CN1628109A - Novel Aryl- and Heteroaryl-Piperazines - Google Patents

Abstract

Novel aryl-and heteroaryl-piperazines, the use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising these compounds and methods of treatment employing these compounds and compositions. These compounds exhibit high selective binding affinity for the histamine H3 receptor, indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, these compounds are useful in the treatment of diseases and disorders related to the histamine H3 receptor.

Description

Novel Aryl- and Heteroaryl-Piperazines

field of invention

The present invention relates to novel aryl- and heteroarylpiperazines, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions comprising these compounds, and to methods of treatment employing these compounds and compositions. The compound of the present invention shows high selective binding affinity to histamine H3 receptor, indicating that it has antagonism, inverse agonism or agonism activity on histamine H3 receptor. As a result, these compounds are useful in the treatment of diseases and disorders involving histamine H3 receptors.

Background of the invention

The existence of the histamine H3 receptor has been known for several years and is currently of interest for the development of new drugs. Recently, the human histamine H3 receptor has been cloned. The histamine H3 receptor is a presynaptic autoreceptor located in the central and peripheral nervous systems, skin and organs such as the lungs, intestines, primarily the spleen and the gastrointestinal tract. Recent evidence suggests that H3 receptors display intrinsic constitutive activity, both in vitro and in vivo (ie, active in the absence of agonists). Compounds that act as inverse agonists are able to inhibit this activity. Histamine H3 receptors have been shown to regulate the release of histamine as well as other neurotransmitters such as serotonin and acetylcholine. Histamine H3 receptor antagonists or inverse agonists would thus be expected to increase the release of these neurotransmitters in the brain. In contrast, histamine H3 receptor agonists cause inhibition of histamine biosynthesis and inhibition of release of histamine and other neurotransmitters, such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists may be important mediators of neuronal activity. Therefore, the histamine H3 receptor is an important target for new therapeutic agents.

Compounds similar to the compounds of the present invention have been disclosed before, see J.Med.Chem.1999, 42, 336, J.Med.Chem.1992, 35, 2369, DE 2804096, J.Org.Chem.1996, 61, 3849, Bull. Soc. Chim. Fr. 1969, 319, WO 00/66578, WO 99/21845 and J. Med. Chem. 1968, 11(6), 1144-1150. However, these references neither disclose nor suggest that these compounds may possess histamine H3 receptor antagonistic or agonistic activity.

Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Most of them are imidazole derivatives. However, some imidazole-free ligands for the histamine H3 receptor have been described recently (see for example Linney et al., J. Med. Chem. 2000, 43, 2362-2370; US 6,316,475, WO 01/66534 and WO 01/ 74810). However, these compounds are structurally different from the compounds of the present invention.

Given the interest in the field in histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds that interact with the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides a contribution to the art based on the discovery that a novel class of aryl- and heteroaryl-piperazines possesses high specific affinity for the histamine H3 receptor.

Due to their interaction with histamine H3 receptors, the compounds of the invention are useful in the treatment of a wide variety of conditions and disorders in which interaction with histamine H3 receptors is beneficial. Thus, these compounds can be used, for example, in the treatment of diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and endocrine system.

definition

In the structural formulas given here and throughout the specification, the following terms have the indicated meanings.

The term "halogen" means F, Cl, Br or I.

The term "alkyl" as used herein represents a saturated straight or branched chain hydrocarbon group having the indicated number of carbon atoms. Thus, the terms "C _1-3 -alkyl", "C _1-8 -alkyl" and "C _1-10 -alkyl" as used herein represent saturated linear or branched hydrocarbon radicals, respectively having 1 to 3 carbon atom, 1 to 8 carbon atoms, and 1 to 10 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.

The term "alkenyl" as used herein denotes a straight or branched chain hydrocarbon group having the indicated number of carbon atoms and at least one double bond. Thus, the terms "C _2-8 -alkenyl" and "C _2-10 -alkenyl" as used herein represent straight or branched chain hydrocarbon radicals, respectively having 2 to 8 carbon atoms and 2 to 10 carbon atoms and at least A double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butene Base, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 2-nonenyl, 2-decenyl, etc.

The term "alkynyl" as used herein denotes a straight or branched chain hydrocarbon group having the indicated number of carbon atoms and at least one triple bond. Thus, the term " _C2-8 -alkyl" as used herein denotes a straight or branched chain hydrocarbon radical having 2 to 8 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, 2-heptynyl, 1-octynyl, 2-octynyl and the like.

The term "branched _C4-6 -alkyl" as used herein denotes a saturated branched hydrocarbon radical having 4 to 6 carbon atoms. Typical branched C _4-8 -alkyl groups include, but are not limited to, 1-methylpropyl, tert-butyl, 1-ethylpropyl, 1,1-(dimethyl)propyl, isopentyl, 1 -Ethylbutyl, 1,1-(dimethyl)butyl, 1,1-(dimethyl)pentyl, 1-ethylpentyl, 1,1-(dimethyl)hexyl, 1- Ethylhexyl etc.

The term "branched _C4-6 -alkenyl" as used herein denotes a branched hydrocarbon group having 4 to 6 carbon atoms and at least one double bond. Typical branched C _4-6 -enyl groups include, but are not limited to, 1-ethylprop-2-enyl, 1,1-(dimethyl)prop-2-enyl, 1-ethylbut-3- Alkenyl, 1,1-(dimethyl)but-2-enyl, 1,1-(dimethyl)pent-3-enyl, 1-ethylpent-2-enyl, 1,1- (Dimethyl)pent-3-enyl, 1,1-(dimethyl)hex-3-enyl, 1-ethylhex-4-enyl and the like.

The term "branched _C4-6 -alkynyl" as used herein denotes a branched hydrocarbon group having 4 to 6 carbon atoms and at least one triple bond. Typical branched C _4-6 -alkynyl groups include, but are not limited to, 1-ethylprop-2-ynyl, 1,1-(dimethyl)prop-2-ynyl, 1-ethylbut-3- Alkynyl, 1,1-(dimethyl)but-2-ynyl, 1,1-(dimethyl)pent-3-ynyl, 1-ethylpent-2-ynyl, 1,1- (Dimethyl)pent-3-ynyl, 1,1-(dimethyl)hex-3-ynyl, 1-ethylhex-4-ynyl and the like.

The term "C _1-6 -alkoxy" as used herein denotes the radical -OC _1-6 -alkyl, wherein C _1-6 -alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyl Oxygen etc.

The term "C _2-10 -alkanoyl" as used herein denotes the radical -C(=O)C _1-9 -alkyl, wherein C _1-9 -alkyl represents a saturated straight-chain or branched hydrocarbon radical having 1 to 9 carbon atoms. Representative examples are acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, and the like.

The term "C _1-6 -alkylamino" as used herein denotes the radical -NH-C _1-6 -alkyl, wherein C _1-6 -alkyl is as defined above. Representative examples are methylamino, ethylamino, isopropylamino, n-propylamino, butylamino, pentylamino, hexylamino, and the like.

The term "di-C _1-6 -alkylamino" as used herein denotes the radical -N(C _1-6 -alkyl) ₂ , wherein C _1-6 -alkyl is as defined above. It should be understood that the C _1-6 -alkyl groups may be the same or different. Representative examples are dimethylamino, methylethylamino, diethylamino, diisopropylamino, di-n-propylamino, dibutylamino, dipentylamino, dihexylamino, and the like.

The term "C _3-5 -cycloalkyl" as used herein represents a monocyclic carbocyclic group having 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl and the like.

In the same manner, the terms "C _3-6 -cycloalkyl" and "C _3-8 -cycloalkyl" as used herein represent monocyclic carbocyclic groups having 3 to 6 carbon atoms and 3 to 8 carbon atoms.

The term "C _3-7 -cycloalkenyl" as used herein denotes a monocyclic carbocyclic non-aromatic group having 3 to 7 carbon atoms and at least one double bond. Representative examples are cyclopropenyl, cyclobutenyl, cyclopentenyl, and the like.

In the same way, the term "C _3-6 -cycloalkenyl" as used herein denotes a monocyclic carbocyclic non-aromatic radical having 3 to 6 carbon atoms and at least one double bond.

The term "C _3-6 -cycloalkyl-C _1-3 -alkyl" as used herein denotes the radical -C _1-3 -alkyl-C _3-6 -cycloalkyl, wherein C _3-6 -cycloalkane Radical and C _1-3 -alkyl are as defined above.

The term "C _3-6 -cycloalkenyl-C _1-3 -alkyl" as used herein denotes the radical -C _1-3 -alkyl-C _3-6 -cycloalkenyl, wherein C _3-6 -cycloalkenyl Radical and C _1-3 -alkyl are as defined above.

The term "C _3-8 -cycloalkoxy" as used herein denotes the radical -OC _3-8 -cycloalkyl, wherein C _3-8 -cycloalkyl is as defined above. Representative examples are cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.

The term "C _4-9 -cycloalkanoyl" as used herein denotes the radical -C(=O)-C _3-8 -cycloalkyl, wherein C _3-8 -cycloalkyl is as defined above. Representative examples are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl and the like.

The term "C _1-6 -alkylsulfonyl" as used herein denotes the radical -S(=O) ₂ -C _1-6 -alkyl, wherein C _1-6 -alkyl is as defined above. Representative examples are methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl, butylsulfonyl, pentylsulfonyl, and the like.

The term "C _1-6 -alkylthio" as used herein denotes the radical -SC _1-6 -alkyl, wherein C _1-6 -alkyl is as defined above. Representative examples are methylthio, ethylthio, isopropylthio, n-propylthio, butylthio, pentylthio, and the like.

The term " _C3-8 -heterocyclyl" as used herein denotes a saturated 3 to 8 membered monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Representative examples are aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, and the like.

The term "C _4-9 -heterocycloalkanoyl" as used herein denotes the radical -C(=O)-C _3-8 -heterocyclyl, wherein C _3-8 -heterocyclyl is as defined above. Representative examples include aziridinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl and the like.

As used herein, the term "aryl" is intended to include carbocyclic aromatic ring systems such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like . Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and the like.

The term "aryloxy" as used herein denotes the radical -O-aryl, wherein aryl is as defined above. Non-limiting examples are phenoxy, naphthyloxy, anthracenyloxy, phenanthryloxy, fluorenyloxy, indenyloxy, and the like.

The term "aroyl" as used herein denotes the radical -C(=O)-aryl, wherein aryl is as defined above. Non-limiting examples are benzoyl, naphthoyl, anthracenylcarbonyl, phenanthrenylcarbonyl, fluorenylcarbonyl, indenylcarbonyl, and the like.

The term "arylamino" as used herein denotes the radical -NH-aryl, wherein aryl is as defined above. Non-limiting examples are phenylamino, naphthylamino, anthracenylamino, phenanthrenylamino, fluorenylamino, indenylamino, 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, for example 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-oxadi Azolyl, 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, indazolyl , Benzimidazolyl, Benzthiazolyl, Benzisothiazolyl, Benzoxazolyl, Benzisoxazolyl, Purinyl, Quinazolinyl, Quinazinyl, Quinolinyl, Isoquinolyl , quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc. Heteroaryl is also intended to include partially hydrogenated derivatives of the heterocyclic ring systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indenyl, indolinyl, oxazolidinyl, oxazole Linyl, oxazepinyl, etc.

The term "heteroaryloxy" as used herein denotes the radical -O-heteroaryl, wherein heteroaryl is as defined above.

The term "heteroaroyl" as used herein denotes the radical -C(=O)-heteroaryl, wherein heteroaryl is as defined above.

The term "heteroarylamino" as used herein denotes the radical -NH-heteroaryl, wherein heteroaryl is as defined above.

Some of the above defined terms may appear more than once in a formula, in which case each term should be defined independently of the other.

"Aryl-C _1-6 -alkyl", "aryl-C _1-6 -alkoxy" etc. represent C _1-6 -alkyl or C _1-6 -alkoxy as defined above, represented by Aryl substitution as defined above, for example:

The term "optionally substituted" as used herein means that the group in question is unsubstituted or substituted with one or more of the specified substituents. When the group concerned is substituted by more than one substituent, the substituents may be the same or different.

The term "treatment" as used herein means the management and care of a patient with the purpose of combating the disease, disorder or condition. The term is intended to include delay in progression of the disease, disorder or condition, alleviation or alleviation of symptoms and complications, and/or cure or elimination of the disease, disorder or condition. The patient to be treated is preferably a mammal, especially a human.

Description of the invention

The present invention relates to compounds of general formula (I):

in

(i) R ¹ represents

branched C _4-8 -alkyl, branched C _4-8 -alkenyl or branched C _4-8 -alkynyl, which may optionally be substituted by one or more halogen substituents,

C _3-5 -cycloalkyl, C _3-7 -cycloalkenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl or C _3-6 -cycloalkenyl-C _1-3 - Alkyl groups, which may optionally be substituted at any position by one or more halogen substituents,

A stands for

或

or

or

(ii) ^R represents ethyl, n-propyl or isopropyl, and

A stands for

Z and X independently represent -N=, -CH=, -CF= or -C(CF ₃ )=,

W represents -N= or -CR ³ =,

Y represents -N= or -CR ⁴ =,

R ^2a , R ^2b , R ³ and R ⁴ independently represent

Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy radical, aryl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkoxy, cyano, nitro , C _1-6 -alkylthio, C _1-6 -alkylsulfonyl or -C(=O)NR ^4a R ^4b , wherein R ^4a and R ^4b are independently hydrogen, C _1-6 -alkyl or Aryl-C _1-6 -alkyl,

· C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -heterocyclyl or C _4-9 -heterocycloalkanoyl, which may optionally be replaced at any position by one or more Substituent substitution, the substituent is selected from aryl, heteroaryl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and C _1-6 -alkoxy, aryl, aryl -C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl,

They may be optionally substituted with one or more substituents selected from halogen, hydroxyl,

Trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, C _1-6 -alkyl, amino, C _1-6 -alkylammonia

radical, di-C _1-6 -alkylamino, cyano, aryl, heteroaryl and C _3-8 -cycloalkyl,

Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted by one or more substituents selected from aryl, heteroaryl , C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, cyano, amino, C _1-6 - Alkylamino, di-C _1-6 -alkylamino and hydroxy,

or two of R ^2a , R ^2b , R ³ and R ⁴ in adjacent positions together form a C _1-6 -alkylene bridge,

The proviso is that the compound must not be

or

and any diastereomer or enantiomer or tautomeric forms thereof, including mixtures thereof, or pharmaceutically acceptable salts thereof.

In one embodiment, R ¹ is branched C _4-8 -alkyl, C _3-5 -cycloalkyl or C _3-6 -cycloalkyl-C _1-3 -alkyl, which may be optionally substituted with one or more halogen substituents.

In another embodiment, R ¹ is branched C _4-8 -alkyl, C _3-5 -cycloalkyl or C _3-6 -cycloalkyl-C _1-3 -alkyl.

In another embodiment, ^R is 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1- Cyclopropyl-1-methylethyl.

In another embodiment, R ¹ is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.

In another embodiment, R ¹ is branched C _4-8 -alkyl or C _3-5 -cycloalkyl, which may be optionally substituted by one or more halogen substituents.

In another embodiment, R ¹ is branched C _4-8 -alkyl or C _3-5 -cycloalkyl.

In another embodiment, R ¹ is 1-ethylpropyl, cyclopropyl or cyclopentyl.

In another embodiment, R ¹ is isopropyl.

In another embodiment, A is

or

Wherein R ^2a , R ^2b , R ³ and R ⁴ are as defined in formula (I).

In another embodiment, A is

Wherein R ^2a , R ³ and R ⁴ are as defined in formula (I).

In another embodiment, A is

Wherein R ^2a , R ³ and R ⁴ are as defined in formula (I).

In another embodiment, A is

Wherein R ^2a , R ^2b , R ³ and R ⁴ are as defined in formula (I).

In another embodiment, R ^2a , R ^2b , R ³ and R ⁴ are independently selected from

hydrogen, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, _C2-10 -alkanoyl, _C4-9 -cycloalkanoyl or _C4-9 -heterocycloalkanoyl, or

aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or aroyl,

They may optionally be substituted as defined in formula (I).

In another embodiment, R ^2a , R ^2b , R ³ and R ⁴ are independently selected from

hydrogen, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl or C _4-9 -heterocycloalkanoyl,

· Phenyl-C _1-6 -alkyl, phenyl-C _1-6 -alkoxy or benzoyl, which may optionally be substituted by one or two substituents selected from halogen and C _{1 -6} -alkoxy.

In another embodiment, ^R2a , ^R2b and ^R4 are hydrogen and ^R3 is not hydrogen.

In another embodiment, ^R3 is halo, trifluoromethyl or trifluoromethoxy.

In another embodiment, the present invention relates to compounds of general formula (I ₁ ):

Wherein A is as defined in formula (I) or any one of the above-mentioned embodiments.

In another embodiment, the present invention relates to compounds of general formula (I ₂ ):

Wherein A is as defined in formula (I) or any one of the above-mentioned embodiments.

In another embodiment, the present invention relates to compounds of general formula (I ₃ ):

where ^R1 is

branched C _4-8 -alkyl, branched C _4-8 -alkenyl or branched C _4-8 -alkynyl, which may optionally be substituted by one or more halogen substituents,

C _3-5 -cycloalkyl, C _3-7 -cycloalkenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl or C _3-6 -cycloalkenyl-C _1-3 - Alkyl groups, which may optionally be substituted at any position by one or more halogen substituents,

Ethyl, n-propyl or isopropyl,

R ^2a , R ^2b , R ³ and R ⁴ are as defined in formula (I).

In another embodiment, the present invention relates to compounds selected from the group consisting of:

4-(4-cyclopentylpiperazin-1-yl)phenol,

1-cyclopentyl-4-[4-(4-fluorobenzyloxy)phenyl]piperazine,

1-(3-Chlorophenyl)-4-cyclopentylpiperazine,

1-[4-(4-cyclopentylpiperazin-1-yl)phenyl]ethanone,

1-(3,4-dichlorophenyl)-4-(1-ethylpropyl)piperazine,

{4-[4-(1-Ethylpropyl)piperazin-1-yl]phenyl}phenylmethanone,

1-(4-benzylphenyl)-4-(1-ethylpropyl)piperazine,

Cyclopropyl-{4-[4-(1-ethylpropyl)piperazin-1-yl]phenyl}methanone,

(2-Chlorophenyl)-{4-[4-(1-ethylpropyl)piperazin-1-yl]phenyl}methanone,

{4-[4-(1-ethylpropyl)piperazin-1-yl]phenyl}-(4-fluorophenyl)methanone,

1-cyclopentyl-4-(6-trifluoromethylpyridin-2-yl)piperazine,

1-cyclopentyl-4-(5-trifluoromethylpyridin-2-yl)piperazine,

1-cyclopentyl-4-(3-trifluoromethylpyridin-2-yl)piperazine,

2-[4-(1-ethylpropyl)piperazin-1-yl]quinoline,

7-chloro-4-[4-(1-ethylpropyl)piperazin-1-yl]quinoline,

[4-(4-cyclopentylpiperazin-1-yl)phenyl]-(3,4-dimethoxyphenyl)methanone,

[4-(4-cyclopentylpiperazin-1-yl)-3,5-difluorophenyl]phenylmethanone,

2-(4-cyclopentylpiperazin-1-yl)quinoxaline,

2-(4-cyclopropylmethylpiperazin-1-yl)quinoxaline,

[6-(4-cyclopentylpiperazin-1-yl)pyridin-3-yl]piperidin-1-ylmethanone,

2-(4-cyclopentylpiperazin-1-yl)quinoline,

2-(4-cyclopentylpiperazin-1-yl)-7-methoxy-3-(4-methoxyphenyl)quinoline,

{6-[4-(1-cyclopropyl-1-methylethyl)piperazin-1-yl]pyridin-3-yl}phenylmethanone,

{4-[4-(1-cyclopropyl-1-methylethyl)piperazin-1-yl]-3,5-difluorophenyl}phenylmethanone,

{4-[4-(1-cyclopropyl-1-methylethyl)piperazin-1-yl]-3,5-difluorophenyl}phenylcarbinol,

[4-(4-cyclopropylmethylpiperazin-1-yl)-3,5-difluorophenyl]-(4-fluorophenyl)methanone,

{4-[4-(1-ethylpropyl)piperazin-1-yl]-3,5-difluorophenyl}-(4-fluorophenyl)methanone,

2-[4-(1-ethylpropyl)piperazin-1-yl]-6,7-dimethoxyquinoline,

2-[4-(1-ethylpropyl)piperazin-1-yl]-4-trifluoromethylquinoline,

2-(4-cyclopropylmethylpiperazin-1-yl)-6-methoxy-4-trifluoromethylquinoline,

[4-(4-Cyclopropylmethylpiperazin-1-yl)-3,5-difluorophenyl]phenylphenone,

[4-(4-cyclopropylmethylpiperazin-1-yl)-3,5-difluorophenyl]-(3-fluoro-4-methoxyphenyl)-methanone,

{6-[4-(1-Ethylpropyl)piperazin-1-yl]pyridin-3-yl}phenylmethanone,

{2-[4-(1-Ethylpropyl)piperazin-1-yl]pyridin-4-yl}phenylmethanone,

{4-[4-(1-ethylpropyl)piperazin-1-yl]phenyl}-(4-hydroxyphenyl)methanone,

{6-[4-(1-Ethylpropyl)piperazin-1-yl]pyridin-3-yl}piperidin-1-yl-methanone,

N-Benzyl-6-[4-(1-ethylpropyl)piperazin-1-yl]-N-methylnicotinamide,

2-[4-(1-ethylpropyl)piperazin-1-yl]-6-methoxyquinoline,

6-[4-(1-Ethylpropyl)piperazin-1-yl]-N-methyl-N-phenylnicotinamide,

{6-[4-(1-ethylpropyl)piperazin-1-yl]pyridin-3-yl}-(4-fluorophenyl)methanone,

2-[4-(1-ethylpropyl)piperazin-1-yl]-4-methylquinoline,

2-[4-(1-ethylpropyl)piperazin-1-yl]-5,6,7,8-tetrahydroquinoline,

2-(4-cyclopropylmethylpiperazin-1-yl)-6-methoxyquinoline,

2-(4-isopropylpiperazin-1-yl)-6-methoxyquinoline,

2-[4-(1-ethylpropyl)piperazin-1-yl]-6-fluoro-4-methylquinoline,

2-(4-cyclopropylpiperazin-1-yl)-6-trifluoromethylquinoline,

2-(4-cyclopropylpiperazin-1-yl)-6-propylquinoline,

2-(4-Ethylpiperazin-1-yl)quinoline, and any diastereomer or enantiomer or tautomeric form thereof, including mixtures thereof, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to compounds of general formula (I"):

in

R ¹ stands for

branched C _4-8 -alkyl, branched C _4-8 -alkenyl or branched C _4-8 -alkynyl, which may optionally be substituted by one or more halogen substituents,

C _3-5 -cycloalkyl, C _3-7 -cycloalkenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl or C _3-6 -cycloalkenyl-C _1-3 - Alkyl groups, which may optionally be substituted by one or more halogen substituents,

A stands for

或

or

Z and X independently represent -N=, -CH=, -CF= or -C(CF ₃ )=,

W represents -N= or -CR ³ =,

Y represents -N= or -CR ⁴ =,

R ² , R ³ and R ⁴ independently represent

Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy radical, aryl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkoxy or cyano, or

C _2-10 -alkanoyl or C _4-9 -cycloalkanoyl,

They may be optionally substituted with one or more substituents selected from aryl, heteroaryl

radical, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and C _1-6 -alkoxy, aryl, aryl-C _1-6 -alkyl, aryl- C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, cyano, aryl, heteroaryl and C _3-8 - Cycloalkyl, or

Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted by one or more substituents selected from aryl, heteroaryl , C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, cyano, amino, C _1-6 - Alkylamino, di-C _1-6 -alkylamino and hydroxy,

The condition is that the compound must not be

或

or

and any diastereomer or enantiomer or tautomeric forms thereof, including mixtures thereof, or pharmaceutically acceptable salts thereof.

In one embodiment, R ¹ is branched C _4-8 -alkyl, C _3-5 -cycloalkyl or C _3-6 -cycloalkyl-C _1-3 -alkyl, which may be optionally substituted with one or more halogen substituents.

In another embodiment, R ¹ is branched C _4-8 -alkyl, C _3-5 -cycloalkyl or C _3-6 -cycloalkyl-C _1-3 -alkyl, for example 1, 1-(Dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl or cyclopentyl, e.g. 1-ethylpropyl, cyclopropylmethyl or cyclo Amyl.

In another embodiment, R ¹ is branched C _4-8 -alkyl or C _3-5 -cycloalkyl, which may optionally be substituted by one or more halogen substituents, such as branched C _{4 -8} -Alkyl or _C3-5 -cycloalkyl, eg 1-ethylpropyl or cyclopentyl.

In a further embodiment, A is

or

wherein R ² , R ³ and R ⁴ are as defined in formula (I").

In another embodiment, A is

wherein R ² , R ³ and R ⁴ are as defined in formula (I").

In a further embodiment, A is

wherein R ² , R ³ and R ⁴ are as defined in formula (I").

