JP4607458B2 - Novel aryl and heteroaryl piperazines - Google Patents

Description

Field of Invention

  The present invention relates to novel aryl and heteroaryl piperazines, the use of these compounds as pharmaceutical compositions, pharmaceutical compositions containing such compounds, and methods of treatment using these compounds and compositions.

  The compounds of the present invention exhibit high and selective binding affinity for the histamine H3 receptor and exhibit histamine H3 receptor antagonist activity, inverse agonist activity, or agonist activity. As a result, the compounds are useful in the treatment of diseases and disorders associated with histamine H3 receptors.

Background of the Invention

  The existence of the histamine H3 receptor has been known for several years, and now the receptor is of interest for the development of new drugs. Recently, the human histamine H3 receptor has been cloned. This histamine H3 receptor is a presynaptic autoreceptor that is also present in both the central and peripheral nervous systems, skin, and organs (eg lung, intestine, possibly spleen and gastrointestinal tract). Recent evidence indicates that the H3 receptor exhibits endogenous constitutive activity in vitro and in vivo (ie, it is active even in the absence of agonist). Compounds that act as inverse agonists can inhibit this activity. The histamine H3 receptor has been shown to regulate the release of histamine as well as the release of other neurotransmitters such as serotonin and acetylcholine. Thus, histamine H3 receptor antagonists or inverse agonists are expected to increase the release of these neurotransmitters in the brain. Conversely, histamine H3 receptor agonists lead to inhibition of histamine biosynthesis and release of histamine, as well as other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists can be important mediators of neuronal activity. Thus, the histamine H3 receptor is an important target for new therapeutic agents.

  Compounds similar to the compounds of the present invention have been prepared previously and their biological properties have been studied. 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, the above references do not disclose or suggest that these compounds have histamine H3 receptor antagonist or agonist activity.

  Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Most of these are imidazole derivatives. More recently, however, several imidazole-free ligands of the rat histamine H3 receptor have been described (eg 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 of the art for histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds that interact with the histamine H3 receptor will have a highly desirable contribution to the art. The present invention provides such a contribution to the art based on the discovery that a novel class of aryl and heteroaryl piperazines has a high and specific affinity for the histamine H3 receptor. Is.

  Due to their interaction with the H3 receptor, the compounds of the invention are useful in the treatment of a wide range of medical conditions and disorders where interaction with the histamine H3 receptor is beneficial. Thus, the compounds will find use in the treatment of diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system, and endocrine system, for example.

Definition

  In the structural formulas given herein, and throughout the specification, the following terms have the meanings specified below.

  The term “halogen” means F, Cl, Br or I.

The term “alkyl” as used herein represents a branched or straight chain saturated hydrocarbon group having the specified number of carbon atoms. Thus, as used herein, the terms “C _1-3 -alkyl”, “C 1-8 -alkyl” and “C _1-10 -alkyl” refer to 1-3 carbon atoms, 1 to 8 carbon atoms and Represents a branched or straight chain saturated hydrocarbon group having 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 represents a branched or straight chain hydrocarbon group having the specified number of carbon atoms and at least one double bond. Thus, as used herein, the terms “C _2-8 -alkenyl” and “C _2-10 -alkenyl” have 2 to 8 carbon atoms and 2 to 10 carbon atoms, respectively, and at least one two It represents a branched or straight chain hydrocarbon group having a heavy bond. Examples of such groups, examples of such groups include ethenyl, 1-propenyl, 2-propenyl, allyl, iso- propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1 pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 2-nonenyl, and 2-decenyl and the like include, but are not limited to.

The term “alkynyl” as used herein refers to a branched or straight chain hydrocarbon group having the specified number of carbon atoms and at least one triple bond. Thus, the term “C _2-8 -alkynyl” as used herein represents a branched or straight chain hydrocarbon group having from 2 to 8 carbon atoms and at least one triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 2-heptynyl, 1-octynyl , And 2-octynyl and the like, but are not limited thereto.

The term “branched C _4-6 -alkyl” as used herein represents a branched saturated hydrocarbon group having from 4 to 6 carbon atoms. Typical branched C _4-8 -alkyl groups include 1-methylpropyl, tert-butyl, 1-ethylpropyl, 1,1- (dimethyl) propyl, isopentyl, 1-ethylbutyl, 1,1- (dimethyl) Examples include but are not limited to butyl, 1,1- (dimethyl) pentyl, 1-ethylpentyl, 1,1- (dimethyl) hexyl, 1-ethylhexyl, and the like.

The term “branched C _4-6 -alkenyl” as used herein represents a branched hydrocarbon atom having from 4 to 6 carbon atoms and at least one double bond. Typical branched C _4-6 -alkenyl groups include 1-ethylprop-2-enyl, 1,1- (dimethyl) prop-2-enyl, 1-ethylbut-3-enyl, 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) hexa-3 -Enyl, 1-ethylhex-4-enyl and the like are included, but are not limited thereto.

The term “branched C _4-6 -alkynyl” as used herein represents a branched hydrocarbon group having from 4 to 6 carbon atoms and at least one triple bond. Typical branched C _4-6 -alkynyl groups include 1-ethylprop-2-ynyl, 1,1- (dimethyl) prop-2-ynyl, 1-ethylbut-3-ynyl, 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) hexa-3 -Inyl, 1-ethylhex-4-ynyl and the like are included, but are not limited thereto.

The term “C _1-6 -alkoxy” as used herein means an —OC _1-6 -alkyl group, where C _1-6 -alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

As used herein, the term “C _2-10 -alkanoyl” means a —C (═O) C _1-9 -alkyl group, where C _1-9 -alkyl represents 1 to 9 carbon atoms. Represents a branched or straight chain saturated hydrocarbon machine. Representative examples are acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, and the like.

The term “C _1-6 -alkylamino” as used herein means a —NH—C _1-6 -alkyl group, wherein C _1-6 -alkyl is as defined above. Representative examples are methylamino, ethylamino, isopropylamino, n-propylamino, butylamino, pentylamino, hexylamino, and the like.

As used herein, the term “di-C _1-6 -alkylamino” refers to the group —N (C _1-6 -alkyl) ₂ , where C _1-6 -alkyl is as defined above. is there. It should be understood that these 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 from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl and the like.

Similarly, the terms “C _3-6 -cycloalkyl” and “C _3-8 -cycloalkyl” as used herein are monocyclic having 3 to 6 carbon atoms and 3 to 8 carbon atoms, respectively. Represents a carbocyclic group.

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

Similarly, “C _3-6 -cycloalkenyl” represents a monocyclic non-aromatic carbocyclic group having from 3 to 6 carbon atoms and at least one double bond.

As used herein, the term “C _3-6 -cycloalkyl-C _1-3 -alkyl” refers to the group —C _1-3 -alkyl-C _3-6 -cycloalkyl, where C _{3- 6} -Cycloalkyl and C _1-3 -alkyl are as defined above.

As used herein, the term “C _3-6 -cycloalkenyl-C _1-3 -alkyl” refers to the group —C _1-3 -alkyl-C _3-6 -cycloalkenyl, where C _{3- 6} -Cycloalkenyl and C _1-3 -alkyl are as defined above.

The term “C _3-8 -cycloalkyloxy” as used herein means an —OC _3-8 -cycloalkyl group, wherein C _3-8 -cycloalkyl is as defined above. Representative examples are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.

As used herein, the term “C _4-9 -cycloalkanoyl” means a —C (═O) —C _3-8 -cycloalkyl group, where C _3-8 -cycloalkyl is as defined above. it is as. Representative examples are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, and the like.

The term “C _1-6 -alkylsulfonyl” as used herein refers to the group —S (═O) ₂ —C _1-6 -alkyl, where C _1-6 -alkyl is as defined above. it is as. Representative examples are methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl, butylsulfonyl, pentylsulfonyl, and the like.

The term “C _1-6 -alkylsulfanyl” as used herein means a —SC _1-6 -alkyl group, wherein C _1-6 -alkyl is as defined above. Representative examples are methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, n-propylsulfanyl, butylsulfanyl, pentylsulfanyl, and the like.

The term “C _3-8 -heterocyclyl” as used herein refers to a 3-8 membered monocyclic saturated ring group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Representative examples are aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl and the like.

As used herein, the term “C _4-9 -heterocycloalkanoyl” means a —C (═O) —C _3-8 -heterocyclyl group, where C _3-8 -heterocyclyl is as defined above. it is as. Representative examples are aziridinyl carbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, a morpholinylcarbonyl, piperazinylcarbonyl, and tetrahydrofuranyl carbonyl like.

  The term “aryl” as used herein is mono, including carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. Aryl also includes the partially hydrogenated derivatives of the carbocyclic systems listed 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 refers to the group —O-aryl, where aryl is as defined above. Non-limiting examples are phenoxy, naphthoxy, anthracenyloxy, phenanthrenyloxy, fluorenyloxy, indenyloxy and the like.

  The term “aroyl” as used herein means a —C (═O) -aryl group, where aryl is as defined above. Non-limiting examples thereof include benzoyl, naphthoyl, anthracenylcarbonyl, phenanthrenylcarbonyl, fluorenylcarbonyl, indenylcarbonyl, and the like.

  The term “arylamino” as used herein refers to the group —NH-aryl, where aryl is as defined above. Non-limiting examples thereof include phenylamino, naphthylamino, anthracenylamino, phenanthrenylamino, fluorenylamino, indenylamino and the like.

  The term “heteroaryl” as used herein refers to a heterocyclic aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, Isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3, 5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4- Thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazo Le, is intended to include benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, and acridinyl and the like. Heteroaryl also includes the partially hydrogenated derivatives of the heterocyclic systems listed above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indanyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.

  The term “heteroaryloxy” as used herein refers to the group —O-heteroaryl, where heteroaryl is as defined above.

  The term “heteroaroyl” as used herein means a —C (═O) -heteroaryl group, where heteroaryl is as defined above.

  The term “heteroarylamino” as used herein refers to the group —NH-heteroaryl, where heteroaryl is as defined above.

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

“Aryl-C _1-6 -alkyl” or “aryl-C _1-6 -alkoxy” or the like is C _1-6 -alkyl or C _1-6-as defined above substituted by aryl as defined above Alkoxy: means for example:

  As used herein, the term “optionally substituted” means that the group in question is unsubstituted or substituted with one or more specified substituents. When the group in question is substituted with two or more substituents, these substituents may be the same or different.

  As used herein, the term “treatment” refers to the management and care of a patient intended to combat a disease, disorder or condition. This term includes the following: delaying the progression of the disease, disorder or condition, alleviating or reducing symptoms and complications, and / or curing or eliminating 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), as well as diastereomers, enantiomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof:

here,
(I) R ¹ represents
Branched C _4-8 -alkyl, branched C _4-8 -alkenyl, or branched C _4-8 -alkynyl
(These may optionally be substituted with 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 (these are optional
And may be substituted with one or more halogen substituents at any position.
I)
A represents:

Or
(Ii) R ¹ represents ethyl, n-propyl, or isopropyl;
A represents:

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 are independently
Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy,
Aryl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkyloxy, cyano, nitro, C _1-6 -alkylsulfa Nyl, C _1-6 -alkylsulfoni, or —C (═O) NR ^4a R ^4b (where 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 (these are optionally in any position,
One or more substituents 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 (these are optionally halogen, hydroxy, trifluoromethyl,
Trifluoromethoxy, C _1-6 - alkoxy, C _1-6 - alkyl, amino, C _1-6 - Al Kiruamino, di -C _1-6 - alkylamino, cyano, aryl, heteroaryl and C _3-8 - Optionally substituted with one or more substituents selected from cycloalkyl),
Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino, or heteroarylamino (these are optionally aryl,
Heteroaryl, C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, cyano, amino,
And optionally substituted with one or more substituents selected from C _1-6 -alkylamino, di-C _1-6 -alkylamino, and hydroxy)
Or two of the adjacent positions of R ^2a , R ^2b , R ³ and R ⁴ are taken together to form a C _1-6 -alkylene bridge or —OC _1-6 -alkylene-O— to form a bridge:
However, the compound must not be:

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

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 ¹ 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 optionally be substituted with 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 represented by the following formula:

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

In another embodiment, A is represented by the following formula:

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

In another embodiment, A is represented by the following formula:

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

In another embodiment, A is represented by the following formula:

Here, R ^2a , R ^2b , R ³ and R ⁴ are as defined for 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, or aryl-C _1-6 -alkyl , Aryl-C _1-6 -alkoxy, or aroyl (which may be optionally 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, orphenyl-C _1-6 -alkyl , Phenyl-C _1-6 -alkoxy, or benzoyl, which may optionally be substituted with one or two substituents selected from halogen and C _1-6 -alkoxy.

In another embodiment, R ^2a , R ^2b , and R ⁴ are hydrogen and R ³ is different from hydrogen.

In another embodiment, R ³ is hydrogen, trifluoromethyl, or trifluoromethoxy.

In another embodiment, the present invention is concerned with compounds of general formula (I ₁ ):

A here is as defined for formula (I) or in any of the above embodiments.

In another embodiment, the present invention is concerned with compounds of general formula (I ₂ ):

A here is as defined for formula (I) or in any of the above embodiments.

In another embodiment, the present invention is concerned with compounds of general formula (I ₃ ):

Where R ¹ is
Branched C _4-8 -alkyl, branched C _4-8 -alkenyl, branched branched C _4-8 -alkynyl (these may be optionally substituted with 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 (these Optionally may be substituted with one or more halogen substituents at any position)
Ethyl, n-propyl, or isopropyl,
And
R ^2a , R ^2b , R ³ and R ⁴ are as defined for formula (I).

In another embodiment, the invention relates to a compound selected from: and diastereomers, enantiomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof:
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-trifluoromethylpiperidin-2-yl) piperazine,
1-cyclopentyl-4- (5-trifluoromethylpiperidin-2-yl) piperazine,
1-cyclopentyl-4- (3-trifluoromethylpiperidin-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} phenylmethanol,
[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] phenylmethanone,
[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.

In another aspect, the invention provides compounds of the following general formula (I ''), as well as its diastereomers, enantiomers, tautomers or mixtures thereof, or to a pharmaceutically acceptable salt thereof:

here,
R ¹ represents:
• Branched C _4-8 -alkyl, branched C _4-8 -alkenyl, or branched C _4-8 -alkynyl (which may optionally be substituted with 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 (these May be optionally substituted with one or more halogen substituents)
A represents:

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 are independently
Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy,
Aryl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkyloxy, or cyano, or C _2-10 -alkanoyl, Or C _4-9 -cycloalkanoyl (which are optionally selected from aryl, heteroaryl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, and C _1-6 -alkoxy 1 May be substituted with the above substituents),
Aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy, or heteroaryl (these are optionally halogen, hydroxy, trifluoromethyl,
Trifluoromethoxy, C _1-6 - alkoxy, C _1-6 - alkyl, amino, C _1-6 - Al Kiruamino, di -C _1-6 - alkylamino, cyano, aryl, heteroaryl and C _3-8 - May be substituted with one or more substituents selected from cycloalkyl), or • Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino, or heteroarylamino (which are optionally aryl,
Heteroaryl, C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, cyano, amino,
And optionally substituted with one or more substituents selected from C _1-6 -alkylamino, di-C _1-6 -alkylamino, and hydroxy)
Represents:
However, the compound must not be:

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

In another embodiment, R ¹ is branched C _4-8 -alkyl, such as 1,1- (dimethyl) propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, C _3-5 -Cycloalkyl, or C _3-6 -cycloalkyl-C _1-3 -alkyl, for example 1-ethylpropyl, 1-cyclopropyl-1-methylethyl or cyclopentyl.

In yet another embodiment, R ¹ is branched C _4-8 -alkyl or C _3-5 -cycloalkyl, such as 1-ethylpropyl or cyclopentyl, optionally substituted with one or more halogen substituents. It is.

In a further embodiment, A is represented by the following formula:

Here, R ² , R ³ and R ⁴ are as defined for formula (I ″).

In another embodiment, A is represented by the following formula:

Here, R ² , R ³ and R ⁴ are as defined for formula (I ″).

In a further embodiment, A is represented by the following formula:

Here, R ² , R ³ and R ⁴ are as defined for 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, orAryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy, or aroyl (These may be optionally substituted as defined in 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, orphenyl-C _1-6 -alkyl, phenyl-C _1-6 -alkoxy, or benzoyl (They may optionally be substituted with one or two substituents selected from halogen and C _1-6 -alkoxy).

In yet another embodiment, R ² and R ⁴ are both hydrogen and R ³ is different from hydrogen.

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

A here is as defined for formula (I ″) or in any of the above embodiments.

In another embodiment, the present invention is concerned with compounds of general formula (I ₂ ):

A here is as defined for formula (I ″) or in any of the above embodiments.

