 Substituted 1,2,3,4-tetrahydronaphthalene derivatives
专利摘要:
(R) -enantiomer, (S) -enantiomer or racemate in the form of a free base or a pharmaceutically acceptable salt or hydrate, wherein X is N or CH; Y is NR 2 CH 2 , CH 2 -NR 2 , NR 2 -CO, CO-NR 2 or NR 2 SO 2 ; R 1 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; R 3 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (CH 2 ) n -aryl, wherein aryl is phenyl or comprises one or two heteroatoms selected from N, O and S Is a heteroaromatic ring) and may be mono- or di-substituted; novel piperidinyl or piperazinyl substituted 1,2,3,4-tetrahydronaphthalene derivatives having Formula I wherein n is 0-4; Pharmaceutical compositions comprising a compound; The use of a compound for treating a disease of 5-hydroxytryptamine mediated; Methods for the preparation of compounds and intermediates for the preparation of compounds. <Formula I> 公开号:KR20000064751A 申请号:KR1019980707506 申请日:1997-03-20 公开日:2000-11-06 发明作者:스테판 베르그；레나르트 플로르발；슈반테 로스；세쓰-올로브 토베르그 申请人:클래스 빌헬름슨；아스트라 악티에볼라그； IPC主号:
专利说明:
Substituted 1,2,3,4-tetrahydronaphthalene derivatives Various species of piperazinyl substituted benzanilide derivatives as 5-HT 1D antagonists are disclosed in particular in EP533266, EP533267, EP533268, GB227930 and International Publication WO95 / 11243. International publication WO94 / 13659 discloses an extremely wide range of fused benzo compounds with para substituted piperadinyl or piperazinyl radicals in the aromatic ring, the species of which are described as binding to the 5-HT 1A -receptor. Doing. International Publication No. WO94 / 21619 discloses in detail an aromatic naphthalene ring system which may be substituted with a piperidinyl or riferazinyl group, which compounds are also described as being potent serotonin (5HT 1 ) agonists and antagonists. EP402923 discloses 1,2,3,4-tetrahydronaphthalene derivatives substituted with 2-aminoalkyl or alkylenearomatics with additional nitrogen substituents at the 5 position of the tetraline ring, which compound is dopamine It is described as an agent. Background of the Invention Various central nervous system disorders such as depression, anxiety and the like appear to involve diseases of the neurotransmitter noradrenaline (NA) and 5-hydroxytryptamine (5-HT), also known as serotonin. Drugs most often used in the treatment of depression are known to work by improving neurotransmission of one or both of these physiological agents. Enhancement of 5-HT neurotransmission first acts on depressed mood and anxiety, while enhancement of noradrenaline neurotransmission acts on retardation symptoms that occur in depressed patients. The present invention relates to compounds that act on 5-HT neurotransmission. Serotonin, or 5-HT activity, is expected to be involved in numerous types of psychiatric disorders. For example, an increase in 5-HT activity is associated with anxiety and a decrease in 5-HT release is expected to be associated with depression. Serotonin is also involved in various conditions such as feeding disorders, gastrointestinal disorders, cardiovascular control, and sexual behavior. 5-HT receptor The various effects of 5-HT may be related to the fact that serotonin neurons stimulate the secretion of several hormones such as, for example, cortisol, prolactin, β-endorphin, vasopressin and the like. The secretion of each of these hormones is regulated on a certain basis by several different 5-HT (serotonin) receptor subtypes. With the help of molecular biology techniques, to date these receptors are referred to as 5-HT 1 (where 5-HT 1 receptors are 5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 1E and 5-HT 1F subtypes). Further divided), 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-ht 5 , 5-ht 6 and 5-ht 7 . Each receptor subtype is associated with different serotonin functions and has different properties. Regulation of 5-HT Delivery The release of 5-HT at nerve endings is feedback regulated by two different subtypes of 5-HT receptors. Inhibitory 5-HT 1A autoreceptors are present on the cell bodies of the striking nucleus, which reduces shock transmission in the case of stimulation by 5-HT in 5-HT neurons, thus reducing 5-HT release at nerve endings. Another inhibitory 5-HT receptor subtype is located on the 5-HT nerve endings and regulates the 5-HT 1D receptor (5 in rodents) by regulating the amount of 5-HT released. HT 1B receptor). Therefore, the antagonists of these terminal autoreceptors increase the amount of 5-HT released by nerve impulses as shown in in vivo and in vitro tests. Thus, use of terminal 5-HT 1D autoreceptor antagonists will increase synaptic 5-HT concentrations and enhance delivery in the 5-HT system. Antagonists therefore provide antidepressant effects to be useful as drug treatments for depression. Other localizations of the 5-HT 1D receptor subtypes also exist. Most of these receptors appear to be located on nerve endings (so-called heteroreceptors) of other nervous systems. Since 5-HT 1D receptors mediate inhibitory responses, antagonists of these receptor subtypes also increase the release of neurotransmitters other than 5-HT. Compounds with 5-HT 1D activity can be divided into pro-, partial and antagonists according to well-known and recognized pharmaceutical tests. Disclosure of the Invention The main object of the present invention is to provide compounds having selective effects on the 5-HT 1D receptor, preferably antagonist properties as well as good bioavailability. For example, the effects on other receptors selected from 5-HT 1A , 5-HT 2A , D 1 , D 2A , D 3 , α 1 and α 2 receptors were investigated. Accordingly, the present invention relates to (R) -enantiomers, which are in the form of free bases or pharmaceutically acceptable salts or hydrates which have a highly selective effect on the 5-HT 1D receptor and also exhibit sufficient bioavailability after oral administration, ( S) -enantiomers or racemates provide the compounds of formula (I). (In the above formula, X is N or CH, Y is NR 2 CH 2 , CH 2 -NR 2 , NR 2 -CO, CO-NR 2 or NR 2 SO 2 , R 1 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, R 2 is H or C 1 -C 6 alkyl, R 3 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (CH 2 ) n -aryl, wherein aryl is phenyl or comprises one or two heteroatoms selected from N, O and S Is a heteroaromatic ring, and may be mono- or di-substituted with R 4 and / or R 5 , R 4 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen, CN, CF 3 , OH, C 1 -C 6 alkoxy, NR 6 R 7 , OCF 3 , SO 3 CH 3 , SO 3 CF 3 , SO 2 NR 6 R 7 , phenyl, phenyl-C 1 -C 6 alkyl, phenoxy, C 1 -C 6 alkylphenyl; C 1 -C 6 alkyl-heterocyclic rings containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO 2 ; And an optionally substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO 2 , wherein any substituent (s) is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and phenyl-C 1 -C 6 alkyl); Or COR 8 , R 5 is H, OH, CF 3 , OCF 3 , halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, R 6 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, R 7 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, R 8 is one or two heteroatoms selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CF 3 , NR 6 R 7 , phenyl, or N, O, S, SO and SO 2 , or A heterocyclic ring containing a substituted heteroatom, n is 0-4) In the present invention, C 1 -C 6 alkyl may be straight or branched chain. C 1 -C 6 alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo- Pentyl, n-hexyl or i-hexyl. In the present invention, C 1 -C 6 alkoxy may be straight or branched chain. C 1 -C 6 alkoxy includes methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i -Pentyloxy, t-pentyloxy, neo-pentyloxy, n-hexyloxy or i-hexyloxy. In the present invention, C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclohexyl. Halogen in the present invention may be fluoro, chloro, bromo or iodo. The heteroaromatic ring containing one or two heteroatoms selected from N, O and S in the present invention is preferably a 5- or 6-membered heteroaromatic ring and is furyl, imidazolyl, isoxazolyl, iso Thiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl. Heteroaromatic rings may be substituted or unsubstituted. In the present invention, the heterocyclic ring containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO 2 may optionally include a carbonyl functional group and preferably 5- , 6- or 7-membered heterocyclic ring and imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidinyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, Pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, preferably piperidino, 1-piperazinyl, morpholino, thiomorpholino and 4-piperidone-1-. A preferred embodiment of the invention relates to compounds of formula (I), wherein piperidinyl or piperazinyl is in the 5 position. The most preferred embodiment of the invention relates to compounds of formula (I), wherein piperidinyl or piperazinyl is in the 8 position. Another possibility is that piperidinyl or piperazinyl is in the 6 or 7 position. Another preferred embodiment of the invention relates to compounds of formula (I), wherein Y is NHCO or CONH, ie amide. Among these compounds, R 3 is unsubstituted phenyl, or mono- or di-substituted phenyl, and especially ortho-, meta- or para-substituted phenyl, specifically substituent R 4 is phenyl, phenyl-C 1- C 6 alkyl, cyclohexyl, piperidino, 1-piperazinyl, morpholino, CF 3 , 4-piperidone-1-yl, n-butoxy or, R 8 is phenyl, cyclohexyl, 4 Preference is given to compounds which are COR 8 which are -piperidone-1-yl, 1-piperazinyl, morpholino, CF 3 , piperidino or NR 6 R 7 . Examples of suitable combinations of substituents include X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 Is piperidinyl, R 5 is H, or X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 is phenyl, phenylmethyl or phenylethyl and R 5 is H, or X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is piperidinyl , R 5 is H, X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is phenyl , Phenylmethyl or phenylethyl, R 5 is H, X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is piperidinyl , R 5 is H, X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, or X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) -phenyl, or X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is phenyl , Phenylmethyl or phenylethyl, R 5 is H, X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is morpholinyl , R 5 is H, X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is morpholinyl, R 5 is H, X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is piperidinyl, R 5 is H, X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is morpholin Nyl, R 5 is H, X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is not known Polyyl, R 5 is H, or X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 is piperidinyl and R 5 is H, X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, or X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is morpholinyl, R 5 is H, X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is piperidinyl, R 5 is H, X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) -phenyl, or X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is phenyl, phenylmethyl Or phenylethyl and R 5 is H, X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, or X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is piperidi Nyl, R 5 is H, X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 is piperidinyl and R 5 is H, X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is phenyl, phenylmethyl or Phenylethyl and R 5 is H, X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is morpholinyl , R 5 is H, X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is piperidi Nyl, R 5 is H, X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, or X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 Is morpholinyl, R 5 is H, X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is COR 8 , R 8 is morpholinyl, X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is phenyl , Phenylmethyl or phenylethyl, R 5 is H, X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 is morpholinyl, R 5 is H, or X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 Is phenyl, phenylmethyl or phenylethyl, R 5 is H, or X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is phenyl, phenylmethyl Or phenylethyl and R 5 is H, X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is pipe Ridinyl, R 5 is H, or X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is COR 8 and R 8 is NR 6 R 7 , R 6 R 7 CH 3 , C 2 H 5 or C 3 H 7, or X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is phenyl, phenylmethyl or Phenylethyl and R 5 is H, X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 Is morpholinyl, R 5 is H, X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, or X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 is phenyl, phenylmethyl or phenylethyl and R 5 is H, or X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is not known Polyyl, R 5 is H, or X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is COR 8 , R 8 is morpholinyl, or X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, or X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 Is phenyl, phenylmethyl or phenylethyl, R 5 is H, or X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is morpholin Nyl, R 5 is H, X is CH, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, or X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, or X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is pipe Ridinyl, R 5 is H, or X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is CH 2 -phenyl, R 4 is phenyl, Phenylmethyl or phenylethyl and R 5 is H, X is CH, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 Is piperidinyl, R 5 is H, or X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is (CH 2 ) 2 -phenyl, R 4 is morpholinyl, R 5 is H, or X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, R 4 is COR 8 , R 8 is cyclohexyl, or X is N, Y is CONR 2 , R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H, R 3 is phenyl, or X is N, Y is NR 2 CO, R 1 is H, CH 3 , C 2 H 5 or C 3 H 7 , R 2 is H and R 3 is CH 2 -phenyl. Preferred compounds are (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (trifluoroacetyl) benzamide, (R) -N- [8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-piperidinobenzamide, (S) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-N, N-diethylaminobenzamide, (R) -N- [8- (4-propylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-ethylbenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonylbenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-butoxybenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (1H-pyrrole-1-yl) benz amides, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-methyl-4-morpholinobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-ethylphenyl) benzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (N, N-dipropylaminosulfonyl Benzamide, (R) -N- [8- (4-ethylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide, (R) -N- [8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-butoxybenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-cyclohexylbenzamide, (R) -N- [8- (methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-piperidone-1-yl) benzamide , (R) -N-8- (piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, N- (4-morpholinocarbonylphenyl) -8- [4- (methylpiperazin-1-yl)]-1,2,3,4-tetrahydronaphthalene-2-carboxamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-morpholinomethyl) benzamide , (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (N, N-dimethylaminocarbonyl) Benzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonylbenzamide or (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-thiomorpholinobenzamide. Other preferred compound groups (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -2-methylbenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-cyanobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-fluorobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-hydroxyphenyl) benzamide, And (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-phenoxybenzamide. The compounds of the present invention are in the form of racemates or (R)-or (S) -enantiomers in the form of a free base or a pharmaceutically acceptable salt or hydrate. Preferred are compounds in the form of (R) -enantiomers. Organic and inorganic acids can be used to prepare the nontoxic pharmaceutically acceptable acid addition salts of the present invention. Illustrated acids include sulfuric acid, nitric acid, phosphoric acid, oxalic acid, hydrochloric acid, formic acid, hydrobromic acid, citric acid, acetic acid, lactic acid, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, palmoic acid, ethanedisulfonic acid, sulfamic acid, succinic acid, propionic acid, Glycolic acid, malic acid, gluconic acid, pyruvic acid, phenylacetic acid, 4-aminobenzoic acid, anthranilic acid, salicylic acid, 4-aminosalicylic acid, 4-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxy Benzoic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfanic acid, naphthalenesulfonic acid, ascorbic acid, cyclohexylsulfonic acid, fumaric acid, Maleic acid and benzoic acid. These salts are readily prepared by methods known in the art. Pharmaceutical composition In a second aspect, the present invention provides a method for activating a therapeutically effective amount of a compound of formula (I) as an enantiomer or racemate, optionally in the form of a free base or a pharmaceutically acceptable salt or hydrate, together with a diluent, excipient or inert carrier. It provides a pharmaceutical composition comprising as a component. According to the invention the compounds of the invention are usually free base or pharmaceutically acceptable such as, for example, hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartarate, oxalate and the like. Nontoxic acid addition salts may be administered orally, rectally or by injection in the form of a pharmaceutical composition comprising the active ingredient in a pharmaceutically acceptable dosage form. Dosage forms may be solid, semisolid or liquid formulations. Usually the active substance will consist of 0.1 to 99% by weight of the formulation, more specifically 0.5 to 20% by weight of the formulation to be injected and 0.2 to 50% by weight of the formulation suitable for oral administration. In order to prepare a pharmaceutical composition comprising a compound of the invention in a dosage form for oral application, the selected compound may be, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch or starch such as amylopectin, cellulose. A derivative, a binder such as gelatin or polyvinylpyrrolidone, or a solid excipient such as a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin and the like. If coated tablets are desired, the nuclei prepared as mentioned above may be coated with a concentrated sugar solution, which may include, for example, gum arabic, gelatin, talc, titanium dioxide and the like. Alternatively, tablets may be coated with polymers dissolved in readily volatile organic solvents or mixtures of organic solvents known to those skilled in the art. Pigments can be easily distinguished among tablets which are added to such coatings and contain different amounts of different active substances or active compounds. For the preparation of soft gelatin capsules, the active substance can be mixed, for example with vegetable oil or polyethylene glycol. Rigid gelatin capsules are granules of the active substance using excipients for the aforementioned tablets such as, for example, lactose, saccharose, sorbitol, mannitol, starch (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. It may include. The drug in liquid or semisolid form may also be filled in rigid gelatin capsules. Dosage units for rectal application may be in solution or suspension, or in the form of suppositories comprising the active substance in admixture with neutral fatty bases, or in the form of gelatin rectal capsules comprising the active substance in admixture with vegetable or paraffin oils. It can be prepared as. Liquid formulations for oral application include, for example, syrups or strings, such as solutions containing from about 0.1 to about 20% by weight of the active substance described herein, and a balance comprising sugars or a mixture of ethanol, water, glycerol and propylene glycol. It may be in the form of a tack solution. Optionally such liquid formulations may include colorants, flavors, saccharin and carboxymethyl-cellulose as thickeners or other excipients known in the art. Parenteral administration solutions by injection may be prepared in an aqueous solution of a soluble pharmaceutically acceptable salt of the active substance, preferably at a concentration of about 0.1 to about 10% by weight. Such solutions may also include stabilizers and / or buffers and may conveniently be provided in various dosage unit ampoule injections. Suitable daily dosages of the compounds of the present invention in human therapeutics are about 0.01-100 mg / kg body weight for oral administration and 0.001-100 mg / kg body weight for parenteral administration. Medical and Pharmaceutical Uses In addition, the present invention provides the use of a compound of formula (I) as a 5-HT 1D antagonist, a partial antagonist or a total antagonist, preferably an antagonist, and a therapeutic use of 5-hydroxytryptamine-mediated disorders in the treatment. Examples include mood disorders (depression, depression, mood modulation, seasonal affective disorders, depressive states of bipolar disorder), anxiety disorders (obsessive compulsive disorder, panic disorder with or without agoraphobia, social phobia, specific phobia) , Generalized anxiety disorder, mental posttraumatic stress disorder), personality disorder (impulse control disorder, hair growth barrier), obesity, anorexia, abnormal appetite, premenstrual syndrome, sexual disorders, alcoholism, excessive smoking, autism, mental and physical function Relief, hyperactivity disorder, migraines, memory disorders (age related memory impairment, elderly and senile dementia), pathological aggregation, schizophrenia, endocrine disorders (eg hyperprolactinemia), seizures, dyskinesia, Parkinson's disease, temperature Disorders of the CNS such as dysregulation, pain and hypertension. Examples of disorders mediated by other 5-hydroxytryptamines include urinary incontinence, vasospasm and tumor (eg, lung carcinoma) growth inhibition. Manufacturing method The invention also relates to a process for preparing the compound of formula (I). It will be understood from the following description of this method that appropriate protecting groups are added to and then removed from the various reactants and intermediates as appropriate in a manner readily understood by those skilled in the art of organic synthesis. Conventional methods using such protecting groups as well as examples of suitable protecting groups are disclosed, for example, in "Protective Groups in Organic Synthesis" Green (T.W. Greene), Wiley-Interscience, New York, 1991. The method described below for the 8-position substituent can also be applied to the 5-position substituent. Method of Making Intermediates One. (i) benzylating a compound of formula (II) that is a racemate or enantiomer Obtaining the compound of formula III can be carried out by reacting with a suitable benzylating agent such as halogenated benzyl such as benzyl bromide or benzyl chloride or activated alcohol such as benzyl mesylate or benzyl tosylate. The reaction can be carried out at a temperature in the range from + 20 ° C. to + 150 ° C., for example with N, N-dimethylformamide, acetone or with a suitable base such as for example trialkylamine of NaOH, NaHCO 3 , K 2 CO 3 or triethylamine. It can be carried out using a salt or base of Chemical II in a suitable solvent such as acetonitrile. For example, the presence of a suitable catalyst such as potassium iodide or sodium iodide may accelerate the reaction. Nitrogen of compound II can also be selected from sodium cyanoborohydride, sodium borohydride or a reducing agent such as H 2 as a catalyst and palladium, platinum, rhodium or nickel in suitable solvents such as, for example, tetrahydrofuran, dioxane, methanol or ethanol. It can be protected by arylaldehyde reductive alkylation in the presence of a suitable catalyst comprising. Proton donors such as p-toluenesulfonic acid can be used to promote imine / enamine formation, and compound III can be obtained by accelerating the reaction