In one embodiment, R ² , R ³ and R ⁴ are independently selected from

hydrogen, hydroxy, halogen, trifluoromethyl, C _2-10 -alkanoyl or C _4-9 -cycloalkanoyl, or

• Aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or aroyl, which may optionally be substituted as defined for formula (I").

In another embodiment, R ² , R ³ and R ⁴ are independently selected from

Hydrogen, hydroxy, halogen, trifluoromethyl, C _2-10 -alkanoyl or C _4-9 -cycloalkanoyl,

· Phenyl-C _1-6 -alkyl, phenyl-C _1-6 -alkoxy or benzoyl, which may optionally be substituted by one or two substituents selected from halogen and C _{1 -6} -alkoxy.

In another embodiment, ^R2 and ^R4 are both hydrogen, and ^R3 is not hydrogen.

In another embodiment, the present invention relates to compounds of general formula (I ₁ ):

Wherein A is as defined in formula (I") or any one of the above-mentioned embodiments.

In another embodiment, the present invention relates to compounds of general formula (I ₂ ):

Wherein A is as defined in formula (I") or any one of the above-mentioned embodiments.

Therefore, the present invention relates in another aspect to a compound of general formula (I) and any diastereomer or enantiomer or tautomeric form thereof, including mixtures thereof, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical composition .

The present invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) or any diastereomer or enantiomer or tautomeric form thereof, including mixtures thereof or pharmaceutically acceptable salts thereof, as an active ingredient, and One or more pharmaceutically acceptable carriers or diluents.

In addition, the present invention relates to compounds of general formula (I')

in

R ¹ stands for

· C _1-8 -alkyl, C _2-8 -alkenyl or C _2-8 -alkynyl, which may optionally be substituted by one or more halogen substituents,

C _3-5 -cycloalkyl, C _3-7 -cycloalkenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl or C _3-6 -cycloalkenyl-C _1-3 - Alkyl groups, which may optionally be substituted by one or more halogen substituents,

A stands for

或

or

Z and X independently represent -N=, -CH=, -CF= or -C(CF ₃ )=,

W represents -N= or -CR ³ =,

Y represents -N= or -CR ⁴ =,

R ^2a , R ^2b , R ³ and R ⁴ independently represent

Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy radical, aryl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-a -cycloalkoxy, cyano, nitro , C _1-6 -alkylthio, C _1-6 -alkylsulfonyl or -C(=O)NR ^4a R ^4b , wherein R ^4a and R ^4b are independently hydrogen, C _1-6 -alkyl or Aryl-C _1-6 -alkyl, or

· C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -heterocyclyl or C _4-9 -heterocycloalkanoyl, which may optionally be replaced at any position by one or more Substituent substitution, the substituent is selected from aryl, heteroaryl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and C _1-6 -alkoxy, aryl, aryl -C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from halogen, hydroxyl, trifluoro Methyl, trifluoromethoxy, C _1-6 -alkoxy, C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, cyano , aryl, heteroaryl and C _3-8 -cycloalkyl, or

Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted by one or more substituents selected from aryl, heteroaryl , C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, cyano, amino, C _1-6 - Alkylamino, di-C _1-6 -alkylamino and hydroxy,

or two of R ^2a , R ^2b , R ³ and R ⁴ in adjacent positions together form a C _1-6 -alkylene bridge, and any diastereomer or enantiomer or tautomeric form thereof, including them Use of the mixture of or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating disorders and diseases involving histamine H3 receptors.

In another aspect, the present invention provides compounds of general formula (II):

in

R ² is hydrogen or C _1-4 -alkyl,

(i) R ¹ represents

branched _C4-6 -alkyl, branched _C4-6 -alkenyl or branched _C4-6 -alkynyl, with the proviso that ^R1 is not isobutyl,

C _3-5 -cycloalkyl, C _3-7 -cycloalkenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl or C _3-6 -cycloalkenyl-C _1-3 - alkyl,

R ¹ and R ² together form a C _3-6 -alkylene bridge, and

A stands for

或

or

or

(ii) R ¹ stands for

Ethyl, n-propyl or isopropyl,

R ¹ and R ² together form a C _3-6 -alkylene bridge, and

A stands for

or

R ³ is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, C _1-6 - Alkoxy, aryl, aryl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkyl, C _3-8 -cycloalkoxy, cyano, nitro, C _1-6 -alkylthio or C _1-6 -alkylsulfonyl,

Z and X independently represent -N=, -C(H)=, -C(F)=, -C(Cl)=, -C(CN)= or -C(CF ₃ )=,

W represents -N= or -C(R ¹⁰ )=,

Y represents -N= or -C(R ¹¹ )=,

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent

hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF ₃ , amino, cyano, nitro or -C(=O)NR ¹⁴ R ¹⁵ ,

C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, _C 1-6 -alkoxy, C _3-8 -cycloalkyl-C _1-6 -alk Oxygen, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkoxy, C _1-6 -alkylthio, C _1-6 -alkylsulfonyl Acyl, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -heterocyclyl or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy, which may be optionally substituted by one or more substituents selected from R ¹⁶ ,

aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from R ¹⁷ ,

Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted by one or more substituents selected from ^R ,

· Or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene bridge or -OC _{1 -6} -alkylene-O-bridge,

R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 -alkyl, aryl-C _1-6 -alkyl, or R ¹⁴ and R ¹⁵ can together form a C _3-6 -alkylene bridge,

R ¹⁶ is independently selected from aryl, heteroaryl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR ¹⁹ R ²⁰ and C _1-6 -alkoxy,

R ¹⁷ is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, C _1-6 -alkyl, amino, C _1-6 -alkylsulfonyl, C _1-6 -alkylamino, di-C _1-6 -alkylamino, cyano, aryl, heteroaryl and C _3-8 -cycloalkyl,

R ¹⁸ is independently selected from aryl, heteroaryl, C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy radical, cyano, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino and hydroxyl,

R ¹⁹ and R ²⁰ are independently hydrogen or C _1-6 -alkyl, R ¹⁹ and R ²⁰ may together form a C _3-6 -alkylene bridge,

The proviso is that the compound must not be

or

and any diastereomer or enantiomer or tautomeric forms thereof, including mixtures thereof, or pharmaceutically acceptable salts thereof.

In another aspect of the invention R ¹ is branched C _4-6 -alkyl, C _3-5 -cycloalkyl or C _3-6 -cycloalkyl-C _1-3 -alkyl with the proviso R ¹ is not isobutyl.

In another aspect of the invention, R is ^1,1- (dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1- Cyclopropyl-1-methylethyl.

In another aspect of the invention, R ¹ is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.

In another aspect of the invention R ¹ is branched C _4-6 -alkyl or C _3-5 -cycloalkyl with the proviso that R ¹ is not isobutyl.

In another aspect of the invention, R ¹ is 1-ethylpropyl, cyclopropyl or cyclopentyl.

In another aspect of the invention, Z is -C(H)=, -N= or -C(F)=.

In another aspect of the invention, Z is -C(H)= or -N=.

In another aspect of the invention, Z is -C(H)=.

In another aspect of the invention, Z is -N=.

In another aspect of the invention, X is -C(H)=, -N= or -C(F)=.

In another aspect of the invention, Z is -C(H)= or -N=.

In another aspect of the invention, Z is -C(H)=.

In another aspect of the invention, Z is -N=.

In another aspect of the invention, W is -N=.

In another aspect of the invention, W is -C(R ¹⁰ )=.

In another aspect of the invention, Y is -N=.

In another aspect of the invention, Y is -C(R ¹¹ )=.

In another aspect of the invention, ^R2 is hydrogen.

In another aspect of the invention, R ² is C _1-4 -alkyl.

In another aspect of the invention, R ² is methyl or ethyl.

The present invention provides the compound of general formula (III) in another aspect

Wherein A and R ³ are as defined for the compound of general formula (II).

In another aspect of the invention, R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _1-6 -alkoxy, aryl, aryl -C _1-6 -Alkyl, amino, C _3-8 -cycloalkyl, C _3-8 -cycloalkoxy, cyano or nitro.

In another aspect of the invention, ^R3 is hydrogen, halogen, hydroxy, trifluoromethyl, _C1-10 -alkyl, _C1-6 -alkoxy, cyano or nitro.

In another aspect of the invention, ^R3 is hydrogen, halogen, hydroxy, trifluoromethyl, _C1-6 -alkyl or cyano.

In another aspect of the invention, ^R3 is hydrogen, halogen or _C1-6 -alkyl.

In another aspect of the invention, ^R3 is hydrogen or methyl.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent

Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF ₃ , amino or cyano,

C _1-10 -alkyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy, C _3-8 -cycloalkoxy, C _2-10 -alkanoyl, C _4-9 - cycloalkanoyl, C _3-8 -heterocyclyl or C _4-9 -heterocycloalkanoyl, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from R ¹⁷ ,

Aroyl, heteroaroyl, aryloxy, heteroaryloxy, which may optionally be substituted by one or more substituents selected from ^R ,

· Or two adjacent positions of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ together form a C _1-6 -alkylene bridge or -OC _1-6 -alkylene-O- bridge.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent

hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, _-SCF or cyano,

C _1-10 -alkyl, C _1-6 -alkoxy, C _3-8 -cycloalkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

· aryl or aryl-C _1-6 -alkyl, which may optionally be substituted by one or more substituents selected from R ¹⁷ ,

Aroyl or aryloxy, which may optionally be substituted by one or more substituents selected from R ¹⁸ , or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ at adjacent positions together Constitutes a C _1-6 -alkylene bridge or -OC _1-6 -alkylene-O- bridge.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent

Hydrogen, halogen or cyano,

C _1-10 -alkyl or C _1-6 -alkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

Aryl, optionally substituted by one or more substituents selected from R ¹⁷ ,

Aroyl or aryloxy, which may optionally be substituted by one or more substituents selected from R ¹⁸ , or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ at adjacent positions together Constitutes a C _1-6 -alkylene bridge or -OC _1-6 -alkylene-O- bridge.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent

Hydrogen, halogen or cyano,

Methyl, ethyl, propyl, isopropyl or C _1-6 -alkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

Aryl, optionally substituted by one or more substituents selected from R ¹⁷ ,

Aroyl or aryloxy, which may optionally be substituted by one or more substituents selected from R ¹⁸ , or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ at adjacent positions together Constitutes a C _1-6 -alkylene bridge or -OC _1-6 -alkylene-O- bridge.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent

Hydrogen, halogen or cyano,

C _1-10 -alkyl, methoxy, ethoxy or propoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

Aryl, optionally substituted by one or more substituents selected from R ¹⁷ ,

Aroyl or aryloxy, which may optionally be substituted by one or more substituents selected from R ¹⁸ , or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ at adjacent positions together Constitutes a C _1-6 -alkylene bridge or -OC _1-6 -alkylene-O- bridge.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent

Hydrogen, halogen or cyano,

C _1-10 -alkyl or methoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

Aryl, optionally substituted by one or more substituents selected from R ¹⁷ ,

Aroyl or aryloxy, which may optionally be substituted by one or more substituents selected from R ¹⁸ , or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ at adjacent positions together Constitutes a C _1-6 -alkylene bridge or -OC _1-6 -alkylene-O- bridge.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent

Hydrogen, halogen or cyano,

C _1-10 -alkyl or C _1-6 -alkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

phenyl, optionally substituted by one or more substituents selected from R ¹⁷ ,

Aroyl or aryloxy, which may optionally be substituted by one or more substituents selected from R ¹⁸ , or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ at adjacent positions together Constitutes a C _1-6 -alkylene bridge or -OC _1-6 -alkylene-O- bridge.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent

Hydrogen, halogen or cyano,

C _1-10 -alkyl or C _1-6 -alkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

Aryl, optionally substituted by one or more substituents selected from R ¹⁷ ,

-C(=O)-phenyl or aryloxy, which may be optionally substituted by one or more substituents selected from R ¹⁸ , or among R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ Two of adjacent positions together form a C _1-6 -alkylene bridge or -OC _1-6 -alkylene-O- bridge.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent

Hydrogen, halogen or cyano,

C _1-10 -alkyl or C _1-6 -alkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

Aryl, optionally substituted by one or more substituents selected from R ¹⁷ ,

Aroyl or -O-phenyl, which can be optionally substituted by one or more substituents selected from R ¹⁸ , or two adjacent positions of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ together form a C _1-6 -alkylene bridge or -OC _1-6 -alkylene-O- bridge.

In another aspect of the invention, R ¹ is ethyl or isopropyl.

In another aspect of the invention, R ¹ is isopropyl.

In another aspect of the invention, R ¹ is ethyl.

In another aspect of the invention, R ¹ and R ² together form a C _3-4 -alkylene bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent

hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano or -C(=O)NR ¹⁴ R ¹⁵ ,

C _1-10 -alkyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -hetero Cyclic or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from R ¹⁷ ,

Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ ,

• Or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent

hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano or -C(=O)NR ¹⁴ R ¹⁵ ,

C _1-10 -alkyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -hetero Cyclic or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from R ¹⁷ ,

Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ , or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene group bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent

Hydrogen, halogen, trifluoromethyl or -C(=O)NR ¹⁴ R ¹⁵ ,

C _1-10 -alkyl, C _1-6 -alkoxy, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _4-9 -heterocycloalkanoyl or C _4-9 - Heterocycloalkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

aryl, aryl-C _1-6 -alkyl or aryl-C _1-6 -alkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁷ ,

Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ , or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene group bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent

Hydrogen, halogen, trifluoromethyl or -C(=O)NR ¹⁴ R ¹⁵ ,

· C _1-10 -alkyl or C _4-9 -heterocycloalkanoyl, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

Aryl, optionally substituted by one or more substituents selected from R ¹⁷ ,

Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ , or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene group bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent

Hydrogen, halogen, trifluoromethyl or -C(=O)NR ¹⁴ R ¹⁵ ,

Methyl, ethyl, propyl or C _4-9 -heterocycloalkanoyl, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

Aryl, optionally substituted by one or more substituents selected from R ¹⁷ ,

Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ , or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene group bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent

Hydrogen, halogen, trifluoromethyl or -C(=O)NR ¹⁴ R ¹⁵ ,

C _1-10 -alkyl, piperidine-alkanoyl or pyrrolidine-alkanoyl, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

Aryl, optionally substituted by one or more substituents selected from R ¹⁷ ,

Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ , or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene group bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent

Hydrogen, halogen, trifluoromethyl or -C(=O)NR ¹⁴ R ¹⁵ ,

· C _1-10 -alkyl or C _4-9 -heterocycloalkanoyl, which may optionally be substituted by one or more substituents selected from R ¹⁶ ,

phenyl, optionally substituted by one or more substituents selected from R ¹⁷ ,

Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ , or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene group bridge.

In another aspect of the invention, R ¹⁴ and R ¹⁵ are independently methyl, ethyl or benzyl.

In another aspect of the invention, R ¹⁶ is halogen, trifluoromethyl, trifluoromethoxy and C _1-6 -alkoxy.

In another aspect of the invention, R ¹⁷ is halogen, hydroxy, trifluoromethyl, C _1-6 -alkoxy, C _1-6 -alkyl, C _1-6 -alkylsulfonyl or cyano.

In another aspect of the invention, R ¹⁷ is halogen, trifluoromethyl, C _1-6 -alkoxy or C _1-6 -alkylsulfonyl.

In another aspect of the invention, R ¹⁸ is C _1-10 -alkyl, halogen, trifluoromethyl, C _1-6 -alkoxy, cyano, amino and hydroxy.

In another aspect of the invention, R ¹⁸ is halogen, C _1-6 -alkoxy and hydroxy.

In another aspect the invention provides the use of a compound according to formula (II) or (III) as a pharmaceutical composition. In another aspect of the present invention, the pharmaceutical composition may comprise at least one compound according to formula (II) or (III) as active ingredient, together with one or more pharmaceutically acceptable carriers or excipients. In another aspect the present invention provides such a pharmaceutical composition in unit dosage form, comprising about 0.05 mg to about 1000 mg, preferably about 0.1 mg to about 500 mg, especially preferably about 0.5 mg to about 200 mg of the compound according to formula (II) or (III). )compound of.

The present invention provides general formula (II ') compound on the other hand

in

R ² is hydrogen or C _1-4 -alkyl,

R ¹ stands for

· C _1-8 -alkyl, C _2-8 -alkenyl or C _2-8 -alkynyl, which may optionally be substituted by one or more halogen substituents,

C _3-5 -cycloalkyl, C _3-7 -cycloalkenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl or C _3-6 -cycloalkenyl-C _1-3 - Alkyl groups, which may optionally be substituted by one or more halogen substituents,

R ¹ and R ² together form a C _3-6 -alkylene bridge,

A stands for

或

or

R ³ is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, C _1-6 - Alkoxy, aryl, aryl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkyl, C _3-8 -cycloalkoxy, cyano, nitro, C _1-6 -alkylthio or C _1-6 -alkylsulfonyl,

Z and X independently represent -N=, -C(H)=, -C(F)=, -C(Cl)=, -C(CN)= or -C(CF ₃ )=,

W represents -N= or -C(R ¹⁰ )=,

Y represents -N= or -C(R ¹¹ )=,

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent

hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF ₃ , amino, cyano, nitro or -C(=O)NR ¹⁴ R ¹⁵ ,

C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, _C 1-6 -alkoxy, C _3-8 -cycloalkyl-C _1-6 -alk Oxygen, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkoxy, C _1-6 -alkylthio, C _1-6 -alkylsulfonyl Acyl, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -heterocyclyl or C _4-9 -heterocycloalkanoyl or C _4-9 -heterocycloalkoxy, which may be optionally substituted by one or more substituents selected from R ¹⁶ ,

aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from R ¹⁷ ,

Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted by one or more substituents selected from ^R ,

· Or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene bridge or -OC _{1 -6} -alkylene-O-bridge,

R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 -alkyl, aryl-C _1-6 -alkyl, or R ¹⁴ and R ¹⁵ can together form a C _3-6 -alkylene bridge,

R ¹⁶ is independently selected from aryl, heteroaryl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR ¹⁹ R ²⁰ and C _1-6 -alkoxy,

R ¹⁷ is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, C _1-6 -alkyl, amino, C _1-6 -alkylsulfonyl, C _1-6 -alkylamino, di-C _1-6 -alkylamino, cyano, aryl, heteroaryl and C _3-8 -cycloalkyl,

R ¹⁸ is independently selected from aryl, heteroaryl, C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy radical, cyano, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino and hydroxyl,

R ¹⁹ and R ²⁰ are independently hydrogen or C _1-6 -alkyl, R ₁₉ and R ₂₀ can together form a C _3-6 -alkylene bridge, and any diastereomer or enantiomer or interconversion thereof forms, including mixtures thereof, or pharmaceutically acceptable salts thereof, for the preparation of pharmaceutical compositions for the treatment of disorders and diseases involving histamine H3 receptors.

In another aspect the present invention provides the use of a compound of general formula (II') as defined above for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which inhibition of the H3 histamine receptor has a beneficial effect.

In another aspect, the present invention provides the use of the compound of general formula (II') as defined above in the preparation of a pharmaceutical composition having histamine H3 antagonist activity or histamine H3 inverse agonist activity.

In another aspect the present invention provides the use of a compound of general formula (II') as defined above for the preparation of a pharmaceutical composition for reducing body weight.

In another aspect, the present invention provides the use of the compound of general formula (II') as defined above in the preparation of a pharmaceutical composition for the treatment of overweight or obesity.

In another aspect, the present invention provides the use of a compound of general formula (II') as defined above for the preparation of a pharmaceutical composition for suppressing appetite or for inducing satiety.

In another aspect the present invention provides the use of a compound of general formula (II') as defined above for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases involving overweight or obesity.

In another aspect the present invention provides the use of a compound of general formula (II') as defined above for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.

In another aspect, the present invention provides the use of the compound of general formula (II') as defined above in the preparation of a pharmaceutical composition for the treatment of IGT.

In another aspect, the present invention provides the use of the compound of general formula (II') as defined above in the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.

Another aspect of the present invention provides the use of the compound of general formula (II') as defined above in the preparation of a pharmaceutical composition for delaying or preventing IGT from developing into type 2 diabetes.

Another aspect of the present invention provides the use of the compound of general formula (II') as defined above in the preparation of a pharmaceutical composition for delaying or preventing non-insulin-demanding type 2 diabetes from developing into insulin-requiring type 2 diabetes.

In another aspect the present invention provides the use of a compound of general formula (II') as defined above for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which stimulation of H3 histamine receptors has a beneficial effect.

In another aspect, the present invention provides the use of the compound of general formula (II') as defined above in the preparation of a pharmaceutical composition having histamine H3 agonistic activity.

In another aspect, the present invention provides the use of the compound of general formula (II') as defined above in the preparation of a pharmaceutical composition for the treatment of allergic rhinitis, ulcer or anorexia.

In another aspect, the present invention provides the use of the compound of general formula (II') as defined above in the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease, narcolepsy or inattention.

In another aspect, the present invention provides a method for treating disorders or diseases involving H3 histamine receptors, the method comprising administering to a subject an effective amount of a compound of general formula (II') as defined above or comprising such A pharmaceutical composition of a compound.

In another aspect, the present invention provides a method for treating disorders or diseases involving H3 histamine receptors, wherein the effective amount of the compound of general formula (II') as defined above is about 0.05 mg to about 2000 mg per day, preferably about 0.1 mg to About 1000 mg, especially preferably about 0.5 mg to about 500 mg.

In another aspect, the present invention provides a method of treating diseases and disorders involving histamine H3 receptors, the method comprising administering to a subject an effective amount of a compound of formula (I) or any diastereomer or opposite thereof enantiomeric or tautomeric forms, mixtures thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.

In one aspect the present invention relates to compounds having histamine H3 receptor antagonistic or inverse agonistic activity, which are therefore useful in the treatment of a variety of conditions and disorders in which histamine H3 receptor blockade is beneficial.

In another aspect the present invention relates to compounds having histamine H3 receptor agonistic activity, which are therefore useful in the treatment of a variety of conditions and disorders in which activation of histamine H3 receptors is beneficial.

In a preferred embodiment of the invention, the compounds of the invention are used for the preparation of pharmaceutical compositions for reducing body weight.

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

In another preferred embodiment of the invention, the compounds of the invention are used for the preparation of pharmaceutical compositions for suppressing appetite or inducing satiety.

In a further preferred embodiment of the invention, the compounds according to the invention are used for the preparation of pharmaceutical compositions for the prophylaxis and/or treatment of disorders and diseases involving overweight or obesity, such as atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes (especially type 2 diabetes mellitus (NIDDM (non-insulin-dependent diabetes mellitus))), dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer (such as those of the endometrium, breast, prostate and colon) cancer).

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

In a further preferred embodiment of the invention, the compound of the invention is used for the preparation of a pharmaceutical composition for the treatment of IGT.

In a further preferred embodiment of the invention, the compound of the invention is used for the preparation of a pharmaceutical composition for treating type 2 diabetes. Such treatment includes, inter alia, treatment for the purpose of delaying or preventing the progression of IGT to type 2 diabetes and of delaying or preventing the progression of non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes.

The compounds of the invention may also be used in the treatment of airway disorders, such as asthma, as antidiarrheal agents, and in the modulation of gastric acid secretion.

In addition, the compounds of the invention can be used in the treatment of disorders associated with sleep regulation and insomnia, and in the treatment of narcolepsy and inattentive disorders.

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

The compounds of the invention are also useful in the treatment of disorders associated with epilepsy. Additionally, the compounds of the invention may be used in the treatment of motion sickness and vertigo. In addition, they can be used as hypothalamic-pituitary secretion modulators, antidepressants, cerebral circulation modulators, and in the treatment of irritable bowel syndrome.

Furthermore, the compounds of the invention can be used in the treatment of dementia and Alzheimer's disease.

The compounds of the invention may also be used in the treatment of allergic rhinitis, ulcers or anorexia.

Compounds of the present invention may additionally be used for the treatment of migraine, see McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50, for the treatment of myocardial infarction, see Mackins et al., Expert Opinion on Investigational Drugs 9 ( 2000), 2537-2542.

In a further inventive aspect, treatment of a patient with a compound of the invention is combined with diet and/or exercise.

In a further aspect of the invention, the compounds of the invention are administered in combination with one or more other active substances in any suitable ratio. Such other active agents may be selected from anti-obesity agents, anti-diabetic agents, anti-dyslipidemic agents, anti-hypertensive agents, therapeutic agents for complications caused by or related to diabetes, and agents caused by or related to obesity Therapeutic agents for complications and disorders.

Thus, in a further inventive aspect, the compounds of the invention are administered in combination with one or more anti-obesity or appetite-regulating agents.

Such drugs may be selected from the group consisting of CART (cocaine amphetamine-regulated transcription) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin Antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 adrenergic agonists (such as CL -316243, AJ-9677, GW-0604, LY362884, LY377267, or AZ-40140), MSH (melanostimulating hormone) agonist, MCH (melanocyte concentrating hormone) antagonist, CCK (cholecystokinin) agonist, serum serotonin reuptake inhibitors (eg, fluoxetine, paroxetine, or citalopram), serotonin and norepinephrine reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) Agonists, bombesin agonists, gangliotin antagonists, growth hormone, growth factors (such as prolactin or placental lactogen), growth hormone releasing compounds, TRH (thyrotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator-activated receptor) modulators agents, RXR (retinoic acid X receptor) modulators, TRβ agonists, AGRP (agouti-related protein) inhibitors, opioid antagonists (e.g. naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.