  Accordingly, in another aspect, the present invention provides a compound of general formula (I), as well as diastereomers, enantiomers, tautomers or mixtures thereof, or a pharmaceutical thereof for use as a pharmaceutical composition Relating to the use of chemically acceptable salts.

  The present invention also includes at least one compound of formula (I) as an active ingredient, together with one or more pharmaceutically acceptable carriers or diluents, as well as diastereomers, enantiomers, tautomers or mixtures thereof. Or a pharmaceutical composition containing a pharmaceutically acceptable salt thereof.

Furthermore, the present invention provides for the preparation of a pharmaceutical composition for treating disorders and diseases associated with histamine H3 receptor, compounds of general formula (I '), as well as its diastereomers, enantiomers, tautomers Or the use of a mixture thereof, or a pharmaceutically acceptable salt thereof:

here,
R ¹ represents:
C _1-8 -alkyl, C _2-8 -alkenyl, or C _2-8 -alkynyl (which may optionally be substituted with 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 (these May be optionally substituted with one or more halogen substituents)
A represents:

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 are independently
Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-10 -alkyl, C _2-10 -alkenyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy,
Aryl-C _1-6 -alkyl, amino, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkyloxy, cyano, nitro, C _1-6 -alkylsulfa Nyl, C _1-6 -alkylsulfoni, or —C (═O) NR ^4a R ^4b (where 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 (optionally at any position,
One or more substituents 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 (these are optionally halogen, hydroxy, trifluoromethyl,
Trifluoromethoxy, C _1-6 - alkoxy, C _1-6 - alkyl, amino, C _1-6 - Al Kiruamino, di -C _1-6 - alkylamino, cyano, aryl, heteroaryl and C _3-8 - May be substituted with one or more substituents selected from cycloalkyl), or • Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino, or heteroarylamino (which are optionally aryl,
Heteroaryl, C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, cyano, amino,
And optionally substituted with one or more substituents selected from C _1-6 -alkylamino, di-C _1-6 -alkylamino, and hydroxy)
Represents.

In another aspect, the present invention provides compounds of the formula (II), as well as its diastereomers, enantiomers, tautomers or mixtures thereof, or a pharmaceutically acceptable salt thereof:

here,
R ² is hydrogen or C _1-4 -alkyl;
(I) R ¹ represents
Branched C _4-6 -alkyl, branched C _4-6 -alkenyl, or branched C _4-6 -alkynyl
(However, R ¹ 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;
A represents:

Or
(Ii) R ¹ represents
Ethyl, n-propyl, or isopropyl,
R ¹ and R ² together form a C _3-6 -alkylene bridge;
A represents:

R ³ is hydrogen, halogen, hydroxy, 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 -cycloalkyloxy, cyano, nitro, C _{Represents 1-6} -alkylsulfanyl, 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 are independently
Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy methoxyethanol, -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 -alkoxy, C _1-6 -alkylamino, di-C _1-6 -alkyl amino, C _3-8 -cycloalkyloxy, C _1-6 -alkylsulfanyl, C _1-6 - Al alkylsulfonyl, C _2-10 - alkanoyl, C _4-9 - cycloalkanoyl, C _3-8 - hetero cyclyl or C _4-9, - heterocycloalkyl alkanoylamino, C _4-9 - heterocycloalkoxy Xy (these may optionally be 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 with one or more substituents selected from R ¹⁷ )
Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino, or heteroarylamino (which may be optionally substituted with one or more substituents selected from R ¹⁸ )
Or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^12, and R ¹³ adjacent to each other are joined together to form C ₁₋ Forming ₆ -alkylene bridges or -OC _1-6 -alkylene-O-bridges;
R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 -alkyl, aryl-C _1-6 -alkyl, or R ¹⁴ and R ^{15 taken} together form a C _3-6 -alkylene bridge. Forming,
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 halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, C _1-6 -alkyl, amino, C _1-6 -alkylsulfonyl, C _1-6 -alkylamino, di- Independently selected from C _1-6 -alkylamino, cyano, aryl, heteroaryl, and C _3-8 -cycloalkyl;
R ¹⁸ is aryl, heteroaryl, C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, cyano, amino, C _1-6- Independently selected from alkylamino, di-C _1-6 -alkylamino, and hydroxy;
R ¹⁹ and R ²⁰ are independently selected from hydrogen or C _1-6 -alkyl, and R ₁₉ and R ₂₀ together may form a C _3-6 -alkylene bridge:
However, the compound must not be:

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, provided that R 1 ¹ is not isobutyl).

In another aspect of the invention, R ¹ 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 (provided 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, R ² 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.

Another aspect of the present invention provides a compound of general formula (III):

Here, 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 -cycloalkyloxy, cyano or nitro.

In another aspect of the invention, R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, C _1-10 -alkyl, C _1-6 -alkoxy, cyano or nitro.

In another aspect of the invention, R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, C _1-6 -alkyl, or cyano.

In another aspect of the invention, R ³ is hydrogen, halogen, or C _1-6 -alkyl.

In another aspect of the invention, R ³ is hydrogen or methyl.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently
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 -cycloalkyl oxy, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _{3- 8} -heterocyclyl,
Or C _4-9 -heterocycloalkanoyl (which may optionally be 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 with one or more substituents selected from R ¹⁷ ),
Aroyl, heteroaroyl, aryloxy, heteroaryloxy (these may be optionally substituted with one or more substituents selected from R ¹⁸ )
Or representing,
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 To do.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently
Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF ₃ , or cyano,
C _1-10 -alkyl, C _1-6 -alkoxy, C _3-8 -cycloalkyloxy (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
Aryl, or aryl-C _1-6 -alkyl, which may optionally be substituted with one or more substituents selected from R ¹⁷ ,
Aroyl or aryloxy (these are optionally selected from R ¹⁸
May be substituted with the above substituents)
Or representing,
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 To do.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently
Hydrogen, halogen or cyano,
C _1-10 -alkyl, or C _1-6 -alkoxy (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
Aryl optionally substituted with one or more substituents selected from R ¹⁷
Aroyl or aryloxy (which may optionally be substituted with one or more substituents selected from R ¹⁸ )
Or representing,
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 To do.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently
Hydrogen, halogen or cyano,
Methyl, ethyl, propyl, isopropyl, or C _1-6 -alkoxy (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
Aryl optionally substituted with one or more substituents selected from R ¹⁷
Aroyl or aryloxy (which may optionally be substituted with one or more substituents selected from R ¹⁸ )
Or
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 To do.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently
Hydrogen, halogen or cyano,
C _1-10 -alkyl, methoxy, ethoxy or propoxy (these are optionally
Optionally substituted with one or more substituents selected from R ¹⁶ ),
Aryl optionally substituted with one or more substituents selected from R ¹⁷
Aroyl or aryloxy (which may optionally be substituted with one or more substituents selected from R ¹⁸ )
Or
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 To do.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently
Hydrogen, halogen or cyano,
C _1-10 -alkyl, or methoxy (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
Aryl optionally substituted with one or more substituents selected from R ¹⁷
Aroyl or aryloxy (which may optionally be substituted with one or more substituents selected from R ¹⁸ )
Or representing,
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 To do.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently
Hydrogen, halogen or cyano,
C _1-10 -alkyl, or C _1-6 -alkoxy (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
Phenyl optionally substituted with one or more substituents selected from R ¹⁷
Aroyl or aryloxy (which may optionally be substituted with one or more substituents selected from R ¹⁸ )
Or representing,
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 To do.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently
Hydrogen, halogen or cyano,
C _1-10 -alkyl, or C _1-6 -alkoxy (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
Aryl optionally substituted with one or more substituents selected from R ¹⁷
-C (= O) -phenyl or aryloxy (these may optionally be substituted with one or more substituents selected from R ¹⁸ )
Or representing,
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 To do.

In another aspect of the invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently
Hydrogen, halogen or cyano,
C _1-10 -alkyl, or C _1-6 -alkoxy (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
Aryl optionally substituted with one or more substituents selected from R ¹⁷
Aroyl or —O-phenyl (which may optionally be substituted with one or more substituents selected from R ¹⁸ )
Or representing,
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 To do.

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 are taken together to form a C _3-4 -alkylene bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently
・ 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 -heterocyclyl or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy (these are optionally one or more substituents selected from R ¹⁶ May be substituted)
Aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy, or heteroaryl (which may optionally be substituted with one or more substituents selected from R ¹⁷ ),
Represents an aroyl optionally substituted with one or more substituents selected from R ¹⁸ ,
Or two adjacent positions of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently
・ 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 -heterocyclyl or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy (these are optionally one or more substituents selected from R ¹⁶ May be substituted)
Aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy, or heteroaryl (which may optionally be substituted with one or more substituents selected from R ¹⁷ )
Represents an aroyl optionally substituted with one or more substituents selected from R ¹⁸ ,
Or two adjacent positions of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently
・ 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 (These may be optionally substituted with 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 with one or more substituents selected from R ¹⁷ )
Represents an aroyl optionally substituted with one or more substituents selected from R ¹⁸ ,
Or two adjacent positions of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently
・ Hydrogen, halogen, trifluoromethyl, or -C (= O) NR ¹⁴ R ¹⁵
C _1-10 -alkyl, or C _4-9 -heterocycloalkanoyl (these are optionally R ¹⁶
Which may be substituted with one or more substituents selected from
Aryl optionally substituted with one or more substituents selected from R ¹⁷
Represents an aroyl optionally substituted with one or more substituents selected from R ¹⁸ ,
Or two adjacent positions of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently
・ Hydrogen, halogen, trifluoromethyl, or -C (= O) NR ¹⁴ R ¹⁵
Methyl, ethyl, propyl, or C _4-9 -heterocycloalkanoyl (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
Aryl optionally substituted with one or more substituents selected from R ¹⁷
Represents an aroyl optionally substituted with one or more substituents selected from R ¹⁸ ,
Or two adjacent positions of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently
・ Hydrogen, halogen, trifluoromethyl, or -C (= O) NR ¹⁴ R ¹⁵
C _1-10 -alkyl, piperidine-alkanoyl, or pyrrolidine-alkanoyl (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
Aryl optionally substituted with one or more substituents selected from R ¹⁷
Represents an aroyl optionally substituted with one or more substituents selected from R ¹⁸ ,
Or two adjacent positions of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene bridge.

In another aspect of the invention, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently
・ Hydrogen, halogen, trifluoromethyl, or -C (= O) NR ¹⁴ R ¹⁵
C _1-10 -alkyl, or C _4-9 -heterocycloalkanoyl (these are optionally R ¹⁶
Which may be substituted with one or more substituents selected from
Phenyl optionally substituted with one or more substituents selected from R ¹⁷
Represents an aroyl optionally substituted with one or more substituents selected from R ¹⁸ ,
Or two adjacent positions of R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together form a C _1-6 -alkylene 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, or 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, or hydroxy.

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

  Another aspect of the present invention provides the use of a compound of formula (II) or formula (III) as a pharmaceutical composition. In another aspect of the invention, the pharmaceutical composition comprises at least one compound according to formula (II) or formula (III) as an active ingredient, one or more pharmaceutically acceptable carriers or excipients. It may be contained together. In another aspect, the 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, particularly preferably about 0.5 mg. Pharmaceutical compositions containing ˜about 200 mg of a compound according to formula (II) or formula (III) are provided.

In another aspect, the present invention provides for the preparation of a pharmaceutical composition for treating disorders and diseases related to the histamine H3 receptor, compounds of the following general formula (II '), as well as its diastereomers, enantiomers Provides the use of a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

here,
R ² is hydrogen or C _1-4 -alkyl;
R ¹ represents:
C1-8-alkyl, C _2-8 -alkenyl, or C _2-8 -alkynyl (these are optionally
May be substituted with 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, these are optional And may be substituted with one or more halogen substituents),
R ¹ and R ² together form a C _3-6 -alkylene bridge,
A represents:

R ³ is hydrogen, halogen, hydroxy, 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 -cycloalkyloxy, cyano, nitro, C _1-6 -alkylsulfanyl, 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 -alkoxy, C _1-6 -alkylamino, di-C _1-6 -alkyl amino, C _3-8 -cycloalkyloxy, C _1-6 -alkylsulfanyl, C _1-6 -alkylsulfonyl, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8 -heterocyclyl or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy (These may be 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 with one or more substituents selected from R ¹⁷ )
Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino (these may be optionally substituted with one or more substituents selected from R ¹⁸ )
Or two of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ adjacent to each other are taken together to form a C _1-6 -alkylene bridge _or- OC _1-6 -alkylene-O-bridges may be formed,
R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 -alkyl, aryl-C _1-6 -alkyl, or R ¹⁴ and R ¹⁵ together form a C _3-6 -alkylene bridge It may be,
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 halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, C _1-6 -alkyl, amino, C _1-6 -alkylsulfonyl, C _1-6 -alkylamino, di- Independently selected from C _1-6 -alkylamino, cyano, aryl, heteroaryl and C _3-8 -cycloalkyl;
R ¹⁸ is aryl, heteroaryl, C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, cyano, amino, C _1-6- Independently selected from alkylamino, di-C _1-6 -alkylamino, and hydroxy;
R ¹⁹ and R ²⁰ are independently hydrogen or C _1-6 -alkyl, and R ₁₉ and R ₂₀ may together form a C _3-6 -alkylene bridge.

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

  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 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 a compound of general formula (II ′) as defined above for the preparation of a pharmaceutical composition for treating 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 that suppresses appetite or induces satiety.

  In another aspect, the present invention provides a compound of general formula (II ′) as defined above for the preparation of a pharmaceutical composition for preventing and / or treating diseases and disorders associated with overweight or obesity. Provide use.

  In another aspect, the present invention provides a compound of general formula (II ′) as defined above for the preparation of a pharmaceutical composition for preventing and / or treating eating disorders such as bulimia and bulimia. Provide use.

  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 treating IGT.

  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 treating 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 delaying or preventing the progression from IGT to type 2 diabetes .

  In another aspect, the invention provides a general formula (II) as defined above for preparing a pharmaceutical composition for delaying or preventing the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes. ') Provide the use of compounds.

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

  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 having H3 histamine 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 treating allergic rhinitis, ulcers or anorexia.

  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 treating Alzheimer's disease, sleep seizures or attention deficit disorder.

  In another aspect, the present invention provides a method of treating a disorder or disease associated with H3 histamine receptors, wherein an effective amount of a general formula (II ′) as defined above is administered to a patient in need thereof. ) Or a pharmaceutical composition containing the compound.

  In another aspect, the invention provides a method of treating a disorder or disease associated with H3 histamine receptors, wherein an effective amount of said compound is from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to Methods are provided that are about 1000 mg, particularly preferably about 0.5 mg to about 500 mg.

  In yet another aspect, the invention provides a method of treating a disorder or disease associated with H3 histamine receptors, wherein an effective amount of a compound of formula (I), or a patient in need thereof, or It relates to a method comprising administering a diastereomer, enantiomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound.

  In one aspect, the present invention relates to compounds that have histamine H3 receptor antagonist activity or inverse agonist activity and are therefore useful in the treatment of a wide range of medical conditions and disorders where histamine H3 receptor blocking is beneficial.

  In another aspect, the invention relates to compounds that have histamine H3 receptor agonist activity and are therefore useful in the treatment of a wide range of medical conditions and disorders in which activation of histamine H3 receptor is beneficial.

  In a preferred embodiment of the invention, the compound is used to prepare a pharmaceutical composition that loses weight.

  In a preferred embodiment of the invention, the compounds are used for preparing a pharmaceutical composition for treating overweight or obesity.

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

  In a further preferred embodiment of the present invention, the compound comprises a disorder and disease associated with overweight or obesity, such as atherosclerosis, hypertension, IGT (depleted glucose tolerance), diabetes, in particular type 2 diabetes (NIDDM (non-insulin dependent) Pharmaceutical composition to prevent and / or treat various types of cancer such as endometriosis, dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis, and endometrial cancer, breast cancer, prostate cancer and colon cancer Used to prepare products.

  In a further preferred embodiment of the invention the present compounds are used for preparing a pharmaceutical composition for preventing and / or treating eating disorders such as bulimia and bulimia.

  In a further preferred embodiment of the invention the present compounds are used for preparing a pharmaceutical composition for treating IGT.

  In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for treating type 2 diabetes. Such treatment includes, inter alia, to delay or prevent progression from IGT to type 2 diabetes and to delay or prevent progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes. Treatment of.

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

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

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

  The compounds of the present invention may also be used to treat conditions associated with epilepsy. In addition, the compounds may be used for the treatment of motion sickness and dizziness. Furthermore, they are useful as regulators of hypothalamic pituitary secretion, antidepressants, cerebral circulation regulators and may be useful in the treatment of irritable bowel syndrome.

  Furthermore, the compounds of the present invention may be useful in the treatment of dementia and Alzheimer's disease.

