-one-(E87)	6-brooethyl-1-methyl isophthalic acid H-quinoline-2-one-	389		4-brooethyl-benzonitrile	333

Embodiment 88

4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-methyl benzoate (E88)

With 4-(2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl]-methyl benzoate (D4) (2.83g, 9.1mmol) and cyclopentanone (1.6ml 18.2mmol) is dissolved in methylene dichloride (30ml) and the acetate (0.5ml).(3.85g, 18.2mmol), solution at room temperature stirred 4 hours to add sodium triacetoxy borohydride.Reaction mixture washs with saturated sodium carbonate solution, and the organic layer dried over mgso is filtered and vacuum concentration.Crude mixture is passed through to use 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (E88); MS (ES+) m/e 380[M+H] ⁺

Embodiment 89

4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenylformic acid (E89)

(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-(3.1g 8.1mmol) is dissolved in the mixture that contains methyl alcohol (90ml), 2 N sodium hydroxide (12ml) and water (30ml) methyl benzoate (E88) with 4-.The mixture of gained stirred 4 hours down at 60 ℃, was cooled to room temperature then.Vacuum concentrated mixture is removed organic solvent, and being acidified to pH then is 6 (2 N hydrochloric acid).Filter resulting throw out, wash with water and vacuum-drying, obtain title compound (E89); MS (ES+) m/e 366[M+H] ⁺

Embodiment 90

1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-tetramethyleneimine-Ji-ketone (E90)

With 4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenylformic acid (E89) (0.201mg, 0.55mmol)), 1, (44 μ l, 0.6mmol) (82mg 0.6mmol) is dissolved in the mixture that contains methylene dichloride (2ml) and dimethyl formamide (1ml) the 3-DIC with the I-hydroxybenzotriazole hydrate.After at room temperature stirring 0.5 hour, (41 μ l 0.5mmol), stir resulting mixture 16 hours to add tetramethyleneimine.With the crude reaction thing be filled to SCX ion-exchange tube (Varian bond-elute, 5g) in, earlier use 0.880 ammoniacal liquor again: methyl alcohol (1: 9) washing with methyl alcohol.The basic moiety that vacuum concentration merges, resulting resistates is passed through to use 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (E90); MS (ES+) m/e419[M+H] ⁺

Embodiment 91-93

Utilization is similar to the method for describing among the embodiment 90 (E90), prepares embodiment 91-93 (E91-E93) by the suitable amine shown in 4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenylformic acid (E89) and the following table.

Embodiment	Amine	LC/MS(M+H ⁺)
Embodiment	Amine	LC/MS(M+H ⁺)	1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-morpholine-4-base-ketone (E91)	Morpholine	435
1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-(4-pyridin-4-yl-piperazine-1-yl)-ketone (E92)	1-pyridin-4-yl-piperazine	511		Morpholine	435
	1-pyridin-4-yl-piperazine	511	1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-[4-(4-fluoro-phenyl)-piperazine-1-yl]-ketone (E93)	1-(4-fluoro-phenyl)-piperazine	528

Embodiment 94

3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-methyl benzoate (E94)

According to the method that is similar to embodiment 88 (E88), by utilize describing example 3 (D3), describing the 7-hydroxyl-1 that the method emphasized among example 4 (D4) and the embodiment 88 (E88) prepares, 2,4,5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (WO 02/40471) and 3-brooethyl-methyl benzoate prepares embodiment 94 (E94); MS (ES+), m/e 380[M+H] ⁺

Embodiment 95

3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenylformic acid (E95)

Utilize steps outlined among the embodiment 89 (E89), prepare embodiment 95 (E95) by 3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H benzo [d] azepine -7-base oxygen ylmethyl)-methyl benzoate; MS (ES+), m/e 366[M+H] ⁺

Embodiment 96

1-[3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-tetramethyleneimine-Ji-ketone (E96)

Utilize steps outlined among the embodiment 90 (E90), prepare embodiment 96 (E96) by tetramethyleneimine and 3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenylformic acid (E95); MS (ES+), m/e 419[M+H] ⁺

Embodiment 97-99

Utilization is similar to the method for describing among the embodiment 96 (E96), prepares embodiment 97-99 (E97-E99) by the suitable amine shown in 3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenylformic acid (E95) and the following table.

Embodiment	Amine	LC/MS(M+H ⁺)
Embodiment	Amine	LC/MS(M+H ⁺)	1-[3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-morpholine-4-base-ketone (E97)	Morpholine	435
1-[3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-(4-pyridin-4-yl-piperazine-1-yl)-ketone (E98)	1-pyridin-4-yl-piperazine	511		Morpholine	435
	1-pyridin-4-yl-piperazine	511	1-[3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-[4-(4-fluoro-phenyl)-piperazine-1-yl]-ketone (E99)	1-(4-fluoro-phenyl)-piperazine	528

Embodiment 100

(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-nicotinic acid nitrile (nicotinonitrile) (E100) for 6-

(60% mineral oil dispersion, 60mg 1.5mmol) are added to 3-cyclobutyl-2,3,4 after the stirring, and (200mg is in methyl-sulphoxide 0.9mmol) (10ml) solution for 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) with sodium hydride.0.5 after hour, (250mg 1.8mmol), is heated to 120 ℃ with reaction mixture, continues 6 hours to add 6-chlorine apellagrin nitrile.Make the reaction cooling, crude mixture is filled to SCX ion-exchange tube, and (Varian bond-elute 10g), uses 0.880 ammoniacal liquor with methyl alcohol earlier: the washing of methyl alcohol (1: 9) mixture again.The basic moiety that vacuum concentration merges obtains title compound (E100); MS (ES+) m/e 320[M+H] ⁺

Embodiment 101-120

Utilization is similar to the method for describing among the embodiment 100 (E100), and by 3-cyclobutyl-2,3,4, the suitable aromatic halide shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepares embodiment 101-120 (E101-E120).

Embodiment	Muriate	LC/MS (M+H ⁺)
Embodiment	Muriate	LC/MS (M+H ⁺)	3-cyclobutyl-7-(pyridine-2-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E101)	2-chloro-pyridine	295
1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-1-morpholine-4-base-ketone (E102)	1-(6-chloro-pyridin-3-yl)-1-morpholine-4-base-ketone (D5)	408		2-chloro-pyridine	295
	1-(6-chloro-pyridin-3-yl)-1-morpholine-4-base-ketone (D5)	408	1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-1-tetramethyleneimine-1-base-ketone (E103)	1-(6-chloro-pyridin-3-yl)-1-tetramethyleneimine-1-base-ketone (D6)	392
6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-niacinamide (E104)	6-chloro-niacinamide (D7)	338			392
	6-chloro-niacinamide (D7)	338	6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N, N-dimethyl-niacinamide (E105)	6-chloro-N, N-dimethyl-niacinamide (D8)	366
6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-ethyl-N-methyl-niacinamide (E106)	6-chloro-N-ethyl-N-methyl-niacinamide (D9)	380		6-chloro-N, N-dimethyl-niacinamide (D8)	366
	6-chloro-N-ethyl-N-methyl-niacinamide (D9)	380	6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen	6-chloro-N-cyclopentyl-niacinamide	406

Base)-N-cyclopentyl-niacinamide (E107)	(D11)
Base)-N-cyclopentyl-niacinamide (E107)	(D11)		1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-1-piperidines-1-base-ketone (E108)	1-(6-chloro-pyridin-3-yl)-1-piperidines-1-base-ketone (D12)	406
1-[2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-4-yl]-1-piperidines-1-base-ketone (E109)	1-(2-chloro-pyridin-4-yl)-1-piperidines-1-base-ketone (D13)	406		1-(6-chloro-pyridin-3-yl)-1-piperidines-1-base-ketone (D12)	406
	1-(2-chloro-pyridin-4-yl)-1-piperidines-1-base-ketone (D13)	406	1-[2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-4-yl]-1-tetramethyleneimine-1-base-ketone (E110)	1-(2-chloro-pyridin-4-yl)-1-tetramethyleneimine-1-base-ketone (D14)	392
1-[2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-4-yl]-1-morpholine-4-base-ketone (E111)	1-(2-chloro-pyridin-4-yl)-1-morpholine-4-base-ketone (D15)	408			392
	1-(2-chloro-pyridin-4-yl)-1-morpholine-4-base-ketone (D15)	408	1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridine-2-yl]-1-piperidines-1-base-ketone (E112)	1-(6-chloro-pyridine-2-yl)-1-piperidines-1-base-ketone (D16)	406
1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridine-2-yl]-1-(1,1-dioxy thiomorpholine-4-yl)-ketone (E113)	1-(6-chloro-pyridine-2-yl)-1-(1,1-dioxy thiomorpholine-4-yl) ketone (D17)	466			406
		466	1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridine-2-yl]-1-tetramethyleneimine-1-base-ketone (E114)	1-(6-chloro-pyridine-2-yl)-1-tetramethyleneimine-1-base-ketone (D18)	392
1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridine-2-yl]-1-morpholine-4-base-ketone (E115)	1-(6-chloro-pyridine-2-yl)-1-morpholine-4-base-ketone (D19)	408			392
	1-(6-chloro-pyridine-2-yl)-1-morpholine-4-base-ketone (D19)	408	1-[2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-1-morpholine-4-base-ketone (E116)	1-(2-chloro-pyridin-3-yl)-1-morpholine-4-base-ketone (D20)	408
1-[2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-1-piperidines-1-base-ketone (E117)	1-(2-chloro-pyridin-3-yl)-1-piperidines-1-base-ketone (D21)	406		1-(2-chloro-pyridin-3-yl)-1-morpholine-4-base-ketone (D20)	408
	1-(2-chloro-pyridin-3-yl)-1-piperidines-1-base-ketone (D21)	406	3-cyclobutyl-7-(pyrazine-2-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E118)	2-chloro-pyrazine	296
3-cyclobutyl-7-(pyrimidine-2-yloxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E119)	2-chloro-pyrimidine	296		2-chloro-pyrazine	296
	2-chloro-pyrimidine	296	7-(5-bromo-pyrimidine-2-yloxy)-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E120)	5-bromo-2-chloro-pyrimidine	375

Embodiment 121

6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-methyl-niacinamide (E121)

(60% mineral oil dispersion, 60mg 1.5mmol) are added to 3-cyclobutyl-2,3,4 after the stirring, and (200mg is in dimethyl sulfoxide (DMSO) 0.9mmol) (10ml) solution for 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) with sodium hydride.0.5 after hour, (400mg, 2.5mmol), reaction mixture is heated to 120 ℃ and continues 6 hours to add 6-chloro-N-methyl-niacinamide (D10).After the reaction cooling, with crude mixture be filled to SCX ion-exchange tube (Varian bond-elute, 10g) in, use 0.880 ammoniacal liquor again with methyl alcohol earlier: the washing of methyl alcohol (1: 9) mixture.The basic moiety that vacuum concentration merges obtains title compound (E121). ¹H NMR(DMSO-d ₆)δ8.56(1H，dd，J＝2.4，0.4Hz)，8.48(1H，br m)，8.20(1H，dd，J＝8.4，2.4Hz)，7.16(1H，d，J＝8.0Hz)，7.03(1H，dd，J＝8.4，0.4Hz)，6.91(1H，d，J＝2.4Hz)，6.86(1H，dd，J＝8.0，2.4Hz)，2.87-2.77(8H，m)，2.36(4H，m)，2.00(2H，m)，1.78(2H，m)，1.58(2H，m)；MS(ES+)m/e 352[M+H] ⁺。

Embodiment 121 (alternative method 1)

Sodium hydride (0.331g, 8.28mmol, 60% mineral oil dispersion) is added to 3-cyclobutyl-2,3,4 after the stirring, and (1.5g is in dimethyl sulfoxide (DMSO) 6.9mmol) (15ml) solution for 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3).0.5 after hour, (2.34g, 13.8mmol), reaction mixture is heated to 100 ℃ and continues 18 hours to add 6-chloro-N-methyl-niacinamide (D10).Reaction is cooled to room temperature, distributes between ethyl acetate and water then.The separating ethyl acetate layer, water layer washs with the ethyl acetate of more volumes.Then with the organic layer water, the salt water washing that merge, dry (Na ₂SO ₄) and filter then.The vacuum concentration miscellany, with resulting resistates by using 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95 1: 9: 90 then) mixture wash-out, obtain title compound (E121), then with it by the toluene recrystallization. ¹H NMR(DMSO-d ₆)δ8.56(1H，dd，J＝2.4，0.4Hz)，8.48(1H，br m)，8.20(1H，dd，J＝8.4，2.4Hz)，7.16(1H，d，J＝8.0Hz)，7.03(1H，dd，J＝8.4，0.4Hz)，6.91(1H，d，J＝2.4Hz)，6.86(1H，dd，J＝8.0，2.4Hz)，2.87-2.77(8H，m)，2.36(4H，m)，2.00(2H，m)，1.78(2H，m)，1.58(2H，m)；MS(ES+)m/e 352[M+H] ⁺。

Embodiment 121 (alternative method 2)

Under 0 ℃, with N-methyl-6-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-3-picolinamide (D40) (1.04g, 3.5mmol) (400 μ L 5.3mmol) handle, and at room temperature stir then 1 hour by dropwise adding cyclobutanone for mixture in the methylene dichloride (12ml) that contains acetate (240 μ L).Mixture is cooled to 0 ℃ subsequently, use sodium triacetoxy borohydride (1.11g 5.3mmol) handles, and at room temperature stirs 16 hours in batches.Solution is careful to be stirred 30 minutes with 2 N sodium-hydroxide treatment, used dichloromethane extraction then.The extraction liquid salt water washing that merges, anhydrous sodium sulfate drying and vacuum concentration.Crude product is by using 0.880 ammoniacal liquor again with methylene dichloride earlier: methyl alcohol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (E121); MS (ES+) m/e 352[M+H] ⁺

Embodiment 122

5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carboxylate methyl ester (E122)

(60% mineral oil dispersion, 332mg 8.3mmol) are added to 3-cyclobutyl-2,3,4 after the stirring, and (1.64g is in dimethyl formamide 7.5mmol) (4ml) solution for 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) with sodium hydride.0.5 after hour, pyrazine-(reaction mixture at room temperature stirred 1 hour the 2-carboxylate methyl ester for 1.95g, dimethyl formamide 11.3mmol) (8ml) solution to add the 5-chloro-.Reaction mixture dilutes with methylene dichloride, organic layer water, salt water washing, dried over mgso.Filter organic layer, vacuum concentration, resulting resistates is by using 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (E122).MS(ES+)m/e 354[M+H] ⁺。

Embodiment 123a

5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carboxylic acid (E123a)

(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-(880mg 2.5mmol) is dissolved in the mixture that contains ethanol (15ml) and 2N sodium hydroxide (4ml) pyrazine-2-carboxylate methyl ester (E122) with 5-.Resulting mixture at room temperature stirred 0.5 hour, and vacuum concentration is removed organic solvent then.Then reaction mixture being acidified to pH is 5 (2N hydrochloric acid), filters resulting throw out, washes with water, and vacuum-drying obtains title compound (E123a); MS (ES+) m/e 340[M+H] ⁺

Embodiment 123

1-[5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-yl]-1-morpholine-4-base-ketone (E123)

Step 1:5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carbonyl chloride

With thionyl chloride (5ml) slowly be added to 5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carboxylic acid (E123a) (485mg) in.Resulting reaction mixture at room temperature stirred 1 hour, continued reflux then 1 hour.Reaction mixture with dilution with toluene and vacuum concentration, obtains title compound, it is directly used no longer further handle.

Step 2:1-[5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-yl]-1-morpholine-4-base-ketone

(0.17ml, (394mg, 1mmol) (1.88g, 3.2mmol/g is in methylene dichloride 6mmol) (10ml) solution with the diethylamino methylated polystyrene 2.0mmol) to be added to 1 product of the step after the stirring with morpholine.Resulting mixture at room temperature stirred 24 hours, filtered.Vacuum concentrated filtrate, resulting thick resistates is by using 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (E123).MS(ES+)m/e 409[M+H] ⁺。

Embodiment 124 and 126-127

Utilization is similar in embodiment 123 steps 2 method of describing, and prepares embodiment 124 and 126-127 (E124 and E126-E127) by the product and the suitable amine shown in the following table of embodiment 123 steps 1.

Embodiment	Amine	LC/MS (M+H ⁺)
Embodiment	Amine	LC/MS (M+H ⁺)	5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrrole	The N-ethylmethylamine	381

Piperazine-2-carboxylic acid ethylmethyl amide (E124)
Piperazine-2-carboxylic acid ethylmethyl amide (E124)			1-[5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-yl]-1-piperidin-4-yl-ketone (E126)	Piperidines	407
1-[5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-yl]-1-tetramethyleneimine-4-base-ketone (E127)	Tetramethyleneimine	393		Piperidines	407

Embodiment 125

5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carboxylic acid methane amide (E125)

The solution of product (1.59mmol) in anhydrous methylene chloride (10ml) of embodiment 123 steps 1 is handled with methylamine (5mol, 10mmol, the THF solution of 2 M), at room temperature stirred 18 hours.Vacuum concentrated mixture, with resulting crude product be filled to SCX ion-exchange tube (Varian bond-elute, 10g) in, earlier use 0.880 ammoniacal liquor again: the washing of methyl alcohol (1: 9) mixture with methyl alcohol.Concentrated alkaline part then, crude product is by using 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (0.2: 1.8: 98 0.4: 3.6: 96 then) mixture wash-out obtains title compound (E125). ¹H NMR (CDCl ₃) δ 8.91 (1H, d, 1.3Hz), 8.26 (1H, d, 1.3Hz), 7.61 (1H, the br quartet, 4.8Hz), 7.15 (1H, m), 6.92 (2H, m), 3.03 (3H, d, 5.1Hz), 2.93 (4H, m), 2.79 (1H, m), 2.47 (4H, m), 2.08 (2H, m), 1.91 (2H, m), 1.70-1.62 (2H, m).