In one embodiment of the invention the anti-obesity agent is leptin.

In another embodiment, the anti-obesity drug is dexamphetamine or amphetamine.

In another embodiment, the anti-obesity agent is fenfluramine or dexfenfluramine.

In another embodiment, the anti-obesity agent is sibutramine.

In a further embodiment, the anti-obesity agent is orlistat.

In another embodiment, the anti-obesity agent is mazindol or phentermine.

In another embodiment, the anti-obesity agent is phendimetrazine, bupropion, fluoxetine, bupropion, topiramate, or ecopipam.

In a further aspect, the compounds of the invention are administered in combination with one or more antidiabetic agents.

Relevant antidiabetic agents include insulin, insulin analogs and derivatives such as those disclosed in EP 0 792 290 (Novo Nordisk A/S), e.g. ^NεB29 -tetradecanoyl des(B30) human insulin EP 0 214 826 and EP 0 705 275 (NovoNordisk A/S), for example Asp ^B28 human insulin; US 5,504,188 (Eli Lilly), for example Lys ^B28 Pro ^B29 human insulin; EP 0 368 187 (Aventis), for example Lantus®, They are all incorporated herein by reference; GLP-1 derivatives, such as those disclosed in WO 98/08871 (Novo Nordisk A/S), are incorporated herein by reference, as well as orally active hypoglycemic agents.

Orally effective hypoglycemic agents preferably comprise imidazolines; sulfonylureas; biguanides; Enzyme inhibitors; drugs acting on ATP-dependent beta-cell potassium channels, such as potassium channel openers, such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S), or mitiglinide; or potassium channel blockers, such as BTS-67582, nateglinide; glucagon antagonists, such as disclosed in WO 99/01423 and WO 00/39088 (Novo those in Nordisk A/S and Agouron Pharmaceuticals, Inc.), incorporated herein by reference; GLP-1 agonists, such as those disclosed in WO00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.) , incorporated herein by reference; DPP-IV (dipeptidyl peptidase-IV) inhibitors; PTPase (protein tyrosine phosphatase) inhibitors; liver enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis Inhibitors; Glucose uptake modulators; GSK-3 (Glycogen Synthase Kinase-3) Inhibitors; Compounds that alter lipid metabolism, such as anti-dyslipidemic agents; Compounds that decrease food intake; activating receptors); RXR (retinoic acid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.

In one embodiment of the invention, the compound of the present invention is administered in combination with insulin or insulin analogs or derivatives, such as N ^{ε B29} -tetradecanoyl des(B30) human insulin, Asp ^B28 human insulin, Lys ^B28 Pro ^B29 Human insulin, Lantus(R), or a mixed preparation containing one or more of them.

In a further embodiment of the invention, the compound of the invention is administered in combination with a sulfonylurea, such as tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, Limepiride, glicazide, or glibenclamide.

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

In another embodiment, the compound of the invention is administered in combination with a meglinide, eg, repaglinide or nateglinide.

In another embodiment of the invention, the compound of the present invention is administered in combination with a thiazolidinedione insulin sensitizer, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone, iglitazone Ketone (isaglitazone), daglitazone, emglitazone, CS-011/CI-1037 or T 174 or disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO00/41121 and WO 98/ Compounds in 45292 (Dr. Reddy's Research Foundation), cited herein as a reference.

In another invention embodiment, the compound of the present invention can be administered in combination with an insulin sensitizer, 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 disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 ( 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), incorporated herein by reference.

In a further embodiment of the invention, the compound of the invention is administered in combination with an alpha-glucosidase inhibitor, eg voglibose, emigretate, miglitol or acarbose.

In another embodiment of the invention, the compound of the present invention is administered in combination with a drug acting on the ATP-dependent potassium channel of β-cells, such as tolbutamide, glibenclamide, glipizide, Gliclazide, BTS-67582, or repaglinide.

In another embodiment of the invention, the compound of the present invention can be administered in combination with nateglinide.

In another embodiment, the compound of the present invention is administered in combination with an antihyperlipidemic agent or antilipidemic agent, such as cholestyramine, colestipol, clofibrate, gemfibrozil, loval Statin, pravastatin, simvastatin, probucol, or dextrothyroxine.

In another embodiment of the invention, the compound of the present invention is administered in combination with an antilipidemic agent, such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, Statin, simvastatin, probucol, or dextrothyroxine.

In another aspect of the invention, the compounds of the invention are administered in combination with more than one of the above compounds, for example metformin and a sulfonylurea such as glibenclamide; a sulfonylurea and acarose; Glinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin insulin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.

In addition, the compounds of the present invention may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are beta-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol; ACE (angiotensin converting 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 alpha-blockers such as doxazosin, urapidil, prazosin, and terazol Zinc. Further reference may be made to Remington: The Science and Practice of Pharmacy, ^19th Edition, Gennaro, Ed., MackPublishing Co., Easton, PA, 1995.

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

The compounds of the present invention may be chiral, meaning that any of the isolated enantiomers, pure or partially purified enantiomers or their racemic mixtures are included within the scope of the present invention.

Furthermore, diastereomers may be formed when double bonds or fully or partially saturated ring systems or more than one asymmetric center or bonds of restricted rotation are present in the molecule. Any separated diastereomers, pure or partially purified diastereomers or mixtures thereof are included within the scope of the present invention.

In addition, some compounds of the present invention may exist in different tautomeric forms, and the tautomeric forms that any compound can generate are included within the scope of the present invention.

The invention also encompasses pharmaceutically acceptable salts of the compounds of the invention. Such salts include pharmaceutically 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 examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, propionic acid, Diacid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bis-methylene salicylic acid, ethanedisulfonic acid, glucose Sugar acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Further examples of pharmaceutically 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 reference. Examples of metal salts include salts of lithium, sodium, potassium, magnesium, and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, etc. .

Also included as pharmaceutically acceptable acid addition salts are hydrates that the compounds of the present invention can form.

Acid addition salts may be obtained as direct products of compound synthesis. In the alternative, the salt can be isolated by dissolving the free base in a suitable solvent with the appropriate acid and evaporating the solvent or separating the salt from the solvent.

The compounds of the present invention can form solvates with standard low molecular weight solvents using methods well known to those skilled in the art. Such solvates are also encompassed within the scope of this invention.

The present invention also encompasses prodrugs of the compounds of the present invention which, after administration, undergo chemical transformations in metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula (I). The general selection and preparation of suitable prodrug derivatives is described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985 .

The invention also encompasses active metabolites of the compounds of the invention.

The compounds of the present invention interact with histamine H3 receptors and are therefore useful in the treatment of a variety of conditions and disorders in which histamine H3 receptor interaction is beneficial.

pharmaceutical composition

The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients in single or multiple doses. The pharmaceutical compositions according to the present invention can be formulated according to conventional techniques, such as those disclosed in Remington: The Science and Practice of Pharmacy, ^19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995, using A pharmaceutically acceptable carrier or diluent and any other known auxiliaries and excipients.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including Subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes, oral routes are preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject, the nature of the condition being treated and the active ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. They may be coated where appropriate, eg enteric coatings, or they may be formulated so as to provide controlled, eg sustained or prolonged release of the active ingredient according to methods well known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use body. Depot injection formulations are also encompassed within the scope of the present invention.

Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, and the like.

Typical oral dosages are in the range of about 0.001 to about 100 mg/kg body weight per day, preferably about 0.01 to about 50 mg/kg body weight per day, more preferably about 0.05 to about 10 mg/kg body weight per day, administered in one or more doses, For example 1 to 3 doses. The precise dosage will depend on the frequency and mode of administration, the sex, age, weight and general condition of the subject, the nature and severity of the condition being treated and any concomitant disease being treated, and other factors apparent 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. Typical unit dosage forms for oral administration one or more times per day, eg 1 to 3 times per day, may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, more preferably from about 0.5 mg to about 200 mg.

For parenteral routes, eg, intravenous, intrathecal, intramuscular and similar administration, typical dosages will be about one-half those employed for oral administration.

The compounds of the present invention are generally employed as free substances or pharmaceutically acceptable salts thereof. An example is an acid addition salt of a compound having free base availability. When the compound of formula (I) contains a free base, such salts are prepared in a conventional manner by treating a solution or suspension of the free base of formula (I) with a stoichiometric equivalent of a pharmaceutically acceptable acid, such as inorganic and organic acid. Representative examples are mentioned above. Physiologically acceptable salts of compounds having a hydroxyl group include the anion of said compound in combination with a suitable cation, such as sodium or ammonium ions.

For parenteral administration, solutions of the novel compounds of formula (I) in sterile aqueous solution, aqueous propylene glycol, or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. The sterile aqueous media employed are all readily available by procedures known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, 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 compositions formed by combining the novel compounds of formula (I) with a pharmaceutically acceptable carrier 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 presented as discrete units such as capsules or tablets, each unit containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be powders or granules, solutions or suspensions in aqueous or non-aqueous liquids or oil-in-water or water-in-oil emulsions.

If a solid carrier is used for oral administration, the preparation can be tabletted, placed in a hard gelatine capsule in powder or granule form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will generally 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, emulsion, soft gelatin capsule or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

A typical tablet can be prepared by conventional tableting techniques and can contain: Tablet core:

Active compound (free compound or its salt) 5.0mg

Lactose Ph.Eur. 67.8mg

Microcrystalline Cellulose (Avicel) 31.4mg

Amberlite® IRP88 ^* 1.0mg

Magnesium stearate Ph.Eur. q.s.

Coating:

Hydroxypropyl Methyl Cellulose About 9mg

Mywacett 9-40T ^** about 0.9mg

^* Polacrillin Potassium NF, tablet disintegrant, Rohm and Haas

^** Acylated monoglycerides, used as film coat plasticizers

The pharmaceutical compositions of the present invention may, if desired, comprise the compound of formula (I) in combination with other pharmacologically active substances, such as those described above.

Example

In the examples, the following terms are intended to have the following general meanings:

DIPEA: Diisopropylethylamine

DMSO: dimethyl sulfoxide

THF: Tetrahydrofuran

HPLC (Method A)

NMR spectra were recorded on Bruker 300MHz and 400MHz instruments. HPLC-MS was performed on a Perkin Elmer instrument (API 100). The column used was X-Terra C18, 5 μm, 50×3 mm, and the elution was carried out at 1.5 ml/min at room temperature using a gradient of 5% to 90% acetonitrile/water/0.01% trifluoroacetic acid, in 7.5 minutes.

HPLC (Method B)

Reverse phase analysis was performed on a 218TP54 4.6 mm x 150 mm C-18 silica column with UV detection at 214 and 254 nm, eluting at 1 ml/min at 42°C. Equilibrate the column with 5% acetonitrile, 85% water and 10% 0.5% trifluoroacetic acid in water, from 5% acetonitrile, 85% water and 10% 0.5% trifluoroacetic acid to 90% acetonitrile and 10% 0.5 % trifluoroacetic acid solution over 15 minutes.

HPLC (Method C)

RP analysis was performed using an Alliance Waters 2695 system equipped with a Waters 2487 dual-band detector. UV detection was collected using a Symmetry C18, 3.5 μm, 3.0 mm×100 mm column. Elution was performed with a linear gradient of 5-90% acetonitrile, 90-0% water, and 5% trifluoroacetic acid (1.0%) in water over 8 minutes at a flow rate of 1.0 mL/min.

General Process (A)

General technique (A) can be used for preparing general formula (Ia) compound:

Wherein -CH(R ²⁰ R ²¹ ) represents ethyl, isopropyl, branched C _4-6 -alkyl, branched C _4-6 -alkenyl, branched C _4-6 -alkynyl, C _{3- 5} -cycloalkyl, C _3-7 -cycloalkenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl or C _3-6 -cycloalkenyl-C _1-3 -alkyl, which can be optionally substituted with one or more halogen substituents.

To a mixture of monosubstituted piperazine (15.2 mmol) in a suitable solvent such as THF is added ketone or aldehyde (22.6 mmol), water, acetic acid (45.0 mmol), then _NaCNBH3 (18 mmol). The mixture was stirred at 55°C for 5.5 hours (ketone) or at room temperature overnight (aldehyde) and then concentrated under reduced pressure. Saturated aqueous NaHCO ₃ (100ml) was added and the mixture was extracted with a solvent such as ethyl acetate (3 x 40ml). The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue can be converted into a suitable salt, such as the hydrochloride, by co-evaporation with an acid, such as 1 molar aqueous hydrochloric acid, ethanol and toluene, and the residue then purified by recrystallization.

General Process (B)

Compounds of general formula (I) can be prepared by means of general process (B):

A mixture of monosubstituted piperazine (2.00mmol), DMSO (1.0ml), the appropriate aryl or heteroaryl halide (2.00mmol) and a base such as DIPEA (0.20ml) was stirred at 100°C for 1 hours, and then stirred at 120 °C for 18 hours. Water and potassium carbonate are added and the mixture is extracted with a solvent such as ethyl acetate (3 x 20ml). Separation and purification are carried out with the general process (A).

Non-commercially available substituted 2-chloroquinolines were prepared as described: F. Effenberger, W. Hartmann, Chemische Berichte 1969, 102, 3260-3267.

General Process (C)

Compounds of general formula (I) can be prepared by general process (C):

Compounds of formula I can be prepared starting from a suitable monosubstituted piperazine and a suitable aryl bromide in the presence of a suitable catalyst such as tris(dibenzylideneacetone)dipalladium in a suitable solvent such as Toluene, at a suitable temperature, for example between 0°C and 150°C.

Example 1

4-(4-Cyclopentylpiperazin-1-yl)phenol

Add cyclopentanone (1.90ml, 22.6mmol), water (0.15ml), acetic acid (2.70ml, 45.0 mmol), followed by _NaCNBH3 (18ml, 1M in THF, 18mmol). The mixture was stirred at 55°C for 5.5 hours, then concentrated under reduced pressure. Sat. aq. NaHCO ₃ (100ml) and ethyl acetate (40ml) were added and the mixture was filtered. The resulting solid was resuspended in methanol (30ml), heated to reflux and left at room temperature overnight. Filtration and drying under reduced pressure afforded the title compound (1.82 g, 49%) as a solid.

¹ H NMR (DMSO-d ₆ ) δ1.34 (m, 2H), 1.49 (m, 2H), 1.60 (m, 2H), 1.79 (m, 2H), 2.43 (m, 1H), 2.51 (m, 4H), 2.92(m, 4H), 6.62(d, J=8Hz, 2H), 6.77(d, J=8Hz, 2H), 8.78(s, 1H); HPLC-MS: m/z 247 (MH ⁺ ); Rf: 2.70min.

Example 2

1-cyclopentyl-4-[4-(4-fluorobenzyloxy)phenyl]piperazine

To a suspension of potassium hydroxide (0.165 g, 2.95 mmol) in ethanol (4 ml) was added 4-(4-cyclopentylpiperazin-1-yl)phenol (0.25 g, 1.02 mmol). After 10 minutes, 4-fluorobenzyl chloride (0.18ml, 0.22g, 1.51mmol) was added and the mixture was stirred at 70°C for 5 hours. Saturated aqueous _NaHCO3 (20ml) was added and the mixture was extracted with ethyl acetate (3x20ml). The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated. Recrystallization from methanol (4ml) gave 0.125g (35%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ1.34(m, 2H), 1.50(m, 2H), 1.62(m, 2H), 1.81(m, 2H), 2.45(m, 1H), 2.51(m, 4H), 2.99(m, 4H), 5.00(s, 2H), 6.87(m, 4H), 7.19(t, J=8Hz, 2H), 7.46(m, 2H); HPLC-MS: m/z 355 (MH ⁺ ); Rf: 4.73min.

Example 3

1-(3-Chlorophenyl)-4-cyclopentylpiperazine

This compound was prepared as described in Example 1 starting from 1-(3-chlorophenyl)-piperazine.

¹ H NMR (DMSO-d ₆ ) δ1.34 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (m, 2H), 2.45 (m, 1H), 2.51 (m, 4H), 3.14(m, 4H), 6.78(d, J=8Hz, 1H), 6.88(m, 2H), 7.19(t, J=8Hz, 1H); HPLC-MS: m/z265(MH ⁺ ) ;Rf: 3.88min.

Example 4

1-[4-(4-Cyclopentylpiperazin-1-yl)phenyl]ethanone

This compound was prepared as described in Example 1 starting from 1-(4-acetylphenyl)-piperazine.

¹ H NMR (DMSO-d ₆ ) δ1.30-1.88 (m, 8H), 2.45 (s, 3H), 2.45 (m, 1H), 2.51 (m, 4H), 3.31 (m, 4H), 6.95 ( d, J=8Hz, 2H), 7.79 (d, J=8Hz, 2H); HPLC-MS: m/z 273 (MH+); Rf: 3.25min.

Example 5

1-(3,4-Dichlorophenyl)-4-(1-ethylpropyl)piperazine

This compound was prepared as described in Example 1 starting from 1-(3,4-dichloro-phenyl)piperazine and 3-pentanone.

¹ H NMR (DMSO-d ₆ ) δ0.88 (t, J=7Hz, 6H), 1.28 (m, 2H), 1.45 (m, 2H), 2.19 (m, 1H), 2.56 (br s, 4H) , 3.12 (br s, 4H), 6.91 (m, 1H), 7.09 (br s, 1H), 7.36 (d, J=8Hz, 1H); HPLC-MS: m/z 301 (MH+); Rf: 4.25 min.

Example 6

{4-[4-(1-Ethylpropyl)piperazin-1-yl]phenyl}phenylphenone hydrochloride

A mixture of 1-(3-pentyl)piperazine (0.31g, 2.00mmol), DMSO (1.0ml), 4-fluorobenzophenone (0.40g, 2.00mmol) and DIPEA (0.20ml) was heated at 100°C Stir for 1 hour and then for 18 hours at 120°C. Water (50ml) and potassium carbonate (2g) were added and the mixture was extracted with ethyl acetate (3 x 20ml). The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was redissolved in ethanol (10ml) and 1M aqueous HCl (4ml) and the solution was concentrated under reduced pressure. After co-evaporation with ethanol and toluene the residue solidified and was recrystallized from acetonitrile (100ml). Obtained 0.20 g (27%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ0.95 (m, 6H), 1.62 (m, 2H), 1.89 (m, 2H), 3.04-3.27 (m, 3H), 3.48 (m, 4H), 4.05 ( m, 2H), 7.08(m, 2H), 7.51(m, 2H), 7.65(m, 5H), 10.75(br s, 1H); HPLC-MS: m/z337(MH ⁺ ); Rf: 4.27min .

Example 7

1-(4-Benzylphenyl)-4-(1-ethylpropyl)piperazine hydrochloride

{4-[4-(1-Ethylpropyl)piperazin-1-yl]phenyl}phenyl ketone hydrochloride (77mg, 0.21mmol), trifluoroacetic acid (2.0ml) and triethyl The mixture of monosilane (0.5ml) was stirred at 60°C for 20 hours. The mixture was concentrated under reduced pressure, mixed with water and potassium carbonate. The mixture was extracted with ethyl acetate (3 x 20ml). The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was redissolved in ethanol and 1M aqueous HCl, and the solution was concentrated under reduced pressure. After co-evaporation with ethanol and toluene the residue solidified. This gave 45 mg (61%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ0.98(t, J=7Hz, 6H), 1.64(m, 2H), 1.89(m, 2H), 3.04-3.23(m, 5H), 3.48(m, 2H ), 3.72(m, 2H), 3.85(s, 2H), 6.93(d, J=8Hz, 2H), 7.10-7.30(m, 7H), 10.05(brs, 1H); HPLC-MS: m/z 323 (MH ⁺ ); Rf: 4.93min.

Example 8

Cyclopropyl-{4-[4-(1-ethylpropyl)piperazin-1-yl]phenyl}methanone hydrochloride

This compound was prepared as described in Example 6 starting from 4-fluorophenyl(cyclopropyl)ketone.

¹ H NMR (DMSO-d ₆ ) δ0.98 (m, 10H), 1.64 (m, 2H), 1.89 (m, 2H), 2.82 (br s, 1H), 3.04-3.23 (m, 3H), 3.49 (m, 4H), 4.04 (m, 2H), 7.07 (d, J=8Hz, 2H), 7.96 (d, J=8Hz, 2H), 10.95 (brs, 1H); HPLC-MS: m/z 301 ( MH ⁺ ); Rf: 4.03min.

Example 9

(2-Chlorophenyl)-{4-[4-(1-ethylpropyl)piperazin-1-yl]phenyl}methanone hydrochloride

This compound was prepared as described in Example 6 starting from 4-fluorophenyl-(2-chlorophenyl)one.

¹ H NMR (DMSO-d ₆ ) δ0.98(t, J=7Hz, 6H), 1.64(m, 2H), 1.88(m, 2H), 3.08-3.23(m, 3H), 3.50(m, 4H ), 4.06(m, 2H), 7.08(d, J=8Hz, 2H), 7.31(m, 1H), 7.48(m, 1H), 7.50-7.61(m, 4H), 10.85(br s, 1H) ; HPLC-MS: m/z 371 (MH ⁺ ); Rf: 4.43min.

Example 10

{4-[4-(1-Ethylpropyl)piperazin-1-yl]phenyl}-(4-fluorophenyl)methanone hydrochloride

This compound was prepared as described in Example 6 starting from 4,4'-difluorobenzophenone.

¹ H NMR (DMSO-d ₆ ) δ0.98(t, J=7Hz, 6H), 1.66(m, 2H), 1.89(m, 2H), 3.08-3.25(m, 3H), 3.41-3.53(m , 4H), 4.05(m, 2H), 7.09(d, J=8Hz, 2H), 7.38(m, 2H), 7.69(d, J=8Hz, 2H), 7.76(m, 2H), 10.80(br s, 1H); HPLC-MS: m/z 355 (MH ⁺ ); Rf: 4.37min.

Example 11

1-cyclopentyl-4-(6-trifluoromethylpyridin-2-yl)piperazine

This compound was prepared as described in Example 1 starting from 1-(6-trifluoromethyl-pyridin-2-yl)piperazine.

¹ H NMR (DMSO-d ₆ ) δ1.34 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (m, 2H), 2.45-2.51 (m, 5H), 3.52 ( m, 4H), 7.02(d, J=8Hz, 1H), 7.11(d, J=8Hz, 1H), 7.71(t, J=8Hz, 1H); HPLC-MS: m/z 300(MH ⁺ ) ;Rf: 4.10min.

Example 12

1-cyclopentyl-4-(5-trifluoromethylpyridin-2-yl)piperazine

This compound was prepared as described in Example 1 starting from 1-(5-trifluoromethyl-pyridin-2-yl)piperazine.

¹ H NMR (DMSO-d ₆ ) δ1.36 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (m, 2H), 2.45-2.52 (m, 5H), 3.58 ( m, 4H), 6.92 (d, J = 8Hz, 1H), 7.78 (br d, J = 8Hz, 1H), 8.39 (s, 1H); HPLC-MS: m/z 300 (MH ⁺ ); Rf: 3.87min.

Example 13

1-cyclopentyl-4-(3-trifluoromethylpyridin-2-yl)piperazine

This compound was prepared as described in Example 1 starting from 1-(3-trifluoromethyl-pyridin-2-yl)piperazine.

¹ H NMR (DMSO-d ₆ ) δ1.29-1.65 (m, 6H), 1.80 (m, 2H), 2.45 (m, 1H), 2.52 (m, 4H), 3.18 (m, 4H), 7.16 ( m, 1H), 8.02 (m, 1H), 8.49 (m, 1H); HPLC-MS: m/z 300 (MH ⁺ ); Rf: 3.70min.

Example 14

2-[4-(1-Ethylpropyl)piperazin-1-yl]quinoline hydrochloride

This compound was prepared as described in Example 6 starting from 2-chloroquinoline.

1H NMR (DMSO-d6) δ0.99(t, J=7Hz, 6H), 1.65(m, 2H), 1.94(m, 2H), 3.12(br s, 1H), 3.33(m, 2H), 3.57 (m, 2H), 3.93(m, 2H), 4.83(m, 2H), 7.44-7.58(m, 2H), 7.76(m, 1H), 7.92(m, 1H), 8.25(br s, 1H) , 8.42 (m, 1H), 11.20 (br s, H); HPLC-MS: m/z 284 (MH ⁺ ); Rf: 3.03min.

Example 15

7-Chloro-4-[4-(1-ethylpropyl)piperazin-1-yl]quinoline hydrochloride

This compound was prepared as described in Example 6 starting from 4,7-dichloroquinoline.

¹ H NMR (DMSO-d ₆ ) δ1.00 (t, J=7Hz, 6H), 1.67 (m, 2H), 1.95 (m, 2H), 3.15 (br s, 1H), 3.30-3.70 (m, 4H), 4.05(m, 2H), 4.20(m, 2H), 7.32(m, 1H), 7.73(m, 1H), 8.28(m, 2H), 8.83(m, 1H), 11.35(br s, H); HPLC-MS: m/z 318 (MH ⁺ ); Rf: 3.13min.