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

  The compounds of the present invention may also be useful for the treatment of migraine (see RL McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50) and for the treatment of myocardial infarction. (See CJ Mackins and R. Levi, Expert Opinion on Investigational Drugs 9 (2000), 2537-2542).

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

  In further aspects of the invention, the compound may be administered in combination with one or more additional pharmacologically active substances in any suitable ratio. Such additional active agents include anti-obesity agents, anti-diabetic agents, antihypertensive agents, drugs for the treatment of complications arising from or related to diabetes, and complications arising from or related to obesity May be selected from drugs for the treatment of Accordingly, in a further aspect of the invention the present compounds are administered in combination with one or more antiobesity agents or appetite regulating agents.

  Such drugs include CART (cocaine amphetamine-regulated transcription) agonist, NPY (neuropeptide Y) antagonist, MC4 (melanocortin 4) agonist, MC3 (melanocortin 3) agonist, orexin antagonist, TNF (tumor necrosis factor) agonist, CRF ( Corticotropin releasing factor) agonist, CRF BP (corticotropin releasing factor binding protein) antagonist, urocortin agonist, β3 adrenergic agonist (eg CL-316243, AJ = 9677, GW-0604, LY362884, LY377267 or AZ-40140), MSH (Melanocyte-stimulating hormone) agonist, MCH (melanocyte-concentrating hormone) antagonist, CCK (cholecystokinin) agonist, serotonin reuptake inhibitor (eg fluoxetine, seroxat or citalopram), serotonin And noradrenaline reuptake inhibitors, mixed serotonin and noradrenaline compounds, 5HT (serotonin) agonist, bombesin agonist, galanin antagonist, growth hormone, growth factor (prolactin or placental lactogen), growth hormone releasing compound, TRH (thyroid stimulating hormone release) Hormone) agonist, UCP2 or 3 (uncoupled protein 2 or 3) modulator, leptin agonist, DA agonist (bromocriptine, doplexin), lipase / amylase inhibitor, PPAR (peroxisome proliferator activated receptor) modulator, RXR (retinoid X Receptor) modulators, TRβ agonists, AGRP (agouti-related protein) inhibitors, opioid antagonists (eg, naltrexone), exendin-4, GLP-1, and cilia Selected from the group consisting of neurotrophic factors.

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

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

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

  In yet another embodiment, the antiobesity agent is sibutramine.

  In yet another embodiment, the antiobesity agent is orlistat.

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

  In yet another embodiment, the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.

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

The association of anti-diabetic agents, insulin, as well as prior art insulin analogues are described in the following, which is incorporated herein as part of the all the specification and derivatives: EP 792 290 (Novo Nordisk A / S), for example, N ^{εB29 -tetradecanoyl} des (B30) human insulin; EP 214 826 and EP 705275 (Novo Nordisk A / S), eg Asp ^B28 human insulin; derivatives described in US 5,504,188 (Eli Lilly), eg Lys ^B28 Pro ^B29 GLP-1 as disclosed in WO 98/08871 (Novo Nordisk A / S), including human insulin; EP 368 187 (Aventis), eg, Lantus, and further incorporated herein by reference. Derivatives as well as orally active hypoglycemic agents are included.

  Orally active hypoglycemic agents are preferably against imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, α-glucosidase inhibitors, β-cell ATP-dependent potassium channels Agents that act in combination, such as the potassium channel openers or mitiglinides disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A / S), which are incorporated by reference herein, or potassium Channel blockers such as BTS-67582, nateglinide, glucagon antagonists disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A / S and Agouron Pharmaceuticals, Inc.), incorporated herein by reference, GLP-1 agonists disclosed in WO 00/42026 (Novo Nordisk A / S and Agouron Pharma-ceuticals, Inc.), which is incorporated by reference herein , DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of liver enzymes involved in gluconeogenesis and / or glycogenolysis, glucose uptake modulators, GSK-3 (glycogen synthase kinase) -3) Inhibitors, compounds that modify lipid metabolism, such as antilipidemic agents, compounds that reduce food intake, PPAR (peroxisome proliferator activated receptor) agonists and RXR (retinoids) X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.

In one embodiment of the invention, the compound is insulin, or an analog or derivative of insulin, such as N ^{εB29 -tetradecanoyl} des (B30) human insulin, Asp ^B28 human insulin, Lys ^B28 Pro ^B29 human insulin, Lantus® Or a combination preparation containing one or more of these.

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

  In another embodiment of the invention the compound is administered in combination with a biguanide such as metformin.

  In yet another embodiment of the invention the compound is administered in combination with a meglitinide such as repaglinide or nateglinide.

  In yet another embodiment of the invention, the compound is a thiazolidinedione insulin sensitizer such as troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011 / CI-1037 or T 174, Or in combination with compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated as part of this specification. Administered.

  In yet another embodiment of the invention the compound is 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 WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO incorporated as part of this specification 00/63193 (Dr. Reddy's Research Founda-tion), as well as WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO It is administered in combination with the compounds disclosed in 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A / S).

  In a further embodiment of the invention the compound is administered in combination with an alpha glucosidase inhibitor such as voglibose, emiglitate, miglitol or acarbose.

  In another embodiment of the invention, the compound is administered in combination with an agent that acts on β-cell ATP-dependent potassium channels, such as tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582, or repaglinide. The

  In yet another embodiment of the invention the compound is administered in combination with nateglinide.

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

  In yet another embodiment of the invention, the compound is administered in combination with a hyperlipidemic agent such as colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.

  In another aspect of the invention, the compound is combined with two or more of the compounds described above, for example, sulfonylureas such as metformin and glyburide; sulfonylureas and acarbose; nateglinide and metformin; acarbose and metformin; Administered in combination with sulfonylurea, metformin and troglitazone; insulin and sulfonylurea; insulin and metformin; insulin, metformin and sulfonylurea; insulin and triglitazone; insulin and lovastatin;

Furthermore, 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 terazosin. In addition, Remington:. The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed, Mack Publishing Co., Easton, reference may be made to the PA, 1995.

  It should be noted that suitable combinations of a compound according to the present invention with diet and / or exercise, one or more of the above compounds, and optionally one or more other active substances are also considered to be within the scope of the present invention. It should be understood.

  The compounds of the present invention may be chiral and any enantiomers such as isolated, pure, or partially purified enantiomers, or racemic mixtures thereof are included within the scope of the present invention. Is.

  In addition, diastereomers may be formed when there are double bonds, fully or partially saturated ring systems, one or more asymmetric centers, or rotationally restricted bonds in the molecule. There is. Any diastereomers such as isolated diastereomers, pure diastereomers, or partially purified diastereomers, or mixtures thereof are included within the scope of the present invention.

  Furthermore, some of the compounds of the present invention may exist in different tautomeric forms, and any tautomeric form that the compounds can form are included within the scope of the present invention.

  The present invention also includes pharmaceutically acceptable salts of the compounds of the present invention. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. Acid addition salts include salts of inorganic and organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, bromic acid, iodic acid, phosphoric acid, sulfuric acid, nitric acid 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, malonic acid, mandel Acid, succinic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid , Palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include pharmaceutically acceptable listed in J. Pharm. Sci. 1977, 66, 2 which is incorporated herein by reference. Contains salt. Examples of the metal salt include lithium salt, sodium salt, potassium salt, magnesium salt and the like. Examples of ammonium salts and alkylated ammonium salts include ammonium salts, methyl ammonium salts, dimethyl ammonium salts, trimethyl ammonium salts, ethyl ammonium salts, hydroxyethyl ammonium salts, diethyl ammonium salts, butyl ammonium salts, tetramethyl ammonium salts, and the like. included.

  Pharmaceutically acceptable acid addition salts also include hydrates that can be formed by the compounds of the present invention.

  These acid addition salts may be obtained as direct products of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing a suitable acid and the solvent can be evaporated to isolate the salt, or the salt and solvent can be separated by other methods.

  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 contemplated to be within the scope of the present invention.

  The present invention also encompasses prodrugs of the compound, which when administered undergo chemical transformation by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of such compounds that are readily convertible in vivo into the required compound of formula (I). Transformation methods for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, 1985, edited by H. Bundgaard, Elsevier.

  The present invention also includes active metabolites of the compounds of the present invention.

  The compounds of the present invention interact with the histamine H3 receptor and are therefore useful for the treatment of a wide range of medical conditions and disorders where interaction with the histamine H3 receptor is beneficial.

<Pharmaceutical composition>:
The compounds of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier or excipient in single or multiple doses. Pharmaceutical compositions according to the present invention, pharmaceutically acceptable carriers or diluents, as well as with any other known adjuvants and excipients, Remington: The Scienceand Practice of Pharmacy , 19 th Edition, Gennaro, Ed. , Mack Publishing Co., Easton, PA, 1995, may be formulated according to conventional techniques.

  The pharmaceutical compositions are oral, rectal, nasal, lung, topical (including buccal and sublingual), transdermal, intrathecal, intraperitoneal, vaginal, and parenteral (subcutaneous, intramuscular, arachnoid It may be specifically formulated for administration by any suitable route, such as the intracavitary, intravenous or intradermal route, with the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the patient to be treated, the nature of the condition to be 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. Where appropriate, they can be prepared with a coating such as an enteric coating, or according to methods well known in the art to provide controlled release of the active ingredient such as sustained or delayed release. Can be prescribed.

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

  Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous injectable sterile solutions, dispersions, suspensions or emulsions, and sterile solutions or dispersions injectable before use. Contains sterile powder to be reconstituted. Depot injectable formulations are also contemplated as being within the scope of the present invention.

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

  Typical oral dosages range from about 0.001 to about 100 mg / kg body weight per day, preferably 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, It is administered in multiple doses, for example 1-3 doses. The exact dosage will be apparent to the frequency and method of administration, sex of the patient being treated, age, weight and general medical condition, the nature and severity of the medical condition being treated, and any concomitant diseases to be treated and to those skilled in the art Will depend on other factors.

  This formulation will conveniently be given in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration (one or more times per day, eg 1 to 3 times per day) is 0.05 to about 1000 mg, preferably about 0.1 to about 500 mg, more preferably about 0.5 to about 200 mg. May be contained.

  For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, the dosage is typically about half that used for oral administration.

  The compounds of the present invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having utility as a free base. When the compound of formula (I) contains a free base, such salts can be used to convert a solution or suspension of the free base of formula (I) into a chemical equivalent of a pharmaceutically acceptable acid, such as an inorganic acid and an organic acid. Prepared in a conventional manner by treatment with acid. Representative examples are as described above. Physiologically acceptable salts of compounds with hydroxy groups include the anion of the compound in combination with a suitable cation such as sodium ion or ammonium ion.

  For parenteral administration, a sterile aqueous solution, aqueous propylene glycol or a solution of the novel compound of formula (I) in sesame oil or peanut oil may be used. Such aqueous solutions should be appropriately buffered as needed, and the diluent is first made isotonic with sufficient saline or glucose. The aqueous solution is particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All sterile aqueous media used are readily available by standard techniques 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, clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, or lower alkyl esters 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 composition formed by combining the novel compound of formula (I) and a pharmaceutically acceptable carrier is then readily administered in a variety of dosage forms suitable for the disclosed route of administration. . These formulations are conveniently given in unit dosage form by methods known in the pharmaceutical arts.

  Formulations of the present invention suitable for oral administration are given in discrete units, such as capsules or tablets each containing a predetermined amount of active ingredient and which may contain suitable excipients. Can be done. These formulations may be in the form of powder or granules, may be a solution or suspension in an aqueous or non-aqueous solution, or may be an oil-in-water or water-in-oil emulsion.

  When using a solid carrier for oral administration, the preparation may be tableted, contained in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. it can. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. When a liquid carrier is used, the preparation may be a syrup, emulsion, soft gelatin capsule, or a sterile injectable solution such as an aqueous or non-aqueous liquid suspension or solution.

A typical tablet that can be prepared by conventional tableting techniques may contain:
<Core>:
Active compound (as free compound or its salt) 5.0mg
Lactose (Lactosum Ph. Eur.) 67.8mg
Cellulose, microcrystal (Avicel) 31.4mg
Amberlite ^TM IRP88 ^* 1.0mg
Magnesium stearas Ph. Eur. Qs
<Coating>:
Hydroxypropyl methylcellulose about 9mg
Mywacett 9-40 T ^** 0.9mg
* Potassium polyacrylate (Polacrillin potasium) NF, tablet disintegrant,
Rohm and Haas.
** Acylated monoglyceride used as plasticizer for film coating
If desired, the pharmaceutical compositions of the invention may contain a compound of formula (I) in combination with further pharmacologically active substances as described above.

In the examples herein, the following terms have the following general meaning:
DIPEA: Diisopropylethylamine
DMSO: Dimethyl sulfoxide
THF: tetrahydrofuran.

HPLC (Method A)
NMR spectra were recorded on Bruker 300 MHz and 400 MHz instruments. HPLC-MS was performed on a Perkin Elmer instrument (API 100). The column used was X-Terra C18, 5 [mu] m, a 50 × 3 mm, elution with 5% to 90% acetonitrile gradient in water containing 0.01% trifluoroacetic acid, 7.5 min at room temperature 1.5mL / min It was performed within.

HPLC (Method B)
Reverse phase analysis was performed on a 218TP54 4.6 mm × 150 mm C-18 silica column eluting at 1 mL / min at 42 ° C. with UV detection at 214 and 254 nm. This column is equilibrated with 5% acetonitrile, 85% water, and 10% solution of 0.5% trifluoroacetic acid in water, and from a solution consisting of 5% acetonitrile, 85% water and 10% 0.5% trifluoroacetic acid. Elute over 15 minutes with a linear gradient to a solution consisting of 90% acetonitrile and 10% 0.5% trifluoroacetic acid.

HPLC (Method C)
RP-analysis was performed using an Alliance Waters 2695 system fitted 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 is performed using a linear gradient of 5-90% acetonitrile in water, 90-0% water, and 5% trifluoroacetic acid (1.0%) over 8 minutes at a flow rate of 1.0 min / min.

General procedure (A):
For the preparation of compounds of general formula (Ia), the general procedure (A) may be used:

In which —CH (R ²⁰ R ²¹ ) is 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, optionally containing one or more halogen substituents And may be substituted.

To a mixture of mono-substituted piperazine (15.2 mmol) in a suitable solvent such as THF, ketone or aldehyde (22.6 mmol), water, acetic acid (45.0 mmol) and then NaCNBH ₃ (18 mmol) were added. The mixture is 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 (100 mL) is added and the mixture is extracted with a solvent such as ethyl acetate (3 × 40 mL). The combined extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue may be converted to a suitable salt such as hydrochloride by co-evaporation with 1 mole of acid such as aqueous hydrochloric acid, ethanol and toluene. The residue is then purified by recrystallization.

General procedure (B):
Compounds of general formula (I) may be prepared by general procedure (B):

A mixture of monosubstituted piperazine (2.00 mmol), DMSO (1.0 mL), appropriate aryl or heteroallyl fluoride (2.00 mmol), and a base such as DIPEA (0.20 mL) is stirred at 100 ° C. for 1 hour, It is 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 × 20 mL). Separation and purification are performed as in general procedure (A).

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

General procedure (C)
Compounds of general formula (I) may be prepared by general procedure (C).

The compound of formula I is prepared in a suitable solvent such as, for example, tris (dibenzylideneacetone) dipalladium in a suitable solvent such as toluene at a suitable temperature between 0 and 150 ° C. Prepared from mono-substituted piperazine and the appropriate aryl bromide.

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

To a suspension of 1- (4-hydroxyphenyl) piperazine (2.70 g, 15.2 mmol) in THF (28 mL) was added cyclopentanone (1.90 mL, 22.6 mmol), water (0.15 mL), acetic acid (2.70 mL, 45.0 mmol) followed by NaCNBH ₃ (18 mL, 1 mol in THF, 18 mmol). The mixture was stirred at 55 ° C. for 5.5 hours and then concentrated under reduced pressure. Saturated aqueous NaHCO ₃ (100 mL) and ethyl acetate (40 mL) were added and the mixture was filtered. The resulting solid was resuspended in methanol (30 mL), heated to reflux and allowed to stand overnight at room temperature. Filtration and drying under reduced pressure gave the title compound (1.82 g, 49%) as a solid.

¹ H NMR (DMSO-d ₆ ) δ 1.34 (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: 2.70 minutes.

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 (0.18 mL, 0.22 g, 1.51 mmol) was added and the mixture was stirred at 70 ° C. for 5 hours. A saturated aqueous NaHCO ₃ solution (20 mL) was added and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. Recrystallization from methanol (4 mL) gave 0.125 g (35%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.34 (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: 4.73 min.

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 ) δ 1.34 (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 / z 265 (MH ⁺ ); Rf: 3.88 minutes.