Embodiment 128

3-cyclobutyl-7-phenoxy group-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E128)

Under 0 ℃, with sodium hydride (60% mineral oil dispersion, 96mg, 2.4mmol) be added to the 3-cyclobutyl-2,3 after the stirring, 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) (435mg, 2.0mmol) and cupric bromide (I) (402mg is in pyridine 2.8mmol) (10ml) solution.At room temperature stirred 0.5 as a child, add iodobenzene (0.45ml, 4.0mmol), with reaction mixture reflux 24 hours.Make the reaction cooling, filter, then vacuum concentrated filtrate.Thick resistates acetic acid ethyl dissolution, water and salt water washing.The organic layer dried over mgso is filtered and vacuum concentration, and resulting resistates is by using 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (0.25: 2.25: 97.5 to 1: 9: 90) mixture wash-out obtains title compound (E128); MS (ES+) m/e 294[M+H] ⁺

Embodiment 129-138

Utilization is similar to the method for describing among the embodiment 128 (E128), and by 3-cyclobutyl-2,3,4, the suitable aromatic halide shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepares embodiment 129-138 (E129-E133).

Embodiment	Aromatic halide	LC/MS (M+H ⁺)
Embodiment	Aromatic halide	LC/MS (M+H ⁺)	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-phenyl]-1-morpholine-4-base-ketone (E129)	1-(4-iodo-phenyl)-1-morpholine-4-base-ketone (D22)	407
4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-cyclopropyl methyl benzamide (E130)	4-iodo-N-cyclopropyl methyl-benzamide (D23)	391		1-(4-iodo-phenyl)-1-morpholine-4-base-ketone (D22)	407
	4-iodo-N-cyclopropyl methyl-benzamide (D23)	391	1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-phenyl]-1-tetramethyleneimine-1-base-ketone (E131)	1-(4-iodo-phenyl)-1-tetramethyleneimine-1-base-ketone (D24)	391
N-cyclobutyl-4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-benzamide (E132)	4-iodo-N-cyclobutyl-benzamide (D25)	391		1-(4-iodo-phenyl)-1-tetramethyleneimine-1-base-ketone (D24)	391
	4-iodo-N-cyclobutyl-benzamide (D25)	391	4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N, N-diethyl-benzamide (E133)	4-iodo-N, N-diethyl-benzamide (D26)	393
N-(2-cyano group-ethyl)-4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-methyl-benzamide (E134)	4-iodo-N-(2-cyano group-ethyl)-N-methyl-benzamide (D27)	404		4-iodo-N, N-diethyl-benzamide (D26)	393
	4-iodo-N-(2-cyano group-ethyl)-N-methyl-benzamide (D27)	404	1-[3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-phenyl]-1-morpholine-4-base-ketone (E135)	1-(3-iodo-phenyl)-1-morpholine-4-base-ketone (D28)	407
3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-cyclopropyl methyl-benzamide (E136)	3-iodo-N-cyclopropyl methyl-benzamide (D29)	391		1-(3-iodo-phenyl)-1-morpholine-4-base-ketone (D28)	407
	3-iodo-N-cyclopropyl methyl-benzamide (D29)	391	3-cyclobutyl-7-[4-(morpholine-4-alkylsulfonyl)-phenoxy group]-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E137)	4-(4-iodo-benzenesulfonyl)-morpholine (D30)	443
4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N, N-diethyl-benzsulfamide (E138)	4-iodo-N, N-diethyl-benzsulfamide (D31)	429		4-(4-iodo-benzenesulfonyl)-morpholine (D30)	443

Embodiment 139

7-benzyloxy-3-cyclohexyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E139)

Utilize the method for describing among the embodiment 1, prepare embodiment 139 (E139) by describing example 2 (D2) and pimelinketone; MS (ES+) m/e 336[M+H] ⁺

Embodiment 140

3-cyclobutyl-7-{[2-(piperidino)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E140)

Under 0 ℃, with sodium hydride (60% mineral oil dispersion, 44mg, 1.1mmol) be added to the 3-cyclobutyl-2,3 after the stirring, 4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) (200mg, 0.92mmol) and cupric bromide (I) (184mg is in pyridine 1.3mmol) (10ml) solution.After at room temperature stirring 0.5 hour, and adding 5-bromo-2-(piperidino) pyrimidine (D32) (0.669g, 2.8mmol), reaction mixture reflux 2 hours.Make the reaction cooling, filter vacuum concentrated filtrate.With thick resistates acetic acid ethyl dissolution, water and salt water washing.Dry organic layer (sal epsom) filters and vacuum concentration.Resulting resistates is by using 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (0.25: 2.25: 97.5 to 1: 9: 90) mixture wash-out obtains title compound (E140).MS(ES+)m/e 379[M+H] ⁺。

Embodiment 141-143

Utilization is similar to the method for describing among the embodiment 140 (E140), and by 3-cyclobutyl-2,3,4, the suitable bromide shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepares embodiment 141-143 (E141-E143).

Embodiment	Bromide	LC/MS (M+H ⁺)
Embodiment	Bromide	LC/MS (M+H ⁺)	3-cyclobutyl-7-{[2-(1-pyrrolidyl)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E141)	5-bromo-2-(1-pyrrolidyl) pyrimidine (D33)	365
3-cyclobutyl-7-{[2-(1,1-dioxo-4-thio-morpholinyl)-and the 5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E142)	4-(5-bromo-2-pyrimidyl) thiomorpholine 1,1-dioxide (D34)	429		5-bromo-2-(1-pyrrolidyl) pyrimidine (D33)	365

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-2-PYRIMITHAMINE (E143)

5-bromo-N-methyl-2-PYRIMITHAMINE (D35)

325

Embodiment 144

3-cyclobutyl-7-{[2-(methoxyl group)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E144)

Utilize the method for describing among the embodiment 140 (E140), by 3-cyclobutyl-2,3,4, (PCT International Application PCT (2002) WO02/62423) prepares embodiment 144 (E144) for 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and 5-bromo-2-(methoxyl group) pyrimidine; MS (ES+) m/e 326[M+H] ⁺

Embodiment 145-147

Utilization is similar to the method for describing among the embodiment 13 (E13), and by 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4, the suitable acid shown in 5-tetrahydrochysene-1H-benzo [d] azepine  (E6) and the following table prepares embodiment 145-147 (E145-E147).

Embodiment	Acid	LC/MS (M+H ⁺)
Embodiment	Acid	LC/MS (M+H ⁺)	1-[4-(4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino } carbonyl) phenyl]-2-Pyrrolidone (E145)	4-(2-OXo-1-pyrrolidine base) phenylformic acid	488
3-cyclobutyl-7-[(1-{[3-(methylsulfonyl) phenyl] carbonyl }-the 4-piperidyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E146)	3-(methyl sulphonyl) phenylformic acid	483		4-(2-OXo-1-pyrrolidine base) phenylformic acid	488
	3-(methyl sulphonyl) phenylformic acid	483	3-cyclobutyl-7-({ 1-[(1,1-dioxo-3,4-dihydro-2H-1-benzo thiapyran-6-yl) carbonyl]-the 4-piperidyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E147)	3,4-dihydro-2H-1-benzo thiapyran-6-carboxylic acid 1 ,-dioxide	509

Embodiment 148-150

Utilize the method that is adopted in the preparation of embodiment 5a (E5a), again by the method described in the preparation of embodiment 5 (E5), by 3-cyclobutyl-2,3,4, the suitable alcohol shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepares embodiment 148-150 (E148-E150).

Embodiment	Alcohol	LC/MS (M+H ⁺)
Embodiment	Alcohol	LC/MS (M+H ⁺)	The 3-cyclobutyl-7-{[(3S)-3-pyrrolidyl methyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E148)	(3S)-and 3-(methylol)-1-pyrrolidine carboxylic acid 1,1-dimethyl ethyl ester	301
The 3-cyclobutyl-7-{[(3S)-the 3-piperidino methyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E149)	(3S)-and 3-(methylol)-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester	315			301
		315	The 3-cyclobutyl-7-[(3S)-3-piperidyl oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E150)	(3S)-and 3-hydroxyl-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester	301

Embodiment 151-153

Utilize the method for describing among the embodiment 52, prepare embodiment 151-153 (E151-E153) by suitable amine shown in the following table and morpholine urea chloride.

Embodiment	Amine	LC/MS (M+H ⁺)
Embodiment	Amine	LC/MS (M+H ⁺)	3-cyclobutyl-7-([(3S)-and 1-(4-morpholinyl carbonyl)-3-piperidyl] methyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E151)	The 3-cyclobutyl-7-{[(3S)-the 3-piperidino methyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E149)	428
3-cyclobutyl-7-([(3S)-and 1-(4-morpholinyl carbonyl)-3-pyrrolidyl] methyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E152)	The 3-cyclobutyl-7-{[(3S)-3-pyrrolidyl methyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E148)	414			428
		414	The 3-cyclobutyl-7-{[(3S)-1-(4-morpholinyl carbonyl)-3-piperidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1 H-3-benzazepine (E153)	The 3-cyclobutyl-7-[(3S)-3-piperidyl oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E150)	414

Embodiment 154-156

Utilize the method for describing among the embodiment 43 (E43), prepare embodiment 154-156 (E154-E156) by suitable amine shown in the following table and 4-cyano-benzoyl chloride.

Embodiment	Amine	LC/MS(M+H ⁺)
Embodiment	Amine	LC/MS(M+H ⁺)	4-[((3S)-and 3-{[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] methyl }-1-	The 3-cyclobutyl-7-{[(3S)-the 3-piperidino methyl] the oxygen base }-2,3,4, the 5-tetrahydrochysene	444

Piperidyl) carbonyl] benzonitrile (E154)	-1H-3-benzazepine (E149)
Piperidyl) carbonyl] benzonitrile (E154)	-1H-3-benzazepine (E149)		4-[((3S)-3-{[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] methyl }-the 1-pyrrolidyl) carbonyl] benzonitrile (E155)	The 3-cyclobutyl-7-{[(3S)-3-pyrrolidyl methyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E148)	430
4-((3S)-3-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino } carbonyl) benzonitrile (E156)	The 3-cyclobutyl-7-[(3S)-3-piperidyl oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E150)	430			430

Embodiment 157-159

Utilization is similar to the method for describing among the embodiment 13 (E13), prepares embodiment 157-159 (E157-E159) by the suitable amine shown in the following table and tetrahydrochysene-pyrans-4-carboxylic acid.

Embodiment	Amine	LC/MS (M+H ⁺)
Embodiment	Amine	LC/MS (M+H ⁺)	3-cyclobutyl-7-([(3S)-and 1-(tetrahydrochysene-2H-pyrans-4-base carbonyl)-3-pyrrolidyl] methyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E157)	The 3-cyclobutyl-7-{[(3S)-3-pyrrolidyl methyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E148)	413
3-cyclobutyl-7-([(3S)-and 1-(tetrahydrochysene-2H-pyrans-4-base carbonyl)-3-piperidyl] methyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E158)	The 3-cyclobutyl-7-{[(3S)-the 3-piperidino methyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E149)	427			413
		427	The 3-cyclobutyl-7-{[(3S)-1-(tetrahydrochysene-2H-pyrans-4-base carbonyl)-3-piperidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E159)	The 3-cyclobutyl-7-[(3S)-3-piperidyl oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E150)	413

Embodiment 160

6-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino }-3-pyridine nitrile (E160)

With 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6) (60mg, 0.2mmol), 6-chlorine apellagrin nitrile (31mg, 0.22mmol) and triethylamine (0.03ml 0.22mmol) is dissolved in the acetonitrile (2ml), in microwave reactor, be heated to 180 ℃, continue 10 minutes.Reaction mixture dilutes with ethyl acetate, water, salt water washing, dry (sal epsom).Filter organic layer, vacuum concentration, resulting resistates is passed through to use 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (0.25: 2.25: 97.5 to 1: 9: 90) mixture wash-out obtains title compound (E160).MS(ES+)m/e403[M+H] ⁺。

Embodiment 161-166

Utilization is similar to the method for describing among the embodiment 160 (E160), by 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4, the suitable muriate shown in 5-tetrahydrochysene-1H-benzo [d] azepine  (E6) and the following table prepares embodiment 161-166 (E161-E166).

Embodiment	Muriate	LC/MS (M+H ⁺)
Embodiment	Muriate	LC/MS (M+H ⁺)	6-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino }-N-(cyclopropyl methyl)-3-pyridine carboxamide (E161)	6-chloro-N-(cyclopropyl methyl)-3-pyridine carboxamide (D36)	475
7-(1-[5-(1-azelidinyl carbonyl)-2-pyridyl]-the 4-piperidyl } the oxygen base)-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E162)	5-(1-azelidinyl carbonyl)-2-chloropyridine (D37)	461			475
	5-(1-azelidinyl carbonyl)-2-chloropyridine (D37)	461	3-cyclobutyl-7-(1-[5-(4-morpholinyl carbonyl)-2-pyridyl]-the 4-piperidyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E163)	1-(6-chloro-pyridin-3-yl)-1-morpholine-4-base-ketone (D5)	491
6-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino }-N-methyl-3-pyridine carboxamide (E164)	6-chloro-N-methyl-niacinamide (D10)	435		1-(6-chloro-pyridin-3-yl)-1-morpholine-4-base-ketone (D5)	491
	6-chloro-N-methyl-niacinamide (D10)	435	2-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino }-4-pyridine nitrile (E165)	2-chloro-4-pyridine nitrile	403
3-cyclobutyl-7-{[1-(2-pyrazinyl)-4-piperidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E166)	The 2-chloropyrazine	379		2-chloro-4-pyridine nitrile	403

Embodiment 167a

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] ethyl butyrate (E167a)

With 4-bromo-butyric acid ethyl ester (2ml 13.8mmol) is added to 3-cyclobutyl-2,3,4 after the stirring, 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) (2.00g, 9.2mmol) and salt of wormwood (3.8g is in 2-butanone 27.6mmol) (50ml) solution.After the stirring and refluxing 24 hours, reaction mixture is cooled to room temperature, filters and vacuum concentration.Resulting crude product is passed through to use methyl alcohol: the column chromatography purifying of methylene dichloride (5: 95) mixture wash-out obtains title compound (E167a).MS(ES+)m/e 332[M+H] ⁺。

Embodiment 167b

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] butyric acid (E167b)

With 4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] (1.5g 4.5mmol) is diluted in the ethanol (30ml) ethyl butyrate (E167a), handles with 2 N sodium hydroxide (7.9ml).After the stirring and refluxing 24 hours, reaction mixture is cooled to room temperature, filters and vacuum concentration.Crude mixture is filled in the SCX ion-exchange tube (Varian bond-elute), and first water, methyl alcohol are used 0.880 ammoniacal liquor again: the mixture washing of methyl alcohol (1: 9).The basic moiety that vacuum concentration merges obtains the title compound (E167b) into ammonium salt.MS(ES+)m/e 303[M+H] ⁺。

Embodiment 167

3-cyclobutyl-7-{[4-oxo-4-(piperidino) butyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E167)

Step 1:3-cyclobutyl-7-{[4-(1H-imidazoles-1-yl)-4-oxo butyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine

With 4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base] butyric acid (E167b) (0.90g 2.8mmol) is dissolved in the dimethyl formamide (10ml), with 1,1 '-(0.59g 3.6mmol) handles carbonyl dimidazoles.After at room temperature stirring 2.5 hours, the vacuum concentration reaction mixture.Thick resistates is dissolved in the methylene dichloride, uses the salt water washing, dry (sodium sulfate).Filter organic layer and vacuum concentration, this thick resistates directly uses not repurity in next step.

Step 2:3-cyclobutyl-7-{[4-oxo-4-(piperidino) butyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E167)

With piperidines (0.1ml 1.1mmol) is added to 3-cyclobutyl-7-{[4-(1H-imidazoles-1-yl)-4-oxo butyl after the stirring] the oxygen base-2,3,4, (E167, (150mg is in methylene dichloride 0.42mmol) (5ml) solution for step 1) for 5-tetrahydrochysene-1H-3-benzazepine.After at room temperature stirring 5 days, the vacuum concentration reaction mixture, resulting resistates is passed through to use 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (E167); MS (ES+) m/e 371[M+H] ⁺

Embodiment 168-170

Utilization is similar to the step of describing in embodiment 167 steps 2, and piperidines is substituted with the suitable amine shown in the following table, prepares embodiment 168-170 (E168-E170) by embodiment 167 steps 1.

Embodiment	Amine	LC/MS(M+H ⁺)
Embodiment	Amine	LC/MS(M+H ⁺)	3-cyclobutyl-7-{[4-oxo-4-(1-pyrrolidyl) butyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E168)	Tetramethyleneimine	357
4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-cyclopentyl butyramide (E169)	Cyclopentamine	371		Tetramethyleneimine	357
	Cyclopentamine	371	4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methylbutyryl amine (E170)	Methylamine	317

Embodiment 171-176

Utilization is similar to the method for describing in embodiment 123 steps 2 (E123), prepares embodiment 171-176 (E171-E176) by the suitable amine shown in embodiment 123 steps 1 and the following table.

Embodiment	Amine	LC/MS(M+H ⁺)
Embodiment	Amine	LC/MS(M+H ⁺)	5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(1-methylethyl)-2-Zinamide (E171)	Isopropylamine	381
5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(tetrahydrochysene-2H-pyrans-4-yl)-2-Zinamide (E172)	Tetrahydrochysene-2H-pyrans-4-amine	423		Isopropylamine	381
	Tetrahydrochysene-2H-pyrans-4-amine	423	7-{[5-(1-azelidinyl carbonyl)-2-pyrazinyl] the oxygen base }-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E173)	Azetidine	379
5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N, N-diethyl-2-Zinamide (E174)	Diethylamine	395		Azetidine	379
	Diethylamine	395	5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-[2-(methoxyl group) ethyl]-2-Zinamide (E175)	2-(methoxyl group) ethamine	397

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-2-Zinamide (E176)

Ethamine

367

Embodiment 177a

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-pyrimidine nitrile (E177a)

Under nitrogen protection, in 0 ℃ with 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-alcohol (E3) (1.81g 8.33mmol) is dissolved in the pyridine (40ml), stir to add sodium hydride (60% mineral oil solution, 0.40g, 10.0mmol).Mixture leaves standstill and stirred 5 minutes.(1.68g 11.7mmol), was warmed to room temperature with mixture in 30 minutes to add cupric bromide (I).(2.30g, pyridine 12.5mmol) (8ml) solution stir mixture 1 hour down at 100 ℃ to add 5-bromo-2-pyrimidine nitrile (D38).Mixture is cooled to room temperature, solvent removed in vacuo.Crude product is by using 0.880 ammoniacal liquor: ethanol: the column chromatography purifying of methylene dichloride (0.2: 1.8: 98) mixture wash-out obtains title compound (E177a); MS (ES+) m/e 321[M+H] ⁺

Embodiment 177b

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-pyrimidine carboxylic (E177b)

With 5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-(1.22g 3.81mmol) is dissolved in the ethanol (20ml) 2-pyrimidine nitrile (E177a), handles reflux 90 minutes with 10% sodium hydroxide solution (20ml).Mixture is cooled to room temperature, be filled to then the SCX ion exchange column (Varian bond-elute, 10g) in, first water, methyl alcohol are used 0.880 ammoniacal liquor again: methyl alcohol (1: 9) mixture wash-out.Merge basic moiety and vacuum concentration, obtain title compound (E 177b); MS (ES+) m/e 340[M+H] ⁺

Embodiment 177

3-cyclobutyl-7-{[2-(4-morpholinyl carbonyl)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E177)

With 5-[(3-cyclobutyl-2; 3; 4; 5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-2-pyrimidine carboxylic (E177b) (130mg; 0.37mmol) be dissolved in the dimethyl formamide (4ml), with 1,1 '-carbonyl dimidazoles (180mg; 1.11mmol) handle, be placed on and at room temperature stirred under the argon shield 5 hours.(0.19ml 2.22mmol) handles mixture, at room temperature stirs 18 hours with morpholine.The vacuum concentration reaction mixture, resulting resistates is by the column chromatography purifying, and use 0.880 ammoniacal liquor: methyl alcohol: methylene dichloride (0.5: 1.5: 95) mixture wash-out obtains title compound (E177).MS(ES+)m/e 409[M+H] ⁺。

Embodiment 178-186

Utilization is similar to the method for describing among the embodiment 177 (E177), prepares embodiment 178-186 (E178-E186) by the suitable amine shown in embodiment 177b (E177b) and the following table.