by adjusting the pH to slightly acidic with an appropriate acid such as acetic acid. (ii) demethylating the compound of formula III to obtain the compound of formula IV With a basic nucleophilic reagent such as Suitable solvents HBr, HI, HBr / CH 3 COOH, BBr 3, AlCl 3, pyridine-acidic reagent such as aqueous -HCl or CH 3 C 6 H 4 S - or C 2 H 5 S This can be done by treating the compound. Suitable solvents may be methylene chloride or chloroform and the reaction may be carried out between -78 ° C and +60 ° C. (iii) The conversion of a compound of Formula IV to a compound of Formula V may be carried out by reaction with a compound of Formula VI. Wherein X represents a leaving group such as, for example, a halogen such as chlorine, bromine or iodine or an alkane- or arenesulfonyloxy group of eg p-toluenesulfonyloxy group and R a and R b represent lower alkyl groups such as hydrogen or methyl This method can be carried out with a salt of a compound of formula IV obtained by reaction with a base such as K 2 CO 3 , Na 2 CO 3 , KOH, NaOH, BuLi or NaH. The reaction can be carried out in a suitable solvent such as, for example, aprotic solvents of dioxane, N, N-dimethylformamide, tetrahydrofuran, toluene, benzene or petroleum ether and the reaction takes place between + 20 ° C and + 150 ° C. Can be. (iv) the displacement reaction from the compound of formula V to the compound of formula VII In the range from + 20 ° C. to + 150 ° C., for example with suitable bases such as K 2 CO 3 , KOH, potassium t-butoxide or NaH, for example N, N-dimethylformamide, dioxane, 1,1,3, It may be carried out in a suitable solvent such as aprotic solvent of 3-tetramethylurea, tetrahydrofuran or hexamethylphosphoric triamide. The presence of a co-solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidone or hexamethylphosphoric triamide at an appropriate concentration in the solvent can accelerate the reaction. . (v) hydrolysis of compound VII to compound VIII is carried out between + 20 ° C. and + 100 ° C., for example, with an acid such as H 2 SO 4 , HCl or HBr in a suitable solvent such as H 2 O, ethanol, methanol or mixtures thereof. It can be carried out under acidic conditions used or under basic conditions using a base such as NaOH or KOH in a suitable solvent such as, for example, H 2 O, ethanol, methanol or mixtures thereof between + 20 ° C. and + 100 ° C. (vi) the conversion of a compound of Formula VIII to a compound of Formula IX (a) an aprotic / anhydrous solvent of tetrahydrofuran or N, N-dimethylformamide in the presence of a compound of Formula X and a coupling agent such as N, N'-carbonyldiimidazole between + 20 ° C and 130 ° C. In a suitable solvent such as Wherein R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, then between + 20 ° C. and reflux temperature, for example in a suitable solvent of diethyl ether or tetrahydrofuran, for example LiAlH 4 Reducing the imide with a suitable reducing agent, or (b) in the range of + 20 ° C. to + 150 ° C., eg with a suitable base such as K 2 CO 3 , NaHCO 3 , or KOH, eg ethanol, butanol, N, N-dimethylformamide, acetonitrile, or water and It may be carried out by reacting with a compound of formula (XI) in a suitable solvent such as a mixture of acetonitrile. Wherein X represents a halogen such as chlorine or bromine or a leaving group such as, for example, an alkane- or areensulfonyloxy group of p-toluenesulfonyloxy group, and R 1 represents C 1 -C 6 alkyl or C 3 -C 6 Cycloalkyl) Alternatively, the compound of formula IX is (vii) a compound of formula (XV) which is a racemate or enantiomer (Wherein R C represents a halogen such as bromine, iodine or trifluoromethylsulfonyloxy group) Suitable benzylating agents such as, for example, benzyl bromide or halogenated benzyl benzyl chloride or benzyl mesylate or benzyl tosylate activating alcohol It may be prepared by benzylation by reaction with to obtain a compound of formula XVI. The reaction can be carried out in the range of + 20 ° C. to + 150 ° C., for example with a suitable base of trialkylamine such as NaOH, NaHCO 3 , K 2 CO 3 or triethylamine, eg N, N-dimethylformamide, acetone or aceto. It can be carried out using a salt or base of formula XV in a suitable solvent of nitrile. For example, the presence of a suitable catalyst of alkali metal iodide such as potassium iodide or sodium iodide can accelerate the reaction to yield compound XVI. Nitrogen in compound XV may also be a reducing agent such as H 2 as sodium cyanoborohydride, sodium borohydride or a catalyst in a suitable solvent such as tetrahydrofuran, dioxane, methanol or ethanol and palladium, platinum, rhodium or nickel It can be protected by arylaldehyde reductive alkylation in the presence of a suitable catalyst comprising. Proton donors such as p-toluenesulfonic acid can be used to promote imine / enamine formation, and adjusting the pH to weakly acidic with an appropriate acid such as acetic acid can accelerate the reaction to produce Compound XVI. ` (viii) The conversion of a compound of formula XVI to a compound of formula IX, wherein R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, can be carried out by reacting with a compound of formula XVII. PdX 2 , L 2 Pd (0) L 2 PdX 2 (X represents a halogen such as chlorine or bromine and L represents triphenylphosphine, tri-o-tololiphosphine, tripurylphosphine, triphenylar Triphenylphosphine, tri-o-tololiphosphine, tripurylphosphine, 2,2'-bis (diphenylphosphino) in the presence of a suitable palladium catalyst such as cinna or dibenzylideneacetone). Suitable bases, such as sodium t-butoxide or lithium bis (trimethylsilyl) amide, with or without additional ligand L ', such as) -1,1-binaphthalene (as racemate or enantiomer) or triphenyllacin And in a suitable solvent, such as aprotic solvents of benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide and the reaction can take place between + 20 ° C and + 150 ° C, and To obtain a compound. The conversion from XVI to IV is also carried out in (N, N-diethylamino) tributyltin and in a suitable solvent such as, for example, an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide. Reagents such as tris (dimethylamino) borane can be used to proceed through the conversion of XVII to aminostanan or aminoborane and the conditions of formula (IX) are then obtained using conditions similar to those described above. Compounds of Formula IX also (ix) a compound of formula XIII, wherein R 1 is hydrogen, wherein R 1 -L, where L is, for example, an alkane- or areensulfo, such as a halogen or a p-toluenesulfonyloxy group, such as chlorine, bromine or iodine; Can be prepared by alkylating with a suitable alkylation reagent, such as a suitable leaving group of the silyloxy group and R 1 is C 1 -C 6 alkyl. The reaction can be carried out in a suitable solvent such as N, N-dimethylformamide, acetone, acetonitrile, or tetrahydrofuran with a suitable base such as K 2 CO 3 , NaHCO 3 , or KOH. The reaction can be carried out at a temperature of +20 ° C to 120 ° C. Alternatively, (x) Conversion of a compound of Formula XIII, wherein R 1 is hydrogen, to Formula IX is, for example, sodium cyanoborohydride, sodium borohydride in a suitable solvent such as tetrahydrofuran, dioxane, methanol or ethanol. in the presence of a suitable catalyst comprising a reducing agent and palladium, platinum, rhodium or nickel, such as H 2 or as a lead catalyst, the compound R 1 -CHO (wherein, R 1 is hydrogen or 5-alkyl C 1 -C), or This can be done by reductive alkylation with C 3 -C 6 cyclic ketones. Proton donors such as p-toluenesulfonic acid can be used to promote imine / enamine formation, and compound IX can be obtained by accelerating the reaction by adjusting the pH to slightly acidic with an appropriate acid such as acetic acid. (xi) when R 1 is methyl, the conversion of the compound of formula XIII to the compound of formula IX a) suitable such as methylene chloride, chloroform, dioxane or diethyl ether together with a suitable base of trialkylamine such as K 2 CO 3 , NaHCO 3 , NaOH or triethylamine at a reaction temperature of -20 ° C. to + 60 ° C. In a solvent, it can be carried out by converting the compound of formula XIII to the compound of formula XLVI, and then (b) The compound of formula XLVI is reduced to the compound of formula IX with a suitable reducing agent such as lithium aluminum hydride in a suitable solvent such as diethyl ether or tetrahydrofuran at a temperature from + 20 ° C. to reflux. (xii) the conversion of a compound of Formula IX to a compound of Formula XII is Wherein R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl a) hydrogenation using a catalyst comprising palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at a temperature between + 20 ° C and + 120 ° C, or b) by debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd / C at a reaction temperature between + 20 ° C. and reflux temperature. (xiii) when R 1 is hydrogen, the conversion of the compound of formula VIII to the compound of formula XIII is It may be carried out by reacting with a compound of formula (XI), wherein X represents a leaving group of an alkane- or arenesulfonyloxy group such as halogen or p-toluenesulfonyloxy group such as chlorine or bromine and R 1 is hydrogen. The process can be carried out in a suitable solvent such as, for example, N, N-dimethylformamide, acetonitrile, or a mixture of water and acetonitrile with a suitable base such as K 2 CO 3 , NaHCO 3 , or KOH and the reaction is It may be carried out at a temperature of +20 ℃ to 150 ℃. (xiv) the conversion of a compound of Formula XIII to a compound of Formula XIV is (Wherein R 1 is hydrogen and R d represents a suitable protecting group) a) hydrogenation using a catalyst comprising palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at reaction temperatures between + 20 ° C and + 120 ° C, or b) by debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd / C at a reaction temperature between + 20 ° C. and reflux temperature. The reaction is followed by a suitable base, such as triethylamine or K 2 CO 3 , at a temperature between -20 ° C. and + 60 ° C., for example in a suitable solvent such as methylene chloride or chloroform, for example di-t-butyl dicarbonate The piperazine ring is protected with an appropriate protective reagent of to give the compound of formula XIV. Alternatively, the compound of formula (XIV) can be prepared by Wherein R d is a suitable protecting group such as benzyl or t-butyloxycarbonyl group (xv) The conversion of a compound of formula XVI to a compound of formula XVIII can be carried out by reacting with a compound of formula XIX. The method represents PdX 2 , L 2 Pd (0) L 2 PdX 2 (X represents a halogen such as chlorine or bromine and L represents triphenylphosphine, tri-o-tololiphosphine, tripurylphosphine, triphenylar Triphenylphosphine, tri-o-tololiphosphine, tripurylphosphine, 2,2'-bis (diphenylphosphino) in the presence of a suitable palladium catalyst such as cinna or dibenzylideneacetone). Suitable bases, such as sodium t-butoxide or lithium bis (trimethylsilyl) amide, with or without additional ligand L ', such as) -1,1-binaphthalene (as racemate or enantiomer) or triphenyllacin And in a suitable solvent, such as aprotic solvents of benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide, and the reaction can take place between + 20 ° C and + 150 ° C and is represented by Formula XVIII To obtain a compound. The conversion from XVI to XVIII is also carried out in (N, N-diethylamino) tributyltin and in suitable solvents such as, for example, aprotic solvents such as benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide and Reagents such as tris (dimethylamino) borane can be used to proceed through the conversion of XIX to aminostanan or aminoborane and the conditions of formula XVIII are then obtained using conditions similar to those described above. (xvi) the conversion of a compound of Formula XVIII to a compound of Formula XX is a) hydrolyzing the t-butyloxycarbonyl group at a temperature between + 20 ° C. and 60 ° C. with a suitable acid, such as trifluoroacetic acid, in a suitable solvent such as methylene chloride or chloroform, and then b) cleaving the benzyl group by suitable catalytic phase hydrogenation comprising palladium, rhodium, platinum or nickel in a suitable solvent such as acetic acid or ethanol at a temperature between + 20 ° C. and 60 ° C., or alternatively, c) debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd / C at a reaction temperature between + 20 ° C. and reflux temperature It can be carried out by removing the protecting group R d of the compound of formula XVIII by methods known in the art. The reaction is followed by a suitable base, such as triethylamine or K 2 CO 3 , at a temperature between -20 ° C. and + 60 ° C., for example in a suitable solvent such as methylene chloride or chloroform, for example di-t-butyl dicarbonate The piperazine ring is protected with an appropriate protective reagent of to give the compound of formula XIV. 2. (i) halogenating the compound of formula XXI, which is a racemate or enantiomer, to obtain a compound of formula XXII It may be carried out by aromatic electrophilic substitution using a suitable halogenating agent such as Br 2 , Cl 2 , I 2 , ICl or SO 2 Cl 2 . The reaction may or may not include a suitable base of an alkali metal acetate, such as sodium acetate, at a reaction temperature between 20 ° C. and room temperature, for example using a salt or base of compound XXI in a suitable solvent such as acetic acid, HCl / ethanol or water. Can be done. (ii) Benzylating a compound of formula (XXII), which is a racemate or enantiomer, to obtain a compound of formula (XXIII) can be carried out by reacting with a suitable benzylating agent of halogenated benzyl, such as benzyl bromide or benzyl chloride. The reaction can be carried out in a suitable solvent such as N, N-dimethylformamide, acetone or acetonitrile with a suitable base such as triethylamine, NaOH, NaHCO 3 or K 2 CO 3 at a temperature of + 20 ° C. to 150 ° C. have. The presence of a suitable catalyst such as an alkali metal halide such as potassium iodide or sodium iodide can accelerate the reaction. Nitrogen in compound XXII may also be a reducing agent such as sodium cyanoborohydride, sodium borohydride or a catalyst such as H 2 and palladium, platinum, rhodium or nickel in a suitable solvent such as, for example, tetrahydrofuran, dioxane, methanol or ethanol. It can be protected by arylaldehyde reductive alkylation in the presence of a suitable catalyst comprising. Proton donors such as p-toluenesulfonic acid can be used to promote imine / enamine formation, and adjusting the pH to weakly acidic with an appropriate acid such as acetic acid can accelerate the reaction to produce compound XXIII. iii) Converting a compound of formula XXIII to a compound of formula XXIV is followed by N-methyl by metal-halogen exchange in a suitable anhydrous solvent such as tetrahydrofuran or diethyl ether using, for example, butyllithium, lithium or magnesium turning. Treatment with an appropriate piperidone, such as -4-piperidone, may then be carried out with a suitable finishing operation. The reaction can be carried out at a reaction temperature in the range of -78 ° C to room temperature. Wherein R 1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl (iv) The compound of formula XXIV is treated with a suitable reducing agent such as sodium borohydride and a proton additive such as CF 3 COOH, CF 3 SO 3 H or HCOOH in a suitable solvent such as tetrahydrofuran or diethyl ether Can be reduced to a compound. The reaction can be carried out at a temperature between 0 ° C. and reflux temperature. (v) It is by demethylating a compound of formula (XXV) to obtain a compound of formula XXVI in a suitable solvent, HBr, HI, HBr / acetic acid, BBr 3, AlCl 3, pyridine-acidic reagent such as aqueous -HCl or C 2 H 5 S - or CH 3 C 6 H 4 S - and it may be carried out by treating the compound with a basic nucleophilic reagent such. Suitable solvents can be methylene chloride or chloroform and the reaction can take place between -78 ° C and + 60 ° C. (vi) The conversion of a compound of formula XXVI to a compound of formula XXVII is methylene chloride or 4 in the presence of a base such as 2,4,6-collidine, triethylamine or pyridine at reaction temperatures ranging from -78 ° C to room temperature. It may be carried out with a compound such as anhydrous trifluoromethanesulfonic acid in a suitable solvent such as carbon chloride. vii) the conversion of a compound of formula XXVII to a compound of formula XXVIII a) hydrogenation using a suitable catalyst comprising palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at reaction temperatures between + 20 ° C and 120 ° C, or b) debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd / C at a reaction temperature between + 20 ° C. and reflux temperature Can be done. Alternatively, the compound of formula XXVIII is (viii) a compound of formula XVI, wherein R c is a halogen such as bromine, to a compound of formula XXIX, wherein R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. It is treated, for example, by metal-halogen exchange in a suitable anhydrous solvent such as tetrahydrofuran or diethyl ether using butyllithium, lithium or magnesium turning, followed by a suitable piperidone such as N-methyl-4-piperidone This can then be done with a suitable finishing operation. The reaction can be carried out at a reaction temperature in the range of -78 ° C to room temperature. (ix) The compound of formula XXIX is treated with a suitable reducing agent such as sodium borohydride and a proton additive such as CF 3 COOH, CF 3 SO 3 H or HCOOH in a suitable solvent such as tetrahydrofuran or diethyl ether Can be reduced to a compound. The reaction can be carried out at a temperature between 0 ° C. and reflux temperature. (x) the conversion of a compound of Formula XXX to a compound of Formula XXVIII, wherein R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl a) hydrogenation using a suitable catalyst comprising palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at a reaction temperature between + 20 ° C and 120 ° C, or b) by debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd / C at a reaction temperature between + 20 ° C. and reflux temperature Can be performed. 3. (i) [Sunkyung L .; Stewart PF; David EN Synth. Commun. 1995, 25 (18), 2775-2780, compounds of formula XXXII, wherein the protected ketones are protected as other ketals, cyclics or cyclics, or by other protecting groups known in the art. Wherein R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl can be carried out by reaction with a compound of formula XVII. <Formula XVII> The method represents PdX 2 , L 2 Pd (0) L 2 PdX 2 (X represents a halogen such as chlorine or bromine and L represents triphenylphosphine, tri-o-tololiphosphine, tripurylphosphine, triphenylar Triphenylphosphine, tri-o-tololiphosphine, tripurylphosphine, 2,2'-bis (diphenylphosphino) in the presence of a suitable palladium catalyst such as cinna or dibenzylideneacetone). Suitable bases, such as sodium t-butoxide or lithium bis (trimethylsilyl) amide, with or without additional ligand L ', such as) -1,1-binaphthalene (as racemate or enantiomer) or triphenyllacin Together with a suitable solvent such as aprotic solvents of benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide and the reaction can take place between + 20 ° C. and + 150 ° C. To obtain a compound. The conversion of XXXI to XXXII is also carried out in (N, N-diethylamino) tributyltin and in suitable solvents such as, for example, aprotic solvents such as benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide. Reagents such as tris (dimethylamino) borane can be used to proceed through the conversion of XVII to aminostanan or aminoborane and the conditions of formula XXXII are then obtained using conditions similar to those described above. (ii) Conversion of a compound of Formula (XXXII) to a compound of Formula (XXXIII) is another method known to those skilled in the art at reaction temperatures between + 20 ° C. and reflux (see Wiley-Interscience, New York, 1991, TW Greene). By using a suitable aqueous solution such as HCl, HBr or acetic acid. After the reaction, the ketone of formula XXXIII is prepared at a temperature between 0 ° C. and + 100 ° C. for 1,2-dimethoxyethane, dimethyl sulfoxide or hexamethylphosphoric triamide containing a small amount of methanol, ethanol or t-butanol. In a suitable solvent such as, for example, in the presence of a suitable base such as potassium t-butoxide to convert to a compound of formula XXXIV by reaction with a suitable cyanating agent such as tosylmethyl isocyanide or to a compound of formula XXXIV via cyanohydrin formation. Switch. (iii) in a suitable solvent such as H 2 O, ethanol, methanol, acetic acid or mixtures thereof at a temperature between hydrolysis + 20 ℃ to the reflux temperature of the of the formula XXXV in the compound of formula XXXIV compound H 2 SO 4, HCl , Under acidic conditions using acids such as HBr or under basic conditions using a base such as NaOH or KOH in a suitable solvent such as H 2 O, ethanol, methanol or mixtures thereof at temperatures between + 20 ° C. and reflux temperature. can do. 4. (i) [Johnson D. W .; Aust of Mander L.N. J. Chem 1974, 27, 1277-1286 to nitrate the compound of formula XXXVI which is a racemate or enantiomer as described above to obtain a compound of formula XXXVII (Where R e is C 1 -C 6 alkyl) at a reaction temperature between -20 ° C. and room temperature, using aromatic nitrifiers such as nitric acid and sulfuric acid in a suitable solvent such as acetic acid, acetic anhydride or water, for example. By electronic substitution. (ii) demethylating a compound of formula XXXVII to obtain a compound of formula XXXVIII By treating the compound with a basic nucleophilic reagent such as - HBr, HI, HBr / acetic acid, BBr 3, AlCl 3, pyridine-acidic reagent such as aqueous -HCl or CH 3 C 6 H 4 S - or C 2 H 5 S Can be done. Suitable solvents can be methylene chloride or chloroform and the reaction can take place between -78 ° C and + 60 ° C. During the demethylation reaction of XXXVII, hydrolysis of the ester can occur and the acid functionality can then be converted back to the ester by methods known to those skilled in the art (Green Wiley-Interscience, New York, 1991). (iii) the conversion of a compound of Formula XXXVIII to a compound of Formula XXXIX Such as trifluoromethanesulfonic anhydride in a suitable solvent such as methylene chloride or carbon tetrachloride in the presence of a suitable base such as triethylamine, pyridine or 2,4,6-collidine at a reaction temperature between -78 ° C and room temperature It can be carried out by reacting with an active trifluoromethanesulfone reagent. (iv) the conversion of a compound of Formula XXXIX to a compound of Formula XL a) hydrogenation using a catalyst comprising palladium, platinum or nickel in a suitable solvent such as ethanol, methanol or acetic acid at a reaction temperature between + 20 ° C and + 120 ° C, or b) by reaction in a suitable solvent such as methanol in the presence of Pd / C and ammonium formate such as triethyl ammonium formate at a reaction temperature between + 20 ° C. and reflux temperature. (v) the conversion of a compound of Formula XL to a compound of Formula XLI By reaction with a compound of formula (XI). <Formula XI> (Wherein X represents a leaving group of an alkane- or arensulfonyloxy group such as halogen or p-toluenesulfonyloxy group such as chlorine or bromine and R 1 is hydrogen) The method is K 2 CO 3 , NaHCO 3 , or It may be carried out in a suitable solvent such as ethanol, butanol, N, N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base such as KOH and the reaction takes place between + 20 ° C and + 150 ° C. During the cyclization reaction of XL, hydrolysis of the ester can occur. (vi) Hydrolysis of the compound of formula XLI is carried out by the reaction of acids such as H 2 SO 4 , HCl, HBr in a suitable solvent such as H 2 O, ethanol, methanol, acetic acid or mixtures thereof at temperatures between + 20 ° C. and reflux. The compound of formula XXXV is carried out under acidic conditions of use or under basic conditions with a base such as NaOH or KOH in a suitable solvent such as H 2 O, ethanol, methanol or mixtures thereof at temperatures between + 20 ° C. and reflux temperature ( R 1 may be hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. <Formula XXXV> (vii) when R is hydrogen, protecting the compound of formula XXXV as a compound of formula XLII Where R d is a protecting group. Di-t-butyl dica in a suitable solvent such as methyl chloride or chloroform at a temperature between -20 ° C. and + 60 ° C. with a suitable base such as triethylamine or K 2 CO 3 This can be done by reacting with a suitable protective reagent such as carbonate. 