HK1180972A

HK1180972A - Histamine h3 receptor antagonists

Info

Publication number: HK1180972A
Application number: HK13108362.8A
Authority: HK
Inventors: Hohl Weg Rolf; Erik Andersen Knud; Lindy Sørensen Jan; Marie Lundbeck Jane
Original assignee: High Point Pharmaceuticals, Llc
Priority date: 2005-07-04
Filing date: 2013-07-16
Publication date: 2013-11-01

Description

Histamine H3 receptor antagonists

The present application is a divisional application of an invention patent application with national application number 200680024608.1(PCT/EP2006/063753) entitled "histamine H3 receptor antagonist" filed on 30.6.2006.

Technical Field

The present invention relates to novel compounds, to the use of these compounds in pharmaceutical compositions, to pharmaceutical compositions comprising said compounds, and to methods of treatment using these compounds or compositions. The compounds of the present invention exhibit high and selective binding affinity to the histamine H3 receptor, exhibiting histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. Accordingly, the compounds are useful for diseases or conditions associated with the histamine H3 receptor.

Background

The existence of the histamine H3 receptor has been known for several years and it is currently of interest to develop new drugs. Recently, the histamine H3 receptor has been cloned. The histamine H3 receptor is a presynaptic autoreceptor, which is located in the central and peripheral nervous system, the skin and organs such as the lung, the intestine, perhaps the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor exhibits intrinsic constitutive activity in vitro as well as in vivo (i.e., it is active in the absence of an agonist). Compounds that are inverse agonists are capable of inhibiting this activity. The histamine H3 receptor has been shown to regulate the release of histamine as well as other neurotransmitters such as serotonin and acetylcholine. Histamine H3 receptor antagonists or inverse agonists are therefore expected to increase the release of these neurotransmitters in the brain. In contrast, histamine H3 receptor agonists result in inhibition of histamine biosynthesis and inhibition of the release of histamine and other neurotransmitters, such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists may be important modulators of neuronal activity. Thus, the histamine H3 receptor is an important target for new therapeutics.

Given the prior art's interest in histamine H3 receptor agonists, inverse agonists, and antagonists, new compounds that interact with the histamine H3 receptor are highly desirable in the art. Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Most of them are imidazole derivatives. However, recently some imidazole-free ligands of histamine H3 have been disclosed (see e.g. Linney et al, J.Med.chem.2000, 43, 2362-.

WO00/66578 claims certain 3-or 4- (imidazol-2-yl) pyridines which are substituted in the 4-position of the imidazole ring. It is mentioned that mammals suffering from diseases or conditions mediated by NPY may be treated with such compounds.

The applicant's earlier application WO2003/066604 (our internal numbering: 6447) claims certain piperazine compounds substituted in the 1 and 4-positions.

The applicant's earlier application WO2005/009976A1 (our internal numbering: 6739) claims certain 3- (4-isopropylpiperazin-1-yl) -6-phenylpyrazine compounds which are substituted in the para-position of the phenyl ring. In the description thereof. No pharmacological data are given for the compounds prepared.

WO2005/028438 claims certain piperidine compounds substituted in the 1 and 4-positions.

It is an object of the present invention to overcome or ameliorate at least some of the disadvantages of the prior art. Thus, not all of the objects mentioned below can be completely overcome or improved. Further objects of the invention are as follows.

Definition of

In this and in the formulae given in the present specification, the following terms have the meanings indicated:

the term "hydroxy" refers to the group-OH, the term "oxy" refers to the group O-, the term "oxo" refers to the group O, the term "carbonyl" refers to the group-C (═ O) -, the term "sulfinyl" refers to the group- (S ═ O) -, the term "sulfonyl" refers to the group-S (═ O)₂The term "carboxy" denotes the radicals- (C ═ O) O-and-C (═ O) OH, and the term "amino" denotes the radical-NH₂The term "nitro" refers to the group-NO₂And the term "cyano" refers to the group-CN.

The term "C_2-6-alkenyl ", as used herein, represents a branched or linear hydrocarbon radical having 2 to 6 carbon atoms and at least one double bond, such as C_2-6-alkenyl, C_3-6Alkenyl and the like. Representative examples are ethenyl, propenyl (e.g. prop-1-enyl and prop-2-enyl), butadienyl (e.g. but-1, 3-dienyl), butenyl (e.g. but-1-en-1-yl and but-2-en-1-yl), pentenyl (e.g. pent-1-en-1-yl and pent-2-en-2-yl), hexenyl (e.g., hex-1-en-2-yl and hex-2-en-1-yl), 1-ethylprop-2-enyl, 1- (dimethyl) prop-2-enyl, 1-ethylbut-3-enyl, 1- (dimethyl) but-2-enyl, and the like.