Example 16

[4-(4-Cyclopentylpiperazin-1-yl)phenyl]-(3,4-dimethoxyphenyl)methanone hydrochloride

This compound was prepared as described in Example 6 starting from 4'-fluoro-3,4-dimethoxybenzophenone.

¹ H NMR (DMSO-d ₆ ) δ1.55 (m, 2H), 1.65-1.90 (m, 4H), 2.02 (m, 2H), 3.05-3.40 (m, 4H), 3.55 (m, 3H), 3.81(s, 3H), 3.88(s, 3H), 4.08(m, 2H), 7.10(m, 3H), 7.29(m, 2H), 7.69(d, J=8Hz, 2H), 10.78(br s , 1H); HPLC-MS: m/z 395 (MH ⁺ ); Rf: 3.03min.

Example 17

[4-(4-Cyclopentylpiperazin-1-yl)-3,5-difluorophenyl]phenylphenone hydrochloride

This compound was prepared as described in Example 6 starting from 3,4,5-trifluorobenzophenone.

¹ H NMR (DMSO-d ₆ ) δ1.55 (m, 2H), 1.65-1.90 (m, 4H), 2.02 (m, 2H), 3.15 (m, 2H), 3.50-3.71 (m, 7H), 7.42(m, 2H), 7.58(m, 2H), 7.68-7.78(m, 3H), 10.90(br s, 1H); HPLC-MS: m/z 371(MH ⁺ ); Rf: 2.77min.

Example 18

2-(4-Cyclopentylpiperazin-1-yl)quinoxaline hydrochloride

This compound was prepared as in Example 6 starting from 2-chloroquinoxaline and using propionitrile as solvent.

¹ H NMR (DMSO-d ₆ ) δ1.55 (m, 2H), 1.64-1.90 (m, 4H), 2.02 (m, 2H), 3.15 (m, 2H), 3.42-3.65 (m, 5H), 4.71 (m, 2H), 7.49 (m, 1H), 7.67 (m, 2H), 7.88 (br d, J=8Hz, 1H), 8.91 (s, 1H), 10.92 (br s, 1H); HPLC- MS: m/z 283 (MH ⁺ ); Rf: 1.70min.

Example 19

2-(4-cyclopropylmethylpiperazin-1-yl)quinoxaline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.41 (m, 2H), 0.66 (m, 2H), 1.18 (m, 1H), 3.02 (m, 2H), 3.13 (m, 2H), 3.52-3.69 ( m, 4H), 4.71(m, 2H), 7.48(m, 1H), 7.66(m, 2H), 7.88(d, J=8Hz, 1H), 8.90(s, 1H), 11.17(br s, 1H ); HPLC-MS: m/z 269 (MH ⁺ ); Rf: 1.73min.

Example 20

[6-(4-Cyclopentylpiperazin-1-yl)pyridin-3-yl]piperidin-1-ylmethanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.45-2.08 (m, 14H), 3.06 (m, 2H), 3.38-3.61 (m, 9H), 4.44 (m, 2H), 7.02 (d, J=8Hz , 1H), 7.70(dd, J=8Hz, 1Hz, 1H), 8.19(d, J=1Hz, 1H); HPLC-MS: m/z(MH ⁺ ).

This compound was prepared as in Example 6 using 1-(6-chloronicotinoyl)piperidine (Thunus, Ann. Pharm. Fr. 1977, 35, 197) (General Procedure B).

Example 21

2-(4-Cyclopentylpiperazin-1-yl)quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.62 (m, 2H), 1.82 (m, 2H), 1.96 (m, 2H), 2.09 (m, 2H), 3.25 (m, 2H), 3.55-3.70 ( m, 5H), 4.83(m, 2H), 7.46-7.60(m, 2H), 7.80(m, 1H), 7.94(m, 1H), 8.13(m, 1H), 8.42(m, 1H), 11.52 (br s, 1H); HPLC-MS: m/z 282 (MH ⁺ ); Rf: 0.34min.

This compound was prepared as in Example 6 starting from 2-chloroquinoline.

Example 22

2-(4-Cyclopentylpiperazin-1-yl)-7-methoxy-3-(4-methoxyphenyl)quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.53 (m, 2H), 1.63-1.86 (m, 4H), 1.98 (m, 2H), 3.05 (m, 2H), 3.33-3.52 (m, 5H), 3.75(m, 2H), 3.82(s, 3H), 3.91(s, 3H), 7.08(d, J=8Hz, 2H), 7.13(dd, J=8Hz, 1Hz, 1H), 7.49(brs, 1H ), 7.61 (d, J=8Hz, 2H), 7.83 (d, J=8Hz, 1H), 8.15 (s, 1H), 11.29 (brs, 1H); HPLC-MS: m/z 418 (MH ⁺ ) ;Rf: 3.40min.

Example 23

{6-[4-(1-cyclopropyl-1-methylethyl)piperazin-1-yl]pyridin-3-yl}phenyl ketone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.48-0.62 (m, 4H), 1.22-1.39 (m, 7H), 3.14 (m, 2H), 3.69 (m, 4H), 4.64 (m, 2H), 7.08(d, J=8Hz, 1H), 7.55(m, 2H), 7.61-7.72(m, 3H), 8.00(dd, J=8Hz, 1Hz, 1H), 8.52(d, J=1Hz, 1H) , 11.27 (br s, 1H); HPLC-MS: m/z 350 (MH ⁺ ); Rf: 3.03min.

Starting from 2-chloro-5-benzoylpyridine (T.D.Penning et al., J.Med.Chem. 2000, 43, 721-735), this compound was prepared as in Example 6.

Example 24

{4-[4-(1-cyclopropyl-1-methylethyl)piperazin-1-yl]-3,5-difluorophenyl}phenylphenone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.48-0.63 (m, 4H), 1.23-1.40 (m, 7H), 3.18 (m, 2H), 3.56 (m, 2H), 3.69 (m, 2H), 3.84(m, 2H), 7.42(m, 2H), 7.58(m, 2H), 7.66-7.76(m, 3H), 10.90(br s, 1H); HPLC-MS: m/z 385(MH ⁺ ) ;Rf: 3.73min.

Example 25

{4-[4-(1-cyclopropyl-1-methylethyl)piperazin-1-yl]-3,5-difluorophenyl}phenylmethanol hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.47-0.61 (m, 4H), 1.23-1.34 (m, 7H), 3.12 (m, 2H), 3.29 (m, 2H), 3.65 (m, 4H), 5.66(m, 1H), 6.08(m, 1H), 7.06(m, 2H), 7.19-7.40(m, 5H), 10.40(br s, 1H); HPLC-MS: m/z 387(MH ⁺ ) ;Rf: 3.40min.

This compound was prepared by reducing Example 24 with sodium borohydride.

Example 26

[4-(4-Cyclopropylmethylpiperazin-1-yl)-3,5-difluorophenyl]-(4-fluorophenyl)methanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.40 (m, 2H), 0.66 (m, 2H), 1.13 (m, 1H), 3.02-3.23 (m, 5H), 3.52-3.68 (m, 5H), 7.40(m, 4H), 7.82(m, 2H), 10.55(br s, 1H); HPLC-MS: m/z 375(MH ⁺ ); Rf: 2.78min.

This compound was prepared in the same manner as in Example 6 using 3,4,5,4'-tetrafluorobenzophenone. The starting material was prepared by Friedel Crafts acylation of fluorobenzene with 3,4,5-trifluorobenzoyl chloride.

Example 27

{4-[4-(1-Ethylpropyl)piperazin-1-yl]-3,5-difluorophenyl}-(4-fluorophenyl)methanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.97(t, J=7Hz, 6H), 1.68(m, 2H), 1.88(m, 2H), 3.06-3.26(m, 3H), 3.52(m, 4H ), 3.75(m, 2H), 7.41(m, 4H), 7.82(m, 2H), 10.31(br s, 1H); HPLC-MS: m/z 391(MH ⁺ ); Rf: 3.00min.

Example 28

2-[4-(1-Ethylpropyl)piperazin-1-yl]-6,7-dimethoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.99 (t, J=7Hz, 6H), 1.66 (m, 2H), 1.91 (m, 2H), 3.11 (m, 1H), 3.29 (m, 2H), 3.56(m, 4H), 3.88(s, 3H), 3.92(s, 3H), 4.72(m, 2H), 7.31-7.43(m, 2H), 7.82(br s, 1H), 8.30(br s, 1H), 10.95 (br s, 1H); HPLC-MS: m/z 344 (MH ⁺ ); Rf: 2.00min.

This compound was prepared as in Example 6 starting from 2-chloro-6,7-dimethoxyquinoline (Pettit, Can. J. Chem. 1964, 42, 1764).

Example 29

2-[4-(1-Ethylpropyl)piperazin-1-yl]-4-trifluoromethylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.99 (t, J=7Hz, 6H), 1.65 (m, 2H), 1.91 (m, 2H), 3.08 (m, 1H), 3.19 (m, 2H), 3.52(m, 2H), 3.75(m, 2H), 4.77(m, 2H), 7.48(t, J=7Hz, 1H), 7.72(m, 2H), 7.88(m, 2H), 11.19(br s , 1H); HPLC-MS: m/z 352 (MH ⁺ ); Rf: 3.70min.

This compound was prepared from 2-chloro-4-trifluoromethylquinoline. The starting material was prepared as described in the literature: R.D. Westland et al. J. Med. Chem. 1973, 16, 319-327.

Example 30

2-(4-Cyclopropylmethylpiperazin-1-yl)-6-methoxy-4-trifluoromethylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.40 (m, 2H), 0.67 (m, 2H), 1.14 (m, 1H), 3.01-3.16 (m, 4H), 3.46 (m, 2H), 3.64 ( m, 2H), 3.87(s, 3H), 4.66(m, 2H), 7.16(br s, 1H), 7.43(dd, J=7Hz, 1Hz, 1H), 7.68(s, 1H), 7.73(d , J=7Hz, 1H), 10.70 (br s, 1H); HPLC-MS: m/z 366 (MH ⁺ ); Rf: 3.63min.

Example 31

[4-(4-Cyclopropylmethylpiperazin-1-yl)-3,5-difluorophenyl]phenylphenone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.40 (m, 2H), 0.67 (m, 2H), 1.14 (m, 1H), 3.03-3.20 (m, 4H), 3.60 (m, 6H), 7.40 ( m, 2H), 7.58 (m, 2H), 7.70 (m, 3H), 10.60 (br s, 1H); HPLC-MS: m/z 357 (MH ⁺ ); Rf: 3.53min.

Example 32

[4-(4-Cyclopropylmethylpiperazin-1-yl)-3,5-difluorophenyl]-(3-fluoro-4-methoxyphenyl)-methanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.41 (m, 2H), 0.65 (m, 2H), 1.15 (m, 1H), 3.06 (m, 2H), 3.18 (m, 2H), 3.50-3.70 ( m, 6H), 3.95(s, 3H), 7.33(t, J=8Hz, 1H), 7.41(m, 2H), 7.60(m, 2H), 10.79(brs, 1H); HPLC-MS: m/ z 405 (MH ⁺ ); Rf: 3.67min.

Example 33

{6-[4-(1-Ethylpropyl)piperazin-1-yl]pyridin-3-yl}phenylphenone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.97(t, J=7Hz, 6H), 1.65(m, 2H), 1.90(m, 2H), 3.02-3.22(m, 3H), 3.49-3.69(m , 4H), 4.60(m, 2H), 7.08(d, J=8Hz, 1H), 7.56(m, 2H), 7.68(m, 3H), 7.99(dd, J=8Hz, 1Hz, 1H), 8.50 (d, J=1 Hz, 1H), 10.90 (brs, 1H); HPLC-MS: m/z 338 (MH ⁺ ); Rf: 3.00 min.

Example 34

{2-[4-(1-Ethylpropyl)piperazin-1-yl]pyridin-4-yl}phenylphenone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.97 (t, J=7Hz, 6H), 1.63 (m, 2H), 1.85 (m, 2H), 3.12 (m, 3H), 3.47 (m, 4H), 4.43(m, 2H), 6.91(d, J=6Hz, 1H), 7.14(s, 1H), 7.58(t, J=8Hz, 2H), 7.70-7.84(m, 3H), 8.33(d, J =6Hz, 1H), 10.43 (br s, 1H); HPLC-MS: m/z 338 (MH ⁺ ); Rf: 2.97min.

This compound was prepared from 2-chloro-4-benzoylpyridine prepared by Friedel-Crafts acylation of benzene with 2-chloro-4-chlorocarbonylpyridine.

Example 35

{4-[4-(1-Ethylpropyl)piperazin-1-yl]phenyl}-(4-hydroxyphenyl)methanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.97(t, J=7Hz, 6H), 1.65(m, 2H), 1.92(m, 2H), 3.05-3.25(m, 3H), 3.35-3.55(m , 4H), 4.02(m, 2H), 6.89(d, J=8Hz, 2H), 7.08(d, J=8Hz, 2H), 7.59(d, J=8Hz, 2H), 7.63(d, J= 8Hz, 2H), 10.36(s, 1H), 10.60(br s, 1H); HPLC-MS: m/z 353 (MH ⁺ ); Rf: 2.13min.

Example 36

{6-[4-(1-Ethylpropyl)piperazin-1-yl]pyridin-3-yl}piperidin-1-yl-methanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.97(t, J=7Hz, 6H), 1.50(m, 4H), 1.63(m, 4H), 1.89(m, 2H), 3.05-3.20(m, 3H) ), 3.50(m, 8H), 4.46(m, 2H), 7.04(m, 1H), 7.70(m, 1H), 8.18(br s, 1H), 10.90(br s, 1H); HPLC-MS: m/z 345 (MH ⁺ ); Rf: 2.27min.

Example 37

N-Benzyl-6-[4-(1-ethylpropyl)piperazin-1-yl]-N-methylnicotinamide hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.97 (t, J=7Hz, 6H), 1.63 (m, 2H), 1.88 (m, 2H), 2.89 (s, 3H), 3.09 (m, 3H), 3.50(m, 4H), 4.45(m, 2H), 4.62(br s, 2H), 7.02(d, J=8Hz, 1H), 7.25-7.41(m, 5H), 7.78(m, 1H), 8.28 (br s, 1H), 10.78 (br s, 1H); HPLC-MS: m/z 381 (MH ⁺ ); Rf: 3.10min.

Example 38

2-[4-(1-Ethylpropyl)piperazin-1-yl]-6-methoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.98 (t, J=7Hz, 6H), 1.66 (m, 2H), 1.92 (m, 2H), 3.11 (m, 1H), 3.31 (m, 2H), 3.57(m, 2H), 3.82(m, 2H), 3.88(s, 3H), 4.74(m, 2H), 7.41(br s, 2H), 7.53(m, 1H), 8.12(br s, 1H) , 8.34 (br s, 1H), 10.95 (br s, 1H); HPLC-MS: m/z 314 (MH ⁺ ); Rf: 2.17min.

Example 39

6-[4-(1-Ethylpropyl)piperazin-1-yl]-N-methyl-N-phenylnicotinamide hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.95 (t, J=7Hz, 6H), 1.62 (m, 2H), 1.83 (m, 2H), 3.05 (m, 3H), 3.34 (s, 3H), 3.43(m, 4H), 4.35(m, 2H), 6.76(d, J=8Hz, 1H), 7.21(m, 3H), 7.31(m, 2H), 7.42(dd, J=8Hz, 1Hz, 1H ), 8.01 (d, J=1Hz, 1H), 10.54 (br s, 1H); HPLC-MS: m/z 367 (MH ⁺ ); Rf: 2.90min.

Example 40

{6-[4-(1-Ethylpropyl)piperazin-1-yl]pyridin-3-yl}-(4-fluorophenyl)methanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.95(t, J=7Hz, 6H), 1.62(m, 2H), 1.83(m, 2H), 3.10(m, 3H), 3.45-3.65(m, 4H ), 4.55(m, 2H), 7.05(d, J=8Hz, 1H), 7.38(d, J=8Hz, 2H), 7.78(dd, J=8Hz, 4Hz, 2H), 7.96(dd, J= 8Hz, 1Hz, 1H), 8.48(d, J=1Hz, 1H), 10.85(br s, 1H); HPLC-MS: m/z 356 (MH ⁺ ); Rf: 2.40min.

Example 41

2-[4-(1-Ethylpropyl)piperazin-1-yl]-4-methylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.98 (t, J=7Hz, 6H), 1.64 (m, 2H), 1.92 (m, 2H), 2.69 (s, 3H), 3.12 (m, 1H), 3.32(m, 2H), 3.57(m, 2H), 3.94(m, 2H), 4.86(m, 2H), 7.53(br s, 2H), 7.80(m, 1H), 8.01(m, 1H), 8.32 (br s, 1H), 11.20 (br s, 1H); HPLC-MS: m/z 298 (MH ⁺ ); Rf: 1.26min.

Example 42

2-[4-(1-Ethylpropyl)piperazin-1-yl]-5,6,7,8-tetrahydroquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.98(t, J=7Hz, 6H), 1.50-2.03(m, 8H), 2.63(m, 2H), 2.90(m, 2H), 3.00-3.33(m , 3H), 3.50(m, 2H), 3.75(m, 2H), 4.48(m, 2H), 7.13(br s, 1H), 7.75(br s, 1H), 11.10(br s, 1H); HPLC - MS: m/z 288 (MH ⁺ ); Rf: 1.83min.

This compound was prepared from 2-chloro-5,6,7,8-tetrahydroquinoline (S. C. Zimmerman, Z. Zeng, J. Org. Chem. 1990, 55, 4789-5791).

Example 43

2-(4-Cyclopropylmethylpiperazin-1-yl)-6-methoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.41 (m, 2H), 0.66 (m, 2H), 1.18 (m, 1H), 3.02 (m, 2H), 3.13 (m, 2H), 3.52-3.69 ( m, 4H), 3.85(s, 3H), 4.71(m, 2H), 7.41(br s, 2H), 7.53(m, 1H), 8.12(br s, 1H), 8.34(br s, 1H), 11.38 (br s, 1H); HPLC-MS: m/z 298 (MH ⁺ ); Rf: 1.87min.

Example 44

2-(4-Isopropylpiperazin-1-yl)-6-methoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.32 (d, J=7Hz, 6H), 3.28 (m, 2H), 3.53 (m, 3H), 3.80 (m, 1H), 3.85 (s, 3H), 4.85(m, 2H), 7.43(br s, 2H), 7.59(d, J=8Hz, 1H), 8.27(br s, 1H), 8.34(br s, 1H), 8.40(d, J=8Hz, 1H), 11.60 (br s, 1H); HPLC-MS: m/z 286 (MH ⁺ ); Rf: 1.77min.

Example 45

2-[4-(1-Ethylpropyl)piperazin-1-yl]-6-fluoro-4-methylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.98 (t, J=7Hz, 6H), 1.64 (m, 2H), 1.92 (m, 2H), 2.67 (s, 3H), 3.12 (m, 1H), 3.32(m, 2H), 3.57-4.00(m, 4H), 4.85(m, 2H), 7.57(br s, 2H), 7.68(m, 1H), 7.82(m, 1H), 8.33(br s, 1H), 11.10 (br s, 1H); HPLC-MS: m/z 316 (MH ⁺ ); Rf: 1.92min.

This compound was prepared from 2-chloro-6-fluoro-4-methylquinoline, starting material by acetoacetylation of 4-fluoroaniline followed by acid-mediated ring closure and treatment with phosphorous oxychloride Quinolones are converted to chloroquinolines.

Example 46

2-(4-Isopropylpiperazin-1-yl)quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.19 (m, 2H), 3.52 (m, 3H), 3.72 (m, 2H), 4.79 (m, 2H), 7.45(m, 2H), 7.68(m, 1H), 7.86(m, 1H), 8.03(m, 1H), 8.31(m, 1H), 11.45(br s, 1H); HPLC-MS: m/z 256 (MH ⁺ ); Rf: 1.47min.

Example 47

2-(4-cyclopropylpiperazin-1-yl)-6-methoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.81 (m, 2H), 1.20 (br s, 2H), 2.86 (br s, 1H), 3.25-3.75 (m, 4H), 3.85 (s, 3H), 4.09(m, 2H), 4.73(m, 2H), 7.41(m, 2H), 7.55(m, 1H), 8.14(m, 1H), 8.37(m, 1H), 11.51(br s, 1H); HPLC-MS: m/z 284 (MH ⁺ ); Rf: 1.80min.

Example 48

2-(4-Isopropyl-piperazin-1-yl)-6-trifluoromethoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.17 (m, 2H), 3.52 (m, 3H), 3.68 (m, 2H), 4.79 (m, 2H), 7.56(d, J=8Hz, 1H), 7.68(br d, J=7Hz, 1H), 7.91(br s, 1H), 8.04(br s, 1H), 8.35(br d, J=7Hz, 1H) , 11.28 (br s, 1H); HPLC-MS: m/z 340 (MH ⁺ ); Rf: 3.04min.

Example 49

6-Chloro-2-(4-cyclopropyl-piperazin-1-yl)-quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.81 (m, 2H), 1.14 (br s, 2H), 2.88 (br s, 1H), 3.25-3.70 (m, 6H), 4.67 (m, 2H), 7.44(d, J=8Hz, 1H), 7.61(d, J=8Hz, 1H), 7.72(m, 1H), 7.91(br s, 1H), 8.18(brd, J=8Hz, 1H), 10.75( br s, 1H); HPLC-MS: m/z 288 (MH ⁺ ); Rf: 1.77min.

Example 50

2-(4-Cyclopropyl-piperazin-1-yl)-6-trifluoromethoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.81 (m, 2H), 1.15 (br s, 2H), 2.88 (br s, 1H), 3.20-3.70 (m, 6H), 4.68 (m, 2H), 7.49 (d, J=8Hz, 1H), 7.59 (br d, J=8Hz, 1H), 7.82 (m, 2H), 8.27 (d, J=8Hz, 1H), 10.89 (br s, 1H); HPLC - MS: m/z 338 (MH ⁺ ); Rf: 2.24min.

Example 51

2-(4-Isopropyl-piperazin-1-yl)-8-trifluoromethylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31(d, J=7Hz, 6H), 3.10(m, 2H), 3.51(m, 5H), 4.72(m, 2H), 7.38(t, J=8Hz , 1H), 7.46(d, J=8Hz, 1H), 7.95(br d, J=7Hz, 1H), 8.05(br d, J=7Hz, 1H), 8.26(d, J=8Hz, 1H), 10.66 (br s, 1H); HPLC-MS: m/z 324 (MH ⁺ ); Rf: 3.08min.

Example 52

2-(4-Isopropyl-piperazin-1-yl)-6-trifluoromethylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.12 (m, 2H), 3.50-3.68 (m, 5H), 4.78 (m, 2H), 7.52 (d, J =7Hz, 1H), 7.88(m, 2H), 8.26(br s, 1H), 8.36(d, J=7Hz, 1H), 10.95(br s, 1H); HPLC-MS: m/z 324 (MH ⁺ ); Rf: 2.11min.

Example 53

2-(4-Isopropyl-piperazin-1-yl)-6-propylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.91(t, J=7Hz, 3H), 1.31(d, J=7Hz, 6H), 1.66(sext, J=7Hz, 2H), 2.70(t, J=7Hz, 2H) 7Hz, 2H), 3.23(m, 2H), 3.48-3.90(m, 5H), 4.81(m, 2H), 7.52(m, 1H), 7.63(m, 1H), 7.70(br s, 1H), 8.09 (br s, 1H), 8.34 (br s, 1H), 11.35 (br s, 1H); HPLC-MS: m/z 298 (MH ⁺ ); Rf: 1.97min.

Example 54

6,8-Difluoro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.09 (m, 2H), 3.51 (m, 5H), 4.66 (m, 2H), 7.45-7.58 (m, 3H ), 8.18 (d, J=7Hz, 1H), 10.92 (br s, 1H).

Example 55

8-fluoro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.09 (m, 2H), 3.52 (m, 5H), 4.70 (m, 2H), 7.24 (m, 1H), 7.40(m, 2H), 7.59(d, J=7Hz, 1H), 8.20(d, J=7Hz, 1H), 10.84(br s, 1H).

Example 56

2-(4-Cyclopropylpiperazin-1-yl)-6-trifluoromethylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ0.81 (m, 2H), 1.19 (br s, 2H), 2.88 (br s, 1H), 3.20-3.70 (m, 6H), 4.73 (m, 2H), 7.52(d, J=8Hz, 1H), 7.88(m, 2H), 8.26(br s, 1H), 8.33(d, J=8Hz, 1H), 11.12(brs, 1H); HPLC-MS: m/ z 322 (MH ⁺ ); Rf: 2.41min.

Example 57

2-(4-Cyclopropylpiperazin-1-yl)-6-propylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.82 (m, 2H), 0.91 (t, J=7Hz, 3H), 1.18 (br s, 2H), 1.66 (sext, J=7Hz, 2H), 2.69 ( t, J=7Hz, 2H), 2.85(br s, 1H), 3.30-3.75(m, 6H), 4.72(m, 2H), 7.51(m, 1H), 7.62(m, 1H), 7.69(br s, 1H), 7.97 (br s, 1H), 8.33 (br s, 1H), 11.20 (br s, 1H); HPLC-MS: m/z 296 (MH ⁺ ); Rf: 1.97min.

