BACKGROUND OF THE INVENTION The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments (see eg Stark, H.; Schlicker, E.; Schunack, W. , Drugs Fut. 1996, 21, 507-520; Leurs, R.; Timmerman, H.; Vollinga, R. C., Progress in Drug Research 1995,45, 107-165). Recently, the human lista- mine H3 receptor has been cloned, cf Lovenberg, T. W. et al, Molecular Pharmacology, June 1999,55, 1101-1107. The histamine H3 receptor is a presynaptic autoreceptor located both in the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor show intrinsic, constitutive activity, in vitro as well as in vivo (ie it is active in the absence of an agonist; see eg Morisset et al., Nature 2000,408, 860-864). Compounds acting as inverse agonists can inhibit this activity. The histamine H3 receptor has been dem- onstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain. A his- tamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of his- tamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists could be important mediators of neuronal activity. Accord- ingly, the histamine H3 receptor is an important target for new therapeutics.

Piperazines similar to the compounds of the present invention have previously been prepared, and their biological properties have been investigated.

JP 57175168, JP 01035827 and WO 81/02421 disclose the compound: JP 63026754 discloses the compound:

Nishi et al. (Chem. Pharm. Bull. ; 31 ; 3; 1983; 852-860) disclose the compound: Tiwari et al. (Drug Des. Discovery 1995; 12 (3); 249-58) and Meanwell et al. (J. Med.

Chem. 1992; 35 (14); 2688-96 disclose the compound: WO 95/00512 discloses the compound: WO 00/51984 discloses indole-containing piperazine derivatives.

DE 19621221 discloses the compound:

US 2,724, 713 discloses the following compound: Dauzonne et al. (J. Med. Chem. Chim. Ther. ; 30; 1; 1995; 53-60) disclose the com- pound: Vejdelek et al. (Res. Inst Pharm. Biochem. Commun.; 48; 10; 1983; 2977-88) dis- close the following compound as a potential antitussive: Brown et al. (J. Am. Chem. Soc.; 119; 14; 1997; 3288-3295) disclose the following compound:

Gayral et al. (Arzneim.-Forsch. ; 45; 10; 1995; 1122-1127) disclose the following compound: WO 00/76970 discloses the compound:

EP 0 203 743 discloses the compound:

WO 92/02498 and Valenta et al. (Collect. Czech. Chem. Commun. 1990; 55 (6); 1613-29) disclose the compound: DE 2360362 discloses the compound: CA59: 13982a discloses the compound:

DE 2141634 discloses the compound:

However, these references neither disclose nor suggest that these substituted piperazines may have a histamine H3 receptor antagonistic or agonistic activity.

Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Most of these are imidazole derivatives (see eg Stark et al., Drugs of the Future 1996, 21, 507-520; Tozer, Kalinddjian, Expert Opinion on Therapeutic Patents, 2000, 10, 1045-1055). However, recently some imidazole-free ligands of the histamine H3 receptor have been described (see eg Walczynski et al., Arch. Pharm. Pharm. Med. Chem. 1999, 332,389-398 ; Linney et al., J. Med. Chem. 2000,43, 2362-2370; Ganellin et al., Arch.

Pharm. Pharm. Med. Chem. 1998, 331, 395-404; Waiczynski et al., II Farmaco 1999,54, 684-694; WO 99/42458, EP 0 978 512, WO 97/17345, US 6,316, 475, WO 01/66534, WO

01/74810, WO 01/44191, WO 01/74815, WO 01/74773, WO 01/74813, WO 01/74814 and WO 02/12190.

However, these compounds differ structurally from the present compounds.

In view of the art's interest in histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that a novel class of substituted piperazines has a high and specific affinity to the histamine H3 receptor.

Due to their interaction with the histamine H3 receptor, the present compounds are useful in the treatment of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial. Thus, the compounds may find use eg in the treatment of diseases of the central nervous system, the peripheral nervous system, the car- diovascular system, the pulmonary system, the gastrointestinal system and the endocrino- logical system.

DEFINITIONS In the structural formulas given herein and throughout the present specification, the following terms have the indicated meaning: The term"halogen"means F, Cl, Br or 1.

The term"C16-alkyl"as used herein represent a saturated, branched or straight hy- drocarbon group having from 1 to 6 carbon atoms. Typical C16-alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

The term"C39-alkyl"as used herein represent a saturated, branched or straight hy- drocarbon group having from 3 to 9 carbon atoms. Typical C3-9-alkyl groups include, but are not limited to, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl and the like.

The term"C26-alkenyl"as used herein represents a branched or straight hydrocar- bon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1, 3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl and the like.

The term"C39-alkenyl"as used herein represents a branched or straight hydrocar- bon group having from 3 to 9 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-buta-

dienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-hept- enyl, 1-octenyl, 2-octenyl, 1-nonenyl and the like.

The term"C26-alkynyl"as used herein represents a branched or straight hydrocar- bon group having from 2 to 6 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1- pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl and the like.

The term"C39-alkynyl"as used herein represents a branched or straight hydrocar- bon group having from 3 to 9 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pent- ynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 1-heptynyl, 2-heptynyl, 1-octynyl, 2-octynyl, 1-nonynyl and the like.

The term "C1-6-alkoxy" as used herein, alone or in combination, refers to the radical -O-C16-alkyl where C16-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The term"C16-alkylthio"as used herein, alone or in combination, refers to the radi- cal-S-C16-alkyl where C16-alkyl is as defined above. Representative examples are methyl- thio, ethylthio, isopropylthio, n-propylthio, butylthio, pentylthio and the like.

The term"C16-alkylsulfonyl"as used herein, alone or in combination, refers to the radical-S (=O) 2-C16-alkyl where C16-alkyl is as defined above. Representative examples are methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl, butylsulfonyl, pentylsulfonyl and the like.

The term"C16-alkanoyl"as used herein, alone or in combination, refers to the radi- cal-C (=O) H or-C (=O) C16-alkyl where C1-6-alkyl is as defined above. Representative exam- ples are formyl, acetyl, propionyl, butanoyl, pentanol, hexanoyl, heptanoyl and the like.

The term"Cl-7-alkanoyl"as used herein, alone or in combination, refers to the radi- cal-C (=O) H or-C (=O) C16-alkyl where C16-alkyl is as defined above. Representative exam- ples are formyl, acetyl, propionyl, butanoyl, pentanol, hexanoyl, heptanoyl and the like.

The term"C38-cycloalkyl"as used herein represents a saturated, monocyclic, car- bocyclic group having from from 3 to 8 carbon atoms. Representative examples are cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term"C58-cycloalkenyl"as used herein represents a monocyclic, carbocyclic, non-aromatic group having from 5 to 8 carbon atoms and at least one double bond. Repre- sentative examples are cyclopentenyl, cyclohexenyl, cyclohepentyl, cyclooctenyl, and the like.

The term"aryl"as used herein is intended to include carbocyclic aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi-and tricyclic, carbocyclic, aromatic ring systems. Representative examples are phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above.

Non-limiting examples of such partially hydrogenated derivatives are 1,2, 3,4-tetrahydro- naphthyl, 1, 4-dihydronaphthyl and the like.

The term"aryloxy"as used herein refers to the radical-O-aryl where aryl is as de- fined above. Non-limiting examples are phenoxy, naphthoxy, anthracenyloxy, phenantrenyl- oxy, fluorenyloxy, indenyloxy and the like.

The term"heteroaryl"as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as 5 to 7 membered monocyclic and 8 to 14 membered bi-and tricyclic aromatic, het- erocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Representative examples are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, inda- zolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, car- bazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. Non- limiting examples of such partially hydrogenated derivatives are 2, 3-dihydrobenzofuranyl, pyr- rolinyl, pyrazolinyl, indanyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.

As used herein, the phrase"4 to 7 membered, saturated or unsaturated ring"is in- tended to include heterocyclic rings which are saturated or contain one or two double bonds.

Certain of the above defined terms may occur more than once in the structural for- mulae, and upon such occurrence each term shall be defined independently of the other.

The term"optionally substituted"as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.

"Aryl-C14-alkyl","aryl-C14-alkoxy"etc. mean C14-alkyl or C1-alkoxy as defined above, substituted by aryl as defined above, for example:

The term"treatment"as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condi- tion. The patient to be treated is preferably a mammal, in particular a human being.

DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula (I) : wherein --- designates a single bond or a double bond, R'is (a) C3-Cg-alkyl, C3-Cg-alkenyl, C3-Cg-alkynyl, which may optionally be substituted with one or more substituents selected from halogen and hydroxy, (b) C38-cycloalkyl, C58-cycloalkenyl, C38-cycloalkyl-C16-alkyl, di (C38-cycloalkyl)-C16-alkyl, C3-8-cycloalkyl-C2-6alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C5-8-cycloalkenyl-C1-6-alkyl, C58-cycloalkenyl-C26-alkenyl, C58-cycloalkenyl-C26-alkynyl, 4-pyridyl or tetrahydropyranyl, wherein the cyclic moieties may optionally be substituted with one or more substitu- ents selected from C16-alkyl, halogen, trifluoromethyl, 2,2, 2-trifluoroethyl and C3 8-cycloalkyl,

X is- (CH2)m-(Z)n-(CR2R3)o-(CH2)p-(V)q-, m and p independently are 0, 1,2, 3 or 4, n, o and q independently are 0 or 1, Z and V independently are -O-, -NH-, -C (=O)-,-S-,-S (=O)-,-S (=O) 2-, -CH=CH- or -C#C-, R2 and R3 independently are hydrogen, C1-6-alyl or hydroxy, Y is (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents se- lected from 'halogen, nitro, cyano, oxo, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, Ci. C1-6-alkoxy, -C(=O)O-C1-6-alkyl, C3-8-cycloalkyl, trifluoromethyl, trifluoro- methoxy,-NR4R5 and-O (C=O) NR4R5, or wherein two substituents in adjacent posi- tions together form a radical -O-(CH2)1-3-O-, wherein R4 and R5 independently are hydrogen, C16-alkyl, C38-cycloalkyl, C17-alkanoyl or aryl, or R4 and R5 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, aryl, aryl-C16-alkyl, aryloxy and aryl-C16-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from o halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR6R7 and -O (C=O) NR6R7, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R6 and R7 independently are hydrogen, C16-alkyl, C3-8-cycloalkyl, C17-alkanoyl or aryl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, (b) C3-8-cycloalyl or C58-cycloalkenyl, which may optionally be substituted with one or more substituents selected from # C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halo- gen,

aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from o halogen, nitro, cyano, hydroxy, Ci. C1-6-alkylthio, C1-6-alkylsulfonyl, C16-alkyl, C16-alkoxy, C38-cycloalkyl, trifluoromethyl, trifluoromethoxy,-NR8R9 and-O (C=O) NR8R9, or wherein two substituents in adjacent positions together form a radical-O-(CH2) 13-O-, wherein R8 and R9 independently are hydrogen, C16-alkyl, C38-cycloalkyl, C17-alkanoyl or aryl, or R8 and R9 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, with the proviso that when Y is selected from the group (a), the sum of m, n, o, p and q must be at least 1, and with the proviso that when R'is cyclohexyl and X is -(CH2)3-O-, Y must not be 1,2, 3, 4-tetrahydro-2-oxo-6-quinolinyl, 1, 2- dihydro-2-oxo-6-quinolinyl or 3-ethyl-2, 3-dihydro-2-oxo-1H-benzimidazol-5-yl, R'is cycloheptyl and X is -(CH2)3-O-, Y must not be 2,3-dihydro-2-oxo-1 H-imidazo [4,5-b]- quinolin-7-yl, R'is cycloheptyl and X is -(CH2)4-O-, Y must not be 2, 3-dihydro-2-oxo-1 H-pyrrolo [2, 3- b] quinolin-6-yl, Y must not be unsubstituted or substituted indolyl, R'is cycloheptyl and X is-CH2-, Y must not be (3-benzyl) phenyl, R'is cyclohexyl and X is-O-CH2-, Y must not be phenyl, R'is cyclohexyl and X is-CH=CH-, Y must not be benzofuran-2-yl, R'is cyclohexyl and X is-NH-, Y must not be cyclohexyl, R1 is 2-propen-1-yl and X is-NH-, Y must not be phenyl,

R'is n-propyl and X is-C-C-, Y must not be phenyl, R'is cyclopentyl and X is-CH2-O-, Y must not be 4-phenyl-1, 2, 3-thiadiazol-5-yl, R'is isopropyl and X is-CH2-, Y must not be 4-oxothiazolidin-3-yl, R'is isopropyl and X is-CH2-, Y must not be 2-oxopyrrolidin-1-yl, R'is isopropyl and X is -O-, Y must not be 6-(5-chloropyridin-2-yl)-2, 3,6, 7-tetrahydro-7-oxo- 5H-1, 4-dithiino [2,3-c] pyrrol-5-yl, R'is isopropyl and X is-CH=CH-, Y must not be 5-nitrofuran-2-yl, R'is isopropyl and X is -O-, Y must not be 3-oxo-2-pyridin-2-yl-2, 3-dihydro-1H-isoindol-1-yl, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention relates to a compound of the general formula (11) : wherein R, X and Y are as defined for formula (I), as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutical acceptable salt thereof.

In another embodiment, the invention relates to a compound of the general formula (12):

wherein R', X and Y are as defined for formula (I), as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutical acceptable salt thereof.

In yet another embodiment, R1 is C38-cycloalkyl, which may optionally be substituted with one or two substituents selected from C16-alkyl and C3-8-cycloalkyl.

In still another embodiment, R'is 1-ethylcyclopropyl, 1-methylcyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a further embodiment, R'is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In yet a further embodiment, R'is C3-8-cycloalkyl-CI-6-alkyl.

In still a further embodiment, R'is cyclopropylmethyl or 1-cyclopropyl-1-methylethyl.

In another embodiment, R'is 1-cyclopropyl-1-methylethyl.

In yet another embodiment, R'is 4-pyridyl.

In still another embodiment, R'is tetrahydropyranyl.

In still a further embodiment, R1 is C3-9-alkenyl, which may optionally be substituted with one or two halogen substituents.

In another embodiment, R'is allyl.

In yet another embodiment, R'is C3-9-alkyl, which may optionally be substituted with one or more hydroxy substituents.

In still another embodiment, R'is 1-ethylpropyl, isopropyl, n-proyl or n-butyl.

In yet another embodiment, R1 is C58-cycloalkenyl.

In a further embodiment, X is -(CH2)0-4-, -(CH2)0-4-CH=CH-(CH2)0-4-, -(CH2)0-4-O-(CH2)0-4, - (CH2) o-4-S- (CH2) o-4-,- (CH2) o-4-C (=0)- (CH2) o-4-,- (CH2) o-4-CH (OH) -,-CH (OH)- (CH2) o-4-, -CH(OH)-(CH2)0-4-C(=O)-, -CH=CH-CH(OH)-, -(CH2)0-4-O-(CH2)1-4-O- or - (CH2) o-4-CH=CH- (CH2) o-4-C (=)-.

In another embodiment, X is-(CH2) 14-,-CH=CH-,-CH=CH-CH2-,-O-,-(CH2) 14-O-, -O-(CH2)1-4-, -(CH2)1-4-S-(CH2)1-4-, -(CH2)1-4-S-, -(CH2)1-4-C(=O)-, -O-(CH2)2-3-O-, -CH=CH-C (=O)-,-CH=CH-CH (OH) -, -CH (OH)-CH2-C (=O)- or -CH(OH)-CH2-CH2-.

In still another embodiment, X is -(CH2)1-4-, -CH=CH-, -(CH2)1-4-O-, -O-(CH2)1-4-, - (CH2)1-4-S-(CH2)1-4-, -(CH2)1-4-S-, -(CH2)1-4-C(=O)-, -O-(CH2)2-3-O- or -CH=CH-C(=O)-.

In a further embodiment, X is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-,-CH=CH-, -CH2-O-, - (CH2)3-O-, -O-(CH2)2-, -CH2-S-CH2-, -CH2-S-, -(CH2)2-C(=O)- or -(CH2)3-C(=O)-.

In still a further embodiment, X is -CH2-, -(CH2)3-, -CH=CH-, -O-(CH2)2- or -(CH2) 2-C (=O)-.

In yet a further embodiment, X is- (CH2) 3-,- (CH2) 2-C (=O)- or -CH2-.

In still a further embodiment, Y is phenyl, pyridyl, naphthyl, benzoxazolyl, indanyl, ben- zothienyl, benzthiazolyl, pyrazolyl or benzofuryl, which may optionally be substituted as de- fined for formula (I).

In yet a further embodiment, Y is phenyl or naphthyl, which may optionally be substituted as defined for formula (I).

In still a further embodiment, Y is phenyl, which may optionally be substituted as defined for formula (I).

In yet a further embodiment, Y is C38-cycloalkyl, which may optionally be substituted as de- fined for formula (I).

In still a further embodiment, Y is cyclohexyl, which may optionally be substituted as defined for formula (I).

In yet another embodiment, Y is unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, Ci. C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, -C(=O)O-C1-6-alkyl, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR4R5 and - O (C=O) NR4R5, or wherein two substituents in adjacent positions together form a radical-0- (CH2) 1-3-0-, wherein R4 and R5 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C17-alkanoyl or aryl, or R4 and R5 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, phenyl, phenoxy and phenyl-C1-6-alkoxy, wherein the ring moieties optionally may be substi- tuted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR6R7 and -O(C=O)NR6R7, or wherein two substituents in adjacent position form a radical - O-(CH2)1-3-O-, wherein R5 and R7 independently are hydrogen, C16-alkyl, C3-8-cycloalkyl, Cl-7-alkanoyl or aryl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring.

In still another embodiment, Y is unsubstituted or substituted with one or more substituents selected from halogen, nitro, hydroxy, C17-alkanoyl, C16-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy,-NR4R5and-O (C=O) NR4R5, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R4 and R5 are C16-alkyl, or R4 and R5 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, phenyl and phenyl-C16-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen and C16-alkyl.

In still another embodiment, Y is unsubstituted or substituted with one to three substituents selected from C16-alkoxy,-CF3, halogen, -N (CI-6-alkyl) 2, phenyl and 4-fluorophenyl, or wherein two substituents in adjacent positions together form a radical-O-(CH2) 13-O-.

In a further embodiment, Y is substituted with one halogen substituent.

In still a further embodiment, Y is substituted with one-N (C16-alkyl) 2 substituent.

In yet a further embodiment, Y is unsubstituted or substituted with one or two substituents selected from aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C17-alkanoyl, C16-alkylthio, C16-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR8R9 and - O (C=O) NR$R9, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R8 and R9 independently are hydrogen, C16-alkyl, C3-8-cycloalkyl, C17-alkanoyl or aryl, or R3 and R9 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring.

In another embodiment, Y is unsubstituted or substituted with one or two substituents se- lected from phenyl and phenoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR8R9 and - O (C=O) NR8R9, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R8 and R9 independently are hydrogen, C16-alkyl, C38-cycloalkyl, C17-alkanoyl or aryl, or R8 and R9 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring.

In yet another embodiment, Y is unsubstituted or substituted with phenyl, which is unsubsti- tuted or substituted with halogen.

In another aspect, the present invention relates to a compound of the general formula (I") : wherein designates a single bond or a double bond, R'is (a) C3-Cg-alkyl, C3-Cg-alkenyl, C3-Cg-alkynyl, which may optionally be substituted with one or more substituents selected from halogen and hydroxy, (b) C38-cycloalkyl, C58-cycloalkenyl, C38-cycloalkyl-C16-alkyl, di (C38-cycloalkyl)-C16-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C5-8-cycloalkenyl-C1-6-alkyl, C5-8-cycloalkenyl-C2-6-alkenyl, C5-8-cycloalkenyl-C2-6-alkynyl, 4-pyridyl or tetrahydropyranyl, wherein the cyclic moieties may optionally be substituted with one or more substitu- ents selected from C1-6-alkyl, halogen, trifluoromethyl, 2,2, 2-trifluoroethyl and C3 8-cycloalkyl, X is- (CH2) m-(Z)n-(CR2R3)o-(V)p-, m and o independently are 0,1, 2,3 or 4, n and p independently are 0 or 1, Z and V independently are-O-,-NH-,-C (=O)-,-S-,-S (=O)-,-S (=O) 2-, -CH=CH- or -C#C-,

R2 and R3 independently are hydrogen, C1-6-alkyl or hydroxy, Y is (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents se- lected from halogen, nitro, cyano, oxo, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR4R5 and - O (C=O) NR4R5, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R4 and R5 independently are hydrogen, C16-alkyl, C38-cycloalkyl, C1-6-alkanoyl or aryl, or R4 and R5 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, # aryl, aryl-C1-6-alkyl and aryl-CI-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from o halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR6R7 and-O (C=O) NR6R7, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R6 and R7 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, (b) C38-cycloalkyl or C58-cycloalkenyl, which may optionally be substituted with one or more substituents selected from # C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halo- gen, aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from o halogen, nitro, cyano, hydroxy, G-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C16-alkyl, C16-alkoxy, C38-cycloalkyl, trifluoromethyl, trifluoromethoxy,-NR8R9 and-O (C=O) NR8R9, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-,

wherein R8 and R9 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C16-alkanoyl or aryl, or R and R9 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, with the proviso that when Y is selected from the group (a), the sum of m, n, o and p must be at least 1, and with the proviso that when R'is cyclohexyl and X is -(CH2)3-O-, Y must not be 1,2, 3, 4-tetrahydro-2-oxo-6-quinolinyl, 1,2- dihydro-2-oxo-6-quinolinyl or 3-ethyl-2, 3-dihydro-2-oxo-1 H-benzimidazol-5-yl, R'is cycloheptyl and X is -(CH2)3-O-, Y must not be 2, 3-dihydro-2-oxo-1 H-imidazo [4,5-b]- quinolin-7-yl, R'is cycloheptyl and X is -(CH2)4-O-, Y must not be 2, 3-dihydro-2-oxo-1 H-pyrrolo [2,3- b] quinolin-6-yl, R'is cyclohexyl and X is- (CH2) 2-, Y must not be 2- (4-chlorophenyl)-1 H-indol-3-yl or 2- (4- bromophenyl)-1 H-indol-3-yl, R'is cycloheptyl and X is-CH2-, Y must not be (3-benzyl) phenyl, R'is cyclohexyl and X is-O-CH2-, Y must not be phenyl, R'is cyclohexyl and X is-CH=CH-, Y must not be benzofuran-2-yl, R'is cyclohexyl and X is-NH-, Y must not be cyclohexyl, R'is 2-propen-1-yl and X is-NH-, Y must not be phenyl, R'is n-propyl and X is -C#C-, Y must not be phenyl, R'is cyclopentyl and X is-CH2-O-, Y must not be 4-phenyl-1, 2, 3-thiadiazol-5-yl,

R'is isopropyl and X is-CH2-, Y must not be 4-oxothiazolidin-3-yl, R'is isopropyl and X is-CH2-, Y must not be 2-oxopyrrolidin-1-yl, R'is isopropyl and X is -O-, Y must not be 6- (5-chloropyridin-2-yl)-2, 3,6, 7-tetrahydro-7-oxo- 5H-1, 4-dithiino [2,3-c] pyrrol-5-yl, R'is isopropyl and X is-CH=CH-, Y must not be 5-nitrofuran-2-yl, R'is isopropyl and X is -O-, Y must not be 3-oxo-2-pyridin-2-yl-2, 3-dihydro-1H-isoindol-1-yl, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutical acceptable salt thereof.

In one embodiment, the invention relates to a compound of the general formula (11) : wherein R', X and Y are as defined for formula (I").

In another embodiment, the invention relates to a compound of the general formula (12) : wherein R', X and Y are as defined for formula (l'').

In yet another embodiment, R'is C3_8-cycloalkyl, which may optionally be substituted with one or two substituents selected from C1-6-alkyl and C38-cycloalkyl : Examples hereof are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a further embodiment, R'is C3-8-cycloalkyl-Cl-6-alkyl.

In still a further embodiment, R'is 4-pyridyl.

In yet a further embodiment, R'is C3-9-alkenyl, which may optionally be substituted with one or two halogen substituents. An example hereof is allyl.

In another embodiment, R1 is C39-alkyl, which may optionally be substituted with one or more hydroxy substituents. Examples hereof are 1-ethylpropyl, isopropyl, n-proyl or n-butyl.

In yet another embodiment, X is-(CH2) 04-,-(CH2) 04-CH=CH-(CH2) 04-,-(CH2) 04-O-(CH2) 04-, -(CH2)0-4-S-(CH2)0-4-, -(CH2)0-4-C(=O)-(CH2)0-4-, -(CH2)0-4-CH(OH)-, -(CH2)0-4-O-(CH2)1-4-O- or-(CH2) 04-CH=CH-(CH2) 04-C (=O)-.

In still another X is -(CH2)1-4-, -CH=CH-, -(CH2)1-4-O-, -O-(CH2)1-4-, -(CH2)1-4-S-(CH2)1-4-, -(CH2)1-4-S-, -(CH2)1-4-C(=O)-, -O-(CH2)2-3-O- or -CH=CH-C(=O)-.

In a further embodiment, X is-CH2-,-(CH2) 2-,-(CH2) 3-,-(CH2) 4-,-CH=CH-,-CH2-O-, -(CH2) 3-O-,-O-(CH2) 2-,-CH2-S-CH2-,-CH2-S-,-(CH2) 2-C (=O)-or-(CH2) 3-C (=O)-, such as -CH2-, -(CH2)3-, -CH=CH-, -O-(CH2)2- or -(CH2)2-C(=O)-, eg -(CH2)2-C(=O)- or -CH2-.

In another embodiment, Y is phenyl, pyridyl, naphthyl, benzoxazolyl, indanyl, benzothienyl, benzthiazolyl or benzofuryl, which may optionally be substituted as defined for formula (I").

In another embodiment, Y is phenyl or naphthyl, which may optionally be substituted as de- fined for formula (I") * In yet another embodiment, Y is phenyl, which may optionally be substituted as defined for formula (l'').

In still another embodiment, Y is C38-cycloalkyl, such as cyclohexyl, which may optionally be substituted as defined for formula (I").

In one embodiment, Y is unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3_8-cycloalkyl, trifluoromethyl, trifluoromethoxy,-NR4R5 and-O (C=O) NR4R5, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R4 and R5 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R4 and R5 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, phenyl and phenyl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C16-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR6R7 and -O (C=O) NR6R, or wherein two substituents in adjacent position form a radical - 0- (CH2) i-3-0-, wherein R6 and R7 independently are hydrogen, C16-alkyl, C38-cycloalkyl, CI-6-alkanoyl or aryl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring.

In another embodiment, Y is unsubstituted or substituted with one or more substituents se- lected from halogen, nitro, hydroxy, Cl-6-alkanoyl, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy,-NR4R5 and-0 (C=O) NR4R5, or wherein two substituents in adjacent positions together form a radicao -O-(CH2)1-3-O-, wherein R4 and R5 are C16-alkyl, or R4 and R5 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, phenyl and phenyl-C16-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen and C1-6-alkyl.

In another embodiment, Y is unsubstituted or substituted with one to three substituents se- lected form C1-6-alkoxy, halogen, -N(C1-6-alkyl)2 and phenyl, or wherein two substituents in adjacent positions together form a radical-O-(CH2) 13-O-.

In still another embodiment, Y is substituted with one halogen substituent.

In yet another embodiment, Y is substituted with one-N (C16-alkyl) 2 substituent.

In a further embodiment, Y is unsubstituted or substituted with one or two substituents se- lected from aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C16-alkyl, C16-alkoxy, C38-cycloalkyl, trifluoromethyl, trifluoromethoxy,-NR8R9 and -O (C=O) NR8R9, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R8 and R9 independentyl are hydrogen, C16-alkyl, C3-8-cycloalkyl, C16-alkanoyl or aryl, or R8 and R9 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring.

In yet a further embodiment, Y is unsubstituted or substituted with one or two substituents selected from phenyl and phenoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR8R9 and -O (C=O) NR8R9, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R8 and R9 independently are hydrogen, C16-alkyl, C3-8-cycloalkyl, CI-6-alkanoyl or aryl, or R8 and R9 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring.

In still a further embodiment, Y is unsubstituted or substituted with phenyl, which is unsubsti- tuted or substituted with halogen.

In a further aspect, the invention relates to a compound of the general formula (I"') :

wherein R'is (a) C3-Cg-alkyl, C3-Cg-alkenyl, C3-Cg-alkynyl, # which may optionally be substituted with one or more halogen atoms, (b) C38-cycloalkyl, Cs 8-cycloalkenyl, C38-cycloalkyl-C16-alkyl, di (C3-8-cycloalkyl)-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkenyl, C5-8-cycloalkenyl-C1-6-alkyl, C5-8-cycloalkenyl-C2-6-alkenyl, C5-8-cycloalkenyl-C2-6-alkynyl or 4-pyridyl, wherein the cyclic moieties may optionally be substituted with one or more substitu- ents selected from C16-alkyl, halogen, trifluoromethyl and 2,2, 2-trifluoroethyl, X is- (CHZ) m (Z) (CH2) o, m and o independently are 0,1, 2,3 or 4, n is 0 or 1, Z is-O-,-NH-,-C (=O)-,-S-,-S (=O)-,-S (=O) 2-, -CH=CH- or -C#C-, Y is (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents se- lected from halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR2R3 and

- O (C=O) NR2R3, or wherein two substituents in adjacent positions form a radical - O-(CH2)1-3-O-, wherein R2 and R3 independently are hydrogen, C16-alkyl, C38-cycloalkyl, C16-alkanoyl or aryl, or R2 and R3 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, # aryl, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from o halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR4R5 and -O (C=O) NR4R5, or wherein two substituents in adjacent positions form a radical -O-(CH2)1-3-O-, wherein R4 and R5 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, Cl-6-alkanoyl or aryl, or R4 and R5 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, (b) C38-cycloalkyl or C5-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from # C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halo- gen, aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from o halogen, nitro, cyano, hydroxy, C16-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR6R7 and-O (C=O) NR6R7, or wherein two substituents in adjacent positions form a radical -O-(CH2)1-3-O-, wherein R6 and R7 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, Cl-6-alkanoyl or aryl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, with the proviso that when Y is selected from the group (a), the sum of m, n and o must be at least 1, and with the proviso that when

R'is cyclohexyl and X is -(CH2)3-O-, Y must not be 1,2, 3, 4-tetrahydro-2-oxo-6-quinolinyl, 1,2- dihydro-2-oxo-6-quinolinyl or 3-ethyl-2, 3-dihydro-2-oxo-1 H-benzimidazol-5-yl, R'is cycloheptyl and X is -(CH2)3-O-, Y must not be 2, 3-dihydro-2-oxo-1H-imidazo [4,5-b]- quinolin-7-yl, R'is cycloheptyl and X is -(CH2)4-O-, Y must not be 2, 3-dihydro-2-oxo-1H-pyrrolo [2, 3- b] quinolin-6-yl, R'is cyclohexyl and X is- (CH2) 2-, Y must not be 2- (4-chlorophenyl)-1 H-indol-3-yl or 2- (4- bromophenyl)-1 H-indol-3-yl, R'is cycloheptyl and X is-CH2-, Y must not be (3-benzyl) phenyl, R'is cyclohexyl and X is -O-CH2-, Y must not be phenyl, R'is cyclohexyl and X is-CH=CH-, Y must not be benzofuran-2-yl, R'is cyclohexyl and X is-NH-, Y must not be cyclohexyl, R1 is 2-propen-1-yl and X is-NH-, Y must not be phenyl, R'is n-propyl and X is-C-C-, Y must not be'phenyl, R'is cyclopentyl and X is-CH2-O-, Y must not be 4-phenyl-1, 2, 3-thiadiazol-5-yl, R'is isopropyl and X is-CH2-, Y must not be 4-oxothiazolidin-3-yl, R'is isopropyl and X is-CH2-, Y must not be 2-oxopyrrolidin-1-yl, R'is isopropyl and X is -O-, Y must not be 6-(5-chloropyridin-2-yl)-2, 3,6, 7-tetrahydro-7-oxo- 5H-1,4-dithiino [2,3-c] pyrrol-5-yl, R'is isopropyl and X is-CH=CH-, Y must not be 5-nitrofuran-2-yl,

R'is isopropyl and X is -O-, Y must not be 3-oxo-2-pyridin-2-yl-2, 3-dihydro-1 H-isoindol-1-yl, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutical acceptable salt thereof.

In one embodiment, R1 is C38-cycloalkyl, such as cyclobutyl, cyclopentyl or cyclohexyl.

In another embodiment, R'is 4-pyridyl.

In yet another embodiment, R1 is C39-alkenyl, such as allyl.

In still another embodiment, R1 is C36-alkyl, such as 1-ethylpropyl, isopropyl, n-proyl or n- butyl.

In one embodiment, X is-(CH2) 14-,-(CH2) 04-CH=CH-(CH2) 04-,-(CH2) 04-O-(CH2) 04-, - (CH2) o-4-S- (CH2) o-4- Or- (CH2) o-4-C (=0)- (CH2) o-4-.

In another embodiment, X is -(CH2)1-4-, -CH=CH-, -(CH2)1-4-O-, -O-(CH2)1-4-, - (CH2)1-4-S-(CH2)1-4-, -(CH2)1-4-S- or -(CH2)1-4-C(=O)-.