Embodiment	Amine	LC/MS (M+H ⁺)
Embodiment	Amine	LC/MS (M+H ⁺)	5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(cyclopropyl methyl)-2-pyrimidine carboxamide (E178)	The cyclopropyl methylamine	393
5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-2-pyrimidine carboxamide (E179)	Ethamine	367		The cyclopropyl methylamine	393
	Ethamine	367	7-([2-(1-azelidinyl carbonyl)-5-pyrimidyl] oxygen base }-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E180)	Azetidine	379
5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-N-methyl-2-pyrimidine carboxamide (E181)	Ethyl (methyl) amine	381		Azetidine	379
	Ethyl (methyl) amine	381	N-cyclobutyl-5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-pyrimidine carboxamide (E182)	The ring butylamine	393
5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(tetrahydrochysene-2H-pyrans-4-yl)-2-pyrimidine carboxamide (E183)	Tetrahydrochysene-2H-pyrans-4-amine	423		The ring butylamine	393
	Tetrahydrochysene-2H-pyrans-4-amine	423	3-cyclobutyl-7-{[2-(1-pyrrolidyl carbonyl)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E184)	Tetramethyleneimine	393
3-cyclobutyl-7-{[2-(piperidino carbonyl)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E185)	Piperidines	407		Tetramethyleneimine	393

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-2-pyrimidine carboxamide (E186)

Methylamine

353

Embodiment 187a

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-Pyridinecarboxylic Acid (E187a)

Utilization is similar to the method for describing among the embodiment 177b (E177b), by 5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-pyridine nitrile (E206) prepares title compound (E187a); MS (ES+) m/e 339[M+H] ⁺

Embodiment 187-195

Utilization is similar to the method for describing among the embodiment 177 (E177), by 5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-Pyridinecarboxylic Acid (E187a) prepares embodiment 187-195 (E187-E195).

Embodiment	Amine	LC/MS (M+H ⁺)
Embodiment	Amine	LC/MS (M+H ⁺)	5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-2-pyridine carboxamide (E187)	Methylamine	352
5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-2-pyridine carboxamide (E188)	Ethamine	366		Methylamine	352
	Ethamine	366	5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-N-methyl-2-pyridine carboxamide (E189)	Ethyl (methyl) amine	380
5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N, N-diethyl-2-pyridine carboxamide (E190)	Diethylamine	394		Ethyl (methyl) amine	380
	Diethylamine	394	5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-N-[2-(methoxyl group) ethyl]-2-pyridine carboxamide (E191)	Ethyl [2-(methoxyl group) ethyl] amine	424
3-cyclobutyl-7-{[6-(1-pyrrolidyl carbonyl)-3-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E192)	Tetramethyleneimine	392		Ethyl [2-(methoxyl group) ethyl] amine	424
	Tetramethyleneimine	392	3-cyclobutyl-7-{[6-(4-morpholinyl carbonyl)-3-pyridyl] the oxygen base }-2,3,4, the 5-tetrahydrochysene	Morpholine	408

-1H-3-benzazepine (E193)
-1H-3-benzazepine (E193)			3-cyclobutyl-7-{[6-(tetrahydrochysene-1,4-oxazapine-4 (5H)-Ji carbonyl)-3-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E194)	Six hydrogen-1, the 4-oxazapine	422
5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-cyclopentyl-2-pyridine carboxamide (E195)	Cyclopentamine	406		Six hydrogen-1, the 4-oxazapine	422

Embodiment 196a

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-pyridine carboxylic acid methyl esters

According to being similar to the method for describing among the E122, by 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and 6-chloro-3-pyridine carboxylic acid methyl esters prepare title compound; MS (ES+) m/e353[M+H] ⁺

Embodiment 196b

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-pyridine carboxylic acid (E196b)

Utilization is similar to the method for describing among the embodiment 123a (E123a), prepares title compound by embodiment 196a (E126a); MS (ES+) m/e 339[M+H] ⁺

Embodiment 196

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-cyclopropyl-3-pyridine carboxamide (E196)

With carbonyl dimidazoles (142mg 0.88mmol) is added to 6-[(3-cyclobutyl-2,3,4 after the stirring, 5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-(150mg is in methylene dichloride 0.44mmol) (5ml) solution for 3-pyridine carboxylic acid (E196b).After at room temperature stirring 3 hours, (0.15ml 2.2mmol), continued to stir the mixture 18 hours to add cyclopropylamine.With reaction mixture be filled to SCX ion-exchange tube (Varian bond-elute, 10g) in, earlier use 0.880 ammoniacal liquor again: the washing of methyl alcohol (1: 9) mixture with methyl alcohol.The basic moiety that vacuum concentration merges obtains title compound (E196).MS(ES+)m/e 378[M+H] ⁺。

Embodiment 197-202

Utilization is similar to the method for describing among the embodiment 196 (E196), by 6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-the suitable amine shown in 3-pyridine carboxylic acid (E196b) and the following table prepares embodiment 197-202 (E197-E202).

Embodiment	Amine	LC/MS (M+H ⁺)
Embodiment	Amine	LC/MS (M+H ⁺)	6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(1-methylethyl)-3-pyridine carboxamide (E197)	Isopropylamine	380
6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-3-pyridine carboxamide (E198)	Ethamine	366		Isopropylamine	380
	Ethamine	366	N-cyclobutyl-6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-pyridine carboxamide (E199)	The ring butylamine	392
6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(tetrahydrochysene-2H-pyrans-4-yl)-3-pyridine carboxamide (E200)	Tetrahydrochysene-2H-pyrans-4-amine	422		The ring butylamine	392
	Tetrahydrochysene-2H-pyrans-4-amine	422	6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N, N-diethyl-3-pyridine carboxamide (E201)	Diethylamine	394
6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-[2-(methoxyl group) ethyl]-3-pyridine carboxamide (E202)	[2-(methoxyl group) ethyl] amine	396		Diethylamine	394

Embodiment 203-205

Utilization is similar to the method for describing among the embodiment 128 (E128), and by 3-cyclobutyl-2,3,4, the suitable aromatics iodide shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepare embodiment 203-205 (E203-205).

Embodiment	Iodide	LC/MS (M+H ⁺)
Embodiment	Iodide	LC/MS (M+H ⁺)	4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-N-[2-(methoxyl group) ethyl] benzamide (E203)	4-iodo-N-ethyl-N-[2-(methoxyl group) ethyl] benzamide (D50)	423

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-benzamide (E204)	4-iodo-N-methyl-benzamide (D51)	351
	4-iodo-N-methyl-benzamide (D51)	351	3-cyclobutyl-7-(3-pyridyl oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E205)	The 3-iodine pyridine	294

Embodiment 206

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-pyridine nitrile (E206)

According to the method for summarizing among the E177a, by 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-alcohol (E3) and 5-iodo-2-pyridine nitrile (Biochemical Journal, 1973,131 (4), 625) prepare title compound (E206); MS (ES+) m/e 320[M+H] ⁺

Embodiment 207-208

Utilization is similar to the method for describing among the embodiment 100 (E100), and by 3-cyclobutyl-2,3,4, the suitable aromatics muriate shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepares embodiment 207-208 (E207-208).

Embodiment	Muriate	LC/MS (M+H ⁺)
Embodiment	Muriate	LC/MS (M+H ⁺)	3-cyclobutyl-7-[(5-iodo-2-pyridyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207)	2-chloro-5-iodine pyridine	421
3-cyclobutyl-7-[(5-nitro-2-pyridyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E208)	2-chloro-5-nitropyridine	340		2-chloro-5-iodine pyridine	421

Embodiment 209

N-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl } ethanamide (E209)

With iron filings (451mg, 8.07mmol) be added to the 3-cyclobutyl-7-[(5-nitro-2-pyridyl after the stirring) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E208) (550mg, 1.62mmol) containing acetate: solution of acetic anhydride (1: 1, in the solution in mixture 10ml), heated 16 hours down at 80 ℃.Reaction mixture in the impouring ice, is regulated pH to 8 with sodium bicarbonate.Product is extracted in the ethyl acetate, then organic extract liquid is used salt water washing, dried over sodium sulfate.Resistates is by using 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out obtains title compound (E209).MS(ES+)m/e 352[M+H]+。

Embodiment 210a

3-cyclobutyl-7-[(5-nitro-1,3-thiazoles-2-yl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E210a)

Under 5 ℃, (60% mineral oil dispersion, 150mg 3.66mmol) are added to 3-cyclobutyl-2,3,4 after the stirring, and the 5-tetrahydrochysene-(530mg is in dimethyl formamide 2.43mmol) (10ml) for 1H-benzo [d] azepine -7-alcohol (E3) with sodium hydride.0.5 after hour, (1.0g, dimethyl formamide 4.78mmol) (5ml) solution is warmed to room temperature with reaction mixture, stirs 2 hours to add 2-bromo-5-nitro-1,3-thiazoles.Reaction mixture is diluted organic layer water, salt water washing, dry (sodium sulfate) and vacuum concentration with ethyl acetate.By using 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.25: 2.25: 97.5) mixture wash-out obtains title compound (E210a); MS (ES+) m/e 346[M+H] ⁺

Embodiment 210

N-{2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-1,3-thiazoles-5-yl } ethanamide (E210)

With iron powder (162mg 2.9mmol) is added to 3-cyclobutyl-7-[(5-nitro-1,3-thiazoles-2-yl after the stirring) oxygen base]-2,3,4, (162mg is in acetate 0.47mmol) (1ml) and diacetyl oxide (1ml) solution for 5-tetrahydrochysene-1H-3-benzazepine (E210a).Reaction mixture was stirred 16 hours down at 80 ℃, and cooling then is in the impouring ice.With solution alkalize to pH be 8 (sodium bicarbonates), with resulting mixture ethyl acetate extraction.Organic layer salt water washing and dry (sodium sulfate).Vacuum concentration, next resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.3: 2.7: 97) mixture wash-out obtains title compound (E210).MS(ES+)m/e 358[M+H] ⁺。

Embodiment 211

3-cyclobutyl-7-[(5-nitro-2-thienyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E211)

With 2-bromo-5-nitrothiophene (478mg, 2.3mmol), 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) (500mg, 2.3mmol) and salt of wormwood (765mg, 5.5mmol) mixture in dimethyl formamide (10ml) stirred 16 hours down in 80 ℃.Reaction mixture, with the ethyl acetate dilution, water, salt water washing and drying (sodium sulfate).Vacuum concentration, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (1: 8: 300) mixture wash-out obtains title compound (E211); MS (ES+) m/e 345[M+H] ⁺

Embodiment 212

N-{5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-thienyl } ethanamide (E212)

Utilization is similar to the method for describing among the embodiment 210 (E210), by 3-cyclobutyl-7-[(5-nitro-2-thienyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E211) prepares embodiment 212 (E212); MS (ES+) m/e 357[M+H] ⁺

Embodiment 213a

3-cyclobutyl-7-{[6-(methoxyl group)-3-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E213a)

Utilize the route of general introduction among the embodiment 128 (E128), by 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and 5-bromo-2-methoxypyridine prepare title compound; MS (ES+) m/e 325[M+H] ⁺

Embodiment 213

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2 (1H)-pyridones (E213)

With 3-cyclobutyl-7-{[6-(methoxyl group)-3-pyridyl] the oxygen base }-2,3,4, (69mg 0.21mmol) is dissolved in the saturated ethanolic soln of usefulness hydrogenchloride (5ml) 5-tetrahydrochysene-1H-3-benzazepine (E213a).Reaction mixture stirring and refluxing 18 hours, cooling and vacuum concentration.Resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (E213).MS(ES+)m/e 311[M+H] ⁺。

Embodiment 214

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl } ethyl ketone (E214)

Utilize the method for describing among the embodiment 100 (E100), by 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and 1-(6-chloropyridine-3-yl) ethyl ketone prepare embodiment 214 (E214); MS (ES+) m/e 337[M+H] ⁺

Embodiment 215

3-cyclobutyl-7-{[5-(1H-pyrazoles-5-yl)-2-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E215)

With (2E)-1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-the 3-pyridyl }-3-(dimethylamino)-2-propylene-1-ketone (D53) (195mg, 0.5mmol) and the mixture of hydrazine hydrate (0.4ml) reflux 24 hours in methyl alcohol (3ml).Reaction mixture, be filled to then SCX ion-exchange tube (Varian bond-elute, 10g) in, earlier use 0.880 ammonia hydroxide/methanol (1: 9) washing again with methyl alcohol.The basic moiety that vacuum concentration merges, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (E215).MS(ES+)m/e 361[M+H] ⁺。

Embodiment 216

3-cyclobutyl-7-{[5-(5-methyl isophthalic acid, 3,4- diazole-2-yl)-2-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E216)

With triethly orthoacetate (3ml) and 6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-(185mg, mixture heating up 0.52mmol) refluxed 16 hours 3-pyridine carbohydrazide (D54).Concentrated reaction mixture, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.1: 5: 95) mixture wash-out obtains title compound (E216).MS(ES+)m/e377[M+H] ⁺。

Embodiment 217

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-2-Pyrrolidone (E217)

With 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) (252mg, 0.6mmol), 2-Pyrrolidone (153mg, 1.8mmol), salt of wormwood (83mg, 0.6mmol), copper powder (126mg, mixture 1.2mmol) in microwave reactor in 150 ℃ of down heating 1 minute.(1g, 12mmol) dilution continue to heat 20 minutes down at 200 ℃ reaction mixture with 2-Pyrrolidone.Reaction mixture, be filled to then SCX ion-exchange tube (Varian bond-elute, 10g) in, wash with 0.880 ammonia hydroxide/methanol mixture more earlier with methyl alcohol.The basic moiety that vacuum concentration merges, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (E217).MS(ES+)m/e 378[M+H] ⁺。

Embodiment 218

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-2-piperidone (E218)

Utilize the method for describing among the embodiment 217 (E217), by 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) and 2-piperidone prepare embodiment 218 (E218); MS (ES+) m/e 392[M+H] ⁺

Embodiment 219

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-2-azetidinone (E219)

(678mg, (308mg is in two  alkane (1ml) solution 4.3mmol) 1.04mmol) to be added to the 2-azetidinone with cesium carbonate.Mixture heated 1 minute down in 150 ℃ in microwave reactor, add then and contain 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) (294mg, 0.7mmol), anti-form-1,2-diamino-cyclohexane (0.02ml) and cupric iodide (I) (126mg, 1.2mmol) mixture, resulting mixture in microwave reactor in 180 ℃ the heating 1 hour.Reaction mixture, be filled to then the SCX tube (Varian bond-elute, 10g) in, earlier use 0.880 ammoniacal liquor again: the washing of methyl alcohol (1: 9) mixture with methyl alcohol.The basic moiety that vacuum concentration merges, resulting resistates obtains title compound (E219) by column chromatography purifying (0.5: 2.5: 97.5).MS(ES+)m/e 364[M+H] ⁺。

Embodiment 220

3-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-1,3- azoles alkane-2-ketone (E220)

Utilize the method for describing among the embodiment 219 (E219), by 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) and 1,3- azoles alkane-2-ketone prepares embodiment 220 (E220); MS (ES+) m/e 380[M+H] ⁺

Embodiment 221

3-cyclobutyl-7-{[5-(1H-pyrazol-1-yl)-2-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E221)

To contain 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) (294mg, 0.7mmol), pyrazoles (58mg, 0.84mmol), cesium carbonate (479mg, 1.5mmol), cupric iodide (I) (7mg, 0.04mmol) and 1, (13mg, the solution of mixture 0.07mmol) in two  alkane (2ml) heated 20 minutes down in 180 ℃ in microwave reactor the 10-phenanthrolene.Reaction mixture is diluted with ethyl acetate, with saturated ammonium chloride solution, water, salt water washing and drying (sal epsom).Filter organic layer, vacuum concentration, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out obtains title compound (E221); MS (ES+) m/e 361[M+H] ⁺

Embodiment 222

3-cyclobutyl-7-{[5-(3, the different  azoles of 5-dimethyl-4-base)-2-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E222)

To contain 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) (252mg, 0.6mmol), 3, the different  azoles of 5-dimethyl-4-ylboronic acid (168mg, 1.2mmol) and the mixture of tetrakis triphenylphosphine palladium (0) stirring and refluxing 14 hours in 2 M sodium carbonate solutions (5ml) and glycol dimethyl ether (10ml).Reaction mixture is diluted with ethyl acetate, with saturated sodium bicarbonate solution, water, salt water washing and drying (sodium sulfate).Filter organic layer, vacuum concentration, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out obtains title compound (E222); MS (ES+) m/e 390[M+H] ⁺

Embodiment 223

6-[(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-3-pyridine carboxamide (E223)