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 ) δ 1.30-1.88 (m, 8H), 2.45 (s, 3H), 2.45 (m, 1H), 2.51 (m, 4H), 3.31 (m, 4H), 6.95 ( d, J = 8 Hz, 2H), 7.79 (d, J = 8 Hz, 2H); HPLC-MS: m / z 273 (MH ⁺ ); Rf: 3.25 min.

Example 5 1- (3,4-Dichlorophenyl) -4- (1-ethylpropyl) piperazine

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

¹ H NMR (DMSO-d ₆ ) δ 0.88 (t, J = 7 Hz, 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 = 8 Hz, 1H); HPLC-MS: m / z 301 (MH ⁺ ); Rf: 4.25 minutes.

Example 6 {4- [4- (1-Ethylpropyl) piperazin-1-yl] phenyl} phenylmethanone hydrochloride

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

¹ H NMR (DMSO-d ₆ ) δ 0.95 (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 / z 337 (MH ⁺ ); Rf: 4.27 Minutes.

Example 7 1- (4-Benzylphenyl) -4- (1-ethylpropyl) piperazine hydrochloride

A mixture of {4- [4- (1-ethylpropyl) piperazin-1-yl] phenyl} phenylmethanone hydrochloride (77 mg, 0.21 mmol), trifluoroacetic acid (2.0 mL), and triethylsilane (0.5 mL) Stir at 60 ° C. for 20 hours. The mixture was concentrated under reduced pressure and mixed with water and potassium carbonate. This mixture was extracted with ethyl acetate (3 × 20 mL). The combined extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was redissolved in ethanol and 1 molar HCl water and the solution was concentrated under reduced pressure. After coevaporation with ethanol and toluene, the residue solidified. 45 mg (61%) of the title compound were obtained.

¹ H NMR (DMSO-d ₆ ) δ 0.98 (t, J = 7 Hz, 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 (br s, 1H); HPLC-MS: m / z 323 (MH ⁺ ); Rf: 4.93 min.

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 ) δ 0.98 (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 (br s, 1H); HPLC-MS: m / z 301 (MH ⁺ ); Rf: 4.03 min.

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) ketone.

¹ H NMR (DMSO-d ₆ ) δ 0.98 (t, J = 7 Hz, 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: 4.43 min.

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 ) δ 0.98 (t, J = 7 Hz, 6H), 1.66 (m, 2H), 1.89 (m, 2H), 3.08-3.25 (m, 3H), 3.4 _1-3 . 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: 4.37 min.

Example 11 1-Cyclopentyl-4- (6-trifluoromethylpyridin-2-yl) piperazine

This compound was prepared as described in Example 1, starting from 1- (6-trifluoromethylpyridin-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: 4.10 minutes.

Example 12 1-Cyclopentyl-4- (5-trifluoromethylpyridin-2-yl) piperazine

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

¹ H NMR (DMSO-d ₆ ) δ 1.36 (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 = 8 Hz, 1H), 7.78 (br d, J = 8 Hz, 1H), 8.39 (s, 1H); HPLC-MS: m / z 300 (MH ⁺ ); Rf: 3.87 minutes.

Example 13 1-Cyclopentyl-4- (3-trifluoromethylpyridin-2-yl) piperazine

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

¹ H NMR (DMSO-d ₆ ) δ 1.29-1.65 (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: 3.70 min.

Example 14 2- [4- (1-Ethylpropyl) piperazin-1-yl] quinoline hydrochloride

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

¹ H NMR (DMSO-d ₆ ) δ0.99 (t, J = 7 Hz, 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: 3.03 min.

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 = 7 Hz, 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: 3.13 min.

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 ) δ 1.55 (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: 3.03 min.

Example 17 [4- (4-Cyclopentylpiperazin-1-yl) -3,5-difluorophenyl] phenylmethanone 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: 2.77 min.

Example 18 2- (4-Cyclopentylpiperazin-1-yl) quinoxaline hydrochloride

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

¹ H NMR (DMSO-d ₆ ) δ 1.55 (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: 1.70 minutes.

Example 19 2- (4-Cyclopropylmethylpiperazin-1-yl) quinoxaline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.41 (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: 1.73 min.

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 = 8 Hz, 1 Hz, 1H), 8.19 (d, J = 1 Hz, 1H); HPLC-MS: m / z (MH ⁺ ).

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

Example 21 2- (4-Cyclopentylpiperazin-1-yl) quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 1.62 (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: 0.34 min.

This compound was prepared as described 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 ) δ 1.53 (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 (br s, 1H), 7.61 (d, J = 8Hz, 2H), 7.83 (d, J = 8Hz, 1H), 8.15 (s, 1H), 11.29 (br s, 1H); HPLC-MS: m / z 418 (MH ⁺ ); Rf: 3.40 minutes.

Example 23 {6- [4- (1-Cyclopropyl-1-methylethyl) piperazin-1-yl] pyridin-3-yl} phenylmethanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.48-0.62 (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, 1 H); HPLC-MS: m / z 350 (MH ⁺ ); Rf: 3.03 min.

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

Example 24 {4- [4- (1-Cyclopropyl-1-methylethyl) piperazin-1-yl] -3,5-difluorophenyl} phenylmethanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.48-0.63 (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: 3.73 minutes.

Example 25 {4- [4- (1-Cyclopropyl-1-methylethyl) piperazin-1-yl] -3,5-difluorophenyl} phenylmethanol hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.47-0.61 (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: 3.40 minutes.

This compound was prepared by reduction with sodium borohydride from Example 24.

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: 2.78 min.

This compound was prepared as described in Example 6 using 3,4,5,4′-tetrafluorobenzophenone. 3,4,5,4′-Tetrafluorobenzophenone was prepared by alkylation of Friedel Crafts 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 ) δ 0.97 (t, J = 7 Hz, 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: 3.00 min.

Example 28 2- [4- (1-Ethylpropyl) piperazin-1-yl] -6,7-dimethoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.99 (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: 2.00 min.

This compound was prepared as described in Example 6 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 ) δ 0.99 (t, J = 7 Hz, 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 (brs, 1H); HPLC-MS: m / z 352 (MH ⁺ ); Rf: 3.70 min.

This compound was prepared from 2-chloro-4-trifluoromethylquinoline. 2-Chloro-4-trifluoromethylquinoline 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), 3.0 1-3 .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 = 7 Hz, 1H), 10.70 (br s, 1H); HPLC-MS: m / z 366 (MH ⁺ ); Rf: 3.63 min.

Example 31 [4- (4-Cyclopropylmethylpiperazin-1-yl) -3,5-difluorophenyl] phenylmethanone 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: 3.53 min.

Example 32 [4- (4-Cyclopropylmethylpiperazin-1-yl) -3,5-difluorophenyl]-(3-fluoro-4-methoxyphenyl) methanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.41 (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 (br s, 1H); HPLC-MS: m / z 405 (MH ⁺ ); Rf: 3.67 min.

Example 33 {6- [4- (1-Ethylpropyl) piperazin-1-yl] pyridin-3-yl} phenylmethanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.97 (t, J = 7 Hz, 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 (br s, 1H); HPLC-MS: m / z 338 (MH ^<+> ); Rf: 3.00 min.

Example 34 {2- [4- (1-Ethylpropyl) piperazin-1-yl] pyridin-4-yl} phenylmethanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.97 (t, J = 7 Hz, 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 = 6 Hz, 1H), 10.43 (br s, 1H); HPLC-MS: m / z 338 (MH ^<+> ); Rf: 2.97 min.

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 ) δ 0.97 (t, J = 7 Hz, 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 = 8 Hz, 2H), 10.36 (s, 1H), 10.60 (brs, 1H); HPLC-MS: m / z 353 (MH ⁺ ); Rf: 2.13 min.

Example 36 {6- [4- (1-Ethylpropyl) piperazin-1-yl] pyridin-3-yl} piperidin-1-yl-methanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.97 (t, J = 7 Hz, 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: 2.27 minutes.

Example 37 N-Benzyl-6- [4- (1-ethylpropyl) piperazin-1-yl] -N-methylnicotinamide hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.97 (t, J = 7 Hz, 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: 3.10 min.

Example 38 2- [4- (1-Ethylpropyl) piperazin-1-yl] -6-methoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.98 (t, J = 7 Hz, 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: 2.17 min.

Example 39 6- [4- (1-Ethylpropyl) piperazin-1-yl] -N-methyl-N-phenylnicotinamide hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.95 (t, J = 7 Hz, 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 = 1 Hz, 1H), 10.54 (br s, 1H); HPLC-MS: m / z 367 (MH ⁺ ); Rf: 2.90 min.

Example 40 {6- [4- (1-Ethylpropyl) piperazin-1-yl] pyridin-3-yl}-(4-fluorophenyl) methanone hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.95 (t, J = 7 Hz, 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 = 8 Hz, 1 Hz, 1 H), 8.48 (d, J = 1 Hz, 1 H), 10.85 (br s, 1 H); HPLC-MS: m / z 356 (MH ⁺ ); Rf: 2.40 min.

Example 41 2- [4- (1-Ethylpropyl) piperazin-1-yl] -4-methylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.98 (t, J = 7 Hz, 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: 1.26 min.

Example 42 2- [4- (1-Ethylpropyl) piperazin-1-yl] -5,6,7,8-tetrahydroquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.98 (t, J = 7 Hz, 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: 1.83 min.

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 ) δ 0.41 (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: 1.87 min.

Example 44 2- (4-Isopropylpiperazin-1-yl) -6-methoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.32 (d, J = 7 Hz, 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: 1.77 min.

Example 45 2- [4- (1-Ethylpropyl) piperazin-1-yl] -6-fluoro-4-methylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.98 (t, J = 7 Hz, 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: 1.92 min.

This compound was prepared from 2-chloro-6-fluoro-4-methylquinoline. The 2-chloro-6-fluoro-4-methylquinoline is obtained by acetoacetylating 4-fluoroaniline, followed by an acid-mediated ring closure reaction, and treating the resulting carbostyril with phosphorus oxychloride. Prepared by conversion to chloroquinoline.

Example 46 2- (4-Isopropylpiperazin-1-yl) quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J = 7 Hz, 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: 1.47 minutes.

Example 47 2- (4-Cyclopropylpiperazin-1-yl) -6-methoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.81 (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: 1.80 min.

Example 48 2- (4-Isopropyl-piperazin-1-yl) -6-trifluoromethoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J = 7 Hz, 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, 1 H); HPLC-MS: m / z 340 (MH ⁺ ); Rf: 3.04 min.

Example 49 6-Chloro-2- (4-cyclopropyl-piperazin-1-yl) -quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.81 (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 (br d, J = 8Hz, 1H), 10.75 (br s, 1H); HPLC-MS: m / z 288 (MH ^<+> ); Rf: 1.77 min.

Example 50 2- (4-Cyclopropyl-piperazin-1-yl) -6-trifluoromethoxyquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.81 (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: 2.24 min.

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: 3.08 min.

¹H NMR(DMSO-d₆)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：2.11分。 Example 52 2- (4-Isopropyl-piperazin-1-yl) -6-trifluoromethylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J = 7 Hz, 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: 2.11 minutes.

¹H NMR(DMSO-d₆)δ0.91(t, J = 7Hz, 3H)，1.31(d, J = 7Hz, 6H)，1.66(sext,J = 7Hz, 2H)，2.70(t,J = 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：1.97分。 Example 53 2- (4-Isopropyl-piperazin-1-yl) -6-propylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.91 (t, J = 7Hz, 3H), 1.31 (d, J = 7Hz, 6H), 1.66 (sext, J = 7Hz, 2H), 2.70 (t, J = 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: 1.97 min.

¹H NMR(DMSO-d₆)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 54 6,8-Difluoro-2- (4-isopropylpiperazin-1-yl) quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J = 7 Hz, 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).

¹H NMR(DMSO-d₆)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 55 8-Fluoro-2- (4-isopropylpiperazin-1-yl) quinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J = 7 Hz, 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).

¹H NMR(DMSO-d₆)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)，7.86(m, 2H)，8.26(br s, 1H)，8.33(d, J =8Hz, 1H)，11.12(br s, 1H)；HPLC-MS：m/z 322(MH⁺)；Rf：2.41分。 Example 56 2- (4-Cyclopropylpiperazin-1-yl) -6-trifluoromethylquinoline hydrochloride

¹ H NMR (DMSO-d ₆ ) δ 0.81 (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), 7.86 (m, 2H), 8.26 (br s, 1H), 8.33 (d, J = 8Hz, 1H), 11.12 (br s, 1H); HPLC-MS: m / z 322 (MH ⁺ ); Rf: 2.41 min.

¹H NMR(DMSO-d₆)δ0.82(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：1.97分。 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: 1.97 min.

S. Cacchi et al., SynLett 1997, 1400-1402にも参照できる。 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 ) δ 1.30 (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: 1.04 min.

この化合物は、1-イソプロピルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-フェニルピリダジンから出発して、一般手順（Ｂ）に従って調製した。 Example 59 (General procedure (B)) 3- (4-Isopropyl-piperazin-1-yl) -6-phenyl-pyridazine, hydrochloride

This compound is prepared according to the general procedure (B) starting from 1-isopropylpiperazine and 3-chloro-6-phenylpyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978). Prepared.

¹ H NMR (D ₂ O): δ 1.46 (d, 6H); 3.28 (m, 2H); 3.48 (m, 2H); 3.64-3.84 (m, 3H); 4.57 (m, 2H); 7.6 _{3 -7 .72 (m, 4H);} 7.90 (m, 2H); 8.12 (d, 1H); HPLC-MS: m / z = 283.2 (M + 1); R t = 1.52 min.

この化合物は、1-シクロペンチルピペラジンおよびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(4-メタンスルホニル-フェニル)-ピリダジンから出発して、一般手順（Ｂ）に従って調製した。 Example 60 (General Procedure (B)) 3- (4-Cyclopentyl-piperazin-1-yl) -6- (4-methanesulfonyl-phenyl) -pyridazine

This compound starts from 1-cyclopentylpiperazine and 3-chloro-6- (4-methanesulfonyl-phenyl) -pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978). Prepared according to general procedure (B).

¹ H NMR (CDCl ₃ ): δ 1.38-1.80 (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 = 2.20 minutes.

この化合物は、1-シクロペンチルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(4-メタンスルホニル-フェニル)-ピリダジンから出発して、一般手順（Ｂ）に従って調製した。 Example 61 (General procedure (B)) 3- (4-cyclopropylmethyl - piperazin-1-yl) -6- (4-methanesulfonyl-phenyl) - - pyridazine

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

¹ H NMR (CDCl ₃ ): δ 0.15 (q, 2H); 0.57 (m, 2H); 0.92 (m, 1H); 2.34 (d, 2H); 2.69 (dd, 4H); 3.10 (s, 3H 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) ); R _t = 2.04 min.

この化合物は、1-イソプロピルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(4-メタンスルホニル-フェニル)-ピリダジンから出発して、一般手順（Ｂ）に従って調製した。 Example 62 (General procedure (B)) 3- (4-isopropyl - piperazine-1-yl) -6- (4-methanesulfonyl-phenyl) - - pyridazine

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

¹ H NMR (DMSO-d ₆ ): δ 1.01 (d, 6H); 2.57 (m, 4H); 2.71 (m, 1H); 3.26 (s, 3H); 3.67 (m, 4H); 7.39 (d , 1H); 8.02 (d, 2H); 8.06 (d, 1H); 8.30 (d, 2H); HPLC-MS: m / z = 360.8 (M + 1); R t = 1.43 min.

この化合物は、1-イソプロピルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された6-クロロ-3-(4-クロロ-フェニル)-4-メチル-ピリダジンから出発して、一般手順（Ｂ）に従って調製した。 Example 63 (General procedure (B)) 3- (4-Chloro-phenyl) -6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridazine, hydrochloride

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

¹ H NMR (D ₂ O): δ 1.08 (d, 6H); 2.10 (s, 1H); 3.01 (m, 2H); 3.23 (m, 2H); 3.28-3.44 (m, 3H); 4.31 ( broad d, 2H); 7.27 ( d, 2H); 7.34 (d, 2H); 7.58 (s, 1H); HPLC-MS: m / z = 331.1 (M + 1); R t = 3.1 min.

C18 H23 N4 Cl, 2 HCl
Calculated value: C 53.54 H 6.24 N 13.88
Found: C 53.34 H 6.31 N 13.70.

この化合物は、1-シクロペンチルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された6-クロロ-3-(4-クロロ-フェニル)-4-メチル-ピリダジンから出発して、一般手順（Ｂ）に従って調製した。 Example 64 (General procedure (B)) 3- (4-Chloro-phenyl) -6- (4-cyclopentyl-piperazin-1-yl) -4-methyl-pyridazine, hydrochloride

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

¹ H NMR (D ₂ O): δ 1.29-1.60 (m, 6H); 1.91 (m, 2H); 2.12 (s, 3H); 3.00 (m, 2H); 3.24 (m, 2H); 3.36 ( 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.