In yet another embodiment, X is-CH2-,-(CH2) 2-,-(CH2) 3-,-(CH2) 4-,-CH=CH-,-CH2-O-, -(CH2)3-O-, -O-(CH2)2-, -CH2-S-CH2-, -CH2-S-, -(CH2)2-C(=O)- or -(CH2)3-C(=O)-.

In still another embodiment, X is -(CH2)3-, -CH=CH-, -O-(CH2)2- or -(CH2)2-C(=O)-, such as -(CH2)2-C(=O)-.

In one embodiment, Y is phenyl, pyridyl, naphthyl, benzoxazolyl, indanyl or benzothiophenyl, which may optionally be substituted as defined for formula (I"'), such as phenyl or naphthyl, which may optionally be substituted as defined for formula (l''').

In another embodiment, Y is C38-cycloalkyl, which may optionally be substituted as defined for formula (I"'), such as cyclohexyl, which may optionally be substituted as defined for for- mula (I"').

In one embodiment, Y is unsubstituted or substituted with one or more substituents selected from halogen, nitro, hydroxy, Ci. C1-6-alkylsulfonyl, C1-6-alkyl C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy,-NR2R3 and-O (C=O) NR2R3, or wherein two substituents in adjacent positions form a radical -O-(CH2)1-3-O-, wherein R2 and R3 independently are hydrogen, C16-alkyl, C38-cycloalkyl, Cl-6-alkanoyl or aryl, or R2 and R3 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, phenyl and phenyl-C16-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR4R5 and - O (C=O) NR4R5, or wherein two substituents in adjacent position form a radical - O-(CH2)1-3-O-, wherein R4 and R5 independently are hydrogen, C16-alkyl, C38-cycloalkyl, C16-alkanoyl or aryl, or R4 and R5 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring.

In another embodiment, Y is unsubstituted or substituted with one or more substituents se- lected from halogen, nitro, hydroxy, C1-6-alkanoyl, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy,-NR2R3 and-O (C=O) NR2R3, or wherein two substituents in adjacent positions form a radical -O-(CH2)1-3-O-, wherein R2 and R3 are C16-alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, phenyl and phenyl-C16-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen and C16-alkyl.

In yet another embodiment, Y is unsubstituted or substituted with one to three substituents selected from C16-alkoxy, halogen and phenyl, or wherein two substituents in adjacent posi- tions form a radical-O-(CH2) 13-O-.

In still another embodiment, Y is substituted with one halogen substituent.

In yet another embodiment, Y is unsubstituted or substituted with one or two substituents se- lected from aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C16-alkyl, C16-alkoxy, C38-cycloalkyl, trifluoromethyl, trifluoromethoxy,-NR6R7 and -O(C=O)NR6R7, or wherein two substituents in adjacent positions form a radical - 0- (CH2) i-s-0-, wherein R6 and R7 independently are hydrogen, C16-alkyl, C38-cycloalkyl, Cl-6-alkanoyl or aryl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring.

In another embodiment, Y is unsubstituted or substituted with one or two substituents se- lected from phenyl and phenoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR6R7 and - O (C=O) NR6R', or wherein two substituents in adjacent positions form a radical - 0- (CH2) i-3-0-, wherein R6 and R7 independently are hydrogen, C16-alkyl, C38-cycloalkyl, C16-alkanoyl or aryl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring.

In yet another embodiment, Y is unsubstituted or substituted with phenyl, which is unsubsti- tuted or substituted with halogen.

The compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention.

Furthermore, when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention.

Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention.

The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutical acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative exam- ples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, gly- colic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedi- sulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glu- tamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharma- ceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977,66, 2, which is incorporated herein by refer- ence. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylam- monium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.

Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds are able to form.

The acid addition salts may be obtained as the direct products of compound synthe- sis. In the alternative, the free base may be dissolved in a suitable solvent containing the ap- propriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.

The compounds of the present invention may form solvates with standard low mo- lecular weight solvents using methods well known to the person skilled in the art. Such sol- vates are also contemplated as being within the scope of the present invention.

The invention also encompasses prodrugs of the present compounds, which on ad- ministration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in"Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The invention also encompasses active metabolites of the present compounds.

The compounds of the present invention interact with the histamine H3 receptor and are accordingly useful for the treatment of a wide variety of conditions and disorders in which histamine H3 receptor interactions are beneficial.

Accordingly, in another aspect the present invention relates to a compound of the general formula (I) as well as any diastereomer or enantiomer or tautomeric form thereof in- cluding mixtures of these or a pharmaceutical acceptable salt thereof for use as a pharma- ceutical composition.

The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula (I) or any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutical acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.

Furthermore, the invention relates to the use of a compound of the general formula (I) : wherein designates a single bond or a double bond, R'is

(a) C3-Cg-alkyl, C3-Cg-alkenyl, C3-Cg-alkynyl, which may optionally be substituted with one or more substituents selected from halogen and hydroxy, (b) C3-8-cycloalkyl, C5-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, di(C3-8-cycloalkyl)-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C5-8-cyloalkenyl-C1-6-alkyl, C5-8-cyclo- alkenyl-C26-alkenyl, C5-8-cycloalkenyl-C2-6-alkynyl, 4-pyridyl or tetrahydropyranyl, # wherein the cyclic moieties may optionally be substituted with one or more substitu- ents selected from C16-alkyl, halogen, trifluoromethyl, 2,2, 2-trifluoroethyl and C3-8-cycloalkyl, X is- (CH2) m-(Z)n-(CR2R3)o-(CH2)p-(V)q-, m and p independently are 0,1, 2,3 or 4, n, o and q independently are 0 or 1, Z and V independently are-O-,-NH-,-C (=O)-,-S-,-S (=O)-,-S (=O) 2-, -CH=CH- or -C#C-, R2 and R3 independently are hydrogen, C16-alkyl or hydroxy, Y is (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents se- lected from halogen, nitro, cyano, oxo, hydroxy, Cl-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, -C(=O)O-C1-6-alkyl, C3-8-cycloalkyl, trifluoromethyl, trifluoro- methoxy,-NR4R5 and-O (C=O) NR4R5, or wherein two substituents in adjacent posi- tions together form a radical -O-(CH2)1-3-O-, wherein R4 and R5 independently are hydrogen, C16-alkyl, C3-8-cycloalkyl, C17-alkanoyl or aryl, or R4 and R5 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

aryl, aryl-C16-alkyl, aryloxy and aryl-C16-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from o halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C16-alkyl, C16-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy,-NR6R7 and-O (C=O) NR6R7, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R6 and R 7independently are hydrogen, C16-alkyl, C38-cycloalkyl, CI-7-alkanoyl or aryl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, (b) C3-8-cycloalkyl or C5-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from # C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halo- gen, aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from o halogen, nitro, cyano, hydroxy, C1-7-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C16-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, -NR8R9 and-O (C=O) NR8R9, or wherein two substituents in adjacent positions together form a radical -O-(CH2)1-3-O-, wherein R8 and R9 independently are hydrogen, C16-alkyl, C38-cycloalkyl, C17-alkanoyl or aryl, or R8 and R9 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, with the proviso that when Y is selected from the group (a), the sum of m, n, o, p and q must be at least 1, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of disorders and diseases related to the histamine H3 receptor.

In still another aspect, the invention relates to a method for the treatment of dis- eases and disorders related to the histamine H3 receptor the method comprising administer- ing to a subject in need thereof an effective amount of a compound of the formula (I') or any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a

pharmaceutical acceptable salt thereof or a pharmaceutical composition comprising the same.

In one aspect the invention relates to compounds with histamine H3 receptor an- tagonistic activity or inverse agonistic activity which may accordingly be useful in the treat- ment of a wide range of conditions and disorders in which histamine H3 receptor blockade is beneficial.

In another aspect the invention relates to compounds with histamine H3 receptor agonistic activity and which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor activation is beneficial.

In a preferred embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the reduction of weight.

In a preferred embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of overweight or obesity.

In another preferred embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the suppression of appetite or satiety induction.

In a further preferred embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity such as atherosclerosis, hyperten- sion, IGT (impaired glucose tolerance), diabetes, especially Type 2 diabetes (NIDDM (non- insulin dependent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder dis- ease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.

In yet a further preferred embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.

In a further preferred embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of IGT.

In a further preferred embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the treatment of Type 2 diabetes.

In another preferred embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the pro- gression from IGT to Type 2 diabetes.

In a further preferred embodiment of the invention, the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the pro- gression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.

The compounds of the present invention may also be used for the treatment of air- way disorders such as asthma, as anti-diarrhoeals and for the modulation of gastric acid se- cretion.

Furthermore, the compounds of the present invention may be used for the treatment of diseases associated with the regulation of sleep and wakefulness and for the treatment of narcolepsy and attention deficit disorder.

Moreover, the compounds of the invention may be used as CNS stimulants or as sedatives.

The present compounds may also be used for the treatment of conditions asso- ciated with epilepsy. Additionally, the present compounds may be used for the treatment of motion sickness and vertigo. Furthermore, they may be useful as regulators of hypothalamo- hypophyseal secretion, antidepressants, modulators of cerebral circulation, and in the treat- ment of irritable bowel syndrome.

Further, the compounds of the present invention may be used for the treatment of dementia and Alzheimer's disease.

The compounds of the present invention may also be useful for the treatment of al- lergic rhinitis, ulcer or anorexia.

The compounds of the present invention may furthermore be useful for the treat- ment of migraine, see R. L. McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50, and for the treatment of myocardial infarction, see C. J.

Mackins and R. Levi, Expert Opinion on Investigational Drugs 9 (2000), 2537-2542.

In a further aspect of the invention the present compounds are combined with diet and/or exercise.

In a further aspect of the invention the present compounds may be administered in combination with one or more further pharmacologically active substances in any suitable ra- tios. Such further active agents may be selected from antiobesity agents, antidiabetics, anti- hypertensive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or associated with obesity.

Thus, in a further aspect of the invention the present compounds may be adminis- tered in combination with one or more antiobesity agents or appetite regulating agents.

Such agents may be selected from the group consisting of CART (cocaine am- phetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releas- ing factor binding protein) antagonists, urocortin agonists, ß3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 orAZ-40140, MSH (melanocyte- stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or cita- lopram, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hor- mone, growth factors such as prolactin or placenta lactogen, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase in- hibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X re- ceptor) modulators, TR ß agonists, AGRP (Agouti related protein) inhibitors, opioid antago- nists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.

In one embodiment of the invention, the antiobesity agent is leptin.

In another embodiment, the antiobesity agent is dexamphetamine or amphetamine.

In another embodiment, the antiobesity agent is fenfluramine or dexfenfluramine.

In still another embodiment, the antiobesity agent is sibutramine.

In a further embodiment, the antiobesity agent is orlistat.

In another embodiment, the antiobesity agent is mazindol or phentermine.

In still another embodiment, the antiobesity agent is phendimetrazine, diethyl- propion, fluoxetine, bupropion, topiramate or ecopipam.

Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference as well as orally active hypoglycaemic agents.

The orally active hypoglycaemic agents preferably comprise imidazolines, sulphony- lureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, a-glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the ß- cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S), which are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon an- tagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1

agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharma- ceuticals, Inc.), which is incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modula- tors, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabo- lism such as antilipidemic agents, compounds lowering food intake, PPAR (peroxisome pro- liferator-activated receptor) and RXR (retinoid X receptor) agonists, such as ALRT-268, LG-1268 or LG-1069.

In one embodiment of the invention, the present compounds are administered in combination with insulin.

In a further embodiment of the invention, the present compounds are administered in combination with a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibencla- mide, glipizide, glimepiride, glicazide or glyburide.

In another embodiment of the invention, the present compounds are administered in combination with a biguanide eg metformin.

In yet another embodiment of the invention, the present compounds are adminis- tered in combination with a meglitinide eg repaglinide or nateglinide.

In still another embodiment of the invention, the present compounds are adminis- tered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by ref- erence.

In still another embodiment of the invention, the present compounds may be admin- istered in combination with an insulin sensitizer eg such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 such as ragaglitazar (NN 622 or (-) DRF 2725) (Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S), which are incorporated herein by reference.

In a further embodiment of the invention, the present compounds are administered in combination with an a-glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.

In another embodiment of the invention, the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the (3-cells eg tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.

In yet another embodiment of the invention, the present compounds may be admin- istered in combination with nateglinide.

In still another embodiment of the invention, the present compounds are adminis- tered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.

In another aspect of the invention, the present compounds are administered in com- bination with more than one of the above-mentioned compounds eg in combination with met- formin and a sulphonylurea such as glyburide ; a sulphonylurea and acarbose; nateglinide and metformin ; acarbose and mefformin ; a sulfonylurea, metformin and troglitazone ; insulin and a sulfonylurea ; insulin and metformin ; insulin, metformin and a sulfonylurea ; insulin and troglitazone ; insulin and lovastatin ; etc.

Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are p-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin con- verting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and a-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed. , Mack Publishing Co., Easton, PA, 1995.

It should be understood that any suitable combination of the compounds according to the invention with diet and/or exercise, one or more of the above-mentioned compounds and optionally one or more other active substances are considered to be within the scope of the present invention.

PHARMACEUTICAL COMPOSITIONS The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with phar- maceutically acceptable carriers or diluents as well as any other known adjuvants and ex- cipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed. , Mack Publishing Co. , Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including sub- cutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route be- ing preferred. It will be appreciated that the preferred route will depend on the general condi- tion and age of the subject to be treated, the nature of the condition to be treated and the ac- tive ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropri- ate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, suspen- sions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as ster- ile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. De- pot injectable formulations are also contemplated as being within the scope of the present invention.

Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.

A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.

The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.

For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral ad- ministration.

The compounds of this invention are generally utilized as the free substance or as a pharmaceutical acceptable salt thereof. One example is an acid addition salt of a com- pound having the utility of a free base. When a compound of the formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxy group include the an- ion of said compound in combination with a suitable cation such as sodium or ammonium ion.

For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be em- ployed. Such aqueous solutions should be suitable buffered if necessary and the liquid dilu- ent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are par- ticularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administra- tion. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, su- crose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compo- sitions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administration may be pre- sented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formula- tions may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be tablette, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emul- sion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liq- uid suspension or solution.

A typical tablet, which may be prepared by conventional tabletting techniques, may contain: Core: Active compound (as free compound or salt thereof) 5.0 mg Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg Ambertite@) IRP88* 1.0 mg Magnesii stearas Ph. Eur. q. s.

Coating: Hydroxypropyl methylcellulose approx. 9 mg Mywacett 9-40 T** approx. 0.9 mg * Polacrillin potassium NF, tablet disintegrant, Rohm and Haas.

** Acylated monoglyceride used as plasticizer for film coating.

If desired, the pharmaceutical composition of the invention may comprise the com- pound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.

EXAMPLES In the examples the following terms are intended to have the following, general meanings: DCM: dichloromethane, methylenechloride DMA : N, N-dimethylacetamide DMF: N, N-dimethyl formamide DMSO: dimethyl sulphoxide EDC: N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride HOBt : N-hydroxybenzotriazole, 1-hydroxybenzotriazole

NMP: N-methylpyrrolidone NMR spectra were recorded on Bruker 300 MHz and 400 MHz instruments. HPLC- MS was performed on a Perkin Elmer instrument (API 100).

HPLC was conducted on a reversed-phase x-Terra column from Waters (5 um, 50 mm x 3 mm), eluting with 5%-90% acetonitrile in 0.05% TFA during 7.5 min at 1.5 ml/min.

General procedure (A) The compounds of formula (la) according to the invention may be prepared by the general procedure (A): 0 N02 Y--XOH N°Z HO Y-X O I H carbodiimide y I H NPS O NPS O O N R1 1 rD R HN) 2 CNoR Y--xi Nu) 1-2 IP y 0 (la) wherein X, Y and R'are as defined for formula (I) with the proviso that X must not start with-O-or-NH-.

The insoluble nitrophenol is prepared by acylating commercially available amino- methyl polystyrene (1 % cross-linked with divinyl benzene, 0.8 mmol/g) with 4-hydroxy-3- nitrobenzoic acid. The resulting support is acylated with a carboxylic acid (DCM/DMF, diiso- propyl carbodiimides, 2 hours, room temperature), filtered and washed with DCM (3 hours), and then treated with less than one equivalent of an amine (DCM/acetonitrile, room tempera- ture, overnight). Filtration and concentration yield the pure products, which are tested di- rectly, or further purified by recrystallization or column chromatography and/or transformed into appropriate salts. The products are analyzed by'H NMR and HPLC-MS.

General procedure (B) The carbamates of formula (lb) according to the invention may be prepared by the general procedure (B): wherein L is chloro or nitrophenol, and R', R2, R3, o, p and Y are as defined for formula (I).

The carbamates of formula (lb) are prepared by activating an alcohol with phosgene or 4-nitrophenyl chloroformate, and treating the resulting chloroformate or 4-nitrophenyl car- bonate with an amine.

General procedure (C) The ureas of formula (Ic) according to the invention may be prepared by the general procedure (C): wherein Y and R'are as defined for formula (I).

The ureas of formula (Ic) are prepared by treating an amine with a suitable isocy- anate.

General procedure (D) The amides of formula (la) can also be prepared in homogeneous phase without the use of a polymeric support:

(la) wherein X, Y and R'are as defined for formula (I) with the proviso that X must not start with-O-or-NH-.

To a mixture of the acid (150 mmol), DMF (200 ml), and N-hydroxybenzotriazole (40.6 g, 301 mmol) is added a solution of N-ethyl-N'- (3-dimethylaminopropyl) carbodiimide hydrochloride (28.8 g, 150 mmol) in DMF (100 ml). The mixture is stirred at room tempera- ture for 1.5 hour, and a solution of the diamine (150 mmol) in DCM (100 ml) is added. The mixture is stirred at room temperature for 4 hours, concentrated under reduced pressure, and the residue is distributed between ethyl acetate (1. 01) and a saturated, aqueous NaHCO3 solution (1. 0 I). The phases are separated, the organic layer is dried (MgS04), and concen- trated, and the residue is re-dissolved in 1 M aqueous hydrochloric acid (150 ml) or in a solu- tion of another suitable acid. The solution is concentrated, and the residue is dried by co-eva- poration with ethanol. Re-crystallization of the residue from ethanol yields the title compound.

Starting materials Most of the 1-alkylpiperazines used were commercially available. Non-commercially available 1-alkylpiperazines were prepared by alkylation of 1-tert-butyloxycarbonylpiperazine, followed by tert-butyloxycarbonyl-group removal by treatment with 50% trifluoroacetic acid in dichloromethane at room temperature for one hour.

4- (1, 1-Dimethylprop-2-ynyl) piperazine-1-carboxylic acid ter-butyl ester To a stirred mixture of 1-tert-butyloxycarbonylpiperazine (1.10 g, 5.91 mmol), 3- chloro-3-methyl-1-butyne (0.88 ml, 7.81 mmol), THF (10 ml), and NEt3 (1.10 ml, 7.91 mmol)

under nitrogen was added copper (l) chloride (45 mg, 0.46 mmol). An exothermic reaction ensued and a precipitate formed. After stirring for 0.5 hours at room temperature water (20 ml) and 1 N aqueous hydrochloric acid (8 ml) were added and the mixture was concentrated under reduced pressure to 2/3 of its original volume. The mixture was washed with ethyl ace- tate (2 x 20 ml) and made basic by addition of potassium carbonate (approx. 4 g). Extraction with ethyl acetate (3 x 20 ml), washing of the combined extracts (30 ml brine), drying with magnesium sulphate, and concentration under reduced pressure yielded 1.15 g (77%) of the title compound as a colourless solid.

'H NMR (CDCI3) 61. 39 (s, 6H), 1.47 (s, 9H), 2.29 (s, 1H), 2.58 (m, 4H), 3.47 (m, 4H); HPLC- MS: m/z 253 (MH+).

4-Cyclobutylpiperazine-1-carboxylic acid tert-butyl ester To a solution of 1-tert-butyloxycarbonylpiperazine (2.24 g, 12.0 mmol) in THF (20 ml) were added water (0.2 ml), cyclobutanone (1.35 ml, 18.1 mmol), acetic acid (2.20 ml) and sodium cyanoborohydride (18 ml of a 1M solution in THF, 18 mmol). The mixture was stirred at 60 °C over night, concentrated, and the residue was mixed with water (50 ml) and 1 N aqueous hydrochloric acid (15 ml). The solution was washed with ethyl acetate (2 x 30 ml), made basic by addition of potassium carbonate, extracted (2 x 20 mi ethyl acetate), and the combined extracts were washed with brine, dried with magnesium sulphate, and concen- trated. 1.1 g (38%) of the title compound was obtained as a colourless oil.

1H NMR (DMSO-d6) 51. 38 (s, 6H), 1.60 (m, 2H), 1.73 (m, 2H), 1.94 (m, 2H), 2.13 (m, 4H), 2.67 (m, 1 H), 3.27 (m, 4H); HPLC-MS: m/z 241 (MH+).

4-Cyclopropylpiperazine-1-carboxylic acid tert-butyl ester

To a solution of 1-teff-butyloxycarbonylpiperazine (1.16 g, 6.23 mmol) in THF (10 ml) and methanol (5 ml) were added 1-ethoxy-1-trimethylsilyloxycyclopropane (2.40 ml, 12.0 mmol), acetic acid (0.75 ml), and sodium cyanoborohydride (7.8 ml of a 1 M solution in THF, 7.8 mmol), and the mixture was stirred at 63 °C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was mixed with water (20 ml) and potassium car- bonate (6.6 g). The product was extracted with ethyl acetate (3 x 30 ml), the combined ex- tracts were dried over magnesium sulphate, and concentrated under reduced pressure. 1.79 g (100%) of the title compound was obtained as an oil, which completely crystallized after a few hours.

'H NMR (DMSO-d6) #0. 29 (m, 2H), 0.42 (m, 2H), 1.38 (s, 9H), 1.60 (m, 1H), 2.43 (m, 4H), 3.23 (m, 4H); HPLC-MS: m/z 227 (MH+).

4-Cyclopropylmethylpiperazine-1-carboxylic acid ter-butyl ester To a solution of 1-tert-butyloxycarbonylpiperazine (2.24 g, 12.0 mmol) in THF (10 ml) were added water (0.15 ml), acetic acid (3.60 ml), formylcyclopropane (1.35 ml, 18.1 mmol), and sodium cyanoborohydride (18 mi of a 1 M solution in THF, 18 mmol). The mixture was stirred at 20 °C for 14 hours. The mixture is concentrated under reduced pressure, and the residue is mixed with water (80 ml) and 1 N aqueous hydrochloric acid (40 ml). After washing with ethyl acetate (20 mi) the aqueous phase is made basic by addition of potas- sium carbonate (approx. 20 g) and extracted with ethyl acetate (4 x 30 ml). The combined extracts were dried with magnesium sulphate and concentrated under reduced pressure, to yield 2.3 g (80%) of the title compound as a colourless oil.

1H NMR (DMSO-d6) 60. 05 (m, 2H), 0.43 (m, 2H), 0.79 (m, 1 H), 1.38 (s, 9H), 2.16 (d, J = 7 Hz, 2H), 2.33 (m, 4H), 3.30 (m, 4H); HPLC-MS: m/z 241 (MH+).

Example 44 (General procedure (A)) 1- (3-Fluoro-4-methoxyphenyl)-4- (4-pyridin-4-yipiperazin-1-yl) butane-1,4-dione

To the polymeric nitrophenol (1.5 g, approx. 1 mmol) was added a solution of 3- (4- methoxy-3-fluorobenzoyl) propionic acid (1.66 g, 7.34 mmol) in a mixture of 1, 2-dichloro- propane (15 ml) and DMF (6 ml), followed by the addition of DIC (0.78 ml, 5.01 mmol). The mixture was shaken at room temperature for 13 hours, filtered, and the polymer was exten- sively washed with DCM, DMF, and 1, 2-dichloropropane. To the polymer was added 1,2-di- chloropropane (5 ml), a solution of 1- (4-pyridyl) piperazine (116 mg, 0.71 mmol) in 1,2-di- chloropropane (10 ml), and triethylamine (0.2 ml). The resulting mixture was shaken at room temperature for 21 hours, filtered, and the polymer was carefully washed with DCM and methanol. The combined filtrates were concentrated to yield the crude product as an oil (0.38 g). Crystallization from acetonitrile (2 ml) at-20 °C yielded 0.19 g (5.1 mmol, 72%) of the title compound as almost colourless solid.

'H NMR (400 MHz, DMSO) : F2. 73 (m, 2H), 3.21 (m, 2H), 3.30-3. 47 (m, 4H), 3.57 (m, 2H), 3.67 (m, 2H), 3.93 (s, 3H), 6.84 (m, 2H), 7.30 (t, J = 7 Hz, 1 H), 7.77 (m, 1 H), 7.89 (m, 1 H), 8.19 (m, 2H); HPLC-MS : 372 (MH+).

Example 188 (General procedure (D)) 1- (4-Chlorophenyl)-4- (4-cyclopentylpiperazin-1-yl) butane-1,4-dione hydrochloride To a mixture of 3- (4-chlorobenzoyl) propionic acid (31.9 g, 150 mmol), DMF (200 ml), and N-hydroxybenzotriazole (40.6 g, 301 mmol) was added a solution of N-ethyl-N'- (3-di-

methylaminopropyl) carbodiimide hydrochloride (28.8 g, 150 mmol) in DMF (100 ml). The mixture was stirred at room temperature for 1.5 hour, and a solution of 1-cyclopentylpiper- azine (23.2 g, 150 mmol) in DCM (100 ml) was added. The mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, and the residue was distributed between ethyl acetate (1. 01) and a saturated, aqueous NaHCO3 solution (1. 0 I).

Phases were separated, the organic layer was dried (MgS04), and concentrated, and the residue was redissolved in 1 molar aqueous hydrochloric acid (150 ml). The solution was concentrated, and the residue was dried by coevaporation with ethanol. Recrystallization of the residue from ethanol yielded 31.1 g (54%) of the title compound. Concentration of the mother liquor gave additional 19.4 g (34%) of product.