(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-(150mg 0.5mmol) is dissolved in methyl alcohol (5ml) solution of 2.5% acetate 3-pyridine carboxamide (D40), and (0.09ml 1mmol) dropwise handles with cyclopentanone with N-methyl-6-.Stirred the mixture 30 minutes, add then (polystyrene ylmethyl) trimethyl ammonium cyano group hydroborate (2.04mmol/g, 490mg, 0.1mmol).Reaction mixture was at room temperature stirred 14 hours, be filled to the SCX tube (Varian bond-elute, 10g) in, wash with 0.880 ammonia hydroxide/methanol mixture more earlier with methyl alcohol.The basic moiety that vacuum concentration merges, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.25: 2.25: 97.5) mixture wash-out obtains title compound (E223).MS(ES+)m/e 366[M+H] ⁺。

Embodiment 224

N-methyl-6-{[3-(2-methylcyclopentyl)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl] the oxygen base }-3-pyridine carboxamide (E224)

Utilize the method for describing among the embodiment 223, prepare embodiment 224 (E224) by N-methyl-6-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-3-pyridine carboxamide (D40) and 2-methyl-cyclopentanone; MS (ES+) m/e 380[M+H] ⁺

Embodiment 225

6-[(3-cyclobutyl-8-iodo-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-3-pyridine carboxamide (E225)

With N-methyl-6-(8-iodo-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-3-pyridine carboxamide (D43) (423mg, 1.0mmol) be dissolved in methyl alcohol (5ml) solution of 2.5% acetate, (0.11ml 1.5mmol) dropwise handles with cyclobutanone.Mixture was stirred 30 minutes, add then (polystyrene ylmethyl) trimethyl ammonium cyano group hydroborate (2.0mmol/g, 1g, 2mmol).Reaction mixture was at room temperature stirred 18 hours, be filled to SCX ion-exchange tube (Varian bond-elute, 10g) in, earlier use 0.880 ammoniacal liquor again: the washing of methyl alcohol (1: 9) mixture with methyl alcohol.The basic moiety that vacuum concentration merges, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 2.25: 97.5) mixture wash-out obtains title compound (E225).MS(ES+)m/e 478[M+H] ⁺。

Embodiment 226

3-cyclobutyl-7-iodo-8-[(phenyl methyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E226)

Utilize the method for describing among the embodiment 225 (E225), by 7-iodo-8-[(phenyl methyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (D45) and cyclobutanone prepare embodiment 226 (E226); MS (ES+) m/e 434[M+H] ⁺

Embodiment 227

3-cyclobutyl-7-{[6-methyl-4-(methoxyl group)-2-quinolyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E227)

To contain 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) (58mg, 0.267mmol), 2-chloro-6-methyl-4-(methoxyl group) quinoline (WO 99/55677) (56mg, 0.027mmol) and cesium carbonate (260mg, mixture 0.801mmol) in dry DMF (3ml) under 150 ℃, heated 2 * 30 minutes in (300W) microwave reactor.With cooled reaction mixture ethyl acetate (3 * 20ml) and water (30ml) between distribute.With organic layer salt solution (2 * 30ml) washings, the dry (Na that merges ₂SO ₄), filter and vacuum concentration.Resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the silica gel column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out obtains title compound (E227); MS (ES+) m/e 389[M+H] ⁺

Embodiment 228-230

Utilization is similar to the method for describing among the embodiment 227, and by 3-cyclobutyl-2,3,4, the suitable aromatic halide shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepares embodiment 228-230 (E228-E230)

Embodiment	The aromatics muriate	LC/MS (M+H ⁺)
Embodiment	The aromatics muriate	LC/MS (M+H ⁺)	3-cyclobutyl-7-{[4-(methoxyl group)-1,7-naphthyridine-2-yl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E228)	2-chloro-4-(methoxyl group)-1, the 7-naphthyridine	376
3-cyclobutyl-7-(naphthyridine-2-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E229)	2-bromo-naphthyridine (J.W.Henk, J. Org.Chem., 1982,47 (9), 1673-1677)	346		2-chloro-4-(methoxyl group)-1, the 7-naphthyridine	376
		346	N-{7-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 6-methyl isophthalic acid, 8-naphthyridine-2-yl } ethanamide (E230)	N-(7-chloro-6-methyl isophthalic acid, 8-naphthyridine-2-yl) ethanamide (S.Carboni, Gazz.Chim. Ital., 1966,96 (11), 1456-1469)	417

Embodiment 231

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2,3-pyridine dicarboxylic acid dimethyl ester (E231)

To contain 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) (1.5g), 6-chloro-2,3-pyridine dicarboxylic acid dimethyl ester (1.58g; People .Bioorg.Med.Chem Lett.12 such as Kenji Niiyama, 21,2002,3041-3054) and the mixture of cesium carbonate (4.4g) in dry DMF (30ml) in 80 ℃ of down heating 3 hours.Cooled mixture (is distributed between 3 * 100ml), with organic extract liquid salt solution (2 * 100ml) washings and the dry (Na that merges at water (20ml) and ethyl acetate ₂SO ₄).Evaporation removes to desolvate and obtains oily matter, and it is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out obtains title compound (E231); MS (ES+) m/e 411[M+H] ⁺

Embodiment 232

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2,3-pyridine dicarboxylic acid disodium salt (E232)

At room temperature, water (3ml) solution with sodium hydroxide (0.66g) is added to 6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-2, (1.69g is in ethanol 4.12mmol) (20ml) solution for 3-pyridine dicarboxylic acid dimethyl ester (E231).With mixture vigorous stirring 4 hours at room temperature, remove by filter resulting throw out, obtain title compound (E232) into colorless solid; MS (ES+) m/e 383[M+H] ⁺

Embodiment 233

2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-5H-pyrrolo-[3,4-b] pyridines-5,7 (6H)-diketone (E233)

With 6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2, (0.2g, diacetyl oxide 0.52mmol) (2ml) suspension stirs and heated 20 minutes at 120 ℃ 3-pyridine dicarboxylic acid disodium salt (E232).The cooled mixture of vacuum concentration adds ethanamide (0.1g) in resistates, mixture was stirred 0.5 hour down at 160 ℃.Then cooled mixture is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out.Resulting light yellow solid is ground with ether (5ml), filter, obtain title compound (E233); MS (ES+) m/e 364[M+H] ⁺

Embodiment 234

2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-7-hydroxyl-6,7-dihydro-5H-pyrrolo-[3,4-b] pyridine-5-ketone (E234)

Under argon shield, magnesium perchlorate (0.89g) is added to 2-[(3-cyclobutyl-2,3,4 in 0 ℃, 5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-5H-pyrrolo-[3,4-b] (0.72g is 1.98mmol) at chloroform: methyl alcohol (1: 1 for pyridine-5,7 (6H)-diketone (E233); 20ml) in the solution in the mixture.Add sodium borohydride (113mg), mixture was stirred 0.5 hour.It is 2 that mixture is adjusted to pH with HCl (2 M), continues to stir 0.5 hour, and using sodium hydroxide (2 N) to be adjusted to pH then is 11.Then with the mixture dichloromethane extraction, the dry organic extract liquid (Na that merges ₂SO ₄) and evaporation.Resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (E234); MS (ES+) m/e 366[M+H] ⁺

Embodiment 235

2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-6,7-dihydro-5H-pyrrolo-[3,4-b] pyridine-5-ketone (E235)

With 2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-7-hydroxyl-6,7-dihydro-5H-pyrrolo-[3,4-b] and pyridine-5-ketone (E234) (90mg, 0.25mmol) and trifluoroacetic acid (0.1ml) mixture of triethyl silicane (0.1ml) vigorous stirring 1 hour at room temperature.Vacuum concentrated mixture passes through to use 0.880 ammoniacal liquor with resistates: methyl alcohol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out; MS (ES+) m/e 350[M+H] ⁺

Embodiment 236

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-pyridine amine (E236)

With 3-cyclobutyl-7-[(5-nitro-2-pyridyl) the oxygen base]-2,3,4, (100mg 0.29mmol) is dissolved in the ethanol (10ml) 5-tetrahydrochysene-1H-3-benzazepine (E208).Add palladium (20mg, 10% is carried on charcoal pastes over), reaction mixture was stirred 12 hours under hydrogen shield (1 normal atmosphere), under room temperature.By diatomite filtration, vacuum concentrated filtrate obtains title compound (E236) with reaction mixture; MS (ES+) m/e 310[M+H] ⁺

Embodiment 237

Morpholine-4-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base-pyridin-3-yl-acid amides (E237)

Under 0 ℃, with morpholine-4-carbonyl chloride (0.15ml, 1.38mmol) be added to the 6-[(3-cyclobutyl-2 after the stirring, 3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-3-pyridine amine (E236) (77mg, 0.25mmol) and triethylamine (0.04ml is in methylene dichloride 0.30mmol) (5ml) solution.Reaction mixture is warmed to room temperature, stirred 24 hours.Reaction mixture be filled to SCX ion-exchange tube (Varianbond-elute, 5g) in, earlier use 0.880 ammoniacal liquor again: the washing of methyl alcohol (1: 9) mixture with methyl alcohol.The basic moiety that vacuum concentration merges, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out obtains title compound; MS (ES+) m/e 423[M+H] ⁺

Embodiment 238-240

Utilization is similar to the method for describing among the embodiment 237 (E237); by 6-[(3-cyclobutyl-2; 3,4,5-tetrahydrochysene-1H-3 benzazepine-7-yl) oxygen base]-suitable carbonyl chloride or the acyl chloride shown in 3-pyridine amine (E236) and the following table prepare embodiment 238-240.

Embodiment	Carbonyl chloride/acyl chloride	LC/MS(M+H ⁺)
Embodiment	Carbonyl chloride/acyl chloride	LC/MS(M+H ⁺)	Piperidines-1-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base-pyridin-3-yl]-acid amides (E238)	Piperidines-1-carbonyl chloride	421
Tetramethyleneimine-1-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-acid amides (E239)	Tetramethyleneimine-1-carbonyl chloride	407		Piperidines-1-carbonyl chloride	421
	Tetramethyleneimine-1-carbonyl chloride	407	N-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl] isobutyramide (E240)	Isobutyryl chloride	380

Embodiment 241

Tetrahydrochysene-pyrans-4-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-acid amides (E241)

With tetrahydrochysene-pyrans-4-carboxylic acid (252mg, 1.94mmol), I-hydroxybenzotriazole hydrate (262mg, 1.94mmol) and N-carbodicyclo hexylimide N '-methylated polystyrene (1.7mmol/g, 2.3g 3.88mmol) at room temperature stirred in methylene dichloride (10ml) 15 minutes.Add 6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-(300mg 0.97mmol), continues to stir 16 hours 3-pyridine amine (E236).With reaction mixture be filled to SCX ion-exchange tube (Varian bond-elute, 5g) in, wash with the mixture of 0.880 ammonia hydroxide/methanol more earlier with methyl alcohol.The basic moiety that vacuum concentration merges, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out obtains title product (E241); MS (ES+) m/e 422[M+H] ⁺

Embodiment 242

3-cyclobutyl-7-[5-(4,6-dimethoxy-pyrimidine-2-base)-pyridine-2-base oxygen base]-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E242)

With 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) (125mg, 0.58mmol), 2-(6-chloro-pyridin-3-yl)-4,6-dimethoxy-pyrimidine (145mg, 0.58mmol), lime carbonate (720mg, 2.2mmol) and dimethyl formamide (4ml) in 180 ℃ microwave reactor (300 W), added for 900 seconds.Mixture is diluted with ethyl acetate, and first water is used salt water washing, dried over sodium sulfate again.Resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.2: 1.8: 98) mixture wash-out obtains title product.MS(ES+)m/e 433[M+H] ⁺。

Embodiment 243-249

Utilization is similar to the method for describing among the embodiment 242 (E242), and by 3-cyclobutyl-2,3,4, the aryl muriate shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepares embodiment 243-249 (E243-E249).

Embodiment	The aryl muriate	LC/MS (M+H ⁺)
Embodiment	The aryl muriate	LC/MS (M+H ⁺)	3-cyclobutyl-7-[5-(4-methylsulfonyl-phenyl)-pyrazine-2-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E243)	2-(6-chloro-pyridin-3-yl)-5-methylsulfonyl-pyrazine	450
N-{4-[5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-yl]-phenyl }-ethanamide (E244)	N-[4-(5-chloro-pyrazine-2-yl)-phenyl]-ethanamide	429		2-(6-chloro-pyridin-3-yl)-5-methylsulfonyl-pyrazine	450
	N-[4-(5-chloro-pyrazine-2-yl)-phenyl]-ethanamide	429	3-cyclobutyl-7-(3,5-dimethyl-pyridine-2-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E245)	2-chloro-3,5-dimethyl-pyridine	323
3-cyclobutyl-7-[5-(morpholine-4-alkylsulfonyl)-pyridine-2-base oxygen base]-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E246)	4-(6-chloro-pyridine-3-alkylsulfonyl)-morpholine	444		2-chloro-3,5-dimethyl-pyridine	323
	4-(6-chloro-pyridine-3-alkylsulfonyl)-morpholine	444	3-cyclobutyl-7-(2-methyl-furo [2,3-c] pyridine-7-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E247)	7-chloro-2-methyl-furo [2,3-c] pyridine	349
2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-4-oxyethyl group-nicotinic acid nitrile (E248)	2-chloro-4-oxyethyl group-nicotinic acid nitrile	364		7-chloro-2-methyl-furo [2,3-c] pyridine	349
	2-chloro-4-oxyethyl group-nicotinic acid nitrile	364	6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-2-methyl-nicotinic acid nitrile (E249)	6-chloro-2-methyl-nicotinic acid nitrile	334

Embodiment 250

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-5-N-methyl-2-2-pyrrolidone N-(E250)

With 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) (294mg, 0.7mmol), 1, the 10-phenanthrolene (38mg, 0.2mmol), 5-N-methyl-2-2-pyrrolidone N-(139mg 1.4mmol) is dissolved in the two  alkane (2ml).Add cupric iodide (I) (39mg, 0.2mmol) and cesium carbonate (479mg 1.5mmol), heats mixture 15 minutes down in 175 ℃ in microwave reactor.After the mixture cooling,, use washed with dichloromethane by diatomite filtration.Vacuum concentrated filtrate, crude product is used 0.880 ammoniacal liquor by elder generation again with methylene dichloride: methyl alcohol: the column chromatography purifying of methylene dichloride (1: 9: 90) mixture wash-out obtains title compound (137mg); MS (ES+) m/e 392[M+H] ⁺

Embodiment 251

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-3-methyl-2-imidazolidone (E251)

With 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) (294mg 0.7mmol), 1-methyl-2-imidazolidone (90mg, 0.9mmol), cesium carbonate (364mg, 1.1mmol), (12mg 0.02mmol) is suspended in the toluene (10ml) xantphos.Adding three (dibenzalacetones) close two palladiums (0), and (6mg 0.007mmol), spends the night the mixture heating up backflow.Then reactant directly is filled to SCX ion-exchange tube (Varian, 5g) in, earlier use 0.880 ammoniacal liquor again: methyl alcohol (1: 9) washing with methyl alcohol.The concentrated alkaline part, crude product obtains title product (104mg) by automatic reverse-phase chromatography purifying; MS (ES+) m/e 393[M+H] ⁺

Embodiment 252

(4R)-and 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-4-hydroxyl-2-Pyrrolidone (E252)

Utilize the method for describing among the E251, by 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) and (4R)-4-{[(1, the 1-dimethyl ethyl) (dimethyl) silyl] the oxygen base }-2-Pyrrolidone (Tetrahedron, 2000,56 (39), 7705-7713) prepare embodiment 252 (E252); MS (ES+) m/e 394[M+H] ⁺

Embodiment 253

N-methyl-6-{[3-(3-methylcyclopentyl)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl] the oxygen base }-3-pyridine carboxamide (E253)

Utilize the method for describing among the embodiment 223, prepare embodiment 253 (E253) by N-methyl-6-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-3-pyridine carboxamide (D40) and 3-methyl-cyclopentanone; MS (ES+) m/e 380[M+H] ⁺

Embodiment 254

5-[(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-2-Zinamide (E254)

Utilize the method for describing among the embodiment 223, prepare embodiment 254 (E254) by N-methyl-5-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-2-Zinamide (D49) and cyclopentanone; MS (ES+) m/e 367[M+H] ⁺

Embodiment 255

N-methyl-5-{[3-(3-methylcyclopentyl)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl] the oxygen base }-2-Zinamide (E255)

Utilize the method for describing among the embodiment 223, prepare embodiment 255 (E255) by N-methyl-5-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base)-2-Zinamide (D49) and 3-methyl-cyclopentanone; MS (ES+) m/e 381[M+H] ⁺

Embodiment 256

1-{3-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-pyrazinyl }-2-Pyrrolidone (E256)

With 3-cyclobutyl-2,3,4, the 5-tetrahydrochysene-(103mg 0.47mmol) is dissolved in the anhydrous dimethyl formamide (3ml) 1H-benzo [d] azepine -7-alcohol (E3), is cooled to 0 ℃, with sodium hydride (60% mineral oil dispersion, 20mg 0.49mmol) handles, and mixture was warmed to room temperature in 40 minutes.(103mg, anhydrous dimethyl formamide 0.52mmol) (1ml) solution at room temperature stirred mixture 2 hours, heated 2.5 hours down at 80 ℃ then to add 1-(3-chloro-2-pyrazinyl)-2-Pyrrolidone (D46).Mixture is cooled to room temperature, is filled to then in the SCX post, use the mixture washing of 0.880 ammonia hydroxide/methanol (1: 9) earlier with methyl alcohol again.Merge basic moiety and vacuum concentration, resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.2: 1.8: 98) mixture wash-out obtains title compound (86mg); MS (ES+) m/e 379[M+H] ⁺

Embodiment 257

7-[(5-chloro-2-pyrazinyl) oxygen base]-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E257)

With 3-cyclobutyl-2,3,4, (184mg 0.85mmol) is dissolved in the anhydrous dimethyl formamide (3ml) 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3), is cooled to 0 ℃, and (60% mineral oil dispersion, 36mg 0.89mmol) handle with sodium hydride.Mixture was warmed to room temperature in 30 minutes.Add 2, (139mg, anhydrous dimethyl formamide 0.94mmol) (1ml) solution at room temperature stirred mixture 5 hours 5-dichloropyrazine (D47).Mixture is filled in the SCX post, uses the washing of 0.880 ammonia hydroxide/methanol (1: 9) mixture again with methyl alcohol earlier.Merge basic moiety and vacuum concentration, obtain title compound (268mg); MS (ES+) m/e 330[M+H] ⁺