C20 H25 N4 Cl, 2 HCl
Calculated value: C 55.89 H 6.33 N 13.04
Found: C 55.83 H 6.47 N 12.93.

この化合物は、1-シクロペンチルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(4-クロロフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。標題化合物を遊離塩基として得た。 Example 65 (General Procedure (B)) 3- (4-Chlorophenyl) -6- (4-cyclopentylpiperazin-1-yl) -pyridazine

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

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); R _t = 2.93 min.

この化合物は、1-シクロペンチルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(3-フルオロ-4-メトキシフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。 Example 66 (General procedure (B)) 3- (4-Cyclopentylpiperazin-1-yl) -6- (3-fluoro-4-methoxyphenyl) -pyridazine, hydrochloride

This compound is derived from 1-cyclopentylpiperazine and 3-chloro-6- (3-fluoro-4-methoxyphenyl) -pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978). Prepared as described in Example 6 starting.

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); R _t = 2.47 min.

この化合物は、1-シクロペンチルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(3,4-ジメトキシフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。標題化合物を遊離塩基として得た。 Example 67 (General procedure (B)) 3- (4-Cyclopentylpiperazin-1-yl) -6- (3,4-dimethoxyphenyl) -pyridazine

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

¹ H NMR (CDCl ₃ ): δ 1.40-1.65 (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.

この化合物は、1-シクロプロピルメチルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(4-クロロフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。標題化合物を遊離塩基として得た。 Example 68 (General procedure (B)) 3- (4-Chlorophenyl) -6- (4-cyclopropylmethylpiperazin-1-yl) -pyridazine

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

_{^{1 H NMR (CDCl 3):}} . Δ0.46 (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 = 2.11 min.

この化合物は、1-シクロペンチルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(4-トリフルオロメチルフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。標題化合物を遊離塩基として得た。 Example 69 (general procedure (B))
[Name]

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

¹ H NMR (CDCl ₃ ): δ 1.40-1.65 (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); R _t = 2.68 minutes.

この化合物は、1-イソプロピルピペラジンおよびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(4-トリフルオロメチルフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。標題化合物を遊離塩基として得た。 Example 70 (General procedure (B)) 3- (4-Isopropylpiperazin-1-yl) -6- (4-trifluoromethylphenyl) -pyridazine

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

¹ H NMR (DMSO-d ₆ ): δ 1.20 (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.

この化合物は、1-シクロプロピルメチルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(4-トリフルオロメチルフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。標題化合物を遊離塩基として得た。 Example 71 (General Procedure (B)) 3- (4-Cyclopropylmethylpiperazin-1-yl) -6- (4-trifluoromethylphenyl) -pyridazine

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

¹ H NMR (CDCl ₃ ): δ 0.15 (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); R _t = 2.65 min .

この化合物は、1-イソプロピルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(4-クロロフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。標題化合物を遊離塩基として得た。 Example 72 (General procedure (B)) 3- (4-Chlorophenyl) -6- (4-isopropylpiperazin-1-yl) -pyridazine

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

¹ H NMR (CDCl ₃ ): δ 1.10 (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 = 2.03 min.

この化合物は、1-シクロプロピルメチルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(3-フルオロ-4-メトキシフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。標題化合物を遊離塩基として得た。 Example 73 (General procedure (B)) 3- (4-Cyclopropylmethylpiperazin-1-yl) -6- (3-fluoro-4-methoxyphenyl) -pyridazine

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

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 = 1.90 minutes.

この化合物は、1-イソプロピルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(3-フルオロ-4-メトキシフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。標題化合物を遊離塩基として得た。 Example 74 (General procedure (B)) 3- (3-Fluoro-4-methoxyphenyl) -6- (4-isopropylpiperazin-1-yl) -pyridazine

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

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); R _t = 1.57 min .

この化合物は、1-イソプロピルピペラジン、およびJ. Heterocycl. Chem., 15, 881(1978)に記載の通りに調製された3-クロロ-6-(3,4-ジメトキシフェニル)-ピリダジンから出発し、例６で説明したようにして調製した。 Example 75 (General procedure (B)) 3- (3,4-Dimethoxyphenyl) -6- (4-isopropylpiperazin-1-yl) -pyridazine, hydrochloride

This compound starts from 1-isopropylpiperazine and 3-chloro-6- (3,4-dimethoxyphenyl) -pyridazine prepared as described in J. Heterocycl. Chem., 15, 881 (1978). Prepared as described in Example 6.

_{^{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.

この化合物は、(9a-R)-オクタヒドロピリド[1,2-a]ピラジンおよび2-クロロ-6-トリフルオロメトキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 76 (General Procedure (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 ) δ 1.40-1.55 (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 = 8 Hz, 1H), 11.60 (br s, 1H); HPLC-MS: m / z 352 (MH ⁺ ); R _t = 2.67 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-7-フルオロ-6-メチルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 77 (General procedure (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 ) δ 1.32 (d, J = 7 Hz, 6H), 2.36 (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, 1H), 8.09 (br s, 1H), 8.35 (d, J = 8Hz, 1H), 11.57 (br s, 1H); HPLC -MS: m / z 287 (MH +); R t = 1.47 min.

この化合物は、1-イソプロピルピペラジンおよび2,7-ジクロロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 78 (General procedure (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 ⁺ ); R _t = 1.61 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-6-フルオロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 79 (General procedure (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 +); R t = 1.21 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-7-フルオロ-6-メチルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 80 (General Procedure (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 ) δ 0.82 (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 ⁺ ); R _t = 1.47 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-7-フルオロ-6-メトキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 81 (General Procedure (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 ) δ 0.82 (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 ⁺ ); R _t = 1.37 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-7-フルオロ-6-メトキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 82 (General procedure (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 = 7 Hz, 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 +); R t = 1.41 min.

この化合物は、(9a-R)-オクタヒドロピリド[1,2-a]ピラジンおよび2-クロロ-7-フルオロ-6-メトキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 83 (General procedure (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 ) δ 1.40-1.55 (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 = 8 Hz, 1H), 11.59 (br s, 1H); HPLC-MS: m / z 315 (MH ⁺ ); R _t = 1.41 min.

この化合物は、(9a-R)-オクタヒドロピリド[1,2-a]ピラジンおよび2-クロロ-6-トリフルオロメチルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 84 (General Procedure (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 ) δ 1.40-1.55 (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 = 8 Hz, 1H), 11.60 (br s, 1H); HPLC-MS: m / z 335 (MH ⁺ ); R _t = 2.27 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-7-フルオロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 85 (General procedure (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 = 7 Hz, 6H), 3.19 (m, 2H), 3.45-4.20 (m, 5H), 4.84 (m, 2H), 7.32 (m, 1H ), 7.45 (d, J = 8 Hz, 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 ⁺ ); R _t = 1.31 min.

この化合物は、1-イソプロピルピペラジンおよび2,6-ジクロロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 86 (General procedure (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 = 7 Hz, 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 +); R t = 1.64 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-6-イソプロピルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 87 (General procedure (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 ) δ 1.27 (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 +); R t = 1.87 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-6-イソプロピルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 88 (General procedure (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 ) δ 0.83 (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 (br s, 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 ⁺ ); R _t = min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 89 (General procedure (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 ) δ 0.83 (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 ⁺ ); R _t = min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-6,7-ジメトキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 90 (General procedure (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 ) δ 0.82 (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 ⁺ ) ; R _t = 1.27 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-6,7-ジメトキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 91 (General procedure (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 = 7 Hz, 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 ⁺ ); R _t = 1.27 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-7-フルオロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 92 (General Procedure (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 ) δ 0.82 (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 ⁺ ); R _t = 1.24 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-6,8-ジフルオロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 93 (General Procedure (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 ) δ 0.82 (m, 2H), 1.19 (m, 2H), 2.87 (br s, 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 +); R t = 2.27 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-6-フルオロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 94 (General Procedure (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 ) δ 0.82 (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 ⁺ ); R _t = 1.27 min.

この化合物は、1-シクロプロピルピペラジンおよび2,7-ジクロロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 95 (General procedure (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 ) δ 0.82 (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, 1 H); HPLC-MS: m / z 288 (MH ⁺ ); R _t = 1.71 min.

この化合物は、(9a-R)-オクタヒドロピリド[1,2-a]ピラジンおよび2-クロロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 96 (General Procedure (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 ) δ 1.40-1.55 (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 +); R t = 1.07 min.

この化合物は、(9a-R)-オクタヒドロピリド[1,2-a]ピラジンおよび2,6-ジクロロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 97 (General Procedure (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 ) δ 1.40-1.55 (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 = 8 Hz, 1H), 11.47 (br s, 1H); HPLC-MS: m / z 302 (MH ⁺ ); R _t = 1.81 min.

この化合物は、(9a-R)-オクタヒドロピリド[1,2-a]ピラジンおよび2-クロロ-7-フルオロ-6-メチルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 98 (General Procedure (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 ) δ 1.40-1.55 (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 = 8 Hz, 1H), 11.77 (br s, 1H); HPLC-MS: m / z 300 (MH ⁺ ); R _t = 1.54 min.

この化合物は、(9a-R)-オクタヒドロピリド[1,2-a]ピラジンおよび2-クロロ-6-プロピルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 99 (General Procedure (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 ) δ 0.91 (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 ⁺ ); R _t = 2.27 Minutes.

この化合物は、1-イソプロピルピペラジンおよび2-クロロキノキサリンから、一般手順（Ｂ）を用いて調製した。 Example 100 (General Procedure (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 = 8 Hz, 1H), 8.91 (s, 1H), 11.15 (br s, 1H); HPLC-MS: m / z 257 (MH ⁺ ); R _t = 1.25 minutes.

この化合物は、1-シクロプロピルピペラジンおよび4-フルオロベンゾフェノンから、一般手順（Ｂ）を用いて調製した。 Example 101 (General Procedure (B)) [4- (4-Cyclopropylpiperazin-1-yl) phenyl] phenylmethanone hydrochloride

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

¹ H NMR (DMSO-d ₆ ) δ 0.82 (m, 2H), 1.16 (m, 2H), 2.92 (br s, 1H), 3.30-3.40 (m, 4H), 3.56 (br s, 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 / z 307 (MH ⁺ ); R _t = 2.00 min.

この化合物は、1-シクロプロピルピペラジンおよび3,4,5-トリフルオロベンゾフェノンから、一般手順（Ｂ）を用いて調製した。 Example 102 (General Procedure (B)) [4- (4-Cyclopropylpiperazin-1-yl) -3,5-difluorophenyl] phenylmethanone hydrochloride

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

¹ H NMR (DMSO-d ₆ ) δ 0.82 (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 +); R t = 2.29 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-5,6,7-トリメトキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 103 (General Procedure (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 ⁺ ); R _t = 1.22 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-5,6,7-トリメトキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 104 (General Procedure (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 ) δ 0.82 (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 +); R t = 1.46 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-6-トリフルオロメチルスルファニルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 105 (General Procedure (B)) 2- (4-Cyclopropylpiperazin-1-yl) -6-trifluoromethylsulfanylquinoline hydrochloride

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

¹ H NMR (DMSO-d ₆ ) δ 0.82 (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 +); R t = 2.61 min.

この化合物は、1-シクロプロピルピペラジンおよび2,7-ジクロロ-6-メトキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 106 (General Procedure (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 ) δ 0.82 (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 +); R t = 1.80 min.

この化合物は、1-シクロプロピルピペラジンおよび2,5,7-トリクロロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 107 (General Procedure (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 ) δ 0.82 (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 / z322 ( MH ⁺ ); R _t = 2.78 min.

必要な2-クロロ-5-(4-トリフルオロフェニル)ピリジンを、R. Church, R. Trust, J. D. Albright, およびD.Powell, J. Org. Chem. 1995, 60, 3750-3758に記載の通り、以下のようにして調製した：
ジメチルホルムアミド(5.98g，0.082mol)およびオキシ塩化リン(22.5g，0.146mol)から10℃で調製したVilsmeier試薬の溶液に、4-(トリフルオロメチル)フェニル酢酸(6.64g，0.033mol)を添加した。この混合物を70℃で８時間撹拌した。周囲温度に冷却した後、この混合物を氷および水の混合物にゆっくりと添加し（温度は＜10℃であった）、次いでNa₂CO₃の溶液を、pH 11に達するまでゆっくりと添加した。このアルカリ性混合物にトルエン(125mL)を添加し、得られた混合物を1.5時間還流させた。周囲温度にまで冷却した後、分離した水層をトルエン(100mL)を用いて抽出した。合体した有機層を水で洗浄し、乾燥させ(Na₂SO₄)、減圧下で濃縮した。得られた固体をジクロロメタンおよびヘプタンの混合物から再結晶化させて、6.98g(87％)の3-ジメチルアミノ-2-(4-トリフルオロメチルフェニル)プロペナールを黄色の結晶で得た，融点97℃。 Example 108 (General procedure (B))
1-cyclopropyl-4- [5- (4-trifluoromethylphenyl) pyridin-2-yl] piperazine hydrochloride

The required 2-chloro-5- (4-trifluorophenyl) pyridine is described in R. Church, R. Trust, JD Albright, and D. Powell, J. Org. Chem. 1995, 60, 3750-3758. Prepared as follows:
4- (Trifluoromethyl) phenylacetic acid (6.64 g, 0.033 mol) was added to a solution of Vilsmeier reagent prepared from dimethylformamide (5.98 g, 0.082 mol) and phosphorus oxychloride (22.5 g, 0.146 mol) at 10 ° C. did. The mixture was stirred at 70 ° C. for 8 hours. After cooling to ambient temperature, the mixture was slowly added to the ice and water mixture (temperature was <10 ° C.) and then a solution of Na ₂ CO ₃ was added slowly until pH 11 was reached. Toluene (125 mL) was added to the alkaline mixture and the resulting mixture was refluxed for 1.5 hours. After cooling to ambient temperature, the separated aqueous layer was extracted with toluene (100 mL). The combined organic layers were washed with water, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting solid was recrystallized from a mixture of dichloromethane and heptane to give 6.98 g (87%) of 3-dimethylamino-2- (4-trifluoromethylphenyl) propenal 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); R _F (SiO ₂ Chloroform / methanol 95: 5) 0.34.

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

¹ H NMR (DMSO-d ₆ ) δ 8.42 (m, 1H), 7.91 (m, 1H), 7.66 (m, 4H); R _F (SiO2, chloroform / methanol 95: 5) 0.18.

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

¹ H NMR (DMSO-d ₆ ) δ 8.71 (d, 1H), 8.43 (d, 1H), 7.96 (m, 2H), 7.81 (m, 2H); R _F (SiO2, chloroform / methanol 95: 5 ): 0.13.

  A mixture of this 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 (250 mL) 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 ) δ 7.79 (dd, 2H), 7.68 (d, 3H), 7.52 (d, 2H), 6.73 (d, 1H); R _F (SiO ₂ , chloroform / methanol 95: 5) 0.23.

A mixture of phosphorus oxychloride (27.6 g, 0.18 mol) and the above 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 (75 mL). To the residue was added water (75 mL) and dichloromethane (75 mL), the dichloromethane layer was separated and the aqueous phase was extracted with dichloromethane (75 mL). The combined extracts are washed with water, then with a solution of sodium bicarbonate, dried (MgSO ₄ ), concentrated under reduced pressure, and 2.95 g (72%) of 2-chloro-5- (4-trimethyl). Fluoromethylphenyl) pyridine was obtained as light brown crystals, mp 98-101 ° C.

¹ H NMR (CDCl ₃ ) δ 8.62 (dd, 1H), 7.86 (dd, 1H), 7.44 (dd, 1H), 7.66 (m, 2H), 7.75 (m, 2H); R _F (SiO ₂ , Chloroform / methanol 95: 5) 0.94.

  This product was treated with 1-cyclopropylpiperazine as described in general procedure (B) to give the title compound.

¹ H NMR (DMSO-d ₆ ) δ 0.83 (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 ⁺ ); R _t = 2.77 min.

この化合物は、1-シクロプロピルピペラジンおよび3-クロロ-6-(4-トリフルオロメチルフェニル)ピリダジンから、一般手順（Ｂ）を用いて調製した。 Example 109 (General Procedure (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 the general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ 0.83 (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 +); R t = 2.40 min.

この化合物は、1-シクロプロピルピペラジンおよび6-クロロ[1,3]ジオキソロ[4,5-g]キノリンから、一般手順（Ｂ）を用いて調製した。 Example 110 (General Procedure (B)) 6- (4-Cyclopropylpiperazin-1-yl)-[1,3] dioxolo [4,5-g] quinoline hydrochloride

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

¹ H NMR (DMSO-d ₆ ) δ 0.83 (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 +); R t = 0.68 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-6-シクロヘキシルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 111 (General Procedure (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 ) δ 0.83 (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 ⁺ ); R _t = 2.55 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-6-シクロヘキシルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 112 (General Procedure (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 ) δ 1.10-1.55 (m, 8H), 1.31 (d, J = 7 Hz, 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 +); R t = 2.50 min.