Using one of the above general procedures, the following compounds were pre- pared: Exa Structure Name Found mple MH+ No OMe 1- (3-Fluoro-4-methoxy- 337 phenyl)-4- (4-isopropyl- F H3CNJ O piperazin-1-yl) butane-1, 4- dione hydrochloride CH, OMe 1- [4- (1-Ethylpropyl)-365 piperazin-1-yl]-4- (3-fluoro-4- N wF N 0 methoxyphenyl) butane-1, 4- H dione hydrochloride HgC 3 1- (3-Fluoro-4-methoxy- 337 OMe phenyl)-4- (4-propyl- O piperazin-1-yl) butane-1, 4- H3C~NJ dione hydrochloride H3C 4 0 1- (4-Cyclopentylpiperazin-1- 393 O CO CH3 yl)-4-(4-methanesulfonyl- 0 phenyl) butane-1, 4-dione N N 0 hydrochloride 5 _ 1-(4-Cyclopentylpiperazin-1-329 yl)-4-phenylpentane-1, 5-di- one hydrochloride Y 6 1- (4-Allylpiperazin-1-yl)-3- 307 naphth-1-ylpropenone N / I ON o 7 0 OMe 4-Cyclopentylpiperazine-l-363 carboxylic acid 2- (3, 4-di- NO OMe N 9 methoxyphenyl) ethyl ester N hydrochloride 8 O 3- (4-Fluorophenyl)-1- (4- propylpiperazin-1-yl)- H propenone F 9 0 3- (4-Bromophenyl)-1- (4- propylpiperazin-1-yl)- propenone Hic Ber Br 10 3-(4-Nitrophenyl)-1-(4-_ rN propylpiperazin-1-yi)- propenone 3 11 0 3- (3-Hydroxyphenyl)-1- (4- 275 N propylpiperazin-1-yl)- OH propenone HsC 12 3-(4-Hydroxyphenyl)-1-(4- propylpiperazin-1-yl)- propenone OH OH 13 0 3- (2-Hydroxyphenyl)-1- (4- OH propylpiperazin-1-yl)- propenone H3c NJ HsC 14 0 1- (4-Propylpiperazin-1-yl)-3- pyridin-3-ylpropenone N N H3C/X/J CN 15 0 ° 3- (6-Nitrobenzo [1, 3] dioxol- CNJw N-O 5-yl)-1-(4-propylpiperazin-1- yl) propenone H c 0 16 3-(2-Nitrophenyl)-1-(4- N propylpiperazin-1-yl)- J _o_ propenone 3 17 3-(2, 4-Dichlorophenyl)-1-(4- propylpiperazin-1-yl)- propenone ci ci 18 0 3- (3, 4-Dichlorophenyl)-1- (4- propylpiperazin-1-yl)- C propenone H NJ /CI 19 O 3-(3-Chlorophenyl)-1-(4- propylpiperazin-1-yl)- N \ CI propenone N HgC" 20 3-(2-Chlorophenyl)-1-(4-293 propylpiperazin-1-yl)- propenone NJ Hic Cl 21 0 3- (4-Chloro-3-nitrophenyl)- 0 1- (4-propylpiperazin-1-yl)- p-propenone N ci cl 22 0 3-(2-Chloro-5-nitrophenyl)- CI _ (4-propylpiperazin-1-yl)- ZON f propenone NJ 0-, N 00 23 H3c 3-(3, 5-Di-teff-butyl-4-387 H3C hydroxyphenyl)-1- (4-propyl- C CH3 piperazin-1-yl) propenone C H C OH Cs 24 0 3- (3-Nitro-4-pyrrolidin-1- CJN) ylphenyl)-1- (4-propyl- H3c 0-piperazin-1-yl) propenone D U t NO 25 0 3- (5-Bromo-2- ber ethoxyphenyl)-1- (4- N NJ propylpiperazin-1-yl)- N propenone H3C 26 0 1- (4-Propylpiperazin-1-yl)-3- o-tolylpropenone NJ H v H3C HgC 27 O 3-Naphth-2-yl-1- (4-propyl- CN +_ piperazin-1-yl) propenone ~NJ t H3c 28 0 3- (4-tert-Butylphenyl)-l- (4- propylpiperazin-1-y)) propen- 0 cl3 MHz HsC HgC 29 0 1- (4-Propylpiperazin-1-yl)-3- pyridin-4-ylpropenone NJ N N H3C 30 0 (4-Cyclohexylphenyl)- (4- propylpiperazin-1-yl)- methanone H3C, J HgC ! j 31 0 3- (3-Hydroxyphenyl)-1- (4- propylpiperazin-1-yl) propan- -one J v H3C OH 32 O 2- (4-Fluorophenoxy)-1- (4- propylpiperazin-1-yl)- ethanone H C F 3 33 F F F 2- (3, 5-Bis-trifluoromethyl- F F phenyl)-1- (4- ° l@) propylpiperazin-1- N F yl) ethanone HgC 34 O 1- (4-Propylpiperazin-1-yl)-2- 347 (4- trifluoromethoxyphenoxy)- u * u yO ethanone F F 35 0 (4'-Ethylbiphenyl-4-yl)- (4- propylpiperazin-1-yl)- methanone 3 CH3 '-CH, 36 0 (4-Isopropylphenyl)- (4- CN <\ propylpiperazin-1-yl)- methanone zu HgC I H3c CH3 37 0 (4-Butylphenyl)- (4-propyl- C'N piperazin-1-yl)-methanone Hic HsC CH3 CH3 38 O (4-Pentylphenyl)-(4-propyl- N piperazin-1-yl) methanone HsC CH3 39 0 3- (3, 5-Bis-trifluoromethyl- rN F F phenyl)-l- (4-propylpiper- azin-1-yl) propan-1-one F F F F 40 1-(4-Propylpiperazin-1-yl)-3- CNX _ \ (4-trifluoromethylphenyl)- H propan-l-one H3c F F F 41 0 3-Cyclohexyl-1- (4-propyl- piperazin-1-yl) propan-1-one N Hic 42 0, CH3 4- (4-Methoxyphenyl)-l- (4- 340 r n CHg O < pyridin-4-ylpiperazin-1-yl)- 0 butan-1-one ru NJ NJ 43 2-(2, 4-Dichloro-5-methyl-397 H 3c phenylsulfanyl)-l- (4-pyridin- 4-ylpiperazin-1-yl) ethanone 0 ci S NJ N 44 O, CH 1- (3-Fluoro-4-methoxy- 372 3 0 F phenyl)-4- (4-pyridin-4-yl- 00 piperazin-1-yl) butane-1, 4- dione Y Nv 45 H 3C, N CH 3 3- (4-Dimethylaminophenyl)- 337 1- (4-pyridin-4-ylpiperazin-1- yl) propenone CNv ncNJ Or Nu 46 O 2- (2-Benzyloxyphenyl)-1- (4- 388 pyridin-4-ylpiperazin-1- N yl) ethanone YNJ 0 N N, J 47 H3C, 3- (3, 4-Dimethoxyphenyl)-1- 356 0 l O (4-pyridin-4-ylpiperazin-1- CNt CH3 yl) propan-1-one 0 0 Nv NU 48 Cl 4-(2, 4-Dichlorophenoxy)-1-395 (4-pyridin-4-ylpiperazin-1- CN9CI yl)-butan-1-one O O o t0NJ N NAZI 49 3- (2-Methoxyphenyl)-l- (4- 326 pyridin-4-ylpiperazin-1-yl)- CNJU propan-1-one N N NJ 50 4-(4-Chloro-2-methyl-374 ß phenoxy)-1-(4-pyridin-4- ylpiperazin-1-yl) butan-1-one 3 CNX N N 51 F 2- (4-Fluorophenylsulfanyl)- 332 1- (4-pyridin-4-ylpiperazin-1- yl)-ethanone NS N < NU 52 0 F F (4-Fluoro-3-trifluoro- 380 CN F methylphenyl)-l- (4-pyridin- NJ F 4-ylpiperazin-1- F yl) propenone 53 F F 1-(4-Pyridin-4-ylpiperazin-1-366 yl)-2- (3-trifluoromethoxy- F T phenyl) ethanone zu N f N3 54 F 2- (4-Fluorophenoxy)-1- (4- 316 pyridin-4-ylpiperazin-1-yl)- ethanone 0 Ru ritz , N, J Nv 55 2-(2, 3-Dichlorophenoxy)-1-367 (4-pyridin-4-ylpiperazin-1- 0 cl yl) ethanone N N N 56 H3C, 2- (4-Methoxyphenoxy)-1- (4- 328 O pyridin-4-ylpiperazin-1- yl) ethanone CN) 4 N" N NEZ 57 O 1-(4-Pyridin-4-ylpiperazin-1-366 yl)-2- (4-trifluoromethoxy- F F phenyl) ethanone Nu N 1 58 0 3-Benzo [1, 3] dioxol-5-yl-1-340 /p (4-pyridin-4-ylpiperazin-1- N yl) propan-1-one N 59 p 2- (Naphth-2-yloxy)-1- (4- 348 pyridin-4-ylpiperazin-1-yl)- ethanone N NJ 60 H3C, o 1- (4-Pyridin-4-ylpiperazin-1- 386 0 , 0 Os yl)-3-(3, 4, 5-trimethoxy- 0 3 3 phenyl) propan-l-one 0 N NU N 61 o, CH3 3-(2, 4-Dimethoxyphenyl)-1-354 0 (4-pyridin-4-ylpiperazin-1- yl) propenone CN 0 Nv NU 62 1-Biphenyl-4-yi-4- (4-pyridin- 400 o < 4-ylpiperazin-1-yl) butane- 1, 4-dione hydrochloride N NU nu N 63 2-(Naphth-2-ylsulfanyl j-1-(4-364 pyridin-4-ylpiperazin-1-yl)- ethanone 0 N NS Nu 64 CH3 3-(3, 5-Dimethoxyphenyl)-1-354 i ( (4-pyridin-4-ylpiperazin-1- HC j [ yl) propenone OUR ZON NJ N 65 CH3 3- (2, 3-Dimethoxyphenyl)-1- 354 3 (4-pyridin-4-ylpiperazin-1- O Wo, CH3 yl) propenone 0 ru N, J N 66 o, CH3 4-(3, 4-Dimethoxyphenyl)-1-370 O XOCH (4-pyridin-4-ylpiperazin-1- O CH yl)-butan-1-one N Nv NAZI 67 wCH3 2-(2, 3-Dimethylphenoxy)-1-326 6 (4-pyridin-4-ylpiperazin-1- 0 CH 3 yl)-ethanone NO Y N, _, J Nv 68 0 ci 2- (8-Chloro-naphth-1-yl-398 0 T"1 sulfanyl)-1- (4-pyridin-4-yl- N piperazin-1-yl) ethanone NJ N 69 2- (Naphth-1-yloxy)-l- (4- 378 o r pyridin-4-ylpiperazin-1-yl)- N tO) ethanone /NU N, J N 70 O CH3 2- (4-Acetylphenoxy)-1- (4- 340 pyridin-4-ylpiperazin-1-yl)- ethanone O NJ ncNJ Nv 71 CH 3- (3-Methoxyphenyl)-1- (4- 326 i O pyridin-4-ylpiperazin-1-yl)- propan-l-one 0 rN N NU 72 N 3-Pyridin-3-yl-l- (4-pyridin-4- 297 0NS- ylpiperazin-1-yl) propan-1- 0 one ZON rN NU 73 3- (4-Benzyloxy-3-methoxy- 430 phenyl)-1- (4-pyridin-4-yl- CH3 0 piperazin-1-yl) propenone I zon 0 os N 1 74 0 3- (5-Bromo-2- 417 CN) O^CH ethoxyphenyl)-1- (4-pyridin- N 0 CH, 4-ylpiperazin-1- N/X yl) propenone Nez Br 75/O 1- (3, 4-Dihydro-2H-benzo [b]- 396 0 CN< XO) [1, 4] dioxepin-7-yl)-4- (4- NJ o pyridin-4-ylpiperazin-1-yl)- / butane-1, 4-dione Nu 76 0 3- (2-Chloro-3, 4-dimethoxy- 388 , phenyl)-1- (4-pyridin-4-yl- N NJ Cleo, CH3 piperazin-1-yl) propenone N H3C H3c 77 0 2- (2-Chloro-4-fluorophenyl- 366 NS/sulfanyl)-1- (4-pyridin-4-yl- piperazin-1-yl)-ethanone CI F N 78 2-(Naphth-1-ylmethyl-378 sulfanyl)-1- (4-pyridin-4-yl- N piperazin-1-yl) ethanone N N,,,) S NJ k 79 3- [3-Oxo-3- (4-pyridin-4-yl- 353 piperazin-1-yl) propyl]-3H- O N benzoxazol-2-one hydro- chloride N Nv NJ 80 O 5-Cyclohexyl-1- (4-pyridin-4- 330 ylpiperazin-1-yl) pentan-1- p 3, N) < one one Nez 81 H3C, 3- (4-Methoxyphenyl)-1- (4- 326 "0 pyridin-4-ylpiperazin-1-yl)- propan-l-one 0 zon N NJ 82 0 [4- (4-Chlorophenyl) cyclo- 384 N hexyl]- (4-pyridin-4-yl- piperazin-1-yl) methanone ff 1 N ci 83 1- (4-Pyridin-4-ylpiperazin-1- 382 yl)-2- (4-trifluoromethoxy- F /N J I/pF phenoxy) ethanone F NEZ 844 2- (2-Acetylphenoxy)-1- (4- 340 pyridin-4-ylpiperazin-1-yl)- CH 0 ethanone hydrochloride NO 0 NJ NJ 85 o Dimethyl-carbamic acid 4-383 rN 0 [3-oxo-3- (4-pyridin-4-yl- piperazin-1-yl) propyl] phenyl CH3 ester 86 2- (5-Chloro-3-methyl- 386 CI benzo [b] thiophen-2-yl)-1- (4- N pyridin-4-ylpiperazin-1-yi)- 'NJ CH3 ethanone N 87, OscH 1-(4-Cyclohexylpiperazin-1-345 yl)-4- (4-methoxyphenyl)- 0 a butan-l-one N 88 Cl 1-(4-Cyclohexylpiperazin-1-402 H 3c yl)-2- (2, 4-dichloro-57methyl- 0 ci phenylsulfanyl) ethanone \NiN S 89 0'CH3 1- (4-Cyclohexylpiperazin-l- 377 0 0 F yl)-4- (34luoro-4-methoxy- '0 oia, phenyl) butane-1, 4-dione 'NN hydrochloride 90 H3CsN, CH3 1-(4-Cyclohexylpiperazin-1-342 N yl)-3- (4-dimethylamino- phenyl) propenone 0 N 91 /2- (2-Benzyloxyphenyl)-1- (4- 393 cyclohexylpiperazin-1-yl)- ethanone 0 92 H3Coo 1-(4-Cyciohexylpiperazin-1-36i yl)-3- (3, 4-dimethoxyphenyl)- CH3 propan-l-one 0 _. 93 CI 1- (4-Cyclohexylpiperazin-1- 400 yl)-4- (2, 4-dichlorophenoxy)- butan-l-one ci 0 O N Z-/ 94 1- (4-Cyclohexylpiperazin-1- 331 0 0 CH yl)-3- (2-methoxyphenyl)- 0 propan-l-one Ne __ 95 CI 4- (4-Chloro-2-methyl- 379 phenoxy)-1- (4-cyclohexyl- piperazin-1-yl) butan-1-one o ro 0 0 0 96 F 1- (4-Cyclohexylpiperazin-l- 337 yl)-2- (4-fluorophenyl- sulfanyl) ethanone O X e N v S NH 97 O F F 1-(4-Cyclohexylpiperazin-1-385 /F yl)-3- (4-fluoro-3-trifluoro- methylphenyl) propenone F 1- (4-Cyclohexylpiperazin-1- 371 yl)-2- (3-trifluoromethoxy- F T phenyl) ethanone 0 r GYN+NJX 99 F 1- (4-Cyclohexylpiperazin-1- 321 yl)-2- (4-fluorophenoxy)- ethanone 0 G N'v O ° N''W f 100 Cl 1- (4-Cyclohexylpiperazin-l- 372 yl)-2- (2, 3-dichlorophenoxy)- Cl ethanone o -NO 101 H C 1- (4-Cyc ! ohexy) piperazin-1- 333 0 yl)-2- (4-methoxyphenoxy)- ethanone 0 N'v O 'Ng+NJX 102 1-(4-Cyclohexylpiperazin-1-371 j yl)-2- (4-trifluoromethoxy- phenyl) ethanone 103 3-Benzo [1, 3] dioxol-5-yl-1-345 +'N% N X o> (4-cyclohexylpiperazin-1-yl)- propan-1-one 104 1- (4-Cyclohexylpiperazin-1- 353 yl)-2- (naphth-2-yloxy)- ethanone 105 H3Cuo 1-(4-Cyclohexylpiperazin-1-391 yl)-3- (3, 4, 5-trimethoxy- 0 O ($ phenyl) propan-1-one O +Nk 106 o, CH3 1-(4-Cyclohexylpiperazin-1-359 yl)-3- (2, 4-dimethoxyphenyl)- propenone O to, CH3 NH . _ 107 1-Biphenyl-4-yl-4- (4-cyclo- 405 o < hexylpiperazin-1-yl) butane- 1, 4-dione o 108 1- (4-Cyclohexylpiperazin-1- 369 yl)-2- (naphth-2-ylsulfanyl)- ethanone O 0 N 109 CH3 1- (4-Cyclohexylpiperazin-1-359 1 H C'O\ (° yl)-3-(3, 5-dimethoxyphenyl)- 3 propenone 0 N 110 CH 1- (4-Cyclohexylpiperazin-1- 359 yl)-3- (2, 3-dimethoxyphenyl)- O Xo, CH3 propenone N 111 o. cH3 1- (4-Cyclohexylpiperazin-1- 375 0 ol CH3 yi)-4- (3, 4-dimethoxyphenyl)- butan-l-one N 112 CH3 1- (4-Cyclohexylpiperazin-l- 331 yl)-2- (2, 3-dimethylphenoxy)- / 0 CH ethanone N 113 0 CI, 2- (8-Chloronaphth-1-yl-404 sulfanyl)-1- (4-cyclohexyl- N N piperazin-1-yl) ethanone 114 0 1- (4-Cyclohexylpiperazin-1- 353 0 yl)-2- (naphth-1-yloxy)- N U ethanone 115 0 CH3 2- (4-Acetylphenoxy)-l- (4- 345 cyclohexylpiperazin-1-yl)- ethanone 0 'N +NJ4/ 116 CH 1- (4-Cyclohexylpiperazin-l- 331 O yl)-3- (3-methoxyphenyl)- propan-l-one 0 /'NN 117 N 1- (4-Cyclohexylpiperazin-l- 302 N yl)-3-pyridin-3-ylpropan-1- 0 one G+Nge 118 8-3- (4-Benzyloxy-3-methoxy- 435 phenyl)-1- (4-cyclohexyl- piperazin-1-yl) propenone CHg 0 PO 0 N 11903- (5-Bromo-2-422 0 CH3 ethoxyphenyl)-l- (4- 3 cyclohexylpiperazin-1- yl) propenone Br 120 0 1- (4-Cyclohexylpiperazin-l- 401 yl)-4- (3, 4-dihydro-2H- N O o benzo [b] [1, 4] dioxepin-7-yl)- butane-1, 4-dione 121 0 3- (2-Chloro-3, 4-dimethoxy- 393 +N) + phenyl)-1-(4-cyclohexyl- Cl MozcH3 piperazin-1-yl) propenone H3c 10 122 2- (2-Chloro-4-fluorophenyl- 371 sulfanyl)-1- (4-cyclohexyl- v'w/' N piperazin-1-yl) ethanone I Z", F 123 1-(4-Cyclohexylpiperazin-1-383 N yl)-2- (naphth-1-ylmethyl- o I S <3 sulfanyl) ethanone 124 3- [3- (4-Cyclohexylpiperazin- 358 1-yl)-3-oxopropyl]-3H-benz- 0 NO oxazol-2-one +'Nge 125 5-Cyclohexyl-1- (4-cyclo- 335 hexylpiperazin-1-yl) pentan- 1-one 126 H3C 1- (4-Cyclohexylpiperazin-1- 331 0 yl)-3- (4-methoxyphenyl)- propan-l-one O N 127 0 [4- (4-Chlorophenyl)-cyclo- 390 hexyl]- (4-cyclohexyl- N piperazin-1-yl) methanone Ct 128 o 1-(4-Cyclohexylpiperazin-1-387 yl)-2- (4-trifiluoromethoxy- Ot phenoxy) ethanone o F P Y) 129 2-(2-Acetylphenoxy)-1-(4-345 O 9CCH3 cyclohexylpiperazin-1-yl)- ethanone 0 130 o Dimethylcarbamic acid 4- [3- 388 N 0 (4-cyclohexylpiperazin-1-yl)- cN 3-oxopropyl] phenyl ester CH3 131 2- (5-Chloro-3-methyl- 391 O sn/C} benzo [b] thiophen-2-yl)-1- (4- N + cyclohexylpiperazin-1-yl)- CH CH3 ethanone 132 < 3-Naphth-1-yl-1-(4-propyl-309 piperazin-1-yl) propenone Hz f" Y o 133 CH 3 1- (4-Butylpiperazin-1-yi)-3- 323 naphth-1-ylpropenone N N ZUT o -34 1- (4-Isopropylpiperazin-1-309 yl)-3-naphth-1-ylpropenone 1 Yj H 3c N 0 zu 0 135 1-(4-Cyclopentylpiperazin-1-335 yl)-3-naphth-1-ylpropenone hydrochloride I Y O 0 136 1- (4-Cyclohexylpiperazin-l- 349 yi)-3-naphth-1-y (propenone L 1 N N nez o 137 3- (3-Nitro-4-pyrrolidin-I-373 N ylphenyl)-1- (4-propyl- HsC N i 3C) piperazin-1-yl) propenone nez I o 138 1- (4-Butylpiperazin-1-yl)-3- 387 CH3 N n (3-nitro-4-pyrrolidin-1-yl- hen I ro enone Y) P Y 0 0 139 +. 0 1- (4-isopropylpiperazin-1-374 O. N+. O ^ N yl)-3- (3-nitro-4-pyrrolidin-1- N ylphenyl) propenone H 3c N 0 0 140 1- (4-Cyclopentylpiperazin-1- 399 O N+. O yl)-3- (3-nitro-4-pyrrolidin-1- ylphenyl) propenone 4, N) J IN ZON 0 141 1- (4-Cyclohexylpiperazin-1- 413 D. + U yl)-3- (3-nitro-4-pyrrolidin-1- ylphenyl) propenone aN yfl 0 142 sw CH3 1-(4-Cyclopentylpiperazin-1-331 r. r CHg yl)-4- (4-methoxyphenyl)- 0 0 butan-l-one hydrochloride owNJ. N 143 ci 1- (4-Cyclopentylpiperazin-I- H3C4 yl)-2-(2, 4-dichloro-5-methyl- phenylsulfanyl) ethanone 0 ci aNi 144 ol CH31- (4-Cyclopentylpiperazin-l- 363 r ! j CHg O vF yl)-4-(3-fluoro-4-methoxy- 0 ou phenyl) butane-1, 4-dione NJ nu 145 2-(8-Chloro-naphth-1-yl- 0 T'1 sulfanyl)-1- (4-cyclopentyl- N''S piperazin-1-yl) ethanone ans 146 _ 1-(4-Cyclopentylpiperazin-1-339 0 ) yl)-2- (naphth-1-yloxy)- ethanone Ans 147 O CH3 2- (4-Acetylphenoxy)-1- (4- 331 cyclopentylpiperazin-1-yl)- ethanone hydrochloride 0 1-51 C Nt aN" 148 CH3 1- (4-Cyclopentylpiperazin-1- 317 i yl)-3- (3-methoxyphenyl)- propan-l-one our N Cri 149 Nt 1-(4-Cyclopentylpiperazin-1- N yl)-3-pyridin-3-ylpropan-1- O \ once rN Cru 150 3- (4-Benzyloxy-3-methoxy- 421 phenyl)-1- (4-cyclopentyl- piperazin-1-yl) propenone O zizi 0 , NJ N,,) 151 O 1- (4-Cyclopentylpiperazin-1- 387 O yl)-4- (3, 4-dihydro-2H- benzo [b] [1, 4] dioxepin-7-yl)- butane-1, 4-dione 152 O 3-(5-Bromo-2-408 0, ^, CH3 ethoxyphenyl)-I- (4- r OCH, cyclopentylpiperazin-1- N yl) propenone r Br 153 O 3- (2-Chloro-3, 4-dimethoxy- 379 / phenyl)-1- (4-cyclopentyl- , CH3 piperazin-1-yl) propenone c lu \-'. 0 HgC 154 0 2- (2-Chloro-4-fluoropheny- g Isulfanyl)-1- (4-cyclopentyl- r N"T i piperazin-1-yl) ethanone C1 F 155 1-(4-Cyclopentyìpiperazin-1-369 CNA 4 yl)-2-(naphth-1-ylmethyl- N NXJ S<jX sulfanyl) ethanone X W 156 3- [3- (4- 344 Cyclopentylpiperazin-1-yl)- O N ° 3-oxopropyl]-3H-benz- oxazol-2-one o"NJ 0 157 5-Cyclohexyl-1-(4-cyclo-321 pentylpiperazin-1-yl) pentan- N J 1-one 158 H3C, 1- (4-Cyclopentylpiperazin-1- 317 0 yl)-3- (4-methoxyphenyl)- propan-1-one our N C 159 0 [4- (4-Chlorophenyl)-cyclo- 376 hexyl]- (4-cyclopentyl- piperazin-1-yl) methanone L 1 Cf 160 O 1-(4-Cyclopentylpiperazin-1-373 yl)-2- (4-trifluoromethoxy- F o, NJ woXF phenoxy) ethanone F 161 2-(2-Acetylphenoxy)-1-(4- cyclopentylpiperazin-1-yl)- \CHg C N) 4O ° ethanone NO O NJ 162 o Dimethylcarbamic acid 4- [3- 374 CNtJv o (4-cyclopentylpiperazin-1- yl)-3-oxopropyl] phenyl ester CH3 163 2-(5-Chloro-3-methyl-378 O s Cl benzo [b] thiophen-2-yi)-l- (4- cyclopentylpiperazin-1-yl)- O'NJ CH3 ethanone 164 H3c, N CH3 1- (4-Cyclopentylpiperazin-l- 328 yl)-3- (4-dimethylamino- phenyl) propenone 0 zon NJ 165 O 2- (2-Benzyloxyphenyl)-1- (4- 379 cyclopentylpiperazin-1-yl)- N ethanone NJ O ans 166 H3C, 1- (4-Cyclopentylpiperazin-1- 347 "0 yl)-3- (3, 4-dimethoxyphenyl)- LJ CN CH3 propan-1-one zu r'N aN",) 167 1-(4-Cyclopentylpiperazin-1-386 yl)-4- (2, 4-dichlorophenoxy)- ci butan-l-one C NJv o r° o, zNJ 168 1-(4-Cyclopentylpiperazin-1-317 CH3yl)-3- (2-methoxyphenyl)- /. CH3 propan-1-one N aNi 169 CI 4- (4-Chloro-2-methyl- 365 ß phenoxy)-1-(4-cyclopentyl- piperazin-1-yl)-butan-1-one cl3 C N raj 170 F 1- (4-Cyclopentylpiperazin-1- yl)-2- (4-fluorophenyl- sulfanyl) ethanone 0 1 CNJ4s aNi 171 O F F 1- (4-Cyclopentylpiperazin-1- 371 rN F yi)-3- (4-fluoro-3-trifiuoro- aNi F methylphenyl) propenone c 172 F F 1- (4-Cyclopentylpiperazin-1- 357 yl)-2- (3-trifluoromethoxy- phenyl) ethanone 0 N NJ 173 F 1- (4-Cyclopentylpiperazin-1- yl)-2- (4-fluorophenoxy)- ethanone 0 ANJ NJ 174 wCI 1-(4-Cyclopentylpíperazin-1- yl)-2- (2, 3-dichlorophenoxy)- C Nto ethanone NO cr 175 H, 1-(4-Cyclopentylpiperazin-1- 0 l (4-methoxyphenoxy)- ethanone zu CN) 4 aN" 176 F 1-(4-Cyclopentylpiperazin-1-357 O l F yl)-2- (4-trifluoromethoxy- phenyl) ethanone aNi 177 03-Benzo [1, 3] dioxol-5-yl-1-331 r'N 0 (4-cyclopentylpiperazin-1- yl) propan-1-one U 178 O 1-(4-Cyclopentylpiperazin-1-339 yl)-2- (naphth-2-yloxy)- I N. J I /ethanone 179 H3CO 1- (4-Cyclopentylpiperazin-1- 377 0 yl)-3- (3, 4, 5-trimethoxy- zozos 3 3 phenyl) propan-l-one ON 0 aNi 180 o, CH3 1- (4-Cyclopentylpiperazin-1- 345 0 yl)-3- (2, 4-dimethoxyphenyl)- 'propenone CN 0 rN Nu 181 1-Biphenyl-4-yl-4-(4-cyclo-391 pentylpiperazin-1-yl) butane- 1, 4-dione N O 182 1- (4-Cyclopentylpiperazin-1- yl)-2- (naphth-2-ylsulfanyl)- ethanone 0 cNJ4S NJ 183 1-(4-Cyclopentylpiperazin-1-345 H C'°\\9° yl)-3-(3, 5-dimethoxyphenyl)- HC j f propenone 0"S' gN\J ans 184 CH 1- (4-Cyclopentylpiperazin-1- 345 1 3 + yl)-3- (2, 3-dimethoxyphenyl)- 0 0 CH3 propenone r'N r 0- 185 0 CH 3 1- (4-Cyclopentylpiperazin-l- 361 yl)-4- (3, 4-dimethoxyphenyl)- 0 D ! s butan-l-one hydrochloride zon zon N 186 CH3 1- (4-Cyclopentylpiperazin-1- yl)-2- (2, 3-dimethylphenoxy)- 0 t O ethanone neo aNi 187 O 1-phenyl-4-(4-pyridin-4-yl-324 0 K ! piperazin-1-yl) butane-1, 4- N diode e0NJ o N 188 1-(4-Chlorophenyl) 4-(4-349 cyclopentylpiperazin-1-yl)- f N r " N butane-1, 4-dione hydrochlo- 0 ride ride 189 0 ol CH3 1- (4-Cyclopentylpiperazin-l- 395 yl)-4- (6-methoxynaphth-2- N o yf) butane-1, 4-dione hydro- chloride 190 F 3- [4- (4-Fluorobenzyloxy)- 418 phenyl]-1- (4-pyridin-4-yl- piperazin-1-yl) propenone o o i CN OS Nv 191 (4-Benzylphenyi)-(4-pyridin-358 / 4-ylpiperazin-1-yl) methan- SNJ vW one 4 192 0 (4-Pyridin-4-ylpiperazin-1-352 yl)- (4-trifluoromethoxy- F F phenyl) methanone IF NJ 193 F F 1- (4-Pyridin-4-yipiperazin-l- 364 il)-3- (4-trifluoromethyl- phenyl) propan-l-one cent N N N, J 194 0 (4'-Ethylbiphenyl-4-yl)- (4- 372 rN pyridin-4-ylpiperazin-1-yl)- NJ methanone NU 195 5 2- (2-Methoxyphenoxy)-1- (4- 328 pyrid in-4-ylpiperazin-1-yl)- 0 0 ethanone N'two Nv NJ 196 3- (2-Methoxyphenyl)-1- (4- 324 pyridin-4-ylpiperazin-1-yl)- \CH 0 0 propenone N N NJ 197 2-(2-Chlorophenoxy)-1-(4-332 | l | pyridin-4-ylpiperazin-1-yl)- CN) 4O ethanone NJ X NJ 198. . 3-Naphth-1-y)-1- (4-pyridin- 344 O 4-ylpiperazin-1- N yl) propenone <, NJ w NJ N 199 O 3-(5-Bromo-2-416 ethoxyphenyl)-l- (4-pyridin- N 0 CH 3 4-ylpiperazin-1- /N yl) propenone Nu Br 200 2-Biphenyl-4-yl-1-(4-pyridin-358 4-ylpiperazin-1-yl) ethanone 0 zon N NU 201 CH 3- (3-Methoxyphenyl)-1- (4- 324 3 pyridin-4-yipiperazin-1-yl)- propenone zu rN NJ NEZ 202 O H 1- (4-Allylpiperazin-1-yl)-4-303 r '3 (4-methoxyphenyl) butan-1- 0 one onze H2cx J 203 1-(4-Allylpiperazin-1-yl)-2-360 Hic (2, 4-dichloro-5-methyl- phenylsulfanyl) ethanone Cl s wXNJ4s H CN V 2 204 O, CH3 - (4-Allylpiperazin-1-yl)-4-335 ! N 3 1 (3-fluoro-4-methoxyphenyl)- O u, F butane-1, 4-dione r" H, J 205 H3CN'CH3 1-(4-Allylpiperazin-1-yl)-3-300 3 3 (4-dimethylaminophenyl)- propenone our UN rN 206 O 1- (4-Allylpiperazin-1-yl)-2-351 , AO"- N benzyloxyphenyl) ethanone H2C) \/N O) 2 207 H3C. 1- (4-Allylpiperazin-1-yl)-3- 319 ( (3, 4-dimethoxyphenyl)- OS 3 propan-1-one 0 N H2C) \/\J 208 Cl 1- (4-Allylpiperazin-1-yl)-4- 358 (2, 4-dichlorophenoxy) butan- 1-one cri 0 CN H2CK \J 2 209 1- (4-Allylpiperazin-1-yl)-3- 289 (2-methoxyphenyl) propan- 1-one H 1-one I-one H2cx 9 210 Cl 1-(4-Allylpiperazin-1-yl)-4-337 (4-chloro-2-methylphenoxy)- butan-l-one CNv 0 0 N H2cx 9 211 F 1- (4-Allylpiperazin-1-yl)-2-295 (4-fluorophenylsulfanyl)- ethanone 0 nus H CN' 2 N 212 0 F F 1- (4-Allylpiperazin-1-yl)-3- 343 rN (4-fluoro-3-t (ifluoromethyl- ' ! 11 C, phenyl) propenone 213 F F 1-(4-Allylpiperazin-1-yl)-2-329 % 0 (3-trifluoromethoxyphenyl)- F T ethanone N H CN v C, 214 F 1- (4-Allylpiperazin-1-yl)-2-279 (4-fluorophenoxy) ethanone 0 Nô H CNJ z 2155 C 1- (4-Allylpiperazin-1-yl)-2-330 (2, 3-dichlorophenoxy)- CI ethanone ° H +wNJ 2 216 H3C 1- (4-Allylpiperazin-1-yl)-2- 291 3 Q (4-methoxyphenoxy)- ethanone o neo HZCNJ 217 F 1- (G4-Allylpiperazin-1-yl)-2-329 n fY ( (4-trifluoromethoxyphenyl)- F ethanone 2 N 218 1-(4-Allylpiperazin-1-yl)-3-303 ru benzo [1, 3] dioxol-5- H2c,--, 9 Vo ylpropan-1-one HzC J O 219 1- (4-Allylpiperazin-1-yl)-2-311 (naphth-2-yloxy) ethanone I// H2cv 9 220 H3C, 1- (4-Allylpiperazin-1-yl)-3- 349 10 0, (3, 4, 5-trimethoxyphenyl)- 0 fNe propan-1-one 0 ZON H C~NJ 2 221 o, CH3 1-(4-Allylpiperazin-1-yl)-3-317 (2, 4-dimethoxyphenyl)- propenone 0 o N H2cx J 222 1- (4-Allylpiperazin-1-yl)-4-363 biphenyl-4-yl-butane-1, 4- 0 dione N H2C\/Ns) O 2 223 1- (4-Allylpiperazin-1-yl)-2-327 (naphth-2-ylsulfanyl)- ethanone 0 0 H C) NJ 2 224 CH3 1- (4-Allylpiperazin-1-yl)-3-317 i H C \ (3, 5-dimethoxyphenyl)- rLC !"i propenone 0 Un HC iN J 225 CH3 1- (4-Allylpiperazin-1-yl)-3- 317 i (2, 3-dimethoxyphenyl)- O wo, CH3 propenone CNJQ ry N 226 o. cH3 1- (4-Allylpiperazin-1-yl)-4- 333 ( (3, 4-dimethoxyphenyl)- O/ O. CH3 butan-l-one N + CH3 1-(4-Allylpiperazin-1-yl)-2-289 H (2, 3-dimethylphenoxy)- 0 CH3 ethanone CNV rN) r J 2 228 O Cl 1-(4-Allylpiperazin-1-yl)-2-361 0 r N CNJ4S> (8-chloronaphth-1- rM " ylsulfanyl) ethanone H2c j 229 0 1- (4-Allyipiperazin-1-yi)-2-311 (naphth-1-yloxy) ethanone H2cx J I W 230 0 CH 2- (4-Acetylphenoxy)-1- (4- 303 3 allylpiperazin-1-yl) ethanone o Nô HzC i UNJ 231 CH3 1- (4-Allylpiperazin-1-yl)-3-289 i O (3-methoxyphenyl) propan- 1-one 1-one zon H2C) \/XJ H 2C.,, :,, N i 232 N 1- (4-Allylpiperazin-1-yl)-3-260 N \N pyridin-3-ylpropan-1-one our dz H2C+/XJ 2333 1- (4-Allylpiperazin-1-yl)-3-393 (4-benzyloxy-3-methoxy- J phenyl) propenone CHg cl 0 I/ ruz HZC 234 1-(4-Allylpiperazin-1-yl)-3-380 CNJX O CH3 (5-bromo-2-ethoxyphenyl)- , 3 H x J) q propenone \fE Br 235/sK°) 1-(4-Allylpiperazin-1-yl)-4-359 (3, 4-dihydro-2H-benzo- N p H2C<NJ ° [b] [1, 4] dioxepin-7-yl)- butane-1, 4-dione 236 o 1- (4-Allylpiperazin-1-yl)-3- 351 (2-chloro-3, 4-dimethoxy- H2c~NJ ClXoCH3 phenyl) propenone HgC" 237 1-(4-Allylpiperazin-1-yl)-2-329 NS/ (2-chloro-4-fluorophenyl- sulfanyl) ethanone H2C F 238 p - (4-Allylpiperazin-1-yl)-2- 341 CN) (naphth-1-ylmethylsulfanyl)- ethanone 2 U 239 3- [3- (4-Allylpiperazin-1-yi)-316 3-oxopropyl]-3H 0 benzooxazol-2-one Zu H CN V 2 240 O 1- (4-Allylpiperazin-1-yl)-5- 293 cyclohexylpentan-1-one H2CX sJ W . 2Al 241 H3Cso 1-(4-Allylpiperazin-1-yl)-3-289 0 (4-methoxyphenyl) propan- 1-one o N H CN v 2 242 p (4-Allyipiperazin-1-yl)- [4- (4- 347 chlorophenyl) cyclohexyl]- methanone .. r- "\ ci 243 o 1-(4-Allylpiperazin-1-yl)-2-345 N TU F Fizz trifluoromethoxyphenoxy)- HZC O F YP Y)' ethanone 244 2- (2-Acetylphenoxy)-l- (4- 303 /CH3 allylpiperazin-1-yl) ethanone O 0 O 0 0 H2cX 9 245 o Dimethyl-carbamic acid 4-346 cN) o [3- (4-allylpiperazin-1-yl)-3- HZCN v ON'CH3 oxopropyl] phenyl ester CH3 246 1- (4-Allylpiperazin-1-yl)-2-349 CI (5-chloro-3-methylbenzo [b]- thiophen-2-yl) ethanone H, C- CH, 247 O 1-phenyl-4-(4-pyridin-4-yl-324 O ) piperazin-1-yl) butane-1, 4- N dione hydrochloride N,, J 0 N 248 0, CH3 1- (3, 4-Dimethoxyphenyl)-4- 375 H3C fN k---Yao CH3 [4- (l-methylcyclopropyl)- t J ° [1, 4]-diazepan-1-yl] butane- 1, 4-dione hydrochloride 249 Cl 1- (4-Chlorophenyl)-4- (4- 363 cyclohexylpiperazin-1-yl)- N butane-1, 4-dione hydrochlo- nu o ride 250 0 1- (4-Cyclopentylpiperazin-l- 315 O yl)-4-phenylbutane-1, 4- ru dione hydrochloride aNi 0 251-1- (4-Allylpiperazin-1-yi)-3-371 O N+. O ( (3-nitro-4-pyrrolidin-1-yl- HZC\ N phenyl) propenone N ZU 0 252 _ 1-(4-Chlorophenyl)-4-(4-377 cycloheptylpiperazin-1-yl)- rNr' butane-1, 4-dione hydrochlo- O ride 253 0/CI 4- (4-Chlorophenyl)-1- (4- 335 cyclopentylpiperazin-1-yl)- fM butan-1-one hydrochloride Nez 254 1- (4-Cyclopentylpiperazin-1- 313 ° Xd yl)-2-indan-2-ylethanone hydrochloride NJ 255 0 c I 1- (4-Chlorophenyl)-4- (4- 392 0 n ! cyclooctylpiperazin-1-yl)- N butane-1, 4-dione hydrochlo- NJ 0 ride Y nde 256 0 1-(4-Cyclopentylpiperazin-1-333 N 0 CH 3 yl)-3- (4-methoxyphenoxy)- propan-l-one hydrochloride N / 257 ci 1- (4-Chlorophenyl)-4- (4- 335 cyclobutylpiperazin-1-yl)- /gNJ O butane-1, 4-dione hydrochlo- ride nde 258 1-(4-Cyclopentylpiperazin-1-317 N 0 CH3 yl)-3- (2-methoxyphenyl)- propan-l-one hydrochloride Nu / 259 0 CH 1- (4-Allylpiperazin-1-yl)-4- 335 N X (3-fluoro-4-methoxyphenyl)- H CNJ I F butane-1, 4-dione hydrochlo- 2 I ride 260 0 ol CH3 1- (4-Cyclopentylpiperazin-l- 375 3 yl)-4- (3, 4-dimethoxyphenyl)- N butane-1, 4-dione hydrochlo- ride 261 o, CH3 1-(4-Cyclopentylpiperazin-1-375 yl)-4- (2, 5-dimethoxyphenyl)- 0 butane-1, 4-dione hydrochlo- N-rr ! 0 ol ride N-,) CH3 3 262 0 ci 1- (4-Chlorophenyl)-4- (4- 321 cyclopropylpiperazin-1-yl)- N v N butane-1, 4-dione hydrochlo- ride 263 0 ci 1- (4-Chlorophenyl)-4- (4- 335 cyclopropylmethylpiperazin- N tXNJ O 1-yl) butane-1, 4-dione hy- drochloride 264 0 ci 1- (4-Chlorophenyl)-4- [4- 347 (1, 1-dimethylprop-2-ynyl)- % < piperazin-1-yl] butane-1, 4- dione hydrochloride H C CH 3 3 265 0 cl 1- (4-Chlorophenyl)-4- (4-iso- 323 propylpiperazin-1-yl) butane- zon H3CANJ O 1, 4-dione hydrochloride CH3 CH, 266 0 CI 1- (4-Chlorophenyl)-4- [4- (1- 351 ethylpropyl) piperazin-1- yl] butane-1, 4-dione hydro- wr' J chloride H3C 267 0 ol CH3 1- (3-Chloro-4-methoxy- 379 ; Rf : phenyl)-4- (4-cyclopentyl- 3. 92 min. ru piperazin-1-yl) butane-1, 4- dione hydrochloride 268 0 Cl 3- (4-Chlorophenyisulfanyl)- 353 ; Rf : o ! r 1- (4-cyclopentylpiperazin-l- 4. 50 min. M NJ yl) propan-1-one hydrochlo- NJ ride 269 ol CH3 1- (5-Chloro-2, 4-dimethoxy- 409 ; Rf : U HgC CHg phenyl)-4- (4-cyclopentyl- 4. 26 min. KN\J o piperazin-1-yl) butane-1, 4- \J dione hydrochloride 270 1- (5-Chloro-2-methoxy- 379 ; Rf : 0 HgC i 1 phenyl)-4- (4-cyclopentyl- 4. 13 min. CI piperazin-1-yl) butane-1, 4- dione hydrochloride 271 F 1- [4- (l-Ethyl propyl)-335 ; Rf : O piperazin-1-yl]-4- (4-fluoro- 3. 83 min. CH3 CN pl phenyl) butane-1, 4-dione N, _) 0 hydrochloride Hic 272 0 ci 1- (4-Chlorophenyl)-4- [4- 351 ; Rf : (1, 1-dimethylpropyl)- 4. 13 min. N piperazin-1-yl] butane-1, 4- Hrx "° H3 CH3 dione hydrochloride H3C CH3 273 0 ci 1- (4-Chlorophenyl)-4- (4- 349 ; Rf : cyclopropylmethyl [1, 4] di- 4. 00 min. N o azepan-1-yl) butane-1, 4- dione hydrochloride 274 0 Cl 1- (4-Chlorophenyl)-4- (4- 335 ; Rf : cyclopropyl [1, 4] diazepan-1- 3. 93 min. yl) butane-1, 4-dione hydro- r"-N o 8 chloride 275 0 ci 1- (4-Chlorophenyl)-4- (4- 363 ; Rf : cyclopentyl [1, 4] diazepan-1- 4. 17 min. v v yl) butane-1, 4-dione hydro- chloride 276 Cf 1- (4-Ch) oropheny))-4- [4- (1- 379 ; Rf : propylbutyl) piperazin-1-yl]- 4. 63 min. N H C NJ o butane-1, 4-dione hydrochlo- 3 ride 277 0 ol CH3 1- (3, 4-Dimethoxyphenyl)-4- 377 ; Rf : 0 t) f CHg CH3 [4- (l-ethyl p ropyl) piperazi n-3. 67 min. 3 1-yi] butane-1, 4-dione hy- nu o drochloride H3C 278 3- (3-Chlorophenylsulfanyl)- 355 ; Rf : ^ 1- [4- (1-ethylpropyl)- 4. 43 min. Lj M-n CtH3 CN S Cl piperazin-1-yl] propan-1-one L [sj J hydrochloride HIC 279 0 Cl 3- (4-Chlorophenoxy)-l- [4- 339 ; Rf : O J ( (1-ethylpropyl) piperazin-1- 4. 27 min. Lj rMD' CH3 C IN O yl] propan-1-one hydrochlo- ride HIC 280 O 2- (5-Chlorobenzothiazol-2- 398 ; Rf : CH3 N) s s yfsulfanyl)-l- [4- (l-ethyl-4. 33 min. 3 r3--ir NJ N propyl) piperazin-1-yl]- ethanone hydrochloride H3C Cl 281 0 2- (4-Chlorophenylsulfanyl)- CH3 N'S 1- [4- (1-ethylpropyl)- L'r) f N ! i piperazin-1-yl] ethanone H 3c HsC 282 0 F 1- [4- (l, 1-Dimethylpropyl)-335 ; Rf : N piperazin-1-yl]-4- (4-fluoro- 3. 67 min. phenyl) butane-1, 4-dione H3C CH3 hydrochloride CH3 283 0 ol CH3 1- (4-Cyclopropyl [1, 4] diaze- 361 ; Rf : n i ! ! a 3 pan-1-yl)-4- (3, 4-dimethoxy- 3. 40 min. u u 3 o phenyl) butane-1, 4-dione hydrochloride 284 O Cl 1-l4-(2-Chloroallyl)-356 ; Rf : piperazin-1-yl]-4- (4- 3. 93 min. H CtNJ O chlorophenyl) butane-1, 4- 0 2 dione hydrochloride 285 ol CH3 1- (4-Cyclopropylmethyl- 361 ; Rf : u r rr L. Hg piperazin-1-yl)-4- (3, 4-di- 3. 53 min 0 methoxyphenyl) butane-1, 4- dione hydrochloride 286 , O, H 1- (4-Cyclobutylpiperazin-1- 361 ; Rf : yl)-4- (3, 4-dimethoxyphenyl)- 3. 40 min. J O butane-1, 4-dione hydrochlo- ride 287 0 0 CH3 1- [4- (2-Chloroallyl)- 381 ; Rf : ci r"N O'CH3 piperazin-I-yi]-4- (3, 4- 3. 43 min. H2c4NJ O dimethoxyphenyl) butane- HC 1, 4-dione hydrochloride 288 4- {3- [4- (l-Ethylpropyl)-330 ; Rf : 0 f< N S piperazin-1-yl]-3-oxo-3. 67 min. CH3 CNzow propoxy} benzonitrile hydro- NJ chloride H3c 289 Cl 1- (4-Cyclopentylpiperazin-1- 371 ; Rf : O A yl)-3-(3, 5-dichlorophenoxy)-4. 53 min. ^ propan-1-one hydrochloride N'v-O Cl NJ 290 O rw 1-(4-Cyclopentylpiperazin-1-371 Rf : ^ yl)-3- (3, 4-dichlorophenoxy)- 4. 47 min. N\J Cl propan-1-one hydrochloride NJ P P Y 291 0 0, CH3 1- (4-Cyclopentylpiperazin-l- 363 ; Rf : 3 CH yl)-3- (3, 4-dimethoxy- 3. 50 min. N O O' phenoxy) propan-1-one hy- \ drochloride 292 0 ci 4- (4-Chlorophenyl)-l- (4- 351 ; Rf : cyclopentylpiperazin-1-yl)-4-3. 70 min. hydroxybutan-1-one hydro- ou J chloride 293 0, o. H 1- (3, 4-Dimethoxyphenyl)-4- 377 ; Rf : f t C"3 lao, CH3 (4- (l, 1-dimethylpropyl)-3. 33 min. H3c/NJ piperazin-1-yl] butane-1, 4- HgC) CH3 dione hydrochloride 3 294 O-CH3 2- [2- (4-Isopropylpiperazin- 359 ; Rf : C 3 -yl)-2-oxoethylidene]-5, 6- 3. 20 min. O O , dimethoxyindan-1-one hy- N drochloride 3 1' 0 I CH3 295o-CHg2- {2- [4- (1-Ethytpropy))-387 ; Rf : /CH3 piperazin-1-yll-2-oxo-3. 50 0 ethyl idene}-5, 6-d imethoxy-min. 387 r N " indan-1-one hydrochloride H3C NJ O CH3 296 O-CH3 2-[2-(4-lsopropylpiperazin-361 ; Rf : /LJ 1-yl)-2-oxoethyl]-5, 6-di- 2. 87 min. methoxyindan-1-one hydro- chlorids f \\ chtoride H3CocNJ O CH 3 297 O-CH3 2- {2- [4- (l-Ethylpropyl)-389 ; Rf : /cl CH3 piperazin-1-yl]-2-oxoethyl}-3. 33 min. 0 5, 6-dimethoxyindan-1-one N NJ o hydrochloride Bk CH 3 298 0 cl 1- (4-Chlorophenyl)-4- [4- 365 ; Rf : (tetrahydropyran-4-yl)-3. 73 min. M NJ Õ piperazin-1-yl] butane-1, 4- nu O dione hydrochloride O 29901- (4-Ch ! oropheny))-4- [4- (2- 353 ; Rf : CH3 CN, hydroxy-2-methylpropyl)-1. 91 min. /piperazin-1-yl] butane-1, 4- OH dione hydrochloride 300 0 1- [4- (l-Ethylpropyl)-375 ; Rf : rN piperazin-1-yl]-2- (4-trifluoro- 4. 50 min. methoxyphenoxy) ethanone F hydrochloride HgC 301F 1- [4- (1-Ethy) propy !)-359 ; Rf : piperazin-1-yl]-2- (4-trifluoro- 4. 33 min. methoxyphenyl) ethanone H C NJ hydrochloride hic Hic 302F'1- [4- (1-Ethy) propy !)-343 ; Rf : 0 F piperazin-1-yl]-2- (4-trifluoro- 4. 37 min. methylphenyl) ethanone hy- ! N l drochloride H3Cv o/ HsC HgC 303 0 Cl 2- (3, 4-Dichlorophenyl)-I- [4- 343 ; Rf : 0 rr (1-ethylpropyl) piperazin-1- 4. 33 min. N Cl yl] ethanone hydrochloride H3CXN,) H 3H-'C 304 2-Biphenyl-4-yi-l- [4- (I- 351 ; Rf : ethylpropyl) piperazin-1-yl]- 4. 63 min. 0 ethanone hydrochloride ZON H3C NJ HsC 305 0 [4- (1-Ethylpropyl) piperazin- 345 ; Rf : F 1-yl]- (3-trifluoromethoxy- 4. 23 min. NJ F phenyl) methanone hydro- HgC Y chloride HIC 306 0 [4- (1-Ethy) propyt) piperazin- 353 ; 4. 50 1-eyl] (3-phenoxyphenyl)- min. H3CXNJ NJ methanone hydrochloride HIC 3c ; 307 O (3-Chloro-4-trifluoro-379 ; Rf : N methoxyphenyl)- [4- (1- 4. 60 min. F N r ethylpropyl) piperazin-1- yl] methanone hydrochloride H3C F F 308 0 [4- (1-Ethylpropyl) piperazin- 345 ; Rf : 1-yl] (4-trifluoromethoxy- 4. 23 min. zon li ! pheny)) methanone hydro- H3 C N 0 F chloride H3C F F 309 0 1- [4- (l-Ethylpropyl)-357 ; Rf. N piperazin-1-yl]-3- (4-trifluoro- 4. 53 min. methylphenyl) propan-1-one hydrochloride 3 F/t F F 310F1- [4- (1-Ethy ! propy))-385 ; Rf : O eF piperazin-1-yl]-4-(4-trifluoro-2. 73 min. methylphenyl) butane-1, 4- N J o dione hydrochloride HgC T HgC 311 0 Cl 1- (3, 4-Dichlorophenyl)-4- [4- 383 ; Rf : (\N4\) CI (1-ethylpropyl) piperazin-1-2. 85 min. H3C~N\J yl] but-2-ene-1, 4-dione hy- H3C 1'' drochloride H, c 31201-Benzo [1, 3] dioxol-5-yl-4- 359 ; Rf : CH3 [4- (1-ethylpropyl) piperazin- 2. 08 min. CH N 1-yl] but-2-ene-1, 4-dione hy- u'O drochloride H 3c 313 0 1- (4-Chlorophenyl)-4- (4-iso- 337 ; Rf : Cl propyl [1, 4] diazepan-1-yl)-3. 93 min. /N r r butane-1, 4-dione hydrochlo- ride 3 cl3 CH3 314 O (4-Cyclopentylpiperazin-1-343 ; Rf : N 0 OEt yl)- (7-ethoxybenzofuran-2- 4. 12 min. yl) methanone hydrochloride NU VJ 315 O (5-Chlorobenzofuran-2-yl)-333 ; Rf : CN) 9\ (4-cyclopentylpiperazin-1-4. 15 min. p \ yl) methanone hydrochloride O 316 0 1- [4- (l-Ethyl propyl)-399 ; Rf : piperazin-1-yl]-4- (4-trifluoro- 4. 63 min. H c J F methoxyphenyl) but-2-ene- s n CH3 1, 4-dione hydrochloride 3 317 O 4-Benzo [1, 3] dioxol-5-yl-1-363 CH3 N 0 [4- (l-ethyl propyl) pi perazi n- (MH+), 3 t 1 i H \ 1-yl]-4-hydroxybutan-1-one 345 (MH+ O hydrochloride-H2O) ; ou HsC Rf : 3. 50 min. 318 [4- (1-Ethylpropyl) piper- 343 ; Rf : O azin-1-yl]-2- (3-trifluoro- 4. 07 min. CH3 CN methylphenyl) ethanone hy- drochloride HIC 319 0 1- [4- (l-Ethylpropyl)-343 ; Rf : O piperazin-1-yl]-2- (2-trifluoro- 3. 90 min. CH3 3 N methylphenyl) ethanone hy- drochloride HIC 320 O O (3-Benzoylphenyl)- [4- (1- 365 ; Rf : CH3 CN \C'JA ethylpropyl) piperazin-1-yl]-4. 03 min. L methanone hydrochloride HIC 3210., N- {3- [4- (1-Ethytpropyt)-318 ; Rf : N D CH3 rN NyCH3 piperazine-I-carbonyl]-2. 57 min. 0 phenyl} acetamide hydro- chloride H3C 322 o 1- [4- (l-Ethylpropyl)-401 ; Rf : o rY" piperazin-1-yl]-4- (4-trifluoro- 4. 40 min. CH3 N methoxyphenyl) butane-1, 4- N o dione hydrochloride Hic 323 CH3 2- (4-Dimethylaminophenyl)- 318 ; Rf : 1 3 0 N, CH 1- [4- (l-ethylpropyl)-0. 43 min. 3 piperazin-1-yl] ethanone di- r'H. M ICH3 j Nl hydrochloride nu Hic 324 O O 2-Benzo [1, 3] dioxol-5-yl-1-319 ; Rf : O > [4- (l-ethyl propyl) piperazi n-3. 30 min. CH3 C O 1-yl] ethanone hydrochloride N X, NJ 325 0, oCH3 2- (4-Butoxyphenyl)-1- [4- (1- 347 ; Rf : r N CH3 C NZ X ethylpropyl) piperazin-1-yl]-4. 47min. N J ethanone hydrochloride Hic 326 CH 2- (2, 5-Dimethoxyphenyl)-1- 335 ; Rf : 1 3 O p/ [4- (1-ethylpropyl) piperazin- 3. 57 min. 1-yljethanone hydrochloride gzNJ CH3 H, C HIC 327 O 2- (4-Acetylphenyl)-1- [4- (1- 333 ; (re- O XCH3 ethylpropyl) píperazin-1-yl]-duced ) i)''3 ethanone hydrochloride methyl X NJ enol enol ether) ; Rif : 3. 27 min. 328 F 1- [4- (1-Methylcyclopropyl)- 369 piperazin-1-yl]-4- (4-trifluoro- methylphenyl) butane-1, 4- N H c NJ dione hydrochloride 'X 329 F 1- (4-Bicyclopropyl-1-yi-395 0 F piperazin-1-yl)-4- (4-trifluoro- methylphenyl) butane-1, 4- Nl--.- dione hydrochloride