Example 58

2-(4-Ethylpiperazin-1-yl)quinoline hydrochloride

See also S. Cacchi et al., SynLett 1997, 1400-1402.

¹ H NMR (DMSO-d ₆ ) δ1.30(t, J=7Hz, 3H), 3.15(m, 4H), 3.55-3.85(m, 4H), 4.81(m, 2H), 7.47(m, 1H ), 7.53(m, 1H), 7.74(m, 1H), 7.89(d, J=8Hz, 1H), 8.13(br s, 1H), 8.40(br s, 1H), 11.34(br s, 1H); HPLC-MS: m/z 242 (MH ⁺ ); Rf: 1.04min.

Embodiment 59 (general technique (B))

3-(4-Isopropyl-piperazin-1-yl)-6-phenyl-pyridazine, hydrochloride

Starting from 1-isopropylpiperazine and 3-chloro-6-phenylpyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978), this compound was prepared according to general procedure (B).

¹ H NMR (D ₂ O): δ1.46 (d, 6H); 3.28 (m, 2H); 3.48 (m, 2H); 3.64-3.84 (m, 3H); 4.57 (m, 2H); 7.72(m, 4H); 7.90(m, 2H); 8.12(d, 1H); HPLC-MS: m/z=283.2(M+1); _Rt =1.52min.

Embodiment 60 (general technique (B))

3-(4-Cyclopentyl-piperazin-1-yl)-6-(4-methylsulfonyl-phenyl)-pyridazine

Starting from 1-cyclopentylpiperazine and 3-chloro-6-(4-methylsulfonyl-phenyl)-pyridazine prepared as described in J.Heterocycl.Chem., 15, 881 (1978), according to general Process (B) prepares this compound.

¹ H NMR (CDCl ₃ ): δ1.38-1.80 (m, 6H), 1.92 (m, 2H); 2.56 (quint, 1H); 2.66 (dd, 4H); 3.10 (s, 3H); 3.97 (dd , 4H); 6.99(d, 1H); 7.69(d, 1H); 8.03(d, 2H); 8.20(d, 2H); HPLC-MS: m/z=387.0(M+1); R _t = 2.20min.

Embodiment 61 (general technique (B))

3-(4-Cyclopropylmethyl-piperazin-1-yl)-6-(4-methylsulfonyl-phenyl)-pyridazine

Starting from 1-cyclopentylpiperazine and 3-chloro-6-(4-methylsulfonyl-phenyl)-pyridazine prepared as described in J.Heterocycl.Chem., 15, 881 (1978), according to general Process (B) prepares this compound.

¹ H NMR (CDCl ₃ ): δ0.15(q, 2H); 0.57(m, 2H); 0.92(m, 1H); 2.34(d, 2H); 2.69(dd, 4H); ); 3.80(dd, 4H); 7.01(d, 1H); 7.70(d, 1H); 8.03(d, 2H); 8.21(d, 2H); HPLC-MS: m/z=373.4(M+1 ); _Rt = 2.04min.

Embodiment 62 (general technique (B))

3-(4-Isopropyl-piperazin-1-yl)-6-(4-methylsulfonyl-phenyl)-pyridazine

Starting from 1-isopropylpiperazine and 3-chloro-6-(4-methylsulfonyl-phenyl)-pyridazine prepared as described in J.Heterocycl.Chem., 15, 881 (1978), the general Process (B) prepares this compound.

¹ H NMR (DMSO-d ₆ ): δ1.01(d, 6H); 2.57(m, 4H); 2.71(m, 1H); 3.26(s, 3H); 3.67(m, 4H); , 1H); 8.02(d, 2H); 8.06(d, 1H); 8.30(d, 2H); HPLC-MS: m/z=360.8(M+1); _Rt =1.43min.

Embodiment 63 (general technique (B))

3-(4-Chloro-phenyl)-6-(4-isopropyl-piperazin-1-yl)-4-methyl-pyridazine, dihydrochloride

Starting from 1-isopropylpiperazine and 6-chloro-3-(4-chloro-phenyl)-4-methyl-pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978) , the compound was prepared according to the general procedure (B).

¹ H NMR (D ₂ O): δ1.08 (d, 6H); 2.10 (s, 1H); 3.01 (m, 2H); 3.23 (m, 2H); 3.28-3.44 (m, 3H); broad d, 2H); 7.27(d, 2H); 7.34(d, 2H); 7.58(s, 1H); HPLC-MS: m/z=331.1(M+1); _Rt =3.1min.

C18H23N4Cl, 2HCl

Calculated value C53.54 H6.24 N13.88

The measured value is C53.34 H6.31 N13.70.

Embodiment 64 (general technique (B))

3-(4-Chloro-phenyl)-6-(4-cyclopentyl-piperazin-1-yl)-4-methyl-pyridazine, hydrochloride

Starting from 1-cyclopentylpiperazine and 6-chloro-3-(4-chloro-phenyl)-4-methyl-pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978) , the compound was prepared according to the general procedure (B).

¹ H NMR (D ₂ O): δ1.29-1.60 (m, 6H); 1.91 (m, 2H); 2.12 (s, 3H); 3.00 (m, 2H); 3.24 (m, 2H); m, 1H); 3.51 (broad d, 2H); 4.29 (broad d, 2H); 7.29 (d, 2H); 7.36 (d, 2H); 7.60 (s, 1H); HPLC-MS: m/z = 357.1 (M+1); R _t = 3.25 min.

C20H25N4Cl, 2HCl

Calculated value C55.89 H6.33 N13.04

The measured value is C55.83 H6.47 N12.93.

Embodiment 65 (general technique (B))

3-(4-Chlorophenyl)-6-(4-cyclopentylpiperazin-1-yl)-pyridazine

Starting from 1-cyclopentylpiperazine and 3-chloro-6-(4-chloro-phenyl)-pyridazine prepared as described in J.Heterocycl.Chem., 15, 881 (1978), as in Example 6 The compound was prepared as described. The free base of the title compound was obtained.

¹ H NMR (CDCl ₃ ): δ1.39-1.81 (m, 6H), 1.91 (m, 2H), 2.56 (q, 1H), 2.66 (dd, 4H), 3.74 (dd, 4H), 6.96 (d , J=9.5Hz, 1H), 7.43(d, J=8.7Hz, 2H), 7.61(d, J=9.5Hz, 1H), 7.93(d, J=8.7Hz, 2H); HPLC-MS (Method #): m/z=343(M+1); _Rt =2.93min.

Embodiment 66 (general technique (B))

3-(4-Cyclopentylpiperazin-1-yl)-6-(3-fluoro-4-methoxyphenyl)-pyridazine, dihydrochloride

Starting from 1-cyclopentylpiperazine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978) , the compound was prepared as described in Example 6.

¹ H NMR (DMSO-d ₆ ): δ1.45-2.15 (m, 8H), 3.17 (m, 2H), 3.40-3.77 (m, 5H), 3.92 (s, 3H), 7.34 (t, J= 8.7Hz, 1H), 7.80(d, J=9.8Hz, 1H), 7.85-8.05(m, 2H), 8.29(d, J=9.8Hz, 1H), 11.75(bs, 1H); HPLC-MS: m/z=357(M+1); _Rt =2.47min.

Embodiment 67 (general technique (B))

3-(4-cyclopentylpiperazin-1-yl)-6-(3,4-dimethoxyphenyl)-pyridazine

Starting from 1-cyclopentylpiperazine and 3-chloro-6-(3,4-dimethoxyphenyl)-pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978), This compound was prepared as described in Example 6. The free base of the title compound was obtained.

¹ H NMR (CDCl ₃ ): δ1.40-1.65(m, 4H), 1.73(m, 2H), 1.91(m, 2H), 2.55(q, 1H), 2.66(t, 4H), 3.72(t , 4H), 3.93(s, 3H), 3.98(s, 3H), 6.93(d, 1H), 6.97(d, 1H), 7.36(dd, 1H), 7.64(d, 1H), 7.86(d, 1H); HPLC-MS: m/z = 370 (M+1); R _t = 1.90 min.

Embodiment 68 (general technique (B))

3-(4-Chlorophenyl)-6-(4-cyclopropylmethylpiperazin-1-yl)-pyridazine

Starting from 1-cyclopropylmethylpiperazine and 3-chloro-6-(4-chlorophenyl)-pyridazine prepared as described in J.Heterocycl.Chem., 15, 881 (1978), as in Example The compound was prepared as described in 6. The free base of the title compound was obtained.

¹ H NMR (CDCl ₃ ): δδ0.46 (m, 2H), 0.88 (m, 2H), 1.33 (m, 1H), 2.90 (d, 2H), 3.1-3.5 (m, 4H), 4.1-4.35 (m, 4H), 7.05(d, 1H), 7.46(d, 2H), 7.72(d, 1H), 7.95(d, 2H); HPLC-MS: m/z=329(M+1); R _t = 2.11min.

Embodiment 69 (general technique (B))

[name]

Starting from 1-cyclopentylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978), as carried out This compound was prepared as described in Example 6. The free base of the title compound was obtained.

¹ H NMR (CDCl ₃ ): δ1.40-1.65 (m, 4H), 1.65-1.80 (m, 2H), 1.92 (m, 2H), 2.55 (q, 1H), 2.65 (t, 4H), 3.76 (t, 4H), 6.99(d, 1H), 7.67(d, 1H), 7.72(d, 2H), 8.12(d, 2H); HPLC-MS): m/z=377(M+1); _Rt = 2.68min.

Embodiment 70 (general technique (B))

3-(4-Isopropylpiperazin-1-yl)-6-(4-trifluoromethylphenyl)-pyridazine

Starting from 1-isopropylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine prepared as described in J.Heterocycl.Chem., 15, 881 (1978), as carried out This compound was prepared as described in Example 6. The free base of the title compound was obtained.

¹ H NMR (DMSO-d ₆ ): δ1.20(d, 6H), 2.8-4.2(m, 9H), 7.47(d, 1H), 7.85(d, 2H), 8.12(d, 1H), 8.28 (d, 2H); HPLC-MS: m/z = 351 (M+1); R _t = 2.51 min.

Embodiment 71 (general technique (B))

3-(4-Cyclopropylmethylpiperazin-1-yl)-6-(4-trifluoromethylphenyl)-pyridazine

Starting from 1-cyclopropylmethylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978), This compound was prepared as described in Example 6. The free base of the title compound was obtained.

¹ H NMR (CDCl ₃ ): δ0.15(m, 2H), 0.57(m, 2H), 0.92(m, 1H), 2.33(d, 2H), 2.69(t, 4H), 3.79(t, 4H ), 7.00(d, 1H), 7.67(d, 1H), 7.72(d, 2H), 8.12(d, 2H); HPLC-MS: m/z=363(M+1); _Rt =2.65min .

Embodiment 72 (general technique (B))

3-(4-Chlorophenyl)-6-(4-isopropylpiperazin-1-yl)-pyridazine

Starting from 1-isopropylpiperazine and 3-chloro-6-(4-chlorophenyl)-pyridazine prepared as described in J.Heterocycl.Chem., 15, 881 (1978), as described in Example 6 The compound was prepared as described. The free base of the title compound was obtained.

¹ H NMR (CDCl ₃ ): δ1.10(d, 6H), 2.68(t, 4H), 2.75(q, 1H), 3.73(t, 4H), 6.97(d, 1H), 7.43(d, 2H ), 7.61(d, 1H), 7.94(d, 2H); HPLC-MS: m/z=317(M+1); R _t =2.03min.

Embodiment 73 (general technique (B))

3-(4-cyclopropylmethylpiperazin-1-yl)-6-(3-fluoro-4-methoxyphenyl)-pyridazine

From 1-cyclopropylmethylpiperazine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridium prepared as described in J.Heterocycl.Chem., 15, 881 (1978) The compound was prepared as described in Example 6 starting from oxazine. The free base of the title compound was obtained.

¹ H NMR (DMSO-d ₆ ): δ0.40(m, 2H), 0.65(m, 2H), 1.15(m, 1H), 2.8-3.7(m, 10H), 3.90(s, 3H), 7.29 (t, 1H), 7.47(d, 1H), 7.88(d, 1H), 7.93(d, 1H), 8.06(d, 1H); HPLC-MS: m/z=343(M+1); R _t = 1.90min,

Embodiment 74 (general technique (B))

3-(3-fluoro-4-methoxyphenyl)-6-(4-isopropylpiperazin-1-yl)-pyridazine

Starting from 1-isopropylpiperazine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978) , the compound was prepared as described in Example 6. The free base of the title compound was obtained.

¹ H NMR (CDCl ₃ ): δ1.11(d, 6H), 2.70(m, 4H), 2.80(q, 1H), 3.74(m, 4H), 3.94(s, 3H), 6.96(d, 1H ), 7.04(t, 1H), 7.57(d, 1H), 7.72(d, 1H), 7.78(m, 1H); HPLC-MS: m/z=331(M+1); _Rt =1.57min .

Embodiment 75 (general technique (B))

3-(3,4-Dimethoxyphenyl)-6-(4-isopropylpiperazin-1-yl)-pyridazine, dihydrochloride

Starting from 1-isopropylpiperazine and 3-chloro-6-(3,4-dimethoxyphenyl)-pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978), This compound was prepared as described in Example 6. The free base of the title compound was obtained.

¹ H NMR (DMSO-d ₆ ): δ1.32 (d, 6H), 3.17 (q, 1H), 3.3-4.1 (m, 6H), 3.84 (s, 3H), 3.87 (s, 3H), 4.56 (d, 2H), 7.09(d, 1H), 7.62(d, 1H), 7.68-7.73(m, 2H), 8.23(d, 1H), 11.35(s, 1H); HPLC-MS: m/z = 343 (M+1); R _t = 1.50 min.

Embodiment 76 (general technique (B))

(9a-R)-2-(6-trifluoromethoxyquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride

This compound was prepared from (9a-R)-octahydropyrido[1,2-a]pyrazine and 2-chloro-6-trifluoromethoxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.40-1.65 (m, 1H), 1.65-2.08 (m, 5H), 2.93 (m, 1H), 3.18 (m, 1H), 3.25-3.55 (m, 4H) ), 3.71(m, 1H), 4.85(m, 2H), 7.61(d, J=8Hz, 1H), 7.70(d, J=8Hz, 1H), 7.93(s, 1H), 8.19(br s, 1H), 8.39 (d, J=8Hz, 1H), 11.60 (br s, 1H); HPLC-MS: m/z 352 (MH ⁺ ); Rt=2.67min.

Embodiment 77 (general technique (B))

7-Fluoro-2-(4-isopropylpiperazin-1-yl)-6-methylquinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-7-fluoro-6-methylquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.32 (d, J=7Hz, 6H), 2.38 (s, 3H), 3.26 (m, 2H), 3.54 (m, 3H), 3.83 (m, 2H), 4.88(br s, 2H), 7.49(d, J=8Hz, 1H), 7.85(d, J=8Hz, H), 8.09(br s, 1H), 8.35(d, J=8Hz, 1H), 11.57 (br s, 1H); HPLC-MS: m/z 287 (MH ⁺ ); Rt=1.47min.

Embodiment 78 (general technique (B))

7-Chloro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2,7-dichloroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3, 23 (m, 2H), 3.53 (m, 3H), 3.79 (m, 2H), 4.87 (br s, 2H), 7.48(d, J=8Hz, 1H), 7.54(d, J=8Hz, 1H), 7.92(d, J=8Hz, 1H), 8.26(br s, 1H), 8.38(d, J= 8Hz, 1H), 11.50 (br s, 1H); HPLC-MS: m/z 289 (MH ⁺ ); Rt=1.61min.

Embodiment 79 (general technique (B))

6-fluoro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-6-fluoroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.22 (m, 2H), 3.53 (m, 3H), 3.79 (m, 2H), 4.85 (br s, 2H) , 7.55-7.70 (m, 2H), 7.45 (d, J=8Hz, 1H), 8.26 (br s, 1H), 8.36 (d, J=8Hz, 1H), 11.52 (br s, 1H); HPLC- MS: m/z 274 (MH ⁺ ); Rt = 1.21 min.

Embodiment 80 (general technique (B))

2-(4-Cyclopropylpiperazin-1-yl)-7-fluoro-6-methylquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-7-fluoro-6-methylquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.20 (m, 2H), 2.36 (s, 3H), 2.87 (m, 1H); 3.25-4.15 (m, 6H), 4.74 ( br s, 2H), 7.43(d, J=8Hz, 1H), 7.80(m, 2H), 8.28(d, J=8Hz, 1H), 11.36(br s, 1H); HPLC-MS: m/z 287 (MH ⁺ ); Rt = 1.47min.

Embodiment 81 (general technique (B))

2-(4-Cyclopropylpiperazin-1-yl)-7-fluoro-6-methoxyquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-7-fluoro-6-methoxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.18 (m, 2H), 2.88 (m, 1H), 3.25-4.10 (m, 6H), 3.93 (s, 3H), 4.64 ( br s, 2H), 7.40(d, J=8Hz, 1H), 7.55(d, J=8Hz, 1H), 7.73(br s, 1H), 8.24(d, J=8Hz, 1H), 11.11(br s, 1H); HPLC-MS: m/z 301 (MH ⁺ ); Rt=1.37min.

Embodiment 82 (general technique (B))

7-fluoro-2-(4-isopropylpiperazin-1-yl)-6-methoxyquinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-7-fluoro-6-methoxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.16 (m, 2H), 3.45-4.05 (m, 5H), 3.93 (s, 3H), 4.72 (m, 2H ), 7.42(d, J=8Hz, 1H), 7.56(d, J=8Hz, 1H), 7.83(br s, 1H), 8.25(d, J=8Hz, 1H), 11.13(br s, 1H) ; HPLC-MS: m/z 303 (MH ⁺ ); Rt = 1.41 min.

Embodiment 83 (general technique (B))

(9a-R)-2-(7-fluoro-6-methoxyquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride

This compound was prepared from (9a-R)octahydropyrido[1,2-a]pyrazine and 2-chloro-7-fluoro-6-methoxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.40-1.55 (m, 1H), 1.65-2.08 (m, 5H), 2.93 (m, 1H), 3.20 (m, 1H), 3.25-3.55 (m, 4H) ), 3.73(m, 1H), 4.81(m, 2H), 7.50(d, J=8Hz, 1H), 7.62(d, J=8Hz, 1H), 8.13(br s, 1H), 8.34(d, J=8Hz, 1H), 11.59 (br s, 1H); HPLC-MS: m/z 315 (MH ⁺ ); Rt=1.41min.

Embodiment 84 (general technique (B))

(9a-R)-2-(6-trifluoromethylquinolin-2-yl)octahydropyrido[1,2-]pyrazine hydrochloride

This compound was prepared from (9a-R)-octahydropyrido[1,2-a]pyrazine and 2-chloro-6-trifluoromethylquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.40-1.55 (m, 1H), 1.65-2.05 (m, 5H), 2.92 (m, 1H), 3.20 (m, 1H), 3.30-3.55 (m, 4H) ), 3.70(m, 1H), 4.88(m, 2H), 7.61(d, J=8Hz, 1H), 7.93(d, J=8Hz, 1H), 8.15(br s, 1H), 8.31(s, 1H), 8.43 (d, J=8Hz, 1H), 11.60 (br s, 1H); HPLC-MS: m/z 335 (MH ⁺ ); Rt=2.27min.

Embodiment 85 (general technique (B))

7-fluoro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-7-fluoroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.19 (m, 2H), 3.45-4.20 (m, 5H), 4.84 (m, 2H), 7.32 (m, 1H) ), 7.45 (d, J=8Hz, 1H), 7.83 (br s, 1H), 7.95 (m, 1H), 8.35 (m, 1H), 11.35 (br s, 1H); HPLC-MS: m/z 274 (MH ⁺ ); Rt = 1.31min.

Embodiment 86 (general technique (B))

6-Chloro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2,6-dichloroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.19 (m, 2H), 3.45-3.80 (m, 5H), 4.82 (m, 2H), 7.55 (d, J =8Hz, 1H), 7.72(d, J=8Hz, 1H), 7.99(s, 1H), 8.07(br s, 1H), 8.29(d, J=8Hz, 1H), 11.38(br s, 1H) ; HPLC-MS: m/z 290 (MH ⁺ ); Rt = 1.64min.

Embodiment 87 (general technique (B))

6-isopropyl-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-6-isopropylquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.27(d, J=7Hz, 6H), 1.32(d, J=7Hz, 6H), 3.05(sept, J=7Hz, 1H), 3.26(m, 2H) , 3.40-3.95(m, 5H), 4.86(m, 2H), 7.55(d, J=8Hz, 1H), 7.72(d, J=8Hz, 1H), 7.77(s, 1H), 8.21(br s , 1H), 8.42 (d, J=8Hz, 1H), 11.55 (br s, 1H); HPLC-MS: m/z 298 (MH ⁺ ); Rt=1.87min.

Embodiment 88 (general technique (B))

2-(4-Cyclopropylpiperazin-1-yl)-6-isopropylquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-6-isopropylquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.20 (m, 2H), 1.27 (d, J=7Hz, 6H), 2.86 (br s, 1H), 3.04 (sept, J= 7Hz, 1H), 3.25-3.85(m, 5H), 4.15(brs, 1H), 4.74(m, 2H), 7.53(m, 1H), 7.70(d, J=8Hz, 1H), 7.75(s, 1H), 8.06 (br s, 1H), 8.38 (m, 1H), 11.41 (br s, 1H); HPLC-MS: m/z (MH ⁺ ); Rt=min.

Embodiment 89 (general technique (B))

2-(4-Cyclopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.19 (m, 2H), 2.87 (br s, 1H), 3.30-3.80 (m, 6H), 4.74 (m, 2H), 7.45 (m, 1H), 7.52(d, J=8Hz, 1H), 7.73(m, 1H), 7.89(d, J=8Hz, 1H), 8.02(br s, 1H), 8.38(m, 1H), 11.22 (br s, 1H); HPLC-MS: m/z (MH ⁺ ); Rt=min.

Embodiment 90 (general technique (B))

2-(4-cyclopropylpiperazin-1-yl)-6,7-dimethoxyquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-6,7-dimethoxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ )δ0.82(m, 2H), 1.20(m, 2H), 2.87(br s, 1H), 3.25-3.75(m, 6H), 3.86(s, 3H), 3.90 (s, 3H), 4.66 (m, 2H), 7.25-7.50 (m, 3H), 8.24 (br s, 1H), 11.38 (br s, 1H); HPLC-MS: m/z 314 (MH ⁺ ) ;Rt=1.27min.

Embodiment 91 (general technique (B))

2-(4-Isopropylpiperazin-1-yl)-6,7-dimethoxyquinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-6,7-dimethoxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.32 (d, J=7Hz, 6H), 3.25 (m, 2H), 3.45-4.00 (m, 5H), 3.87 (s, 3H), 3.91 (s, 3H) ), 4.80 (m, 2H), 7.39 (m, 2H), 7.96 (br s, 1H), 8.34 (br s, 1H), 11.50 (br s, 1H); HPLC-MS: m/z 316 (MH ⁺ ); Rt＝1.27min.

Embodiment 92 (general technique (B))

2-(4-Cyclopropylpiperazin-1-yl)-7-fluoroquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-7-fluoroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.22 (m, 2H), 2.87 (br s, 1H), 3.30-3.80 (m, 6H), 4.79 (m, 2H), 7.34 (m, 1H), 7.47(d, J=8Hz, 1H), 7.85(br s, 1H), 7.96(m, 1H), 8.37(m, 1H), 11.55(br s, 1H); HPLC-MS : m/z 271 (MH ⁺ ); Rt=1.24min.

Embodiment 93 (general technique (B))

2-(4-cyclopropylpiperazin-1-yl)-6,8-difluoroquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-6,8-difluoroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.19 (m, 2H), 2.87 (brs, 1H), 3.20-3.70 (m, 6H), 4.63 (m, 2H), 7.48 ( m, 3H), 8.19 (d, J=8Hz, 1H), 11.11 (br s, 1H); HPLC-MS: m/z 290 (MH ⁺ ); Rt=2.27min.

Embodiment 94 (general technique (B))

2-(4-Cyclopropylpiperazin-1-yl)-6-fluoroquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-6-fluoroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.21 (m, 2H), 2.87 (br s, 1H), 3.30-3.80 (m, 6H), 4.73 (m, 2H), 7.56 (d, J=8Hz, 1H), 7.62(m, 1H), 7.71(d, J=8Hz, 1H), 8.09(br s, 1H), 8.33(d, J=8Hz, 1H), 11.42(br s, 1H); HPLC-MS: m/z 272 (MH ⁺ ); Rt = 1.27min.

Embodiment 95 (general technique (B))

7-Chloro-2-(4-cyclopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2,7-dichloroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.20 (m, 2H), 2.87 (br s, 1H), 3.25-3.75 (m, 6H), 4.72 (m, 2H), 7.40 (d, J=8Hz, 1H), 7.46(d, J=8Hz, 1H), 7.87(d, J=8Hz, 1H), 7.94(br s, 1H), 8.29(d, J=8Hz, 1H) , 11.29 (br s, 1H); HPLC-MS: m/z 288 (MH ⁺ ); Rt=1.71min.