5. (i) The conversion of a compound of formula XII, wherein R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, to a compound of formula XLIII is R 2 -Z (Z is for example A halogenated group such as chlorine, bromine or iodine or a leaving group such as an alkane- or arensulfonyloxy group such as p-toluenesulfonyloxy group and R 1 is C 1 -C 6 alkyl) By alkylation. The reaction may be carried out at a temperature between + 20 ° C. and + 120 ° C., for example with a suitable base of trialkylamine such as K 2 CO 3 , NaHCO 3 , NaOH or triethylamine, for example N, N-dimethylformamide, acetone or aceto. It may be carried out in a suitable solvent of nitrile. (ii) when R 2 is methyl, the conversion of the compound of formula XII to the compound of formula XLIII is a) suitable such as methylene chloride, chloroform, dioxane or diethyl ether together with a suitable base of trialkylamine such as K 2 CO 3 , NaHCO 3 , NaOH or triethylamine at a reaction temperature of -20 ° C. to + 60 ° C. In a solvent, for example, a reagent such as alkyl chloroformate of ethyl chloroformate is converted from a compound of formula XII to a compound of formula XLIV, and then b) by reducing the compound of formula XLVI to the compound of formula XLIII with a suitable reducing agent such as lithium aluminum hydride in a suitable solvent such as diethyl ether or tetrahydrofuran at a temperature from + 20 ° C. to reflux temperature. Process of Preparation of Final Product Method A (i) Acylation of the compound of formula XII, wherein X is N or compound XXVIII, X is CH and R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is between -20 ° C. and reflux temperature R 3 -COL, wherein R 3 is specified in claim 1 and L is for example chlorine in a suitable solvent such as methylene chloride or chloroform with a suitable base of trialkylamine such as triethylamine at the temperature of N, N'-carbonyldiimidazole or N, in a suitable solvent such as N, N-dimethylformamide or tetrahydrofuran at a temperature between + 20 ° C. and + 150 ° C. A compound of formula I according to the invention, wherein the compound of formula (I) according to the invention is carried out by using a carboxylic acid R 3 -COOH, wherein R 3 is specified in claim 1 together with an activator such as R 2 is hydrogen And, X is N or CH and R 1 is either C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl and R 3 is to obtain the same) as in claim 1. Method A (ii) Acylation of compounds of formula XIVa, wherein X is N or CH and R d is a protecting group, is carried out at a temperature between -20 ° C. and reflux temperature with a suitable base of trialkylamine, such as triethylamine, with methylene chloride or chloroform A temperature between + 20 ° C and + 150 ° C, together with R 3 -COL, wherein R 3 is specified in claim 1 and L is a leaving group such as, for example, halogen of chlorine, which is a suitable activated carboxylic acid R 3 which is a carboxylic acid with an activator such as N, N'-carbonyldiimidazole or N, N'-dicyclohexylcarbodiimide in a suitable solvent such as N, N-dimethylformamide or tetrahydrofuran Compounds of formula (I) according to the invention, carried out by the use of —COOH, wherein R 3 is specified in claim 1, wherein Y is NR 2 CO, R 1 and R 2 are hydrogen, and X and R 3 Is the same as in claim 1) Get Method A (iii) The acylation of the compound of formula XLIIIa, wherein X is N or CH and R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl and R 2 is C 1 -C 6 alkyl, is -20 ° C. R 3 -COL, wherein R 3 is specified in claim 1 which is a suitable activated carboxylic acid in a suitable solvent such as methylene chloride or chloroform with a suitable base of trialkylamine such as triethylamine at a temperature between reflux temperature L is for example N, N'-carbonyldiimine in a suitable solvent such as N, N-dimethylformamide or tetrahydrofuran together with or at a temperature between + 20 ° C and + 150 ° C. Of the formula (I) according to the invention by the use of R 3 -COOH (wherein R 3 is specified in claim 1), which is a carboxylic acid with an activator such as dazole or N, N'-dicyclohexylcarbodiimide compound (where, Y is NR 2 CO is , R 2 is C 1 -C 6 alkyl, R 1 is a C 1 -C 6 alkyl or or C 3 -C 6 cycloalkyl, X and R 3 is to obtain the same) as in claim 1. Method B (i) A compound of formula I according to the invention in which a compound of formula XXXVa wherein X is N or CH and R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, wherein Y is CONR 2 R 2 is hydrogen or C 1 -C 6 alkyl, R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl and X and R 3 are the same as in claim 1). Suitable solvents such as methylene chloride, chloroform, toluene, N, N-dimethylformamide, dioxane or tetrahydrofuran by activation of the acid functionality of the compound of formula XXXVa which is an acid halide such as an acid chloride at a temperature between 120 ° C In an activator such as N, N'-carbonyldiimidazole or N, N-dicyclohexylcarbodiimide, followed by addition of the appropriate amine or aniline HNR 2 R 3 . Method B (ii) In a compound of formula XLIIa, wherein X is N or CH and R d is a protecting group, the compound of formula I according to the invention, wherein Y is CONR 2 and R 2 is hydrogen or C 1 -C 6 alkyl, R 1 is hydrogen and X and R 3 are the same as in claim 1), by activation of the acid functional group of the compound of formula XLIIa or an acid halide such as an acid chloride at a temperature between 0 ° C. and 120 ° C., or by activation of methylene chloride, Activators such as N, N'-carbonyldiimidazole or N, N-dicyclohexylcarbodiimide in a suitable solvent such as chloroform, toluene, N, N-dimethylformamide, dioxane or tetrahydrofuran and then followed by addition of an appropriate amine or aniline HNR 2 R 3 and, then + trifluoroacetate at a temperature between 20 ℃ to + 60 ℃, such as methylene chloride or chloroform with a suitable acid such as acetic acid enemy It may be carried out by removing the protecting group R d by a solvent from a well-known method to those skilled in the art, such as hydrolysis. Method C A compound of formula (I) according to the invention in compounds of formula (XIIa) wherein X is N or CH and R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, wherein Y is NR 2 SO 2 and R 2 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl and X and R 3 are as in claim 1), for example triethyl amine at temperatures between -20 ° C and + 60 ° C. It may be carried out by reacting with a suitable activated sulfonic acid R 3 SO 2 L (where L is a leaving group such as, for example, halogen of chlorine) in a suitable solvent such as methylene chloride or chloroform with a suitable base such as trialkyl amine. Method D (i) Compounds of formula I according to the invention and obtained by process A (i) A (ii) or A (iii), wherein X is N or CH and Y is NR 2 CO and R 2 is hydrogen or C 1- C 6 alkyl, R 1 is hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl and X and R 3 are as in claim 1 (I a above )) according to the invention Reduction to a compound wherein Y is NR 2 CH 2 and X, R 1 , R 2 and R 3 are as in claim 1 (I b above ) is diethyl at a temperature between + 20 ° C. and reflux temperature. It may be carried out with a suitable reducing agent such as lithium aluminum hydride in a suitable solvent such as ether or tetrahydrofuran. Method D (ii) Compounds of formula (I) according to the invention and obtained by the processes B (i) and B (ii), wherein X is N or CH and Y is CONR 2 , R 2 is hydrogen or C 1 -C 6 alkyl, R 1 is hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl and X and R 3 are as defined in claim 1 (I c above ), wherein the compound of formula (I) according to the invention Is CH 2 NR 2 , and X, R 1 , R 2 and R 3 are the same as in claim 1 (I d ) above) diethyl ether or tetrahydrofuran at a temperature between + 20 ° C. and reflux temperature. In a suitable solvent such as lithium aluminum hydride. Method E A compound of formula XIIa, wherein X is N or CH and R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl and R 2 is hydrogen, or a compound of formula XIVa, wherein X is N or CH and R d is a protecting group and R 2 is hydrogen, or a compound of formula XLIIIa, wherein X is N or CH and R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl and R 2 is C The alkylation from 1 -C 6 alkyl to the compound of formula I according to the invention is R 3 CH 2 -L wherein L is an alkyl such as halogen or p-toluene sulfonyloxy group such as chlorine, bromine or iodine- Or a leaving group of the arylsulfonyloxy group). The reaction can be carried out in a suitable solvent such as N, N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran with a suitable base of trialkylamine such as K 2 CO 3 , NaHCO 3 , NaOH or triethylamine. . The reaction can be carried out at a temperature between + 20 ° C and + 120 ° C. If R 1 is R d , after alkylation, the protecting group R d is removed in a suitable solvent such as methylene chloride or chloroform with a suitable acid such as trifluoroacetic acid at a temperature between + 20 ° C. and + 60 ° C. Method F Compounds of formula (Ie) according to the invention and obtained by process A (ii), wherein X is N or CH and Y is NR 2 CO, R 2 is hydrogen or C 1 -C 6 alkyl and R 3 is as defined in claim 1 And compounds of formula If according to the invention in which Y is NR 2 CO, R 2 is hydrogen or C 1 -C 6 alkyl and R 1 is C 1 -C 6 alkyl and X and R 3 are claimed Alkylation to the same as in 1 is suitable such as R 1 -L where L is a suitable leaving group of an alkyl- or arylsulfonyloxy group such as a halogen or p-toluene sulfonyloxy group such as chlorine, bromine or iodine It can be performed with an alkylating agent. The reaction can be carried out in a suitable solvent such as N, N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran with a suitable base of trialkylamine such as K 2 CO 3 , NaHCO 3 , NaOH or triethylamine. . The reaction can be carried out at a temperature between + 20 ° C and + 120 ° C. Intermediate The invention also relates to novel intermediates, ie intermediates of the formula Wherein Z = NH 2 or COOH, X = CH or N and R 1 = H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl The invention is illustrated by, but not limited to, the following examples. Unless otherwise indicated, essential starting materials for all preparations and examples are purchased commercially. The present invention relates to 1,2,3,4 substituted piperidinyl or piperazinyl as (R) -enantiomers, (S) -enantiomers or racemates in the form of their free base or pharmaceutically acceptable salts. Novel compounds, tetrahydronaphthalene derivatives, methods for their preparation, pharmaceutical compositions containing said therapeutically active compounds and the use of said active compounds in therapy. It is an object of the present invention to provide compounds for therapeutic use, in particular compounds having a selective effect on a subgroup of 5-hydroxy-tryptamine receptors, designated 5-HT 1D -receptors in mammals, including humans. It is also an object of the present invention to provide compounds having a therapeutic effect after oral administration. <Example 1> (R) -2-N, N-dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene Potassium carbonate (53 g, 0.39 mol) in a solution of (R) -8-methoxy-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride (24 g, 0.11 mol) in acetonitrile (600 ml) , Potassium iodide (catalyst amount) and benzyl bromide (34 ml, 0.28 mol) are added. The reaction mixture is stirred at reflux for 35 hours. The precipitate is filtered off and the acetonitrile is removed in vacuo and the residue is partitioned between diethyl ether and water. The organic phase is separated, dried (Na 2 SO 4 ) and evaporated in vacuo and purified on silica gel column using hexane / ethyl acetate (3: 1) as eluent. Yield: 36 g (91%) of the title compound as a white solid: mp 105-107 ° C .; [α] 21 D + 124 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 357 (100, M + ) <Example 2> (S) -2-N, N-dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene Synthesis of the title compound is carried out according to the procedure of Example 1 using the (S) -form: mp 106-107 ° C .; [α] 21 D -118 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 357 (100, M + ) <Example 3> (R) -7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthol (R) -2-N, N-dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene (43 g, 0.12 mol) is dissolved in diethyl ether (800 ml) and the excess Ether HCl solution is added dropwise. The precipitate is filtered off and dried in vacuo to give a white solid. This crude product (42 g, 0.11 mol) is dissolved in anhydrous methylene chloride (1 L) and cooled to -60 ° C. To this solution was added dropwise anhydrous boron tribromide (16 ml, 0.15 mol) dissolved in methylene chloride (100 mL). The reaction temperature is brought to -5 ° C and maintained overnight. To the ice-cooled solution is added dropwise 2 M aqueous ammonium hydroxide solution and the mixture is extracted twice with methylene chloride. The combined organic phases are dried (Na 2 SO 4 ), filtered and the solvent is evaporated in vacuo to afford a crude residue. Chromatography on silica (eluent: methylene chloride) afforded 34 g (93% yield) of the title compound as a viscous colorless oil: [α] 21 D + 118 ° (c 1.5, chloroform); EIMS (70 eV) m / z (relative strength) 343 (53, M + ) <Example 4> (S) -7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthol Synthesis of the title compound is carried out according to the procedure of Example 3 using the (S) -form: [α] 21 D -116 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 343 (100, M + ) Example 5 (R) -2- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy) -2-methylpropanamide (R) -2-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthol (10 g, 29 mmol) was added sodium hydride (80% in oil, 0.96 g, 32 mmol) and dissolved in anhydrous dioxane (150 mL). 2-bromo-2-methylpropanamide (4.8 g, 29 mmol; Coutts, IGC, Southcott, disclosed in MRJ Chem. Soc. Perkin Trans. 1 1990, 767-770) was added and the reaction mixture was 100 for 2.5 hours. Heat at 캜. After cooling, the precipitated sodium bromide is filtered off, the filtrate is dried in vacuo and the residue is partitioned between water and methylene chloride. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated to afford a crude residue which is purified on a silica gel column using methylene chloride as eluent. Yield: 9.6 g (76%) of title compound as white crystals: mp 125-126 ° C .; [α] 21 D + 98 ° (c 1.1, chloroform); EIMS (70 eV) m / z (relative strength) 428 (13, M + ) <Example 6> (S) -2- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy) -2-methylpropanamide Synthesis of the title compound according to the procedure of Example 5 using (S) -form: mp 124-125 ° C .; [α] 21 D- 100 ° (c 0.52, chloroform); EIMS (70 eV) m / z (relative strength) 428 (4, M + ) <Example 7> (R) -N- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -2-hydroxy-2-methylpropanamide (R) -2- (in dry 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (10 mL) and dry N, N-dimethylformamide (100 mL) Sodium hydride (80% in oil, in a 7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy) -2-methylpropanamide (9.1 g, 21 mmol) solution 1.4 g, 47 mmol) is added and the reaction is heated at 130 ° C. for 8 h. The solution is poured into a mixture of ice and water and extracted three times with ethyl acetate. The combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Chromatography on silica (eluent: chloroform / ethanol saturated with NH 3 ; 100: 0.5) afforded 7.6 g (84% yield) of white crystals: mp 134-135 ° C .; [α] 21 D + 130 ° (c 1.1, chloroform); EIMS (70 eV) m / z (relative strength) 428 (1, M + ) <Example 8> (S) -N- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -2-hydroxy-2-methylpropanamide Synthesis of the title compound was carried out following the procedure of Example 7 using the (S) -form: mp 132-134 ° C .; [α] 21 D -132 ° (c 0.53, chloroform); EIMS (70 eV) m / z (relative strength) 428 (<1, M + ) Example 9 (R) -2-N, N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene (R) -N- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -2-methylpropionamide (7.4 g, 17 mmol) was added to ethanol (200 mL) and 20% aqueous HCl solution (300 mL) and heated to reflux for 8 hours. Ethanol is evaporated in vacuo and the remaining solution is washed twice with diethyl ether and cooled on an ice bath. After alkalizing with 45% aqueous sodium hydroxide solution, the mixture is extracted with methylene chloride. The combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Purification on a silica gel column using chloroform as eluent yields 3.8 g (76% yield) of the title compound as a light brown oil: [α] 21 D + 124 ° (c 0.9, chloroform); EIMS (70 eV) m / z (relative strength) 342 (92, M + ). <Example 10> (S) -2-N, N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene Synthesis of the title compound is carried out according to the procedure of Example 9 using the (S) -form: [α] 21 D -127 ° (c 0.53, chloroform); EIMS (70 eV) m / z (relative strength) 342 (89, M + ). <Example 11> (R) -1- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -4-N-methylpiperazine-2,6-dione 1,1-carbonyldiimidazole (6.0 g, 37 mmol) is added to a stirred suspension of methyliminodiiacetic acid (2.7 g, 18 mmol) in anhydrous tetrahydrofuran (250 mL). The reaction mixture is heated at reflux for 1.5 hours. (R) -2-N, N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene (5.7 g, 17 mmol) is then added and stirring at reflux is continued for 17 hours. 1,1'-carbonyldiimidazole (2.9 g, 18 mmol) is added and heating at reflux is continued for another 17 hours. The solvent is evaporated in vacuo and the crude product is purified on a silica gel column using chloroform / ethanol (100: 0.5) saturated with NH 3 as eluent. Yield: 6.6 g (87%) of the title compound as an oil: [α] 21 D + 90 ° (c 0.52, chloroform); EIMS (70 eV) m / z (relative strength) 453 (8, M + ). <Example 12> (R) -2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -1- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -4-methylpiperazine-2,6-dione (1.4 g, 3.1 mmol) is added to a suspension of lithium aluminum hydride (0.57 g, 15 mmol) in anhydrous diethyl ether (70 mL). The reaction mixture is heated at reflux for 7 hours. The reaction is quenched by addition of water (0.60 mL), 15% sodium hydroxide (0.60 mL) and again water (1.8 mL). The mixture is filtered, dried (Na 2 SO 4 ) and evaporated in vacuo. Purification on a silica gel column using chloroform / ethanol (100: 2) saturated with NH 3 as eluent gave 1.0 g (87% yield) of the title compound as a viscous oil: [α] 21 D + 53 ° (c 0.5 Chloroform); EIMS (70 eV) m / z (relative strength) 425 (2, M + ). Example 13 (S) -2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (S) -2-N, N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene (3.0 g, 8.8 mmol), potassium iodide (73 mg, 0.4 mmol) and N-methyl Bis (2-chloroethyl) amine hydrochloride (3.4 g, 17.6 mmol) is mixed with acetonitrile (100 mL) and water (17 mL) under nitrogen atmosphere. The mixture is refluxed for 7 hours. The temperature of the reaction mixture is allowed to come to room temperature before adding 2 M sodium hydroxide (20 mL). The solvent is removed in vacuo until approximately 70 mL is left. The residue is extracted twice with ethyl acetate. The organic layer is combined and dried (Na 2 SO 4 ). The solvent is removed in vacuo to give the crude product and purified on silica gel column using methylene chloride / ethanol / concentrated ammonium hydroxide (90: 9.5: 0.5) as eluent. Yield: g of the title compound II as an oil (53%): [α] 21 D −60 ° (c 1, MeOH); EIMS (70 eV) m / z (relative strength) 425 (0.2, M + ). <Example 14> (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (4.0 g, 9.4 in methanol (250 mL) mmol) solution is added ammonium formate (14 g, 56 mmol) and palladium (10%) on activated carbon (1.4 g). The mixture is refluxed for 3 hours and then palladium is filtered off. The solvent is evaporated in vacuo and the residue is partitioned between methylene chloride and 2M ammonium hydroxide solution. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (90: 9: 0.5) as eluent. . Yield: 1.9 g (83% yield) as oil: [α] 21 D -2.7 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 245 (5, M + ). Alternative: (R) -2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (1.0 g, 2.4 mmol) in acetic acid (70 mL) and palladium on activated carbon (100 mg) (10%) are added and the mixture is hydrogenated at 50-55 ° C. The catalyst is filtered off and the solvent is evaporated in vacuo. The residue is dissolved in water (20 mL) and cooled in an ice bath. After alkalizing with 2 M aqueous sodium hydroxide solution, the mixture is extracted twice with methylene chloride. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (90: 9: 0.5) as eluent yields 330 mg (57% yield) of the title compound. <Example 15> (S) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (S) -2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (0.8 g, 1.9 mmol), activated carbon ( 10%, 400 mg), ammonium formate (1.8 g, 28 mmol), methanol (25 mL) and water (10 mL) are mixed under nitrogen atmosphere. The mixture is refluxed for 7 hours. The temperature of the reaction mixture is allowed to come to room temperature before adding 2 M sodium hydroxide (20 mL). The solvent is removed in vacuo until approximately 70 mL is left. The residue is extracted twice with ethyl acetate. The organic layer is combined and dried (Na 2 SO 4 ). Removal of the solvent in vacuo afforded 0.35 g (75% yield) of the title compound as an oil: [α] 21 D -22 ° (c 1, MeOH); EIMS (70 eV) m / z (relative strength) 245 (5, M + ). <Example 16> (R) -2-N, N-dibenzylamino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene (9.8 g, 39 mmol) and bis (2-chloroethyl) amine hydrochloride (5.5 g, 32 mmol) is dissolved in butanol (80 mL). The reaction mixture is stirred at 100 ° C. and after 65 hours the mixture is filtered and the solvent is evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent yields 6.0 g (51% yield) of the title compound as a viscous oil: [α] 21 D + 72 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 411 (2, M + ). <Example 17> (R) -2-amino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (5.5 g, 13 mmol) in methanol (400 mL) Ammonium formicate (20 g, 0.32 mol) and palladium on activated carbon (10%, 1.9 g) are added. The mixture is refluxed for 1 hour and the palladium is then filtered off. The solvent is zual in vacuo and the residue is partitioned between methylene chloride and 2 M ammonium hydroxide solution. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using chloroform / ethanol / concentrated ammonium hydroxide (80: 20: 2.5) as eluent. Yield: 2.4 g (76%) of the title compound as an oil: [α] 21 D + 9.9 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 231 (24, M + ). Example 18 t-butyl (R) -4- (7-amino-5,6,7,8-tetrahydro-1-naphthyl) piperazine-1-carboxylate (R) -2-N, N-amino-8-amino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (1.5 g, 6.5 in methylene chloride (400 mL) mmol) and triethylamine (1.0 mL, 7.5 mmol) were added dropwise to di-t-butyl dicarbonate (1.5 mL, 6.5 mmol) in methylene chloride (50 mL). After addition the reaction is stirred at ambient temperature for 1 hour and then washed with dilute aqueous sodium hydrocarbon solution. The methylene chloride phase was dried (Na 2 SO 4 ), filtered and evaporated in vacuo and the crude product was purified on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent to give a colorless viscous oil. Obtain 1.0 g (45% yield) of the title compound as follows: [α] 21 D + 34 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 331 (100, M + ). Example 19 (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethyl in methylene chloride (25 mL) To an ice cold solution of amine (110 μL, 0.82 mmol) is added acetyl chloride (31 μL, 0.43 mmol) in methylene chloride (10 mL). After addition, the reaction is brought to room temperature and then washed with water. The phases are separated, the combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo to give the crude product, which is a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 4: 0.5) as eluent. Phase is purified. Yield: 110 mg (90%) of the title compound as an oil. Crystallization from ethyl acetate / hexanes gave 52 mg of white crystals: mp 152-154 ° C .; [α] 21 D + 66 ° (c 0.13, chloroform); EIMS (70 eV) m / z (relative strength) 289 (9, M + ). Example 20 (R) -N- [8- (piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide T-butyl (R) -4- (7-amino-5,6,7,8-tetrahydro-1-naphthyl) piperazine-1-carboxylate (120 mg, 0.36) in methylene chloride (30 mL) mmol) and triethylamine (110 μL, 0.72 mmol) were added dropwise to acetyl chloride (26 μL, 0.36 mmol) in methylene chloride (5 mL). After addition, the reaction is stirred at ambient temperature for 20 minutes and washed with water. The methylene chloride phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo and the crude product is purified on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent to give a viscous oil 130 Obtain mg (92% yield): EIMS (70 eV) m / z (relative strength) 373 (40, M + ). The oil is dissolved in methylene chloride (25 mL) and trifluoroacetic acid (1.0 mL) is added without further properties. The reaction is stirred at ambient temperature for 7 hours, water is added and the mixture is cooled on an ice bath. After alkalizing with 2 M aqueous sodium hydroxide solution, the mixture is extracted twice with methylene chloride. The combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as the crude eluate gave 60 mg of the title compound as a viscous oil (t-butyl (R) -4- (7-amino-5, 61% yield from 6,7,8-tetrahydro-1-naphthyl) piperazine-1-carboxylate) is obtained: [α] 21 D + 31 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 273 (100, M + ). Example 21 (R) -N- [8- (4-ethylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide (R) -N- [8- (piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide (100 mg, 0.37 mmol) in acetone (20 mL), To a mixture of potassium carbonate (76 mg, 0.54 mmol) and potassium iodide (15 mg, 0.10 mmol) is added ethyl bromide (56 μL, 0.74 mmol) and the mixture is stirred vigorously overnight. The reaction is filtered and the solvent is evaporated in vacuo. The residue is purified on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent. The title compound, which is an oil, is obtained and crystallized from ethyl acetate / hexanes. Yield: 55 mg (50%) of white crystals: mp 142-143 ° C .; [α] 21 D + 27 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 301 (100, M + ). <Example 22> (R) -2-N, N-dibenzylamino-8- (4-propylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (200 mg, 0.49 mmol) in acetone (15 mL) and To a mixture of potassium carbonate (100 mg, 0.74 mmol) was added propyl iodide (72 μL, 0.74 mmol) and the reaction mixture was stirred vigorously at 50 ° C. overnight, filtered and the solvent was evaporated in vacuo. The residue is purified on a silica gel column using ethanol (100: 1) saturated with chloroform / NH 3 as eluent. 180 mg of the title compound as an oil is obtained: EIMS (70 eV) m / z (relative strength) 453 (5, M + ). <Example 23> (R) -2-amino-8- (4-propylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (4-propylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (180 mg, 0.4 in methanol) mmol) solution is added ammonium formate (0.60 g, 2.4 mmol) and palladium on activated carbon (10%, 60 mg). The mixture is refluxed for 2 hours and then palladium is filtered off. The solvent is evaporated in vacuo and the residue is partitioned between methylene chloride and 2 M ammonium hydroxide solution. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the title compound as an oil. Yield: 85 mg (78%): EIMS (70 eV) m / z (relative strength) 273 (4, M + ). <Example 24> (R) -N- [8- (4-propylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide (R) -2-amino-8- (4-propylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (85 mg, 0.31 mmol) and triethyl in methylene chloride (15 mL) To an ice cold solution of amine (38 μL, 0.37 mmol) is added dropwise acetyl chloride (23 μL, 0.31 mmol) in methylene chloride (5 mL). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The methylene chloride phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The residue is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. 91 mg (93% yield) of the title compound as an oil are obtained and crystallized from ethyl acetate / hexanes. Yield: 61 mg (62%) as white crystals: mp 139-140 ° C .; [α] 21 D + 26 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 315 (78, M + ). <Example 25> (R) -2-N, N-dibenzylamino-8- (4-butylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (300 mg, 0.73 mmol in N, N-dimethylformamide (25 mL) ), Butyl bromide (130 mg, 0.95 mmol) is added to a mixture of potassium carbonate (150 mg, 1.1 mmol) and potassium iodide (catalyst amount) and the reaction mixture is stirred vigorously overnight at 60 ° C. The reaction is filtered and the solvent is evaporated in vacuo. The residue is purified on a silica gel column using ethanol (100: 1) saturated with chloroform / NH 3 as eluent. 300 mg (86% yield) of the title compound as an oil are obtained: [α] 21 D + 68 ° (c 0.72, chloroform); EIMS (70 eV) m / z (relative strength) 467 (5, M + ). Example 26 (R) -2-amino-8- (4-butylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (butylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (300 mg, 0.63 mmol) in methanol (20 mL) Is added ammonium formicate (0.95 g, 3.8 mmol) and palladium on activated carbon (10%, 90 mg). The mixture is refluxed for 2 hours and the palladium is then filtered off. The solvent is evaporated in vacuo and the residue is partitioned between methylene chloride and 2 M aqueous ammonium hydroxide solution. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the title compound. Yield: 100 mg (56%): [α] 21 D -4.6 ° (c 1.3, chloroform); EIMS (70 eV) m / z (relative strength) 287 (10, M + ). Example 27 (R) -N- [8- (4-butylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide (R) -2-amino-8- (4-butylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (100 mg, 0.35 mmol) and triethyl in methylene chloride (25 mL) To an ice cold solution of amine (53 μL, 0.53 mmol) is added dropwise acetyl chloride (25 μL, 0.35 mmol) in methylene chloride (10 mL). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The methylene chloride phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The residue is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. After crystallization from diethyl ether, 100 mg (89% yield) of the title compound as white crystals are obtained: mp 118-120 ° C .; [α] 21 D + 25 ° (c 0.54, chloroform); EIMS (70 eV) m / z (relative strength) 329 (41, M + ). <Example 28> (R) -2-N, N-dibenzylamino-8- (4-pentylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (500) in N, N-dimethylformamide (30 mL) mg, 1.2 mmol), pentyl bromide (220 mg, 1.5 mmol) was added to a mixture of potassium carbonate (250 mg, 1.8 mmol) and potassium iodide (catalyst amount), and the reaction mixture was stirred vigorously at 60 ° C. overnight, filtered and solvent Is evaporated in vacuo. The residue is purified on a silica gel column using ethanol (100: 1) saturated with chloroform / NH 3 as eluent. 46 g (79% yield) of the title compound as an oil are obtained: [α] 21 D + 55.4 ° (c 1.1, chloroform); EIMS (70 eV) m / z (relative strength) 481 (3, M + ). <Example 29> (R) -2-amino-8- (4-pentylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (4-pentylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (450 mg, 0.94 in methanol (20 mL) mmol) is added ammonium formate (1.4 g, 5.6 mmol) and palladium on activated carbon (10%, 0.14 g). The mixture is refluxed for 2 hours and the palladium is then filtered off. The solvent is evaporated in vacuo and the residue is partitioned between methylene chloride and 2 M aqueous ammonium hydroxide solution. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the title compound as an oil. Yield: 180 mg (64%): [α] 21 D -3.7 ° (c 0.57, chloroform); EIMS (70 eV) m / z (relative strength) 301 (47, M + ). <Example 30> (R) -N- [8- (4-pentylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide (R) -2-amino-8- (4-pentylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (170 mg, 0.57 mmol) and triethyl in methylene chloride (30 mL) To an ice cold solution of amine (86 μL, 0.86 mmol) is added dropwise acetyl chloride (41 μL, 0.57 mmol) in methylene chloride (10 mL). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The methylene chloride phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The residue is crystallized from ether / hexanes. 120 mg (62% yield) of the title compound as white crystals are obtained: mp 119-120 ° C .; [α] 21 D + 25 ° (c 0.97, chloroform); EIMS (70 eV) m / z (relative strength) 343 (49, M + ). <Example 31> (R) -2-N, N-dibenzylamino-8- (4-hexylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (4-hexylpiperazin-1-yl) -1,2,3,4-tetra in N, N-dimethylformamide (25 mL) Hexyl bromide (320 μg, 2.3 mmol) is added to a mixture of hydronaphthalene (440 mg, 1.1 mmol), potassium carbonate (220 mg, 1.8 mmol) and potassium iodide (catalyst amount) and the reaction mixture is vigorously stirred at 60 ° C. overnight. The reaction is filtered and the solvent is evaporated in vacuo. The residue is purified on a silica gel column using ethanol (100: 1) saturated with chloroform / NH 3 as eluent. 460 mg (79% yield) of the title compound as an oil are obtained: [α] 21 D + 37 ° (c 1.2, chloroform); EIMS (70 eV) m / z (relative strength) 495 (3, M + ). <Example 32> (R) -2-amino-8- (4-hexylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (4-hexylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (300 mg, in methanol (30 mL) 0.60 mmol) is added ammonium formate (0.90 g, 3.6 mmol) and palladium on activated carbon (10%, 90 mg). The mixture is refluxed for 2 hours and the palladium is then filtered off. The solvent is evaporated in vacuo and the residue is partitioned between methylene chloride and 2 M aqueous ammonium hydroxide solution. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the title compound as an oil. Yield: 130 mg (68%): [α] 21 D -2.3 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 315 (91, M + ). <Example 33> (R) -N- [8- (4-hexylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide (R) -2-amino-8- (4-hexylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (97 mg, 0.31 mmol) and methylene chloride (15 mL) To an ice cold solution of ethylamine (51 μL, 0.37 mmol) is added dropwise acetyl chloride (23 μL, 0.32 mmol) in methylene chloride (5 mL). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The methylene chloride phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The residue is purified on silica gel using ethanol saturated with chloroform / NH 3 as eluent. After crystallization from diethyl ether / hexane, 92 mg (83% yield) of the title compound as white crystals are obtained: mp 117-118 ° C .; [α] 21 D + 19 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 357 (43, M + ). <Example 34> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] trifluoroacetamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol), pyridine in methylene chloride (10 mL) 100 μL, 1.2 mmol) and trifluoroacetic anhydride (72 μL, 0.51 mmol) were added dropwise to an ice cold solution of 4-dimethylaminopyridine (20 mg, 0.16 mmol). After addition, the reaction is stirred at ambient temperature for 1 hour and then washed with water. The methylene chloride phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The residue is purified on silica gel using acetate / methanol / concentrated ammonium hydroxide (96: 4: 0.5) as eluent. After crystallization from diethyl ether / hexane, 41 mg (24% yield) of the title compound as white crystals are obtained: mp 158-159 ° C .; [α] 21 D + 39 ° (c 0.25, chloroform); EIMS (70 eV) m / z (relative strength) 341 (82, M + ). <Example 35> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] methanesulfonamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) and triatylamine in pyridine (15 mL) Methanesulfonyl chloride (62 μL, 0.54 mmol) is added dropwise to (0.50 mL, 3.6 mmol) ice-cold solution. After addition, the reaction is stirred at ambient temperature for 1 hour. The solvent is evaporated in vacuo and the residue is purified on silica gel using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent. After crystallization from diethyl ether, 100 mg (63% yield) of the title compound as white crystals are obtained: mp 135-137 ° C .; [α] 21 D + 22 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 323 (59, M + ). <Example 36> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -cyclohexanecarboxamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethyl in methylene chloride (20 mL) To an ice cold solution of amine (92 μL, 0.66 mmol) is added dropwise cyclohexanecarbonyl chloride (67 μL, 0.46 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 10 minutes and then washed with dilute aqueous sodium hydrocarbon solution. The organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo and the residue is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / ethanol / NH 3 as eluent. 71 mg (45% yield) of the title compound as white crystals are obtained: mp 183-184 ° C .; [α] 21 D + 12 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 355 (56, M + ). <Example 37> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] butanamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (300 mg, 1.2 mmol) and triethyl in methylene chloride (50 mL) To an ice cold solution of amine (260 μL, 1.8 mmol) is added dropwise butyryl chloride (140 μL, 1.3 mmol) in methylene chloride (10 mL). After addition, the reaction is stirred for 1 hour at room temperature and then washed with dilute sodium hydrogen carbonate. The phases are separated, the combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo to give the crude product, which is a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 4: 0.5) as eluent. Phase is purified. Yield: 330 mg (86%) of the title compound as white crystals. mp 131-132 ° C; [α] 21 D + 24 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 315 (39, M + ). <Example 38> (R) -2-N-butylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] butanamide (290) in anhydrous diethyl ether (35 mL) mg, 0.92 mmol) is added lithium aluminum hydride (100 mg, 2.8 mmol). The reaction mixture is stirred at reflux for 7 hours, then cooled and quenched by addition of water (100 μL), 15% aqueous sodium hydroxide solution (100 μL) and again water (530 μL). The mixture is filtered, dried (Na 2 SO 4 ) and evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 170 mg (63% yield) of the title compound as a viscous oil: [α] 21 D + 3.1 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 301 (52, M + ). Oxalate is precipitated from diethyl ether with 70 mg base. The crude salt is recrystallized from anhydrous ethanol and 77 mg (69% yield) of white crystals are isolated: mp 167-168 ° C. <Example 39> (R) -N-butyl-N- [8- (4-hexylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide (R) -2-N-butylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (91 mg, 0.30 mmol) in methylene chloride (15 mL) And acetyl chloride (23 μL, 0.36 mmol) in methylene chloride (5 mL) is added dropwise to an ice cold solution of triethylamine (50 μL, 0.36 mmol). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The methylene chloride phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Purification on silica gel using chloroform / methanol / concentrated ammonium hydroxide as eluent yields 99 mg (96% yield) of the title compound as a viscous oil. [α] 21 D + 14 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 343 (30, M + ). Oxalate is precipitated from diethyl ether and the crude salt is recrystallized from anhydrous ethanol / diethylether and 97 mg (73% yield) of white crystals are isolated: mp 153-154 ° C. <Example 40> (R) -2-N-methylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (250 mg, 1.0 mmol) and tri in 1,4-dioxane anhydride Ethyl chloromate (110 μL, 1.2 mmol) is added dropwise to a solution of ethylamine (210 μL, 1.5 mmol) and the reaction is stirred at room temperature for 15 minutes. The pale yellow, cloudy solution is evaporated in vacuo and the residue is partitioned between chloroform and water. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is dissolved in diethyl ether (30 mL) and a small amount of tetrahydrofuran (8.0 mL). Lithium aluminum hydride (230 mg, 6.3 mmol) was added and the reaction mixture was heated to reflux for 20 hours, cooled and then water (240 μL), 15% aqueous sodium hydroxide solution (240 μL) and again water (720 μL) Quench with. The mixture is filtered, dried (Na 2 SO 4 ) and evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 120 mg (47% yield) of the title compound as a viscous oil: [α] 21 D + 20 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 259 (64, M + ). <Example 41> (R) -N-methyl-N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide (R) -2-N-methylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (85 mg, 0.33 mmol) in methylene chloride (20 mL) And acetyl chloride (25 μL, 0.35 mmol) in methylene chloride (5 mL) was added dropwise to an ice cold solution of triethylamine (55 μL, 0.4 mmol). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases were separated and the combined organic phases were dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which was purified on silica gel using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent. do. Yield: 61 mg (66%) of the title compound as an oil: [α] 21 D + 54 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 301 (18, M + ). <Example 42> (R) -2-N-isopropylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-amino-8- (methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (200 mg, 0.81 mmol) is dissolved in methanol (5.0 ml). Adjust the pH to 6 with acetic acid and add sodium cyanoborohydride (66 mg, 1.1 mmol). After 3 hours the solvent is evaporated in vacuo at ambient temperature and the residue is partitioned between chloroform and water. The water phase is alkalized with 2 M aqueous sodium hydroxide solution and the phases are separated. The organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Chromatography on silica (eluent: chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5)) yields 110 mg (47% yield) of the title compound as a viscous clear oil: [α] 21 D + 3 ° (c 1.0) Chloroform); EIMS (70 eV) m / z (relative strength) 287 (23, M + ). <Example 43> (R) -N-isopropyl-N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide (R) -2-N-isopropylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (110 mg, 0.38 mmol in methylene chloride (20 mL) ) And acetyl chloride (31 μL, 0.40 mol) in methylene chloride (5 mL) are added dropwise to an ice cold solution of triethylamine (63 μL, 0.46 mmol). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on silica gel using chloroform / methanol / concentrated ammonium hydroxide as eluent. Yield: 120 mg (92%) of the title compound as an oil. [α] 21 D -24 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 329 (31, M + ). Oxalate is precipitated from diethyl ether and the crude salt is recrystallized from anhydrous ethanol / diethylether and 85 mg (48% yield) of white crystals are isolated: mp 181-183 ° C. <Example 44> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -1,1'-biphenyl-4-carbox amides (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethyl in methylene chloride (20 mL) To an ice cold solution of amine (62 μL, 0.45 mmol) is added dropwise 4-biphenylcarbonyl chloride (89 mg, 0.41 mol) in methylene chloride (5 mL). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on silica gel using ethanol saturated with chloroform / NH 3 as eluent. Yield: 100 mg (59%) of the title compound as white crystals: mp 232-233 ° C .; EIMS (70 eV) m / z (relative strength) 425 (11, M + ). <Example 45> (R) -8- (4-methylpiperazin-1-yl) -2-N- (4-phenyl) benzylamino-1,2,3,4-tetrahydronaphthalene (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2 in anhydrous diethyl ether (75 mL) and tetrahydrofuran (8 mL) To a solution of -naphthyl] -1,1'-biphenyl-4-carboxamide (210 mg, 0.49 mmol) is added lithium aluminum hydride (95 mg, 2.5 mmol). The reaction mixture is stirred at reflux for 4 hours, cooled and then quenched by addition of water (95 μL), 15% aqueous sodium hydroxide solution (95 μL) and again water (290 μL). The mixture is filtered, dried (Na 2 SO 4 ) and evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 4: 0.5) as eluent gave 180 mg (87% yield) of the title compound as a viscous oil: [α] 21 D + 15 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 411 (7, M + ). Example 46 (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -2-phenylthiazole-4-carboxamide To a solution of 4-carboxy-2-phenylthiazole (88 mg, 0.43 mmol) in anhydrous N, N-dimethylformamide (25 mL) was added 1,1'-carbonyldiimidazole (73 mg, 0.45 mmol). The reaction is heated at 75 ° C. When carbon dioxide release ceased (after 30 minutes), the reaction was cooled to room temperature and (R) -2-amino-8- (4-methylpiperazin-1-yl in anhydrous N, N-dimethylformamide (5 mL) ) -1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) solution is added. The reaction is stirred for 17 hours at ambient temperature and the solvent is evaporated in vacuo. Purification on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent gave 99 mg (56% yield) of the title compound as white crystals: mp 175-176 ° C .; [α] 21 D −85 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 432 (6, M + ). <Example 47> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -2- (4-pyridyl) thiazole-4 Carboxamide 1,1'-carbonyldiimidazole (73 mg, 0.45) in a solution of 4-carboxy-2 (4-pyridyl) thiazole (89 mg, 0.43 mmol) in anhydrous N, N-dimethylformamide (25 mL) mmol) is added and the reaction is heated at 75 ° C. The carbon dioxide release stopped (after 30 minutes), the reaction was cooled to room temperature and (R) -2-amino-8- (4-methylpiperazin-1-yl) in anhydrous N, N-dimethylformamide (5 mL) A solution of -1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) is added. The reaction is stirred for 17 hours at ambient temperature and the solvent is evaporated in vacuo. Purification on silica gel using ethanol (100: 3) saturated with chloroform / NH 3 as eluent gave 110 mg (61% yield) of the title compound as white crystals: mp 187-188 ° C .; [α] 21 D -82 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 433 (2, M + ). <Example 48> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] benzamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (210 mg, 0.86 mmol) and triethyl in methylene chloride (30 mL) To an ice cold solution of amine (180 μL, 1.28 mmol) is added dropwise benzoyl chloride (130 mL, 0.90 mmol) in methylene chloride (5 mL). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on silica gel using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. . Yield: 250 mg (84%) of the title compound as white crystals: mp 195-196 ° C .; [α] 21 D −31 ° (c 1.0, CHCL 3 ); EIMS (70 eV) m / z (relative strength) 349 (53, M + ). <Example 49> (R) -N- [8- (methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-methoxybenzamide (R) -2- [8- (methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthalene (130 mg, 0.53 mmol) and triethyl in methylene chloride (30 mL) To a ice cold solution of amine (110 μL, 0.80 mmol) is added dropwise 4-methoxybenzoyl chloride (95 mg, 0.56 mmol). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on silica gel using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. . Yield: 143 mg (71%) of the title compound as white crystals: mp 186-187 ° C .; [α] 21 D −52 ° (c 0.50, CHCL 3 ); EIMS (70 eV) m / z (relative strength) 379 (23, M + ). <Example 50> (R) -N- [8- (methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-cyanobenzamide (R) -2-amino-8- (methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine in methylene chloride (25 mL) ( To 110 μL, 0.80 mmol) of ice-cold solution, dropwise add 4-chloro cyanobenzoyl chloride (92 mg, 0.56 mmol) in methylene chloride (5 mL). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on silica gel using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. . Yield: 120 mg (61%) of the title compound as white crystals: mp 184-186 ° C .; [α] 21 D −47 ° (c 1.0, CHCL 3 ); EIMS (70 eV) m / z (relative strength) 374 (54, M + ). <Example 51> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylsulfonyloxybenzamide 4-carboxyphenyl trifluoromethanesulfonate (0.40 g, 1.5 mmol; Looker, JH; Hays, CH; Thatcher, described in DNJAm. Chem. Soc. 1957, 79, 741-4) thionyl chloride (10 mL) and heat at 40 ° C. for 45 minutes. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (280 mg, 0.96 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (20 mL). Dissolve in an ice cold solution of 2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylamine (96 μL, 0.69 mmol). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases were separated and the combined organic phases were dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which was purified on silica gel using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. do. Yield: 100 mg (44%) of the title compound as white crystals: mp 178-180 ° C .; [α] 21 D −31 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 497 (17, M + ). <Example 52> (R) -N- [8- (4-t-butyloxycarbonylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide 4-morpholinobenzoic acid (0.59 g, 2.8 mmol; Degutis, J .; Rasteikiene, A. Zh. Org.Khim. 1978, 14 (10), 2060- in anhydrous N, N-dimethylformamide (30 mL) 1,1'-carbonyldiimidazole (0.48 g, 3.0 mmol) is added to the solution and the reaction is heated at 75 ° C. When carbon dioxide emission stopped (after 30 minutes), the reaction was cooled to room temperature and t-butyl (R) -4- (7-amino-5,6,7, in anhydrous N, N-dimethylformamide (15 mL) A solution of 8-tetrahydro-1-naphthyl) piperazine-1-carboxylate (0.90 g, 2.7 mmol) is added. The reaction is stirred at ambient temperature for 24 hours and the solvent is evaporated in vacuo. Purification on silica gel using ethanol (100: 2) saturated with chloroform / NH 3 as eluent gave 1.5 g (84% yield) of the title compound as a dark red viscous oil: [α] 21 D -45 ° (c 0.50) Chloroform); EIMS (70 eV) m / z (relative strength) 520 (5, M + ). <Example 53> (R) -N- [8- (piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (R) -N- [8- (4-t-butyloxycarbonylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl]-in methylene chloride (100 mL) Dissolve trifluoroacetic acid (3 mL) in 4-morpholinophenylcarboxamide (1.0 g, 2 mmol) ice-cold solution. The reaction is stirred at ambient temperature for 7 hours. The solvent is evaporated in vacuo and the residue is dissolved in water (20 mL), alkalized with 2 M aqueous sodium hydroxide solution and extracted twice with methylene chloride. The phases are separated and the combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 580 mg (70% yield) of the title compound as white crystals: mp 202-203 ° C .: [α] 21 D- 56 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 420 (5, M + ). <Example 54> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide 4-morpholinobenzoic acid (0.89 g, 4.3 mmol; Degutis, J .; Rasteikiene, L.; Degutiene, A. Zh. Org.Khim. 1978, 14 in anhydrous N, N-dimethylformamide (30 mL) 10), described in 2060-2064) 1,1'-carbonyldiimidazole (0.73 g, 4.3 mmol) is added and the reaction is heated at 75 ° C. When carbon dioxide release ceased (after 30 minutes), the reaction was cooled to room temperature and (R) -2-amino-8- (4-methylpiperazin-1-yl in anhydrous N, N-dimethylformamide (5 mL) ) -1,2,3,4-tetrahydronaphthalene (1.0 g, 4.1 mmol) solution is added. The reaction is stirred at ambient temperature for 24 hours and the solvent is evaporated in vacuo. Purification on silica gel using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 1.5 g (85% yield) of the title compound as white crystals: mp 230-231 ° C .; [α] 21 D −49 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 434 (10, M + ). <Example 55> (S) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide The title compound is synthesized following the procedure of Example 54 using the (S) -form: mp 228-230 ° C .; [α] 21 D + 35 ° (c 1, MeOH); EIMS (70 eV) m / z (relative strength) 434 (1, M + ). <Example 56> (R) -N- [8- (4-ethylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (R) -N- [8- (piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (90 mL) in acetone (20 mL) (90) To a solution of mg, 0.21 mmol) potassium carbonate (44 mg, 0.32 mmol) and iodoethane (26 μL, 0.32 mmol) are added and the reaction is stirred at ambient temperature for 48 hours. The reaction mixture is filtered and the solvent is evaporated in vacuo. The residue is partitioned between methylene chloride and water, the phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Purification on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent gave 63 mg (66% yield) of the title compound as white crystals: [α] 21 D -67 ° (c 1.0). Chloroform); EIMS (70 eV) m / z (relative strength) 448 (21, M + ). <Example 57> (R) -N- [8- (4-propylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (R) -N-8- (piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (120 mg) in acetone (20 mL) , 0.29 mmol) was added potassium carbonate (59 mg, 0.43 mmol) and 1-iodopropane (42 μL, 0.43 mmol) and the reaction was stirred at ambient temperature for 4 days. The reaction mixture is filtered and the solvent is evaporated in vacuo. The residue is partitioned between methylene chloride and water, the phases are separated and the organic phase is dried (Na 2 SO 4 ) and evaporated in vacuo. Purification on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent gave 58 mg (44% yield) of the title compound as an amorphous solid. Crystallization from ethyl acetate / diethyl ether gave 11 mg (8% yield) of white crystals: mp 183-185 ° C .; [α] 21 D −60 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 462 (25, M + ). <Example 58> (R) -8- (4-methylpiperazin-1-yl) -2- [N- (4-morpholino) benzylamino] -1,2,3,4-tetrahydronaphthalene (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morph in anhydrous tetrahydrofuran (25 mL) To a solution of polynovenzamide (200 mg, 0.46 mmol) is added lithium ammonium hydride (200 mg, 5.3 mmol). The reaction mixture is stirred at reflux for 15 minutes, then cooled and quenched by addition of water (200 μL), 15% aqueous sodium hydroxide solution (200 μL) and water (600 μL) again. The mixture is filtered, dried (Na 2 SO 4 ) and evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 61 mg (32% yield) of the title compound as a white solid: [α] 21 D + 19 ° (c). 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 420 (8, M + ). <Example 59> 3-methyl-4-morpholinobenzonitrile Morpholine (15 g, 15 g, in a solution of 4-bromo-3-methylbenzonitrile (11 mg, 56 mmol) and potassium fluoride (3.3 g, 56 mmol) in anhydrous N, N-dimethylformamide (150 mL) 170 mmol) is added and the reaction is heated at 145 ° C. for 4 days. The solvent is evaporated in vacuo and the residue is partitioned between diethyl ether and water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Purification on a silica gel column using toluene and then chloroform as eluent gave 1.3 g (11%) of the title compound as white crystals: mp 85-86 ° C .; EIMS (70 eV) m / z (relative strength) 202 (71, M + ). <Example 60> 3-Methyl-4-morpholinobenzoic acid To a solution of 3-methyl-4-morpholinobenzonitrile (1.0 g, 4.9 mmol) in glacial acetic acid (10 mL) is added 20% aqueous hydrochloric acid solution (60 ml) and the reaction is heated at reflux for 35 hours. Acetic acid is evaporated in vacuo and the remaining aqueous solution is alkalized to pH 8 with 2 M aqueous sodium hydroxide solution. The solution is washed twice with chloroform and the water phase is adjusted to pH 4 with 2M aqueous hydrochloric acid solution. The product was filtered off and dried in vacuo to yield 1.0 g (91% yield) of the title compound as white crystals: mp 220-221 ° C .; EIMS (70 eV) m / z (relative strength) 221 (100, M + ). <Example 61> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-methyl-4-morpholinobenzamide To a solution of 3-methyl-4-morpholinobenzoic acid (110 mg, 0.51 mmol) in anhydrous N, N-dimethylformamide (10 mL) was added 1,1'-carbonyldiimidazole (87 mg, 0.54 mmol). And the reaction is heated at 75 ° C. When carbon dioxide release ceased (after 30 minutes), the reaction was cooled to room temperature and (R) -2-amino-8- (4-methylpiperazin-1-yl in anhydrous N, N-dimethylformamide (5 mL) ) -1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) solution is added. The reaction is stirred at ambient temperature for 15 hours and the solvent is evaporated in vacuo. Purification on a silica gel column using ethanol (100: 2) saturated with chloroform / NH 3 as eluent gave 110 mg (50% yield) of the title compound as white crystals: mp 172-175 ° C .; [α] 21 D −47 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 448 (5, M + ). <Example 62> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-piperidinobenzamide 4-piperidinobenzoic acid (88 mg, 0.43 mmol; Weringa, WD; Janssen, MJ Recl. Chim. Pays-Bas 1968, 87 (12), 1372-1380 in anhydrous N, N-dimethylformamide (5 mL) 1,1'-carbonyldiimidazole (73 mg, 0.45 mmol) is added to the solution and the reaction is heated at 75 ° C. When carbon dioxide release ceased (after 30 minutes), the reaction was cooled to room temperature and (R) -2-amino-8- (4-methylpiperazin-1-yl in anhydrous N, N-dimethylformamide (5 mL) ) -1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) solution is added. The reaction is stirred for 17 hours at ambient temperature and the solvent is evaporated in vacuo. Purification on a silica gel column using ethanol (100: 2) saturated with chloroform / NH 3 as eluent gave 75 mg (42% yield) of the title compound as white crystals: mp 196-198 ° C .; [α] 21 D -63 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 432 (2, M + ). <Example 63> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-cyclohexylbenzamide 4-cyclohexylbenzoic acid (0.50 g, 2.4 mmol) is dissolved in thionyl chloride (20 mL) and heated at reflux for 30 minutes. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (96 mg, 0.43 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (20 mL) -1 To an ice cold solution of 2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (62 μL, 0.45 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases were separated and the combined organic phases were dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product using a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent. Phase is purified. Yield: 150 mg (85%) of the title compound as white crystals: mp 224-226 ° C .; [α] 21 D −43 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 431 (2, M + ). <Example 64> (S) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-N, N-diethylaminobenzamide 4- (diethylamino) benzoic acid (94 mg, 0.5 mmol) and 1,1'-carbonyldiimidazole (86 mg, 0.5 mmol) were dissolved in N, N-dimethylformamide (4 mL) under nitrogen atmosphere. And stirred at 70 ° C. for 30 minutes. (S) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (0.1) dissolved in N, N-dimethylformamide (4 mL) g, 0.4 mmol), before the reaction mixture is brought to room temperature. The mixture is diluted with ethyl acetate, stirred at room temperature for 10 days before being washed with 2 M ammonia and dried (MgSO 4 ). The solvent is removed in vacuo to give a residue, which is purified by flash chromatography on silica gel with methylene chloride / ethyl acetate 20: 1 (containing 0.5% ammonia) as eluent. Yield 40 mg (23%): mp 168-170 ° C. (dec); [α] 21 D + 25 ° (c 0.25, MeOH); EIMS (70 eV) m / z (relative strength) 420 (13, M + ). <Example 65> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (110 mg, 0.44 mmol) and triethyl in methylene chloride (20 mL) To an ice cold solution of amine (91 μL, 0.66 mmol) is added dropwise 4- (trifluoromethyl) benzoyl (96 mg, 0.46 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute sodium sodium hydroxide. The phases were separated and the combined organic phases were dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product on silica gel column using ethanol (100: 2) saturated with chloroform / NH 3 as eluent. Purify. Yield: 150 mg (81%) of the title compound as white crystals: mp 203-204 ° C .: [α] 21 D −20 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 417 (10, M + ). Example 66 (S) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide The title compound is synthesized following the procedure of Example 65 using (S) -form: mp 202-204 ° C .: [α] 21 D -13 ° (c 1, MeOH); EIMS (70 eV) m / z (relative strength) 417 (5, M + ). <Example 67> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-methylsulfonyloxybenzamide 4-methylsulfonyloxybenzoic acid in thionyl chloride (10 mL) (0.60 g, 2.8 mmol; Looker, JH; Hays, CH; Thatcher, DNJ Am. Chem. Soc. 1957, 79, 741-4) The suspension of is heated at reflux for 30 minutes (mixture is homogenized). More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (110 mg, 0.47 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (20 mL). To an ice cold solution of 2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (94 μL, 0.68 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate solution. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. . Yield: 160 mg (78%) of the title compound as white crystals: mp 199-200 ° C .; [α] 21 D −20 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 443 (3, M + ). <Example 68> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-hydroxybenzamide A suspension of sodium 4-acetoxybenzoate (1.0 g, 5.4 mmol) in thionyl chloride (15 mL) is heated at reflux for 1 h (mixture is homogenized). More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (150 mg, 0.77 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (20 mL). To the ice-cold solution of 2,3,4-tetrahydronaphthalene (180 mg, 0.73 mmol) and triethylamine (150 μL, 1.1 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate solution. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The residue is dissolved in 99.5% ethane (15 mL) and concentrated hydrochloric acid (5 mL) is added. After 17 hours, the pH is adjusted to 8 and the solvent is evaporated in vacuo. The residue is partitioned between water and chloroform. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. Yield: 70 mg (26%) of the title compound as an oil: [α] 21 D −17 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 365 (24, M + ). <Example 69> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-ethylbenzamide, (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (110 mg, 0.41 mmol) and triethyl in methylene chloride (20 mL) To an ice cold solution of amine (95 μL, 0.68 mmol) is added dropwise 4-ethylbenzoyl chloride (81 mg, 0.48 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. . Yield: 120 mg (66%) of the title compound as white crystals: mp 177-178 ° C .: [α] 21 D −43 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 377 (27, M + ). <Example 70> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-butoxybenzamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (110 mg, 0.41 mmol) and triethyl in methylene chloride (20 mL) To an ice cold solution of amine (95 μL, 0.69 mmol) is added dropwise 4-butoxybenzoyl chloride (103 mg, 0.48 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute sodium hydrogen carbonate. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 2) saturated with chloroform / NH 3 as eluent. . Yield: 150 mg (75%) of the title compound as white crystals: mp 190-191 ° C .: [α] 21 D −49 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 421 (0.6, M + ). <Example 71> (S) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-butoxybenzamide The title compound is synthesized following the procedure of Example 70 using the (S) -form: mp 190-192 ° C .: [α] 21 D + 8 ° (c 1, MeOH); EIMS (70 eV) m / z (relative strength) 421 (1, M + ). <Example 72> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-fluorobenzamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine in methylene chloride (25 mL) To (110 μL, 0.79 mmol) ice-cold solution is added dropwise 4-fluorobenzoyl chloride (89 mg, 0.56 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate solution. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. . Yield: 130 mg (65%) of the title compound as white crystals: mp 189-190 ° C .: [α] 21 D −30 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 367 (11, M + ). <Example 73> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-bromobenzamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine in methylene chloride (25 mL) To (110 μL, 0.79 mmol) ice-cold solution is added dropwise 4-bromobenzoyl chloride (112 mg, 0.56 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate solution. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. . Yield: 120 mg (51%) of the title compound as white crystals: mp 200-201 ° C .: [α] 21 D −32 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 427 and 429 (3, M + ). <Example 74> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-chlorobenzamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine in methylene chloride (25 mL) To (93 μL, 0.67 mmol) ice-cold solution is added dropwise 4-chlorobenzoyl chloride (83 mg, 0.47 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate solution. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. . Yield: 97 mg (56%) of the title compound as white crystals: mp 204-205 ° C .: [α] 21 D −46 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 383 (19, M + ). <Example 75> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-benzylbenzamide 4-benzylbenzoic acid (0.50 g, 2.4 mmol) is dissolved in thionyl chloride (10 mL) and heated at reflux for 20 minutes. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (100 mg, 0.46 mmol) is dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (25 mL). To an ice cold solution of 2,3,4-tetrahydronaphthalene (110 mg, 0.44 mmol) and triethylamine (90 μL, 0.65 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute sodium hydrogen carbonate. The phases were separated and the combined organic phases were dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product on silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. Purify. Yield: 130 mg (62%) of the title compound as white crystals: mp 191-192 ° C .; [α] 21 D −39 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 439 (28, M + ). <Example 76> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-benzoylbenzamide 4-benzoylbenzoic acid (0.50 g, 2.2 mmol) is dissolved in thionyl chloride (15 mL) and heated at reflux for 15 minutes. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (150 mg, 0.60 mmol) is dissolved in methylene chloride (30 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (30 mL) To an ice cold solution of 2,3,4-tetrahydronaphthalene (140 mg, 0.57 mmol) and triethylamine (120 μL, 0.86 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute sodium hydrogen carbonate. The phases were separated and the combined organic phases were dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product on silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. Purify. Yield: 120 mg (48%) of the title compound as white crystals: mp 194-195 ° C .; [α] 21 D -51 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 453 (2, M + ). <Example 77> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (trifluoroacetyl) benzamide 4- (trifluoroacetyl) benzoic acid (0.50 g, 2.4 mmol) is dissolved in thionyl chloride (15 mL) and heated at reflux for 20 minutes. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (97 mg, 0.43 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (35 mL). To the ice-cold solution of 2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (85 μL, 0.61 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute sodium hydrogen carbonate. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. . Yield: 98 mg (54%) of the title compound as light yellow crystals: mp 91-93 ° C .; [α] 21 D −47 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 453 (27, M + ). <Example 78> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (1H-pyrrole-1-yl) benz amides 1,1'-carbonyldiimidazole (87 mg, 0.54 mmol) in 4- (1H-pyrrole-1-yl) benzoic acid (96 mg, 0.51 mmol) in anhydrous N, N-dimethylformamide (25 mL) ) Is added and the reaction is heated at 75 ° C. When carbon dioxide release ceased (after 30 minutes), the reaction was cooled to room temperature and (R) -2-amino-8- (4-methylpiperazin-1-yl in anhydrous N, N-dimethylformamide (5 mL) A solution of) -1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) is added. The reaction is stirred for 17 hours at ambient temperature and the solvent is evaporated in vacuo. Purification on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent gave 128 mg (62% yield) of the title compound as white crystals: mp 245-247 ° C .; [α] 21 D -69 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 414 (15, M + ). <Example 79> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (N, N-dipropylaminosulfonyl Benzamide 1,1'-carbonyldiimidazole (73 mg, in a solution of 4- (N, N-dipropylaminosulfonyl) benzoic acid (120 mg, 0.43 mmol) in anhydrous N, N-dimethylformamide (25 mL) 0.45 mmol) is added and the reaction is heated at 75 ° C. When carbon dioxide release ceased (after 30 minutes), the reaction was cooled to room temperature and (R) -2-amino-8- (4-methylpiperazin-1-yl in anhydrous N, N-dimethylformamide (5 mL) A solution of) -1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) is added. The reaction is stirred at ambient temperature for 24 hours and the solvent is evaporated in vacuo. Purification on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent gave 58 mg (27% yield) of the title compound as a viscous oil: [α] 21 D -37 ° (c 0.50) Chloroform); EIMS (70 eV) m / z (relative strength) 512 (11, M + ). <Example 80> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -phenylacetamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (110 mg, 0.43 mmol) and triethylamine in methylene chloride (25 mL) To (88 μL, 0.64 mmol) ice-cold solution is added dropwise phenylacetyl chloride (70 mg, 0.45 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 10 minutes and then washed with water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. . Yield: 95 mg (61%) of the title compound as white crystals: mp 151-152 ° C .: [α] 21 D −4.3 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 363 (20, M + ). <Example 81> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-phenylpropanamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (99 mg, 0.40 mmol) and triethylamine in methylene chloride (20 mL) To (83 μL, 0.42 mmol) ice-cold solution is added dropwise 3-phenylpropionyl chloride (72 mg, 0.42 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. . Yield: 120 mg (61%) of the title compound as white crystals: mp 184-186 ° C .: [α] 21 D + 6.5 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 374 (54, M + ). <Example 82> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-phenylbutanamide 4-phenylbutyric acid (1.0 g, 6.1 mmol) is dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (86 mg, 0.47 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (15 mL). To an ice cold solution of 2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (93 μL, 0.68 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. . Yield: 150 mg (82%) of the title compound as white crystals: mp 137-139 ° C .; [α] 21 D + 8.4 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 391 (23, M + ). <Example 83> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -5-phenylpentanamide 5-phenylvaleric acid (1.0 g, 5.6 mmol) is dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (93 mg, 0.47 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (15 mL). To an ice cold solution of 2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (93 μL, 0.68 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. . Yield: 120 mg (66%) of the title compound as a viscous oil: [α] 21 D + 7.4 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 405 (11, M + ). <Example 84> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-ethylphenyl) benzamide 4'-ethyl-4-biphenylcarboxylic acid (1.0 g, 4.4 mmol) is dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (130 mg, 0.53 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (20 mL) -1 To an ice cold solution of 2,3,4-tetrahydronaphthalene (120 mg, 0.48 mmol) and triethylamine (99 μL, 0.72 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. . Yield: 140 mg (53%) of the title compound as white crystals: mp 234-235 ° C .; [α] 21 D -73 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 453 (10, M + ). <Example 85> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-hydroxyphenyl) benzamide 4'-hydroxy-4-biphenylcarboxylic acid (0.40 g, 1.9 mmol) is dissolved in thionyl chloride (10 mL) and heated at reflux for 1 h. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (120 mg, 0.51 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (20 mL). To the ice-cold solution of 2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (100 μL, 0.74 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases were separated and the organic phase was dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which was purified on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 6: 0.5) as eluent. do. Yield: 95 mg (44%) of the title compound as white crystals: mp 261-262 ° C .; EIMS (70 eV) m / z (relative strength) 441 (2, M + ). <Example 86> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-trifluoromethylbenzamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (100 mg, 0.42 mmol) and triethylamine in methylene chloride (15 mL) To (88 μL, 0.63 mmol) ice-cold solution is added dropwise 3- (trifluoromethyl) benzoyl (93 mg, 0.44 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. . Yield: 130 mg (71%) of the title compound as a viscous oil: [α] 21 D -25 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 417 (25, M + ). <Example 87> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-phenoxybenzamide 3-phenoxybenzoic acid (1.0 g, 4.7 mmol) is dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (99 mg, 0.42 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (20 mL). To an ice cold solution of 2,3,4-tetrahydronaphthalene (99 mg, 0.41 mmol) and triethylamine (83 μL, 0.42 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. . Yield: 120 mg (68%) of the title compound as an oil: mp 136-137 ° C .; [α] 21 D −9.0 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 441 (31, M + ). <Example 88> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-hydroxybenzamide A solution of 3-acetoxybenzoic acid (130 g, 0.69 mol) in thionyl chloride (400 mL) is stirred at ambient temperature for 4 days. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (100 mg, 0.52 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (20 mL) -1 To an ice cold solution of 2,3,4-tetrahydronaphthalene (120 mg, 0.50 mmol) and triethylamine (100 μL, 0.75 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate solution. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The residue is dissolved in 99.5% ethanol (25 mL) and concentrated hydrochloric acid (5 mL) is added. After 17 hours, the pH is adjusted to 8 and the solvent is evaporated in vacuo. The residue is partitioned between water and methylene chloride. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. Yield: 93 mg (51%) of title compound as white crystals: mp 117 ° C. dec; [α] 21 D −10 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 365 (22, M + ). <Example 89> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-methylsulfonyloxybenzamide 3-methanesulfonyloxybenzoic acid in thionyl chloride (5 mL) (0.20 g, 0.90 mmol; Looker, JH; Hays, CH; Thatcher, DNJ Am. Chem. Soc. 1957, 79, 741-4) The suspension of is heated at 40 ° C. for 45 minutes (mixture is homogenized). More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (120 mg, 0.50 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (20 mL) -1 To an ice cold solution of 2,3,4-tetrahydronaphthalene (120 mg, 0.48 mmol) and triethylamine (100 μL, 0.72 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate solution. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 4) saturated with chloroform / NH 3 as eluent. . Yield: 87 mg (41%) of the title compound as white crystals: mp 159-160 ° C .; [α] 21 D −27 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 443 (21, M + ). <Example 90> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -2-methylbenzamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine in methylene chloride (15 mL) To (85 μL, 0.62 mmol) ice-cold solution is added dropwise 2-methylbenzoyl chloride (66 mg, 0.43 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 3.5) saturated with chloroform / NH 3 as eluent. . Yield: 100 mg (80%) of the title compound as white crystals: mp 179-180 ° C .; [α] 21 D -22 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 363 (21, M + ). <Example 91> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -2-ethoxybenzamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (110 mg, 0.43 mmol) and triethylamine in methylene chloride (15 mL) To (90 μL, 0.65 mmol) ice cold solution is added dropwise 2-ethoxybenzoyl chloride (84 mg, 0.45 mmol) in methylene chloride (5 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with water. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. . Yield: 110 mg (64%) of the title compound as a white solid: [α] 21 D -36 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 393 (15, M + ). Hydrochloride is precipitated from diethyl ether and 110 mg (59% yield) of white crystals are isolated; mp sintered at 176 ℃ <Example 92> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -2-hydroxybenzamide (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (180 mg, 0.74 mmol) and triethylamine in methylene chloride (20 mL) To (150 μL, 1.1 mmol) ice-cold solution is added dropwise acetylsalicyloyl chloride (160 mg, 0.78 mmol) in methylene chloride (10 mL). After addition the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate solution. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo. The residue is dissolved in 99.5% ethanol (25 mL) and concentrated hydrochloric acid (3 mL) is added. After 17 hours, the pH is adjusted to 8 and the solvent is evaporated in vacuo. The residue is partitioned between water and methylene chloride. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. Yield: 170 mg (63%) of the title compound as white crystals: mp 87 ° C. degradation; [α] 21 D -18 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 365 (33, M + ). <Example 93> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -methylsulfonyloxybenzamide 2-methanesulfonyloxybenzoic acid in thionyl chloride (10 mL) (0.30 g, 1.4 mmol; Looker, JH; Hays, CH; Thatcher, DNJ Am. Chem. Soc. 1957, 79, 741-4) The solution of is heated at 40 ° C. for 45 minutes. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (120 mg, 0.49 mmol) is dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (20 mL) To the ice-cold solution of 2,3,4-tetrahydronaphthalene (120 mg, 0.47 mmol) and triethylamine (98 μL, 0.72 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate solution. The phases were separated and the combined organic phases were dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product on silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. Purify. Yield: 110 mg (55%) of the title compound as white crystals: mp 144-145 ° C .; [α] 21 D −7.1 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 443 (10, M + ). <Example 94> (R) -2-amino-8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene (R) -N-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (5.0 g, 23 mmol) is dissolved in acetic acid (300 mL) under a nitrogen atmosphere. Sodium acetate (5.5 g, 70 mmol) is added and bromine (3.5 g, 23 mmol) is then added in part. The mixture is stirred at room temperature for 5 minutes. The solvent is removed in vacuo to give a solid residue which is partitioned between ethyl acetate and NaOH (2 M). The layers are separated and the aqueous layer is extracted twice with ethyl acetate. The organic layer is combined and dried (Na 2 SO 4 ). The solvent is removed in vacuo to give a brown oily residue. The HCl salt is precipitated from diethyl ether / methylene chloride by adding HCl in diethyl ether (3 M). Yield 7.7 g (94%). Recrystallization from methanol gives the title compound as acicular crystals: mp 264-265 ° C .; [α] 21 D + 54 ° (c 1.0, MeOH); EIMS (70 eV) m / z (relative intensity) 257 (30, M + , 81 Br), 255 (31, M + , 79 Br). <Example 95> (R) -8-bromo-2-N, N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene (R) -2-amino-8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.5 g, 17.5 mmol), benzyl bromide (6.6 g, 38 mmol), potassium carbonate ( 9.7 g, 70 mmol) and potassium iodide (100 mg, catalytic amount) are mixed with acetonitrile (250 mL) under nitrogen atmosphere and refluxed for 18 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and ammonia (2 M). The layers are separated and the organic layer is dried (Na 2 SO 4 ). The solvent is removed in vacuo to give a residue which is purified by flash chromatography on silica gel using hexane / methylene chloride (8: 2) as eluent. Obtain the title compound as an oil. Yield 7.5 g (98%): [α] 21 D + 87 ° (c 1, MeOH); EIMS (70 eV) m / z (relative strength) 437 (12, M + , 81 Br), 435 (13, M + , 79 Br). <Example 96> (R) -2-N, N-dibenzylamino-8- (1-methylpiperidin-4-yl) -5-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydronaphthalene (R) -8-bromo-2-N, N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene (6.8 g, 16 mmol) was dissolved in anhydrous tetrahydrofuran under nitrogen atmosphere. Mix in (100 mL). The solution is cooled before adding n-butyllithium (11.7 mL, 1.6 M, 19 mmol) for 3 minutes. The mixture is stirred for 5 minutes and N-methyl-4-piperidone (5.4 g, 48 mmol) is added for 3 minutes. The temperature is raised to 0 ° C. before quenching the reaction by removing the cooling bath and quenching with water. The layers are separated and the organic layer is dried (Na 2 SO 4 ). The solvent is removed in vacuo to give a residue which is purified by crystallization (ethyl acetate / hexane). EIMS (70 eV) m / z (relative strength) 470 (2, M + ). Crystals are dissolved in tetrahydrofuran under a nitrogen atmosphere. Sodium borohydride (5.9 g, 0.16 mol) is added and the mixture is cooled to 0 ° C. Trifluoroacetic acid (10 mL) is added dropwise for 1 hour. The cooling bath is removed and the mixture is stirred for 1 hour at room temperature and diluted with water and diethyl ether before pouring into the NaOH solution (40% -ig) carefully. The layers are separated and the organic phase is dried (MgSO 4 ). The solvent was removed in vacuo to give a solid residue [EIMS (70 eV) m / z (relative strength) 454 (12, M + )], suspended in hydrobromic acid (48%, 200 mL) and refluxed for 2 hours ( All dissolved). The mixture is brought to room temperature. The crystals formed are filtered and partitioned between ethyl acetate and ammonia (2 M). The layers are separated and the organic layer is dried (MgSO 4 ). The solvent is evaporated in vacuo and a solid residue [EIMS (70 eV) m / z (relative strength) 440 (5, M + )] is obtained and suspended in methylene chloride (150 mL). 2,4,6-collidine (2 g, 16 mmol) is added and the mixture is cooled to -78 ° C. Anhydrous trifluoromethanesulfonic acid (4.4 g, 15 mmol) is added for 5 minutes. The cooling bath is removed and the temperature of the reaction mixture is raised to -5 ° C. The reaction mixture is washed with ammonia (2 M) and dried (MgSO 4 ). The solvent is removed in vacuo to give a solid residue which is purified by flash chromatography on silica gel using methylene chloride / ethanol (10: 1) containing 0.5% ammonia as eluent. Yield 4 g (44%): [α] 21 D + 45 ° (c 1, CHCl 3 ); EIMS (70 eV) m / z (relative strength) 572 (2, M + ). <Example 97> (R) -2-N, N-dibenzylamino-8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (1-methylpiperidin-4-yl) -5-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydronaphthalene (4 g, 7.0 mmol), triethylamine (2.8 g, 28 mmol), formic acid (1.3 g, 28 mmol), triphenylphosphine (0.4 g, 1.4 mmol) and palladium (II) acetate (85 mg, 0.35 mmol) is dissolved in N, N-dimethylformamide (20 mL) under a nitrogen atmosphere. The solution is stirred at 60 ° C. for 18 hours. The solvent is removed in vacuo to give a residue, partitioned between ethyl acetate and ammonia (2 M). The layers are separated and the organic layer is dried (Na 2 SO 4 ). The solvent is removed in vacuo to give a dark brown oily residue which is purified by flash chromatography on silica gel using chloroform / ethanol (20: 1) containing 0.5% ammonia as eluent. Obtain the title compound as an oil. Yield 1.7 g (57%): [α] 21 D + 53 ° (c 1, CHCl 3 ); EIMS (70 eV) m / z (relative strength) 424 (1, M + ). <Example 98> (R) -2-amino-8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydronaphthalene (1.7 g, 4.0 mmol), ammonium formate (5.0 g, 80 mmol), palladium (10% on activated carbon, 0.8 g), methanol (30 mmol), water (15 mL) and tetrahydrofuran (40 mL) are mixed under nitrogen atmosphere and refluxed for 3 hours. (Excess hydrogen gas outlet is equipped). The crystals are filtered off and washed thoroughly with ethanol. The solvent is removed in vacuo until about 30 mL remains. The residue is partitioned between ethyl acetate and NaOH (2 M). The layers are separated and the aqueous layer is extracted twice with ethyl acetate. The organic layer was combined and the solvent removed in vacuo to yield 0.8 g of the title compound as an oil (82% yield): [α] 21 D + 36 ° (c 0.5, CHCl 3 ); EIMS (70 eV) m / z (relative strength) 244 (1, M + ). <Example 99> (R) -N- [8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide α, α, α-trifluorouro-p-toluic acid (0.15 g, 0.8 mmol) is suspended in thionyl chloride (3 mL) and refluxed for 30 minutes (all minutes dissolved). Excess thionyl chloride is removed in vacuo. The residue is dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (1-methylpiperidin-4-yl) -1,2,3,4- in methylene chloride (5 mL). To an ice cold solution of tetrahydronaphthalene (0.15 g, 0.6 mmol) and triethylamine (92 mg, 0.9 mmol) is added dropwise. The mixture is stirred for 15 minutes and then diluted with ethyl acetate, washed with ammonia (2 M) and dried (MgSO 4 ). The solvent is removed in vacuo. The residue is purified by flash chromatography on silica gel using methylene chloride / ethanol (5: 1) containing 0.5% ammonia as eluent. Obtain the title compound as off-white crystals. Yield: 140 mg (55%): mp 163-166 ° C .; [α] 21 D + 36 ° (c 0.5, CHCl 3 ); EIMS (70 eV) m / z (relative strength) 416 (48, M + ). <Example 100> (R) -N- [8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-butoxybenzamide 4-butoxybenzoic acid (0.16 g, 0.8 mmol) is dissolved in thionyl chloride (3 mL) and refluxed for 30 minutes. Excess thionyl chloride is removed in vacuo with toluene. The residue is dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (1-methylpiperidin-4-yl) -1,2,3,4- in methylene chloride (5 mL). To an ice cold solution of tetrahydronaphthalene (0.15 g, 0.6 mmol) and triethylamine (92 mg, 0.9 mmol) is added dropwise. The mixture is stirred for 30 minutes and then diluted with ethyl acetate, washed with ammonia (2 M) and dried (MgSO 4 ). The solvent is removed in vacuo. The residue is purified by flash chromatography on silica gel using methylene chloride / ethanol (5: 1) containing 0.5% ammonia as eluent. The title compound is obtained, which is white crystals. Yield: 170 mg (50%): mp 162-164 ° C .; [α] 21 D −2 ° (c 0.5, CHCl 3 ); EIMS (70 eV) m / z (relative strength) 420 (40, M + ). <Example 101> (R) -N- [8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide 4-M-morpholinobenzoic acid (0.4 g, 1.6 mmol) is dissolved in thionyl chloride (3 mL) under a nitrogen atmosphere and stirred for 5 minutes at room temperature. The excess thionyl chloride is removed in vacuo to give a pale yellow residue. The residue is dissolved in methylene chloride (10 mL) and (R) -2-amino-8- (1-methylpiperidin-4-yl) -1,2,3,4- in methylene chloride (10 mL). To the solution of tetrahydronaphthalene (0.4 g, 1.9 mmol) and triethylamine (0.4 g, 4.0 mmol) was added dropwise for 5 minutes. The mixture is stirred for 15 minutes at room temperature, then washed with ammonia (2 M) and dried (MgSO 4 ). The solvent is removed in vacuo to give a residue which is purified by flash chromatography on silica gel using methylene chloride / ethanol (5: 1) containing 0.5% ammonia. Yield: 100 mg (12%): mp 196-198 ° C .; [α] 21 D −19 ° (c 1, CHCl 3 ); EIMS (70 eV) m / z (relative strength) 433 (27, M + ). <Example 102> (R) -2-N, N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene Potassium carbonate (68 g, 0.49 mol) in a solution of (R) -5-methoxy-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride (30 g, 0.14 mmol) in acetonitrile (600 mL) ), Potassium iodide (catalyst amount) and benzyl bromide (42 mL, 0.35 mol) are added. The reaction mixture is stirred at reflux for 48 hours. After the precipitate is filtered off and the acetonitrile is removed in vacuo, the residue is partitioned between diethyl ether and water. The organic phase is separated, dried (Na 2 SO 4 ), evaporated in vacuo and the crude product is obtained and purified on a silica gel column using hexane / ethyl acetate (3: 1) as eluent. Yield: 46 mg (92%) of the title compound as white crystals: mp 112-114 ° C .; [α] 21 D + 61 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 357 (38, M + ). <Example 103> (S) -2-N, N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene The title compound is synthesized following the procedure of Example 102 using the (S) -form: mp 113-115 ° C .; [α] 21 D −59 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 357 (74, M + ). <Example 104> (R) -6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthol (R) -2-N, N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene (46 g, 0.13 mL) was dissolved in diethyl ether (900 mL) and exceeded Ether HCl solution is added dropwise. The precipitate is filtered off and dried in vacuo to give a white solid. This crude product (45 g, 0.11 mol) is dissolved in anhydrous methylene chloride (500 mL) and cooled to -60 ° C. To this solution is added dropwise boron tribromide (14 mL, 0.15 mol) dissolved in anhydrous methylene chloride (50 mL). The reaction temperature is brought to -5 ° C and maintained overnight. To the ice-cooled solution is added dropwise 2 M aqueous ammonium hydroxide solution and the mixture is extracted twice with methylene chloride. The combined organic phases are dried (Na 2 SO 4 ), filtered and the solvent is removed in vacuo to afford a crude residue. Chromatography on silica (eluent: methylene chloride) affords 33 g (83% yield) of the title compound as a clear viscous oil: [α] 21 D + 72 ° (c 0.66, Chloroform); EIMS (70 eV) m / z (relative strength) 343 (11, M + ). <Example 105> (S) -6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthol Synthesis following the procedure of Example 104 using the (S) -form: [α] 21 D -71 ° (c 0.71, chloroform); EIMS (70 eV) m / z (relative strength) 343 (12, M + ). <Example 106> (R) -2- (6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy) -2-methylpropanamide (R) -6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthol (28 g, 81 mmol) was added sodium hydride (60-65% in oil, 2.2 for 1 hour). g, 90 mmol) in anhydrous dioxane (500 mL). 2-bromo-2-methylpropanamide (15 g, 90 mmol; Coutts, IGC, Southcott, disclosed in MRJ Chem. Soc. Perkin Trans. 1 1990, 767-770) was added and the reaction mixture was allowed to 80 for 2.5 hours. Heat at 캜. After cooling, the precipitated sodium bromide is filtered off, the filtrate is evaporated in vacuo and the residue is partitioned between water and methylene chloride. The organic phase is separated, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the title compound as a viscous oil. Yield: 24 g (70% yield). This crude product is used directly in the next step without further purification. Analytical samples (0.50 g) are purified on silica gel using hexanes / ethyl acetate as eluent. Yield: 0.46 g of the title compound as a viscous oil: [α] 21 D + 42 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 428 (1, M + ) <Example 107> (S) -2- (6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy) -2-methylpropanamide Synthesis of the title compound is carried out according to the procedure of Example 106 using (S) -form: [α] 21 D -42 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 428 (8, M + ) <Example 108> (R) -N- (6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -2-hydroxy-2-methylpropanamide (R) -2- (in dry 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (10 mL) and dry N, N-dimethylformamide (250 mL) Sodium hydride (60-65 in oil) in a 6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy) -2-methylpropanamide (23 g, 54 mmol) solution %, 5.4 g, 135 mmol) is added and the reaction is heated at 130 ° C. for 10 h. Additional amounts of incidental 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (15 mL) and sodium hydride (0.5 molar equivalents) were added and the reactions were all at 130 ° C. for 21 hours. Heat at The solution is poured into a mixture of ice and water and extracted three times with ethyl acetate. The combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the title compound as a viscous oil. Yield: 20 g (86% yield). This crude product is used directly in the next step without further purification. An analytical sample (0.50 g) is purified on a silica gel column using hexanes / ethyl acetate (5: 1) as eluent. Yield: 0.24 g of the title compound as a viscous oil: [α] 21 D + 35 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 428 (1, M + ) <Example 109> (S) -N- (6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -2-hydroxy-2-methylpropanamide Synthesis of the title compound was carried out according to the procedure of Example 108 using (S) -form: [α] 21 D + 33 ° (c 1.1, chloroform); EIMS (70 eV) m / z (relative strength) 428 (4, M + ) <Example 110> (R) -2-N, N-dibenzylamino-5-amino-1,2,3,4-tetrahydronaphthalene (R) -N- (6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -2-hydroxy-2-methylpropanamide (19 g, 44 mmol ) Is dissolved in ethanol (500 mL) and 20% aqueous HCl solution (500 mL) and heated to reflux for 8 hours. Ethanol is evaporated in vacuo and the remaining solution is washed twice with diethyl ether and cooled on an ice bath. After alkalizing with 45% aqueous sodium hydroxide solution, the mixture is extracted with methylene chloride. The combined organic phases are dried (Na 2 SO 4 ), filtered and evaporated in vacuo. Purification on a silica gel column using chloroform as eluent gave 6.1 g (40% yield) of the title compound as a light brown viscous oil: [α] 21 D + 54 ° (c 0.97, chloroform); EIMS (70 eV) m / z (relative strength) 342 (19, M + ). <Example 111> (S) -2-N, N-dibenzylamino-5-amino-1,2,3,4-tetrahydronaphthalene Synthesis of the title compound was carried out according to the procedure of Example 110 using (S) -form: [α] 21 D -53 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 342 (20, M + ). <Example 112> (R) -1- (6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -4-methylpiperazin-2,6-dione 1,1′-Carbonyldiimidazole (5.5 g, 34 mmol) is added to a stirred suspension of methyliminodiiacetic acid (2.5 g, 17 mmol) in anhydrous N, N-dimethylformamide (250 mL). The reaction mixture is heated at 80 ° C. for 1 hour. (R) -2-N, N-dibenzylamino-5-amino-1,2,3,4-tetrahydronaphthalene (5.3 g, 15 mmol) dissolved in N, N-dimethylformami (75 mL) ) Is then added and stirring is continued for 10 hours. The solvent is evaporated in vacuo and the crude product is purified on a silica gel column using ethanol (100: 0.5) saturated with chloroform / NH 3 as eluent. Yield: 5.0 g (87% yield) of the title compound as a viscous oil: [α] 21 D + 51 ° (c 1.1, chloroform); EIMS (70 eV) m / z (relative strength) 453 (16, M + ). <Example 113> (S) -1- (6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -4-methylpiperazin-2,6-dione Synthesis of the title compound is carried out according to the procedure of Example 112 using (S) -form: [α] 21 D -50 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 453 (22, M + ). <Example 114> (R) -2-N, N-dibenzylamino-5- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -1- (6-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -4-methylpiperazine-2,6-dione (4.0 g, 8.8 mmol) is added to a suspension of lithium aluminum hydride (1.7 g, 44 mmol) in anhydrous tetrahydrofuran (125 mL). The reaction mixture is heated at reflux for 5 hours. The reaction is quenched by addition of water (1.7 mL), 15% sodium hydroxide (1.7 mL) and again water (5.1 mL). The mixture is filtered, dried (Na 2 SO 4 ) and evaporated in vacuo. Purification on a silica gel column using ethanol (100: 1) saturated with chloroform / NH 3 as eluent gave 1.4 g (38% yield) of the title compound as a viscous oil: [α] 21 D + 7.0 ° (c 1.0) Chloroform); EIMS (70 eV) m / z (relative strength) 425 (7, M + ). <Example 115> (S) -2-N, N-dibenzylamino-5- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene Synthesis of the title compound was carried out