Embodiment 258

1-{5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-pyrazinyl }-2-Pyrrolidone (E258)

With 7-[(5-chloro-2-pyrazinyl) the oxygen base]-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E257) (132mg, 0.40mmol), pyrrolidone (0.06ml, 0.80mmol), salt of wormwood (200mg, 1.45mmol), cupric iodide (I) (23mg, 0.12mmol) and N, (0.01ml 0.12mmol) heated 30 minutes down in 175 ℃ in microwave reactor in anhydrous two  alkane (3ml) N '-dimethyl-ethylenediamine together.Mixture is diluted with methyl alcohol, be filled to then in the SCX post, use 0.880 ammonia hydroxide/methanol (1: 9) washing again with methyl alcohol earlier.Merge basic moiety and vacuum concentration, by the column chromatography purifying, use 0.880 ammoniacal liquor: methyl alcohol: methylene dichloride (0.2: 1.8: 98) mixture wash-out obtains title compound (64mg) with resulting resistates; MS (ES+) m/e 379[M+H] ⁺

Embodiment 259

7-[(5-bromo-2-pyrazinyl) oxygen base]-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E259)

Utilize the method for embodiment 257 (E257), by 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and 2,5-two bromo-pyrazines (D48) prepare title compound; MS (ES+) m/e 375[M+H] ⁺

Embodiment 260

3-{5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-pyrazinyl }-1,3- azoles alkane-2-ketone (E260)

Utilize the method for embodiment 258 (E258), by 7-[(5-bromo-2-pyrazinyl) the oxygen base]-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E259) and  oxazolidone prepare title compound; MS (ES+) m/e 381[M+H] ⁺

Embodiment 261

3-cyclobutyl-7-[5-(1,1-dioxo-2-isothiazolidine-2-yl)-pyridine-2-base oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E261)

With 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) (200mg, 0.48mmol), isothiazolidine 1,1-dioxide (116mg, 0.96mmol) (Evans, Brian J.; Takahashi Doi, Joyce; Musker, W.Kenneth; J.Org.Chem.; 55; 9; 1990; 2580-2586), salt of wormwood (238mg, 1.73mmol), cupric iodide (I) (27mg, 0.14mmol) and N, N-dimethyl-ethylenediamine (0.02ml, 0.14mmol) heating 20 minutes in 140 ℃ microwave reactor in anhydrous two  alkane (3ml) together.Mixture dilutes with methyl alcohol, is filled to then in the SCX post, uses 0.880 ammonia hydroxide/methanol (1: 9) washing again with methyl alcohol earlier.Merge basic moiety and vacuum concentration.Resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out obtains title compound (145mg); MS (ES+) m/e 414[M+H] ⁺

Embodiment 262

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-2-imidazolidone (E262)

Utilize the method for embodiment 261, by 3-cyclobutyl-7-[(5-iodo-2-pyridyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E207) and 2-imidazolidone prepare title compound; MS (ES+) m/e 379[M+H] ⁺

Embodiment 263

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-Zinamide (E263)

With 5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-2-pyrazine carboxylic acid (E123a) (168mg, 0.47mmol) be dissolved in the anhydrous dimethyl formamide (5ml), with 1,1 '-carbonyl dimidazoles (230mg, 1.42mmol) handle, resulting mixture was at room temperature stirred 1.5 hours.(0.14ml 2.84mmol) handles and stirs 4 hours to mixture with 0.880 ammoniacal liquor.The vacuum concentration reaction mixture with the column chromatography purifying of resulting resistates by the mixture wash-out of usefulness (0.5: 4.5: 95), obtains title compound; MS (ES+) m/e 339[M+H] ⁺

Embodiment 264

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-3-(methoxyl group) benzamide (E264)

Step 1:7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

With the 7-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (2.0g, 5.06mmol) (Bioorg.Med.Chem.Lett.; 10; 22; 2000; 2553-2556), two (any oxygen base pin acolato frequently) two boron (1.41g, 5.57mmol), 1,1 '-two (diphenylphosphine) ferrocene palladium chloride (II) complex compound (0.22g, 0.30mmol), 1,1 '-two (diphenylphosphine) ferrocene (0.17g, 0.30mmol) and Potassium ethanoate (1.49g 15.2mmol) is added in the anhydrous two  alkane together, with resulting mixture 80 ℃ of down heating 3 hours.Mixture is cooled to room temperature, with the ethyl acetate dilution, and water and salt water washing.With organic moiety with dried over mgso and vacuum-evaporation.Resulting resistates is passed through to use ethyl acetate: the column chromatography purifying of the mixture wash-out of pentane (1: 9) obtains title compound (1.60g); MS (ES+) m/e 274[(M+H)-CO ₂ ^tBu] ⁺

Step 2:(3-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) boric acid

With 7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E264, (1.60g 4.29mmol) is dissolved in the acetone (25ml) step 1), with sodium periodate (2.75g, 12.9mmol), ammonium acetate (0.73g, 9.44mmol) and water (25ml) handle, resulting mixture was at room temperature stirred 18 hours.Acetone is removed in vacuum-evaporation, with water layer ethyl acetate and the dichloromethane extraction of remnants.Merge organic layer,, obtain title compound (1.06g) with dried over mgso and vacuum-evaporation; MS (ES+) m/e 192[(M+H)-CO ₂ ^tBu] ⁺

Step 3:7-(2-(methoxyl group)-4-[(methoxyl group) and carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

With (3-{[(1,1-dimethyl ethyl) oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) (500mg 1.72mmol) is dissolved in the anhydrous methylene chloride (15ml) boric acid (E264, step 2), use vanillic acid methyl esters (313mg successively, 1.72mmol), molecular sieve (4A, 1.0g), neutralized verdigris (467mg, 2.58mmol) and triethylamine (1.20ml, 8.60mmol) handle, resulting mixture was at room temperature stirred 18 hours.Mixture is diluted with methylene dichloride, by diatomite filtration and vacuum-evaporation.Resistates is dissolved in the ethyl acetate, washs with saturated sodium bicarbonate solution.With organic moiety with dried over mgso and vacuum-evaporation.With the column chromatography purifying of resulting resistates, obtain title compound (240 mg) by the mixture wash-out of usefulness (0.1: 9.9).MS(ES+)m/e 328，[(M+H)-CO ₂ ^tBu] ⁺。

Step 4:4-[(3-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-(methoxyl group) phenylformic acid

With 7-({ 2-(methoxyl group)-4-[(methoxyl group) carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E264, (240mg 0.56mmol) is dissolved in the ethanol (2ml) step 3), handle with 2 M sodium hydroxide (1ml), resulting mixture was stirred 1.5 hours.Mixture is used ethyl acetate extraction with 2 M hcl acidifyings.The combined ethyl acetate layer with dried over mgso and vacuum-evaporation, obtains title compound (0.15g); MS (ES+) m/e 314[(M+H)-CO ₂ ^tBu] ⁺

Step 5:7-{[4-[(methylamino) carbonyl]-2-(methoxyl group) phenyl] the oxygen base }-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

With 4-[(3-{[(1, the 1-dimethyl ethyl) oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-(methoxyl group) phenylformic acid (E264, step 4) (145mg, 0.35mmol) be dissolved in the anhydrous dimethyl formamide (5ml), with 1,1 '-carbonyl dimidazoles (85mg, 0.53mmol) handle, resulting mixture was at room temperature stirred 3 hours.Mixture is handled with methylamine (0.53ml, 1.05mmol, the THF solution of 2 M), stirs 4 hours.The vacuum concentration reaction mixture passes through column chromatography purifying (1: 1 ethyl acetate: pentane), obtain title compound (0.10g) with resulting resistates; MS (ES+) m/e 327[(M+H)-CO ₂ ^tBu] ⁺

Step 6:N-methyl-3-(methoxyl group)-4-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base) benzamide

With the 7-{[4-[(methylamino) carbonyl]-2-(methoxyl group) phenyl] the oxygen base }-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E264, (100mg 0.23mmol) is dissolved in the anhydrous methylene chloride (2ml) step 5), handle with trifluoroacetic acid (1ml), resulting mixture at room temperature stirred 2 hours.Solvent removed in vacuo is dissolved in resistates in the methyl alcohol, is filled to then in the SCX post, uses 0.880 ammoniacal liquor again with methyl alcohol earlier: methyl alcohol (1: 9) mixture wash-out.Merge basic moiety and vacuum concentration, obtain title compound (78mg); MS (ES+) m/e 327[M+H] ⁺

Step 7:4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-3-(methoxyl group) benzamide

With N-methyl-3-(methoxyl group)-4-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base) benzamide (E264, (78mg 0.24mmol) is dissolved in the anhydrous methylene chloride (5ml) step 6), with cyclobutanone (0.04ml, 0.48mmol) and acetate (1) processing, resulting mixture was stirred 15 minutes.(102mg 0.48mmol), stirs mixture 30 minutes to add sodium triacetoxy borohydride.Mixture is diluted with methyl alcohol, be filled to then in the SCX post, use 0.880 ammonia hydroxide/methanol (1: 9) wash-out again with methyl alcohol earlier.Merge basic moiety and vacuum concentration.Resulting resistates is by using 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out obtains title compound (20mg); MS (ES+) m/e 381[M+H] ⁺

Embodiment 265

2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] benzonitrile (E265)

With 3-cyclobutyl-2,3,4; the 5-tetrahydrochysene-(300mg 1.38mmol) is dissolved in the pyridine (10ml) 1H-benzo [d] azepine -7-alcohol (E3), cools off in ice-water bath; (66mg 1.66mmol) handles with sodium hydride (60% mineral oil dispersion) under argon shield then.Resulting mixture was stirred 5 minutes, and (277mg 1.93mmol) handles, and is warmed to room temperature then in 30 minutes with cupric bromide (I).(mixture heating up refluxed 2.5 hours for 948mg, pyridine 4.14mmol) (2ml) solution to add 2-iodine benzonitrile.Mixture is cooled to room temperature, solvent removed in vacuo.Resulting resistates is passed through to use ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.2: 1.8: 98) mixture wash-out obtains title compound (180mg); MS (ES+) m/e 319[M+H] ⁺

Embodiment 266

3-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-4-(methoxyl group) benzamide (E266)

Step 1:7-(2-(methoxyl group)-5-[(methoxyl group) and carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

Utilize the method for embodiment 264 steps 3, by (3-{[(1,1-dimethyl ethyl) oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) boric acid (E264, step 2) and 3-hydroxyl-4-methoxyl methyl benzoate prepare title compound; MS (ES+) m/e 328[(M+H)-CO ₂ ^tBu] ⁺

Step 2:3-[(3-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-4-(methoxyl group) phenylformic acid

Utilize the method for embodiment 264 steps 4, by 7-({ 2-(methoxyl group)-5-[(methoxyl group) carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E266, step 1) prepares title compound; MS (ES+) m/e 314[(M+H)-CO ₂ ^tBu] ⁺

Step 3:7-{[5-[(methylamino) carbonyl]-2-(methoxyl group) phenyl] the oxygen base }-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

Utilize the method for embodiment 264 steps 5, by 3-[(3-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-4-(methoxyl group) phenylformic acid (E266, step 2) and methylamine prepare title compound; MS (ES+) m/e 327[(M+H)-CO ₂ ¹Bu] ⁺

Step 4:N-methyl-4-(methoxyl group)-3-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base) benzamide

Utilize the method for embodiment 264 steps 6, by the 7-{[5-[(methylamino) carbonyl]-2-(methoxyl group) phenyl] the oxygen base }-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E266, step 3) prepares title compound; MS (ES+) m/e 327[M+H] ⁺

Step 5:3-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-4-(methoxyl group) benzamide

Utilize the method for embodiment 264 steps 7, by N-methyl-4-(methoxyl group)-3-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base) benzamide (E266, step 4) prepares title compound; MS (ES+) m/e 381[M+H] ⁺

Embodiment 267

3-chloro-4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-benzamide (E267)

Step 1:7-(2-chloro-4-[(methoxyl group) and carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

Utilize the method for general introduction in embodiment 264 steps 3, by 3-chloro-4-methyl hydroxybenzoate (320mg, 1.72mmol) and (3-{[(1, the 1-dimethyl ethyl) oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) boric acid (E264, step 2) prepares title compound (211mg, 29%); NMR (CDCl ₃) δ 1.49 (9H, s), 2.88 (4H, m), 3.56 (4H, m), 3.91 (3H, s), 6.78-6.89 (3H, m), 7.12 (H, m), 7.84 (H, m), 8.14 (H, s).

Step 2:3-chloro-4-[(3-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl] the oxygen base] phenylformic acid

Utilize in embodiment 264 steps 4 method of general introduction, by 7-({ 2-chloro-4-[(methoxyl group) carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E267, step 1) prepares title compound; MS (ES-), m/e 416﹠amp; 418[M-H].

Step 3:7-(2-chloro-4-[(methylamino) and carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

Utilize the method for general introduction in embodiment 264 steps 5, by 3-chloro-4-[(3-{[(1,1-dimethyl ethyl) the oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] phenylformic acid (E267, step 2) and methylamine prepare title compound (82mg, 52%); MS (ES+), m/e 431﹠amp; 433[M+H] ⁺

Step 4:3-chloro-N-methyl-4-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base) benzamide

Utilize in embodiment 264 steps 6 method of general introduction, by 7-({ 2-chloro-4-[(methylamino) carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E267, step 3) prepares title compound (54mg, 94%); MS (ES+), m/e 331﹠amp; 333[M+H] ⁺

Step 5:3-chloro-4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-benzamide

Utilize the method for general introduction in embodiment 264 steps 7, by 3-chloro-N-methyl-4-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base) benzamide (E267, step 4) and cyclobutanone prepare title compound (36mg, 57%) MS (ES+), m/e 385﹠amp; 387[M+H] ⁺

Embodiment 268

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N, 3-dimethyl benzamide (E268)

Step 1:7-(2-methyl-4-[(methoxyl group) and carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

Utilize the method for general introduction among the embodiment 128, by 7-hydroxyl-1,2,4,5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (PCT international application (2002), WO 02/40471) and 4-bromo-3-methyl-toluate prepare title compound (211mg, 29%); NMR (CDCl ₃) δ 1.49 (9H, s), 2.32 (3H, m), 2.86 (4H, m), 3.55 (4H, m), 3.89 (3H, s), 6.71-6.81 (3H, m), 7.08 (H, m), 7.80 (H, m), 7.94 (H, s).

Step 2:4-[(3-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-tolyl acid

Utilize the method for general introduction in embodiment 264 steps 4, by 7-({ 2-methyl-4-[(methoxyl group) carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1, and 1-dimethyl ethyl ester (E268, step 1) prepares title compound (247mg, 94%) MS (ES-), m/e 396[M-H].

Step 3:7-(2-methyl-4-[(methylamino) and carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

Utilize the method for general introduction in embodiment 264 steps 5, by 4-[(3-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-tolyl acid (E268, step 2) and methylamine prepare title compound (136mg, 53%); MS (ES+), m/e 411[M+H] ⁺

Step 4:N, 3-dimethyl-4-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base) benzamide

Utilize in embodiment 264 steps 6 method of general introduction, by 7-({ 2-methyl-4-[(methylamino) carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E268, step 3) prepares title compound (90mg, 88%); MS (ES+), m/e 311[M+H] ⁺

Step 5:4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N, the 3-dimethyl benzamide

Utilize the method for general introduction in embodiment 264 steps 7, by N, 3-dimethyl-4-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base) benzamide (E268, step 4) (90mg, 0.29mmol) and cyclobutanone (50 μ l 0.58mmol) prepare title compound (71mg, 67%); MS (ES+), m/e 365[M+H] ⁺

Embodiment 269

3-cyclobutyl-8-[(phenmethyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-nitrile (E269)

With 3-cyclobutyl-7-iodo-8-[(phenmethyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E226) (250mg, 0.58mmol), tetrakis triphenylphosphine palladium (0) (33mg, 0.029mol), cupric iodide (I) (11mg, 0.058mmol) and sodium cyanide (56mg, 1.15mmol) mixture heating up in tetrahydrofuran (THF) (5ml) refluxed 16 hours.Mixture is cooled off, and dilute with ethyl acetate, by diatomite filtration, first water is used the salt water washing again, through dried over sodium sulfate and vacuum concentration.Crude mixture obtains title compound by the reversed-phase HPLC purifying; MS (ES+) m/e 333[M+H] ⁺

Embodiment 270

3-cyclobutyl-7-[(2-fluorophenyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E270)

Utilize the method for describing among the embodiment 128, by 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H benzo [d] azepine -7-alcohol (E3) and 2-fluorine iodobenzene prepare embodiment 270 (E270); MS (ES+) m/e 312[M+H] ⁺

Embodiment 271

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-fluorine benzonitrile (E271)

With 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-alcohol (E3) (100mg, 0.46mmol), 3,4-difluoro benzonitrile (70mg, 0.51mmol) and salt of wormwood (159mg, 1.15mmol) mixture in dimethyl sulfoxide (DMSO) (2ml) is 85 ℃ of down heating 2 hours.Reaction mixture, be filled to then SCX ion-exchange tube (Varian bond-elute, 10g) in, earlier use the washing of 0.880 ammonia hydroxide/methanol (1: 9) mixture again with methyl alcohol.The basic moiety that vacuum concentration merges obtains title compound (E271).MS(ES+)m/e 337[M+H] ⁺。

Embodiment 272

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-fluorobenzoic acid (E272)

With 4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-(150mg 0.45mmol) is dissolved in the mixture of ethanol (1ml) and water (1.5ml) 3-fluorine benzonitrile (E271), with sodium hydroxide (150mg, 4.5mmol) handle, and reflux 2 hours.Should react then with acetate (0.39ml, 6.75mmol) processing and vacuum concentration.Resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (2: 18: 80) mixture wash-out obtains title compound.MS(ES+)m/e 356[M+H] ⁺。

Embodiment 273

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-fluoro-N-methyl-benzamide (E273)

With 4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) oxygen base]-the 3-fluorine lift formic acid (E272) (164mg, 0.36mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl- hexafluorophosphate (438mg, dimethyl formamide 1.15mmol) (2ml) solution diisopropylethylamine (0.40ml, 2.3mmol) handle, use tetrahydrofuran (THF) (2ml) solution-treated of 2 M methylamines subsequently.To react and at room temperature stir 4 hours, be filled to the SCX ion exchange column (Varian bond-elute, 10g) in, wash earlier the vacuum concentration basic moiety again with 0.880 ammonia hydroxide/methanol with methyl alcohol.Resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95) mixture wash-out obtains title compound.MS(ES+)m/e 369[M+H] ⁺。