Spectral data for selected examples : Example 1 1- (3-Fluoro-4-methoxyphenyl)-4- (4-isopropylpiperazin-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) # 1. 29 (d, J = 7 Hz, 6H), 2.70-2. 92 (m, 3H), 3.00-3. 23 (m, 4H), 3.32-3. 71 (m, 4H), 3.92 (s, 3H), 4.18 (m, 1H), 4.43 (m, 1H), 7.29 (t, J= 7 Hz, 1H), 7.76 (dd, J = 14 Hz, 1 Hz, 1H), 7.84 (br d, J = 7 Hz, 1 H), 10.95 (brs, 1H).

Example 2 1- [4- (1-Ethylpropyl) piperazin-1-yl]-4- (3-fluoro-4-methoxyphenyl) butane-1,4-dione hydrochlo- ride 'H NMR (DMSO-d6) # 0. 98 (t, J = 7 Hz, 6H), 1.61 (sept, J = 7 Hz, 2H), 1.87 (m, 2H), 2.72 (m, 2H), 2. 85-3. 28 (m, 6H), 3.40 (m, 2H), 3.72 (m, 1H), 3.93 (s, 3H), 4.11 (m, 1H), 4.39 (m, 1H), 7.29 (t, J = 7 Hz, 1 H), 7.76 (br d, J = 14 Hz, 1H), 7.84 (br d, J = 7 Hz, 1 H), 10.75 (br s, 1H).

Example 3 1- (3-Fluoro-4-methoxyphenyl)-4- (4-propylpiperazin-1-yl) butane-1, 4-dione hydrochloride 'H NMR (DMSO-d6) J0. 91 (t, J = 7 Hz, 3H), 1.69 (sext, J = 7 Hz, 2H), 2.69-3. 10 (m, 7H), 3.20 (t, J= 7 Hz, 2H), 3.48 (m, 3H), 3.92 (s, 3H), 4.16 (m, 1H), 4.39 (m, 1H), 7.29 (t, J= 7 Hz, 1H), 7.78 (dd, J= 14 Hz, 1 Hz, 1H), 7.84 (br d, J = 7 Hz, 1H), 10.15 (brs, 1H).

Example 4 1- (4-Cyclopentylpiperazin-1-yl)-4- (4-methanesulfonylphenyl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) 61. 55 (m, 2H), 1.65-1. 88 (m, 4H), 1.98 (m, 2H), 2.75-3. 14 (m, 5H), 3.29 (s, 3H), 3.32 (m, 2H), 3.45-3. 64 (m, 4H), 4.14 (m, 1H), 4.39 (m, 1H), 8.08 (d, J= 8 Hz, 2H), 8.19 (d, J=8Hz, 2H), 10.95 (brs, 1H).

Example 5 1- (4-Cyclopentylpiperazin-1-yl)-4-phenylpentane-1, 5-dione hydrochloride 'H NMR (DMSO-d6) # 1. 45-2.05 (m, 10H), 2.43 (m, 2H), 2.82-3. 16 (m, 5H), 3. 40-3. 62 (m, 4H), 4.05 (m, 1H), 4.45 (m, 1H), 7.52 (t, J = 8 Hz, 2H), 7.63 (t, J = 8 Hz, 1H), 7.96 (d, J = 8 Hz, 2H), 11.28 (br s, 1 H).

Example 7 4-Cyclopentylpiperazine-1-carboxylic acid 2- (3, 4-dimethoxyphenyl) ethyl ester hydrochloride This compound was prepared by treatment of a solution of 2- (3, 4-dimethoxyphenyl)- ethanol (1.82 g, 10 mmol) in DCM (30 ml) with pyridine (1.6 ml) and then with a solution of 4- nitrophenyl chloroformate (2.0 g, 10 mmol) in DCM (25 ml). The mixture was stirred at room temperature for 2 hours, and was then washed with dilute hydrochloric acid and with water.

After drying with magnesium sulfate the solution of the crude carbonate was concentrated, to yield 3.8 g of a yellow oil. To a solution of 0.69 g (2 mmol) of this oil in acetonitrile (10 ml) was added 1-cyclopentylpiperazine (0.6 g, 4 mmol). The resulting mixture was stirred at room temperature for 2 days, concentrated under reduced pressure, and the residue was redissolved in DCM and extracted with dilute hydrochloric acid. The aqueous phase was made alkaline by addition of solid NaHC03, and extracted three times with DCM. The combined extracts were dried over magnesium sulphate, concentrated, and the residue was redissolved in 1 M hydrochloric acid (5 ml) and ethanol. The mixture was concentrated, and the residue recrystallized from ethanol, to yield 82 mg of the title compound as colorless solid.

'H NMR (DMSO-d6) s 1. 53 (m, 2H), 1.65-1. 83 (m, 4H), 1.98 (m, 2H), 2.82 (t, J = 7 Hz, 2H), 2.85-3. 00 (m, 2H), 3.24-3. 49 (m, 5H), 3.71 (s, 3H), 3.74 (s, 3H), 4.01 (m, 2H), 4.21 (t, J = 7 Hz, 2H), 6.74 (m, 1 H), 6.87 (m, 2H), 11.05 (br s, 1 H).

Example 62 1-Biphenyl-4-yl-4- (4-pyridin-4-ylpiperazin-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) s2. 78 (t, J= 7 Hz, 2H), 3.29 (t, J= 7 Hz, 2H), 3.61-3. 86 (m, 8H), 7.19 (m, 2H), 7.42 (m, 1 H), 7.52 (m, 2H), 7.73 (d, J = 7 Hz, 2H), 7.83 (d, J = 7 Hz, 2H), 8.07 (d, J = 7 Hz, 2H), 8.29 (d, J = 7 Hz, 2H), 13.80 (brs, 1H).

Example 79 3- [3-Oxo-3- (4-pyridin-4-ylpiperazin-1-yl) propyl]-3H-benzoxazol-2-one hydrochloride 1H NMR (DMSO-d6) 2. 89 (t, J = 7 Hz, 2H), 3.59-3. 78 (m, 8H), 4.06 (t, J = 7 Hz, 2H), 7.10- 7.40 (m, 6H), 8.28 (d, J = 7 Hz, 2H), 13.95 (br s, 1 H).

Example 84 2- (2-Acetylphenoxy)-l- (4-pyridin-4-ylpiperazin-1-yl) ethanone hydrochloride 1H NMR (DMSO-d6) 92. 63 (s, 3H), 3.62-3. 86 (m, 8H), 5.11 (s, 2H), 7.02 (t, J = 7 Hz, 1 H), 7.15 (d, J = 7 Hz, 1H), 7.20 (d, J = 7 Hz, 2H), 7.49 (br t, J=7Hz, 1H), 7.58 (br d, J = 7 Hz, 1 H), 8.29 (d, J = 7 Hz, 2H), 13.90 (br s, 1H).

Example 89 1- (4-Cyclohexylpiperazin-1-yl)-4- (3-fluoro-4-methoxyphenyl) butane-1, 4-dione hydrochloride 'H NMR (DMSO-d6) #1. 03-1.49 (m, 5H), 1.60 (m, 1H), 1.82 (m, 2H), 2.10 (m, 2H), 2.72 (m, 2H), 2.80-3. 23 (m, 6H), 3.41 (m, 2H), 3.63 (m, 1H), 3.93 (s, 3H), 4.17 (m, 1H), 4.42 (m, 1H), 7.29 (t, J = 8 Hz, 1H), 7.76 (dd, J = 11 Hz, 1 Hz, 1H), 7.87 (brd, J= 8 Hz, 1H), 10.80 (br s, 1H).

Example 135 1- (4-Cyclopentylpiperazin-1-yl)-3-naphth-1-ylpropenone hydrochloride 'H NMR (DMSO-d6) #1. 56 (m, 2H), 1.69-1. 85 (m, 4H), 2.02 (m, 2H), 2.95-3. 15 (m, 3H), 3.53 (m, 4H), 4.58 (m, 2H), 7.34 (d, J = 14 Hz, 1H), 7.55-7. 65 (m, 3H), 8.01 (m, 3H), 8.19 (d, J = 7 Hz, 1H), 8.35 (d, J= 14 Hz, 1H), 10.85 (brs, 1H).

Example 142 1- (4-Cyclopentylpiperazin-1-yl)-4- (4-methoxyphenyl) butan-1-one hydrochloride 'H NMR (DMSO-d6) 61. 53 (m, 2H), 1.65-1. 87 (m, 6H), 1.96 (m, 2H), 2.33 (t, J = 7 Hz, 2H), 2.53 (t, J= 7 Hz, 2H), 2.80-3. 13 (m, 3H), 3.38-3. 58 (m, 4H), 3.71 (s, 3H), 3.97 (m, 1H), 4.42 (m, 1H), 6.84 (d, J = 8 Hz, 2H), 7.11 (d, J = 8 Hz, 2H), 11.30 (brs, 1H).

Example 144 1- (4-Cyclopentylpiperazin-1-y1)-4- (3-fluoro-4-methoxyphenyl) butane-1,4-dione 1H NMR (DMSO-d6) #1. 25-1.66 (m, 6H), 1.79 (m, 2H), 2.28-2. 49 (m, 4H), 2.67 (m, 2H), 3.16 (m, 2H), 3.38-3. 55 (m, 4H), 3.93 (s, 3H), 7.29 (t, J = 8 Hz, 1H), 7.75 (d, J = 13 Hz), 7.85 (d, J = 8 Hz).

Example 147 2- (4-Acetylphenoxy)-1- (4-cyclopentylpiperazin-1-yl) ethanone hydrochloride 'H NMR (DMSO-d6) 61. 56 (m, 2H), 1.67-1. 88 (m, 4H), 1.98 (m, 2H), 2.52 (s, 3H), 2.85-3. 18 (m, 3H), 3.51 (m, 4H), 4.01 (m, 1 H), 4.40 (m, 1 H), 5.01 (d, J = 2 Hz, 2H), 7.02 (d, J = 8 Hz, 2H), 7. 91 (d, J = 8 Hz, 2H), 10.90 (br s, 1 H).

Example 181 1-Biphenyl-4-yl-4- (4-cyclopentylpiperazin-1-yl) butane-1, 4-dione 'H NMR (DMSO-d6) 51. 32 (m, 2H), 1.45-1. 63 (m, 4H), 1.79 (m, 2H), 2.33 (m, 2H), 2.43 (m, 3H), 2.72 (t, J = 7 Hz, 2H), 3. 24 (t, J = 7 Hz, 2H), 3.41 (m, 2H), 3.51 (m, 2H), 7.40-7. 53 (m, 3H), 7.76 (d, J = 7 Hz, 2H), 7.82 (d, J = 8 Hz, 2H), 8.07 (d, J = 8 Hz, 2H).

Example 185 1- (4-Cyclopentylpiperazin-1-yl)-4- (3, 4-dimethoxyphenyl) butan-1-one hydrochloride 'H NMR (DMSO-d6) J1. 53 (m, 2H), 1.65-1. 83 (m, 6H), 1.96 (m, 2H), 2.34 (t, J= 7 Hz, 2H), 2.53 (m, 2H), 2.80-3. 12 (m, 3H), 3.44 (m, 4H), 3.71 (s, 3H), 3.73 (s, 3H), 3.98 (m, 1H), 4.43 (m, 1 H), 6.69 (brd, J= 8 Hz, 1 H), 6.78 (br s, 1 H), 6.84 (d, J = 8 Hz), 11.05 (br s, 1 H).

Example 188 1- (4-Chlorophenyl)-4- (4-cyclopentylpiperazin-1-yl) butane-1, 4-dione hydrochloride 'H NMR (DMSO-d6) #1. 53 (m, 2H), 1.64-1. 90 (m, 4H), 1.98 (m, 2H), 2.71-3. 18 (m, 5H), 3.23 (t, J = 7 Hz, 2H), 3.42-3. 67 (m, 4H), 4.15 (m, 1 H), 4.39 (m, 1H), 7.60 (d, J = 8 Hz, 2H), 7.99 (d, J = 8 Hz, 2H), 11.20 (br s, 1 H).

Example 189 1- (4-Cyclopentylpiperazin-1-yl)-4- (6-methoxynaphth-2-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) J1. 56 (m, 2H), 1.63-1. 90 (m, 4H), 1.99 (m, 2H), 2.21-3. 17 (m, 5H), 3.30- 3.68 (m, 6H), 3.91 (s, 3H), 4.18 (m, 1H), 4.41 (m, 1H), 7.28 (m, 1H), 7.40 (brs, 1H), 7.89 (d, J = 7 Hz, 1H), 7.97 (br d, J = 7 Hz, 1H), 8.05 (d, J = 7 Hz, 1 H), 8. 61 (br s, 1H), 11.10 (br s, 1H).

Example 190 3-14- (4-Fluorobenzyloxy) phenyl]-1- (4-pyridin-4-ylpiperazin-1-yl) propenone 'H NMR (DMSO-d6) #3. 32-3.50 (m, 4H), 3.65-3. 88 (m, 4H), 5.12 (s, 2H), 6.84 (d, J = 7 Hz, 2H), 7.03 (d, J= 9 Hz, 2H), 7. 13-7.24 (m, 3H), 7. 46-7. 53 (m, 3H), 7.69 (d, J = 9 Hz, 2H), 8.18 (d, J = 7 Hz, 2H).

Example 247 1-Phenyl-4- (4-pyridin-4-ylpiperazin-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) 2. 78 (t, J= 7 Hz, 2H), 3.28 (t, J= 7 Hz, 2H), 3.59-3. 84 (m, 8H), 7.19 (d, J = 7 Hz, 2H), 7.53 (t, J = 7 Hz, 2H), 7.63 (m, 1 H), 7.99 (d, J = 7 Hz, 2H), 8.29 (d, J = 7 Hz, 2H), 13.95 (br s, 1 H).

Example 248 1- (3, 4-Dimethoxyphenyl)-4- [4- (1-methylcyclopropyl)- [1, 4]-diazepan-1-yl] butane-1, 4-dione hy- drochloride 'H NMR (DMSO-d6) #0. 74 (m, 2H), 1.31 (s, 2H), 1.38 (m, 3H), 1.95-2. 20 (m, 2H), 2.25-2. 80 (m, 4H), 3.10-3. 75 (m, 6H), 3.81 (s, 3H), 3.85 (s, 3H), 4.00-4. 22 (m, 2H), 7.08 (d, J = 8 Hz, 1 H), 7.45 (s, 1 H), 7.68 (d, J = 8 Hz, 1 H), 10 28 (br s, 1 H) ; HPLC-MS: m/z 375 (MH+) ; Rf: 2.20 min.

Example 249 1- (4-Chlorophenyl)-4- (4-cyclohexylpiperazin-1-yl) butane-1, 4-dione hydrochloride 'H NMR (DMSO-d6) J1. 05-1.65 (m, 6H), 1.82 (m, 2H), 2.11 (m, 2H), 2. 72-2.98 (m, 3H), 3.04- 3.28 (m, 5H), 3.42 (m, 2H), 3.63 (m, 1H), 4.14 (m, 1H), 4.41 (m, 1H), 7.61 (d, J = 8 Hz, 2H), 7.99 (d, J = 8 Hz, 2H), 10.80 (br s, 1 H).

Example 250 1-(4-Cyclopentylpiperazin-1-yl)-4-phenylbutane-1, 4-dione hydrochloride 'H NMR (DMSO-d6) 61. 54 (m, 2H), 1.65-1. 90 (m, 4H), 1.98 (m, 2H), 2.73-3. 15 (m, 5H), 3.26 (t, J = 7 Hz, 2H), 3.42-3. 67 (m, 4H), 4.15 (m, 1H), 4.39 (m, 1H), 7.52 (t, J = 7 Hz, 2H), 7.63 (t, J = 7 Hz, 1H), 7. 99 (d, J = 7 Hz, 2H), 11.15 (brs, 1H).