Similarly, the term "C_3-8-alkenyl ", as used herein, represents a branched or linear hydrocarbon radical having 3 to 8 carbon atoms and at least one double bond, such as C_3-6Alkenyl and the like. Representative examples are propenyl (e.g. prop-1-enyl and prop-2-enyl), butadienyl (e.g. but-1, 3-dienyl), butenyl (e.g. but-1-en-1-yl and but-2-en-1-yl), pentenyl (e.g. pent-1-en-1-yl and pent-2-en-2-yl), hexenyl (e.g. hex-1-en-2-yl and hex-2-enyl)2-en-1-yl), 1-ethylprop-2-enyl, 1- (dimethyl) prop-2-enyl, 1-ethylbut-3-enyl, 1- (dimethyl) but-2-enyl, and the like.

The term "C_1-6-alkoxy ", as used herein, means a group C_1-6-alkyl-O-. Representative examples are methoxy, ethoxy, propoxy (e.g., 1-propoxy and 2-propoxy), butoxy (e.g., 1-butoxy, 2-butoxy and 2-methyl-2-propoxy), pentoxy (1-pentoxy and 2-pentoxy), hexoxy (1-hexoxy and 3-hexoxy), and the like.

The term "C_1-6-alkoxy-C_1-6-alkyl ", as used herein, means substituted by C on any carbon atom_1-6-alkoxy-substituted C_1-6-an alkyl group. Representative examples are methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxyprop-1-yl and the like.

The term "C_1-6Alkoxycarbonyl ", as used herein, refers to the radical C_1-6-alkoxy-C (═ O) -. Representative examples are methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2-propoxycarbonyl, 1-butoxycarbonyl, 2-methyl-2-propoxycarbonyl, 3-methylbutoxycarbonyl, 1-hexyloxycarbonyl and the like.

The term "C_1-6-alkyl ", as used herein, represents a saturated branched or linear hydrocarbon radical having from 1 to 6 carbon atoms, such as C_1-3Alkyl radical, C_1-4Alkyl radical, C_2-6Alkyl radical, C_3-6Alkyl groups and the like. Representative examples are methyl, ethyl, propyl (e.g., propan-1-yl and propan-2-yl (or isopropyl)), butyl (e.g., 2-methylprop-2-yl (or tert-butyl), butan-1-yl and butan-2-yl), pentyl (e.g., pentan-1-yl, pentan-2-yl and pentan-3-yl), 2-methylbutan-1-yl, 3-methylbutan-1-yl, hexyl (e.g., hex-1-yl), heptyl (e.g., hept-1-yl), and the like.

Similarly, the term "C_1-8-alkyl ", as used herein, represents a saturated branched or linear hydrocarbon radical having from 1 to 8 carbon atoms, such as C_1-3-an alkyl group,C_1-4Alkyl radical, C_1-6Alkyl radical, C_2-6Alkyl radical, C_3-6Alkyl radical, C_1-8Alkyl groups and the like. Representative examples are methyl, ethyl, propyl (e.g., propan-1-yl and propan-2-yl (and isopropyl)), butyl (e.g., 2-methylprop-2-yl (or t-butyl), butan-1-yl and butan-2-yl), pentyl (e.g., pentan-1-yl, pentan-2-yl and pentan-3-yl), 2-methylbutan-1-yl, 3-methylbutan-1-yl, hexyl (e.g., hex-1-yl), heptyl (e.g., hept-1-yl), octyl (e.g., oct-1-yl), and the like.

The term "C_1-6-alkylcarbonyl ", as used herein, refers to the radical C_1-6-alkyl-C (═ O) -. Representative examples are acetyl (e.g., methylcarbonyl), propionyl (e.g., ethylcarbonyl), butyryl (e.g., prop-1-ylcarbonyl and prop-2-ylcarbonyl), and the like.

The term "C_1-6-alkylcarbonylamino ", as used herein, refers to the radical C_1-6-alkyl-C (═ O) -NH-. Representative examples are acetylamino, propionylamino, pivaloylamino, valerylamino and the like.