必要な2-クロロ-6,7-ジメトキシ-3-メチルキノリンを、Tetrahedron Letters 1979, 4885で公開された手順に従い、次のように調製した：
ジクロロメタン(50mL)中の3,4-ジメトキシアニリン(4.70g，30.7mmol)の溶液に、ピリジン(8.0mL，3当量)を添加し、次いでプロピオニル塩化物(3.5mL，40.5mmol)を滴下添加した。室温で１時間50分撹拌した後、水(200mL)および濃塩酸(8mL)の混合物中に注いだ。相を分離し、水相をジクロロメタンで１度抽出した。合体した有機相を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濃縮して6.89gの油状物を得、これを数分後に結晶化させた。酢酸エチルおよびヘプタン混合物からの再結晶化により3.60g(49％)のN-(3,4-ジメトキシフェニル)プロピオンアミドを暗色の結晶で得た。 Example 113 (General Procedure (B))
2- (4-Cyclopropylpiperazin-1-yl) -6,7-dimethoxy-3-methylquinoline hydrochloride

The required 2-chloro-6,7-dimethoxy-3-methylquinoline was prepared according to the procedure published in Tetrahedron Letters 1979, 4885 as follows:
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 the dropwise addition of propionyl chloride (3.5 mL, 40.5 mmol). . After stirring at room temperature for 1 hour 50 minutes, it was poured into a mixture of water (200 mL) and concentrated hydrochloric acid (8 mL). The phases were separated and the aqueous phase was extracted once with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to give 6.89 g of an oil that crystallized after a few minutes. Recrystallization from a mixture of ethyl acetate and heptane yielded 3.60 g (49%) of N- (3,4-dimethoxyphenyl) propionamide as dark crystals.

This 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 is complete, the mixture is stirred at 75 ° C. for 2 hours. The mixture was poured into ice water (100 mL), stirred for 30 minutes and filtered. The solid was stripped with toluene and acetonitrile to give 1.60 g (67%) of 2-chloro-6,7-dimethoxy-3-methylquinoline as a solid. This product was treated with 1-cyclopropylpiperazine to give the title compound.

¹ H NMR (DMSO-d ₆ ) δ 0.83 (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 ⁺ ); R _t = 1.63 min.

この化合物は、1-イソプロピルピペラジンおよび6-クロロ[1,3]ジオキソロ[4,5-g]キノリンから、一般手順（Ｂ）を用いて調製した。 Example 114 (General Procedure (B)) 6- (4-Isopropylpiperazin-1-yl)-[1,3] dioxolo [4,5-g] quinoline hydrochloride

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

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J = 7 Hz, 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 ⁺ ); R _t = 0.65 min .

この化合物は、一般手順（Ｂ）を用いて、1-イソプロピルピペラジンの3,4,5-トリフルオロ安息香酸ピペリジンとの反応により調製した。この反応で２つの生成物、すなわち本例と例121が得られた。 Example 115 (General Procedure (B)) [3,5-Difluoro-4- (4-isopropyl-piperazin-1-yl) -phenyl] -piperidin-1-yl-methanone hydrochloride

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

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J = 7 Hz, 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 ⁺ ); R _t = 3.75 min.

この化合物は、(9a-R)-オクタヒドロピリド[1,2-a]ピラジンおよび2-クロロ-6,7-ジメトキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 116 (General Procedure (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 ) δ 1.40-1.55 (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 +); R t = 0.97 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-5,6,7,8-テトラヒドロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 117 (General procedure (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 ) δ 0.81 (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 ⁺ ); R _t = 0.62 min.

この化合物は、1-シクロプロピルピペラジンおよび5,6-ジクロロニコチン酸ピペリジンから、一般手順（Ｂ）を用いて調製した。 Example 118 (General Procedure (B)) [5-Chloro-6- (4-cyclopropylpiperazin-1-yl) pyridin-3-yl] piperidin-1-ylmethanone hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and piperidine 5,6-dichloronicotinate using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ 0.82 (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 = 1.50 min.

この化合物は、(9a-R)-オクタヒドロピリド[1,2-a]ピラジンおよび6-クロロニコチン酸ピペリジンから、一般手順（Ｂ）を用いて調製した。 Example 119 (General Procedure (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 piperidine 6-chloronicotinate 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 ⁺ ); R _t = 1.31 min.

この化合物は、1-シクロプロピルピペラジンおよび6-クロロニコチン酸ピペリジンから、一般手順（Ｂ）を用いて調製した。 Example 120 (General Procedure (B)) [6- (4-Cyclopropylpiperazin-1-yl) pyridin-3-yl] piperidin-1-ylmethanone hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and piperidine 6-chloronicotinate using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ 0.81 (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 +); R t = 1.22 min.

この化合物は、一般手順（Ｂ）を用いて、1-イソプロピルピペラジンの3,4,5-トリフルオロ安息香酸ピペリジンとの反応により調製した。この反応により２つの生成物、すなわち本例と例115が得られた。 Example 121 (General Procedure (B)) [3,4-Difluoro-5- (4-isopropyl-piperazin-1-yl) -phenyl] -piperidin-1-yl-methanone hydrochloride

This compound was prepared by reaction of 1-isopropylpiperazine with piperidine 3,4,5-trifluorobenzoate using general procedure (B). This reaction yielded 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 ⁺ ); R _t = 3.95 min.

この化合物は、一般手順（Ｂ）を用いて、1-イソプロピルピペラジンの4-フルオロ-3-トリフルオロメチル安息香酸ピペリジンとの反応により調製した。 Example 122 (General Procedure (B)) [4- (4-Isopropyl-piperazin-1-yl) -3-trifluoromethyl-phenyl] -piperidin-1-yl-methanone hydrochloride

This compound was prepared by reaction of 1-isopropylpiperazine with 4-fluoro-3-trifluoromethylbenzoic acid piperidine using general procedure (B).

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 +); R t = 4.21 min.

この化合物は、Tetrahedron Lett. 1995, 36(41), 7399-7402におけるGillaspy, M. L.；Lefker, B.A.；Hada, W. A.；およびHoover, D. J.による記載の通り、6,7-ジメトキシ-2-(3-メチルピペラジン-1-イル)キノリンの還元シクロプロピル化により調製した。 Example 123 2- (4-Cyclopropyl-3-methyl-piperazin-1-yl) -6,7-dimethoxy-quinoline hydrochloride

This compound can be obtained as described by Gillaspy, ML; Lefker, BA; Hada, WA; and Hoover, DJ in Tetrahedron Lett. 1995, 36 (41), 7399-7402, 6,7-dimethoxy-2- (3- Prepared by reductive cyclopropylation of methylpiperazin-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 +); R t = 3.09 min.

この化合物は、1-シクロプロピルピペラジンおよび6-クロロニコチン酸ピロリジンから、一般手順（Ｂ）を用いて調製した。 Example 124 (General Procedure (B))
[6- (4-Cyclopropylpiperazin-1-yl) pyridin-3-yl] pyrrolidin-1-yl-methanone hydrochloride

This compound was prepared from 1-cyclopropylpiperazine and pyrrolidine 6-chloronicotinate using general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ 0.81 (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 / z 301 (MH ⁺ ); R _t = 1.22 min.

3,3-ジエトキシプロピオン酸エチル(62g，326mmol)および水(100mL)の混合物に、NaOH(16.0g)を撹拌しながら添加した。110℃で攪拌（開口フラスコ）。40分後に混合物は均質になり、加熱を中断し、この混合物を室温にまで冷却した。この混合物を酸性にし(約35mL 濃HCl，pH 3-2)、抽出した(4×ジクロロメタン)。合体した抽出物を塩水で洗浄し(1×50mL)、乾燥させ(硫酸マグネシウム)、濃縮した。48gの油状物が得られた。 Example 125 (General procedure (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 (open flask). After 40 minutes the mixture became homogeneous, heating was discontinued and the mixture was cooled to room temperature. The mixture was acidified (ca. 35 mL concentrated HCl, pH 3-2) and extracted (4 × dichloromethane). The combined extracts were washed with brine (1 × 50 mL), dried (magnesium sulfate) and concentrated. 48 g of an oil was obtained.

  To this oil was added thionyl chloride (80 mL). The mixture was stirred at reflux temperature (80 ° C.) for 1 hour 30 minutes. Carefully concentrated and the residue was 48 g (should be 43 g in theoretical weight). The acid chloride was left at −20 ° C. overnight.

  This product is mixed with dichloromethane (70 mL) and 5/7 (approximately 230 mmol) of this solution is added to a solution of 4-bromoaniline (34.5 g, 201 mmol) and pyridine (50 mL) in dichloromethane (150 mL). 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. To this filtrate was added a mixture of water (700 mL) and concentrated hydrochloric acid (50 mL). The solid precipitated by shaking was filtered off, washed with dichloromethane and AcOEt and dried. An additional 14.4 g of product was obtained.

  The filtrate was extracted (3 × dichloromethane), washed once with brine, dried and concentrated. An additional 18 g of product was obtained. Total yield: 53.4g.

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

The quinoline (6.28 g, 28.0 mmol) is mixed with copper (I) cyanide (5.02 g, 56.1 mmol) and NMP (15 mL) and the mixture is stirred at reflux for 6 hours (202 ° C.), then at room temperature. And stirred overnight. Water (150 mL) was added, the mixture was filtered and the solid was washed with water. This solid was resuspended in 1N hydrochloric acid (200 mL) and iron (III) chloride hexahydrate (17.8 g) was added. The resulting mixture was stirred at room temperature for 3 days, filtered, the solid washed once with water, stripped with ethanol, dried under reduced pressure and 4.33 g (91%) of 6-cyano-2-quinoline. Was obtained as a gray solid. The product was treated with POCl ₃ and then with 1-isopropylpiperazine as described in general procedure (B) to give 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 ⁺ ); R _t = 1.62 min.

この化合物は、1-シクロプロピルピペラジンおよび3-クロロ-6-フェニルピリダジンから、一般手順（Ｂ）を用いて調製した。 Example 126 (General Procedure (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 ) δ 0.82 (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 +); R t = 1.43 min.

この化合物は、1-シクロプロピルピペラジンおよび3-クロロ-6-(3,4-ジメトキシフェニル)ピリダジンから、一般手順（Ｂ）を用いて調製した。 Example 127 (General Procedure (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 the general procedure (B).

¹ H NMR (DMSO-d ₆ ) δ 0.83 (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 +); R t = 1.45 min.

この化合物は、1-イソプロピルピペラジンおよび7-クロロ-2,3-ジヒドロ[1,4,]ジオキシノ[2,3-g]キノリンから、一般手順（Ｂ）を用いて調製した。 Example 128 (General procedure (B)) 7- (4-Isopropylpiperazin-1-yl) -2,3-dihydro- [1,4] dioxyno [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).

¹ H NMR (DMSO-d ₆ ) δ1.00 (d, J = 7 Hz, 6H), 2.67 (hept, J = 7 Hz, 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 ⁺ ); R _t = 1.14 min.

この化合物は、Tetrahedron Lett. 1995, 36(41), 7399-7402におけるGillaspy, M. L.；Lefker, B.A.；Hada, W. A.；およびHoover, D. J.による記載の通り、2-(3-メチルピペラジン-1-イル)キノリンの還元シクロプロピル化により調製した。 Example 129 2- (4-Cyclopropyl-3-methylpiperazin-1-yl) quinoline hydrochloride

This compound is 2- (3-methylpiperazin-1-yl as described by Gillaspy, ML; Lefker, BA; Hada, WA; and Hoover, DJ in Tetrahedron Lett. 1995, 36 (41), 7399-7402. ) Prepared by reductive cyclopropylation of quinoline.

¹ H NMR (DMSO-d ₆ ) δ 0.82 (m, 1H), 1.00 (m, 2H), 1.41 (m, 1H), 1.56 (d, J = 7 Hz, 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 ⁺ ); R _t = 1.18 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-6-(シクロプロピルメチルオキシ)キノリンから、一般手順（Ｂ）を用いて調製した。所望の2-クロロ-6-(シクロプロピルメチルオキシ)キノリンは、6-(シクロプロピルメチルオキシ)-2-キノリンをPOCl₃で処理することにより調製された。6-(シクロプロピルメチルオキシ)-2-キノリンは、対応する6-ヒドロキシキノリンから、ジメチルホルムアミド中で触媒量のヨウ化ナトリウムの存在下で、(ブロモメチル)シクロプロパンおよび炭酸カリウムを用いた処理により調製された。 Example 130 (General procedure (B)) 6-Cyclopropylmethoxy-2- (4-cyclopropylpiperazin-1-yl) quinoline hydrochloride

This compound was prepared from 1-isopropylpiperazine and 2-chloro-6- (cyclopropylmethyloxy) quinoline using general procedure (B). The desired 2-chloro-6- (cyclopropylmethyloxy) quinoline was prepared by treating 6- (cyclopropylmethyloxy) -2-quinoline with POCl ₃ . 6- (Cyclopropylmethyloxy) -2-quinoline is obtained from the corresponding 6-hydroxyquinoline by treatment with (bromomethyl) cyclopropane and potassium carbonate in dimethylformamide in the presence of a catalytic amount of sodium iodide. Prepared.

¹ H NMR (DMSO-d ₆ ) δ 0.35 (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 +); R t = 1.94 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-6-(1-ピラゾリール)キノリンから、一般手順（Ｂ）を用いて調製した。所望の2-クロロ-6-(1-ピラゾリール)キノリンは、6-(1-ピラゾリール)-2-キノリンをPOCl₃をで処理することにより調製した。6-(1-ピラゾリール)-2-キノリンは次のように調製された：
6-ブロモ-2-キノリン(3.58g，16.0mmol)、DMF(15mL)、ピラゾール(1.66g，24.4mmol)、炭酸カリウム(3.33g，24.1mmol)、およびヨウ化銅(I)(0.76g，3.99mmol)の混合物を160℃で22時間撹拌した。水(300mL)を添加し、完全に粉砕した後、この混合物を濾過し、固体をで洗浄した。この固体をEtOHでストリッピングし、アセトニトリルおよびエタノール(100mL，1:1)の混合物中に再び懸濁させ、加熱還流し、室温で一晩維持した。濾過し、少量のアセトニトリルで洗浄し、減圧下で乾燥させ、1.7g(50％)の6-(1-ピラゾリール)-2-キノリンをメタリックな緑色の固体で得た。 Example 131 (General Procedure (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-quinoline with POCl ₃ . 6- (1-pyrazolyl) -2-quinoline was prepared as follows:
6-bromo-2-quinoline (3.58 g, 16.0 mmol), DMF (15 mL), pyrazole (1.66 g, 24.4 mmol), potassium carbonate (3.33 g, 24.1 mmol), and copper (I) iodide (0.76 g, 3.99 mmol) was stirred at 160 ° C. for 22 hours. After adding water (300 mL) and triturating thoroughly, the mixture was filtered and the solid washed with. The solid was stripped with EtOH, resuspended in a mixture of acetonitrile and ethanol (100 mL, 1: 1), heated to reflux and maintained at room temperature overnight. Filtration, washing with a small amount of acetonitrile and drying under reduced pressure gave 1.7 g (50%) of 6- (1-pyrazolyl) -2-quinoline as a metallic green solid.

¹ H NMR (DMSO-d ₆ ) δ1.32 (d, J = 7 Hz, 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 +); R t = 1.67 min.

この化合物は、1-イソプロピルピペラジンおよび2-クロロ-6-ヒドロキシキノリンから、一般手順（Ｂ）を用いて調製した。 Example 132 (General Procedure (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 = 7 Hz, 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 (br s, 1H), 11.41 (br s, 1H ); HPLC-MS: m / z 272 (MH ⁺ ); R _t = 0.40 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-6-シアノキノリンから、一般手順（Ｂ）を用いて調製した。 Example 133 (General Procedure (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 ) δ 0.83 (m, 2H), 1.15 (m, 2H), 2.87 (br s, 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 (br s, 1H); HPLC-MS: m / z 279 (MH ⁺ ); R _t = 1.43 min.

この化合物は、(9a-R)-オクタヒドロピリド[1,2-a]ピラジンおよび2-クロロ-6-シアノキノリンから、一般手順（Ｂ）を用いて調製した。 Example 134 (General Procedure (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 ) δ 1.40-1.60 (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 +); R t = 1.72 min.

この化合物は、1-イソプロピルピペラジンおよび4,6-ジクロロ-3-フェニルピリダジンから、一般手順（Ｂ）を用いて調製した。 Example 135 (General procedure (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 = 7 Hz, 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 ⁺ ); R _t = 2.11 min.