Example 251 1- (4-Allylpiperazin-1-yl)-3- (3-nitro-4-pyrrolidin-1-ylphenyl) propenone 'H NMR (CDC13) #2. 01 (m, 4H), 2.51 (br s, 4H), 3.03 (d, J = 7 Hz, 2H), 3.28 (m, 4H), 3.65- 3.80 (m, 4H), 5.19-5. 25 (m, 2H), 5.80-5. 92 (m, 1H), 6.73 (d, J= 14 Hz, 1H), 6.89 (d, J= 8 Hz, 1 H), 7.49 (d, J = 8 Hz, 1 H), 7.58 (d, J = 14 Hz, 1 H), 7.92 (br s, 1 H).

Example 252 1- (4-Chlorophenyl)-4- (4-cycloheptylpiperazin-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) 61. 35-1.78 (m, 10H), 2.12 (m, 2H), 2.73 (m, 2H), 2.90 (m, 1H), 3.08- 3.36 (m, 7H), 3.68 (m, 1H), 4.13 (m, 1H), 4.42 (m, 1H), 7.59 (d, J = 8 Hz, 2H), 7.98 (d, J = 8 Hz, 2H), 10.85 (br s, 1H).

Example 253 4- (4-Chlorophenyl)-1- (4-cyclopentylpiperazin-1-yl) butan-1-one hydrochloride 'H NMR (DMSO-d6) #1. 54 (m, 2H), 1.65-1. 80 (m, 6H), 1.97 (m, 2H), 2.35 (m, 2H), 2.60 (m, 2H), 2.85-3. 05 (m, 3H), 3.27-3. 55 (m, 4H), 3.99 (m, 1 H), 4.44 (m, 1 H), 7.23 (d, J = 8 Hz, 2H), 7.34 (d, J = 8 Hz, 2H), 10.39 (br s, 1 H).

Example 254 1- (4-Cyclopentylpiperazin-1-yl)-2-indan-2-ylethanone hydrochloride 'H NMR (DMSO-d6) J1. 52 (m, 2H), 1.62-1. 89 (m, 4H), 1.98 (m, 2H), 2.55 (m, 2H), 2.72 (sept, J = 7 Hz, 1 H), 2.90 (m, 3H), 3.06 (dd, J = 15 Hz, 7 Hz, 2H), 3.46 (m, 6H), 4.04 (br d, J = 7 Hz, 1H), 4.47 (brd, J= 7 Hz, 1H), 7.09 (m, 2H), 7.18 (m, 2H), 11.29 (brs, 1H).

Example 255 1- (4-Chlorophenyl)-4- (4-cyclooctylpiperazin-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) 9 1. 41-1.76 (m, 12H), 2.02 (m, 2H), 2.75 (m, 2H), 2.92 (m, 1H), 3.06- 3.45 (m, 7H), 3.64 (m, 1H), 4.13 (m, 1H), 4.41 (m, 1H), 7.61 (d, J=8Hz, 2H), 7. 99 (d, J=8 Hz, 2H), 10.85 (br s, 1H).

Example 256 1- (4-Cyclopentylpiperazin-1-yl)-3- (4-methoxyphenoxy) propan-l-one hydrochloride 'H NMR (DMSO-d6) 1. 53 (m, 2H), 1.65-1. 88 (m, 4H), 1.98 (m, 2H), 2.83 (t, J = 7 Hz, 2H), 2.88-3. 15 (m, 3H), 3.48 (m, 4H), 3.69 (s, 3H), 4.10 (brd, J= 7 Hz, 1H), 4.13 (t, J= 7 Hz, 2H), 4.46 (brd, J= 7 Hz, 1 H), 6.85 (s, 4H), 11.07 (br s, 1 H).

Example 257 1-(4-Chlorophenyl)-4-(4-cyclobutylpiperazin-1-yl) butane-1,4-dione hydrochloride 1H NMR (DMSO-d6) #1. 65-1.83 (m, 2H), 2.18 (m, 2H), 2.38 (m, 2H), 2.61-2. 93 (m, 4H), 3.07 (m, 1H), 3.23 (t, J = 7 Hz, 2H), 3.32 (m, 2H), 3.50-3. 71 (m, 2H), 4.15 (m, 1H), 4.40 (m, 1H), 7.60 (d, J = 8 Hz, 2H), 7.99 (d, J = 8 Hz, 2H), 11.43 (br s, 1 H).

Example 258 1- (4-Cyclopentylpiperazin-1-yl)-3- (2-methoxyphenyl) propan-1-one hydrochloride 'H NMR (DMSO-d6) #1. 53 (m, 2H), 1.63-1. 85 (m, 4H), 1.97 (m, 2H), 2.58 (m, 2H), 2.78 (t, J = 7 Hz, 2H), 2.82-3. 11 (m, 3H), 3.37-3. 56 (m, 4H), 3.79 (s, 3H), 4.01 (m, 1H), 4.43 (m, 1H), 6.86 (br t, J = 7 Hz, 1 H), 6.93 (d, J = 7 Hz, 1H), 7.18 (m, 2H), 11.05 (brs, 1H).

Example 259 1- (4-Allylpiperazin-1-yl)-4- (3-fluoro-4-methoxyphenyl) butane-1, 4-dione hydrochloride 1H NMR (DMSO-d6) #2. 70-3.13 (m, 5H), 3.19 (t, J=7 Hz, 2H), 3.35-3. 62 (m, 3H), 3.76 (m, 2H), 3.93 (s, 3H), 4.18 (m, 1H), 4.40 (m, 1H), 5.51 (m, 2H), 5.99 (m, 1H), 7.29 (t, J= 7 Hz, 1H), 7.76 (brd, J= 14 Hz, 1H), 7. 85 (brd, J= 7 Hz, 1H), 11.31 (brs, 1H).

Example 260 1- (4-Cyclopentylpiperazin-1-yl)-4- (3, 4-dimethoxyphenyl) butane-1, 4-dione hydrochloride 'H NMR (DMSO-d6), 51. 50-2.08 (m, 8H), 2.72 (m, 2H), 2.79-3. 16 (m, 3H), 3.21 (t, J= 7 Hz, 2H), 3.42-3. 66 (m, 4H), 3.81 (s, 3H), 3.85 (s, 3H), 4.16 (m, 1H), 4.40 (m, 1H), 7.08 (d, J= 8 Hz, 1H), 7.46 (d, J= 1 Hz, 1H), 7.68 (dd, J= 8 Hz, 1 Hz, 1H), 11.18 (brs, 1H).

Example 261 1- (4-Cyclopentylpiperazin-1-yl)-4- (2, 5-dimethoxyphenyl) butane-1,4-dione hydrochloride 1H NMR (DMSO-d6) #1. 54 (m, 2H), 1.65-1. 88 (m, 4H), 1.99 (m, 2H), 2.69 (m, 2H), 2.80-3. 20 (m, 5H), 3.50 (m, 4H), 3.72 (s, 3H), 3.83 (s, 3H), 4.12 (m, 1 H), 4.40 (m, 1 H), 7.09 (m, 1 H), 7.13 (m, 2H), 10. 90 (brs, 1H).

Example 262 1-(4-Chlorophenyl)-4-(4-cyclopropylpiperazin-1-yl)butane-1,4 -dione hydrochloride 1 H NMR (DMSO-d6), 5 0. 80 (br d, J = 7 Hz, 2H), 1. 12 (m, 2H), 2.71-2. 89 (m, 3H), 3.08 (m, 2H), 3.23 (t, J = 7 Hz, 2H), 3. 44-3.62 (m, 4H), 4.15 (m, 1H), 4.40 (m, 1H), 7.60 (d, J = 8 Hz, 2H), 7.98 (d, J = 8 Hz, 2H), 11.00 (br s, 1 H).

Example 263 1- (4-Chlorophenyl)-4- (4-cyclopropylmethylpiperazin-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) 50. 39 (m, 2H), 0.64 (m, 2H), 1.11 (m, 1 H), 2.77 (quart, J = 7 Hz, 2H), 2.80-3. 18 (m, 5H), 3.22 (t, J= 7 Hz, 2H), 3.46-3. 62 (m, 3H), 4.18 (m, 1H), 4.40 (m, 1H), 7.58 (d, J = 8 Hz, 2H), 7.98 (d, J = 8 Hz, 2H), 10.82 (brs, 1H).

Example 264 1- (4-Chlorophenyl)-4- [4- (1, 1-dimethylprop-2-ynyl) piperazin-1-yl] butane-1, 4-dione hydrochlo- ride 'H NMR (DMSO-d6) #1. 69 (br s, 6H), 2.70-2. 93 (m, 3H), 3.02-3. 29 (m, 3H), 3.64 (m, 4H), 4.03 (brs, 1H), 4.19 (m, 1H), 4.48 (m, 1H), 7.60 (d, J = 8 Hz, 2H), 7.99 (d, J = 8 Hz, 2H), 12.05 (br s, 1 H).

Example 265 1- (4-Chlorophenyl)-4- (4-isopropylpiperazin-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) a 1.28 (d, J = 7 Hz, 6H), 2.73 (m, 2H), 2.85 (m, 1 H), 3.09 (m, 2H), 3.22 (m, 2H), 3.33-3. 67 (m, 4H), 4.16 (m, 1H), 4.42 (m, 1H), 7.60 (d, J= 8 Hz, 2H), 7.99 (d, J= 8 Hz, 2H), 10.75 (br s, 1 H).

Example 266 1- (4-Chlorophenyl)-4- [4- (1-ethylpropyl) piperazin-1-yl] butane-1, 4-dione hydrochloride 'H NMR (DMSO-d6) #0. 98 (t, J = 7 Hz, 6H), 1.62 (m, 2H), 1.85 (m, 2H), 2.74 (m, 2H), 2.88- 3.26 (m, 6H), 3.39 (m, 2H), 3.68 (m, 1H), 4.12 (m, 1H), 4.39 (m, 1 H), 7.59 (d, J = 8 Hz, 2H), 7.98 (d, J = 8 Hz, 2H), 10.45 (br s, 1 H).

Example 267 1- (3-Chloro-4-methoxyphenyl)-4- (4-cyclopentylpiperazin-1-yl) butane-1, 4-dione hydrochloride 'H NMR (DMSO-d6) 61. 55 (m, 2H), 1.65-1. 88 (m, 4H), 2.00 (m, 2H), 2.73 (q, J = 7 Hz, 2H), 2.80-3. 15 (m, 3H), 3.22 (t, J= 7 Hz, 2H), 3.44-3. 65 (m, 4H), 3.96 (s, 3H), 4.15 (m, 1H), 4.39 (m, 1H), 7.28 (d, J = 8 Hz, 1H), 7.98 (m, 2H), 11.15 (br s, 1 H).

Example 268 3- (4-Chlorophenylsulfanyl)-1- (4-cyclopentylpiperazin-1-yl) propan-1-one hydrochloride 1H NMR (DMSO-d6) 51. 53 (m, 2H), 1.62-1. 88 (m, 4H), 1.96 (m, 2H), 2.71 (t, J= 7 Hz, 2H), 2.80-3. 12 (m, 3H), 3.17 (t, J = 7 Hz, 2H), 3.35-3. 59 (m, 4H), 3.97 (m, 1 H), 4.43 (m, 1 H), 7.36 (m, 4H), 11.21 (br s, 1 H).

Example 269 1-(5-Chloro-2,4-dimethoxyphenyl)-4-(4-cyclopentylpiperazin-1 -yl) butane-1,4-dione hydrochlo- ride 'H NMR (DMSO-d6) a 1. 55 (m, 2H), 1.65-1. 90 (m, 4H), 1.98 (m, 2H), 2.69 (q, J = 7 Hz, 2H), 2.88 (m, 1H), 3.00-3. 10 (m, 2H), 3.14 (t, J= 7 Hz, 2H), 3.40-3. 63 (m, 4H), 3.98 (s, 6H), 4.13 (m, 1H), 4.39 (m, 1H), 6.87 (s, 1H), 7.65 (s, 1H), 11.07 (brs, 1H).

Example 270 1- (5-Chloro-2-methoxyphenyl)-4- (4-cyclopentylpiperazin-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) 51. 54 (m, 2H), 1.64-1. 94 (m, 4H), 1.85 (m, 2H), 2.70 (q, J= 7 Hz, 2H), 2.85 (m, 1 H), 3.06 (m, 2H), 3.14 (t, J = 7 Hz, 2H), 3.40-3. 66 (m, 4H), 3.90 (s, 3H), 4.12 (m, 1 H), 4.39 (m, 1 H), 7.24 (d, J = 8 Hz, 1 H), 7.51 (s, 1 H), 7.59 (d, J = 8 Hz, 1 H), 11.31 (br s, 1H).

Example 271 1- [4- (1-Ethylpropyl) piperazin-1-yl]-4- (4-fluorophenyl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) 50. 97 (t, J = 7 Hz, 6H), 1.62 (m, 2H), 1.88 (m, 2H), 2.75 (m, 2H), 2.85- 3.30 (m, 5H), 3.38 (m, 2H), 3.73 (m, 1H), 4.14 (m, 1H), 4.40 (m, 1H), 7.36 (t, J= 8 Hz, 2H), 8.07 (t, J= 8 Hz, 2H), 10.76 (brs, 1H).

Example 272 1- (4-Chlorophenyl)-4- [4- (1, 1-dimethylpropyl) piperazin-1-yl] butane-1, 4-dione hydrochloride 'H NMR (DMSO-d6) #0. 92 (t, J = 7 Hz, 3H), 1.31 (s, 6H), 1.72 (q, J = 7 Hz, 2H), 2.76 (t, J = 7 Hz, 2H), 2.88 (m, 1H), 3.15 (m, 2H), 3.24 (q, J = 7 Hz, 2H), 3.47 (m, 2H), 3.68 (m, 1H), 4.14 (m, 1H), 4.43 (m, 1H), 7.61 (d, J= 8 Hz, 2H), 7.99 (d, J= 8 Hz, 2H), 10.22 (brs, 1H).

Example 273 1- (4-Chlorophenyl)-4- (4-cyclopropylmethyl [1,4] diazepan-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) #0. 39 (m, 2H), 0.64 (m, 2H), 1.13 (m, 1H), 1.95-2. 45 (m, 3H), 2.74 (m, 2H), 3.01 (m, 3H), 3.35-3. 90 (m, 7H), 4. 08 (m, 1 H), 7.60 (d, J = 8 Hz, 2H), 7.99 (d, J = 8 Hz, 2H), 10.55 (brs, 1H).

Example 274 1-(4-Chlorophenyl)-4-(4-cyclopropyl[1, 4] diazepan-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) #0. 82 (m, 2H), 1.15 (m, 2H), 1.95-2. 45 (m, 2H), 2.74 (m, 2H), 2.90 (m, 1H), 3.15 (m, 1H), 3.25 (m, 2H), 3.35-3. 80 (m, 6H), 3.95-4. 15 (m, 1H), 7.61 (d, J= 8 Hz, 2H), 8.00 (d, J= 8 Hz, 2H), 10.75 (m, 1H).

Example 275 1- (4-Chlorophenyl)-4- (4-cyclopentyl [1,4] diazepan-1-yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) #1. 54 (m, 2H), 1.72 (m, 4H), 1.90-2. 30 (m, 4H), 2.74 (m, 2H), 2.85-3. 25 (m, 4H), 3.35-3. 69 (m, 4H), 3.80 (m, 1H), 4.02 (m, 2H), 7.61 (d, J = 8 Hz, 2H), 8.00 (d, J=8 Hz, 2H), 10.55 (m, 1H).

Example 276 1- (4-Chlorophenyl)-4- [4- (l-propylbutyl) piperazin-1-yl] butane-1, 4-dione hydrochloride 'H NMR (DMSO-d6) #0. 92 (t, J = 7 Hz, 6H), 1.28-1. 60 (m, 6H), 1.80 (m, 2H), 2.76 (m, 2H), 2.93 (m, 1H), 3.05-3. 55 (m, 7H), 3.64 (m, 1H), 4.15 (m, 1H), 4.42 (m, 1H), 7.61 (d, J= 8 Hz, 2H), 8.00 (d, J = 8 Hz, 2H), 10.24 (m, 1H).

Example 277 1- (3, 4-Dimethoxyphenyl)-4- [4- (1-ethylpropyl) piperazin-1-yl] butane-1, 4-dione hydrochloride 'H NMR (DMSO-d6) 60. 97 (t, J= 7 Hz, 6H), 1.63 (m, 2H), 1.84 (m, 2H), 2.72 (m, 2H), 2.95 (m, 1H), 3.00-3. 25 (m, 5H), 3.39 (m, 2H), 3.63 (m, 1H), 3.81 (s, 3H), 3.85 (s, 3H), 4.14 (m, 1 H), 4.42 (m, 1 H), 7.08 (d, J = 8 Hz, 1 H), 7.45 (s, 1 H), 7.66 (d, J = 8 Hz, 1 H), 10.12 (br s, 1H).

Example 278 3- (3-Chlorophenylsulfanyl)-1- [4- (1-ethylpropyl) piperazin-1-yl] propan-1-one hydrochloride 'H NMR (DMSO-d6) 5 0. 95 (t, J = 7 Hz, 6H), 1.61 (m, 2H), 1.82 (m, 2H), 2.73 (m, 2H), 2.85- 3.15 (m, 3H), 3.20 (t, J= 7 Hz, 2H), 3.28-3. 60 (m, 4H), 3.96 (m, 1H), 4.45 (m, 1H), 7.22-7-40 (m, 4H), 10.07 (br s, 1 H).

Example 279 3- (4-Chlorophenoxy)-l- [4- (l-ethylpropyl) piperazin-1-yl] propan-1-one hydrochloride 1H NMR (DMSO-d6) #0. 96 (t, J = 7 Hz, 6H), 1.62 (m, 2H), 1.85 (m, 2H), 2.87 (t, J = 7 Hz, 2H), 2.90-3. 28 (m, 4H), 3.41 (m, 2H), 3.65 (m, 1 H), 4.08 (m, 1 H), 4.20 (t, J = 7 Hz, 2H), 4.47 (m, 1 H), 6.96 (d, J = 8 Hz, 2H), 7.33 (d, J = 8 Hz, 2H), 10.45 (br s, 1 H).

Example 280 <BR> <BR> <BR> 2- (5-Chlorobenzothiazol-2-ylsulfanyl)-1- [4- (1-ethylpropyl) piperazin-1-yl] ethanone hydrochlo- ride 'H NMR (DMSO-d6) #0.98 (t, J = 7 Hz, 6H), 1.63 (m, 2H), 1.87 (m, 2H), 3.08 (m, 2H), 3.15- 3.50 (m, 4H), 3.83 (m, 1H), 4.16 (m, 1H), 4.43 (m, 1H), 4.60 (s, 2H), 7.44 (d, J= 8 Hz, 1H), 7.93 (s, 1 H), 8.06 (d, J = 8 Hz, 1 H), 10.84 (br s, 1 H).

Example 282 1- [4- (1, 1-Dimethylpropyl) piperazin-1-yl]-4- (4-fluorophenyl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) #0. 92 (t, J = 7 Hz, 3H), 1. 31 (s, 6H), 1.72 (quart, J = 7 Hz, 2H), 2.75 (t, J = 7 Hz, 2H), 2.86 (m, 1H), 3.00-3. 31 (m, 4H), 3.50 (m, 2H), 3.71 (m, 1H), 4.14 (m, 1H), 4.43 (m, 1H), 7.36 (t, J= 9 Hz, 2H), 8. 06 (dd, J= 8 Hz, 9 Hz, 2H), 10.37 (br s, 1H).

Example 283 1- (4-Cyclopropyl [1,4] diazepan-1-yl)-4- (3, 4-dimethoxyphenyl) butane-1,4-dione hydrochloride 1H NMR (DMSO-d6) 60. 82 (m, 2H), 1.15 (m, 2H), 2.00-2. 45 (m, 3H), 2.71 (m, 2H), 2.91 (m, 1H), 3.13 (m, 1H), 3.24 (m, 2H), 3.35-3. 75 (m, 5H), 3.82 (s, 3H), 3.85 (s, 3H), 4.11 (m, 1H), 7.07 (d, J = 8 Hz, 1 H), 7.46 (s, 1 H), 7.67 (d, J = 8 Hz, 1 H), 10.7 (br s, 1 H).

Example 284 1- [4- (2-Chloroallyl) piperazin-1-yl]-4- (4-chlorophenyl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) #2. 75 (m, 2H), 2. 80-3. 15 (m, 2H), 3.24 (t, J= 7 Hz, 2H), 3.30-3. 80 (m, 6H), 4.11 (m, 2H), 5.81 (br s, 1H), 5.94 (brs, 1H), 7.61 (d, J = 8 Hz, 2H), 8.00 (d, J = 8 Hz, 2H), 11.14 (brs, 1H).

Example 285 1- (4-Cyclopropylmethylpiperazin-1-yi)-4- (3, 4-dimethoxyphenyl) butane-1,4-dione hydrochlo- ride 1H NMR (DMSO-d6) d0. 40 (m, 2H), 0.64 (m, 2H), 1.09 (m, 1H), 2.73 (m, 2H), 2.80-3. 15 (m, 5H), 3.22 (m, 2H), 3.54 (m, 3H), 3.81 (s, 3H), 3.85 (s, 3H), 4.19 (m, 1H), 4.40 (m, 1H), 7.07 (d, J = 8 Hz, 1 H), 7.45 (s, 1 H), 7.66 (d, J = 8 Hz, 1 H), 10.73 (br s, 1 H).

Example 286 1- (4-Cyclobutylpiperazin-1-yl)-4- (3, 4-dimethoxyphenyl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) #1. 75 (m, 2H), 2.17 (m, 2H), 2.39 (m, 2H), 2.60-2. 95 (m, 4H), 3.00-3. 35 (m, 5H), 3.63 (m, 2H), 3. 81 (s, 3H), 3.85 (s, 3H), 4.17 (m, 1 H), 4.41 (m, 1 H), 7.07 (d, J = 8 Hz, 1 H), 7.45 (s, 1 H), 7.66 (d, J = 8 Hz, 1 H), 10.53 (br s, 1 H).

Example 287 1-[4-(2-Chloroallyl)piperazin-1-yl]-4-(3,4-dimethoxyphenyl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) #2. 72 (br s, 2H), 2.86-3. 57 (m, 10H), 3.81 (s, 3H), 3.85 (s, 3H), 4.09 (m, 2H), 5.80 (brs, 1H), 5.94 (brs, 1H), 7.07 (d, J=8 Hz, 1H), 7.45 (s, 1H), 7.67 (d, J= 8 Hz, 1H), 11.15 (brs, 1H).

Example 288 4- {3- [4- (1-Ethylpropyl) piperazin-1-yl]-3-oxo-propoxy} benzonitrile hydrochloride 'H NMR (DMSO-d6) #0. 96 (t, J = 7 Hz, 6H), 1.61 (m, 2H), 1.83 (m, 2H), 2.91 (t, J = 7 Hz, 2H), 2. 92-3. 45 (m, 6H), 3.71 (m, 1H), 4.07 (m, 1H), 4.30 (t, J= 7 Hz, 2H), 4.46 (m, 1H), 7.10 (d, J = 8 Hz, 2H), 7.77 (d, J = 8 Hz, 2H), 10.76 (br s, 1H).

Example 289 1- (4-Cyclopentylpiperazin-1-yl)-3- (3, 5-dichlorophenoxy) propan-1-one hydrochloride 'H NMR (DMSO-d6) # 1. 55 (m, 2H), 1.75 (m, 4H), 1.98 (m, 2H), 2.87 (t, J = 7 Hz, 2H), 2.95- 3.20 (m, 3H), 3.35-3. 60 (m, 4H), 4.08 (m, 1 H), 4.26 (t, J = 7 Hz, 2H), 4.45 (m, 1 H), 7.04 (s, 2H), 7.16 (s, 1H), 11.07 (brs, 1H).

Example 290 1- (4-Cyclopentylpiperazin-1-yl)-3- (3, 4-dichlorophenoxy) propan-1-one hydrochloride 'H NMR (DMSO-d6) # 1. 54 (m, 2H), 1.75 (m, 4H), 1.98 (m, 2H), 2.88 (t, J = 7 Hz, 2H), 2.90- 3.15 (m, 2H), 3.39-3. 65 (m, 5H), 4.09 (m, 1 H), 4.24 (t, J = 7 Hz, 2H), 4.45 (m, 1 H), 6.97 (m, 1 H), 7.23 (s, 1H), 7.51 (d, J = 8 Hz, 1 H), 11.15 (brs, 1H).

Example 291 1- (4-Cyclopentylpiperazin-1-yl)-3- (3, 4-dimethoxyphenoxy) propan-1-one hydrochloride 'H NMR (DMSO-d6) # 1. 54 (m, 2H), 1.75 (m, 4H), 1.97 (m, 2H), 2.84 (t, J = 7 Hz, 2H), 2.87- 3.18 (m, 2H), 3.35-3. 60 (m, 5H), 3.68 (s, 3H), 3.73 (s, 3H), 4.09 (m, 1H), 4.15 (t, J= 7 Hz, 2H), 4.45 (m, 1 H), 6.44 (d, J = 8 Hz, 1 H), 6.52 (s, 1 H), 6.84 (d, J = 8 Hz, 1 H), 11.23 (br s, 1H).

Example 292 4-(4-Chlorophenyl)-1-(4-cyclopentylpiperzin-1-yl)-4-hydroxyb utan-1-one hydrochloride 'H NMR (DMSO-d6) 61. 55 (m, 2H), 1.75 (m, 4H), 1.95 (m, 2H), 2.40 (m, 2H), 2.80-3. 10 (m, 3H), 3.45 (m, 5H), 3.97 (m, 1 H), 4.42 (m, 1 H), 4.57 (m, 1 H), 5.36 (br s, 1 H), 7.36 (m, 4H), 10.64 (br s, 1 H).

Example 293 1- (3, 4-Dimethoxyphenyl)-4- [4- (1, 1-dimethylpropyl) piperazin-1-yl] butane-1, 4-dione hydrochlo- ride H NMR (DMSO-d6) #0. 92 (t, J = 7 Hz, 3H), 1.32 (s, 6H), 1.73 (quart, J = 7 Hz, 2H), 2.72 (t, J = 7 Hz, 2H), 2.85 (m, 1 H), 3.05-3. 30 (m, 4H), 3.50 (m, 2H), 3.72 (m, 1 H), 3.81 (s, 3H), 3. 85 (s, 3H), 4.15 (m, 1H), 4.44 (m, 1H), 7.07 (d, J = 8 Hz, 1H), 7.45 (s, 1H), 7.67 (d, J = 8 Hz, 1H), 10.47 (brs, 1H).

Example 294 2-[2-(4-Isopropylpieprazin-1-yl)-2-oxoethylidene]-5, 6-dimethoxyindan-1-one hydrochloride 'H NMR (DMSO-d6) 61. 28 (d, J= 7 Hz, 6H), 2.90-3. 55 (m, 5H), 3.71 (m, 1H), 3.83 (s, 3H), 3.91 (br s, 4H), 4. 23 (m, 1H), 4.58 (m, 1H), 7.12 (s, 1H), 7.21 (s, 2H), 11.11 (brs, 1H).

Example 295 2-{2-[4-(1-Ethylpropyl)piperazin-1-yl]-2-oxoethylidene}-5,6- dimethoxyindan-1-one hydrochlo- ride 'H NMR (DMSO-d6) #0. 97 (t, J= 7 Hz, 6H), 1.62 (m, 2H), 1.86 (m, 2H), 3.05 (m, 2H), 3.10- 3.50 (m, 3H), 3.76 (m, 1H), 3.83 (s, 3H), 3.91 (br s, 4H), 4.19 (m, 1 H), 4.55 (m, 1 H), 7.12 (s, 1 H), 7.21 (s, 2H), 10.66 (br s, 1 H).

Example 296 2- [2- (4-lsopropylpiperazin-1-yl)-2-oxoethyl]-5, 6-dimethoxyindan-1-one hydrochloride 1H NMR (DMSO-d6) a 1. 27 (d, J = 7 Hz, 6H), 2.60-3. 65 (m, 12H), 3.80 (s, 3H), 3.86 (s, 3H), 4.06 (m, 1H), 4.44 (m, 1H), 7.07 (s, 1H), 7.09 (s, 1H), 10. 88 (brs, 1H).

Example 297 2-{2-[4-(1-Ethylpropyl)pieprazin-1-yl]-2-oxoethyl}-5,6-dimet hoxyindan-1-one hydrochloride 'H NMR (DMSO-d6) #0. 96 (t, J= 7 Hz, 6H), 1.62 (m, 2H), 1.86 (m, 2H), 2.60-3. 50 (m, 11H), 3.65 (m, 1 H), 3.80 (s, 3H), 3. 86 (s, 3H), 4.03 (m, 1 H), 4.40 (m, 1 H), 7.07 (s, 1 H), 7.09 (s, 1 H), 10. 53 (br s, 1 H).

Example 298 1- (4-Chlorophenyl)-4- [4- (tetrahydro-pyran-4-yl) piperazin-1-yl] butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) 91. 72 (m, 2H), 1.99 (m, 2H), 2.76 (m, 2H), 2.85 (m, 1H), 3.10 (m, 2H), 3.21-3. 68 (m, 8H), 3.97 (m, 2H), 4.16 (m, 1H), 4.41 (m, 1H), 7.60 (d, J= 8 Hz, 2H), 7.99 (d, J = 8 Hz, 2H), 11.15 (br s, 1 H).

Example 299 1- (4-Chlorophenyl)-4- [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl] butane-1, 4-dione hydro- chloride 'H NMR (DMSO-d6) #1. 28 (s, 6H), 2.76 (m, 2H), 3.05 (m, 1 H), 3.24 (t, J = 7 Hz, 2H), 3.36 (m, 4H), 3.57 (m, 2H), 3.78 (m, 1H), 4.05 (m, 1H), 4.19 (m, 1H), 5.31 (br s, 1H), 7.60 (d, J = 8 Hz, 2H), 8.00 (d, J = 8 Hz, 2H), 9.97 (br s, 1 H).

Example 300 1- [4- (1-Ethylpropyl) piperazin-1-yl]-2- (4-trifluoromethoxyphenoxy) ethanone hydrochloride 'H NMR (DMSO-d6) 0. 97 (t, J= 7 Hz, 6H), 1.61 (m, 2H), 1.86 (m, 2H), 2.90-3. 10 (m, 2H), 3.22 (m, 2H), 3.39 (m, 2H), 3.69 (m, 1 H), 3.98 (m, 1 H), 4.40 (m, 1 H), 4. 94 (s, 2H), 7.04 (m, 2H), 7.29 (m, 2H), 10.61 (br s, 1H).

Example 301 1- [4- (1-Ethylpropyl) piperazin-1-yl]-2- (4-trifluoromethoxyphenyl) ethanone hydrochloride 1H NMR (DMSO-d6) #0. 96 (t, J = 7 Hz, 6H), 1.62 (m, 2H), 1.84 (m, 2H), 2.85-3. 46 (m, 6H), 3.65 (m, 1H), 3.82 (m, 2H), 4.14 (m, 1H), 4.43 (m, 1H), 7.32 (m, 4H), 10.53 (brs, 1H).

Example 302 1- [4- (1-Ethylpropyl) piperazin-1-yl]-2- (4-trifluoromethylphenyl) ethanone hydrochloride 1H NMR (DMSO-d6) #0. 96 (t, J= 7 Hz, 6H), 1.61 (m, 2H), 1. 85 (m, 2H), 2.90-3. 50 (m, 6H), 3.69 (m, 1H), 3.90 (m, 2H), 4.15 (m, 1H), 4.45 (m, 1H), 7.45 (d, J= 8 Hz, 2H), 7.68 (d, J= 8 Hz, 2H), 10.71 (brs, 1H).

Example 303 2- (3, 4-Dichlorophenyl)-l- [4- (l-ethylpropyl) piperazin-1-yl] ethanone hydrochloride 'H NMR (DMSO-d6) #0. 96 (t, J = 7 Hz, 6H), 1.61 (m, 2H), 1.88 (m, 2H), 2.90-3. 50 (m, 6H), 3.74 (m, 1H), 3.81 (s, 2H), 4.14 (m, 1H), 4.43 (m, 1H), 7.21 (m, 1H), 7.49 (s, 1H), 7.57 (d, J = 8Hz, 1H), 10.96 (br s, 1 H).

Example 304 2-Biphenyl-4-yl-1- [4- (1-ethylpropyl) piperazin-1-yl] ethanone hydrochloride 'H NMR (DMSO-d6) #0. 95 (t, J = 7 Hz, 6H), 1.62 (m, 2H), 1.82 (m, 2H), 2.80-3. 50 (m, 6H), 3.60 (m, 1H), 3.82 (m, 2H), 4.17 (m, 1H), 4.45 (m, 1H), 7.25-7. 55 (m, 5H), 7.64 (m, 4H), 10.29 (br s, 1 H).

Example 305 [4- (1-Ethylpropyl) piperazin-1-yl]- (3-trifluoromethoxyphenyl) methanone hydrochloride 'H NMR (DMSO-d6) #0. 97 (t, J= 7 Hz, 6H), 1.62 (m, 2H), 1.90 (m, 2H), 3.05 (m, 1H), 3.18 (m, 2H), 3.25-3. 60 (m, 5H), 4.54 (br s, 1 H), 7.51 (m, 3H), 7.63 (m, 1 H), 10.69 (br s, 1 H).