according to the procedure of Example 114 using (S) -form: [α] 21 D -8.0 ° (c 1.1, chloroform); EIMS (70 eV) m / z (relative strength) 425 (6, M + ). <Example 116> (R) -2-amino-5- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-5- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (1.3 g, 3.0 in methanol) mmol) solution is added ammonium formate (4.6 g, 73 mmol) and palladium (10%) on activated carbon (0.45 g). The mixture is refluxed for 2 hours and then palladium is filtered off. The solvent is evaporated in vacuo and the residue is purified on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent. Yield: 360 mg (49%) as light brown crystals: [α] 21 D + 21 ° (c 1.1, chloroform); EIMS (70 eV) m / z (relative strength) 245 (41, M + ). <Example 117> (S) -2-amino-5- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene Synthesis of the title compound was carried out following the procedure of Example 116 using (S) -form: mp 97-98 ° C .; [α] 21 D -21 ° (c 1.1, chloroform); EIMS (70 eV) m / z (relative strength) 245 (55, M + ). <Example 118> (R) -N- [5- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide To a solution of 4-morpholinobenzoic acid (110 mg, 0.51 mmol) in anhydrous N, N-dimethylformamide (10 mL) was added 1,1'-carbonyldiimidazole (87 mg, 0.54 mmol) and the reaction was 75 Heat at 캜. When carbon dioxide emission ceased (after 30 minutes), the reaction was cooled to room temperature and (R) -2-amino-5- (4-methylpiperazin-1-yl in anhydrous N, N-dimethylformamide (5 mL) ) -1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) solution is added. The reaction is stirred at 70 ° C. for 18 hours and the solvent is evaporated in vacuo. The residue is purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. After crystallization from acetonitrile, 65 mg (30% yield) of the title compound as white crystals are obtained: mp 127-128 ° C .; [α] 21 D + 51 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 434 (14, M + ). <Example 119> (S) -N- [5- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide Synthesis of the title compound was carried out according to the procedure of Example 118 using (S) -form: mp 129-131 ° C .; [α] 21 D -52 ° (c 0.50, chloroform); EIMS (70 eV) m / z (relative strength) 434 (8, M + ). <Example 120> (R) -N- [5- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-phenoxybenzamide 3-phenoxybenzoic acid (1.0 g, 4.7 mmol) is dissolved in thionyl chloride (15 mL) and heated at reflux for 30 minutes. More thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (70 mg, 0.30 mmol) is dissolved in methylene chloride (5 mL) and (R) -2-amino-5- (4-methylpiperazin-1-yl) -1 in methylene chloride (25 mL) To an ice cold solution of 2,3,4-tetrahydronaphthalene (70 mg, 0.28 mmol) and triethylamine (55 μL, 0.42 mmol) is added dropwise. After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrocarbon solution. The phases were separated and the organic phase was dried (Na 2 SO 4 ), filtered and evaporated in vacuo in vacuo to afford the crude product which was purified on a silica gel column using ethanol (100: 3) saturated with chloroform / NH 3 as eluent. do. Yield: 45 mg (36%) of the title compound in solid form: [α] 21 D + 24 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 441 (18, M + ). <Example 121> (S) -N- [5- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-phenoxybenzamide Synthesis of the title compound was carried out according to the procedure of Example 120 using (S) -form: [α] 21 D -23 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 441 (20, M + ). <Example 122> (R) -N-methyl-N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylenebenzamide (R) -2-N-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (100 mg, 0.39 mmol) in methylene chloride (25 mL) and To an ice cold solution of triethylamine (80 μL, 0.58 mmol) is added dropwise 4- (trifluoromethyl) benzoyl (90 mg, 0.43 mmol) in methylene chloride (5 mL). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute sodium hydrogen carbonate. The phases are separated, the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product which is purified on a silica gel column using ethanol (100: 2) saturated with chloroform / NH 3 as eluent. . Yield: 89 mg (53%) of title compound as clear crystals: mp 123-125 ° C .; [α] 21 D + 104 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 431 (13, M + ). <Example 123> (R) -8- (4-methylpiperazin-1-yl) -2- [N- (4-trifluoromethyl) benzylamino] -1,2,3,4-tetrahydronaphthalene To a solution of (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (200 mg, 0.81 mmol) in acetonitrile (35 mL) Potassium carbonate (169 mg, 1.2 mmol), potassium iodide (catalyst amount) and 4- (trifluoromethyl) benzyl bromide (194 mg, 0.81 mmol) are added. The reaction mixture is stirred at reflux for 8 hours. After the precipitate is filtered off and the acetonitrile is removed in vacuo, the residue is purified on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent. Yield: 72 mg (22%) of the title compound as a clear oil: [α] 21 D + 12 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 403 (1, M + ). Oxalate is precipitated from diethyl ether and light brown crystals are isolated. Yield: 81 mg (17%): mp 95 ° C, sintered. <Example 124> 4-thiomorpholinobenzoic acid 4-thiomorpholinobenzonitrile (1 g, 4.9 mmol: Beach, SF; Hepworth, JD: Sawyer, J .; Hallas, G .; Marsden, R .; Mitchell, MM; Ibbitson in glacial acetic acid (20 mL) To a solution of DA, Jones, AM; Neal, GTJ Chem. Soc.Perkin Trans. II, 1984, 217-221), 20% aqueous hydrochloric acid solution (20 ml) was added and the reaction heated at reflux for 15 hours. do. Acetic acid is evaporated in vacuo and the remaining aqueous solution is alkalized to pH 12 with a 2 M aqueous sodium hydroxide solution. The solution is washed twice with diethyl ether and the water phase is adjusted to pH 3 with 20% aqueous hydrochloric acid solution. The product was filtered and dried in vacuo to yield 1.0 g (91% yield) of the title compound as white crystals: mp 233-235 ° C .; EIMS (70 eV) m / z (relative strength) 223 (50, M + ). <Example 125> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-thiomorpholinobenzamide 4-thiomorpholinobenzoic acid (0.25 g, 1.1 mmol) is dissolved in thionyl chloride (25 mL). The excess thionyl chloride is immediately evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride (107 mg, 0.44 mmol) was dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1 in methylene chloride (35 mL). Dissolve in an ice cold solution of 2,3,4-tetrahydronaphthalene (104 mg, 0.42 mmol) and triethylamine (68 μL, 0.87 mmol). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate solution. The phases were separated and the organic phase was dried (Na 2 SO 4 ), filtered and evaporated in vacuo to afford the crude product, which was purified on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent. do. Yield: 58 mg (31%) of the title compound as white crystals: mp 190-191 ° C .; [α] 21 D -86 ° (c 0.25, chloroform); EIMS (70 eV) m / z (relative strength) 450 (2, M + ). <Example 126> 4- (4-benzylpiperazin-1-yl) benzonitrile To a solution of 4-fluorobenzonitrile (3.0 g, 25 mmol) in N, N-dimethylformamide (15 mL) was dissolved 1-benzylpiperazine (4.3 mL, 25 mmol) and potassium carbonate (3.4 g, 25 mmol). Add. The reaction mixture is stirred at 120 ° C. for 13 hours. The solvent is evaporated and the residue is partitioned between ethyl acetate (100 mL) and water (15 mL). The aqueous phase is extracted with ethyl acetate (30 mL) and the combined organic phases are washed with brine (10 mL) and dried (MgSO 4 ). The solvent is evaporated to give 7.6 g of crude product. Purification on a silica gel column using ethyl acetate / methylene chloride (1: 9) as eluent gave 4.0 g (59% yield) of the title compound as a white solid: mp 104-105 ° C .; EIMS (70 eV) m / z (relative strength) 277 (20, M + ). <Example 127> 4- (4-benzylpiperazin-1-yl) benzoic acid 4- (4-benzylpiperazin-1-yl) benzonitrile (4.0 g, 15 mmol) is dissolved in glacial acetic acid (40 mL), 6 M hydrochloric acid (50 mL) is added and the reaction mixture is 100 ° C. for 17 h. Stir at. The solvent is evaporated and the residue is suspended in water (10 mL) and adjusted to pH 3 by addition of 2 M sodium hydroxide (35 mL). The slurry is stirred at 50 ° C. for 2 hours, collected and the precipitate is dried in vacuo to give 4.1 g of crude product. The solid is partitioned between 2 M sodium hydroxide (8 mL) between methylene chloride (40 mL) and water (220 mL). The aqueous phase is washed with methylene chloride (40 mL) and the pH is adjusted to 5 with 2 M hydrochloric acid. Cool the aqueous phase, filter the precipitate and dry in vacuo to give 1.6 g (38% yield) of the title compound: mp 226 ° C. (dec); EIMS (70 eV) m / z (relative strength) 296 (44, M + ). <Example 128> (R) -N-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl-4- (4-benzylpiperazin-1-yl) benz amides 4- (4-benzylpiperazin-1-yl) benzoic acid (57 mg, 0.19 mmol) and 1,1'-carbonyldiimidazole (33 mg, 0.20 mmol in N, N-dimethylformamide (2 mL) ) Suspension is stirred at 75 ° C. for 2 hours. The solution was cooled and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro dissolved in N, N-dimethylformamide (1 mL) Naphthalene (45 mg, 0.18 mmol) is added. The reaction mixture is stirred at ambient temperature for 40 hours. The solvent is evaporated and the residue is dried in vacuo to give 149 mg of crude product. Purify the residue by preparative TLC (silica), eluting with chloroform / NH 3 saturated ethanol (15: 1) to give 63 mg (63% yield) of the title compound as a white solid: mp 209-210 ° C .; [α] 21 D -65 (c 0.5, chloroform); EIMS (70 eV) m / z (relative strength) 523 (13, M + ). <Example 129> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonylbenzamide 3-morpholinocarbonylbenzoic acid (130 mg, 0.54 mmol; J. Med. Chem. 1994, 37 (26), 4538-4554) is dissolved in thionyl chloride (5 mL). When dissolving the acid, excess thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride is dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4- in methylene chloride (20 mL). Add dropwise to an ice cold solution of tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (100 μL, 0.73 mmol). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrocarbon solution. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo in vacuo to give the crude product over a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 4: 0.5) as eluent. Purify. Yield: 160 mg (72%) of the title compound as white crystals: mp 124-127 ° C .; [α] 21 D −40 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 462 (2, M + ). <Example 130> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (N, N-dimethylaminocarbonyl) Benzamide 4- (N, N-dimethylaminocarbonyl) benzoic acid (100 mg, 0.54 mmol; described in US Patent 3607918, 1971) is dissolved in thionyl chloride (5 mL). When dissolving the acid, excess thionyl chloride is evaporated in vacuo, the residue is treated with toluene and the solvent is again removed in vacuo. Crude acid chloride is dissolved in methylene chloride (5 mL) and (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4- in methylene chloride (20 mL). Add dropwise to an ice cold solution of tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (100 μL, 0.73 mmol). After addition, the reaction is stirred at ambient temperature for 15 minutes and then washed with dilute aqueous sodium hydrocarbon solution. The phases are separated and the organic phase is dried (Na 2 SO 4 ), filtered and evaporated in vacuo in vacuo to give the crude product over a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 4: 0.5) as eluent. Purify. Yield: 160 mg (79%) of the title compound as a white foam: [α] 21 D -30 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 420 (10, M + ). <Example 131> 4- (4-piperidone-1-yl) benzoic acid 2 M NaOH (10 mL), 4- (8-aza-1,4-dioxaspiro [4,5] de-8-sil) benzonitrile (820 mg, 3.4 mmol; Taylor EC; Skotnicki JS Synthesis 1981, 8, 606-608), and ethanol (7.5 mL) solution are heated at reflux for 3 hours. External heating is stopped and the reaction mixture is stirred overnight at ambient temperature. The ethanol solvent is removed in vacuo and the remainder is acidified to pH 4 with 2 M HCl and then extracted with ethyl acetate (50 mL). The layers are separated and the pH is adjusted to 6 with 2 M NaOH and then extracted again with ethyl acetate (50 mL). The combined organic layers are concentrated in vacuo and the solid residue is dissolved in 6 M HCl (10 mL). The reaction mixture is stirred at 75 ° C. to 55 ° C. overnight for 2.5 hours. The temperature is raised to 75 ° C. for 2 hours and the reaction mixture is then cooled. Adjust the pH to 4 and extract the solution with ethyl acetate (50 mL). The layers are separated and the pH is adjusted to 5 and then extracted with ethyl acetate. The combined organic layers are dried (MgSO 4 ) and the solvent is removed in vacuo. The crude product was recrystallized from ethyl acetate to give 300 mg (41% yield) of the title compound as yellow crystals: mp> 215 ° C. (sintered); EIMS (70 eV) m / z (relative strength) 219 (M + , 100). <Example 132> (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-piperidone-1-yl) Benzamide 4- (piperidone-1-yl) benzoic acid (230 mg, 1.0 mmol) and N, N-diisopropylethylamine (180 μL, 1.0 mmol) were dissolved in dry N, N-dimethylformamide (10 mL). And cooled to -20 ° C. Isobutylchloroformate (130 μL, 1.0 mmol) is added and the reaction mixture is stirred for 30 minutes at −20 ° C. to 1 hour at room temperature. The solvent is evaporated and the residue is partitioned between ethyl acetate (100 mL) and 2 M NH 3 (15 mL). The organic phase is washed with brine (15 mL), dried (MgSO 4 ) and the solvent is evaporated to give 390 mg of crude product. Purification by column chromatography on silica using chloroform / methanol / concentrated NH 3 (50: 50: 5) yields 124 mg (27% yield) of the title compound as a white solid: mp> 223 ° C. (sinter); EIMS (70 eV) m / z (relative strength) 446 (M + , 8); [α] 22 D -78 ° (c 0.28, chloroform). <Example 133> 3, '4'-Dihydro-8'-[4-methyl (piperazin-1-yl)]-spiro- [1,3-dioxolane-2,2 '(1H) -naphthalene] 8'-Bromo-3 ', 4'-dihydrospiro- [1,3-dioxolane-2,2'-(1H) -naphthalene] (6.0 g, 22 mmol; Sunkyun L .; Stewart PF; David EN Synth.Commun. 1995, 25 (18), described in 2775-2780) is dissolved in toluene (180 mL) and flushed with argon. N-methylpiperazine (3.0 mL, 27 mmol), R (+)-bis (diphenylphosphino) -1,1'-binafthyl (830 mg, 1.3 mmol), tetrakis (dibenzylideneacetone) Dipalladium (0) (510 mg, 0.45 mmol) and sodium t-butoxide (3.0 g, 31 mmol) are added and the reaction mixture is stirred at 85 ° C. for 2.5 h. After cooling to room temperature, ethyl acetate (400 mL) and 2 M ammonia (60 mL) are added. The phases are separated and the organic layer is washed with 2 M ammonia (30 mL) and brine (40 mL) and dried (MgSO 4 ). Evaporate the solvent to afford 7.5 g of crude product. Purification by column chromatography on silica using chloroform / methanol / concentrated NH 3 (180: 5: 0.5) as eluent gave 5.5 g (84% yield) of the title compound as a yellow solid: mp 127-128 ° C. (sintered) ; EIMS (70 eV) m / z (relative strength) 288 (43, M + ). <Example 134> 8- [4-methyl (piperazin-1-yl)]-2-tetraron 3 ', 4'-dihydro-8'-[4-methyl (piperazin-1-yl)]-spiro- [1,3-dioxolane-2,2 '(1H) -naphthalene] (1.0 g, 3.5 mmol) is dissolved in freshly distilled tetrahydrofuran (50 mL) and the solution is cooled to 0 ° C. 2 M hydrochloric acid (10 mL) is added to the solution and after 5 minutes the cooling bath is removed. The reaction mixture is stirred at ambient temperature for 3.5 hours. Tetrahydrofuran is removed in vacuo and the residue is mixed with methylene chloride (100 mL) and cooled on an ice bath. To the mixture is added sodium hydroxide (10 mL) and the phases are separated. The organic layer is washed with brine (105 mL) and dried (MgSO 4 ). Evaporate the solvent to give 810 mg (95% yield) of the title compound as yellow crystals: mp> 85 ° C. (sinter); EIMS (70 eV) m / z (relative strength) 244 (51, M + ). <Example 135> 2-cyano-3,4-dihydro-8- [4-methyl (piperazin-1-yl)]-naphthalene 8- [4-methyl (piperazin-1-yl)]-2-tetraron (420 mg, 1.7 mmol) was dissolved in diethyl ether (50 mL) and 3 in diethyl ether (1 mL, 3 mmol) Precipitate by adding M HCl. The solvent is evaporated to give 520 mg of salt. The precipitate is mixed with water (20 mL) and an aqueous solution of potassium cyanide (450 mg, 7.0 mmol in 15 mL) is added to obtain a slurry. After another 30 minutes, the slurry (pH-10) is extracted with ethyl acetate (100 mL). The organic phase is washed with water (15 mL) and brine (15 mL) and dried (MgSO 4 ). Evaporate the solvent to give 460 mg of crude cyanohydrin. The crude is dissolved in pyridine (10 mL) and cooled to 0 ° C. Phosphorous acid chloride (320 μL, 3.5 mmol) is added and the reaction mixture is stirred at 0 ° C. for 20 minutes. The cooling bath is removed and the reaction mixture is stirred for 13 hours at room temperature. The solvent is evaporated and the residue is mixed with water (15 mL) and the pH is adjusted to 11 with 2 M sodium hydroxide. Extract with ethyl acetate (120 mL) and wash the organic phase with water (15 mL) and brine (15 mL) and dry (MgSO 4 ) using chloroform / methanol / concentrated NH 3 (180: 5: 0.5) as eluent. Purification by column chromatography on silica yields 330 mg (75% yield) of the title compound as a yellow solid: mp 104-105 ° C .; EIMS (70 eV) m / z (relative strength) 253 (47, M + ). <Example 136> 2-cyano-1,2,3,4-tetrahydro-8- [4-methyl (piperazin-1-yl)]-naphthalene 2-cyano-3,4-dihydro-8- [4-methyl (piperazin-1-yl)]-naphthalene (230 mg, 0.90 mmol) was dissolved in dry methanol (15 mL) and cooled to 0 ° C. Let's do it. Magnesium turning (440 mg, 18 mmol) is added and the reaction mixture is stirred at 0 ° C. for 45 minutes and at room temperature for 4 hours. Evaporate the solvent and add 2 M hydrochloric acid (20 mL) to the residue. The mixture is stirred for 1 h, cooled on an ice bath and alkalinized to pH 10 with 2 M ammonia. The solution is extracted with ethyl acetate (60 + 2x30 mL) and the organic phase is washed with brine (15 mL). Dry (MgSO 4 ) and evaporate the solvent to afford 210 mg of crude product. Purification by preparative TLC using chloroform / methanol / concentrated NH 3 (95: 5: 0.5) yields 160 mg (7% yield) of the title compound as a white solid: mp 111-112 ° C .; EIMS (70 eV) m / z (relative intensity) 255 (34, M + ). <Example 137> N- (4-morpholinocarbonylphenyl) -8- [4- (methylpiperazin-1-yl)]-1,2,3,4-tetrahydronaphthalene-2-carboxamide 2-cyano-1,3,4-trihydro-8- [4-methyl (piperazin-1-yl)]-naphthalene in methanol (2 mL) and 2 M sodium hydroxide (1.7 mL, 3.4 mmol) 170 mg, 0.67 mmol) is added. The reaction mixture is heated at reflux for 1 hour and then concentrated to about half the volume. The mixture is stirred for 8 h at 100 ° C. and then cooled on ice. 2 M sodium hydroxide (1.7 mL, 3.4 mmol) is added to give a thick slurry. Water is removed with a stream of nitrogen and the solids are dried at 60 ° C. in vacuo. The crude product is stirred N, N-dimethyl formamide (10 mL) at 90 ° C. for 10 minutes and the poorly soluble material is filtered off. The solvent is evaporated and the residue is dried in vacuo at 60 ° C. to give 179 mg (97% yield) of crude acid: CIMS (CH 4 ) m / z (relative strength) 275 (100, M ++ 1). Acid (119 mg, 0.43 mmol) is mixed with N, N-dimethyl formamide (2 mL), 4-methylmorpholine (95 μL, 0.86 mmol) is added and the mixture is cooled to 0 ° C. Dichlorophosphine chloride (91 μg, 0.43 mmol) is added and the reaction mixture is stirred for 5 minutes on an ice bath and at room temperature for 7 hours. Evaporate the solvent and add 2 M hydrochloric acid (20 mL) to the residue. The mixture is stirred for 1 hour. 4- (morpholinocarbonyl) aniline (89 mg, 0.43 mmol; described in Delvin JP et al., Described in J. Chem. Soc.Perkin Trans. 1. 1975 (9) 830-841) and the reaction mixture was added for 16 hours. Stir at room temperature. The solvent is evaporated and the residue is partitioned between ethyl acetate (60 mL) and 2 M ammonia (5 mL). The organic phase is washed with brine (5 mL) and dried (MgSO 4 ). The solvent is evaporated to give 185 mg of crude product. Purification by preparative TLC on silica using chloroform / methanol / concentrated NH 3 (180: 5: 0.5) gives 70 mg (35% yield) of the title compound as a white foam: EIMS (70 eV) m / z (relative strength) ) 462 (49, M + ). Example 138 (R) -N- [8- (4-methylpiperazin-1-yl)]-1,2,3,4-tetrahydro-2-naphthyl] -4- (4-morpholinomethyl) benz amides 4- (4-morpholinomethyl) benzoic acid (91 mg, 0.41 mmol; Grabenko, AD; Shevchenko, LI; Perkis, PS Fiziol.Akt.Veshchestva 1976, 8, 78-83) and 1,1'-carbo Nyldiimidazole (70 mg, 0.43 mmol) is dissolved in dry N, N-dimethylformamide (3 mL) and stirred at 75 ° C. for 2 hours. The reaction mixture was cooled to 50 ° C. and (R) -amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetra in dry N, N-dimethylformamide (2 mL). Hydronaphthalene (96 mg, 0.39 mmol) solution is added. The reaction mixture is stirred at 50 ° C. for 60 hours and then the solvent is evaporated and dried in vacuo to give 290 mg of crude product. Purification by column chromatography on silica using chloroform / methanol / concentrated NH 3 (95: 5: 0.5) as eluent gave 40 mg (23% yield) of the title compound as a white solid: mp 173-174 ° C .; EIMS (70 eV) m / z (relative strength) 448 (18, M + ); [α] 22 D −0.8 ° (c 0.20, chloroform). Pharmacy Potassium (K + ) or electric field stimulation of [ 3 H] released from the occipital cortex of guinea pigs [ 3 H] -5-HT is released from the laryngeal cortex pieces of guinea pigs preincubated with [ 3 H] -5-HT by electric field stimulation. This release is similar to that caused by nerve stimulation, ie extracellular outflow, from serotonin nerve endings, depending on the presence of Ca 2+ in the culture medium. In guinea pigs (as in humans) 5-HT release is regulated by the level of nerve endings by autoreceptors, which belongs to the 5-HT 1D receptor subtype. Therefore, agonists of the 5-HT 1D receptors reduce the amount of [3H] -5-HT released by (K + ) or electric field stimulation, while release is increased by antagonists of the receptor form. Therefore, testing compounds in this manner is a convenient screening test that measures the efficacy and functional effects of novel 5-HT 1D receptor agonists and antagonists. Method and substance Buffer composition (mM) NaHCO 3 (25), NaH 2 PO 4 . H 2 O (1.2), NaCl (117), KCl (6), MgSO 4 , 7H 2 O (1.2), CaCl 2 (1.3), EDTA Na 2 (0.03). Treat the buffer with gas for at least 30 minutes before using it. The pH of the buffer is about 7.2 at room temperature but rises to about 7.4 at 37 ° C. Preparation of Laryngeal Cortex Pieces Cut the neck of a guinea pig (200-250 g) and remove the entire brain. The laryngeal cortex is excised and cut into 0.4 x 4 mm pieces with a Mcllwain chopper machine. Carefully remove the white part of the tissue with tweezers before cutting it out. The pieces are incubated in 5 ml buffer in the presence of 5 mM pargiline chloride. After incubation with 0.1 mM [ 3 H] -5-HT for an additional 30 minutes, the pieces are transferred to a test tube and washed three times with the same volume of buffer. The pieces are transferred to a melting chamber with a plastic pipette and washed for 40 minutes with a buffer flowing at 0.5 ml / min in the presence of the absorption inhibitor citalopram (2.5 μM). Electric field stimulation of 5-HT emission Melt buffer is collected in 2 ml fractions. The pieces are stimulated for 3 minutes by a series of electricity of frequency 3 Hz, duration 2 ms and current 30 mA in the fourth and thirteenth fractions. The tested drug is added from the eighth fraction to the end of the experiment. result The first electric field (or + K) represents the standard amount of [ 3 H] 5-HT released (S 1 ). A 5-HT 1D antagonist is added between the first and second stimuli, which is the amount following the rise in release (S 2 ) after the second stimulus. See FIG. 1. The S 2 / S 1 ratio, which is the percentage of [ 3 H] -5-HT released after the second stimulus (S 2 ) divided by the one released after the first stimulus (S 1 ), shows the drug effect on delivery agent release. Used to evaluate The compounds of the present invention may also be less toxic, work longer, more potent, have a wider range of activity, produce fewer side effects, are readily absorbed or have other useful pharmaceutical properties.