この化合物は、1-シクロプロピルピペラジンおよび3-クロロ-6-(3-トリフルオロメチルフェニル)ピリダジンから、一般手順（Ｂ）を用いて調製した。 Example 136 (General Procedure (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 ) δ 0.83 (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 +); R t = 2.43 min.

この生成物は、2-(4-イソプロピルピペラジン-1-イル)キノリン-6-カルボニトリルを、テトラヒドロフラン中の過剰の臭化メチルマグネシウムで処理することにより調製した。 Example 137 1- [2- (4-Isopropylpiperazin-1-yl) quinolin-6-yl] ethanone hydrochloride

This product was prepared by treating 2- (4-Isopropylpiperazin-1-yl) quinolin-6-carbonitrile with excess methylmagnesium bromide in tetrahydrofuran.

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J = 7 Hz, 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 ⁺ ); R _t = 1.47 min.

この化合物は、1-イソプロピルピペラジンおよび3-クロロ-6-フェニルピリダジン-4-カルボニトリルから、一般手順（Ｂ）を用いて調製した。 Example 138 (General procedure (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 the 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 = 7 Hz, 2H), 8.72 (s, 1H), 10.67 (br s, 1H); HPLC-MS: m / z 308 (MH ⁺ ); R _t = 2.16 min.

この化合物は、1-イソプロピルピペラジンおよび6-ブロモ-2-クロロキノリンから、一般手順（Ｂ）を用いて調製した。 Example 139 (General Procedure (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).

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-6-ピラゾール-1-イルキノリンから、一般手順（Ｂ）を用いて調製した。 Example 140 (General Procedure (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 ) δ 0.83 (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 ⁺ ); R _t = 1.64 min.

この化合物は、1-シクロプロピルピペラジンおよび2,7-ジクロロ-6-ヒドロキシキノリンから、一般手順（Ｂ）を用いて調製した。必要とされる2,7-ジクロロ-6-ヒドロキシキノリンは、3-クロロ-4-メトキシアニリンから、F.EffenbergerおよびW. Hartmann がChemische Berichte 1969, 102, 3260-3267に記載したようにして調製された2,7-ジクロロ-6-メトキシキノリンの、ジクロロメタン中における三臭化ボロンを用いた脱メチル化により調製された。 Example 141 (General Procedure (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 required 2,7-dichloro-6-hydroxyquinoline was prepared from 3-chloro-4-methoxyaniline as described by F. Effenberger and W. Hartmann in Chemische Berichte 1969, 102, 3260-3267. Was prepared by demethylation of 2,7-dichloro-6-methoxyquinoline with boron tribromide in dichloromethane.

¹ H NMR (DMSO-d ₆ ) δ 0.83 (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 ⁺ ); R _t = 1.06 min.

この生成物は、2-(4-シクロプロピルピペラジン-1-イル)キノリン-6-カルボニトリルを、テトラヒドロフラン中の過剰の臭化(4-フルオロフェニル)マグネシウムで処理することにより調製した。 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) quinolin-6-carbonitrile with excess (4-fluorophenyl) magnesium bromide in tetrahydrofuran.

¹ H NMR (DMSO-d ₆ ) δ 0.84 (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 ⁺ ); R _t = 2.61 min.

この生成物は、2-(4-シクロプロピルピペラジン-1-イル)キノリン-6-カルボニトリルを、テトラヒドロフラン中の過剰の臭化シクロプロピルマグネシウムで処理することにより調製した。 Example 143 (General Procedure (B)) Cyclopropyl- [2- (4-cyclopropylpiperazin-1-yl) quinolin-6-yl] methanone hydrochloride

This product was prepared by treating 2- (4-cyclopropylpiperazin-1-yl) quinolin-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 +); R t = 1.98 min.

この化合物は、1-シクロプロピルピペラジンおよび2-クロロ-6-(4-フルオロベンジルオキシ)キノリンから、一般手順（Ｂ）を用いて調製した。 Example 144 (General Procedure (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 ) δ 0.83 (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 = 8 Hz, 2H), 7.54 (m, 5H), 8.08 (br s, 1H), 8.33 (m, 1H), 11.34 (br s, 1H); HPLC-MS: m / z 378 (MH ⁺ ); R _t = 2.53 min.

この生成物は、6-ブロモ-2-(4-イソプロピルピペラジン-1-イル)キノリンをブチルリチウムで処理し、次いでシクロヘキサノンで処理することにより調製した。酸性にワークアップ(acidic workup)すると、第３アルコールが脱離して標題化合物が得られた。 Example 145 6-Cyclohexyl-1-enyl-2- (4-isopropylpiperazin-1-yl) quinoline hydrochloride

This product was prepared by treating 6-bromo-2- (4-isopropylpiperazin-1-yl) quinoline with butyllithium and then with cyclohexanone. Upon acidic workup, the tertiary alcohol was eliminated and the title compound was obtained.

¹ H NMR (DMSO-d ₆ ) δ1.31 (d, J = 7 Hz, 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 ⁺ ); R _t = 2.50 min.

トルエン(11mL)中の3-ブロモビフェニル(300mg，1.28mmol)、1-シクロペンチルピペラジン(238mg，1.54mmol)、ナトリウムtert-ブトキシド(173mg，1.8mmol)、tris(ジベンジリデンアセトン)ジパラジウム(12mg，0.01mmol)、およびラセミ体の2,2'-bis(ジフェニルホスフィノ)-1,1'ビナフチル(24mg，0.04mmol)の混合物を、密閉した反応容器内で窒素下にて混合した。この反応混合物を、80℃で３日間、密閉した反応容器内で撹拌した。これを室温にまで冷却し、水を用いて洗浄した(2×10mL)。合体した有機層を1N 塩酸(2×20mL)を用いて抽出した。合体した水性抽出物を1N 水酸化ナトリウム水溶液をで塩基性にし、tert-ブチルメチルエーテル(3×20mL)を用いて抽出した。tert-ブチルメチルエーテル層を硫酸マグネシウム上で乾燥させた。溶媒を真空下で除去して220mgの標題化合物を得た。 Example 146 (General Procedure (C))
1- (biphenyl-3-yl) -4- (cyclopentyl) piperazine

3-bromobiphenyl (300 mg, 1.28 mmol), 1-cyclopentylpiperazine (238 mg, 1.54 mmol), sodium tert-butoxide (173 mg, 1.8 mmol), tris (dibenzylideneacetone) dipalladium (12 mg, in toluene (11 mL) 0.01 mmol) and a racemic 2,2′-bis (diphenylphosphino) -1,1′binaphthyl (24 mg, 0.04 mmol) were mixed under nitrogen in a sealed reaction vessel. The reaction mixture was stirred in a sealed reaction vessel at 80 ° C. for 3 days. This was cooled to room temperature and washed with water (2 × 10 mL). The combined organic layer was extracted with 1N hydrochloric acid (2 × 20 mL). The combined aqueous extracts were basified with 1N aqueous sodium hydroxide solution and extracted with tert-butyl methyl ether (3 × 20 mL). The tert-butyl methyl ether layer was dried over magnesium sulfate. The solvent was removed under vacuum to give 220 mg of the title compound.

¹ H-NMR (CDCl ₃ , two sets of signals, wide signals) δ 1.35-1.85 (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: Elution at 10.45 minutes.

The title compound was converted to the hydrochloride salt by dissolving in ethyl acetate (5 mL). A 3.2 M hydrogen chloride solution in ethyl acetate (5 mL) was added. The solvent was removed under vacuum. The residue was dissolved in ethanol (50 mL). The solvent was removed under vacuum.

86mgの標題化合物を、3-ブロモビフェニルの代わりに1-(ビフェニル-3-イル)-4-(シクロペンチル)ピペラジンを用いて、1-(2-(4-ブロモフェノキシ)エチル)ピロリジンについて説明しのと同様にして調製した。 Example 147 (General Procedure (C)) 1-Cyclopentyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] piperazine

Explain 86 mg of the title compound for 1- (2- (4-bromophenoxy) ethyl) pyrrolidine using 1- (biphenyl-3-yl) -4- (cyclopentyl) piperazine instead of 3-bromobiphenyl. Prepared in the same manner as

¹ H-NMR (DMSO-d ₆ ) δ 1.55 (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: Elution at 2.24 minutes. MS: calcd for [M + H] ⁺ : 344; found: 344.

The title compound was converted to the hydrochloride salt by dissolving in ethyl acetate (5 mL). A 3.2 M hydrogen chloride solution in ethyl acetate (5 mL) was added. The solvent was removed under vacuum. The residue was dissolved in ethanol (50 mL). The solvent was removed under vacuum.

180mgの標題化合物を、3-ブロモビフェニルの代わりに4-ブロモビフェニルを用いて、1-(ビフェニル-3-イル)-4-(シクロペンチル)ピペラジンについて説明したのと同様にして調製した。 Example 148 (General Procedure (C)) 1- (Biphenyl-4-yl) -4- (cyclopentyl) piperazine

180 mg of the title compound was prepared as described for 1- (biphenyl-3-yl) -4- (cyclopentyl) piperazine using 4-bromobiphenyl instead of 3-bromobiphenyl.

¹ H-NMR (CDCl ₃ ) δ 1.80-2.00 (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: Elution at 4.52 minutes.

The title compound was converted to the hydrochloride salt by dissolving in ethyl acetate (5 mL). A 3.2 M solution of hydrogen chloride in ethyl acetate (5 mL) was added. The solvent was removed under vacuum. The residue was dissolved in ethanol (50 mL). The solvent was removed under vacuum.

300mgの標題化合物を、3-ブロモビフェニルの代わりに3-ブロモ-4'-フルオロベンゾフェノンを用い、1-(ビフェニル-3-イル)-4-(シクロペンチル)ピペラジンについて説明したのと同様にしてして調製した。 Example 149 (General Procedure (C)) [3- (4- (Cyclopentyl) piperazin-1-yl) phenyl]-(4-fluorophenyl) methanone

Use 300 mg of the title compound as described for 1- (biphenyl-3-yl) -4- (cyclopentyl) piperazine using 3-bromo-4'-fluorobenzophenone instead of 3-bromobiphenyl. Prepared.

¹ H-NMR (CDCl ₃ ) δ 1.45 (m, 2H); 1.60 (m, 2H); 1.75 (m, 2H); 1.90 (m, 2H); 2.55 (quintet, 1H); 2.70 (m, 4H) 3.30 (m, 4H); 7.15 (m, 4H); 7.35 (m, 2H); 7.85 (m, 2H). HPLC Method C: Elution at 4.22 minutes. MS: calcd for [M + H] ⁺ : 353; found: 353.

The title compound was converted to the hydrochloride salt by dissolving in ethyl acetate (5 mL). A 3.2 M hydrogen chloride solution in ethyl acetate (5 mL) was added. The solvent was removed under vacuum. The residue was dissolved in ethanol (50 mL). The solvent was removed under vacuum.

＜薬理学的方法＞
ヒスタミンH3受容体と相互作用する化合物の能力は、以下のインビトロでの結合試験によって決定することができる。 The following compounds are also within the scope of the present invention:

<Pharmacological method>
The ability of a compound to interact with the histamine H3 receptor can be determined by the following in vitro binding studies.

Binding assay (I):
Rat cerebral cortex was homogenized in ice-cold K-Hepes, 5 mM MgCl ₂ pH 7.1 buffer. After two different centrifugations, the final pellet is resuspended in fresh Hepes buffer containing 1 mg / ml bacitracin. An aliquot of this membrane suspension (400 ug / ml) was added at 25 ° C. with 30 pM [ ¹²⁵ I] -iodoproxifan, a known histamine H3 receptor antagonist, and various concentrations of test compound. Incubate for 60 minutes. The incubation is stopped with ice refrigerant quality followed by rapid filtration through Whatman GF / B filters pretreated with 0.5% polyethyleneimine for 1 hour. Radioactivity retained on the filter is counted using a Cobra II automatic gamma counter. The radioactivity of the filter is indirectly proportional to the binding affinity of the test compound. The result is analyzed by nonlinear regression analysis.

Binding assay (II):
R-α-methyl [ ³ H] histamine (RAMHA), an H3 receptor agonist ligand, is incubated with isolated rat cortical cell membranes for 1 hour at 25 ° C, followed by incubation through Whatman GF / B filters. Filter. The radioactivity retained on the filter is measured using a β counter.

Male Wistar rats (150-200g) are decapitated, the cerebral cortex is quickly cut and immediately frozen on dry ice. Tissues are maintained at -80 ° C until membrane preparation. Keep tissue on ice at all times during membrane preparation. Rat cerebral epithelium is homogenized for 30 seconds in a 10-fold volume of ice-cold Hepes buffer (20 mm Hepes, 5 mm MgCl ₂ pH 7.1 (KOH) +1 mg / ml bacitracin) using an Ultra-Turrax homogenizer. The homogenate is centrifuged at 140G for 10 minutes. Transfer the supernatant to a new tube and centrifuge at 23000 G for 30 minutes. Resuspend the pellet in 5-10 mL of Hepes buffer, homogenize and centrifuge at 23000 G for 10 minutes. Repeat this short centrifugation step twice. After the final centrifugation, the pellet is resuspended in 2-4 mL Hepes buffer and the protein concentration is measured. The membrane is 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 μR of R-α-methyl [ ³ H] histamine (1 nM) are mixed in a test tube. The compound to be tested is dissolved in DMSO and further diluted to the desired concentration in H ₂ O. Radioligand and membrane are diluted in Hepes buffer + 1 mg / mL bacitracin. This mixture is incubated at 25 ° C. for 60 minutes. Incubation is terminated by adding 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 filtrate is washed with 2 × 5 mL of ice cold NaCl. Add 3 mL scintillation cocktail to each filter and measure the retained radioactivity using a Packard Tri-Carb beta counter.

IC ₅₀ values are calculated by nonlinear regression analysis of binding curves (minimum 6 points) using the Windows program GraphPad Prism (GraphPad software, USA).

Binding assay (III):
The human H3 receptor is cloned by PCR and subcloned into a pcDNA3 expression vector. This H3 expression vector is transfected into HEK 293 cells, and G3 is used to select H3 clones to generate cells that stably express the H3 receptor. This human H3-HEK 293 clone was cloned at 37 ° C. and 5% in DMEM (GIBCO-BRL) containing glutamax, 10% fetal bovine, 1% penicillin / streptavidin, and 1 mg / mL G418. Incubate with CO ₂ . Prior to harvesting, confluent cells are rinsed with PBS and incubated with Versene (proteinase; GIBCO-BRL) for approximately 5 minutes. The cells are flushed with PBS and DMEM and the cell suspension is collected in a tube and centrifuged in Heraeus Sepatech Megafuge 1.0 at 1500 rpm for 5-10 minutes. The pellets Hepes buffer 10-20 volumes resuspended in _{(20mm Hepes, 5 mM MgCl 2} , pH 7.1 (KOH)), homogenized 10-20 seconds using an Ultra-Turrax homogenizer. The homogenate is centrifuged at 23000G for 30 minutes. The resulting pellet is resuspended in 5-10 mL of Hepes buffer, homogenized with Ultra-Turrax for 5-10 seconds, and centrifuged at 23000 G for 10 minutes. Following this centrifugation step, the membrane pellet is resuspended in 2-4 mL of Hepes buffer and homogenized using a syringe or a Teflon homogenizer to determine protein concentration. The membrane is diluted in Hepes buffer to a protein concentration of 1-5 mg / mL, aliquoted and maintained at -80 ° C until use.

An aliquot of this membrane suspension is incubated for 60 minutes at 25 ° C with 30 pM [ ¹²⁵ 1] -iodoproxyphan (a known compound with high affinity for the H3 receptor) and various concentrations of test compound To do. Incubation is stopped by diluting with ice refrigerant, followed by rapid filtration through Whatman GF / B Furuta pretreated with 0.5% polyethyleneimine for 1 hour. Radioactivity retained on the filter is counted using a Cobra II automatic gamma counter. The radioactivity of this filter is indirectly proportional to the binding affinity of the test compound. The result is analyzed by non-linear regression analysis.

  When tested, some compounds show strong inverse agonist activity at the human histamine H3 receptor.

Preferably, a compound according to the invention has an IC ₅₀ value measured by one or more assays of less than 10 μM, more preferably less than 1 μM, even more preferably less than 500 nM (eg less than 100 nM).

Functional assay (I):
The ability of a compound to interact with the histamine H3 receptor as an agonist, inverse agonist and / or antagonist is measured by an in vitro functional assay utilizing membranes derived from HEK 293 cells expressing the human H3 receptor.

The H3 receptor is cloned by PCR and subcloned into a pcDNA3 expression vector. This H3 expression vector is transfected into HEK 293 cells, and G3 is used to select H3 clones to generate cells that stably express the H3 receptor. This human H3-HEK 293 clone was cloned at 37 ° C. and 5% in DMEM (GIBCO-BRL) containing glutamax, 10% fetal bovine, 1% penicillin / streptavidin, and 1 mg / mL G418. Incubate with CO ₂ .