Embodiment 96 (general technique (B))

(9a-R)-2-quinolin-2-yl-octahydropyrido[1,2-a]pyrazine hydrochloride

This compound was prepared from (9a-R)-octahydropyrido[1,2-a]pyrazine and 2-chloroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.40-1.55 (m, 1H), 1.65-2.10 (m, 5H), 2.92 (m, 1H), 3.25 (m, 1H), 3.35-3.90 (m, 5H) ), 4.90(m, 2H), 7.49(m, 1H), 7.59(d, J=8Hz, 1H), 7.77(m, 1H), 7.92(d, J=8Hz, 1H), 8.32(br s, 1H), 8.46 (m, 1H), 11.69 (br s, 1H); HPLC-MS: m/z 268 (MH ⁺ ); Rt=1.07min.

Embodiment 97 (general technique (B))

(9a-R)-2-(6-Chloroquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride

This compound was prepared from (9a-R)-octahydropyrido[1,2-a]pyrazine and 2,6-dichloroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.40-1.55 (m, 1H), 1.65-2.05 (m, 5H), 2.93 (m, 1H), 3.18 (m, 1H), 3.25-3.55 (m, 4H) ), 3.68(m, 1H), 4.90(m, 2H), 7.56(d, J=8Hz, 1H), 7.71(d, J=8Hz, 1H), 7.98(s, 1H), 8.07(br s, 1H), 8.29 (d, J=8Hz, 1H), 11.47 (br s, 1H); HPLC-MS: m/z 302 (MH ⁺ ); Rt=1.81min.

Embodiment 98 (general technique (B))

(9a-R)-2-(7-fluoro-6-methylquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride

This compound was prepared from (9a-R)-octahydropyrido[1,2-a]pyrazine and 2-chloro-7-fluoro-6-methylquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.40-1.55 (m, 1H), 1.65-2.10 (m, 5H), 2.36 (s, 3H), 2.92 (m, 1H), 3.23 (m, 1H), 3.30-3.60(m, 4H), 3.80(m, 1H), 4.87(m, 2H), 7.51(d, J=8Hz, 1H), 7.84(d, J=8Hz, 1H), 8.13(br s, 1H), 8.36(d, J=8Hz, 1H), 11.77(br s, 1H); HPLC-MS: m/z 300 (MH ⁺ ); Rt=1.54min.

Embodiment 99 (general technique (B))

(9a-R)-2-(6-Propylquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride

This compound was prepared from (9a-R)-octahydropyrido[1,2-a]pyrazine and 2-chloro-6-propylquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.91(t, J=7Hz, 3H), 1.40-1.55(m, 1H), 1.60-2.10(m; 7H), 2.70(t, J=7Hz, 2H) , 2.92(m, 1H), 3.24(m, 1H), 3.30-3.85(m, 5H), 4.88(m, 2H), 7.57(d, J=8Hz, 1H), 7.65(d, J=8Hz, 1H), 7.72(s, 1H), 8.28(br s, 1H), 8.41(m, 1H), 11.69(br s, 1H); HPLC-MS: m/z 309(MH ⁺ ); Rt=2.27min .

Embodiment 100 (general process (B))

2-(4-Isopropylpiperazin-1-yl)quinoxaline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloroquinoxaline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.13 (m, 2H), 3.45-3.65 (m, 5H), 4.75 (m, 2H), 7.48 (m, 1H ), 7.66(m, 2H), 7.88(d, J=8Hz, 1H), 8.91(s, 1H), 11.15(br s, 1H); HPLC-MS: m/z257(MH ⁺ ); Rt=1.25 min.

Embodiment 101 (general technique (B))

[4-(4-Cyclopropylpiperazin-1-yl)phenyl]phenylphenone hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 4-fluorobenzophenone using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.16 (m, 2H), 2.92 (br s, 1H), 3.30-3.40 (m, 4H), 3.56 (brs, 2H), 4.09 (m, 2H), 7.12 (d, J=8Hz, 2H), 7.54 (m, 2H), 7.60-7.75 (m, 5H), 10.82 (br s, 1H); HPLC-MS: m/z307 (MH ⁺ ); Rt＝2.00min.

Embodiment 102 (general technique (B))

[4-(4-Cyclopropylpiperazin-1-yl)-3,5-difluorophenyl]phenylphenone hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 3,4,5-trifluorobenzophenone using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.16 (m, 2H), 2.96 (br s, 1H), 3.30-3.75 (m, 8H), 7.43 (d, J=8Hz, 2H), 7.58(t, J=8Hz, 2H), 7.65-7.78(m, 3H), 10.90(br s, 1H); HPLC-MS: m/z 343(MH ⁺ ); Rt=2.29min.

Embodiment 103 (general technique (B))

2-(4-Isopropylpiperazin-1-yl)-5,6,7-trimethoxyquinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-5,6,7-trimethoxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.21 (m, 2H), 3.45-3.85 (m, 5H), 3.82 (s, 3H), 3.93 (s, 3H) ), 3.99(s, 3H), 4.78(m, 2H), 7.31(m, 1H), 7.56(m, 1H), 8.31(m, 1H), 11.36(br s, 1H); HPLC-MS: m /z 346(MH ⁺ ); Rt=1.22min.

Embodiment 104 (general technique (B))

2-(4-cyclopropylpiperazin-1-yl)-5,6,7-trimethoxyquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-5,6,7-trimethoxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ )δ0.82 (m, 2H), 1.22 (m, 2H), 2.87 (br s, 1H), 3.30-4.10 (m, 6H), 3.83 (s, 3H), 3.93 (s, 3H), 4.00 (s, 3H), 4.76 (m, 2H), 7.33 (m, 1H), 7.65 (br s, 1H), 8.34 (m, 1H), 11.62 (br s, 1H); HPLC-MS: m/z 344 (MH ⁺ ); Rt = 1.46 min.

Embodiment 105 (general technique (B))

2-(4-Cyclopropylpiperazin-1-yl)-6-trifluoromethylthioquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-6-trifluoromethylthioquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.20 (m, 2H), 2.86 (br s, 1H), 3.20-3.70 (m, 6H), 4.75 (m, 2H), 7.53 (m, 1H), 7.86(m, 2H), 8.20-8.40(m, 2H), 11.28(br s, 1H); HPLC-MS: m/z 354(MH ⁺ ); Rt=2.61min.

Embodiment 106 (general technique (B))

7-Chloro-2-(4-cyclopropylpiperazin-1-yl)-6-methoxyquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2,7-dichloro-6-methoxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.16 (m, 2H), 2.88 (m, 1H), 3.25-3.70 (m, 6H), 3.94 (s, 3H), 4.62 ( m, 2H), 7.45(d, J=8Hz, 1H), 7.51(s, 1H), 7.96(br s, 1H), 8.23(d, J=8Hz, 1H), 10.98(br s, 1H); HPLC-MS: m/z 318 (MH ⁺ ); Rt = 1.80 min.

Embodiment 107 (general technique (B))

5,7-Dichloro-2-(4-cyclopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2,5,7-trichloroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.19 (m, 2H), 2.86 (m, 1H), 3.20-3.65 (m, 6H), 4.69 (m, 2H), 7.51 ( d, J=8Hz, 1H), 7.56(s, 1H), 7.68(s, 1H), 8.30(d, J=8Hz, 1H), 11.24(br s, 1H); HPLC-MS: m/z 322 (MH ⁺ ); Rt = 2.78min.

Embodiment 108 (general technique (B))

1-Cyclopropyl-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazine hydrochloride

The desired 2-chloro-5-(4-trifluorophenyl)pyridine is as described by R.Church, R.Trust, J.D.Albright, and D.Powell, J.Org.Chem.1995, 60, 3750-3758 Prepared as described, in the following manner:

4-(Trifluoromethyl)phenylacetic acid (6.64 g, 0.033mol). The mixture was stirred at 70°C for 8 hours. After cooling to ambient temperature, the mixture was slowly added to ice-water mixture (temperature < 10° C.), followed by Na ₂ CO ₃ solution until pH 11 was reached. Toluene (125 ml) was added to the basic mixture, and the resulting mixture was refluxed for 1.5 hours. After cooling to ambient temperature, the aqueous layer was separated and extracted with toluene (100ml). The organic layers were combined, washed with water, _dried ( _Na2SO4 ), concentrated under reduced pressure. The resulting solid was recrystallized from a mixture of dichloromethane and heptane to afford 6.98 g (87%) of 3-dimethylamino-2-(4-trifluoromethylphenyl)acrolein as yellow crystals, mp. 97°C.

¹ H NMR spectrum (CDCl ₃ ) δ9.10(s, 1H), 7.57(m, 2H), 7.32(m, 2H), 6.95(s, 1H), 2.85(s, 6H); _RF (SiO ₂ , chloroform/methanol 95:5) 0.34.

To a solution of sodium methoxide (3.64g, 0.068mol) in methanol (68ml) was added cyanoacetamide (6.95g, 0.082mol) and the previous product (6.98g, 0.029mol). The mixture was stirred at ambient temperature for 1.5 hours, then refluxed for 8 hours. During this time a yellow solid precipitated out. The reaction mixture was diluted with water (75ml) and acidified with 10% aqueous hydrochloric acid. The yellow solid was filtered off, washed with water, ethanol, diethyl ether, then hexane. 2-Hydroxy-5-(4-trifluoromethylphenyl)nicotinonitrile (6.66 g, 87%) was obtained as a yellow solid, mp. 235-242°C.

¹ H NMR (DMSO-d ₆ ) δ8.42 (m, 1H), 7.91 (m, 1H), 7.66 (m, 4H); _RF (SiO ₂ , chloroform/methanol 95:5) 0.18.

To a mixture of acetic acid (100ml) and concentrated hydrochloric acid (70ml) was added the preceding product (6.66g, 0.025mol). The reaction mixture was refluxed for 18 hours, diluted with water (200ml) and cooled to room temperature with stirring. The solid was filtered off and washed with water then 50% aqueous ethanol to give 5.42 g (77%) of 2-hydroxy-5-(4-trifluoromethylphenyl)nicotinic acid as a light gray solid, mp.305-315 ℃.

¹ H NMR (DMSO-d ₆ ) δ8.71 (d, 1H), 8.43 (d, 1H), 7.96 (m, 2H), 7.81 (m, 2H); _RF (SiO ₂ , chloroform/methanol 95: 5) 0.13.

A mixture of the preceding product (5.42 g, 0.019 mol) and freshly distilled quinoline (50 ml) was stirred at 215°C for 12 hours. The reaction mixture was cooled to ambient temperature and heptane (250ml) was added. The solid was filtered off, washed with heptane and recrystallized from a mixture of dichloromethane and heptane to give 3.92 g (86%) of 2-hydroxy-5-(4-trifluoromethylphenyl)pyridine, mp.178 -182°C.

¹ H NMR (CDCl ₃ ) δ7.79 (dd, 2H), 7.68 (d, 3H), 7.52 (d, 2H), 6.73 (d, 1H); _RF (SiO ₂ , chloroform/methanol 95:5) 0.23.

A mixture of phosphorus oxychloride (27.6 g, 0.18 mol) and the previous product (3.92 g, 0.016 mol) was stirred at 105°C for 10 hours. Excess phosphorus oxychloride was evaporated under reduced pressure and the residue was stripped once with toluene (75ml). Water (75ml) and dichloromethane (75ml) were added to the residue, the dichloromethane layer was separated, and the aqueous phase was extracted with dichloromethane (75ml). The combined extracts were washed with water, then sodium bicarbonate solution, dried ( _MgSO4 ) and concentrated under reduced pressure to afford 2.95 g (72%) of 2-chloro-5-(4-trifluoromethylphenyl)pyridine , as light brown crystals, mp.98-101°C.

¹ H NMR (CDCl ₃ ) δ8.62(dd, 1H), 7.86(dd, 1H), 7.44(dd, 1H), 7.66(m, 2H), 7.75(m, 2H); _RF (SiO ₂ , Chloroform/methanol 95:5) 0.94.

Treatment of this product with 1-cyclopropylpiperazine as described in General Procedure (B) afforded the title compound.

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.13 (m, 2H), 2.85 (m, 1H), 3.25-3.75 (m, 6H), 4.51 (m, 2H), 7.12 ( d, J=8Hz, 1H), 7.79(d, J=8Hz, 2H), 7.89(d, J=8Hz, 2H), 8.05(m, 1H), 8.59(m, 1H), 10.56(br s, 1H); HPLC-MS: m/z 348 (MH ⁺ ); Rt=2.77min.

Embodiment 109 (general technique (B))

3-(4-cyclopropylpiperazin-1-yl)-6-(4-trifluoromethylphenyl)pyridazine hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)pyridazine using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.19 (m, 2H), 2.89 (m, 1H), 3.30-3.70 (m, 6H), 4.61 (m, 2H), 7.61 ( d, J=8Hz, 1H), 7.88(d, J=8Hz, 2H), 8.22(d, J=8Hz, 1H), 8.29(d, J=8Hz, 2H), 11.11(br s, 1H); HPLC-MS: m/z 349 (MH ⁺ ); Rt = 2.40 min.

Embodiment 110 (general technique (B))

6-(4-Cyclopropylpiperazin-1-yl)-[1,3]dioxolane[4,5-g]quinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 6-chloro[1,3]dioxolano[4,5-g]quinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.15 (m, 2H), 2.88 (m, 1H), 3.20-3.70 (m, 6H), 4.59 (m, 2H), 6.17 ( s, 2H), 7.29 (m, 3H), 8.13 (m, 1H), 10.80 (br s, 1H); HPLC-MS: m/z 298 (MH ⁺ ); Rt=0.68min.

Embodiment 111 (general technique (B))

6-cyclohexyl-2-(4-cyclopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-6-cyclohexylquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.10-1.55 (m, 8H), 1.70-1.93 (m, 4H), 2.65 (m, 1H), 2.86 (m, 1H), 3.30-3.70(m, 6H), 4.72(m, 2H), 7.50(m, 1H), 7.66(m, 1H), 7.72(m, 1H), 7.99(br s, 1H), 8.35(br s, 1H), 11.29 (br s, 1H); HPLC-MS: m/z 336 (MH ⁺ ); Rt=2.55min.

Embodiment 112 (general technique (B))

6-cyclohexyl-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-6-cyclohexylquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.10-1.55 (m, 8H), 1.31 (d, J=7Hz, 6H), 1.70-1.93 (m, 4H), 2.65 (m, 1H), 3.23 (m , 2H), 3.50-3.85(m, 3H), 4.80(m, 2H), 7.51(m, 1H), 7.67(m, 1H), 7.73(m, 1H), 8.08(br s, 1H), 8.36 (br s, 1H), 11.31 (br s, 1H); HPLC-MS: m/z 338 (MH ⁺ ); Rt=2.50min.

Embodiment 113 (general technique (B))

2-(4-cyclopropylpiperazin-1-yl)-6,7-dimethoxy-3-methylquinoline hydrochloride

The required 2-chloro-6,7-dimethoxy-3-methylquinoline is prepared according to the technique disclosed in Tetrahedron Letters 1979,4885, in the following manner:

To a solution of 3,4-dimethoxyaniline (4.70 g, 30.7 mmol) in dichloromethane (50 ml) was added pyridine (8.0 ml, 3 eq) followed by dropwise addition of propionyl chloride (3.5 ml, 40.5 mmol). After stirring at room temperature for 1 hour and 50 minutes, the mixture was poured into a mixture of water (200ml) and concentrated hydrochloric acid (8ml). The phases were separated and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, washed with brine, dried over magnesium sulfate and concentrated to give 6.89 g of an oil which crystallized after a few minutes. Recrystallization from a mixture of ethyl acetate and heptane gave 3.60 g (49%) of N-(3,4-dimethoxyphenyl)propanamide as dark crystals.

The anilide (2.1 g, 10.0 mmol) was mixed with DMF (1.1 ml, 15 mmol), and POCl ₃ (6.5 ml, 70 mmol) was added dropwise to the mixture at room temperature. When the addition was complete, the mixture was stirred at 75°C for 2 hours. The mixture was poured into ice water (100ml), stirred for 30 minutes and filtered. The solid was stripped with toluene and acetonitrile to afford 1.60 g (67%) of 2-chloro-6,7-dimethoxy-3-methylquinoline as a solid. Treatment of this product with 1-cyclopropylpiperazine as described in General Procedure (B) afforded the title compound.

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.23 (m, 2H), 2.42 (s, 3H), 2.94 (m, 1H), 3.40-4.50 (m, 8H), 3.88 ( s, 3H), 3.91 (s, 3H), 7.29 (s, 1H), 7.48 (br s, 1H), 8.12 (br s, 1H), 11.24 (br s, 1H); HPLC-MS: m/z 328 (MH ⁺ ); Rt = 1.63min.

Embodiment 114 (general technique (B))

6-(4-Isopropylpiperazin-1-yl)-[1,3]dioxolane[4,5-g]quinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 6-chloro[1,3]dioxolano[4,5-g]quinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.40 (m, 2H), 3.45-4.00 (m, 5H), 4.72 (m, 2H), 6.21 (s, 2H) ), 7.34 (m, 2H), 7.62 (br s, 1H), 8.21 (m, 1H), 11.12 (br s, 1H); HPLC-MS: m/z 300 (MH ⁺ ); Rt=0.65min.

Embodiment 115 (general technique (B))

[3,5-Difluoro-4-(4-isopropyl-piperazin-1-yl)-phenyl]-piperidin-1-yl-methanone hydrochloride

This compound was prepared by the reaction of 1-isopropylpiperazine with piperonyl 3,4,5-trifluorobenzoate using general procedure (B). This reaction gave two products, this Example and Example 121.

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 1.40-1.62 (m, 6H), 3.09 (m, 2H), 3.20-3.65 (m, 11H), 7.12 (m , 2H), 10.42 (br s, 1H); HPLC-MS: m/z 352 (MH ⁺ ); Rt=3.75min.

Embodiment 116 (general technique (B))

(9a-R)-2-(6,7-dimethoxyquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride

This compound was prepared from (9a-R)octahydropyrido[1,2-a]pyrazine and 2-chloro-6,7-dimethoxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.40-1.55 (m, 1H), 1.65-2.05 (m, 5H), 2.93 (m, 1H), 3.22 (m, 1H), 3.25-3.60 (m, 4H) ), 3.65-4.20(m, 1H), 3.87(s, 3H), 3.90(s, 3H), 4.79(m, 2H), 7.40(m, 2H), 8.00(br s, 1H), 8.33(br s, 1H), 11.55 (br s, 1H); HPLC-MS: m/z 328 (MH ⁺ ); Rt=0.97min.

Embodiment 117 (general technique (B))

2-(4-cyclopropylpiperazin-1-yl)-5,6,7,8-tetrahydroquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-5,6,7,8-tetrahydroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.81 (m, 2H), 1.17 (m, 2H), 1.67-1.82 (m, 4H), 2.62 (m, 2H), 2.75-2.95 (m, 3H), 3.20-3.65 (m, 6H), 4.37 (m, 2H), 7.02 (br s, 1H), 7.63 (br s, 1H), 11.10 (br s, 1H); HPLC-MS: m/z 258 (MH ⁺ ); Rt＝0.62min.

Embodiment 118 (general technique (B))

[5-Chloro-6-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl]piperidin-1-ylmethanone hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 5,6-dichloronicotinic acid piperine using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 2H), 1.12 (m, 2H), 1.45-1.65 (m, 6H), 2.96 (m, 1H), 3.30-3.60 (m, 10H), 3.96(m, 2H), 7.89(s, 1H), 8.27(s, 1H), 10.68(br s, 1H); HPLC-MS: m/z 349(MH ⁺ ); Rt=1.50min.

Embodiment 119 (general technique (B))

(9a-R)-[6-(Octahydropyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl]piperidin-1-ylmethanone hydrochloride

This compound was prepared from (9a-R)-octahydropyrido[1,2-a]pyrazine and 6-chloronicotinic acid piperonide using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.51(m, 3H), 1.60(m, 2H), 1.78-1.98(m, 3H), 2.90-3.25(m, 4H), 3.30-3.50(m, 5H ), 3.74(m, 6H), 4.50(m, 2H), 7.02(d, J=7Hz, 1H), 7.66(d, J=7Hz, 1H), 8.19(s, 1H), 10.86(br s, 1H); HPLC-MS: m/z 329 (MH ⁺ ); Rt=1.31min.

Embodiment 120 (general technique (B))

[6-(4-Cyclopropylpiperazin-1-yl)pyridin-3-yl]piperidin-1-ylmethanone hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 6-chloronicotinic acid piperin using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.81 (m, 2H), 1.17 (m, 2H), 1.51 (m, 4H), 1.60 (m, 2H), 2.87 (m, 1H), 3.20-3.60 ( m, 10H), 4.47(m, 2H), 7.01(d, J=7Hz, 1H), 7.67(d, J=7Hz, 1H), 8.21(s, 1H), 11.04(br s, 1H); HPLC - MS: m/z 315 (MH ⁺ ); Rt = 1.22min.

Embodiment 121 (general technique (B))

[3,4-Difluoro-5-(4-isopropyl-piperazin-1-yl)-phenyl]-piperidin-1-yl-methanone hydrochloride

This compound was prepared by the reaction of 1-isopropylpiperazine with piperonyl 3,4,5-trifluorobenzoate using general procedure (B). This reaction gave two products, this Example and Example 115.

¹ H NMR (DMSO-d ₆ ) δ1.31(d, J=7Hz, 6H), 1.40-1.65(m, 6H), 3.12-3.62(m, 13H), 6.89(d, J=8Hz, 1H) , 7.09 (m, 1H), 11.09 (br s, 1H); HPLC-MS: m/z 352 (MH ⁺ ); Rt=3.95min.

Embodiment 122 (general technique (B))

[4-(4-Isopropyl-piperazin-1-yl)-3-trifluoromethyl-phenyl]-piperidin-1-yl-methanone hydrochloride

This compound was prepared using general procedure (B) via 1-isopropylpiperazine and 4-fluoro-3-trifluoromethylpiperylbenzoate.

¹ H NMR (DMSO-d ₆ ) δ1.31(d, J=7Hz, 6H), 1.40-1.65(m, 6H), 3.05(m, 1H), 3.15(m, 1H), 3.28(m, 8H ), 3.52 (m, 3H), 7.57 (br d, J=8Hz, 1H), 7.68 (br s, 1H), 7.71 (br d, J=8Hz, 1H), 10.39 (br s, 1H); HPLC - MS: m/z 384 (MH ⁺ ); Rt = 4.21 min.

Example 123

2-(4-cyclopropyl-3-methyl-piperazin-1-yl)-6,7-dimethoxy-quinoline hydrochloride

As described by Gillaspy, M.L.; Lefker, B.A.; Hada, W.A.; and Hoover, D.J. in Tetrahedron Lett. This compound was prepared by reductive cyclopropylation of (piperazin-1-yl)quinoline.

¹ H NMR (DMSO-d ₆ ) δ 0.82 (m, 1H), 0.99 (m, 2H), 1.40 (m, 1H), 1.55 (d, J=7Hz, 3H), 2.76 (m, 1H), 3.30-3.80(m, 5H), 3.87(s, 3H), 3.90(s, 3H), 4.65-4.83(m, 2H), 7.38(br s, 2H), 7.82(br s, 1H), 8.31( br s, 1H), 11.30 (br s, 1H); HPLC-MS: m/z 328 (MH ⁺ ); Rt=3.09min.

Embodiment 124 (general technique (B))

[6-(4-Cyclopropylpiperazin-1-yl)pyridin-3-yl]pyrrolidin-1-yl-methanone hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 6-chloronicotinic acid pyrrolidide using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.81 (m, 2H), 1.15 (m, 2H), 1.84 (m, 4H), 2.88 (m, 1H), 3.15-3.60 (m, 10H), 4.49 ( m, 2H), 7.00(d, J=7Hz, 1H), 7.83(d, J=7Hz, 1H), 8.38(s, 1H), 10.91(br s, 1H); HPLC-MS: m/z301( MH ⁺ ); Rt=1.22min.

Embodiment 125 (general technique (B))

2-(4-Isopropylpiperazin-1-yl)quinoline-6-carbonitrile hydrochloride

To a mixture of ethyl 3,3-diethoxypropionate (62 g, 326 mmol) and water (100 ml) was added NaOH (16.0 g) with stirring. Stir at 110°C (flask opened). After 40 minutes, the mixture was homogeneous and the heating was discontinued and the mixture was allowed to cool to room temperature. The mixture was acidified (ca. 35 ml cone. HCl, pH 3-2) and extracted (4 x dichloromethane). The combined extracts were washed with brine (1 x 50ml), dried (magnesium sulfate) and concentrated. 48 g of oil are obtained.

Thionyl chloride (80ml) was added dropwise to the oil. The mixture was stirred at reflux (80° C.) for 1 hour and 30 minutes. After careful concentration, the residue weighed 48 g (theoretical weight should be 43 g). The acid chloride was kept at -20°C overnight.