权利要求:
Claims (32) [1" claim-type="Currently amended] A compound of formula (I) which is (R) -enantiomer, (S) -enantiomer or racemate in the form of a free base or a pharmaceutically acceptable salt or hydrate. <Formula I> (In the above formula, X is N or CH, Y is NR 2 CH 2 , CH 2 -NR 2 , NR 2 -CO, CO-NR 2 or NR 2 SO 2 , R 1 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, R 2 is H or C 1 -C 6 alkyl, R 3 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (CH 2 ) n -aryl, wherein aryl is phenyl or comprises one or two heteroatoms selected from N, O and S Is a heteroaromatic ring, and may be mono- or di-substituted with R 4 and / or R 5 , R 4 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen, CN, CF 3 , OH, C 1 -C 6 alkoxy, NR 6 R 7 , OCF 3 , SO 3 CH 3 , SO 3 CF 3 , SO 2 NR 6 R 7 , phenyl, phenyl-C 1 -C 6 alkyl, phenoxy, C 1 -C 6 alkylphenyl; C 1 -C 6 alkyl-heterocyclic rings containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO 2 ; And an optionally substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO 2 , wherein any substituent (s) is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and phenyl-C 1 -C 6 alkyl); Or COR 8 , R 5 is H, OH, CF 3 , OCF 3 , halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, R 6 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, R 7 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, R 8 is one or two heteroatoms selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CF 3 , NR 6 R 7 , phenyl, or N, O, S, SO and SO 2 , or A heterocyclic ring containing a substituted heteroatom, n is 0-4) [2" claim-type="Currently amended] The compound of claim 1 in the form of a (R) -enantiomer. [3" claim-type="Currently amended] The compound of claim 1 or 2, wherein piperidinyl or piperazinyl is in the 8 position. [4" claim-type="Currently amended] The compound of claim 1 or 2, wherein piperidinyl or piperazinyl is in the 5 position. [5" claim-type="Currently amended] The compound of any one of claims 1-4, wherein Y is NR 2 CO and R 2 is H or CH 3 . [6" claim-type="Currently amended] The compound of any one of claims 1-4, wherein Y is CONR 2 and R 2 is H or CH 3 . [7" claim-type="Currently amended] 7. The compound of claim 1, wherein R 3 is (CH 2 ) n -phenyl, wherein phenyl is para substituted with R 4 and n is 0. 8. [8" claim-type="Currently amended] 8. The compound of claim 1, wherein R 4 is C 1 -C 6 alkyl, phenyl, phenyl-C 1 -C 6 alkyl, cyclohexyl, piperidino, morpholino, CF 3 , 4-pipe Ferridone-1-yl, 1-pyrrolyl, C 1 -C 6 alkoxy or COR 8 , wherein R 8 is phenyl, cyclohexyl, piperidino, 1-piperazinyl, morpholino, CF 3 or 4- Piperidone-1-yl). [9" claim-type="Currently amended] The compound of claim 1, wherein Y is NHCO, R 1 is H or C 1 -C 6 alkyl, R 2 is H, and R 3 is (CH 2 ) n -phenyl, wherein phenyl is para substituted with R 4 . N is 0 and R 4 is piperidino, morpholino, thiomorpholino, 4-piperidone-1-yl or n-butoxy. [10" claim-type="Currently amended] Free base or in the form of a pharmaceutically acceptable salt or hydrate (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (trifluoroacetyl) benzamide, (R) -N- [8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-piperidinobenzamide, (S) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-N, N-diethylaminobenzamide, (R) -N- [8- (4-propylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-ethylbenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonylbenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-butoxybenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (1H-pyrrole-1-yl) benz amides, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-methyl-4-morpholinobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-ethylphenyl) benzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (N, N-dipropylaminosulfonyl Benzamide, (R) -N- [8- (4-ethylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide, (R) -N- [8- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-butoxybenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-cyclohexylbenzamide, (R) -N- [8- (methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-piperidone-1-yl) benzamide , (R) -N-8- (piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, N- (4-morpholinocarbonylphenyl) -8- [4- (methylpiperazin-1-yl)]-1,2,3,4-tetrahydronaphthalene-2-carboxamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-morpholinomethyl) benzamide , (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (N, N-dimethylaminocarbonyl) Benzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonylbenzamide, or Compound which is (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-thiomorpholinobenzamide [11" claim-type="Currently amended] Free base or in the form of a pharmaceutically acceptable salt or hydrate (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -2-methylbenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-cyanobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-fluorobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- (4-hydroxyphenyl) benzamide, And (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -3-phenoxybenzamide. [12" claim-type="Currently amended] Pharmaceuticals comprising a therapeutically effective amount of the compound of any one of claims 1 to 11 as an active substance, which is an enantiomer or racemate in the form of a free base or a pharmaceutically acceptable salt or hydrate, optionally in the form of a diluent, excipient or inert carrier. Composition. [13" claim-type="Currently amended] The pharmaceutical composition according to claim 12, which is used in a disease of 5-hydroxytryptamine mediated. [14" claim-type="Currently amended] The method of claim 12, wherein the mood disorder, anxiety disorder, personality disorder, obesity, anorexia, abnormal appetite, premenstrual syndrome, sexual disorders, alcoholism, excessive smoking, autism, mental and mental function, hyperactivity disorder, migraine, memory Pharmaceutical compositions for use in the treatment of disorders, pathological aggregation, schizophrenia, endocrine disorders, seizures, dyskinesia, Parkinson's disease, thermoregulation disorders, pain, hypertension, incontinence, vasospasm and tumor growth inhibition. [15" claim-type="Currently amended] A compound as defined in any one of claims 1 to 11 for use in therapy. [16" claim-type="Currently amended] A compound as defined in any one of claims 1 to 11 for use as a 5-HT 1D antagonist. [17" claim-type="Currently amended] A compound as defined in any one of claims 1 to 11 for use in the treatment of a 5-hydroxytryptamine mediated disease. [18" claim-type="Currently amended] A compound as defined in claim 17 for use in the treatment of 5-hydroxytryptamine mediated diseases in the central nervous system. [19" claim-type="Currently amended] Mood disorders, anxiety disorders, personality disorders, obesity, anorexia, abnormal appetite, premenstrual syndrome, sexual disorders, alcoholism, excessive smoking, autism, mental and mental dysfunction, hyperactivity disorder, migraine, memory disorders, pathological aggregation, A compound as defined in claim 18 for use in the treatment of schizophrenia, endocrine disorders, seizures, dyskinesia, Parkinson's disease, thermoregulation disorders, pain and hypertension. [20" claim-type="Currently amended] A compound as defined in claim 17 for use in the treatment of 5-hydroxytryptamine-mediated incontinence, vasospasm and tumor growth inhibition. [21" claim-type="Currently amended] Use of a compound as defined in any one of claims 1 to 11 in the manufacture of a medicament for the treatment of a disease of 5-hydroxytryptamine mediated. [22" claim-type="Currently amended] Use of a compound as defined in any of claims 1 to 11 in the manufacture of a medicament for the treatment of 5-hydroxytryptamine-mediated diseases in the central nervous system. [23" claim-type="Currently amended] Mood disorders, anxiety disorders, personality disorders, obesity, anorexia, abnormal appetite, premenstrual syndrome, sexual disorders, alcoholism, excessive smoking, autism, mental and mental dysfunction, hyperactivity disorder, migraine, memory disorders, pathological aggregation, Use of a compound as defined in any one of claims 1 to 11 in the manufacture of a medicament for the treatment of schizophrenia, endocrine disorders, seizures, dyskinesia, Parkinson's disease, temperature control disorders, pain and hypertension. [24" claim-type="Currently amended] Use of a compound as defined in any one of claims 1 to 11 in the manufacture of a medicament for the treatment of 5-hydroxytryptamine mediated incontinence, treatment of vasospasm and tumor growth inhibition. [25" claim-type="Currently amended] Use of a compound as defined in any one of claims 1 to 11 in the manufacture of a medicament that acts as a 5-HT 1D antagonist. [26" claim-type="Currently amended] A method of treating a 5-hydroxytryptamine mediated disease, wherein a mammal, including a human being in need thereof, is administered to a therapeutically effective amount of a compound as defined in claim 1. [27" claim-type="Currently amended] The method of claim 26, wherein the 5-hydroxytryptamine mediated disease is treated in the central nervous system. [28" claim-type="Currently amended] The method of claim 27, wherein 5-HT 1D antagonist is required for treatment. [29" claim-type="Currently amended] 29. The method of claim 27, wherein mood disorders, anxiety disorders, personality disorders, obesity, anorexia, abnormal appetite, premenstrual syndrome, sexual disorders, alcoholism, excessive smoking, autism, mental and mental function, hyperactivity disorder, migraine, memory Disorders, pathological aggregation, schizophrenia, endocrine disorders, seizures, dyskinesia, Parkinson's disease, thermoregulation disorders, pain and hypertension. [30" claim-type="Currently amended] The method of claim 27, for 5-hydroxytryptamine mediated incontinence, treatment of vasospasm, and tumor growth inhibition. [31" claim-type="Currently amended] A (i). R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, Y is NR 2 CO, R 2 is hydrogen, X is N or CH, and R 3 is defined in formula I of claim 1 As described above, the compounds of formula (XII) or (XXVIII) may be acylated using activated carboxylic acid R 3 -COL, wherein L is a leaving group, or R 3 -COOH, which is a carboxylic acid with an activator. Or A (ii). When R 1 is hydrogen, Y is NR 2 CO, R 2 is hydrogen, X is N or CH, and R 3 is as defined in formula (I) of claim 1, R 3 -COL ( Wherein L is a leaving group) or a carboxylic acid R 3 -COOH with an activator to acylate the compound of formula XIVa and then remove the protecting group R d , A (iii). R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, Y is NR 2 CO, R 2 is C 1 -C 6 alkyl, X is N or CH and R 3 is the chemical formula of claim 1 As defined in I, acylation of the compound of formula XLIIIa using R 3 -COL, wherein L is a leaving group, or carboxylic acid R 3 -COOH together with an activator, is used. Or B (i). R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, Y is CONR 2 , R 2 is hydrogen or C 1 -C 6 alkyl, X is N or CH, and R 3 is first When as defined in formula I of claim 1, the activated carboxylic acid of the compound of formula XXXVa is reacted with aniline or amine HNR 2 R 3 , or B (ii). R 1 is hydrogen, Y is CONR 2 , R 2 is hydrogen or C 1 -C 6 alkyl, X is N or CH, R d is a protecting group, and R 3 is as defined in formula I of claim 1 If the same, the activated carboxylic acid of the compound of formula XLIIa is reacted with aniline or amine HNR 2 R 3 and then the protecting group R d is removed, C. R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, Y is NR 2 SO 2 , R 2 is hydrogen, X is N or CH, and R 3 is of formula (I) As defined herein, reacting a compound of formula XIIa with an activated sulfonic acid R 3 -SO 2 L, wherein L is a leaving group, or D. (i) reducing the compound of formula (I) obtained from process A (i), A (ii) or A (iii), wherein R 1 is hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, Y Is NR 2 CH 2 and R 2 is hydrogen or C 1 -C 6 alkyl and X is N or CH and R 3 is a compound of formula I as defined in formula I of claim 1, or (ii) reducing the compound of formula (I) obtained from process B (i) or B (ii), wherein R 1 is hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, and Y is CH 2 NR 2 Or R 2 is hydrogen or C 1 -C 6 alkyl, X is N or CH, and R 3 obtains a compound of formula I as defined in formula I of claim 1, E. R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, Y is NR 2 CH 2 , R 2 is hydrogen or C 1 -C 6 alkyl, X is N or CH, R When 3 is as defined in formula (I) of claim 1, the compound of formula (XIIa), (XIVa) or (XLIIIa) is substituted with R 3 CH 2 -L, wherein L is halogen such as bromine or chlorine or alkyl such as mesylate or tosylate; Or an leaving group of an arylsulfonyloxy group) and then optionally removing the protecting group, F. R 1 is C 1 -C 6 alkyl, Y is NR 2 CO, R 2 is hydrogen or C 1 -C 6 alkyl, X is N or CH, and R 3 is defined in formula I of claim 1 Alkylation of the compound of formula (Ie) with R 1 -L, wherein L is a halogen or broth or chlorinated alkyl group such as mesylate or tosylate or a leaving group of an arylsulfonyloxy group A process for preparing the compound of formula I according to claim 1. [32" claim-type="Currently amended] A compound of formula Wherein Z is NH 2 or COOH, X is CH or N, and R 1 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl
类似技术:
公开号 | 公开日 | 专利标题 US9708280B2|2017-07-18|Phenyl-piperazine derivatives as serotonin reuptake inhibitors DK1836179T3|2015-05-26|Piperidine and piperazine-1-carboxylic acid amide derivatives and related compounds as modulators of fat acid amide hydralase | for the treatment of ancient, pain and other conditions DE60312998T2|2007-12-13|1-amido-4-phenyl-4-benzyloxymethyl-piperidine derivative and related compounds as neurokinin-1 | antagonsists for the treatment of crush, depressions, anxieties and husten ES2444370T3|2014-02-24|Histamine 3 receptor antagonists DE60014083T2|2006-03-02|Substituted heterocyclyl condensed gamma carboline US5545643A|1996-08-13|Azaheterocyclylmethyl-chromans JP5031745B2|2012-09-26|Metaindole glutamate receptor potentiating isoindolone CA2780218C|2018-10-16|Morpholinothiazoles as alpha 7 positive allosteric modulators US5424313A|1995-06-13|Bibyclic heteroacrylpiperazine derivatives having psychotropic activity, and pharmaceutical compositions containing these derivatives KR101432112B1|2014-08-21|New Carbonylated |cyclohexanes as dopamine D3 receptor ligands EP1527048B1|2008-01-09|N-[phenyl|methyl]benzamide derivatives, preparation thereof, and use thereof in therapy CN102395558B|2015-09-02|Aminotetralin derivatives, the pharmaceutical composition containing described Aminotetralin derivatives and purposes in the treatment thereof ES2206963T3|2004-05-16|Derivatives of indol and 2,3-dihydroindol, its preparation and use. JP4400566B2|2010-01-20|Benzamide derivatives or salts thereof US5652246A|1997-07-29|Piperidine compounds JP3421323B2|2003-06-30|Piperidine CCR-3 receptor antagonist EP1562918B1|2008-01-16|Substituted benzoxazinones and uses thereof US6084098A|2000-07-04|Benzylpiperazinyl and piperidinyl ethanone derivatives: dopamine receptor subtype specific ligands KR100687992B1|2007-02-27|4-piperidinyl alkylamine derivatives as muscarinic receptor antagonists ES2280417T3|2007-09-16|Derivatives of benzoxazinona, its preparation and use. CA2529126C|2011-11-08|Azetidine compounds CN100374440C|2008-03-12|Spirosubstituted piperidines as selective melanin concentrating hormone receptor antagonists for the treatment of obesity JP5209480B2|2013-06-12|Compounds having activity at the M1 receptor and their use in medicine US7056921B2|2006-06-06|Substituted chroman derivatives JP5502733B2|2014-05-28|Dual modulators of 5-HT2A and D3 receptors
同族专利:
公开号 | 公开日 US6410530B1|2002-06-25| IL145681D0|2002-06-30| YU40998A|1999-09-27| BR9708093A|1999-07-27| PL329121A1|1999-03-15| ID16298A|1997-09-18| AU2186597A|1997-10-10| NO984385D0|1998-09-21| HU9902454A2|1999-11-29| HU9902454A3|2002-01-28| CN1073101C|2001-10-17| US6124283A|2000-09-26| SK282359B6|2002-01-07| SK118898A3|1999-03-10| WO1997034883A1|1997-09-25| IS4844A|1998-09-09| DE69718771T2|2003-10-23| DE69718771D1|2003-03-06| CZ301998A3|1999-05-12| HRP970166A2|1998-04-30| CA2247940A1|1997-09-25| AT231847T|2003-02-15| AU709856B2|1999-09-09| IL126070D0|1999-05-09| SE9601110D0|1996-03-22| AR010080A1|2000-05-17| EE9800300A|1999-02-15| NO311803B1|2002-01-28| EP0888319B1|2003-01-29| AR006360A1|1999-08-25| ZA9702056B|1997-09-22| JP2000506883A|2000-06-06| CN1219170A|1999-06-09| EP0888319A1|1999-01-07| NZ331613A|2000-03-27| TR199801868T2|1998-12-21| NO984385L|1998-11-23|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
1996-03-22|Priority to SE9601110-1 1996-03-22|Priority to SE9601110A 1997-03-20|Application filed by 클래스 빌헬름슨, 아스트라 악티에볼라그 1997-03-20|Priority to PCT/SE1997/000469 2000-11-06|Publication of KR20000064751A
优先权:
[返回顶部]
申请号 | 申请日 | 专利标题 SE9601110-1|1996-03-22| SE9601110A|SE9601110D0|1996-03-22|1996-03-22|Substituted 1,2,3,4-tetrahydronaphthalene derivatives| PCT/SE1997/000469|WO1997034883A1|1996-03-22|1997-03-20|Substituted 1,2,3,4-tetrahydronaphthalene derivatives| 相关专利
Sulfonates, polymers, resist compositions and patterning process
Washing machine
Washing machine
Device for fixture finishing and tension adjusting of membrane
Structure for Equipping Band in a Plane Cathode Ray Tube
Process for preparation of 7 alpha-carboxyl 9, 11-epoxy steroids and intermediates useful therein an
国家/地区
|