The H3 receptor-expressing cells are washed once with phosphate buffered saline (PBS) and collected using versene (GIBCO-BRL). PBS is added and the cells are centrifuged at 188 G for 5 minutes. The cell pellet is resuspended in stimulation buffer to a concentration of 1 × 10 ⁶ cells / mL. Measure cAMP accumulation using the Flash Plate ^™ cAMP assay (NEN Life Science Products). This assay is generally performed according to the manufacturer's instructions. Briefly, in each well containing 25 μL of 40 μM isoprenaline to stimulate cAMP production and 25 micron L of test compound (agonist or inverse agonist alone or in combination with agonist and antagonist) Add 50 μL of cell suspension. The assay can be performed in an “agonist mode”, which means that a test compound is added to cells in increasing its own concentration and cAMP is measured. If cAMP increases, it is an inverse agonist; if cAMP does not change, it is a neutral antagonist; if cAMP decreases, it is an agonist. The assay can also be performed in “antagonist mode”, which means adding test compounds at increasing concentrations with increasing concentrations of a known H3 agonist (eg, RAMHA). If the compound is an antagonist, its increasing concentration causes a right shift in the dose-response curve of the H3 agonist. The final volume in each well is 100 μL. The test compound is dissolved in DMSO and diluted in H ₂ O. The mixture is infiltrated for 5 minutes and left at room temperature for 25 minutes. This reaction is stopped with 100 μL of “Detection Mix” per well. The plate is then sealed with plastic, shaken for 30 minutes, allowed to stand overnight, and finally counted with a Cobra II automatic gamma top counter. EC ₅₀ values are calculated by non-linear regression of dose-response curves (minimum 6 points) using GraphPad Prism. Kb values are calculated by Schild plot analysis.

Functional assay (II):
The ability of a compound to bind and interact with the human H3 receptor as an agonist, inverse agonist and / or antagonist is measured by a functional assay referred to as a [ ³⁵ S] GTPγS assay. The assay measures G protein activation by catalyzing the exchange of guanosine 5'-diphosphate (GDP) for guanosine 5'-triphosphate (GTP) in the G protein alpha subunit. It is. G protein bound by _GTP dissociates into two subunits, Gα _GTP and Gβγ, which then regulate intracellular enzymes and ion channels. GTP is rapidly hydrolyzed by the Gα subunit (GTPase), inactivating the G protein and ready for a new GTP exchange cycle. To study the function of ligand-induced G protein-coupled receptor (GPCR) activation by increasing guanine nucleotide exchange at the G protein, [ ³⁵ S] -guanosine-5′-O- (3-thio ) The binding of triphosphate [ ³⁵ S] GTPγS, a non-hydrolyzed analog of GTP, is measured. This process can be monitored in vitro by incubating cell membranes containing the G protein coupled receptor H3 with GDP and [ ³⁵ S] GTPγS. The cell membrane is obtained from CHO cells that stably express the human H3 receptor. The cells are washed twice in PBS, collected with PBS + 1 mM EDTA (pH 7.4), and centrifuged at 1000 rpm for 5 minutes. The cell pellet is homogenized for 30 seconds in 10 mL ice-cold Hepes buffer (20 mM Hepes, 10 mM EDTA pH7.4 (NaOH)) using an Ultra-Turrax homogenizer and centrifuged at 20,000 rpm for 15 minutes. . Following this centrifugation step, the membrane pellet is resuspended and homogenized in 10 mL of ice-cold Hepes buffer (20 mM Hepes, 10 mM EDTA pH 7.4 (NaOH)) as described above. This procedure is repeated twice, except for the last homogenization step, the protein concentration is measured, the curtain is diluted to a protein concentration of 2 mg / mL, divided into aliquots, and kept at −80 ° C. until use.

To study the presence and ability of the inverse agonist / antagonist, the H3 receptor agonist ligand R-α-methylhistamine (RAMHA) is added. The ability of the test compound to counteract the effects of RAMHA is measured. When studying the effects of agonists, RAMHA is not added to the assay medium. Test compounds are diluted at various concentrations in assay buffer (20 mM Hepes, 10 mM NaCl, 10 mM MgCl ₂ pH 7.4 (NaOH)) followed by 10 ⁻⁸ nM RAMHA (inverse agonist / antagonist). Only), add 3 μM GDP, 2.5 μg membrane, 0.5 mg SPA beads and 0.1 nM [ ³⁵ S] GTPγS and incubate for 2 hours by slight permeation at room temperature. The plate is centrifuged at 1500 rpm for 10 minutes and the radioactivity is measured using a Top counter. The results are analyzed by non-linear regression to determine IC ₅₀ values. RAMHA and other H3 agonists stimulate [ ³⁵ S] GTPγS binding to membranes expressing the H3 receptor. In the antagonist / inverse agonist test, the ability to increase the amount of test compound to inhibit [ ³⁵ S] GTPγS binding increased by 10 ⁻⁸ M RAMHA is measured as a decrease in the radioactivity signal. The IC ₅₀ value measured for an antagonist is the ability of this compound to inhibit the effect of the IC ₅₀ value by 50%. In agonist testing, the ability to increase the amount of test compound is measured as an increase in radioactivity signal. The EC ₅₀ value measured for an agonist is the ability of this compound to increase the signal by 50% of the maximum signal obtained by 10 ⁻⁵ M RAMHA.

Preferably, antagonists and agonists according to the present invention have an IC ₅₀ / EC ₅₀ value of less than 10 μM, more preferably less than 1 μM, even more preferably less than 500 nM, such as less than 100 nM, as measured by one or more assays.

Open cage schedule feeding rat model:
The ability of the compounds of the invention to lose weight is measured using an in vivo open cage schedule fed rat model.

  Sprague-Dawley (SD) male rats approximately 11/2 to 2 months old and weighing approximately 200 to 250 g are purchased from Moellegaerd Breeding and Research Center A / S (Denmark). Upon arrival, they are acclimatized for a few days before being placed in individual open plastic cages. These rats are accustomed to the presence of food (Altromin pelleted rat chow) in their home cage for only one week every day for 7 hours from 7:30 to 14:30 in the morning . Water is present as appropriate. The animals are ready for use when food consumption stabilizes after 7-9 days.

  Each animal is used only once to avoid carryover effects during treatment. During a test session, test compounds are administered intraperitoneally or orally 30 minutes before the start of the session. One group of animals is administered the test compound at different doses and the control group is given vehicle. Food and water intake is monitored at 1, 2, and 3 hours after dosing.

  The animals were kept in a clear plastic cage to allow continuous monitoring, so any side effects (barrel rollover, bushy fur) can be observed quickly.

Claims (39)

A compound of the following formula (II), and diastereomers, enantiomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof:

here,
R ² is hydrogen or C _1-4 -alkyl;
R ¹ represents:
Branched C _4-6 -alkyl, branched C _4-6 -alkenyl, or branched C _4-6 -alkynyl
(However, R ¹ 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 or
R ¹ and R ² together form a C _3-6 -alkylene bridge;
A represents:

R ³ is hydrogen, halogen, hydroxy, 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 -cycloalkyloxy, cyano, nitro, C _{Represents 1-6} -alkylsulfanyl, or C _1-6 -alkylsulfonyl,
Z represents -C (H) =
X represents -N =
W represents -C (R ¹⁰ ) =
Y represents -N =
R ⁴ and R ¹⁰ are independently
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 -alkoxy, C _1-6 -alkylamino, di-C _1-6 -alkylamino, C _3-8 -cycloalkyloxy, C _1-6 -alkylsulfanyl, C _1-6-
Alkylsulfonyl, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _3-8-
Heterocyclyl, or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy (these may optionally be 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 with one or more substituents selected from R ¹⁷ ) or Aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino, or heteroarylamino (which may be optionally substituted with one or more substituents selected from R ¹⁸ )
Represents
R ¹⁴ and R ¹⁵ are independently hydrogen, C _1-6 -alkyl, aryl-C _1-6 -alkyl, or R ¹⁴ and R ^{15 taken} together form a C _3-6 -alkylene bridge. Forming,
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 halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, C _1-6 -alkyl, amino, C _1-6 -alkylsulfonyl, C _1-6 -alkylamino, di- Independently selected from C _1-6 -alkylamino, cyano, aryl, heteroaryl, and C _3-8 -cycloalkyl;
R ¹⁸ is aryl, heteroaryl, C _1-10 -alkyl, C _3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 -alkoxy, cyano, amino, C _1-6- Independently selected from alkylamino, di-C _1-6 -alkylamino, and hydroxy;
R ¹⁹ and R ²⁰ are independently selected from hydrogen or C _1-6 -alkyl, and R ₁₉ and R ₂₀ may be taken together to form a C _3-6 -alkylene bridge. A compound 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. , R ¹ is not isobutyl). 3. The compound of claim 2, wherein R ¹ is 1,1- (dimethyl) propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, or 1-cyclopropyl-1-methylethyl. A compound. A compound according to claim 3, R ¹ is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl, compound. A compound according to claim 1, R ¹ is branched C _4-6 - alkyl or C _3-5 - compound cycloalkyl (wherein, R ¹ is not isobutyl). A compound according to claim 5, R ¹ is 1-ethylpropyl, compounds cyclopropyl or cyclopentyl. A compound according to any one of claims 1-6, compounds wherein R ² is hydrogen. The compound according to any one of claims 1 to 6, wherein R ² is C _1-4 -alkyl. A compound according to claim 8, compounds wherein R ² is methyl or ethyl. The compound according to claim 1, wherein the compound of the following general formula (III):

Here, A and R ³ are as defined in claim 1. A compound according to any one of claims 1 to 10, 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 -cycloalkyloxy, cyano or nitro. A compound according to claim 11, R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, C _1-10 - alkyl, C _1-6 - alkoxy, compounds cyano or nitro. A compound according to claim 12, R ³ is hydrogen, halogen, hydroxy, trifluoromethyl, C _1-6 - alkyl or compounds is cyano. A compound according to claim 13, R ³ is hydrogen, halogen or C _1-6, - alkyl, compound. A compound according to claim 13, and R ³ is hydrogen or methyl. The compound according to any one of claims 1 to 15, wherein R ⁴ is-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 -cycloalkyl oxy, C _2-10 -alkanoyl, C _4-9 -cycloalkanoyl, C _{3- 8} -heterocyclyl,
Or C _4-9 -heterocycloalkanoyl (which may optionally be 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 with one or more substituents selected from R ¹⁷ ) or Aroyl, heteroaroyl, aryloxy, heteroaryloxy (these may be optionally substituted with one or more substituents selected from R ¹⁸ )
A compound representing The compound of claim 16, wherein R ⁴ is
Hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF ₃ , or cyano,
C _1-10 -alkyl, C _1-6 -alkoxy, C _3-8 -cycloalkyloxy (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
• aryl, or aryl-C _1-6 -alkyl (which may optionally be substituted with one or more substituents selected from R ¹⁷ ) or • aroyl, or aryloxy (these are optionally R 1 selected from ¹⁸
May be substituted with the above substituents)
A compound representing The compound of claim 16, wherein R ⁴ is
Hydrogen, halogen or cyano,
C _1-10 -alkyl, or C _1-6 -alkoxy (which may optionally be substituted with one or more substituents selected from R ¹⁶ ),
• aryl optionally substituted with one or more substituents selected from R ¹⁷ • aroyl or aryloxy (which may optionally be substituted with one or more substituents selected from R ¹⁸ )
A compound representing 19. A compound according to claim 18, wherein _C1-10 -alkyl represents methyl, ethyl, propyl or isopropyl. 19. A compound according to claim 18, wherein _C1-6 -alkoxy represents methoxy, ethoxy or propoxy. 21. A compound according to claim 20, wherein _C1-6 -alkoxy represents methoxy. 19. A compound according to claim 18, wherein aryl represents phenyl. 19. A compound according to claim 18, wherein aroyl represents -C (= O) -phenyl. 19. A compound according to claim 18, wherein aryloxy represents -O-phenyl. The compound of claim 1 , wherein R ¹ and R ² together form a C _3-4 -alkylene bridge. The compound of claim 1, wherein R ¹⁰ is
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 -heterocyclyl or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy (these are optionally one or more substituents selected from R ¹⁶ May be substituted)
Aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy, or heteroaryl (which may optionally be substituted with one or more substituents selected from R ¹⁷ ) or A compound representing aroyl optionally substituted with one or more substituents selected from R ¹⁸ . A compound according to claim 26, R ¹⁰ is,
・ 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 -heterocyclyl or C _4-9 -heterocycloalkanoyl, C _4-9 -heterocycloalkoxy (these are optionally one or more substituents selected from R ¹⁶ May be substituted)
Aryl, aryl-C _1-6 -alkyl, aryl-C _1-6 -alkoxy, or heteroaryl (which may optionally be substituted with one or more substituents selected from R ¹⁷ ) or A compound representing aroyl optionally substituted with one or more substituents selected from R ¹⁸ . 28. The compound of claim 27, wherein R ¹⁰ is
・ 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 (These may be optionally substituted with 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 with one or more substituents selected from R ¹⁷ ) or R ¹⁸ A compound representing aroyl optionally substituted with one or more substituents selected from: 29. The compound of claim 28, wherein R ¹⁰ is
・ Hydrogen, halogen, trifluoromethyl, or -C (= O) NR ¹⁴ R ¹⁵
C _1-10 -alkyl, or C _4-9 -heterocycloalkanoyl (these are optionally R ¹⁶
Which may be substituted with one or more substituents selected from
A compound representing aryl optionally substituted with one or more substituents selected from R ¹⁷ or aroyl optionally substituted with one or more substituents selected from R ¹⁸ 30. A compound according to claim 29, wherein _C1-10 -alkyl represents methyl, ethyl or propyl. 30. The compound of claim 29, wherein _C4-9 -heterocycloalkanoyl represents piperidine-alkanoyl or pyrrolidine-alkanoyl. 30. The compound of claim 29, wherein aryl represents phenyl. A compound according to any one of claims 1 to 32, the R ¹⁴ and R ¹⁵ are independently methyl, compound is ethyl or benzyl. The compound according to any one of claims 1 to 33, wherein R ¹⁶ is halogen, trifluoromethyl, trifluoromethoxy, or C _1-6 -alkoxy. 35. A compound according to any one of claims 1 to 34, wherein R ¹⁷ is halogen, hydroxy, trifluoromethyl, C _1-6 -alkoxy, C _1-6 -alkyl, C _1-6 -alkylsulfonyl. Or a compound that is cyano. A compound according to claim 35, R ¹⁷ is halogen, trifluoromethyl, C _1-6 - alkoxy or C _1-6, - compound alkylsulfonyl. A compound according to any one of claims 1 to 36, R ¹⁸ is C _1-10 - alkyl, halogen, trifluoromethyl, C _1-6 - alkoxy, cyano, amino or compound is hydroxy, . A compound according to claim 37, R ¹⁸ is halogen, C _1-6 - alkoxy or hydroxy, compound. 3- (4-cyclopentyl-piperazin-1-yl) -6- (4-methanesulfonyl-phenyl) -pyridazine,
3- (4-cyclopropylmethyl-piperazin-1-yl) -6- (4-methanesulfonyl-phenyl) -pyridazine,
3- (4-chloro-phenyl) -6- (4-cyclopentyl-piperazin-1-yl) -4-methyl-pyridazine,
3- (4-chlorophenyl) -6- (4-cyclopentylpiperazin-1-yl) -pyridazine,
3- (4-cyclopentylpiperazin-1-yl) -6- (3-fluoro-4-methoxyphenyl) -pyridazine,
3- (4-cyclopentylpiperazin-1-yl) -6- (3,4-dimethoxyphenyl) -pyridazine,
3- (4-chlorophenyl) -6- (4-cyclopropylmethylpiperazin-1-yl) -pyridazine,
3- (4-cyclopentylpiperazin-1-yl) -6- (4-trifluoromethylphenyl) -pyridazine,
3- (4-cyclopropylmethylpiperazin-1-yl) -6- (4-trifluoromethylphenyl) -pyridazine,
3- (4-cyclopropylmethylpiperazin-1-yl) -6- (3-fluoro-4-methoxyphenyl) -pyridazine,
3- (4-cyclopropylpiperazin-1-yl) -6- (4-trifluoromethylphenyl) pyridazine,
3- (4-cyclopropylpiperazin-1-yl) -6-phenylpyridazine,
3- (4-cyclopropylpiperazin-1-yl) -6- (3,4-dimethoxyphenyl) pyridazine and
3- (4-Cyclopropylpiperazin-1-yl) -6- (3-trifluoromethylphenyl) pyridazine or a diastereomer, enantiomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof 2. A compound according to claim 1 selected from the group consisting of various salts.