Example 306 [4- (1-Ethylpropyl) piperazin-1-yl]- (3-phenoxyphenyl) methanone hydrochloride 'H NMR (DMSO-d6) 0. 96 (t, J= 7 Hz, 6H), 1.62 (m, 2H), 1.87 (m, 2H), 3.04 (m, 1H), 3.14 (m, 2H), 3.30-3. 80 (m, 5H), 4.50 (brs, 1H), 7.05-7. 15 (m, 4H), 7.16-7. 25 (m, 2H), 7.40-7. 51 (m, 3H), 10. 51 (br s, 1H).

Example 307 <BR> <BR> <BR> (3-Chloro-4-trifluoromethoxyphenyl)- [4- (1-ethylpropyl) piperazin-1-yl] methanone hydrochlo- ride 1H NMR (DMSO-d6)n #0. 97 (t, J= 7 Hz, 6H), 1.61 (m, 2H), 1.87 (m, 2H), 3.06 (m, 1H), 3.10- 3.80 (m, 7H), 4.52 (br s, 1 H), 7.50 (m, 1 H), 7.68 (m, 1 H), 7.86 (s, 1 H), 10.59 (br s, 1 H).

Example 308 [4- (1-Ethylpropyl) piperazin-1-yl]- (4-trifluoromethoxyphenyl) methanone hydrochloride H NMR (DMSO-d6) #0. 97 (t, J= 7 Hz, 6H), 1.61 (m, 2H), 1.88 (m, 2H), 3.06 (m, 1H), 3.17 (m, 2H), 3.40-3. 90 (m, 5H), 4.53 (br s, 1 H), 7.47 (d, J = 8 Hz, 2H), 7.65 (d, J = 8 Hz, 2H), 10.63 (br s, 1 H).

Example 309 1- [4- (1-Ethylpropyl) piperazin-1-yl]-3- (4-trifluoromethylphenyl) propan-1-one hydrochloride 1H NMR (DMSO-d6) #0. 95 (t, J= 7 Hz, 6H), 1.62 (m, 2H), 1.84 (m, 2H), 3.04 (m, 1H), 2.75 (m, 2H), 2. 80-3. 50 (m, 7H), 3.64 (m, 1 H), 4.05 (m, 1 H), 4.43 (m, 1 H), 7.48 (d, J = 8 Hz, 2H), 7.64 (d, J = 8 Hz, 2H), 10.71 (br s, 1H).

Example 310 1- [4- (1-Ethylpropyl) piperazin-1-yl]-4- (4-trifluoromethylphenyl) butane-1,4-dione hydrochloride 1H NMR (DMSO-d6) #0. 97 (t, J= 7 Hz, 6H), 1.62 (m, 2H), 1. 85 (m, 2H), 2.79 (m, 2H), 2.95 (m, 1H), 3.00-3. 50 (m, 7H), 3. 68 (m, 1 H), 4.14 (m, 1H), 4.41 (m, 1H), 7.91 (d, J= 8 Hz, 2H), 8.18 (d, J = 8 Hz, 2H), 10.42 (br s, 1H).

Example 311 1- (3, 4-Dichloropheny )-4- [4- (1-ethylpropyl) piperazin-1-yl] but-2-ene-1,4-dione hydrochloride 1H NMR (DMSO-d6) #0. 97 (t, J = 7 Hz, 6H), 1.62 (m, 2H), 1.85 (m, 2H), 3.06 (m, 2H), 3.20 (m, 1H), 3.39-3. 55 (m, 3H), 3.75 (m, 1 H), 4.21 (m, 1 H), 4.54 (m, 1H), 7.45 (d, J = 15 Hz, 1H),

7. 76 (d, J = 15 Hz, 1 H), 7.86 (d, J = 8 Hz, 1 H), 8.01 (brd, J= 8 Hz, 1 H), 8.22 (s, 1 H), 10.65 (brs, 1H).

Example 312 1-Benzo [1,3] dioxol-5-yl-4-[4-(1-ethylpropyl)piperazin-1-yl] but-2-ene-1,4-dione hydrochloride 'H NMR (DMSO-d6), 50. 97 (t, J = 7 Hz, 6H), 1.62 (m, 2H), 1.85 (m, 2H), 3.06 (m, 2H), 3.20 (m, 1H), 3.39-3. 55 (m, 3H), 3.78 (m, 1H), 4.20 (m, 1H), 4.54 (m, 1H), 6.18 (s, 2H), 7.09 (d, J = 8 Hz, 1H), 7.40 (d, J= 15 Hz, 1H), 7.51 (d, J= 1 Hz, 1H), 7.72 (dd, J= 1 Hz, 8 Hz, 1H), 7.77 (d, J = 15 Hz, 1 H), 10.83 (br s, 1 H).

Example 313 1- (4-Chlorophenyl)-4- (4-isopropyl [1,4] diazepan-1-yl) butane 1, 4-dione hydrochloride 1H NMR (DMSO-d6) # 1. 26 (m, 6H), 1.95-2. 45 (m, 3H), 2.60-3. 30 (m, 6H), 3.40-3. 85 (m, 5H), 4.03 (m, 1 H), 7.61 (d, J = 8 Hz, 2H), 8. 00 (d, J = 8 Hz, 2H), 10.05 (br s, 1 H).

Example 314 (4-Cyclopentylpiperazin-1-yl)- (7-ethoxybenzofuran-2-yl) methanone hydrochloride 1H NMR (DMSO-d6) # 1. 41 (t, J= 7 Hz, 3H), 1.55 (m, 2H), 1.65-1. 92 (m, 4H), 2.01 (m, 2H), 3.13 (m, 2H), 3.54 (m, 5H), 4.26 (quart, J= 7 Hz, 2H), 4.51 (m, 2H), 7.06 (brd, J= 8 Hz, 1H), 7.21-7. 32 (m, 2H), 7.48 (s, 1 H), 11.25 (br s, 1 H).

Example 315 (5-Chlorobenzofuran-2-yl)- (4-cyclopentylpiperazin-1-yl) methanone hydrochloride 1H NMR (DMSO-d6) # 1. 55 (m, 2H), 1.65-1. 92 (m, 4H), 2.01 (m, 2H), 3.13 (m, 2H), 3.53 (m, 5H), 4.51 (m, 2H), 7.51 (m, 2H), 7.74 (d, J = 8 Hz, 1 H), 7.86 (d, J = 1 Hz, 1 H), 11.45 (br s, 1H).

Example 316 1- [4- (1-Ethylpropyl) piperazin-1-yl]-4- (4-trifluoromethoxyphenyl) but-2-ene-1,4-dione hydro- chloride 1H NMR (CDCl3) # 0.91 (t, J= 7 Hz, 6H), 1.31 (m, 2H), 1.44 (m, 2H), 2.21 (m, 1H), 2.56 (m, 4H), 3.59 (m, 2H), 3.71 (m, 2H), 7.32 (d, J= 8 Hz, 2H), 7.53 (d, J = 14 Hz, 1H), 7.90 (d, J = 14Hz, 1H), 8.10 (d, J=8Hz, 2H).

Example 317 4-Benzo [1,3] dioxol-5-yl-1- [4- (1-ethylpropyl) piperazin-1-yl]-4-hydroxybutan-1-one hydrochlo- ride 'H NMR (DMSO-d6) #0. 91 (t, J= 7 Hz, 6H), 1.58 (m, 2H), 1.80 (m, 4H), 2.35 (m, 2H), 2.90- 3.20 (m, 6H), 3.50 (m, 1 H), 3.98 (m, 1 H) ; 4.46 (m, 2H), 5.20 (br s, 1 H), 5.97 (s, 2H), 6.75- 6.88 (m, 3H), 9.90 (br s, 1 H).

Example 318 1- [4- (1-Ethylpropyl) piperazin-1-yl]-2- (3-trifluoromethylphenyl) ethanone hydrochloride 'H NMR (DMSO-d6) 60. 97 (t, J = 7 Hz, 6H), 1.61 (m, 2H), 1.86 (m, 2H), 2.90-3. 33 (m, 4H), 3.41 (m, 2H), 3.70 (m, 1H), 3.90 (m, 2H), 4.18 (m, 1H), 4.45 (m, 1H), 7.48-7. 64 (m, 4H), 10.69 (br s, 1 H).

Example 319 1- [4- (1-Ethylpropyl) piperazin-1-yl]-2- (2-trifluoromethylphenyl) ethanone hydrochloride 1H NMR (DMSO-d6) #0. 97 (t, J= 7 Hz, 6H), 1.64 (m, 2H), 1.86 (m, 2H), 2.90-3. 28 (m, 4H), 3.43 (m, 2H), 3.69 (m, 1H), 3.93 (s, 2H), 4.18 (m, 1H), 4.45 (m, 1H), 7.38 (d, J= 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1 H), 7.62 (t, J = 8 Hz, 1 H), 7.70 (d, J = 8 Hz, 1 H), 10.38 (br s, 1 H).

Example 320 (3-Benzoylphenyl)- [4- (1-ethylpropyl) piperazin-1-yl] methanone hydrochloride 'H NMR (DMSO-d6) 60. 96 (t, J = 7 Hz, 6H), 1.61 (m, 2H), 1.87 (m, 2H), 3.00-3. 25 (m, 3H), 3.30-3. 85 (m, 5H), 4.54 (br s, 1 H), 7.55-7. 87 (m, 9H), 10.62 (br s, 1 H).

Example 321 N-{3- [4- (1-Ethylpropyl) piperazine-1-carbonyl] phenyl} acetamide hydrochloride 'H NMR (DMSO-d6) 60. 96 (t, J = 7 Hz, 6H), 1.61 (m, 2H), 1.87 (m, 2H), 3.00-3. 21 (m, 3H), 3.30-3. 85 (m, 5H), 4.53 (brs, 1H), 7.14 (d, J = 8 Hz, 1H), 7. 38 (t, J = 8 Hz, 1H), 7.61 (d, J = 8 Hz, 1H), 7.78 (brs, 1H), 10.20 (s, 1H), 10.58 (brs, 1H).

Example 322 1- [4- (1-Ethylpropyl) piperazin-1-yl]-4- (4-trifluoromethoxyphenyl) butane-1,4-dione hydrochlo- ride 'H NMR (DMSO-d6) 5 0. 97 (t, J = 7 Hz, 6H), 1.63 (m, 2H), 1.85 (m, 2H), 2.77 (m, 2H), 2.95 (m, 1H), 3.00-3. 31 (m, 5H), 3.35-3. 55 (m, 2H), 3.68 (m, 1H), 4.14 (m, 1H), 4.41 (m, 1H), 7.52 (d, J= 8 Hz, 2H), 8. 12 (d, J= 8 Hz, 2H), 10.47 (brs, 1H).

Example 323 2- (4-Dimethylaminophenyl)-1- [4- (1-ethylpropyl) piperazin-1-yl] ethanone dihydrochloride 'H NMR (DMSO-d6) J0. 96 (t, J = 7 Hz, 6H), 1.61 (m, 2H), 1.85 (m, 2H), 2.90-3. 15 (m, 7H), 3.24 (m, 1 H), 3.38 (m, 2H), 3.62-4. 30 (m, 6H), 4.43 (m, 1 H), 7.25-7. 55 (m, 4H), 10.87 (br s, 1H).

Example 324 2-Benzo [1,3] dioxol-5-yl-1- [4- (1-ethylpropyl) piperazin-1-yl] ethanone hydrochloride 'H NMR (DMSO-d6) #0. 95 (t, J= 7 Hz, 6H), 1.60 (m, 2H), 1.84 (m, 2H), 2.85-3. 10 (m, 3H), 3.21 (m, 1H), 3.38 (m, 2H), 3.55-3. 78 (m, 3H), 4.13 (m, 1H), 4.43 (m, 1H), 5.98 (s, 2H), 6.68 (d, J= 8 Hz, 1H), 6.78 (s, 1H), 6.85 (d, J=8 Hz, 1H), 10.77 (brs, 1H).

Example 325 2- (4-Butoxyphenyl)-1- [4- (1-ethylpropyl) piperazin-1-yl] ethanone hydrochloride 'H NMR (DMSO-d6) #0. 89 (m, 9H), 1.42 (sext, J = 7 Hz, 2H), 1.50-1. 74 (m, 4H), 1.85 (m, 2H), 2.85-3. 07 (m, 3H), 3. 18 (m, 1H), 3.30-3. 46 (m, 2H), 3.55-3. 78 (m, 3H), 3.93 (t, J= 7 Hz, 2H), 4.11 (m, 1H), 4.44 (m, 1H), 6. 86 (d, J = 8 Hz, 2H), 7.12 (d, J = 8 Hz, 2H), 10.68 (br s, 1H).

Example 326 2- (2, 5-Dimethoxyphenyl)-1- [4- (1-ethylpropyl) piperazin-1-yl] ethanone hydrochloride 'H NMR (DMSO-d6) 5 0. 96 (t, J = 7 Hz, 6H), 1.62 (m, 2H), 1.85 (m, 2H), 2.90-3. 10 (m, 3H), 3.24 (m, 1H), 3.40 (m, 2H), 3.53-3. 80 (m, 9H), 4.11 (m, 1H), 4.43 (m, 1H), 6.71 (s, 1H), 6.79 (d, J = 8 Hz, 1 H), 6.90 (d, J = 8 Hz, 1 H), 10.85 (br s, 1 H).

Example 327 2- (4-Acetylphenyl)-1- [4- (1-ethylpropyl) piperazin-1-yl] ethanone hydrochloride 'H NMR (DMSO-d6) d0. 97 (t, J= 7 Hz, 6H), 1.62 (m, 2H), 1.86 (m, 2H), 2.52 (s, 3H), 2.90- 3.10 (m, 3H), 3.15-3. 50 (m, 3H), 3.71 (m, 1H), 3.99 (m, 1H), 4.41 (m, 1H), 5.02 (s, 2H), 7.05 (d, J = 8 Hz, 2H), 7.92 (d, J = 8 Hz, 2H), 10.64 (br s, 1H).

Example 328 1- [4- (1-Methylcyclopropyl) piperazin-1-yl]-4- (4-trifluoromethylphenyl) butane-1,4-dione hydro- chloride This compound was prepared from 1-acetyl-4- (tert-butyloxycarbonyl) piperazine ac- cording to the procedure reported by H. Winsel et al. (Synlett, 1999,1999-2003).

'H NMR (DMSO-d6) #0. 74 (br s, 2H), 1.32 (s, 3H), 1.38 (br s, 2H), 2.81 (br s, 2H), 3.10-3. 45 (m, 7H), 3.71 (m, 1H), 4.15 (m, 1H), 4.46 (m, 1H), 7.92 (d, J = 8 Hz, 2H), 8.18 (d, J = 8 Hz, 2H), 10.90 (br s, 1 H) ; HPLC-MS: mlz 369 (MH+) ; Rf: 4.07 min.

Example 329 1- (4-Bicyclopropyl-1-ylpiperazin-1-yl)-4- (4-trifluoromethylphenyl) butane-1, 4-dione hydrochlo- ride This compound was prepared from 1-cyclopropanoyl-4-(tert-butyloxycarbonyl)- piperazine according to the procedure reported by H. Winsel et al. (Synlett, 1999,1999- 2003).

'H NMR (DMSO-d6) #0. 19 (br s, 2H), 0.55 (m, 2H), 0.64 (br s, 2H), 1.27 (br s, 2H), 1.47 (m, 1H), 2.81 (m, 2H), 3.15-3. 80 (m, 8H), 4.17 (m, 1H), 4.47 (m, 1H), 7.92 (d, J= 8 Hz, 2H), 8.18 (d, J = 8 Hz, 2H), 10.78 (br s, 1 H) ; HPLC-MS: m/z 395 (MH+) ; Rf: 4.37 min.

Example 330 4- (l-Ethylpropyl) piperazine-l-carboxylic acid 4-nitrophenyl ester hydrochloride To a stirred mixture of 1-(1-ethylpropyl) piperazine (156 mg, 1.0 mmol) and dry DCM (10 ml) was added 4-nitrophenyl chloroformate (201 mg, 1.0 mmol). The mixture was stirred

overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3 x 20 ml) and water (3 x 20 ml) and dried (MgS04). The organic solution was concentrated to yield an oil that was dissolved in a 0.5 N HCI solution (15 ml).

The acidic solution was concentrated and re-evaporated twice with acetonitrile to give 290 mg (81%) of the title compound as a solid. M. p. 251-253 °C.

'H NMR (400 MHz, DMSO-d6) : 51. 08 (t, 6H), 1.65-1. 80 (m, 2H), 1.93-2. 06 (m, 2H), 3.12- 3.21 (m, 1H), 3.22-3. 41 (m, 2H), 3. 50-3.59 (m, 2H), 3.62-3. 90 (m, 2H), 4. 15-4.35 (m, 2H), 7.58 (d, 2H), 8.40 (d, 2H), 10.9 (brs, 1H).

Example 331 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 4-methoxyphenyl ester To a stirred mixture of 1- (1-ethylpropyl) piperazine (156 mg, 1.0 mmol) and dry DCM (10 mi) was added 4-methoxyphenyl chloroformate (190 mg, 1.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mix- ture was washed with 1 N NaOH (3 x 20 ml) and water (3 x 20 ml) and dried (MgS04). The organic solution was concentrated to yield an oil that was dissolved in a 0.5 N HCI solution (30 ml). The acidic solution was washed with diethyl ether (2 x 20 ml) and 4 N NaOH was added until pH 11. The resulting mixture was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were dried (MgS04). The solvent was evaporated to give an oil that crystallized on standing. This afforded 185 mg (60%) of the title compound as a solid.

M. p. 52-54 °C.

'H NMR (400 MHz, CDCI3) : 60. 92 (t, 6H), 1.25-1. 40 (m, 2H), 1.40-1. 55 (m, 2H), 2.15-2. 26 (m, 1 H), 2.50-2. 60 (m, 4H), 3.45-3. 65 (m, 4H), 3.78 (s, 3H), 6.86 (d, 2H), 7.00 (d, 2H).

Example 332 4- (1-Ethylpropyl) piperazine-1-carboxylic acid benzyl ester hydrochloride

To a stirred mixture of 1- (1-ethylpropyl) piperazine (156 mg, 1.0 mmol) and dry DCM (10 ml) was added benzyl 4-nitrophenylcarbonate (273 mg, 1.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 mut). The reaction mix- ture was washed with 1 N NaOH (3 x 20 ml) and water (3 x 20 ml). The organic phase was concentrated and the oily residue was dissolved in a 0.5 N HCI solution (50 ml). The acidic solution was washed with diethyl ether (2 x 20 ml) and 4 N NaOH was added until pH 11.

The resulting mixture was extracted with ethyl acetate (2 x 20 mi) and the combined organic extracts were dried (MgS04). The solvent was evaporated to give an oil that was dissolved in 0.5 N HCI (10 ml). The acidic solution was concentrated and re-evaporated twice with ace- tonitrile to give 200 mg (61%) of the title compound as a solid. M. p. 168-170 °C.

'H NMR (400 MHz, DMSO-d6) : 30. 97 (t, 6H), 1.52-1. 68 (m, 2H), 1.80-1. 92 (m, 2H), 2.96- 3. 13 (m, 3H), 3.3-3. 65 (m, 4H), 4.01-4. 11 (m, 2H), 5.10 (s, 2H), 7.3-7. 4 (m, 5H), 10.8 (brs, 1H).

Example 333 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 2- (4-methoxyphenyl) ethyl ester hydrochloride Step 1: 2- (4-Methoxyphenvl) ethvl 4-nitrophenvlcarbonate

A stirred mixture of 2- (4-methoxyphenyl) ethanol (1.52 g, 10 mmol) and dry DCM (20 ml) was placed on an ice-bath under an atmosphere of nitrogen. A solution of 4-nitrophenyl chloroformate (2.0 g, 10 mmol) in DCM (10 ml) was added dropwise. The mixture was stirred for 15 min and then a solution of pyridine (0. 85 ml) in DCM (6 ml) was added dropwise keep- ing the temperature at 0-5 °C. Stirring was continued at this temperature for another 3 hours.

The reaction mixture was washed with cold water (2 x 25 ml) and then dried (MgSO4). The solvent was evaporated and the residue crystallized on standing to give 3.0 g (95%) of 2- (4- methoxyphenyl) ethyl 4-nitrophenylcarbonate as a solid. M. p. 53-55 °C.

'H NMR (400 MHz, CDCI3) : 63. 00 (t, 2H), 3.78 (s, 3H), 4.45 (t, 2H), 6.88 (d, 2H), 7.16 (d, 2H), 7.33 (d, 2H), 8.25 (d, 2H).

Step 2: To a stirred mixture of 1- (1-ethylpropyl) piperazine (156 mg, 1.0 mmol) and dry DCM (10 ml) was added 2- (4-methoxyphenyl) ethyl 4-nitrophenylcarbonate (310 mg, 1.0 mmol).

The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml).

The reaction mixture was washed with 1 N NaOH (3 x 20 mi) and water (3 x 20 ml). The or- ganic phase was concentrated and the oily residue was dissolved in a 0.5 N HCI solution (50 ml). The acidic solution was washed with diethyl ether (2 x 20 ml), concentrated and re- evaporated twice with acetone to give 200 mg (55%) of the title compound as a solid. M. p.

160-162 °C.

'H NMR (400 MHz, DMSO-d6) : d0. 95 (t, 6H), 1.52-1. 67 (m, 2H), 1.78-1. 92 (m, 2H), 2.81 (t, 2H), 2.90-3. 06 (m, 3H), 3.3-3. 5 (m, 4H), 3.71 (s, 3H), 3.9-4. 1 (m, 2H), 4.17 (t, 2H), 6.86 (d, 2H), 7.17 (d, 2H), 10.7 (brs, 1H).

Example 334 4-(2-Propyl) piperazine-1-carboxylic acid 2- (4-chlorophenoxy) ethyl ester hydrochloride Step 1: 2- (4-Chlorophenoxv) ethyl 4-nitrophenvlcarbonate

A stirred mixture of dry THF (20 mi) and 1.0 M lithiumaluminiumhydride (9.0 ml, 9.0 mmol) was placed under an atmosphere of nitrogen. A solution of 4-chlorophenoxyacetic acid (1.9 g, 10 mmol) in dry THF (10 ml) is slowly added dropwise. When addition was com- plete the reaction mixture was stirred for 30 min and then heated at reflux temperature for 10 min. The cooled reaction mixture was quenched with small amounts of water and 4 N NaOH and ethyl acetate was added. The mixture was dried (MgS04) and then concentrated. The residue was re-evaporated with DCM to give crude 2- (4-chlorophenoxy) ethanol as an oil.

A stirred mixture of the crude 2- (4-chlorophenoxy) ethanol and dry DCM (20 mi) was placed on an ice-bath under an atmosphere of nitrogen. A solution of 4-nitrophenyl chloro- formate (2.2 g, 11 mmol) in DCM (10 ml) was added dropwise. The mixture was stirred for 15 min and then a solution of pyridine (0.90 ml) in DCM (6 ml) was added dropwise keeping the temperature at 0-5 °C. Stirring was continued at this temperature for another 3 hours. The reaction mixture was washed with cold water (2 x 25 ml) and then dried (MgS04). The sol- vent was evaporated and the residue crystallized on standing to give 3.15 g (93%) of 2- (4- chlorophenoxy) ethyl 4-nitrophenylcarbonate as a solid. M. p. 58-60 °C.

'H NMR (400 MHz, CDCI3) : d4. 26 (t, 2H), 4.63 (t, 2H), 6.85 (d, 2H), 7.26 (d, 2H), 7.37 (d, 2H), 8.27 (d, 2H).

Step 2: To a stirred mixture of 1-(2-propyl) piperazine (130 mg, 1.0 mmol) and dry DCM (10 ml) was added 2- (4-chlorophenoxy) ethyl 4-nitrophenylcarbonate (330 mg, 1.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (30 ml). The reaction mixture was washed with 0.5 N NaOH (3 x 20 ml) and water (3 x 20 ml). The organic phase was concentrated and the oily residue was dissolved in a 0.5 N HCI solution (15 ml).

The acidic solution was washed with diethyl ether (10 ml), concentrated and re-evaporated twice with acetonitrile to give 300 mg (82%) of the title compound as a solid. M. p. 174-176 °C. oh NMR (400 MHz, DMSO-d6) : S1. 25 (d, 6H), 2.88-3. 02 (m, 2H), 3.3-3. 5 (m, 5H), 3.95-4. 10 (m, 2H), 4.20 (t, 2H), 4.35 (t, 2H), 7.00 (d, 2H), 7.34 (d, 2H), 11.0 (brs, 1 H).

Example 335 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 2- (4-chlorophenoxy) ethyl ester hydrochloride

By a similar procedure as described in Example 334 and starting from 1- (1-ethyl- propyl) piperazine (160 mg, 1.0 mmol) and 2- (4-chlorophenoxy) ethyl 4-nitrophenylcarbonate (330 mg, 1.0 mmol), 330 mg (84%) of the title compound was isolated as a solid. M. p. 144- 146 °C.

'H NMR (400 MHz, DMSO-d6) : 60. 92 (t, 6H), 1.52-1. 68 (m, 2H), 1.78-1. 93 (m, 2H), 2.95- 3.10 (m, 3H), 3.3-3. 5 (m, 4H), 3.9-4. 1 (m, 2H), 4.20 (t, 2H), 4.35 (t, 2H), 7.00 (d, 2H), 7.33 (d, 2H), 10.7 (brs, 1H).

Example 336 4-(2-Propyl) piperazine-1-carboxylic acid 3- (4-chlorophenoxy)-l-propyl ester hydrochloride Step 1: 3-(4-Chlorophenyloxy)-1-propyl 4-nitrophenylcarbonate A mixture of 4-chlorophenol (13 g, 100 mmol) and crushed NaOH (5 g, 125 mmol) in DMF (60 mi) was stirred for 1 hour under an atmosphere of nitrogen. 3-Bromo-1-propanol (14 g, 100 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature and then the mixture was poured into cold water (600 ml). The mixture was ex- tracted with diethyl ether (2 x 250 ml) and the combined organic extracts were washed with 1 N NaOH (2 x 100 ml). The organic phase was concentrated to give 14 g of an oily residue

that was purified on silica gel (200 g) eluting with a mixture of heptane and ethyl acetate (1: 1). This afforded 9.0 g (48%) of 3- (4-chlorophenoxy)-1-propanol.

A stirred mixture of 3- (4-chlorophenoxy)-1-propanol (1.87 g, 10 mmol) and dry DCM (25 ml) was placed on an ice-bath under an atmosphere of nitrogen. A solution of 4-nitro- phenyl chloroformate (2.2 g, 11 mmol) in DCM (10 ml) was added dropwise. The mixture was stirred for 15 min and then a solution of pyridine (0.90 ml) in DCM (6 ml) was added dropwise keeping the temperature at 0-5 °C. Stirring was continued at this temperature for another 3 hours. The reaction mixture was washed with cold water (2 x 25 mi) and then dried (MgSO4).

The solvent was evaporated and the residue crystallized on standing to give 3.48 g (98%) of 3- (4-chlorophenoxy)-1-propyl 4-nitrophenylcarbonate as a solid. M. p. 56-57 °C.

'H NMR (400 MHz, CDCl3) : S2. 23 (pent. 2H), 4.09 (t, 2H), 4.50 (t, 2H), 6.85 (d, 2H), 7.25 (d, 2H), 7.38 (d, 2H), 8.27 (d, 2H).

Step 2: By a similar procedure as described in Example 334 and starting from 1- (2-propyl)- piperazine (0.2 ml, 1.0 mmol) and 3- (4-chlorophenoxy)-1-propyl 4-nitrophenylcarbonate (350 mg, 1.0 mmol), 330 mg (91%) of the title compound was isolated as a solid. M. p. 184-185 °C.

'H NMR (400 MHz, DMSO-d6) : 5 1. 26 (d, 6H), 2.03 (pent. 2H), 2.88-3. 02 (m, 2H), 3.3-3. 5 (m, 5H), 4.02-4. 10 (m, 4H), 4.16 (t, 2H), 6.96 (d, 2H), 7.32 (d, 2H), 11.0 (brs, 1H).

Example 337 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 3- (4-chlorophenoxy)-1-propyl ester hydrochlo- ride By a similar procedure as described in Example 334 and starting from 1- (1-ethyl- propyl) piperazine (160 mg, 1.0 mmol) and 3- (4-chlorophenoxy)-1-propyl 4-nitrophenyl- carbonate (350 mg, 1.0 mmol), 260 mg (64%) of the title compound was isolated as a solid.

M. p. 136-138 °C.

'H NMR (400 MHz, DMSO-d6) : 60. 96 (t, 6H), 1.52-1. 68 (m, 2H), 1.78-1. 92 (m, 2H), 2.04 (pent. , 2H), 2.95-3. 08 (m, 3H), 3.3-3. 65 (m, 4H), 4.00-4. 10 (m, 4H), 4.17 (t, 2H), 6.98 (d, 2H), 7.32 (d, 2H), 10.7 (brs, 1H).

Example 338 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 2- (3, 4-dimethoxyphenoxy) ethyl ester hydro- chloride

Step 1: 2-(3w4-Dimethoxyphenoxy) ethanol A mixture of 3, 4-dimethoxyphenol (155 mg, 1.0 mmol) and 60% sodium hydride (50 mg, 1.25 mmol) in DMA (6 ml) was stirred for 20 min under an atmosphere of nitrogen. 2- (2- Pyranyloxy) ethylbromide (220 mg, 1.0 mmol) was added dropwise. The reaction mixture was stirred for 6 hours at room temperature and then the mixture was poured into water (100 ml).

The mixture was extracted with ethyl acetate (2 x 30 ml) and the combined organic extracts were dried (MgS04). The organic phase was concentrated and the residue was dissolved in 2-propanol (30 ml) and 4 N HCI (20 ml) was added. The mixture was heated at reflux tem- perature for 30 min and then stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (50 ml). The organic solu- tion was dried (MgS04) and the solvent was evaporated. The oily residue was purified on sil- ica gel (50 g) eluting with a mixture of heptane and ethyl acetate (3: 2). This afforded 100 mg (50%) of 2- (3, 4-dimethoxyphenoxy) ethanol.

Step 2: By a similar procedure as described in Example 333 and starting from 1- (1-ethyl- propyl) piperazine (80 mg, 0.5 mmol) and 2- (3, 4-dimethoxyphenoxy) ethanol (100 mg, 0.5 mmol), 80 mg (38%) of the title compounds contaminated with 4- (1-ethylpropyl) piperazine-1- carboxylic acid 4-nitrophenyl ester hydrochloride, was isolated as a solid.

'H NMR (400 MHz, DMSO-d6) 51. 05 (t, 6H), 1.51-1. 70 (m, 2H), 1.77-1. 94 (m, 2H), 2.95-3. 10 (m, 3H), 3.3-3. 5 (m, 4H), 3.68 (s, 3H), 3.74 (s, 3H), 3.9-4. 1 (m, 2H), 4.15 (t, 2H), 4.34 (t, 2H), 6.40-6. 47 (m, 1 H), 6.58 (s, 1 H), 6.84 (d, 1 H), 10.9 (brs, 1 H).

Example 339 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 3-(3,4-dimethoxyphenoxy)-1-propyl ester hy- drochloride

By a similar procedure as described in Example 338 and starting from 1- (1-ethyl- propyl) piperazine (310 mg, 2.0 mmol) and 3- (3, 4-dimethoxyphenoxy)-1-propanol (2.0 mmol, prepared similarly as described in Example 338), 650 mg (75%) of the title compound was isolated as a solid. M. p. 145-147 °C.

'H NMR (400 MHz, DMSO-d6) : #0. 93 (t, 6H), 1.50-1. 68 (m, 2H), 1. 78-1.91 (m, 2H), 2.01 (pent. , 2H), 2.93-3. 08 (m, 3H), 3.3-3. 6 (m, 4H), 3.66 (s, 3H), 3.71 (s, 3H), 3.93-4. 08 (m, 4H), 4.16 (t, 2H), 6.38-6. 43 (m, 1H), 6.55 (s, 1H), 6.81 (d, 1H), 10.7 (brs, 1H).

The following examples were prepared according to one of the above general pro- cedures.

Example 340 1- (3, 4-Dimethoxyphenyl)-4- [4- (1-ethylcyclopropyl) piperazin-1-yl] butane-1, 4-dione hydrochlo- ride 'H NMR (DMSO-d6) #0. 79 (t, J = 7 Hz, 3H), 0.87 (br s, 2H), 1.31 (br s, 2H), 1.85 (quart, J = 7 Hz, 2H), 2.72 (m, 2H), 3.15-3. 78 (m, 8H), 3.81 (s, 3H), 3.85 (s, 3H), 4.15 (m, 1H), 4.46 (m, 1H), 7.07 (d, J= 8 Hz, 1H), 7.45 (d, J= 1 Hz, 1H), 7.67 (dd, J= 1 Hz, 8 Hz, 1H), 10.57 (br s, 1 H) ; HPLC-MS: m/z 375 (MH+) ; Rf: 2.50 min.