This product was mixed with dichloromethane (70ml) and 5/7 of this solution (about 230mmol) was added to a solution of 4-bromoaniline (34.5g, 201mmol) and pyridine (50ml) in dichloromethane (150ml), The mixture was shaken overnight at room temperature. The mixture was filtered and the resulting solid was washed with dichloromethane and dried to give 21 g of N-(4-bromophenyl)-3-ethoxyacrylamide as a colorless solid. A mixture of water (700ml) and concentrated hydrochloric acid (50ml) was added to the filtrate. A solid precipitated out after shaking, which was filtered off, washed with dichloromethane and AcOEt, and dried. Another 14.4 g of product were obtained. The filtrate was extracted (3 x dichloromethane), washed once with brine, dried and concentrated. Another 18 g of product were obtained. Total yield: 53.4 g.

The product (58.8g, 218mmol) was mixed with ice-cold concentrated sulfuric acid (390ml), and the mixture was first stirred at 0°C for 15 minutes (until almost all acrylamide was dissolved), and then stirred at room temperature for 4 hours. The mixture was then poured into ice water (3 L) and left overnight. The mixture was filtered and the solid was washed with water. The solid was transferred to a flask with the aid of acetonitrile, ethanol and dichloromethane, and the suspension was concentrated under reduced pressure. The residue was resuspended in acetonitrile (300ml), heated to reflux and left at room temperature overnight. Filtration and drying of the solid under reduced pressure afforded 31.3 g (64%) of 6-bromo-2-quinolone as a yellow solid.

The quinolone (6.28g, 28.0mmol) was mixed with copper(I) cyanide (5.02g, 56.1mmol) and NMP (15ml), and the mixture was stirred at reflux (202° C.) for 6 hours, then at room temperature overnight . Water (150ml) was added, the mixture was filtered and the solid washed with water. The solid was resuspended in 1N hydrochloric acid (200ml) and iron(III) chloride hexahydrate (17.8g) was added. The resulting mixture was stirred at room temperature for 3 days, filtered, the solid was washed once with water, stripped with ethanol and dried under reduced pressure to yield 4.33 g (91%) of copper 6-cyano-2-quinol as a gray solid . This product was treated with _POCl3 followed by 1-isopropylpiperazine as described in general procedure (B) to afford the title compound.

¹ H NMR (DMSO-d ₆ ) δ1.31(d, J=7Hz, 6H), 3.10(m, 2H), 3.52(m, 5H), 4.79(m, 2H), 7.49(d, J=8Hz , 1H), 7.71(d, J=8Hz, 1H), 7.86(d, J=8Hz, 1H), 8.23(d, J=8Hz, 1H), 8.35(s, 1H), 10.73(br s, 1H ); HPLC-MS: m/z 281 (MH ⁺ ); Rt = 1.62min.

Embodiment 126 (general technique (B))

3-(4-Cyclopropylpiperazin-1-yl)-6-phenylpyridazine hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 3-chloro-6-phenylpyridazine using general procedure (B).

¹ H NMR (DMSO-d ₆ )δ0.82(m, 2H), 1.22(m, 2H), 2.88(br s, 1H), 3.37(m, 2H), 3.59(m, 4H), 4.57(m , 2H), 7.53(m, 3H), 7.80(d, J=8Hz, 1H), 8.06(m, 2H), 8.29(d, J=8Hz, 1H), 11.47(br s, 1H); HPLC- MS: m/z 281 (MH ⁺ ); Rt = 1.43min.

Embodiment 127 (general technique (B))

3-(4-cyclopropylpiperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyridazine hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 3-chloro-6-(3,4-dimethoxyphenyl)pyridazine using general procedure (B).

¹ H NMR (DMSO-d ₆ )δ0.83(m, 2H), 1.22(m, 2H), 2.88(br s, 1H), 3.36(m, 2H), 3.60(m, 4H), 3.84(s, 3H), 3.87(s, 3H), 4.53(m, 2H), 7.14(d, J=8Hz, 1H), 7.66(m, 2H), 7.86(d, J=8Hz, 1H), 8.37(d, J=8Hz, 1H), 11.43 (br s, 1H); HPLC-MS: m/z 341 (MH ⁺ ); Rt=1.45min.

Embodiment 128 (general technique (B))

7-(4-Isopropylpiperazin-1-yl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline

This compound was prepared from 1-isopropylpiperazine and 7-chloro-2,3-dihydro[1,4,]dioxino[2,3-g]quinoline using general procedure (B). compound.

¹ H NMR (DMSO-d ₆ ) δ1.00(d, J=7Hz, 6H), 2.67(hept, J=7Hz, 1H), 3.33(s, 4H), 3.56(m, 4H), 4.29(m , 4H), 6.95(s, 1H), 7.02(d, J=8Hz, 1H), 7.13(s, 1H), 7.84(d, J=8Hz, 1H); HPLC-MS: m/z 314 (MH ⁺ ); Rt＝1.14min.

Example 129

2-(4-cyclopropyl-3-methylpiperazin-1-yl)quinoline hydrochloride

As described by Gillaspy, M.L.; Lefker, B.A.; Hada, W.A.; and Hoover, D.J. in Tetrahedron Lett. The compound was prepared by reductive cyclopropylation of a line.

¹ H NMR (DMSO-d ₆ ) δ0.82 (m, 1H), 1.00 (m, 2H), 1.41 (m, 1H), 1.56 (d, J=7Hz, 3H), 2.76 (m, 1H), 3.25-3.80(m, 5H), 4.81(m, 2H), 7.44(br s, 1H), 7.55(m, 1H), 7.72(m, 1H), 7.88(m, 1H), 8.11(br s, 1H), 8.37 (br s, 1H), 11.40 (br s, 1H); HPLC-MS: m/z 268 (MH ⁺ ); Rt=1.18min.

Embodiment 130 (general technique (B))

6-Cyclopropylmethoxy-2-(4-cyclopropylpiperazin-1-yl)quinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-6-(cyclopropylmethoxy)quinoline using general procedure (B). The desired 2-chloro-6-(cyclopropylmethoxy)quinoline was prepared by treating 6-(cyclopropylmethoxy)-2-quinolone with _POCl3 . 6-(Cyclopropylmethoxy)-2-quinolone was prepared from the corresponding 6-hydroxyquinolone in dimethylformamide in the presence of a catalytic amount of sodium iodide with a (bromomethyl) ring Propane and potassium carbonate handling.

¹ H NMR (DMSO-d ₆ )δ0.35(m, 2H), 0.60(m, 2H), 0.82(m, 2H), 1.20(m, 2H), 1.28(m, 1H), 2.87(br s , 1H), 3.25-4.20(m, 6H), 3.92(d, J=7Hz, 2H), 4.70(m, 2H), 7.30-7.60(m, 3H), 8.08(br s, 1H), 8.32( br s, 1H), 11.37 (br s, 1H); HPLC-MS: m/z 324 (MH ⁺ ); Rt=1.94min.

Embodiment 131 (general technique (B))

2-(4-Isopropylpiperazin-1-yl)-6-pyrazol-1-ylquinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-6-(1-pyrazolyl)quinoline using general procedure (B). The desired 2-chloro-6-(1-pyrazolyl)quinoline was prepared by treating 6-(1-pyrazolyl)-2-quinolone with _POCl3 . 6-(1-pyrazolyl)-2-quinolone was prepared in the following manner:

6-bromo-2-quinolone (3.58g, 16.0mmol), DMF (15ml), pyrazole (1.66g, 24.4mmol), potassium carbonate (3.33g, 24.1mmol) and copper iodide (I) (0.76g , 3.99 mmol) was stirred at 160°C for 22 hours. Water (300ml) was added and after trituration the mixture was filtered and the solid washed with water. The solid was stripped with EtOH, resuspended in a mixture of acetonitrile and ethanol (100ml, 1:1), heated to reflux and kept at room temperature overnight. Filtration, washing with a little acetonitrile and drying under reduced pressure gave 1.7 g (50%) of 6-(1-pyrazolyl)-2-quinolone as a metallic green solid.

¹ H NMR (DMSO-d ₆ ) δ1.32 (d, J=7Hz, 6H), 3.10-3.70 (m, 7H), 4.81 (m, 2H), 6.60 (m, 1H), 7.56 (d, J =8Hz, 1H), 7.81(s, 1H), 8.09(m, 1H), 8.22(d, J=8Hz, 1H), 8.32(s, 1H), 8.38(d, J=8Hz, 1H), 8.58 (m, 1H), 11.11 (br s, 1H); HPLC-MS: m/z 322 (MH ⁺ ); Rt=1.67min.

Embodiment 132 (general technique (B))

2-(4-Isopropylpiperazin-1-yl)quinolin-6-ol hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-6-hydroxyquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.15-3.90 (m, 7H), 4.79 (m, 2H), 7.22 (m, 1H), 7.33 (d, J =8Hz, 1H), 7.53(d, J=8Hz, 1H), 8.13(br s, 1H), 8.35(d, J=8Hz, 1H), 10.17(brs, 1H), 11.41(br s, 1H) ; HPLC-MS: m/z 272 (MH ⁺ ); Rt = 0.40 min.

Embodiment 133 (general technique (B))

2-(4-Cyclopropylpiperazin-1-yl)quinoline-6-carbonitrile hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-6-cyanoquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.15 (m, 2H), 2.87 (brs, 1H), 3.20-3.65 (m, 6H), 4.74 (m, 2H), 7.49 ( d, J=8Hz, 1H), 7.72(d, J=8Hz, 1H), 7.86(d, J=8Hz, 1H), 8.24(d, J=8Hz, 1H), 8.35(s, 1H), 10.88 (brs, 1H); HPLC-MS: m/z 279 (MH ⁺ ); Rt=1.43min.

Embodiment 134 (general technique (B))

(9a-R)-2-(octahydropyrido[1,2-a]pyrazin-2-yl)quinoline-6-carbonitrile hydrochloride

This compound was prepared from (9a-R)-octahydropyrido[1,2-a]pyrazine and 2-chloro-6-cyanoquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.40-1.60 (m, 1H), 1.65-2.00 (m, 5H), 2.85-3.65 (m, 7H), 4.80 (m, 2H), 7.53 (d, J =8Hz, 1H), 7.79(d, J=8Hz, 1H), 7.89(d, J=8Hz, 1H), 8.26(d, J=8Hz, 1H), 8.37(s, 1H), 11.31(br s , 1H); HPLC-MS: m/z 293 (MH ⁺ ); Rt=1.72min.

Embodiment 135 (general technique (B))

4-Chloro-6-(4-isopropylpiperazin-1-yl)-3-phenylpyridazine hydrochloride

This compound was prepared from 1-isopropylpiperazine and 4,6-dichloro-3-phenylpyridazine using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 3.13 (m, 2H), 3.40-3.65 (m, 5H), 4.63 (m, 2H), 7.50 (m, 3H) ), 7.63 (m, 2H), 7.78 (s, 1H), 11.01 (br s, 1H); HPLC-MS: m/z 317 (MH ⁺ ); Rt=2.11min.

Embodiment 136 (general technique (B))

3-(4-cyclopropylpiperazin-1-yl)-6-(3-trifluoromethylphenyl)pyridazine hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 3-chloro-6-(3-trifluoromethylphenyl)pyridazine using general procedure (B).

¹ H NMR (DMSO-d ₆ )δ0.83(m, 2H), 1.22(m, 2H), 2.89(br s, 1H), 3.35(m, 2H), 3.59(m, 4H), 4.63(m , 2H), 7.68(d, J=8Hz, 1H), 7.77(m, 1H), 7.84(m, 1H), 8.32(d, J=8Hz, 1H), 8.40(m, 2H), 11.40(br s, 1H); HPLC-MS: m/z 349 (MH ⁺ ); Rt = 2.43min.

Example 137

1-[2-(4-Isopropylpiperazin-1-yl)quinolin-6-yl]ethanone hydrochloride

This compound is prepared by treating 2-(4-isopropylpiperazin-1-yl)quinoline-6-carbonitrile with excess methylmagnesium bromide in tetrahydrofuran.

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 2.65 (s, 3H), 3.18 (m, 2H), 3.40-3.80 (m, 5H), 4.82 (m, 2H) ), 7.52(d, J=8Hz, 1H), 7.91(br s, 1H), 8.15(d, J=8Hz, 1H), 8.40(d, J=8Hz, 1H), 8.54(s, 1H), 11.16 (br s, 1H); HPLC-MS: m/z 298 (MH ⁺ ); Rt = 1.47min.

Embodiment 138 (general technique (B))

3-(4-Isopropylpiperazin-1-yl)-6-phenylpyridazine-4-carbonitrile hydrochloride

This compound was prepared from 1-isopropylpiperazine and 3-chloro-6-phenylpyridazine-4-carbonitrile using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.32 (d, J=7Hz, 6H), 3.23 (m, 2H), 3.50-3.75 (m, 5H), 4.46 (m, 2H), 7.55 (m, 3H) ), 8.13 (d, J=7Hz, 2H), 8.72 (s, 1H), 10.67 (br s, 1H); HPLC-MS: m/z 308 (MH ⁺ ); Rt=2.16min.

Embodiment 139 (general technique (B))

6-Bromo-2-(4-isopropylpiperazin-1-yl)quinoline

This compound was prepared from 1-isopropylpiperazine and 6-bromo-2-chloroquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ1.00(d, J=7Hz, 6H), 2.52(m, 4H), 2.69(sept, J=7Hz, 1H), 3.68(m, 4H), 7.28(d , J=8Hz, 1H), 7.48(d, J=8Hz, 1H), 7.60(dd, J=1Hz, 8Hz, 1H), 7.93(d, J=1Hz, 1H), 8.00(d, J=8Hz , 1H).

Embodiment 140 (general technique (B))

2-(4-Cyclopropylpiperazin-1-yl)-6-pyrazol-1-ylquinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-6-pyrazol-1-ylquinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.22 (m, 2H), 2.88 (m, 1H), 3.30-3.80 (m, 6H), 4.79 (m, 2H), 6.61 ( m, 1H), 7.59(d, J=6Hz, 1H), 7.81(s, 1H), 8.10-8.30(m, 2H), 8.34(s, 1H), 8.41(d, J=6Hz, 1H), 8.59 (s, 1H), 11.47 (br s, 1H); HPLC-MS: m/z 320 (MH ⁺ ); Rt = 1.64min.

Embodiment 141 (general technique (B))

7-Chloro-2-(4-cyclopropylpiperazin-1-yl)quinolin-6-ol hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2,7-dichloro-6-hydroxyquinoline using general procedure (B). The desired 2,7-dichloro-6-hydroxyquinoline was prepared by demethylation of 2,7-dichloro-6-methoxyquinoline with boron tribromide in dichloromethane , the latter being prepared from 3-chloro-4-methoxyaniline as described by F. Effenberger and W. Hartmann in Chemische Berichte 1969, 102, 3260-3267.

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.14 (m, 2H), 2.88 (m, 1H), 3.20-3.80 (m, 6H), 4.61 (m, 2H), 7.32 ( s, 1H), 7.42(m, 1H), 7.96(m, 1H), 8.21(m, 1H), 10.65(br s, 1H), 10.84(br s, 1H); HPLC-MS: m/z304( MH ⁺ ); Rt=1.06min.

Example 142

[2-(4-Cyclopropylpiperazin-1-yl)quinolin-6-yl]-(4-fluorophenyl)methanone hydrochloride

This product was prepared by treating 2-(4-cyclopropylpiperazin-1-yl)quinoline-6-carbonitrile with excess (4-fluorophenyl)magnesium bromide in tetrahydrofuran.

¹ H NMR (DMSO-d ₆ ) δ0.84 (m, 2H), 1.14 (m, 2H), 2.89 (m, 1H), 3.25-3.90 (m, 6H), 4.77 (m, 2H), 7.44 ( m, 3H), 7.76(m, 1H), 7.86(m, 2H), 7.98(m, 1H), 8.21(s, 1H), 8.34(d, J=8Hz, 1H), 10.65(br s, 1H ); HPLC-MS: m/z 376 (MH ⁺ ); Rt=2.61min.

Embodiment 143 (general technique (B))

Cyclopropyl-[2-(4-cyclopropylpiperazin-1-yl)quinolin-6-yl]methanone hydrochloride

This product was prepared by treating 2-(4-cyclopropylpiperazin-1-yl)quinoline-6-carbonitrile with excess cyclopropylmagnesium bromide in tetrahydrofuran.

¹ H NMR (DMSO-d ₆ ) δ 0.83 (m, 2H), 1.07 (m, 4H), 1.18 (m, 2H), 2.88 (m, 1H), 3.00 (quint, J=7Hz, 1H), 3.30-3.70(m, 6H), 4.76(m, 2H), 7.50(d, J=8Hz, 1H), 7.82(br s, 1H), 8.18(d, J=8Hz, 1H), 8.37(d, J=8Hz, 1H), 8.66(s, 1H), 11.05(br s, 1H); HPLC-MS: m/z 322 (MH ⁺ ); Rt=1.98min.

Embodiment 144 (general technique (B))

2-(4-cyclopropylpiperazin-1-yl)-6-(4-fluorobenzyloxy)quinoline hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and 2-chloro-6-(4-fluorobenzyloxy)quinoline using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ0.83 (m, 2H), 1.20 (m, 2H), 2.87 (m, 1H), 3.30-3.80 (m, 6H), 4.70 (m, 2H), 5.18 ( s, 2H), 7.25 (t, J=8Hz, 2H), 7.54 (m, 5H), 8.08 (br s, 1H), 8.33 (m, 1H), 11.34 (brs, 1H); HPLC-MS: m /z 378 (MH ⁺ ); Rt = 2.53min.

Example 145

6-cyclohex-1-enyl-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride

This product is prepared by treating 6-bromo-2-(4-isopropylpiperazin-1-yl)quinoline with butyllithium followed by cyclohexanone. After acid work-up, the tertiary alcohol undergoes elimination to afford the title compound.

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J=7Hz, 6H), 1.60-1.80 (m, 4H), 2.22 (m, 2H), 2.45 (m, 2H), 3.23 (m, 2H ), 3.45-4.00(m, 5H), 4.78(m, 2H), 6.34(m, 1H), 7.50(m, 1H), 7.86(m, 2H), 7.98(br s, 1H), 8.34(m , 1H), 11.06 (br s, 1H); HPLC-MS: m/z 336 (MH ⁺ ); Rt=2.50min.

Embodiment 146 (general technique (C))

1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine

3-Bromobiphenyl (300mg, 1.28mmol), 1-cyclopentylpiperazine (238mg, 1.54mmol), sodium tert-butoxide (173mg, 1.8mmol), tris(dibenzylideneacetone) dipalladium (12mg , 0.01 mmol) was mixed with a mixture of racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (24 mg, 0.04 mmol) in toluene (11 ml) under nitrogen in a sealed reaction in the container. In a sealed reaction vessel, the reaction mixture was stirred at 80 °C for 3 days. It was cooled to room temperature and washed with water (2 x 10ml). The combined organic layers were extracted with 1N hydrochloric acid (2 x 20ml). The combined aqueous extracts were made basic with 1N aqueous sodium hydroxide solution and extracted with tert-butyl methyl ether (3 x 20 mL). The tert-butyl methyl ether layer was dried over magnesium sulfate. The solvent was removed in vacuo to give 220 mg of the title compound.

¹ H-NMR (CDCl ₃ , two sets of signals, broad signal) δ1.35-1.85 (m, 6H); 1.95 (m, 2H); 2.55 (m, 1H); 2.70 (m, 4H); 3.30 (m , 4H); 6.95(d, 1H); 7.05(d, 1H); 7.15(s, 1H); 7.35(t, 2H); 7.45(t, 2H); 7.60(d, 2H).HPLC Method B: Eluted at 10.45 minutes

The title compound was converted to its hydrochloride salt by dissolving it in ethyl acetate (5ml). A 3.2M solution of hydrogen chloride in ethyl acetate (5ml) was added. Solvent was removed in vacuo. The residue was dissolved in ethanol (50ml). Solvent was removed in vacuo.

Embodiment 147 (general technique (C))

1-cyclopentyl-4-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]piperazine

Use 1-(2-(4-bromophenoxy)ethyl)pyrrolidine instead of 3-bromobiphenyl as described for 1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine , synthesized 86 mg of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ1.55(m, 2H); 1.75(m, 2H); 1.85(m, 4H); 2.00(m, 4H); 3.10(m, 6H); 3.40-3.70 (m, 9H); 4.30 (t, 2H); 7.00 (AB, 4H); 10.80 (br, 1H); 11.10 (br, 1H). HPLC method C: elutes at 2.24 minutes. MS: Calculated for [M+H] ⁺ : 344; Found: 344.

The title compound was converted into its hydrochloride salt which was dissolved in ethyl acetate (5ml) as follows. A 3.2M solution of hydrogen chloride in ethyl acetate (5ml) was added. Solvent was removed in vacuo. The residue was dissolved in ethanol (50ml). Solvent was removed in vacuo.

Embodiment 148 (general technique (C))

1-(biphenyl-4-yl)-4-(cyclopentyl)piperazine

180 mg of the title compound were synthesized as described for 1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine, using 4-bromobiphenyl instead of 3-bromobiphenyl.

¹ H-NMR (CDCl ₃ ) δ1.80-2.00 (m, 8H); 2.55 (m, 1H); 2.70 (m, 4H); 3.20 (m, 4H); 7.00 (d, 2H); 7.30 (m , 1H); 7.40 (t, 2H); and 7.55 (m, together 4H), HPLC method C: elutes at 4.52 minutes.

The title compound was converted into its hydrochloride salt which was dissolved in ethyl acetate (5ml) as follows. A 3.2M solution of hydrogen chloride in ethyl acetate (5ml) was added. Solvent was removed in vacuo. The residue was dissolved in ethanol (50ml). Solvent was removed in vacuo.

Embodiment 149 (general technique (C))

[3-(4-(cyclopentyl)piperazin-1-yl)phenyl]-(4-fluorophenyl)methanone

300 mg of the title compound were synthesized as described for 1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine, using 3-bromo-4&apos;-fluorobenzophenone in place of 3-bromobiphenyl.

¹ H-NMR (CDCl ₃ ) δ1.45 (m, 2H); 1.60 (m, 2H); 1.75 (m, 2H); 1.90 (m, 2H); 2.55 (quintet, 1H); ); 3.30 (m, 4H); 7.15 (m, 4H); 7.35 (m, 2H); 7.85 (m, 2H). HPLC method C: elutes at 4.22 min. MS: Calculated for [M+H] ⁺ : 353; Found: 353.

The title compound was converted into its hydrochloride salt which was dissolved in ethyl acetate (5ml) as follows. A 3.2M solution of hydrogen chloride in ethyl acetate (5ml) was added. Solvent was removed in vacuo. The residue was dissolved in ethanol (50ml). Solvent was removed in vacuo.

The following compounds also belong to the scope of the present invention:

pharmacological method

The following in vitro binding assays enable the determination of the ability of compounds to interact with the histamine H3 receptor.

Binding Assay I

Rat cerebral cortex was homogenized in ice-cold K-Hepes, 5 mM MgCl2 pH _7.1 buffer. After two differential centrifugations, the latter pellet was resuspended in fresh Hepes buffer containing 1 mg/ml bacitracin. Aliquots (400 μg/ml) of the membrane suspension were incubated for 60 minutes at 25°C with 30 pM [ ¹²⁵ I]-iodoproxifan (a known antagonist of histamine H3 receptors) and various concentrations of the test compound. Incubation was terminated by dilution with ice-cold medium followed by rapid filtration through Whatman GF/B filters pretreated with 0.5% polyethyleneimine for 1 hour. The radioactivity retained on the filters was counted using a Cobra II automated gamma counter. The radioactivity of the filter is indirectly proportional to the binding affinity of the test compound. Analyze the results with the help of nonlinear regression analysis.

Binding Assay II

The H3 receptor agonist ligand R-α-methyl[ ^3H ]histamine (RAMHA) was incubated with isolated rat cortical cell membranes for 1 hour at 25°C, followed by filtration of the culture through Whatman GF/B filters . The radioactivity retained on the filter was measured using a beta counter.

Male Wistar rats (150-200 g) were decapitated, and the cerebral cortex was quickly dissected and immediately frozen on dry ice. Tissues were stored at -80°C until membrane preparation. During membrane preparation, the tissue was kept on ice. Homogenize the rat cerebral cortex in 10 volumes (w/w) of ice-cold Hepes buffer (20mM Hepes, 5mM MgCl pH _7.1 (KOH) + 1mg/ml bacitracin) using an Ultra-Turrax homogenizer 30 seconds. The homogenate was centrifuged at 140g for 10 minutes. The supernatant was transferred to a new tube and centrifuged at 23000g for 30 minutes. The discarded pellet was resuspended in 5-10 ml Hepes buffer, homogenized, and centrifuged at 23000 g for 10 min. This short centrifugation step was repeated twice. After the final centrifugation, the pellet was resuspended in 2-4 ml Hepes buffer and the protein concentration was determined. The membrane was diluted with Hepes buffer to a protein concentration of 5 mg/ml, aliquoted, and stored at -80°C until use.