Embodiment 274

3-cyclobutyl-7-[(2-fluoro-4-iodophenyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E274)

Step 1:7-[(2-fluoro-4-nitrophenyl) oxygen base]-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

With 3,4-difluoro nitrobenzene (664mg, 4.18mmol) be added to 7-hydroxyl-1,2,4, and 5-tetrahydrochysene-benzo [d] azepine -3-carboxylic acid tert-butyl ester (WO 02/40471) (1g, 3.8mmol) and salt of wormwood (1.3g, 9.49mmol) dimethyl formamide (10ml) solution in, will be reflected at 130 ℃ of down heating 3 hours.Cool off this reaction, and dilute with ethyl acetate, first water is water again: the washing of salt solution (1: 1) mixture, and through dried over sodium sulfate and vacuum concentration.Resulting resistates is passed through to use ethyl acetate: the column chromatography purifying of pentane (1: 10) mixture wash-out obtains title compound.MS(ES+)m/e 303[M-COOtBu] ⁺。

Step 2:7-[(4-amino-2-fluorophenyl) oxygen base]-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

To 7-[(2-fluoro-4-nitrophenyl) the oxygen base]-1; 2; 4; 5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1; 1-dimethyl ethyl ester (E274; (1.37g adds palladium-carbon (10 weight % palladium) (300mg) to step 1) in ethanol 3.40mmol) (25ml) solution, be reflected at hydrogen (1 normal atmosphere) protection down in stirring at room 3 hours.Reaction mixture is passed through diatomite filtration, and vacuum concentration, title compound obtained.MS(ES+)m/e273[M-M-COOtBu] ⁺。

Step 3:7-[(2-fluoro-4-iodophenyl) oxygen base]-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

To 7-[(4-amino-2-fluorophenyl) the oxygen base]-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E274, step 2) (0.5g, 1.34mmol) and iodoform (1g, 2.69mmol) tetrahydrofuran (THF) (10ml) solution in dropwise add the nitrous acid tertiary butyl ester (0.32ml, 2.69mol).Should react reflux 1 hour, cooling and vacuum concentration, resulting resistates is passed through to use ethyl acetate: the column chromatography purifying of pentane (1: 10) mixture wash-out obtains title compound.MS(ES+)m/e 384[M-COOtBu] ⁺。

Step 4:7-[(2-fluoro-4-iodophenyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine

Utilization is similar to describes the method for describing in the example 2 (D2), by 7-[(2-fluoro-4-iodophenyl) the oxygen base]-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1, (E274, step 3) prepares title compound to 1-dimethyl ethyl ester.MS(ES+)m/e 384[M+H] ⁺。

Step 5:3-cyclobutyl-7-[(2-fluoro-4-iodophenyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine

Utilization is similar to the method for describing among the embodiment 1 (E1), by 7-[(2-fluoro-4-iodophenyl) the oxygen base]-2,3,4, (E274, step 4) prepares title compound to 5-tetrahydrochysene-1H-3-benzazepine.MS(ES+)m/e 438[M+H] ⁺。

Embodiment 275

1-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-fluorophenyl }-2-Pyrrolidone (E275)

Utilization is similar to the method for describing among the embodiment 258 (E258), by 3-cyclobutyl-7-[(2-fluoro-4-iodophenyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E274) prepares title product.MS(ES+)m/e 395[M+H] ⁺。

Embodiment 276

N-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-fluorophenyl } ethanamide (E276)

Step 1:7-{[4-(acetylamino)-2-fluorophenyl] the oxygen base }-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

To 7-[(4-amino-2-fluorophenyl) the oxygen base]-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E274, step 2) (250mg, 0.67mmol) methylene dichloride (10ml) solution in add triethylamine (0.19ml, 1.34mmol) and Acetyl Chloride 98Min. (50 μ L, 0.74ml), the reaction at room temperature stirred 16 hours.To react then with methylene dichloride dilution, earlier with 3 N aqueous citric acid solutions, use saturated sodium bicarbonate, water and washed with dichloromethane more again, through dried over sodium sulfate and vacuum concentration.Resulting resistates is passed through to use ethyl acetate: the column chromatography purifying of pentane (1: 1) mixture wash-out obtains title compound.MS(ES+)m/e 413[M-H] ^-。

Step 2:N-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-fluorophenyl } ethanamide

By being similar to the two-step approach of describing among the embodiment 274 step 4-5, by 7-{[4-(acetylamino)-2-fluorophenyl] the oxygen base }-1,2; 4; 5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1, (E276, step 1) prepares title compound to 1-dimethyl ethyl ester.MS(ES+)m/e 369[M+H] ⁺。

Embodiment 277

Utilization is similar to the method for describing among the embodiment 128 (E128), and by 3-cyclobutyl-2,3,4, the suitable aromatics iodide shown in 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and the following table prepare embodiment 277 (E277).

Embodiment	The aromatics iodide	LC/MS (M+H ⁺)
Embodiment	The aromatics iodide	LC/MS (M+H ⁺)	1-[3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-phenyl]-1-tetramethyleneimine-1-base-ketone (E277)	The 1-[(3-iodophenyl) carbonyl] tetramethyleneimine (D52)	391

Embodiment 278

Utilization is similar to the method for describing among the embodiment 177 (E177), by 5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the suitable amine shown in 2-Pyridinecarboxylic Acid (E187a) and the following table prepares embodiment 278 (E278).

Embodiment	Amine	LC/MS (M+H ⁺)
Embodiment	Amine	LC/MS (M+H ⁺)	5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(tetrahydrochysene-2H-pyrans-4-yl)-2-pyridine carboxamide (E278)	Tetrahydrochysene-2H-pyrans-4-amine	422

Embodiment 279

3-cyano group-4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1 H-3-benzazepine-7-yl) the oxygen base]-N-methyl-benzamide (E279)

Step 1:3-cyano group-4-(methoxyl group) phenylformic acid

Utilize the method for embodiment 264 steps 4, prepare title compound by 3-cyano group-4-(methoxyl group) methyl benzoate; ¹H NMR (CDCl ₃) 8.32 (1H, d), 8.29-8.27 (1H, dd), 7.06-7.04 (1H, d), 4.03 (3H, s).

Step 2:3-cyano group-N-methyl-4-(methoxyl group) benzamide

Utilize the method for embodiment 264 steps 5, by 3-cyano group-4-(methoxyl group) phenylformic acid (E279, step 1) prepares title compound; MS (ES+) m/e 191[M+H] ⁺

Step 3:3-cyano group-4-hydroxy-n-methyl benzamide

(346mg 1.82mmol) is dissolved in the anhydrous methylene chloride (10ml), is cooled to 0 ℃, and (9.11ml 9.11mmol) handles with boron tribromide (dichloromethane solution of 1M) with 3-cyano group-N-methyl-4-(methoxyl group) benzamide (E279, step 2).Mixture was stirred 30 minutes, be warmed to room temperature and stirred simultaneously 18 hours.Place ice-water bath to cool off in mixture, dropwise add water treatment, be warmed to room temperature then.In mixture impouring 2 M hydrochloric acid (10ml), use ethyl acetate extraction.The combined ethyl acetate layer is with dried over mgso and vacuum-evaporation.Resulting resistates is passed through to use ethyl acetate: the column chromatography purifying of methylene dichloride (1: 1) mixture wash-out obtains title compound (86mg); MS (ES+) m/e 177[M+H] ⁺

Step 4:7-(2-cyano group-4-[(methylamino) and carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester

Utilize the method for embodiment 264 steps 3, by 3-cyano group-4-hydroxy-n-methyl benzamide (E279, step 3) and (3-{[(1, the 1-dimethyl ethyl) oxygen base] carbonyl }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) boric acid (E264, step 2) prepares title compound; MS (ES+) m/e 322[(M+H)-CO ₂ ^tBu] ⁺

Step 5:3-cyano group-N-methyl-4-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base) benzamide

Utilize the method for embodiment 264 steps 6, by 7-({ 2-cyano group-4-[(methylamino) carbonyl] phenyl } the oxygen base)-1,2,4,5-tetrahydrochysene-3H-3-benzazepine-3-carboxylic acid 1,1-dimethyl ethyl ester (E279, step 4) prepares title compound; MS (ES+) m/e 322[M+H] ⁺

Step 6:3-cyano group-4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-benzamide

Utilize the method for embodiment 264 steps 7, by 3-cyano group-N-methyl-4-(2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-base oxygen base) benzamide (E279, step 5) prepares title compound; MS (ES+) m/e 376[M+H] ⁺

Embodiment 280

3-cyclobutyl-7-{[6-(4-morpholinyl carbonyl)-3-pyridazinyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E280)

Step 1:4-[(6-chloro-3-pyridazinyl) carbonyl] morpholine

With 6-oxo-1,6-dihydro-3-pyridazine carboxylic acid (people such as A.E Mourad, J.Het.Chem, 1992; 29 (6), 1583-1592; 0.5g) mixture heating up in phosphorus oxychloride (2ml) refluxed 2 hours.Excessive phosphorus oxychloride is removed in evaporation, adds THF (5ml) then in resistates.Solution is cooled to 0 ℃ then, adds triethylamine (1.1ml), add morpholine (1.87ml) again.Mixture is warmed to room temperature, stirred 16 hours, use ethyl acetate (10ml) dilution and filtration then.Evaporated filtrate, the silica gel chromatography purifying by with eluent ethyl acetate obtains title compound; MS (ES+) m/e 228 [M+H] ⁺

Step 2:3-cyclobutyl-7-{[6-(4-morpholinyl carbonyl)-3-pyridazinyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine

With 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-alcohol (E3) (84mg, 0.385mmol), 4-[(6-chloro-3-pyridazinyl) carbonyl] morpholine (E280, step 1) (70mg, 0.308mmol) and salt of wormwood (85mg, 0.616mmol) mixture in anhydrous propanone (3ml) heated 2 * 15 minutes in 140 ℃ microwave reactor (300 W).Filter cooled reaction mixture, vacuum concentration, and by using 0.880 ammoniacal liquor: methyl alcohol: the silica gel column chromatography purifying of methylene dichloride (0.5: 4.5: 190) mixture wash-out obtains title compound; MS (ES+) m/e 409[M+H] ⁺

Embodiment 281-282

Utilize the two-step approach of describing among the embodiment 280, by 3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-alcohol (E3) and 6-oxo-1, the suitable amine shown in 6-dihydro-3-pyridazine carboxylic acid and the following table prepares embodiment 281-282 (E281-282).

Embodiment	Amine	LC/MS (M+H ⁺)
Embodiment	Amine	LC/MS (M+H ⁺)	6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-3-pyridazine carboxamides (E281)	Methylamine	353
6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-N-methyl-3-pyridazine carboxamides (E282)	Ethyl (methyl) amine	381		Methylamine	353

Embodiment 283

3-cyclobutyl-7-{[4-(4-morpholinyl)-4-oxo butyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E283)

Step 1:4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] butyric acid

With 4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] (2.2g 6.6mmol) is dissolved in the methyl alcohol (40ml) ethyl butyrate (E167a), handles with 2 N sodium hydroxide (10.0ml).Reflux and stir after 1 hour, reaction mixture is cooled to room temperature, vacuum concentration.Crude mixture is filled in the SCX ion-exchange tube (Varian bond-elute), and first water is used methanol wash again.The vacuum concentration organic moiety obtains title compound (E283); MS (ES+) m/e 304[M+H] ⁺

Step 2:3-cyclobutyl-7-{[4-(4-morpholinyl)-4-oxo butyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine

With 4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] butyric acid (E283, step 1) (0.15g, 0.50mmole) be dissolved in anhydrous methylene chloride (5ml) and the anhydrous dimethyl formamide (2ml), (0.14g is 1.0mmole) with the N-carbodicyclo hexylimide with the I-hydroxybenzotriazole hydrate, N '-methylated polystyrene HL (0.53g, 1.0mmol, 1.7mmol/g) handle, and stirred 45 minutes.(0.056ml 0.65mmol), stirred mixture 3 hours at ambient temperature to add morpholine.Crude product mixture is filled in the SCX ion-exchange tube (Varian bond-elute), and first water, methyl alcohol are used 0.880 ammoniacal liquor again: the mixture washing of methyl alcohol (1: 9).The basic moiety that vacuum concentration merges.Resulting resistates is passed through to use 0.880 ammoniacal liquor: methyl alcohol: the column chromatography purifying of methylene dichloride (0.5: 4.5: 95 to 1: 9: 90) mixture wash-out obtains title compound (E283); MS (ES+) m/e 373[M+H] ⁺

Embodiment 284-285

Utilization is similar to the method for describing among the embodiment 13 (E13), and by 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4, the suitable acid shown in 5-tetrahydrochysene-1H-benzo [d] azepine  (E6) and the following table prepares embodiment 284-285 (E284-285).

Embodiment	Acid	LC/MS (M+H ⁺)
Embodiment	Acid	LC/MS (M+H ⁺)	3-cyclobutyl-7-[(1-{[4-(4-morpholinyl) phenyl] carbonyl }-the 4-piperidyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E284)	4-(4-morpholinyl)-phenylformic acid	490
3-cyclobutyl-7-{[1-(cyclopropyl ethanoyl)-4-piperidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E285)	Cyclopropyl acetate	383		4-(4-morpholinyl)-phenylformic acid	490

Embodiment 286

3-cyclobutyl-7-[(1-{[(2R, 6S)-2,6-dimethyl-4-morpholinyl] carbonyl }-the 4-piperidyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E286)

Utilize the method for describing among the embodiment 61 (E61), by 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6) and cis-2, the 6-thebaine prepares embodiment 286 (E286); MS (ES+) m/e 442[M+H] ⁺

Embodiment 287

3-cyclobutyl-7-{[is trans-4-(4-morpholinyl carbonyl) cyclohexyl] and the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E287)

Utilize the method for describing among the embodiment 5a (E5a), by 3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine  (E6) and cis-4-(4-morpholinyl carbonyl)-hexalin (D55) prepare embodiment 287 (E287); MS (ES+) m/e 413[M+H] ⁺

All publications of quoting in this specification sheets comprise but are not restricted to various patents and patent application all is incorporated herein by reference in this article, its degree that is incorporated herein by reference like these publications by concrete and referred individually.

Embodiment 288

3-cyclobutyl-7-{[6-(4-morpholinyl)-2-pyrazinyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine (E288)

Utilization is similar to the method for describing among the embodiment 242 (E242), by 3-cyclobutyl-2,3,4, and 5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol (E3) and 4-(6-chloro-2-pyrazinyl) morpholine [Zagulyaeva, O.A., J.Org.Chem.USSR, EN, 14; 1978; 377-380] prepare embodiment 288 (E288); MS (ES+) m/e 381[M+H] ⁺

Biological data

The membrane product that contains histamine H 3 receptor can prepare according to following step:

(i) generation of histamine H 3 clones

DNA (Huvar with human histamine H 3 genes of coding, A. wait the people. (1999) Mol.Pharmacol.55 (6), 1101-1107) be cloned in the holding carrier (holding vector), by plasmid DNA being carried out restriction digest with enzyme BamH1 and Not-1, isolate pCDNA3.1 TOPO (InVitrogen) and its cDNA by this carrier, be connected into then in the inducible expression vector pGene (InVitrogen) of same enzyme digestion.According to United States Patent (USP) 5,364,791; 5,874,534; With 5,935,934 described methods are finished GeneSwitch ^TMSystem (this be a kind of when not having inductor transgene expression close (switch off), and transgene expression is opened the system of (switch on) when having inductor).The DNA that is connected into is transformed in competence DH5 α intestinal bacteria (E.coli) the host bacteria cell, with 50 μ gml ^-1Cultivation is laid on and contains Zeocin ^TMLuria Broth (LB) agar (Zeocin ^TMBe that a kind of permission is carried out the microbiotic that cell expressing is selected to the sh ble gene that is present on pGene and the pSwitch).Containing this bacterium colony that reconnects (re-ligated) plasmid differentiates by restriction analysis.The host bacteria culture that is contained pGene H3 plasmid by 250ml prepares the DNA that is used for being transfected into mammalian cell, uses DNA to prepare test kit (Qiagen Mid-Prep) simultaneously and separates according to manufacturers's guide (Qiagen).Will be seeded in 2 * 10e6 cell/T75 flask and contain Hams F12 (GIBCOBRL with the CHO K1 cell of pSwitch adjustment type plasmid (InVitrogen) transfection, Life Technologies) in the perfect medium of medium, this perfect medium 24 hours before use replenishes fetal bovine serum, L-glutaminate and Totomycin (the 100 μ gmls of 10%v/v through dialysis ^-1).Utilize Lipofectamine plus according to manufacturers's guide (InVitrogen) with plasmid DNA transfection in cell.The cell of transfection after 48 hours places with 500 μ gml ^-1Zeocin ^TMIn the perfect medium that replenishes.

Select back 10-14 days, 10nM mifepristone (InVitrogen) is added substratum to induce receptor expression.Induce back 18 hours cell to use ethylenediamine tetraacetic acid (EDTA) (EDTA; 1: 5000; InVitrogen) from flask, separate, then with pH be the washing of 7.4 phosphate buffered saline (PBS) for several times, and be suspended in again in the no phenol red sorting substratum that contains minimum essential medium (MEM), described culture medium supplemented Earles salt and 3%Foetal Clone II (Hyclone).The rabbit polyclonal antibody 4a that excites with the N-end region to histamine H 3 receptor dyes, and is incubated 60 minutes on ice then, follows washed twice in the sorting substratum, detects the expression of receptor of nearly 1 * 10e7 cell.By cell is being incubated 60 minutes with goat anti-rabbit antibody on ice, in conjunction with using Alexa 488 fluorescent marks (Molecular Probes), detect the antibody of receptors bind then.After the further washed twice of sorting substratum, cell is passed through 50 μ m Filcon ^TM(BD Biosciences) filters, and analyzes on the FACS Vantage SE flow cytometer that is equipped with automated cell sedimentation unit (Automatic Cell Deposition Unit) then.Control cells be according to similarity method handle without the inductive cell.The cell of positive staining is sorted into as individual cells and contains 500 μ lml ^-1Zeocin ^TMThe 96-orifice plate of perfect medium in, make its expansion (expand), expression of receptor is analyzed in conjunction with research by antibody and part subsequently.Select clone 3H3 as membrane prepare thing (membrane preparation).