Example 341 1- [4- (1-Ethylpropyl) piperazin-1-yl]-2- (3-fluoro-4-hydroxyphenyl) ethanone hydrochloride

'H NMR (DMSO-d6) #0. 95 (t, J = 7 Hz, 6H), 1.59 (m, 2H), 1.82 (m, 2H), 2.88-3. 25 (m, 9H), 4. 08 (m, 1 H), 4.42 (m, 1 H), 6.80-7. 00 (m, 3H), 9.82 (s, 1 H), 10.45 (br s, 1 H) ; HPLC-MS: m/z 309 (MH+) ; Rf: 1. 28 min.

Example 342 1- (4-Cyclopropylmethylpiperazin-1-yl)-4- (3, 4-dimethoxyphenyl) butane-1, 4-dione hydrochlo- ride 'H NMR (DMSO-d6) #0. 40 (br s, 2H), 0.65 (m, 2H), 1.12 (m, 1H), 2.65-3. 15 (m, 7H), 3.20 (t, J= 7 Hz, 2H), 3.50-3. 65 (m, 3H), 3.93 (s, 3H), 4.17 (m, 1H), 4.40 (m, 1H), 7.30 (t, J= 8 Hz, 1H), 7.77 (d, J= 8 Hz, 1H), 7.86 (d, J= 7 Hz, 1H), 10.84 (br s, 1H) ; HPLC-MS: m/z 349 (MH+) ; Rf: 1. 98 min.

Example 343 1-[4-(1-Cyclopropyl-1-methylethyl)piperazin-1-yl]-4-(3,4-dim ethoxyphenyl)butane-1, 4-dione hydrochloride H NMR (DMSO-d6) F0. 50 (m, 2H), 0.58 (m, 2H), 1.22 (m, 7H), 2.72 (m, 2H), 2.92 (m, 1H), 3.07-3. 26 (m, 4H), 3.58-3. 76 (m, 3H), 3.81 (s, 3H), 3.85 (s, 3H), 4.18 (m, 1H), 4.47 (m, 1H),

7.07 (d, J = 8 Hz, 1 H), 7.46 (br s, 1 H), 7.67 (br d, J = 8 Hz, 1 H), 10.69 (br s, 1 H); HPLC-MS: m/z 389 (MH+) ; Rf: 1. 93 min.

Example 344 4- [3- (4-Cyclopropylmethyl-piperazin-1-yl)-3-oxo-propoxy]-benzonit rile hydrochloride The acid required for the synthesis of this amide was prepared as described in the literature : R. Sarges, R. C. Schnur, J. L. Belletire, M. J. Peterson, J. Med. Chem. 1988, 31, 230-243.

'H NMR (DMSO-d6) s0. 39 (m, 2H), 0.63 (m, 2H), 1.10 (m, 1H), 2.84-3. 20 (m, 7H), 3.52 (m, 3H), 4.11 (m, 1 H), 4.29 (t, J = 7 Hz, 2H), 4.46 (m, 1 H), 7.09 (d, J = 8 Hz, 2H), 7.77 (d, J = 8 Hz, 2H), 10.86 (br s, 1H) ; HPLC-MS: m/z 314 (MH+) ; Rf: 1.90 min.

Example 345 1- [4- (l-Cyclopropyl-1-methylethyl) piperazin-I-yll-4- (3, 4-dihydro-2H-benzo [b] [1, 4] dioxepin-7- yl) butane-1,4-dione hydrochloride 'H NMR (DMSO-d6) #0. 48 (m, 2H), 0. 58 (m, 2H), 1.20 (m, 7H), 2.16 (m, 2H), 2.72 (m, 2H), 2.91 (m, 1H), 3. 08-3. 22 (m, 3H), 3.58-3. 70 (m, 3H), 4.12-4. 26 (m, 5H), 4.46 (m, 1H), 7.06 (d, J = 8 Hz, 1 H), 7.52 (d, J = 1 Hz, 1 H), 7.59 (dd, J = 8 Hz, 1 Hz, 1 H), 10.44 (br s, 1H) ; HPLC- MS: m/z 401 (MH+) ; Rf: 2.43 min.

Example 346 4-{3-[4-(1-Cyclopropyl-1-methylethyl)piperazin-1-yl]-3-oxo-p ropoxy}benzonitrile hydrochloride

'H NMR (DMSO-d6) #0. 49 (m, 2H), 0.56 (m, 2H), 1.20 (m, 7H), 2.86-3. 31 (m, 3H), 3.52-3. 83 (m, 5H), 4.11 (m, 1H), 4.31 (t, J=7Hz, 2H), 4.50 (m, 1H), 7.11 (d, J=8Hz, 2H), 7.77 (d, J= 8 Hz, 2H), 10.99 (br s, 1H) ; HPLC-MS: m/z342 (MH+) ; Rf: 2.20 min.

Example 347 1- [4- (1-Cyclopropyl-1-methylethyl) piperazin-1-yl]-4- (3-fluoro-4-methoxyphenyl) butane-1,4- dione hydrochloride 'H NMR (DMSO-d6) #0. 45-0.62 (m, 4H), 1.22 (m, 7H), 2.72 (m, 2H), 2.93 (m, 1H), 3.05-3. 25 (m, 4H), 3.57-3. 77 (m, 3H), 3.93 (s, 3H), 4.16 (m, 1H), 4.45 (m, 1H), 7.29 (t, J= 8 Hz, 1H), 7.75 (dd, J = 8 Hz, 1 Hz, 1 H), 7.87 (brd, J= 7 Hz, 1 H), 10.70 (br s, 1 H) ; HPLC-MS: mlz 377 (MH+) ; Rf: 2.40 min.

Example 348 3- (5-Chlorobenzofuran-3-yl)-1- [4- (1-cyclopropyl-1-methylethyl) piperazin-1-yl] propan-1-one hydrochloride The acid required for the synthesis of this amide was prepared as described in the literature : Hallmann, Hagel, Liebigs Ann. Chem. 1963,662, 147.

'H NMR (DMSO-d6) #0. 42-0.61 (m, 4H), 1.20 (m, 7H), 2.71-3. 25 (m, 7H), 3.51-3. 71 (m, 3H), 4.08 (m, 1 H), 4.52 (m, 1 H), 7.32 (dd, J = 8 Hz, 1 Hz, 1 H), 7.58 (d, J = 8 Hz, 1 H), 7.76 (d, J = 1 Hz, 1H), 7.88 (s, 1H), 10.72 (br s, 1H) ; HPLC-MS: m/z 375 (MH+) ; Rf: 3.10 min.

Example 349 1- [4- (1-Cyclopropyl-1-methylethyl) piperazin-1-yl]-4- (2, 3-dihydrobenzo [1,4] dioxin-6-yl) butane- 1,4-dione hydrochloride 'H NMR (DMSO-d6) JO. 45-0.62 (m, 4H), 1.21 (m, 7H), 2.71 (m, 2H), 2.93 (m, 1H), 3.05-3. 28 (m, 4H), 3.56-3. 76 (m, 3H), 4.16 (m, 1H), 4.31 (m, 4H), 4.46 (m, 1H), 6.98 (d, J= 8 Hz, 1H), 7.45 (d, J = 1 Hz, 1 H), 7.52 (dd, J = 8 Hz, 1 Hz, 1 H), 10.80 (br s, 1 H) ; HPLC-MS: milz 387 (MH+) ; Rf: 2.30 min.

Example 350 4-{3-[4-(1-Cyclopropyl-1-methylethyl)piperazin-1-yl]-3-oxopr openyl}benzonitrile hydrochloride 1H NMR (DMSO-d6) JO. 45-0.62 (m, 4H), 1.23 (m, 7H), 2.93-3. 20 (m, 2H), 3.40 (m, 1H), 3.55- 3.87 (m, 3H), 4.58 (m, 2H), 7.47 (d, J = 15 Hz, 1 H), 7.59 (d, J = 15 Hz, 1 H), 7.39 (d, J = 8 Hz, 2H), 7.95 (d, J= 8 Hz, 2H), 11.10 (br s, 1H) ; HPLC-MS: m/z 324 (MH+) ; Rf: 2.23 min.

Example 351 1- [4- ( 1-Cyclopropyl-1-methylethyl) piperazin-1-yl]-3- (3, 4-dimethoxyphenoxy) propan-1-one hydrochloride

The acid required for the synthesis of this amide was prepared as described in the literature : R. Sarges, R. C. Schnur, J. L. Belletire, M. J. Peterson, J. Med. Chem.. 1988, 31, 230-243.

1H NMR (DMSO-d6) #0. 45-0.60 (m, 4H), 1.22 (m, 7H), 2.82 (t, J= 7 Hz, 2H), 2.89-3. 32 (m, 3H), 3.56-3. 80 (m, 3H), 3.68 (s, 3H), 3.72 (s, 3H), 4.12 (m, 1 H), 4.14 (t, J = 7 Hz, 2H), 4.52 (m, 1 H), 6.42 (dd, J = 8 Hz, 1 Hz, 1 H), 6.53 (d, J = 1 Hz, 1H), 6.83 (d, J = 8 Hz, 1 H), 11.00 (br s, 1 H) ; HPLC-MS: m/z 377 (MH+) ; Rf: 2.07 min.

Example 352 2-Biphenyl-4-yl-1- [4- (1-cyclopropyl-1-methylethyl) piperazin-1-yl] ethanone hydrochloride

1H NMR (DMSO-d6) #0. 43-0.59 (m, 4H), 1.20 (m, 7H), 2.96 (m, 2H), 3.21 (m, 1H), 3.52-3. 88 (m, 5H), 4.20 (m, 1 H), 4.52 (m, 1 H), 7.32 (m, 3H), 7.45 (t, J = 8 Hz, 2H), 7.63 (m, 4H), 10.68 (br s, 1 H) ; HPLC-MS: m/z 363 (MH+) ; Rf: 3.40 min.

Example 353 1- [4- (1-Cyclopropyl-1-methylethyl) piperazin-1-yl]-2- (3-phenoxyphenyl) ethanone hydrochlo- ride

1H NMR (DMSO-d6) #0. 43-0.59 (m, 4H), 1.20 (m, 7H), 2.98 (m, 2H), 3.19 (m, 1H), 3.52-3. 85 (m, 5H), 4.14 (m, 1H), 4.48 (m, 1H), 6.89 (m, 2H), 7.01 (m, 3H), 7.14 (t, J = 8 Hz, 1H), 7.29- 7.43 (m, 3H), 10.72 (br s, 1 H) ; HPLC-MS: m/z 379 (MH+) ; Rf : 3.43 min.

Example 354 1- [4- (1-Cyclopropyl-1-methylethyl) piperazin-1-yl]-2- (4-phenoxyphenyl) ethanone hydrochlo- ride

'H NMR (DMSO-d6) 60. 43-0.60 (m, 4H), 1.20 (m, 7H), 2.96 (m, 2H), 3.18 (m, 1H), 3.53-3. 84 (m, 5H), 4.18 (m, 1H), 4.51 (m, 1H), 6.98 (m, 4H), 7.13 (t, J=8 Hz, 1H), 7.22 (d, J = 8 Hz, 2H), 7.39 (t, J = 8 Hz, 2H), 10.62 (br s, 1 H) ; HPLC-MS: m/z 379 (MH+) ; Rf: 3.43 min.

Example 355 1- [4- (1-Cyclopropyl-1-methylethyl) piperazin-1-yl]-4- (4-trifluoromethylphenyl) butane-1,4-dione hydrochloride

'H NMR (DMSO-d6) S0. 46-0.62 (m, 4H), 1.22 (m, 7H), 2.80 (m, 2H), 2.94 (m, 1H), 3.07-3. 40 (m, 4H), 3.56-3. 80 (m, 3H), 4.17 (m, 1H), 4.43 (m, 1H), 7.90 (d, J= 8 Hz, 2H), 8.17 (d, J= 8 Hz, 2H), 10.75 (br s, 1 H) ; HPLC-MS: m/z 397 (MH+) ; Rf: 3.27 min.

Example 356 3-Benzo [1,3] dioxol-5-yl-1- [4- (1-cyclopropyl-1-methylethyl) piperazin-1-yl] propenone hydro- chloride 'H NMR (DMSO-d6) 9 0. 44-0.62 (m, 4H), 1.22 (m, 7H), 3.05 (m, 2H), 3.28 (m, 1H), 3.65 (m, 3H), 4.58 (m, 2H), 6.07 (s, 2H), 6.95 (d, J= 8 Hz, 1H), 7.12-7. 20 (m, 2H), 7.44-7. 51 (m, 2H), 10.80 (br s, 1 H) ; HPLC-MS: m/z 343 (MH+) ; Rf: 2.67 min.

Example 357 1- (3-Chloro-4-methoxyphenyl)-4- [4- (1-cyclopropyl-1-methylethyl) piperazin-1-y ] butane-1, 4- dione hydrochloride 'H NMR (DMSO-d6) #0. 45-0.62 (m, 4H), 1.22 (m, 7H), 2.74 (m, 2H), 2.93 (m, 1H), 3.09-3. 25 (m, 4H), 3.56-3. 78 (m, 3H), 3.95 (s, 3H), 4.16 (m, 1H), 4.44 (m, 1H), 7.28 (m, 1H), 7.99 (m, 2H), 10.70 (br s, 1 H) ; HPLC-MS: m/z 393 (MH+) ; Rf: 3.00 min.

Example 358 4- (3, 4-Dichlorophenyl)-1- [4- (1-ethylpropyl) piperazin-1-yl]-2-hydroxybutane-1, 4-dione hydro- chloride

The acid required for the synthesis of this amide was prepared in the following way: A mixture of 3, 4-dichloroacetophenone (3.84 g, 20.3 mmol), glacial acetic acid (20.0 ml), and glyoxylic acid hydrate (1.85 g, 20.1 mmol) was stirred at 90 °C for 23 hours. More glyoxylic acid hydrate (0.93 g) was added, and heating was continued for 41 hours. Water (200 ml) was added, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgS04), and concentrated under reduced pressure.

Recrystallization of the residue from ethyl acetate/heptane yielded 2.01 g (38%) of 4- (3, 4- dichlorophenyl)-4-oxo-2-hydroxybutyric acid. This acid was used to prepare the title amide using General Procedure (D).

'H NMR (DMSO-d6) 5 0. 97 (t, J = 7 Hz, 6H), 1.61 (m, 2H), 1.85 (m, 2H), 2.87-3. 72 (m, 9H), 4.23-4. 45 (m, 2H), 4.89 (m, 1H), 7.82 (d, J= 8 Hz, 1H), 7.91 (dd, J= 8 Hz, 1 Hz, 1H), 8.12 (d, J = 1 Hz, 1 H), 10.28 (br s, 1 H) ; HPLC-MS: m/z401 (MH+) ; Rf: 3.10 min.

Example 359 1- (3, 4-Dimethoxyphenyl)-4- [4- (tetrahydropyran-4-yl) piperazin-1-yl] butane-1,4-dione hydro- chloride 'H NMR (DMSO-d6) 61. 71 (m, 2H), 2.02 (m, 2H), 2. 68-3. 65 (m, 13H), 3.81 (s, 3H), 3.85 (s, 3H), 3.98 (m, 2H), 4.19 (m, 1H), 4.42 (m, 1H), 7.08 (d, J= 8 Hz, 1H), 7.43 (d, J = 1 Hz, 1H), 7.68 (dd, J = 8 Hz, 1 Hz, 1H), 10.90 (brs, 1H) ; HPLC-MS: m/z 391 (MH+) ; Rf: 2.07 min.

Example 360 1- (4-Cyclopentyl [1,4] diazepan-1-yl)-4- (3, 4-dimethoxyphenyl) butane-1,4-dione hydrochloride

'H NMR (DMSO-d6) 5 1. 42-2.45 (m, 10H), 2.69 (m, 2H), 2.90-3. 67 (m, 9H), 3.81 (s, 3H), 3. 84 (s, 3H), 3.93-4. 13 (m, 2H), 7.08 (d, J= 8 Hz, 1H), 7.44 (d, J= 1 Hz, 1H), 7.68 (dd, J= 8 Hz, 1 Hz, 1 H), 10.75 (br s, 1 H) ; HPLC-MS: m/z 389 (MH+) ; Rf: 2.43 min.

Example 361 [4- (1-Cyclopropyl-1-methylethyl) piperazin-1-yl]- [5- (3-fluoro-4-methoxy-phenyl)-2H-pyrazol-3- yl] methanone hydrochloride hydrochloride The acid required for the synthesis of this amide was prepared in the following way: To a solution of 3-fluoro-4-methoxyacetophenone (2.59 g, 15.4 mmol) and dimethyl oxalate (2.0 g, 16.9 mmol) in THF (25 ml) was portionwise added a 1.7 M solution of potas- sium tert-amylate in toluene (25 ml, 42.5 mmol). The mixture was stirred at room temperature for 14 hours. Water (1.0 ml) and more THF (25 ml) were added, and stirring at room tem- perature was continued for 30 hours. Water (250 ml) was added, and the mixture was washed with a mixture of heptane and toluene. The aqueous phase was filtered, acidified with concentrated hydrochloric acid (6.0 ml), and filtered. After drying, 3.09 g (84%) of 4- (3- fluoro-4-methoxyphenyl)-4, 2-dioxobutyric acid was obtained. A mixture of this acid (1.99 g, 8.29 mmol), ethanol (75 ml), and hydrazine hydrate (0.80 mi, 2 equiv. ) was refluxed for 18 hours. Water (250 ml) and concentrated hydrochloric acid (4.0 ml) were added, and the mix- ture was filtered. After drying under reduced pressure 1.76 g (90%) of 5- (3-fluoro-4-methoxy- phenyl)-2H-pyrazole-3-carboxylic acid acid was obtained as a solid. This acid was used to prepare the title amide using General Procedure (D).

'H NMR (DMSO-d6) #0. 45-0.65 (m, 4H), 1.22 (m, 7H), 3.11 (m, 2H), 3.60 (m, 2H), 3.70 (m, 2H), 3.87 (s, 3H), 4.64 (m, 1 H), 5.16 (m, 1 H), 7.07 (br s, 1 H), 7.26 (m, 1 H), 7.60-7. 80 (m, 2H), 10.62 (br s, 1 H), 13.69 (br s, 1 H) ; HPLC-MS: m/z 387 (MH+) ; Rf: 2.90 min.

Example 362 1- [4- (1-Cyclopropyl-1-methylethyl) piperazin-1-yl]-2- (4'-fluorobiphenyl-4-yl) ethanone hydro- chloride 'H NMR (DMSO-d6) F0. 45-0.60 (m, 4H), 1.22 (m, 7H), 2.97 (m, 2H), 3.23 (m, 1H), 3.52-3. 90 (m, 5H), 4.21 (m, 1 H), 4.52 (m, 1 H), 7.28 (m, 4H), 7.59 (d, J = 8 Hz, 2H), 7.68 (m, 2H), 10.80 (br s, 1 H) ; HPLC-MS: m/z 381 (MH+) ; Rf: 3.63 min.

Example 363 1- (4-Cyclopropylmethylpiperazin-1-yl)-3- (3, 4-dichlorophenoxy) propan-1-one hydrochloride 'H NMR (DMSO-d6) S0. 39 (m, 2H), 0.63 (m, 2H), 1.12 (m, 1 H), 2.85-3. 20 (m, 7H), 3.50-3. 65 (m, 3H), 4.11 (m, 1H), 4.24 (t, J = 7 Hz, 2H), 4.46 (m, 1H), 6.97 (dd, J = 8 Hz, 1 Hz, 1H), 7.23 (d, J = 1 Hz, 1 H), 7.52 (d, J = 8 Hz, 1 H), 11.14 (br s, 1 H) ; HPLC-MS: m/z 357 (MH+) ; Rf: 3.37 min.

Example 364 1- [4- (1-Ethylpropyl) piperazin-1-yl]-4- (3-fluoro-4-methoxyphenyl)-2-hydroxybutane-1, 4-dione hydrochloride

The acid required for this synthesis was prepared as in example 358.

'H NMR (DMSO-d6) 90. 97 (t, J = 7 Hz, 6H), 1.62 (m, 2H), 1.88 (m, 2H), 2.85-3. 49 (m, 8H), 3.73 (m, 1 H), 3.93 (s, 3H), 4.25-4. 43 (m, 2H), 4.88 (m, 1 H), 5.16 (br s, 1 H), 7.29 (t, J = 8 Hz, 1 H), 7.72 (dd, J = 8 Hz, 1 Hz, 1 H), 7.83 (m, 1 H), 10.76 (br s, 1 H) ; HPLC-MS: m/z 381 (MH+) ; Rf: 2.63 min.

Example 365 [4- (1-Ethylpropyl) piperazin-1-yl]- [5- (3-fluoro-4-methoxyphenyl)-2H-pyrazol-3-yl] methanone hydrochloride

'H NMR (DMSO-d6) 50. 97 (t, J = 7 Hz, 6H), 1.65 (m, 2H), 1.89 (m, 2H), 3.02-3. 56 (m, 6H), 3. 78 (m, 1 H), 3. 89 (s, 3H), 4.61 (m, 1 H), 5.09 (br s, 1 H), 7.08 (br s, 1 H), 7.26 (t, J = 8 Hz, 1 H), 7.62 (br d, J = 7 Hz, 1 H), 7.72 (br d, J = 8 Hz, 1 H), 10.53 (br s, 1 H), 13.71 (br s, 1 H) ; HPLC-MS: m/z 375 (MH+) ; Rf: 2.90 min.

Example 366 <BR> <BR> 3- (3, 4-Dichlorophenoxy)-1- [4- (tetrahydropyran-4-yl) piperazin-1-yl] propan-1-one hydrochlo- ride

1H NMR (DMSO-d6) 61. 71 (m, 2H), 2.00 (m, 2H), 2.80-3. 68 (m, 11H), 4.00 (m, 2H), 4.12 (m, 1H), 4.25 (t, J = 7 Hz, 2H), 4.49 (m, 1H), 7.02 (dd, J = 8 Hz, 1 Hz, 1H), 7.25 (d, J = 1 Hz, 1H), 7. 58 (d, J = 8 Hz, 1 H), 11.25 (br s, 1H) ; HPLC-MS: m/z 387 (MH+) ; Rf: 3.23 min.

Example 367 4- (4-Chlorophenyl)-1- (4-cyclopropylmethylpiperazin-1-yl) butan-1-one hydrochloride 'H NMR (DMSO-d6) #0. 39 (m, 2H), 0.63 (m, 2H), 1.10 (m, 1H), 1.79 (quint, J= 7 Hz, 2H), 2.38 (m, 2H), 2.60 (t, J = 7 Hz, 2H), 2.83-3. 12 (m, 5H), 3.50 (m, 3H), 4.03 (m, 1 H), 4.45 (m, 1 H), 7.23 (d, J = 8 Hz, 2H), 7.34 (d, J = 8 Hz, 2H), 10.65 (br s, 1 H) ; HPLC-MS : m/z 321 (MH+) ; Rf: 3.23 min.

Example 368 4- (4-Chlorophenyl)-1- [4- (tetrahydropyran-4-yl) piperazin-1-yl] butan-1-one hydrochloride 'H NMR (DMSO-d6) #1. 68 (m, 2H), 1.81 (quint, J= 7 Hz, 2H), 1.98 (m, 2H), 2.36 (m, 2H), 2.60 (t, J = 7 Hz, 2H), 2.83-3. 12 (m, 3H), 3.26-3. 55 (m, 6H), 3.94-4. 08 (m, 3H), 4.47 (m, 1H), 7.23 (d, J = 8 Hz, 2H), 7.35 (d, J = 8 Hz, 2H); HPLC-MS: m/z 351 (MH+) ; Rf: 3.07 min.

Example 369 1- (4-Cyclopropylmethylpiperazin-1-yl)-2- (4'-fluorobiphenyl-4-yl) ethanone hydrochloride

'H NMR (DMSO-d6) 5 0. 39 (m, 2H), 0.63 (m, 2H), 1.10 (m, 1H), 2.89-3. 22 (m, 5H), 3.53 (m, 3H), 3.79 (d, J= 17 Hz, 1H), 3.85 (d, J= 17 Hz, 1H), 4.21 (m, 1H), 4.47 (m, 1H), 7.29 (m, 4H), 7.60 (d, J = 8 Hz, 2H), 7.69 (m, 2H), 10.20 (br s, 1 H); HPLC-MS: m/z 353 (MH+) ; Rf: 3.47 min.

Example 370 2- (4'-Fluorobiphenyl-4-yl)-1- [4- (tetrahydropyran-4-yl) piperazin-1-yl] ethanone hydrochloride 'H NMR (DMSO-d6) 61. 70 (m, 2H), 2.00 (m, 2H), 2.95 (m, 2H), 3.15-3. 70 (m, 7H), 3.75-3. 89 (m, 2H), 3.98 (m, 2H), 4.21 (m, 1 H), 4.48 (m, 1 H), 7.29 (m, 4H), 7.60 (d, J = 8 Hz, 2H), 7.69 (m, 2H); HPLC-MS: m/z 383 (MH+) ; Rf: 3.30 min.

Example 371 1- (4-Cyclopropylmethylpiperazin-1-yl)-4- (3-fluoro-4-methoxyphenyl) butan-1-one hydrochlo- ride

The acid required for this synthesis was prepared from 4- (3-fluoro-4-methoxy- phenyl)-4-oxobutyric acid by reduction with triethylsilane/trifluoroacetic acid (70 °C, 25 hours, 92% yield).

'H NMR (DMSO-d6) J0. 39 (m, 2H), 0.63 (m, 2H), 1.10 (m, 1H), 1.79 (quint, J= 7 Hz, 2H), 2.38 (m, 2H), 2.60 (t, J = 7 Hz, 2H), 2.83-3. 12 (m, 5H), 3.50 (m, 3H), 3.76 (s, 3H), 4.03 (m, 1 H), 4.45 (m, 1 H), 6.94 (br d, J = 8 Hz, 1 H), 7.05 (m, 2H), 11.05 (br s, 1 H); HPLC-MS: m/z 335 (MH+) ; Rf: 2.80 min.

Example 372 1- [4- (1-Ethylpropyl) piperazin-1-yl]-4- (3-fluoro-4-methoxyphenyl)-2-hydroxybutan-1-one hy- drochloride The acid required for this synthesis was prepared from 4- (3-fluoro-4-methoxy- phenyl)-2, 4-dioxobutyric acid (for preparation, see Example 361) by reduction with triethyl- silane/trifluoroacetic acid (70 °C, 17 hours, 88% yield).

'H NMR (DMSO-d6) 5 0. 97 (t, J = 7 Hz, 6H), 1.55-1. 92 (m, 6H), 2.60 (m, 2H), 2.88-3. 10 (m, 3H), 3.20-3. 45 (m, 3H), 3.69 (m, 1H), 3.78 (s, 3H), 4.12-4. 29 (m, 2H), 4.40 (m, 1H), 5.25 (br s, 1 H), 6.96 (m, 1 H), 7.05 (m, 2H), 10.85 (br s, 1 H) ; HPLC-MS: m/z 367 (MH+) ; Rf: 2.70 min.

Example 373 1- (4-Cyclopent-3-enylpiperazin-1-yl)-4- (3-fluoro-4-methoxyphenyl) butan-1-one hydrochloride 'H NMR (DMSO-d6) 61. 79 (quint, J= 7 Hz, 2H), 2.34 (t, J= 7 Hz, 2H), 2.49-3. 15 (m, 9H), 3.31-3. 60 (m, 3H), 3.80 (s, 3H), 3.89 (m, 1 H), 4.01 (m, 1H), 4.47 (m, 1 H), 5.73 (s, 2H), 6.94 (brd, J= 8 Hz, 1 H), 7.05 (m, 2H), 11.61 (br s, 1 H) ; HPLC-MS: m/z 347 (MH+) ; Rf: 2.87 min.

Example 374 4- (3, 4-Dichlorophenyl)-1- [4- (1-ethylpropyl) piperazin-1-yl] but-2-en-1-one hydrochloride

The acid required for this synthesis was prepared from 4- (3, 4-dichlorophenyl)-4-oxo- 2-butenoic acid (prepared as described in DE 2047806) by reduction with triethylsilane/tri- fluoroacetic acid (70 °C, 24 hours, 41 % yield).

'H NMR (DMSO-d6) 60. 97 (t, J = 7 Hz, 6H), 1.60 (m, 2H), 1.85 (m, 2H), 2.91-3. 25 (m, 4H), 3.38 (m, 4H), 3.65 (m, 1 H), 4.05 (m, 1 H), 4.45 (m, 1 H), 6.47 (m, 2H), 7.43 (dd, J = 8 Hz, 1 Hz, 1H), 7.58 (d, J= 8 Hz, 1H), 7.71 (d, J= 1 Hz, 1H), 10.50 (br s, 1H) ; HPLC-MS: m/z 369 (MH+) ; Rf: 2.95 min.

Example 375 4- (3, 4-Dichlorophenyl)-1- [4- (1-ethylpropyl) piperazin-1-yl]-4-hydroxybut-2-en-1-one hydro- chloride The acid required for this synthesis was prepared from 4- (3, 4-dichlorophenyl)-4-oxo- 2-butenoic acid (prepared as described in DE 2047806) by reduction with sodium boro- hydride.

'H NMR (main conformer, DMSO-d6) E0. 95 (t, J = 7 Hz, 6H), 1.60 (m, 2H), 1.85 (m, 2H), 2.88-3. 30 (m, 4H), 3.40 (m, 3H), 3.65 (m, 1 H), 4.20 (m, 1 H), 4.47 (m, 1 H), 5.33 (br s, 1 H), 6.07 (br s, 1 H), 6.72 (s, 2H), 7.34 (m, 1 H), 7.60 (m, 2H), 10.40 (br s, 1H) ; HPLC-MS: m/z 385 (MH+) ; Rf: 3. 10 min.

Example 376 1- (4-Cyclopropylmethylpiperazin-1-yl)-2- (2-fluorobiphenyl-4-yl) ethanone hydrochloride

The acid required for this synthesis was prepared according to the literature: NL 6500865.

'H NMR (DMSO-d6) 9 0. 39 (m, 2H), 0. 63 (m, 2H), 1.10 (m, 1H), 2.89-3. 22 (m, 5H), 3.53 (m, 3H), 3.83 (m, 2H), 4.21 (m, 1 H), 4.47 (m, 1 H), 7.30 (m, 4H), 7.40 (m, 1 H), 7.50 (m, 3H), 10.75 (br s, 1H) ; HPLC-MS: m/z353 (MH+) ; Rf: 2.61 min.

Example 377 1- (4-Cyclopropylmethylpiperazin-1-yl)-4- (3, 4-dichlorophenyl) but-2-en-1-one hydrochloride 'H NMR (DMSO-d6) 9 0. 39 (m, 2H), 0.63 (m, 2H), 1.10 (m, 1H), 2.85-3. 25 (m, 4H), 3.30-3. 68 (m, 6H), 4.05 (m, 1 H), 4.45 (m, 1 H), 6.45 (m, 2H), 7.43 (dd, J = 8 Hz, 1 Hz, 1 H), 7.58 (d, J = 8 Hz, 1H), 7.71 (d, J= 1 Hz, 1H), 11.15 (br s, 1H) ; HPLC-MS: m/z353 (MH+) ; Rf: 2.66 min.

Example 378 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 3-trifluoromethylphenyl ester hydrochloride To a stirred mixture of 1-(1-ethylpropyl) piperazine (175 u1, 1.0 mmol) and dry DCM (10 ml) was added 3-trifluoromethylphenyl chloroformate (250 mg, 1.1 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3 x 25 mi) and water (2 x 25 ml). The organic solution

was concentrated and the residue was dissolved in a 0.5 N HCI solution (15 ml) and a small portion of acetonitrile. The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 330 mg (86%) of the title compound as a solid.

M. p. 260-261 °C.

'H NMR (400 MHz, DMSO-d6) : #0. 98 (t, 6H), 1.63 (hept, 2H), 1.86-1. 98 (m, 2H), 3.03-3. 12 (m, 1H), 3.12-3. 31 (m, 2H), 3.41-3. 49 (m, 2H), 3.52-3. 85 (m, 2H), 4.05-4. 35 (m, 2H), 7.47- 7.70 (m, 4H), 11.0 (brs, 1 H).

Example 379 4- (1-Ethylpropyl) piperazine-1-carboxylic acid naphthalen-1-yl ester hydrochloride To a stirred mixture of 1-(1-ethylpropyl) piperazine (175 ul, 1.0 mmol) and dry DCM (10 ml) was added 1-napthalenyl chloroformate (225 mg, 1.1 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3 x 25 ml) and water (2 x 25 ml). The organic solution was concen- trated and the residue was dissolved in a 0.5 N HCI solution (15 ml) and a small portion of acetonitrile. The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 310 mg (85%) of the title compound as a solid.

M. p. 288-290 °C.

1H NMR (400 MHz, DMSO-d6) : S1. 00 (t, 6H), 1.63 (hept, 2H), 1.86-2. 02 (m, 2H), 3.07-3. 18 (m, 1H), 3.18-3. 42 (m, 2H), 3.42-3. 55 (m, 2H), 3.55-3. 73 (m, 1H), 3.78-3. 95 (m, 1H), 4.05- 4.25 (m, 1 H), 4.35-4. 55 (m, 1 H), 7.35 (d, 1 H), 7.53 (t, 1 H), 7.56-7. 7.61 (m, 2H), 7.85 (d, 1H), 7.90-8. 05 (m, 2H), 10.75 (brs, 1H).