50 μl of test compound, 100 μl of membrane (200 μg/ml), 300 μl of Hepes buffer and 50 μl of R-α-methyl[ ³ H]histamine (1 nM) were mixed in a test tube. The compounds to be tested were dissolved in DMSO and further diluted in _H2O to the desired concentration. Radioligands and membranes were diluted in Hepes buffer + 1 mg/ml bacitracin. The mixture was incubated at 25°C for 60 minutes. Incubation was terminated by the addition of 5 ml of ice-cold 0.9% NaCl, followed by rapid filtration through Whatman GF/B filters pretreated with 0.5% polyethyleneimine for 1 hour. The filter was washed with 2 x 5 ml ice-cold NaCl. 3 ml of scintillation cocktail reagent was added to each filter and the retained radioactivity was measured using a Packard Tri-Carb beta counter. _IC50 values were calculated by means of nonlinear regression analysis of binding curves (minimum 6 points) using the Windows program GraphPadPrism, GraphPad Software, USA.

Binding Assay III

The human H3 receptor was cloned by PCR and subcloned into the pcDNA3 expression vector. Cells stably expressing the H3 receptor were generated by transfecting H3 expression vectors into HEK 293 cells and using G418 to select for H3 clones. Human H3-HEK 293 clones were grown in DMEM (GIBCO- _BRL ) containing glutamax, 10% fetal bovine serum, 1% penicillin/streptavidin, and 1 mg/ml G418 at 37°C and 5% CO2 . Fused cells were washed with PBS and incubated with Versene (Protease, GIBCO-BRL) for about 5 minutes before harvesting. The cells were washed with PBS and DMEM, and the cell suspension was collected in a test tube and centrifuged in a Heraeus Sepatech Megafuge 1.0 at 1500 rpm for 5-10 minutes. The discarded pellet was resuspended in 10-20 volumes of Hepes buffer (20 mM Hepes, 5 mM MgCl ₂ , pH 7.1 (KOH)) and homogenized using an Ultra-Turrax homogenizer for 10-20 seconds. The homogenate was centrifuged at 23000g for 30 minutes. The discarded pellet was resuspended in 5-10ml Hepes buffer, homogenized for 5-10 seconds using an Ultra-Turrax, and centrifuged at 23000g for 10 minutes. Following this centrifugation step, the membrane pellet was resuspended in 2-4 ml Hepes buffer, homogenized using a syringe or Teflon homogenizer, and the protein concentration determined. Dilute the membrane with Hepes buffer to a protein concentration of 1-5 mg/ml, aliquot and store at -80°C for future use.

Aliquots of the membrane suspension were incubated for 60 minutes at 25°C with 30 pM [ ¹²⁵ I]-iodoproxifan, a known compound with high affinity for the H3 receptor, and various concentrations of the test compound. Incubation was terminated by dilution with ice-cold medium followed by rapid filtration through Whatman GF/B filters pretreated with 0.5% polyethyleneimine for 1 hour. The radioactivity retained on the filters was counted using a Cobra II automated gamma counter. The radioactivity of the filter is indirectly proportional to the binding affinity of the test compound. Analyze the results with the help of nonlinear regression analysis.

Compounds of formula (I) according to the invention generally exhibit high binding affinity for the histamine H3 receptor when tested.

Preferably, compounds according to the invention have an _IC50 value of less than 10 μM, more preferably less than 1 μM, even more preferably less than 500 nM, eg less than 100 nM, as determined by one or more assays.

Functional Assay I

The ability of compounds to interact with the histamine H3 receptor and act as agonists, inverse agonists and/or antagonists was determined by means of in vitro functional assays using membranes of HEK 293 cells expressing the human H3 receptor.

The H3 receptor was cloned by PCR and subcloned into the pcDNA3 expression vector. Cells stably expressing the H3 receptor were generated by transfecting the H3 expression vector into HEK 293 cells and using G418 to select for H3 clones. Human H3-HEK 293 clones were cultured in DMEM containing glutamax, 10% fetal bovine serum, 1% penicillin/streptavidin, and 1 mg/ml G418 at 37 °C and 5% _CO2 .

H3 receptor expressing cells were washed once with phosphate buffered saline (PBS) and harvested with Versene (GIBCO-BRL). PBS was added and the cells were centrifuged at 188g for 5 minutes. Resuspend the cell pellet in stimulation buffer to a concentration of 1 x ¹⁰⁶ cells/ml. Accumulation of cAMP was measured using the FlashPlate(R) cAMP assay (NEN ^(TM) Life Science Products). Assays are generally performed as described by the manufacturer. Briefly, 50 μl of cell suspension was added to each well of the Flashplate, which also contained 25 μl of 40 μM isoproterenol to stimulate cAMP production, and 25 μl of the test compound (agonist or inverse agonist alone, or agonist and antagonist combinations of agents). Assays can be performed in "agonist mode", meaning that individual increasing concentrations of the test compound are added to the cells and cAMP is measured. If cAMP goes up, then it's an inverse agonist; if cAMP doesn't change, then it's a neutral antagonist; if cAMP goes down, then it's an agonist. Assays can also be performed in "antagonist mode", meaning that increasing concentrations of the test compound are added along with increasing concentrations of a known H3 agonist (eg RAMHA). If the compound is an antagonist, then increasing concentrations of it result in a rightward shift of the H3 agonist dose response curve. The final volume in each well was 100 μl. The test compound was dissolved in DMSO and diluted with _H2O . The mixture was shaken for 5 minutes and left at room temperature for 25 minutes. The reaction was stopped with 100 μl of "Assay Mix" per well. The plates were then sealed with plastic, shaken for 30 minutes, left overnight, and finally radioactivity was counted in a Cobra II automatic gamma Top counter. _EC50 values were calculated by nonlinear regression analysis of dose response curves (minimum 6 points) using GraphPad Prism. Kb values were calculated by means of Schild plot analysis.

Functional Assay II

The ability of compounds to bind and interact with human H3 receptors, acting as agonists, inverse agonists and/or antagonists was determined by means of a functional assay called the [ ^35S ]GTPyS assay. The assay measures G protein activation by catalyzing the displacement of guanosine 5'-diphosphate (GDP) by guanosine 5'-triphosphate (GTP) on the α-subunit. G protein bound to GTP dissociates into two subunits, _GαGTP and Gβγ, which in turn regulate intracellular enzymes and ion channels. GTP is rapidly hydrolyzed by the Gα subunit (GTPase), and the G protein is inactivated, ready to enter a new GTP replacement cycle.

In order to study the function of ligand-induced activation of G protein-coupled receptors (GPCRs) due to increased guanine nucleotide substitution of G proteins, [ ³⁵ S]-guanosine-5'-O-(3-thio generation) the binding of [ ³⁵ S]GTPγS triphosphate, which is a non-hydrolyzable analogue of GTP. This process can be monitored in vitro by incubating cell membranes containing G protein-coupled receptor H3 with GDP and [ ³⁵ S]GTPyS. Cell membranes were obtained from CHO cells stably expressing the human H3 receptor. Cells were washed twice with PBS, harvested with PBS+1 mM EDTA, pH 7.4, and centrifuged at 1000 rpm for 5 minutes. Cell pellets were homogenized in 10 ml of ice-cold Hepes buffer (20 mM Hepes, 10 mM EDTA pH 7.4 (NaOH)) for 30 seconds using an Ultra-Turrax homogenizer and centrifuged at 20,000 rpm for 15 minutes. After this centrifugation step, membrane pellets were resuspended in 10 ml ice-cold Hepes buffer (20 mM Hepes, 0.1 mM EDTA pH 7.4 (NaOH)) and homogenized as above. The process was repeated twice, except for the final homogenization step, where the protein concentration was determined, and the membrane was diluted to a protein concentration of 2 mg/ml, aliquoted, and stored at -80°C until use.

To investigate the presence and potency of inverse agonists/antagonists, the H3 receptor agonist ligand R-alpha-methylhistamine (RAMHA) was added. The ability of test compounds to counteract the effects of RAMHA is measured. When studying the effect of agonists, no RAMHA was added to the assay medium. The test compound was diluted to different concentrations in the assay buffer (20mM HEPES, 120mM NaCl, 10mM MgCl ₂ pH 7.4 (NaOH)), followed by the addition of 10 ^-8 nM RAMHA (only when checking the inverse agonist/antagonist case), 3 μM GDP, 2.5 μg membrane, 0.5 mg SPA beads and 0.1 nM [ ³⁵ S]GTPγS, incubated at room temperature for 2 hours with gentle shaking. Plates were centrifuged at 1500 rpm for 10 minutes and radioactivity was measured using a Top counter. _IC50 values were determined by means of non-linear regression analysis results.

RAMHA and other H3 agonists stimulate the binding of [ ³⁵ S]GTPγS to membranes expressing H3 receptors. In the antagonist/inverse agonist assay, the ability of increasing amounts of the test compound to inhibit increased [ ³⁵ S]GTPyS binding by 10 ^-8 MRAMHA was measured, as indicated by a reduction in the radioactive signal. The antagonist _IC50 value determined is the ability of the compound to inhibit the effect of 10 ^-8 M RAMHA by 50%. In agonist assays, the ability to measure increasing amounts of a test compound is manifested as an increase in radioactive signal. The agonist _EC50 value determined is the ability of the compound to increase the signal by 50% of the maximum signal obtained with 10 ^-5 M RAMHA.

Preferably, antagonists and agonists according to the invention have an _IC50 / _EC50 value of less than 10 μM, preferably less than 1 μM, even more preferably less than 500 nM, such as less than 100 nM, as determined by one or more assays.

Open Cage Program Feeding Rat Model

The ability of the compounds of the invention to reduce body weight was determined using an in vivo open cage programmed feeding rat model.

Sprague-Dawley (SD) male rats, approximately 1.5 to 2 months old in size and weighing approximately 200-250 g, were purchased from Mφllegrd Breeding and Research Center A/S (Denmark). Upon arrival, they were allowed to acclimate for a few days before being placed in individual open plastic cages. They were habituated to the presence of food (Altromin pelleted rat chow) in the cage for only 7 hours per day, from 07.30 to 14.30, for one week. Water is freely available. Animals are ready for use as food consumption plateaus after 7 to 9 days.

Each animal was used only once to avoid lag effects between treatments. During the test period, the compounds were administered intraperitoneally or orally 30 minutes before the start. One group of animals is given different doses of the test compound, and a control group of animals is given vehicle. Food and water intake was monitored 1, 2 and 3 hours after dosing.

Any adverse effects (barrel rolling, bushy hair, etc.) can be detected quickly, as animals are confined in clear plastic cages, enabling continuous monitoring.

Claims (74)

1. The compound of general formula (II):

in R ² is hydrogen or C _1-4 -alkyl, (i) R ¹ represents branched _C4-6 -alkyl, branched _C4-6 -alkenyl or branched _C4-6 -alkynyl, with the proviso that ^R1 is not isobutyl, C _3-5 -cycloalkyl, C _3-7 -cycloalkenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl or C _3-6 -cycloalkenyl-C _1-3 - alkyl, R ¹ and R ² together form a C _3-6 -alkylene bridge, and A stands for or

or (ii) R ¹ stands for Ethyl, n-propyl or isopropyl, R ¹ and R ² together form a C _3-6 -alkylene bridge, and A stands for or R ³ is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, C _1-6 - Alkoxy, aryl, aryl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkyl, C _3-8 -cycloalkoxy, cyano, nitro, C _1-6 -alkylthio or C _1-6 -alkylsulfonyl, Z and X independently represent -N=, -C(H)=, -C(F)=, -C(Cl)=, -C(CN)= or -C(CF ₃ )=, W represents -N= or -C(R ¹⁰ )=, Y represents -N= or -C(R ¹¹ )=, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF ₃ , amino, cyano, nitro or -C(=O)NR ¹⁴ R ¹⁵ , C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, _C 1-6 -alkoxy, C _3-8 -cycloalkyl-C _1-6 -alk Oxygen, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkoxy, C _1-6 -alkylthio, C _1-6 -alkylsulfonyl Acyl, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -heterocyclyl or C _4-9 -heterocycloalkanoyl, C _4-9 heterocycloalkoxy, which can optionally substituted with one or more substituents selected from R ¹⁶ , aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from R ¹⁷ , Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted by one or more substituents selected from ^R , · Or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene bridge or -OC _{1 -6} -alkylene-O-bridge, R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 -alkyl, aryl-C _1-6 -alkyl, or R ¹⁴ and R ¹⁵ can together form a C _3-6 -alkylene bridge, R ¹⁶ is independently selected from aryl, heteroaryl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR ¹⁹ R ²⁰ and C _1-6 -alkoxy, R ¹⁷ is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, C _1-6 -alkyl, amino, C _1-6 -alkylsulfonyl, C _1-6 -alkylamino, di-C _1-6 -alkylamino, cyano, aryl, heteroaryl and C _3-8 -cycloalkyl, R ¹⁸ is independently selected from aryl, heteroaryl, C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy radical, cyano, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino and hydroxyl, R ¹⁹ and R ²⁰ are independently hydrogen or C _1-6 -alkyl, R ₁₉ and R ₂₀ may together form a C _3-6 -alkylene bridge, The proviso is that the compound must not be

or and any diastereomer or enantiomer or tautomeric forms thereof, including mixtures thereof, or pharmaceutically acceptable salts thereof. 2. Compounds according to claim 1, wherein R ¹ is branched C _4-6 -alkyl, C _3-5 -cycloalkyl or C _3-6 -cycloalkyl-C _1-3 -alkyl, which with the proviso that ^R1 is not isobutyl. 3. The compound according to claim 2, wherein R is ^1,1- (dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl. 4. A compound according to claim 3, wherein ^R1 is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl. 5. Compounds according to claim 1, wherein ^R1 is branched _C4-6 -alkyl or _C3-5 -cycloalkyl, with the proviso that ^R1 is not isobutyl. 6. A compound according to claim 5, wherein ^R1 is 1-ethylpropyl, cyclopropyl or cyclopentyl. 7. A compound according to any one of claims 1 to 6, wherein Z is -C(H)=, -N= or -C(F)=. 8. The compound according to claim 7, wherein Z is -C(H)= or -N=. 9. A compound according to claim 8, wherein Z is -C(H)=. 10. A compound according to claim 8, wherein Z is -N=. 11. A compound according to any one of claims 1 to 10, wherein X is -C(H)=, -N= or -C(F)=. 12. The compound according to claim 11, wherein Z is -C(H)= or -N=. 13. A compound according to claim 12, wherein Z is -C(H)=. 14. A compound according to claim 12, wherein Z is -N=. 15. A compound according to any one of claims 1 to 14, wherein W is -N=. 16. A compound according to any one of claims 1 to 14, wherein W is -C(R ¹⁰ )=. 17. A compound according to any one of claims 1 to 16, wherein Y is -N=. 18. A compound according to any one of claims 1 to 16, wherein Y is -C(R ¹¹ )=. 19. A compound according to any one of claims 1 to 18, wherein ^R2 is hydrogen. 20. Compounds according to any one of claims 1 to 18, wherein ^R2 is _C1-4 -alkyl. 21. A compound according to claim 20, wherein ^R2 is methyl or ethyl. 22. The compound of general formula (III) according to claim 1

wherein A and ^R3 are as defined in claim 1. 23. Compounds according to any one of claims 1 to 22, wherein R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _1-6 -alkoxy radical, aryl, aryl-C _1-6 -alkyl, amino, C _3-8 -cycloalkyl, C _3-8 -cycloalkoxy, cyano or nitro. 24. Compounds according to claim 23, wherein ^R3 is hydrogen, halogen, hydroxy, trifluoromethyl, _C1-10 -alkyl, _C1-6 -alkoxy, cyano or nitro. 25. Compounds according to claim 24, wherein ^R3 is hydrogen, halogen, hydroxy, trifluoromethyl, _C1-6 -alkyl or cyano. 26. Compounds according to claim 25, wherein ^R3 is hydrogen, halogen or _C1-6 -alkyl. 27. The compound according to claim 25, wherein ^R3 is hydrogen or methyl. 28. The compound according to any one of claims 1 to 27, wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF ₃ , amino or cyano, C _1-10 -alkyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy, C _3-8 -cycloalkoxy, C _2-10 -alkanoyl, C _4-9 - cycloalkanoyl, C _3-8 -heterocyclyl or C _4-9 -heterocycloalkanoyl, which may optionally be substituted by one or more substituents selected from R ¹⁶ , aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from R ¹⁷ , Aroyl, heteroaroyl, aryloxy, heteroaryloxy, which may optionally be substituted by one or more substituents selected from ^R , Or two adjacent positions of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ together form a C _1-6 -alkylene bridge or -OC _1-6 -alkyl-O- bridge. 29. The compound according to claim 28, wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, _-SCF or cyano, C _1-10 -alkyl, C _1-6 -alkoxy, C _3-8 -cycloalkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ , · aryl or aryl-C _1-6 -alkyl, which may optionally be substituted by one or more substituents selected from R ¹⁷ , Aroyl or aryloxy, which may optionally be substituted by one or more substituents selected from R ¹⁸ , Or two adjacent positions of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ together form a C _1-6 -alkylene bridge or -OC _1-6 -alkyl-O- bridge. 30. The compound according to claim 28, wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represent Hydrogen, halogen or cyano, C _1-10 -alkyl or C _1-6 -alkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ , Aryl, optionally substituted by one or more substituents selected from R ¹⁷ , Aroyl or aryloxy, which may optionally be substituted by one or more substituents selected from R ¹⁸ , Or two adjacent positions of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ together form a C _1-6 -alkylene bridge or -OC _1-6 -alkyl-O- bridge. 31. Compounds according to claim 30, wherein C _1-10 -alkyl represents methyl, ethyl, propyl or isopropyl. 32. Compounds according to claim 30, wherein C _1-6 -alkoxy represents methoxy, ethoxy or propoxy. 33. Compounds according to claim 32, wherein C _1-6 -alkoxy represents methoxy. 34. A compound according to claim 30, wherein aryl represents phenyl. 35. A compound according to claim 30, wherein aroyl represents -C(=O)-phenyl. 36. A compound according to claim 30, wherein aryloxy represents -O-phenyl. 37. The compound according to claim 1, wherein ^R1 is ethyl or isopropyl. 38. The compound according to claim 37, wherein ^R1 is isopropyl. 39. The compound according to claim 37, wherein ^R1 is ethyl. 40. Compounds according to claim 39, wherein ^R1 and ^R2 together form a _C3-4 -alkylene bridge. 41. A compound according to any one of claims 37 to 40, wherein R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano or -C(=O)NR ¹⁴ R ¹⁵ , C _1-10 -alkyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -hetero Cyclic, C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ , aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from R ¹⁷ , Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ , or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene group bridge. 42. The compound according to claim 41, wherein R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano or -C(=O)NR ¹⁴ R ¹⁵ , C _1-10 -alkyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -hetero Cyclic or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ , aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from R ¹⁷ , Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ , or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene group bridge. 43. The compound according to claim 42, wherein ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent Hydrogen, halogen, trifluoromethyl or -C(=O)NR ¹⁴ R ¹⁵ , C _1-10 -alkyl, C _1-6 -alkoxy, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _4-9 -heterocycloalkanoyl or C _4-9 - Heterocycloalkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁶ , aryl, aryl-C _1-6 -alkyl or aryl-C _1-6 -alkoxy, which may optionally be substituted by one or more substituents selected from R ¹⁷ , Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ , or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene group bridge. 44. The compound according to claim 43, wherein R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent Hydrogen, halogen, trifluoromethyl or -C(=O)NR ¹⁴ R ¹⁵ , · C _1-10 -alkyl or C _4-9 -heterocycloalkanoyl, which may optionally be substituted by one or more substituents selected from R ¹⁶ , Aryl, optionally substituted by one or more substituents selected from R ¹⁷ , Aroyl, optionally substituted by one or more substituents selected from R ¹⁸ , or two of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in adjacent positions together form a C _1-6 -alkylene group bridge. 45. Compounds according to claim 44, wherein C _1-10 -alkyl represents methyl, ethyl or propyl. 46. Compounds according to claim 44, wherein _C4-9 -heterocycloalkanoyl represents piperidine-alkanoyl or pyrrolidine-alkanoyl. 47. A compound according to claim 44, wherein aryl represents phenyl. 48. A compound according to any one of claims 1 to 47, wherein ^R14 and ^R15 are independently methyl, ethyl or benzyl. 49. Compounds according to any one of claims 1 to 48, wherein ^R16 is halogen, trifluoromethyl, trifluoromethoxy and _C1-6 -alkoxy. 50. Compounds according to any one of claims 1 to 49, wherein R ¹⁷ is halogen, hydroxy, trifluoromethyl, C _1-6 -alkoxy, C _1-6 -alkyl, C _1-6 -alk Sulfonyl or cyano. 51. Compounds according to claim 50, wherein R ¹⁷ is halogen, trifluoromethyl, C _1-6 -alkoxy or C _1-6 alkylsulfonyl. 52. Compounds according to any one of claims 1 to 51, wherein ^R18 is _C1-10 -alkyl, halogen, trifluoromethyl, _C1-6 -alkoxy, cyano, amino and hydroxy. 53. Compounds according to claim 52, wherein ^R18 is halogen, _C1-6 -alkoxy and hydroxy. 54. The use of a compound according to any one of the preceding claims 1 to 53 as a pharmaceutical composition. 55. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 53 as active ingredient together with one or more pharmaceutically acceptable carriers or excipients. 56. The pharmaceutical composition according to claim 55, in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg, especially preferably from about 0.5 mg to about 200 mg, of a compound according to any one of claims 1 to 53 . 57. Compounds of general formula (II')

in R ² is hydrogen or C _1-4 -alkyl, R ¹ stands for · C _1-8 -alkyl, C _2-8 -alkenyl or C _2-8 -alkynyl, which may optionally be substituted by one or more halogen substituents, C _3-5 -cycloalkyl, C _3-7 -cycloalkenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl or C _3-6 -cycloalkenyl-C _1-3 - Alkyl groups, which may optionally be substituted by one or more halogen substituents, R ¹ and R ² together form a C _3-6 -alkylene bridge, A stands for or

R ³ is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, C _1-6 - Alkoxy, aryl, aryl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkyl, C _3-8 -cycloalkoxy, cyano, nitro, C _1-6 -alkylthio or C _1-6 -alkylsulfonyl, Z and X independently represent -N=, -C(H)=, -C(F)=, -C(Cl)=, -C(CN)= or -C(CF ₃ )=, W represents -N= or -C(R ¹⁰ )=, Y represents -N= or -C(R ¹¹ )=, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF ₃ , amino, cyano, nitro or -C(=O)NR ¹⁴ R ¹⁵ , C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, _C 1-6 -alkoxy, C _3-8 -cycloalkyl-C _1-6 -alk Oxygen, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkoxy, C _1-6 -alkylthio, C _1-6 -alkylsulfonyl Acyl, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -heterocyclyl or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy, which may be optionally substituted by one or more substituents selected from R ¹⁶ , aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy or heteroaryl, which may optionally be substituted by one or more substituents selected from R ¹⁷ , Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted by one or more substituents selected from ^R , · Or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene bridge or -OC _{1 -6} -alkylene-O-bridge, R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 -alkyl, aryl-C _1-6 -alkyl, or R ¹⁴ and R ¹⁵ can together form a C _3-6 -alkylene bridge, R ¹⁶ is independently selected from aryl, heteroaryl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR ¹⁹ R ²⁰ and C _1-6 -alkoxy, R ¹⁷ is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, C _1-6 -alkyl, amino, C _1-6 -alkylsulfonyl, C _1-6 -alkylamino, di-C _1-6 -alkylamino, cyano, aryl, heteroaryl and C _3-8 -cycloalkyl, R ¹⁸ is independently selected from aryl, heteroaryl, C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy radical, cyano, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino and hydroxyl, R ¹⁹ and R ²⁰ are independently hydrogen or C _1-6 -alkyl, R ¹⁹ and R ²⁰ may together form a C _3-6 -alkylene bridge, Use of any diastereomer or enantiomer or tautomeric form thereof, including mixtures thereof, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the treatment of receptors involving histamine H3 physical disorders and diseases. 58. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which inhibition of the H3 histamine receptor has a beneficial effect. 59. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition having histamine H3 antagonist activity or histamine H3 inverse agonist activity. 60. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for reducing body weight. 61. Use of a compound as defined in claim 57 for the manufacture of a pharmaceutical composition for the treatment of overweight or obesity. 62. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for suppressing appetite or inducing satiety. 63. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases involving overweight or obesity. 64. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating. 65. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of IGT. 66. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes. 67. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for delaying or preventing the progression of IGT to type 2 diabetes. 68. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for delaying or preventing the progression from non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes. 69. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which stimulation of H3 histamine receptors has a beneficial effect. 70. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition having histamine H3 agonistic activity. 71. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis, ulcers or anorexia. 72. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease, narcolepsy or inattention disorder. 73. A method of treating disorders or diseases involving H3 histamine receptors, the method comprising administering to the subject an effective amount of a compound as defined in claim 57 or a pharmaceutical composition according to claim 55 or 56 in need . 74. The method according to claim 73, wherein the effective amount of the compound is about 0.05 mg to about 2000 mg, preferably about 0.1 mg to about 1000 mg, especially about 0.5 mg to about 500 mg per day.