(ii) prepare film by cultured cells

The institute of this programme all uses in advance refrigerative reagent to finish at 4 ℃ in steps.Cell precipitation is resuspended among the buffered soln A2 of 10 times of volumes, this buffered soln contains 50mM N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid (HEPES) (pH7.40), and additional 10e-4M leupeptin (ethanoyl-leucyl-leucyl-arginine; SigmaL2884), 25 μ g/ml bacitracins (bacitracin) (Sigma B0125) and 1mM ethylenediamine tetraacetic acid (EDTA) (EDTA), 1mM phenylmethylsulfonyl fluoride (PMSF) and 2 * 10e-6Mpepstain A (Sigma).Then this cell is carried out homogenate by 2 * 15 pulse per second (PPS)s (burst) in 1 liter of glass Wei Lin Shi agitator (glass Waringblender), then centrifugal 20 minutes at 500g.Then with supernatant liquor 48,000g rotation 30 minutes.By 5 seconds of whirlpool, cell precipitation is resuspended among the buffered soln A2 of 4 times of volumes then homogenize in Dounce pressure-even pulp crusher (10-15 stroke (stroke)).Pack resulting goods branch in the polypropylene test tube into this moment ,-70 ℃ of storages.

According to following measuring method, can test the external biological activity of The compounds of this invention.

(I) histamine H 3 is in conjunction with measuring

For each tested compound, in clean 96 orifice plates of Bai Bi, bottom, add:

(a) 10 μ l test compounds (perhaps 10 μ l iodophenpropit (a kind of known histamine H 3 antagonists), ultimate density is 10mM) are diluted to desired concn in 10%DMSO;

(b) with 10 μ l ¹²⁵) 4-[3-(4-iodobenzene methoxyl group) propyl group]-1H-imidazoles  (iodoproxyfan) (Amersham; 1.85MBq/ μ l or 50 μ Ci/ml; Specific activity-2000Ci/mmol) in measuring damping fluid (pH is 7.4 50mM three (methylol) aminomethane buffer solution (TRIS), 0.5mM ethylenediamine tetraacetic acid (EDTA) (EDTA)), be diluted to 200pM, ultimate density is 20 μ M; With

(c) be prepared as follows 80 μ l pearl/film mixtures: by with scintillation proximity assay (ScintillationProximity Assay) (SPA) pearl type WGA-PVT be suspended in 100mg/ml and measure in the buffered soln, mixed with film (according to previously described method preparation) then, to obtain final volume be 80 μ l (containing 7.5g protein and 0.25mg pearl/hole mixture) in dilution in measuring damping fluid, and on cylinder (roller) goes up premix 60 minutes in room temperature.

With culture plate jolting 5 minutes, placed room temperature 3-4 hour, according to 1 minute standard deuterium counting process (lminute normalized tritium count protocol) from Wallac Microbeta calculating instrument reading.Data use 4-parameter logarithmic equation (4-parameter logistic equation) to analyze.

(III) histamine H 3 function antagonists are measured

For each test compound, in clean 96 orifice plates of Bai Bi, bottom, add:

(a) 10 μ l test compounds (perhaps 10 μ l guanosine-s 5 '-triphosphate (GTP) is (Sigma) as non-specific binding contrast), measure slow in solution (20mM N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid (HEPES)+100mM NaCl+10mM MgCl ₂, pH is 7.4 NaOH) in be diluted to desired concn;

(b) be prepared as follows 60 μ l pearl/film/GDP mixtures: measure in the damping fluid by wheat germ agglutinin-polyethylene toluene (WGA-PVT) scintillation proximity assay (SPA) pearl is suspended in 100mg/ml, mixed with film (according to previously described method preparation) then, to obtain final volume be 60 μ l (containing 10 μ g protein and 0.5mg pearl/hole) in dilution in measuring buffered soln, with this mixture 4 ℃ of premixs 30 minutes on cylinder, be added to immediately then in the culture plate, adding final concentration is guanosine-5 ' diphosphate (GDP) (Sigma of 10 μ M; In measuring buffered soln, dilute);

Described plate is incubated 30 minutes with balance antagonist and acceptor/pearl in room temperature under jolting, adds then:

(c) 10 μ l histamine (Tocris), ultimate density is 0.3 μ M; With

(d) with 20 μ l guanosine-s 5 ' [γ 35-S] thio triphosphates salt, triethylamine salt (Amersham; Radioactivity concentration=37kBq/ μ l or 1mCi/ml; Specific activity 1160Ci/mmol) in measuring buffered soln, is diluted to 1.9nM, makes that ultimate density is 0.38nM.

Culture plate was hatched 30 minutes centrifugal 5 minutes then at 1500rpm on shaking table in room temperature.Between the 3rd and 6 hour that finishes after centrifugal, according to 1 minute stdn deuterium counting scheme from WallacMicrobeta calculating instrument reading.Data use 4-parameter logarithmic equation to analyze.The basis is active in minimum value, promptly histamine is not added in the hand-hole.

Conclusion

Detected the compound of embodiment E 1-3, E5-149, E151-230, E233-235, E237-256, E258, E260-270, E273 and E275-288 in histamine H 3 function antagonists are measured, their antagonistic activity is 6.5-10.5pK _bMore particularly, the antagonistic activity of embodiment 1,52,121,125 and 217 compound is 9.0-10.5pK _bMore particularly, the antagonistic activity＞9.5pK of the compound of embodiment 121 _b

Claims

1. formula (I) compound or pharmaceutically acceptable salt thereof or solvate,

Wherein:

R ¹Expression is optional by C _1-3Alkyl replaces-C _3-7Cycloalkyl;

X represents chemical bond or C _1-6Alkyl;

Y represents chemical bond, C _1-6Alkyl, CO, COC _2-6Alkenyl, O or SO ₂

N is 0,1 or 2;

R wherein ²In described alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical can choose wantonly by one or more and identical or different be selected from following substituting group and replace: halogen, hydroxyl, cyano group, nitro ,=O, trifluoromethyl, trifluoromethoxy, fluoro methoxyl group, difluoro-methoxy, C _1-6Alkyl, pentafluoroethyl group, C _1-6Alkoxyl group, aryl C _1-6Alkoxyl group, C _1-6Alkylthio, C _1-6Alkoxy C _1-6Alkyl, C _3-7Cycloalkyl C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl, C _1-6Alkyl sulphinyl, C _1-6Alkylsulfonyloxy, C _1-6Alkyl sulphonyl C _1-6Alkyl, alkylsulfonyl, aryl sulfonyl, aryl-sulfonyl oxygen, aryl sulfonyl C _1-6Alkyl, aryloxy, C _1-6Alkyl sulfonyl amino, C _1-6Alkylamino, C _1-6Alkyl amido ,-R ⁴,-CO ₂R ⁴,-COR ⁴, C _1-6The amino C of alkyl sulfonyl _1-6Alkyl, C _1-6Alkyl amido C _1-6Alkyl, Arenesulfonyl amino, aryl formamido group, Arenesulfonyl amino C _1-6Alkyl, aryl formamido group C _1-6Alkyl, aroyl, aroyl C _1-6Alkyl, aryl C _1-6Alkyloyl or group-NR ⁵R ⁶,-C _1-6Alkyl-NR ⁵R ⁶,-C _3-8Cycloalkyl-NR ⁵R ⁶,-CONR ⁵R ⁶,-NR ⁵COR ⁶,-NR ⁵SO ₂R ⁶,-OCONR ⁵R ⁶,-NR ⁵CO ₂R ⁶,-NR ⁴CONR ⁵R ⁶Or-SO ₂NR ⁵R ⁶, R wherein ⁴, R ⁵And R ⁶Represent hydrogen, C independently _1-6Alkyl ,-C _3-8Cycloalkyl ,-C _1-6Alkyl-C _3-8Cycloalkyl, aryl, heterocyclic radical or heteroaryl, perhaps NR ⁵R ⁶Expression nitrogen heterocyclic ring group, wherein said R ⁴, R ⁵And R ⁶Group can be chosen wantonly by one or more identical or different following substituting group that is selected from and replace: halogen, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, cyano group, amino ,=O or trifluoromethyl; And wherein work as R ²Expression-X-heterocyclic radical ,-X-heterocyclic radical-Y-C _3-8Cycloalkyl ,-X-heterocyclic radical-Y-aryl ,-X-heterocyclic radical-Y-heteroaryl or-during X-heterocyclic radical-Y-heterocyclic radical, described heterocyclic radical links to each other with X by carbon atom.

As in the claim 1 definition formula (I) compound or pharmaceutically acceptable salt thereof or solvate, wherein R ¹Represent unsubstituted cyclobutyl, cyclopentyl or cyclohexyl.

As in the claim 2 definition formula (I) compound or pharmaceutically acceptable salt thereof or solvate, wherein R ¹Represent unsubstituted cyclobutyl.

4. as formula (I) compound or pharmaceutically acceptable salt thereof or solvate, the wherein R of claim 1 definition ²Expression:

Hydrogen;

Optional quilt-CO ₂R ⁴Or-CONR ⁵R ⁶Group replaces-C _1-6Alkyl;

-X-C _3-8Cycloalkyl-Y-heterocyclic radical;

-X-aryl-Y-C _3-8Cycloalkyl;

Optional by one or two halogen, C _1-6Alkyl, C _1-6Alkoxyl group ,-CO ₂R ⁴,-CONR ⁵R ⁶,-NR ⁵COR ⁶,-SO ₂NR ⁵R ⁶Or the cyano group replacement-the X-aryl;

Optional by one or two=O, halogen or R ⁴Group replaces-X-aryl-Y-heterocyclic radical;

Optional by one or two halogen, C _1-6Alkyl, C _1-6Alkoxyl group, cyano group, nitro ,-OR ⁴,-COR ⁴,-CO ₂R ⁴,-NR ⁵R ⁶,-NR ⁵COR ⁶,-CONR ⁵R ⁶Or=replacement of O group-the X-heteroaryl;

Optional by C _1-6Alkyl sulphonyl or-NR ⁵COR ⁶Group replaces-X-heteroaryl-Y-aryl;

Optional by C _1-6Alkyl replaces-X-heteroaryl-Y-heteroaryl;

Optional by one or two=O, C _1-6Alkyl ,-OR ⁴Or the halogen group replacement-X-heteroaryl-Y-heterocyclic radical;

Optional by C _1-6Alkyl sulphonyl, C _1-6Alkoxy carbonyl ,-CO ₂R ⁴,-COR ⁴Or-COR ⁵R ⁶Group replaces-the X-heterocyclic radical;

Optional by halogen, cyano group, C _1-6Alkyl sulphonyl, R ⁴Or-CONR ⁵R ⁶Group replaces-X-heterocyclic radical-Y-aryl;

Optional by one or two=O or R ⁴Group replaces-X-heterocyclic radical-Y-heterocyclic radical;

-X-heterocyclic radical-Y-C _3-8Cycloalkyl; Perhaps

Optional by one or two C _1-6Alkyl ,=O, cyano group or-CONR ⁵R ⁶Group replaces-X-heterocyclic radical-Y-heteroaryl.

As in the claim 4 definition formula (I) compound or pharmaceutically acceptable salt thereof or solvate, wherein R ²Expression:

Optional by one or two halogen, C _1-6Alkyl, C _1-6Alkoxyl group, cyano group, nitro ,-OR ⁴,-CO ₂R ⁴,-COR ⁴,-NR ⁵R ⁶,-NR ⁵COR ⁶,-CONR ⁵R ⁶Or=replacement of O group-the X-heteroaryl;

Optional by one or two=O, C _1-6Alkyl ,-OR ⁴Or the halogen group replacement-X-heteroaryl-Y-heterocyclic radical; Perhaps

Optional by one or two=O or R ⁴Group replaces-X-heterocyclic radical-Y-heterocyclic radical.

As in the claim 5 definition formula (I) compound or pharmaceutically acceptable salt thereof or solvate, wherein R ²Expression:

Optional by one or two halogen, C _1-6Alkoxyl group ,-CONR ⁵R ⁶,-NR ⁵COR ⁶, or cyano group replace-the X-aryl;

Optional by one or two=O or halogen group replace-X-aryl-Y-heterocyclic radical;

Unsubstituted-X-heterocyclic radical-Y-heterocyclic radical;

Optional by CON (H) (Me) replace-the X-heteroaryl; Perhaps

-X-heteroaryl-Y-heterocyclic radical, the optional quilt=O group of wherein said heterocyclic radical replaces.

As in the claim 6 definition formula (I) compound or pharmaceutically acceptable salt thereof or solvate, wherein R ²Expression:

Optional by one or two fluorine, methoxyl group ,-CON (H) (Me) ,-NHCOMe or cyano group replace-phenyl;

Optional by one or two=O or fluorin radical replace-phenyl-pyrrolidyl;

Unsubstituted-piperidyl-the CO-morpholinyl;

Optional by CON (H) (Me) replace-the 2-pyridyl or-the 2-pyrazinyl; Perhaps-and 2-pyridyl-N-pyrrolidyl, the optional quilt=O group of wherein said pyrrolidyl replaces.

As in the claim 7 definition formula (I) compound or pharmaceutically acceptable salt thereof or solvate, wherein R ²Expression 4-methylamino carbonyl pyridine-2-base.

9. as formula (I) compound or pharmaceutically acceptable salt thereof or the solvate of each definition among the claim 1-6, wherein X represent chemical bond or-CH ₂-.

10. as formula (I) compound or pharmaceutically acceptable salt thereof or the solvate of definition in the claim 9, wherein X represents chemical bond.

11. as formula (I) compound or pharmaceutically acceptable salt thereof or the solvate of each definition among the claim 1-6, wherein Y represents chemical bond, CO, SO ₂Or-CO-CH=CH-.

12. as formula (I) compound or pharmaceutically acceptable salt thereof or the solvate of definition in the claim 11, wherein Y represents chemical bond.

13. formula (I) compound or pharmaceutically acceptable salt thereof or solvate, wherein R as each definition among the claim 1-5 ⁴Expression hydrogen, C _1-6Alkyl ,-C _1-6Alkyl-C _3-8Cycloalkyl, aryl, heterocyclic radical or heteroaryl, it is optional by halogen or C _1-6Alkoxyl group replaces.

14. formula (I) compound or pharmaceutically acceptable salt thereof or solvate, wherein R as each definition among the claim 1-6 ⁵And R ⁶Represent hydrogen, C independently _1-6Alkyl ,-C _3-8Cycloalkyl ,-C _1-6Alkyl-C _3-8Cycloalkyl, aryl or heterocyclic radical, it is optional by halogen, cyano group or C _1-6Alkoxyl group replaces, perhaps-and NR ⁵R ⁶Expression optional by one or two=nitrogen heterocycle that the O group replaces.

15. formula (I) compound or pharmaceutically acceptable salt thereof or solvate, wherein R as definition in the claim 14 ⁵And R ⁶Represent hydrogen, C independently _1-6Alkyl ,-C _3-8Cycloalkyl or-C _1-6Alkyl-C _3-8Cycloalkyl.

16. as formula (I) compound or pharmaceutically acceptable salt thereof or the solvate of each definition among the claim 1-8, wherein n represents 0 or 1.

17. as formula (I) compound or pharmaceutically acceptable salt thereof or the solvate of definition in the claim 16, wherein n represents 1, and R ³Expression halogen atom or cyano group.

18. as formula (I) compound or pharmaceutically acceptable salt thereof or the solvate of definition in the claim 16, wherein n represents 0.

19. according to the compound of claim 1, it is selected from:

7-benzyloxy-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

7-benzyloxy-3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol;

3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-alcohol;

4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid-tert-butyl ester;

3-cyclopentyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-(piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1 H-benzo [d] azepine ;

3-cyclobutyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-((R)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-((R)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-((S)-tetramethyleneimine-3-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-((S)-1-tetramethyleneimine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclopentyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

4-{1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-formyl radical }-benzonitrile;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(tetrahydrochysene-pyrans-4-yl)-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-cyclohexyl-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-isoquinolyl-1-ketone;

4-{ (E)-3-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-3-oxo-propenyl }-benzonitrile;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-isoquinoline 99.9-6-base-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(5-methyl-different  azoles-3-yl)-ketone;

1-benzothiazole-6-base-1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-pyridin-4-yl-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-[4-(1-tetramethyleneimine-1-base-formyl radical)-phenyl]-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-thiene-3-yl--ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-furans-3-base-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-piperidines-1-yl]-1-tetrahydrochysene-pyrans-4-yl)-ketone;

1-[(R)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-tetramethyleneimine-1-yl]-1-(tetrahydrochysene-pyrans-4-yl)-ketone;

1-[(R)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-1-(tetrahydrochysene-pyrans-4-yl)-ketone;

1-[(S)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-1-(tetrahydrochysene-pyrans-4-yl)-ketone;

1-[(S)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-1-(tetrahydrochysene-pyrans-4-yl)-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(methylsulfonyl-phenyl)-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-pyrazine-2-base-ketone;

5-{1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-formyl radical }-the 1H-pyridone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(2,3-dihydro-cumarone-5-yl)-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-3-methoxyl group-third-1-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-(2,3-dihydro-cumarone-7-yl)-ketone;

4-{1-{4-(3-cyclopentyl-7-(piperidin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl) piperidines-1-yl]-formyl radical }-benzonitrile;

1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-piperidines-1-yl]-1-[4-(1-tetramethyleneimine-1-base-formyl radical)-phenyl]-ketone;

4-{1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-formyl radical }-benzonitrile;

1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-pyridin-4-yl-ketone;

1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-quinoline-6-base-ketone;

1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-[4-(1-tetramethyleneimine-1-base-formyl radical)-phenyl] ketone;

1-biphenyl-4-base-1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-cyclopentyl-ketone;

4-{1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-piperidines-1-yl]-formyl radical }-benzonitrile;

4-{1-[(R)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-tetramethyleneimine-1-yl]-formyl radical }-benzonitrile;

4-{1-[(R)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-formyl radical }-benzonitrile;

4-{1-[(S)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-formyl radical }-benzonitrile;

4-{1-[(S)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-formyl radical }-benzonitrile;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-2,2-dimethyl-third-1-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-cyclopropyl-ketone;

1-cyclobutyl-1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-ketone;

4-{1-{4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-morpholine-4-base-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-piperidines-1-yl]-1-morpholine-4-base-ketone;

1-[(R)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-tetramethyleneimine-1-yl]-1-morpholine-4-base-ketone;