Example 380 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 4-fluorophenyl ester hydrochloride

To a stirred mixture of 1- (1-ethylpropyl) piperazine (350 µl, 2.0 mmol) and dry DCM (15 ml) was added 4-fluorophenyl chloroformate (350 mg, 2.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3 x 25 ml) and water (2 x 25 ml). The organic solution was concen- trated and the residue was re-evaporated twice with acetonitrile to give 590 mg of the free base. The hydrochloride salt was prepared from 465 mg free base by addition of a 0.5 N HCI solution (15 ml) and a small portion of acetonitrile. The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 470 mg (90%) of the title compound as a solid. M. p. 275-277 °C.

'H NMR (400 MHz, DMSO-d6) : 50. 98 (t, 6H), 1.64 (hept, 2H), 1.85-1. 95 (m, 2H), 3.02-3. 11 (m, 1 H), 3.11-3. 28 (m, 2H), 3.38-3. 46 (m, 2H), 3.50-3. 80 (m, 2H), 4.00-4. 30 (m, 2H), 7.18- 7.26 (m, 4H), 10.85 (brs, 1H).

Example 381 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 2-nitrophenyl ester hydrochloride To a stirred mixture of 1- (1-ethylpropyl) piperazine (175 NI, 1.0 mmol) and dry DCM (10 ml) was added 2-nitrophenyl chloroformate (201 mg, 1.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3 x 25 mi) and water (2 x 25 ml). The organic solution was concen- trated and the residue was dissolved in a 0.5 N HCI solution (15 ml). The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 310 mg (86%) of the title compound as a solid. M. p. 251-253 °C.

'H NMR (400 MHz, DMSO-d6) : W0. 96 (t, 6H), 1.65 (hept, 2H), 1.83-1. 95 (m, 2H), 3.06-3. 25 (m, 3H), 3.42-3. 53 (m, 2H), 3.53-3. 83 (m, 2H), 4.02-4. 13 (m, 1H), 4.20-4. 34 (m, 1H), 7.50- 7.55 (m, 2H), 7.83 (t, 1H), 8.13 (d, 1H), 10.9 (brs, 1H).

Example 382 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 4-methoxycarbonylphenyl ester hydrochloride

To a stirred mixture of 1-(1-ethylpropyl) piperazine (350, ul, 2.0 mmol) and dry DCM (15 ml) was added 4-methoxycarbonylphenyl chloroformate (430 mg, 2.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3 x 25 ml) and water (2 x 25 ml). The organic solution was concentrated and re-evaporated twice with acetonitrile. The residue was dissolved in a 0.5 N HCI solution (15 mi) and a small portion of acetonitrile. The acidic solution was concen- trated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 670 mg (90%) of the title compound as a solid. M. p. 248 °C decomp..

'H NMR (400 MHz, DMSO-d6) : (50. 97 (t, 6H), 1.63 (hept, 2H), 1.85-1. 95 (m, 2H), 3.02-3. 11 (m, 1 H), 3.11-3. 30 (m, 2H), 3.40-3. 48 (m, 2H), 3.50-3. 80 (m, 2H), 3.85 (s, 3H), 4.05-4. 33 (m, 2H), 7.33 (d, 2H), 8.00 (d, 2H) ), 10.7 (brs, 1H).

Example 383 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 2- (3, 4-dimethoxyphenyl) ethyl ester hydrochlo- ride A stirred mixture of 2- (3, 4-dimethoxyphenyl) ethanol (1.02 g, 5.6 mmol) and dry DCM (35 ml) was placed on an ice-bath under an atmosphere of nitrogen. 4-Nitrophenyl chloro- formate (1.1 g, 5.5 mmol) was added and the mixture was stirred for 15 minutes. Pyridine (0.48 ml) was added and stirring was continued on an ice-bath for 4 hours. The reaction mix- ture was diluted with DCM (40 ml) and then washed with water (2 x 30 ml) and then dried

(MgS04). The solvent was evaporated to give an oily residue of crude 2- (3, 4-dimethoxy- phenyl) ethyl 4-nitrophenylcarbonate.

The above carbonate was dissolved in DCM (25 ml) and 1- (1-ethylpropyl) piperazine (800 mg, 5.1 mmol) was added. The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3 x 25 ml) and water (3 x 25 ml). The organic phase was dried (MgS04) and the solvent was evapo- rated. The residue was dissolved into a 1 N HCI solution and the acidic solution was evapo- rated to give a residue that was re-evaporated several times with acetonitrile. The residue was crystallised from ethyl acetate to give 1.75 g (78%) of the title compound as a solid.

M. p. 161-162°C.

'H NMR (400 MHz, DMSO-d6) : 60. 94 (t, 6H), 1.55-1. 65 (m, 2H), 1.80-1. 92 (m, 2H), 2.82 (t, 2H), 2.92-3. 05 (m, 3H), 3.32-3. 53 (m, 4H), 3.71 (s, 3H), 3.73 (s, 3H), 3.93-4. 05 (m, 2H), 4.21 (t, 2H), 6.72-6. 87 (m, 3H), 10.75 (brs, 1H).

Example 384 4- (1-Ethylpropyl) piperazine-1-carboxylic acid 2- (4-methanesulfonylphenoxy) ethyl ester hy- drochloride Step 1 : 2- (4-Methanesulfonylphenoxy) ethanol A mixture of 4-methanesulfonylphenol (1.72 g, 10 mmol), DMA (25 ml) and 4 N so- dium hydroxide (7 ml) was stirred under an atmosphere of nitrogen. 2- (2-Pyranyloxy) ethyl- bromide (2.8 g, 14 mmol) was added dropwise and then the mixture was stirred overnight at ambient temperature. The solvent was evaporated in vacuo and the residue was taken up in water (100 ml). The aqueous mixture was extracted with ethyl acetate (2 x 100 ml) and the combined organic extracts were washed with a 0.5 N sodium hydroxide solution and brine.

The organic phase was concentrated to give an oily residue that was dissolved in methanol (50 ml). A solution of 5 N HCI (20 ml) was added and the mixture was stirred at ambient tem- perature for 2 hours. The reaction mixture was concentrated and a small portion of ice was added followed by 4 N sodium hydroxide until approximately pH 10. The alkaline mixture was extracted with ethyl acetate (3 x 75 ml) and the combined organic extracts were washed with water and dried (MgS04). The solvent was evaporated to give 0.82 g (38%) of 2- (4-methane- sulfonylphenoxy) ethanol. M. p. 89-90 °C.

'H NMR (400 MHz, CDCI3) : 2. 11 (t, 1H), 3.03 (s, 3H), 4.02 (q, 2H), 4.18 (t, 2H), 7.05 (d, 2H), 7.87 (d, 2H).

Step 2: By a similar procedure as described in Example 333 and starting from 1- (1- ethylpropyl) piperazine (350 mg, 2.2 mmol) and 2- (4-methanesulfonylphenyl) ethanol (540 mg, 2.5 mmol), 875 mg (89%) of the title compound was isolated as a solid.

'H NMR (400 MHz, DMSO-d6) 60. 94 (t, 6H), 1.53-1. 67 (m, 2H), 1.77-1. 90 (m, 2H), 2.95-3. 08 (m, 3H), 3.17 (s, 3H), 3.30-3. 65 (m, 4H), 3.92-4. 07 (m, 2H), 4.3-4. 4 (m, 4H), 7.19 (d, 1H), 7. 84 (d, 1H), 10.7 (brs, 1H).

PHARMACOLOGICAL METHODS The ability of the compounds to interact with the histamine H3 receptor can be de- termined by the following in vitro binding assays.

Binding assay I Rat cerebral cortex is homogenized in ice cold K-Hepes, 5 mM MgCtz pH 7.1 buffer.

After two differential centrifugations the last pellet is resuspended in fresh Hepes buffer con- taining 1 mg/ml bacitracin. Aliquots of the membrane suspension (400 ug/ml) are incubated for 60 min at 25°C with 30 pM [1251]-iodoproxifan, a known histamine H3 receptor antagonist, and the test compound at various concentrations. The incubation is stopped by dilution with ice-cold medium, followed by rapid filtration through Whatman GF/B filters pretreated for 1 hour with 0.5% polyethyleneimine. The radioactivity retained on the filters is counted using a Cobra II auto gamma counter. The radioactivity of the filters is indirectly proportional to the binding affinity of the tested compound. The results are analyzed by nonlinear regression analysis.

Binding assay 11 The H3-receptor agonist ligand R-a-methyll3H] histamine (RAMHA) is incubated with isolated rat cortex cell-membranes at 25 °C for 1 hour, followed by a filtration of the incubate through Whatman GF/B filters. Radioactivity retained on the filters is measured using a beta counter.

Male Wistar rats (150-200 g) are decapitated and cerebral cortex is quickly dis- sected out and frozen immediately on dry ice. Tissue is kept at-80 °C until membrane pre- paration. During the membrane preparation the tissue is kept on ice all the time. Rat cerebral cortex is homogenized in 10 volumes (w/w) ice-cold Hepes buffer (20 mM Hepes, 5 mM MgCl2 pH 7.1 (KOH) + 1 mg/ml bacitracin) using an Ultra-Turrax homogenizer for 30 sec- onds. The homogenate is centrifuged at 140 g in 10 min. The supernatant is transferred to a new test tube and centrifuged for 30 min at 23 000 g. Pellet is resuspended in 5-10 ml Hepes buffer, homogenized and centrifuged for 10 min at 23 000 g. This short centrifugation step is repeated twice. After the last centrifugation the pellet is resuspended in 2-4 ml Hepes buffer and the protein concentration is determined. The membranes are diluted to a protein concen- tration of 5 mg/ml using Hepes buffer, aliquote and stored at-80 °C until use.

50 jut test-compound, 100 ptl membrane (200 jug/mi), 300 jut Hepes buffer and 50 jut R-a-methyl [3H] histamine (1 nM) are mixed in a test tube. The compounds to be tested are dissolved in DMSO and further diluted in H20 to the desired concentrations. Radioligand and membranes are diluted in Hepes buffer + 1 mg/ml bacitracin. The mixture is incubated for 60 min at 25'C. Incubation is terminated by adding 5 mi ice-cold 0.9% NaCI, followed by rapid filtration through Whatman GF/B filters pre-treated for 1 hour with 0.5% polyethyleneimine.

The filters are washed with 2 x 5 mi ice-cold NaCI. To each filter a 3 mi scintillation cocktail is added and the radioactivity retained is measured with a Packard Tri-Carb beta counter. tCeo values are calculated by non-linear regression analysis of binding curves (6 points minimum) using the windows program GraphPad Prism, GraphPad software, USA.

Binding assay III The human H3 receptor is cloned by PCR and subcloned into the pcDNA3 expres- sion vector. Cells stably expressing the H3 receptor are generated by transfecting the H3- expression vectors into HEK 293 cells and using G418 to select for H3 clones. The human H3-HEK 293 clones are cultured in DMEM (GIBCO-BRL) with glutamax, 10% foetal calf se- rum, 1 % penicillin/streptavidin and 1 mg/ml G 418 at 37 °C and 5% C02. Before harvesting, the confluent cells are rinsed with PBS and incubated with Versene (proteinase, GIBCO- BRL) for approximately 5 min. The cells are flushed with PBS and DMEM and the cellsus-

pension collected in a tube and centrifuged for 5-10 min at 1500 rpm in a Heraeus Sepatech Megafuge 1.0. The pellet is resuspended in 10-20 vol. Hepes buffer (20 mM Hepes, 5 mM MgCi2, pH 7.1 (KOH) ) and homogenized for 10-20 seconds using an Ultra-Turrax homoge- nizer. The homogenate is centrifuged for 30 min at 23 000 g. The pellet is resuspended in 5- 10 ml Hepes buffer, homogenized 5-10 seconds with the Ultra-Turrax and centrifuged for 10 min at 23 000 g. Following this centrifugation step, the membrane pellet is resuspended in 2- 4 mi Hepes buffer, homogenized with a syringe or teflonhomogenizer, and the protein con- centration determined. The membranes are diluted to a protein concentration of 1-5 mg/ml in Hepes buffer, aliquote and kept at-80 °C until use.

Aliquots of the membrane suspension are incubated for 60 min at 25 °C with 30 pM [1251]-iodoproxifan, a known compound with high affinity for the H3 receptor, and the test compound at various concentrations. The incubation is stopped by dilution with ice-cold me- dium, followed by rapid filtration through Whatman GF/B filters pretreated for 1 hour with 0.5% polyethyleneimine. The radioactivity retained on the filters is counted using a Cobra II auto gamma counter. The radioactivity of the filters is indirectly proportional to the binding affinity of the tested compound. The results are analysed by nonlinear regression analysis.

When tested, the present compounds of the formula (I) generally show a high bind- ing affinity to the histamine H3 receptor.

Preferably, the compounds according to the invention have an ICgo value as deter- mined by one or more of the assays of less than 10 pM, more preferred of less than 1 uM, and even more preferred of less than 500 nM, such as of less than 100 nM.

Functional assay I The ability of the compounds to interact with the histamine H3 receptor as agonists, inverse agonists and/or antagonists, is determined by an in vitro functional assay utilizing membranes from HEK 293 cell expressing the human H3 receptors.

The H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vec- tor. Cells stably expressing the H3 receptor are generated by transfecting the H3-expression vectors into HEK 293 cells and using G418 to select for H3 clones. The human H3-HEK 293 clones are cultured in DMEM with glutamax, 10% foetal calf serum, 1 % penicillin/streptavidin and 1 mg/ml G 418 at 37 °C and 5% C02.

The H3 receptor expressing cells are washed once with phosphate buffered saline (PBS) and harvested using versene (GIBCO-BRL). PBS is added and the cells are centri- fuged for 5 min at 188 g. The cell pellet is resuspended in stimulation buffer to a concentra- tion of 1 x 106 cells/ml. cAMP accumulation is measured using the Flash Plate@ cAMP assay

(NEN Tm Life Science Products). The assay is generally performed as described by the manu- facturer. Briefly, 50 go cela suspension is added to each well of the Flashplate which also con- tained 25 vul 40, uM isoprenaline, to stimulate cAMP generation, and 25, ul of test compound (either agonists or inverse agonists alone, or agonist and antagonist in combination). The assay can be run in"agonist-mode"which means that the test compound is added, in in- creasing concentration, on its own, to the cells, and cAMP is measured. If cAMP goes up, it is an inverse agonist; if cAMP does not change, it is a neutral antagonist, and if cAMP goes down, it is an agonist. The assay can also be run in the"antagonist-mode"which means that a test compound is added, in increasing concentrations, together with increasing concentra- tions of a known H3 agonist (eg RAMHA). If the compound is an antagonist, increasing con- centrations of it cause a right-ward shift in the H3-agonist's dose-response curves. The final volume in each well is 100 lli. Test compounds are dissolved in DMSO and diluted in H20.

The mixture is shaken for 5 min, and allowed to stand for 25 min at room temperature. The reaction is stopped with 100 pH'Detection Mix"per well. The plates are then sealed with plas- tic, shaken for 30 min, allowed to stand overnight, and finally the radioactivity is counted in the Cobra II auto gamma topcounter. EC50 values are calculated by non-linear regression analysis of dose response curves (6 points minimum) using GraphPad Prism. Kb values are calculated by Schild plot analysis.

Functional assay 11 The ability of the present compounds to reduce weight is determined using the in vivo open cage Schedule-fed rat model.

The ability of the compounds to bind and interact with the human, monkey or rat H3 receptor as agonists, inverse agonists and/or antagonists, is determined by a functional as- say, named [35S] GTPyS assay.

The human H3 receptor has the following sequence: Met-Glu-Arg-Ala-Pro-Pro-Asp-Gly-Pro-Leu-Asn-Ala-Ser-Gly-Ala- Leu-Ala- Gly-Glu-Ala-Ala-Ala-Ala-Gly-Gly-Ala-Arg-Gly-Phe-Ser-Ala-Ala- Trp-Thr- <BR> <BR> <BR> <BR> Ala-Val-Leu-Ala-Ala-Leu-Met-Ala-Leu-Leu-Ile-Val-Ala-Thr-Val- Leu-Gly-<BR> <BR> <BR> <BR> <BR> <BR> <BR> Asn-Ala-Leu-Val-Met-Leu-Ala-Phe-Val-Ala-Asp-Ser-Ser-Leu-Arg- Thr-Gln- Asn-Asn-Phe-Phe-Leu-Leu-Asn-Leu-Ala-Ile-Ser-Asp-Phe-Leu-Val- Gly-Ala- Phe-Cys-Ile-Pro-Leu-Tyr-Val-Pro-Tyr-Val-Leu-Thr-Gly-Arg-Trp- Thr-Phe- Gly-Arg-Gly-Leu-Cys-Lys-Leu-Trp-Leu-Val-Val-Asp-Tyr-Leu-Leu- Cys-Thr- <BR> <BR> <BR> <BR> Ser-Ser-Ala-Phe-Asn-Ile-Val-Leu-Ile-Ser-Tyr-Asp-Arg-Phe-Leu- Ser-Val-<BR> <BR> <BR> <BR> <BR> <BR> <BR> Thr-Arg-Ala-val-ser-Tyr-Arg-Ala-Gln-Gln-Gly-Asp-Thr-Arg-Arg- Ala-Val-

Arg-Lys-Met-Leu-Leu-Val-Trp-Val-Leu-Ala-Phe-Leu-Leu-Tyr-Gly- Pro-Ala- Ile-Leu-Ser-Trp-Glu-Tyr-Leu-Ser-Gly-Gly-Ser-Ser-Ile-Pro-Glu- Gly-His- Cys-Tyr-Ala-Glu-Phe-Phe-Tyr-Asn-Trp-Tyr-Phe-Leu-Ile-Thr-Ala- Ser-Thr- Leu-Glu-Phe-Phe-Thr-Pro-Phe-Leu-Ser-Val-Thr-Phe-Phe-Asn-Leu- Ser-Ile- <BR> <BR> Tyr-Leu-Asn-Ile-Gln-Arg-Arg-Thr-Arg-Leu-Arg-Leu-Asp-Gly-Ala- Arg-Glu- Ala-Ala-Gly-Pro-Glu-Pro-Pro-Pro-Glu-Ala-Gln-Pro-Ser-Pro-Pro- Pro-Pro- <BR> <BR> Pro-Gly-Cys-Trp-Gly-Cys-Trp-Gln-Lys-Gly-His-Gly-Glu-Ala-Met- Pro-Leu- His-Arg-Tyr-Gly-Val-Gly-Glu-Ala-Ala-Val-Gly-Ala-Glu-Ala-Gly- Glu-Ala- Thr-Leu-Gly-Gly-Gly-Gly-Gly-Gly-Gly-Ser-Val-Ala-Ser-Pro-Thr- Ser-Ser- Ser-Gly-Ser-Ser-Ser-Arg-Gly-Thr-Glu-Arg-Pro-Arg-Ser-Leu-Lys- Arg-Gly- Ser-Lys-Pro-Ser-Ala-Ser-Ser-Ala-Ser-Leu-Glu-Lys-Arg-Met-Lys- Met-Val- Ser-Gln-Ser-Phe-Thr-Gln-Arg-Phe-Arg-Leu-Ser-Arg-Asp-Arg-Lys- Val-Ala- Lys-Ser-Leu-Ala-Val-Ile-Val-Ser-Ile-Phe-Gly-Leu-Cys-Trp-Ala- Pro-Tyr- <BR> <BR> Thr-Leu-Leu-Met-Ile-Ile-Arg-Ala-Ala-Cys-His-Gly-His-Cys-Val- Pro-Asp- Tyr-Trp-Tyr-Glu-Thr-Ser-Phe-Trp-Leu-Leu-Trp-Ala-Asn-Ser-Ala- Val-Asn- <BR> <BR> Pro-Val-Leu-Tyr-Pro-Leu-Cys-His-His-Ser-Phe-Arg-Arg-Ala-Phe- Thr-Lys- Leu-Leu-Cys-Pro-Gln-Lys-Leu-Lys-Ile-Gln-Pro-His-Ser-Ser-Leu- Glu-His- Cys-Trp-Lys The monkey H3 receptor has the following sequence: Met-Glu-Arg-Ala-Pro-Pro-Asp-Gly-Pro-Leu-Asn-Ala-Ser-Gly-Ala- Leu-Ala- Gly-Glu-Ala-Ala-Ala-Ala-Gly-Gly-Ala-Arg-Gly-Phe-Ser-Ala-Ala- Trp-Thr- <BR> <BR> Ala-Val-Leu-Ala-Ala-Leu-Met-Ala-Leu-Leu-Ile-Val-Ala-Thr-Val- Leu-Gly- Asn-Ala-Leu-Val-Met-Leu-Ala-Phe-Val-Ala-Asp-Ser-Ser-Leu-Arg- Thr-Gln- <BR> <BR> Asn-Asn-Phe-Phe-Leu-Leu-Asn-Leu-Ala-Ile-Ser-Asp-Phe-Leu-Val- Gly-Ala- Phe-Cys-Ile-Pro-Leu-Tyr-Val-Pro-Tyr-Val-Leu-Thr-Gly-Arg-Trp- Thr-Phe- Gly-Arg-Gly-Leu-Cys-Lys-Leu-Trp-Leu-Val-Val-Asp-Tyr-Leu-Leu- Cys-Thr- Ser-Ser-Ala-Phe-Asn-Ile-Val-Leu-Ile-Ser-Tyr-Asp-Arg-Phe-Leu- Ser-Val- Thr-Arg-Ala-Val-Ser-Tyr-Arg-Ala-Gln-Gln-Gly-Asn-Thr-Arg-Arg- Ala-Val- Arg-Lys-Met-Leu-Leu-Val-Trp-Val-Leu-Ala-Phe-Leu-Leu-Tyr-Gly- Pro-Ala- Ile-Leu-Ser-Trp-Glu-Tyr-Leu-Ser-Gly-Gly-Ser-Ser-Ile-Pro-Glu- Gly-His- Cys-Tyr-Ala-Glu-Phe-Phe-Tyr-Asn-Trp-Tyr-Phe-Leu-Ile-Thr-Ala- Ser-Thr- Leu-Glu-Phe-Phe-Thr-Pro-Phe-Leu-Ser-Val-Thr-Phe-Phe-Asn-Leu- Ser-Ile- Tyr-Leu-Asn-Ile-Gln-Arg-Arg-Thr-Arg-Leu-Arg-Leu-Asp-Gly-Ala- Arg-Glu- <BR> <BR> Ala-Gly-Gly-Pro-Glu-Pro-Pro-Pro-Glu-Ala-Gln-Pro-Ser-Pro-Pro- Pro-Pro- Pro-Gly-Cys-Trp-Gly-Cys-Trp-Gln-Lys-Gly-His-Gly-Glu-Ala-Met- Pro-Leu- <BR> <BR> His-Arg-Tyr-Gly-Val-Gly-Glu-Ala-Ala-Ala-Gly-Ala-Glu-Ala-Gly- Glu-Thr-

Ala-Leu-Gly-Gly-Gly-Gly-Gly-Gly-Gly-Ser-Ala-Ala-Ser-Pro-Thr- Ser-Ser- Ser-Gly-Ser-Ser-Ser-Arg-Gly-Thr-Glu-Arg-Pro-Arg-Ser-Leu-Lys- Arg-Gly- Ser-Lys-Pro-Ser-Ala-Ser-Ser-Ala-Ser-Leu-Glu-Lys-Arg-Met-Lys- Met-Val- Ser-Gln-Ser-Phe-Thr-Gln-Arg-Phe-Arg-Leu-Ser-Arg-Asp-Arg-Lys- Val-Ala- Lys-Ser-Leu-Ala-Val-Ile-Val-Ser-Ile-Phe-Gly-Leu-Cys-Trp-Ala- Pro-Tyr- <BR> <BR> Thr-Leu-Leu-Met-Ile-Ile-Arg-Ala-Ala-Cys-His-Gly-His-Cys-Val- Pro-Asp- Tyr-Trp-Tyr-Glu-Thr-Ser-Phe-Trp-Leu-Leu-Trp-Ala-Asn-Ser-Ala- Val-Asn- <BR> <BR> Pro-Val-Leu-Tyr-Pro-Leu-Cys-His-His-Ser-Phe-Arg-Arg-Ala-Phe- Thr-Lys- Leu-Leu-Cys-Pro-Gln-Lys-Leu-Lys-Ile-Gln-Pro-His-Ser-Ser-Leu- Glu-Gln- Cys-Trp-Lys The rat H3 receptor has the following sequence: <BR> Met-Glu-Arg-Ala-Pro-Pro-Asp-Gly-Leu-Met-Asn-Ala-Ser-Gly-Thr- Leu-Ala-<BR> <BR> Gly-Glu-Ala-Ala-Ala-Ala-Gly-Gly-Ala-Arg-Gly-Phe-Ser-Ala-Ala- Trp-Thr-<BR> <BR> Ala-Val-Leu-Ala-Ala-Leu-Met-Ala-Leu-Leu-Ile-Val-Ala-Thr-Val- Leu-Gly- Asn-Ala-Leu-Val-Met-Leu-Ala-Phe-Val-Ala-Asp-Ser-Ser-Leu-Arg- Thr-Gln- <BR> <BR> Asn-Asn-Phe-Phe-Leu-Leu-Asn-Leu-Ala-Ile-Ser-Asp-Phe-Leu-Val- Gly-Ala-<BR> <BR> Phe-Cys-Ile-Pro-Leu-Tyr-Val-Pro-Tyr-Val-Leu-Thr-Gly-Arg-Trp- Thr-Phe- Gly-Arg-Gly-Leu-Cys-Lys-Leu-Trp-Leu-Val-Val-Asp-Tyr-Leu-Leu- Cys-Ala- Ser-Ser-Val-Phe-Asn-Ile-Val-Leu-Ile-Ser-Tyr-Asp-Arg-Phe-Leu- Ser-Val- <BR> <BR> Thr-Arg-Ala-Val-Ser-Tyr-Arg-Ala-Gln-Gln-Gly-Asp-Thr-Arg-Arg- Ala-Val-<BR> <BR> Arg-Lys-Met-Ala-Leu-Val-Trp-Val-Leu-Ala-Phe-Leu-Leu-Tyr-Gly- Pro-Ala-<BR> <BR> Ile-Leu-Ser-Trp-Glu-Tyr-Leu-Ser-Gly-Gly-Ser-Ser-Ile-Pro-Glu- Gly-His- Cys-Tyr-Ala-Glu-Phe-Phe-Tyr-Asn-Trp-Tyr-Phe-Leu-Ile-Thr-Ala- Ser-Thr- Leu-Glu-Phe-Phe-Thr-Pro-Phe-Leu-Ser-Val-Thr-Phe-Phe-Asn-Leu- Ser-Ile- Tyr-Leu-Asn-Ile-Gln-Arg-Arg-Thr-Arg-Leu-Arg-Leu-Asp-Gly-Gly- Arg-Glu- <BR> <BR> Ala-Gly-Pro-Glu-Pro-Pro-Pro-Asp-Ala-Gln-Pro-Ser-Pro-Pro-Pro- Ala-Pro- Pro-Ser-Cys-Trp-Gly-Cys-Trp-Pro-Lys-Gly-His-Gly-Glu-Ala-Met- Pro-Leu- His-Arg-Tyr-Gly-Val-Gly-Glu-Ala-Gly-Pro-Gly-Val-Glu-Ala-Gly- Glu-Ala- Ala-Leu-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Ala-Ala-Ala-Ser-Pro-Thr- Ser-Ser- <BR> <BR> Ser-Gly-Ser-Ser-Ser-Arg-Gly-Thr-Glu-Arg-Pro-Arg-Ser-Leu-Lys- Arg-Gly- Ser-Lys-Pro-Ser-Ala-Ser-Ser-Ala-Ser-Leu-Glu-Lys-Arg-Met-Lys- Met-Val- <BR> <BR> Ser-Gln-Ser-Ile-Thr-Gln-Arg-Phe-Arg-Leu-Ser-Arg-Asp-Lys-Lys- Val-Ala-<BR> <BR> Lys-Ser-Leu-Ala-Ile-Ile-Val-Ser-Ile-Phe-Gly-Leu-Cys-Trp-Ala- Pro-Tyr-<BR> <BR> Thr-Leu-Leu-Met-Ile-Ile-Arg-Ala-Ala-Cys-His-Gly-Arg-Cys-Ile- Pro-Asp- Tyr-Trp-Tyr-Glu-Thr-Ser-Phe-Trp-Leu-Leu-Trp-Ala-Asn-Ser-Ala- Val-Asn- <BR> <BR> pro-Val-Leu-Tyr-Pro-Leu-Cys-His-Tyr-Ser-Phe-Arg-Arg-Ala-Phe- Thr-Lys-

Leu-Leu-Cys-Pro-Gln-Lys-Leu-Lys-Val-Gln-Pro-His-Gly-Ser-Leu- Glu-Gln- Cys-Trp-Lys The assay measures the activation of G proteins by catalyzing the exchange of guanosine 5'-diphosphate (GDP) by guanosine 5'-triphosphate (GTP) at the a-subunit. The GTP-bounded G proteins dissociate into two subunits, GAGTP and and Gpy, which in turn regulate intracellular enzymes and ion channels. GTP is rapidly hydrolyse by the Ga-subunit (GTPases) and the G protein is deactivated and ready for a new GTP exchange cycle. To study the function of ligand induced G protein coupled receptor (GPCR) activation by an in- crease in guanine nucleotide exchange at the G proteins, the binding of [35S]-guanosine-5'- 0- (3-thio) triphosphate ([35S] GTPyS), a non-hydrolysed analogue of GTP, is determined.

This process can be monitored in vitro by incubating cell membranes containing the G pro- tein coupled receptor H3 with GDP and [35S] GTPyS. Cell membranes are obtained from CHO cells stably expressing the human H3 receptor or from HEK 293 cells stably expressing the rat or monkey H3 receptor. The cells are washed twice in PBS, harvested with PBS+1 mM EDTA, pH 7.4 and centrifuged at 280 g for 5 min. The cell pellet is homogenized in 10 ml ice-cold Hepes buffer (20 mM Hepes, 10 mM EDTA pH 7.4 (NaOH) ) using an Ultra-Turrax homogenizer for 30 seconds and centrifuged for 15 min at 30.000 g. Following this centrifu- gation step, the membrane pellet is resuspended in 10 ml ice-cold Hepes buffer (20 mM Hepes, 0.1 mM EDTA pH 7.4 (NaOH) ) and homogenized as describe above. This procedure is repeated twice except for the last homogenization step, the protein concentration is deter- mined and membranes are diluted to a protein concentration of 2 mg/ml, aliquote and kept at-80 °C until use.

In order to study the presence and the potency of an inverse agonist/antagonist the H3-receptor agonist ligand R-a-methyl histamine (RAMHA) is added. The ability of the test compound to counteract the effect of RAMHA is measured. When studying the effect of an agonist RAMHA is not added to the assay medium. The test compound is diluted in the as- say buffer (20 mM HEPES, 120 mM NaCI, 10 mM MgCI2 pH 7.4 (NaOH) ) at various concen- trations followed by addition of 1 o-8 nM RAMHA (only in the case where an inverse ago- nist/antagonist is examined), 3 uM GDP, 2. 5 ug membranes, 0.5 mg SPA beads and 0.1 nM [35S] GTPγS and incubated for 2 hours by slightly shaking at room temperature. For the rat and monkey H3 receptor 10 µg membranes including 10 µg/ml saponin are used. The plates are centrifuged at 420 g for 10 min and the radioactivity is measured using a Top-counter.

The results are analyzed by non linear regression and the IC50 value is determined.

RAMHA and other H3 agonists stimulate the binding of [35S] GTPyS to membranes expressing the H3 receptor. In the antagonist/inverse agonist test, the ability of increasing

amounts of test compound to inhibit the increased [35S] GTPyS binding by 10-8 M RAMHA is measured as a decrease in radioactivity signal. The ICSO value determined for an antagonist is the ability of this compound to inhibit the effect of 10-8 M RAMHA by 50%. In the agonist test, the ability of increasing amounts of test compound is measured as an increase in radio- activity signal. The EC50 value determined for an agonist, is the ability of this compound to increase the signal by 50% of the maximal signal that is obtained by 10-5 M RAMHA.

Preferably, the antagonists and agonists according to the invention have an IC50/EC50 value as determined by one or more of the assays of less than 10 uM, more pre- ferred of less than 1 jM, and even more preferred of less than 500 nM, such as of less than 100 nM.

The open cage Schedule-fed rat model Sprague-Dawley (SD) male rats of an age of about 15/2 to 2 months and a weight of about 200-250 g are purchased from Mllegård Breeding and Research Centre A/S (Denmark). On arrival they are allowed some days of acclimatisation before being placed in individual open plastic cages. They are habituated to the presence of food (Altromin pelleted rat chow) in their home cage only during 7 hours in the morning from 07.30 to14. 30 all days a week. Water is present ad libitum. As the consumption of food has sta- bilised after 7 to 9 days, the animals are ready for use.

Each animal is used only once to avoid carry-over effects between treatments.

During the test sessions, the test compound is administered intraperitoneally or orally 30 min before the start of the sessions. One group of animals is administered the test com- pound at different doses and a control group of animals is given a vehicle. Food and wa- ter intake are monitored at 1,2 and 3 hours post administration.

Any side effects may rapidly be discovered (barrel-rolling, bushy fur etc. ) since the animals are kept in transparent plastic cages to enable continuous monitoring.