1-[(R)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-1-morpholine-4-base-ketone;

1-[(S)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-yl]-1-morpholine-4-base-ketone;

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid diisopropylamide;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-tetramethyleneimine-1-base-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-piperidines-1-base-ketone;

1-[(S)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-tetramethyleneimine-1-yl]-1-morpholine-4-base-ketone;

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid diethylamide;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(1,3-dihydro-isoindole-2-yl)-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-1-(2,3,5,6-tetrahydrochysene-[1,2 '] connection pyrazine-4-yl)-ketone;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid sec.-propyl-(2-methoxyl group-ethyl) acid amides;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-yl]-(1,1-dioxo-thiomorpholine-4-yl)-ketone;

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid sec.-propyl acid amides;

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-carboxylic acid (4-fluoro-phenyl)-acid amides;

2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N, N-dimethyl-ethanamide;

2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-phenyl-ethanamide;

2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-1-tetramethyleneimine-1-base-ethyl ketone;

2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-1-morpholine-4-base-ethyl ketone;

3-cyclobutyl-7-(1-methylsulfonyl-piperidin-4-yl oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

4-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-piperidines-1-alkylsulfonyl]-benzonitrile;

3-cyclobutyl-7-[1-(3,5-dimethyl-different  azoles-4-alkylsulfonyl)-piperidin-4-yl oxygen base]-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

4-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-piperidines-1-alkylsulfonyl]-benzonitrile;

4-[(R)-2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-tetramethyleneimine-1-alkylsulfonyl]-benzonitrile;

4-[(R)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-alkylsulfonyl]-benzonitrile;

4-[(S)-3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-tetramethyleneimine-1-alkylsulfonyl]-benzonitrile;

3-cyclobutyl-7-(2,4-two fluoro-benzyloxies)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-benzonitrile;

3-cyclobutyl-7-(3-methoxyl group-benzyloxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-(pyridine-2-ylmethoxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-(pyridin-3-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-(pyridin-4-yl methoxyl group)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-benzonitrile;

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-benzonitrile;

6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-1-methyl isophthalic acid H-quinoline-2-one-;

4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-methyl benzoate;

4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenylformic acid;

1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-tetramethyleneimine-Ji-ketone;

1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-morpholine-4-base-ketone;

1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-(4-pyridin-4-yl-piperazine-1-yl)-ketone;

1-[4-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-[4-(4-fluoro-phenyl)-piperazine-1-yl]-ketone;

3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-methyl benzoate;

3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenylformic acid;

1-[3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-tetramethyleneimine-Ji-ketone;

1-[3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-morpholine-4-base-ketone;

1-[3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-(4-pyridin-4-yl-piperazine-1-yl)-ketone;

1-[3-(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen ylmethyl)-phenyl]-1-[4-(4-fluoro-phenyl)-piperazine-1-yl]-ketone;

6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-cigarette nitrile;

3-cyclobutyl-7-(pyridine-2-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-1-morpholine-4-base-ketone;

1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-1-tetramethyleneimine-1-base-ketone;

6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-niacinamide;

6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N, N-dimethyl-niacinamide;

6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-ethyl-N-methyl-niacinamide;

6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-cyclopentyl-niacinamide;

1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-1-piperidines-1-base-ketone;

1-[2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-4-yl]-1-piperidines-1-base-ketone;

1-[2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-4-yl]-1-tetramethyleneimine-1-base-ketone;

1-[2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-4-yl]-1-morpholine-4-base-ketone;

1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridine-2-yl]-1-piperidines-1-base-ketone;

1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridine-2-yl]-1-(1,1-dioxy thiomorpholine-4-yl)-ketone;

1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridine-2-yl]-1-tetramethyleneimine-1-base-ketone;

1-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridine-2-yl]-1-morpholine-4-base-ketone;

1-[2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-1-morpholine-4-base-ketone;

1-[2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-1-piperidines-1-base-ketone;

3-cyclobutyl-7-(pyrazine-2-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-(pyrimidine-2-yloxy)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

7-(5-bromo-pyrimidine-2-yloxy)-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-methyl-niacinamide;

5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carboxylate methyl ester;

5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carboxylic acid;

1-[5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-yl]-1-morpholine-4-base-ketone;

5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carboxylic acid ethylmethyl amide;

1-[5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-yl]-1-piperidin-4-yl-ketone;

1-[5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-yl]-1-tetramethyleneimine-4-base-ketone;

5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carboxylic acid methyl acid amides;

3-cyclobutyl-7-phenoxy group-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-phenyl]-1-morpholine-4-base-ketone;

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-cyclopropyl methyl-benzamide;

1-[4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1 H-benzo [d] azepine -7-base oxygen base)-phenyl]-1-tetramethyleneimine-1-base-ketone;

N-cyclobutyl-4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-benzamide;

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N, N-diethyl-benzamide;

N-(2-cyano group-ethyl)-4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-methyl-benzamide;

1-[3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-phenyl]-1-morpholine-4-base-ketone;

3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-cyclopropyl methyl-benzamide;

3-cyclobutyl-7-[4-(morpholine-4-alkylsulfonyl)-phenoxy group]-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

4-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N, N-diethyl-benzsulfamide;

7-benzyloxy-3-cyclohexyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-{[2-(piperidino)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[2-(1-pyrrolidyl)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[2-(1,1-dioxo-4-thio-morpholinyl)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-2-PYRIMITHAMINE;

3-cyclobutyl-7-{[2-(methoxyl group)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

1-[4-(4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino } carbonyl) phenyl]-2-Pyrrolidone;

3-cyclobutyl-7-[(1-{[3-(methylsulfonyl) phenyl] carbonyl }-the 4-piperidyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-(1-[(1,1-dioxo-3,4-dihydro-2H-1-benzo thiapyran-6-yl) carbonyl]-the 4-piperidyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

The 3-cyclobutyl-7-{[(3S)-3-pyrrolidyl methyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

The 3-cyclobutyl-7-{[(3S)-the 3-piperidino methyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

The 3-cyclobutyl-7-[(3S)-3-piperidyl oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-([(3S)-and 1-(4-morpholinyl carbonyl)-3-piperidyl] methyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-([(3S)-and 1-(4-morpholinyl carbonyl)-3-pyrrolidyl] methyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

The 3-cyclobutyl-7-{[(3S)-1-(4-morpholinyl carbonyl)-3-piperidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

4-[((3S)-and 3-{[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] methyl }-piperidino) carbonyl] benzonitrile;

4-[((3S)-and 3-{[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] methyl }-the 1-pyrrolidyl) carbonyl] benzonitrile;

4-((3S)-and 3-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino } carbonyl) benzonitrile;

3-cyclobutyl-7-([(3S)-and 1-(tetrahydrochysene-2H-pyrans-4-base carbonyl)-3-pyrrolidyl] methyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-([(3S)-and 1-(tetrahydrochysene-2H-pyrans-4-base carbonyl)-3-piperidyl] methyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

The 3-cyclobutyl-7-{[(3S)-1-(tetrahydrochysene-2H-pyrans-4-base carbonyl)-3-piperidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

6-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino }-the 3-pyridine carbonitrile;

6-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino }-N-(cyclopropyl methyl)-3-pyridine carboxamide;

7-(1-[5-(1-azelidinyl carbonyl)-2-pyridyl]-the 4-piperidyl } the oxygen base)-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-(1-[5-(4-morpholinyl carbonyl)-2-pyridyl]-the 4-piperidyl } the oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

6-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino }-N-methyl-3-pyridine carboxamide;

2-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-piperidino }-the 4-pyridine carbonitrile;

3-cyclobutyl-7-{[1-(2-pyrazinyl)-4-piperidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] ethyl butyrate;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] butyric acid;

3-cyclobutyl-7-{[4-oxo-4-(piperidino) butyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[4-oxo-4-(1-pyrrolidyl) butyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-cyclopentyl butyramide;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methylbutyryl amine;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(1-methylethyl)-2-Zinamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(tetrahydrochysene-2H-pyrans-4-yl)-2-Zinamide;

7-{[5-(1-azelidinyl carbonyl)-2-pyrazinyl] the oxygen base }-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N, N-diethyl-2-Zinamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-[2-(methoxyl group) ethyl]-the 2-Zinamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-2-Zinamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-pyrimidine formonitrile HCN;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-pyrimidine carboxylic;

3-cyclobutyl-7-{[2-(4-morpholinyl carbonyl)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(cyclopropyl methyl)-2-pyrimidine carboxamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-2-pyrimidine carboxamide;

7-{[2-(1-azelidinyl carbonyl)-5-pyrimidyl] the oxygen base }-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-N-methyl-2-pyrimidine carboxamide;

N-cyclobutyl-5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-pyrimidine carboxamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(tetrahydrochysene-2H-pyrans-4-yl)-2-pyrimidine carboxamide;

3-cyclobutyl-7-{[2-(1-pyrrolidyl carbonyl)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[2-(piperidino carbonyl)-5-pyrimidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-2-pyrimidine carboxamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2-Pyridinecarboxylic Acid;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-2-pyridine carboxamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-2-pyridine carboxamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-N-methyl-2-pyridine carboxamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N, N-diethyl-2-pyridine carboxamide;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-N-[2-(methoxyl group) ethyl]-the 2-pyridine carboxamide;

3-cyclobutyl-7-{[6-(1-pyrrolidyl carbonyl)-3-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[6-(4-morpholinyl carbonyl)-3-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[6-(tetrahydrochysene-1,4-oxygen azepine -4 (5H)-Ji carbonyl)-3-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-cyclopentyl-2-pyridine carboxamide;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-pyridine carboxylic acid methyl esters;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridine carboxylic acid;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-cyclopropyl-3-pyridine carboxamide;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(1-methylethyl)-3-pyridine carboxamide;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-3-pyridine carboxamide;

N-cyclobutyl-6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridine carboxamide;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(tetrahydrochysene-2H-pyrans-4-yl)-3-pyridine carboxamide;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N, N-diethyl-3-pyridine carboxamide;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-[2-(methoxyl group) ethyl]-the 3-pyridine carboxamide;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-N-[2-(methoxyl group) ethyl] benzamide;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-benzamide;

3-cyclobutyl-7-(3-pyridyl oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-pyridine carbonitrile;

3-cyclobutyl-7-[(5-iodo-2-pyridyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-[(5-nitro-2-pyridyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

N-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl } ethanamide;

3-cyclobutyl-7-[(5-nitro-1,3-thiazoles-2-yl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

N-{2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-1,3-thiazoles-5-yl } ethanamide;

3-cyclobutyl-7-[(5-nitro-2-thienyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

N-{5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-thienyl } ethanamide;

3-cyclobutyl-7-{[6-(methoxyl group)-3-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2 (1H)-pyridones;

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl } ethyl ketone;

3-cyclobutyl-7-{[5-(1H-pyrazoles-5-yl)-2-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[5-(5-methyl isophthalic acid, 3,4- diazole-2-yl)-2-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-the 2-piperidone;

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-the 2-azetidinone;

3-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-1,3- azoles alkane-2-ketone;

3-cyclobutyl-7-{[5-(1H-pyrazol-1-yl)-2-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[5-(3, the different  azoles of 5-dimethyl-4-base)-2-pyridyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

6-[(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-3-pyridine carboxamide;

N-methyl-6-{[3-(2-methylcyclopentyl)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl] the oxygen base }-the 3-pyridine carboxamide;

6-[(3-cyclobutyl-8-iodo-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-3-pyridine carboxamide;

3-cyclobutyl-7-iodo-8-[(phenmethyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[6-methyl-4-(methoxyl group)-2-quinolyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[4-(methoxyl group)-1,7-naphthyridine-2-yl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-(naphthyridine-2-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

N-{7-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 6-methyl isophthalic acid, 8-naphthyridine-2-yl } ethanamide;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2,3-pyridine dicarboxylic acid dimethyl ester;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-2,3-pyridine dicarboxylic acid disodium;

2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-5H-pyrrolo-[3,4-b] pyridines-5,7 (6H)-diketone;

2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-7-hydroxyl-6,7-dihydro-5H-pyrrolo-[3,4-b] pyridine-5-ketone;

2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-6,7-dihydro-5H-pyrrolo-[3,4-b] pyridine-5-ketone;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-pyridine amine;

Morpholine-4-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base-pyridin-3-yl-acid amides;

Piperidines-1-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base-pyridin-3-yl]-acid amides;

Tetramethyleneimine-1-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-acid amides;

N-[6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl] isobutyramide;

Tetrahydrochysene-pyrans-4-carboxylic acid [6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyridin-3-yl]-acid amides;

3-cyclobutyl-7-[5-(4,6-dimethoxy-pyrimidine-2-base)-pyridine-2-base oxygen base]-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-[5-(4-methylsulfonyl-phenyl)-pyrazine-2-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

N-{4-[5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-yl]-phenyl }-ethanamide;

3-cyclobutyl-7-(3,5-dimethyl-pyridine-2-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-[5-(morpholine-4-alkylsulfonyl)-pyridine-2-base oxygen base]-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

3-cyclobutyl-7-(2-methyl-furo [2,3-c] pyridine-7-base oxygen base)-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine ;

2-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-4-oxyethyl group-cigarette nitrile;

6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-11H-benzo [d] azepine -7-base oxygen base)-2-methyl-cigarette nitrile;

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-the 5-N-methyl-2-2-pyrrolidone N-;

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-3-methyl-2-imidazolidine;

(4R)-and 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-4-hydroxyl-2-Pyrrolidone;

N-methyl-6-{[3-(3-methylcyclopentyl)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl] the oxygen base }-the 3-pyridine carboxamide;

5-[(3-cyclopentyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-2-Zinamide;

N-methyl-5-{[3-(3-methylcyclopentyl)-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl] the oxygen base }-the 2-Zinamide;

1-{3-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-pyrazinyl }-2-Pyrrolidone;

7-[(5-chloro-2-pyrazinyl) oxygen base]-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

1-{5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-pyrazinyl }-2-Pyrrolidone;

7-[(5-bromo-2-pyrazinyl) oxygen base]-3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-{5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-pyrazinyl }-1,3- azoles alkane-2-ketone;

3-cyclobutyl-7-[5-(1,1-dioxo-2-isothiazolidine-2-yl)-pyridine-2-base oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-pyridyl }-the 2-imidazolidone;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 2-Zinamide;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-3-(methoxyl group) benzamide;

2-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base] benzonitrile;

3-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-4-(methoxyl group) benzamide;

3-chloro-4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-benzamide;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N, the 3-dimethyl benzamide;

3-cyclobutyl-8-[(phenmethyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-formonitrile HCN;

3-cyclobutyl-7-[(2-fluorophenyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-fluorine benzonitrile;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-fluorobenzoic acid;

4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-3-fluoro-N-methyl-benzamide;

3-cyclobutyl-7-[(2-fluoro-4-iodophenyl) oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

1-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-fluorophenyl }-2-Pyrrolidone;

N-{4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-the 3-fluorophenyl } ethanamide;

1-[3-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-phenyl]-1-tetramethyleneimine-1-base-ketone;

5-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-(tetrahydrochysene-2H-pyrans-4-yl)-2-pyridine carboxamide;

3-cyano group-4-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-benzamide;

3-cyclobutyl-7-{[6-(4-morpholinyl carbonyl)-3-pyridazinyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-methyl-3-pyridazine carboxamides;

6-[(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine-7-yl) the oxygen base]-N-ethyl-N-methyl-3-pyridazine carboxamides;

3-cyclobutyl-7-{[4-(4-morpholinyl)-4-oxo butyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-[(1-{[4-(4-morpholinyl) phenyl] carbonyl }-the 4-piperidyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[1-(cyclopropyl ethanoyl)-4-piperidyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-[(1-{[(2R, 6S)-2,6-dimethyl-4-morpholinyl] carbonyl }-the 4-piperidyl) the oxygen base]-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[is trans-4-(4-morpholinyl carbonyl) cyclohexyl] and the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

3-cyclobutyl-7-{[6-(4-morpholinyl)-2-pyrazinyl] the oxygen base }-2,3,4,5-tetrahydrochysene-1H-3-benzazepine;

Or its pharmacologically acceptable salt or solvate.

20. as formula (I) compound of definition in the claim 19, it is selected from:

5-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-pyrazine-2-carboxylic acid methane amide; Perhaps

Or its pharmacologically acceptable salt or solvate.

21. as formula (I) compound of definition in the claim 19, it is 6-(3-cyclobutyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -7-base oxygen base)-N-methyl-niacinamide or its pharmacologically acceptable salt or solvate.

22. the formula that is used for the treatment of (I) compound or pharmaceutically acceptable salt thereof or solvate as each definition among the claim 1-21.

23. be used for the treatment of purposes in the medicine of neurological disorder in preparation as formula (I) compound or pharmaceutically acceptable salt thereof of each definition among the claim 1-21 or solvate.

24. be used for the treatment of the pharmaceutical composition of neurological disorder, described composition contains just like the formula of each definition among the claim 1-21 (I) compound or pharmaceutically acceptable salt thereof or solvate and pharmaceutically acceptable carrier.

25. a pharmaceutical composition, described composition contain just like the formula of each definition among the claim 1-21 (I) compound or pharmaceutically acceptable salt thereof or solvate and pharmaceutically acceptable carrier or vehicle.

26. preparation is as formula (I) compound or pharmaceutically acceptable salt thereof of definition in the claim 1 or the method for solvate, described method comprises:

(a) with formula (II) compound

R wherein ¹, R ³With definition in n such as the claim 1, with formula R ^{2 '}-L ¹Compound reaction, wherein R ^{2 '}As in the claim 1 to R ²Definition or can be converted into described R ²Group, L ¹The leavings group that expression is suitable; Perhaps

(b) with (III) compound

R wherein ², R ³With definition in n such as the claim 1, with formula R ^{1 '}-L ²Compound reaction, wherein R ^{1 '}As in the claim 1 to R ¹Definition or can be converted into described R ¹Group, L ²The leavings group that expression is suitable; Perhaps

(c) incite somebody to action as above middle formula (III) compound and the formula R that defines of step (b) ^{1 '}The reactive ketone of=O, wherein R ^{1 '}As in the claim 1 to R ¹Definition or can be converted into described R ¹Group; Perhaps

(d) with protected formula (I) compound deprotection base; Perhaps

(e) change becomes other formula (I) compound.

27. as the method for definition in the claim 26, wherein L ¹The hydroxyl of expression halogen atom or optional activation, and L wherein ²The expression halogen atom.