The term "C_1-6-alkylcarbonylamino-C_1-6-alkyl ", as used herein, means substituted by C on any carbon atom_1-6-alkylcarbonylamino substituted C_1-6-an alkyl group. Representative examples are acetylaminomethyl, 1- (acetylamino) ethyl, propionylaminomethyl, and the like.

The term "C_1-6-alkylcarboxy ", as used herein, means crystalline C_1-6-alkyl-C (═ O) O-.

Representative examples are methylcarboxyl, ethylcarboxyl, propylcarboxyl (e.g., prop-1-ylcarboxyl, prop-2-ylcarboxyl), and the like.

The term "C_1-6-alkylthio ", as used herein, means a radical C_1-6-alkyl-S-. Representative examples are methylthio, ethylthio, propylthio (e.g., 1-propylthio, 2-propylthio and 3-propylthio), butylthio, pentylthio, hexylthio and the like.

The term "C_1-6-alkylsulfinyl ", as used herein, means the radical C_1-6-alkyl-S (═ O) -. Representative examples are methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like.

The term "C_1-6-alkylsulfonyl ", as used herein, refers to the radical C_1-6-alkyl-S (═ O)₂-. Representative examples are methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.

The term "C_3-8-alkynyl ", as used herein, represents a branched or linear hydrocarbon radical having 3 to 8 carbon atoms and at least one triple bond. Representative examples are propynyl (e.g., prop-1-ynyl and prop-2-ynyl), butynyl (e.g., but-1-ynyl and but-2-ynyl), pentynyl (e.g., pent-1-ynyl and pent-2-ynyl), hexynyl (e.g., hex-1-ynyl and hex-2-ynyl), 1-ethylprop-2-ynyl, 1- (dimethyl) prop-2-ynyl, 1-ethylbut-3-ynyl, 1- (dimethyl) but-2-ynyl, and the like.

The term "aryl", as used herein, is intended to include monocyclic, bicyclic, or polycyclic carbocyclic aromatic rings. Representative examples are phenyl, naphthyl (e.g., naphthalen-1-yl and naphthalen-2-yl), anthracenyl (e.g., anthracen-1-yl and anthracen-9-yl), phenanthrenyl (e.g., phenanthren-1-yl and phenanthren-9-yl), and the like. Aryl is also meant to include monocyclic, bicyclic or polycyclic carbocyclic aromatic rings substituted with carbocyclic aromatic rings. Representative examples are biphenyl (e.g., biphenyl-2-yl, biphenyl-3-yl, and biphenyl-4-yl), phenylnaphthyl (e.g., 1-phenylnaphthalen-2-yl, and 2-phenylnaphthalen-1-yl), and the like. Aryl is also meant to include partially saturated bicyclic or polycyclic carbocyclic rings having at least one unsaturated moiety (e.g., a benzo moiety). Representative examples are indanyl (e.g., indan-1-yl, indanyl,

Indan-5-yl), indenyl groups (e.g., inden-1-yl and inden-5-yl), naphthalen-2-yl and 1, 2, 3, 4-tetrahydronaphthalen-6-yl), 1, 2-dihydronaphthalenyl groups (e.g., 1, 2-dihydronaphthalen-1-yl, 1, 2-dihydronaphthalen-4-yl and 1, 2-dihydronaphthalen-6-yl), fluorenyl groups (e.g., fluoren-1-yl, fluoren-4-yl and fluoren-9-yl), and the like. Aryl is also meant to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or two bridges. Representative examples are benzonorbornenyl (e.g., benzonorbornen-3-yl and benzonorbornen-6-yl), 1, 4-ethano-1, 2, 3, 4-tetrahydronaphthyl (e.g., 1, 4-ethano-1, 2, 3, 4-tetrahydronaphthalen-2-yl and 1, 4-ethano-1, 2, 3, 4-tetrahydronaphthalen-1O-yl), and the like. Aryl is also meant to include bicyclic or polycyclic carbocyclic aromatic rings containing one or more spiro atoms. Representative examples are spiro [ cyclopentane-1, 1 ' -indan ] -4-yl, spiro [ piperidine-4, 1 ' -indan ] -1-yl, spiro [ piperidine-3, 2 ' -indan ] -1-yl, spiro [ piperidine-4, 1 ' -indan ] -3 ' -yl, spiro [ pyrrolidine-3, 2 ' -indan ] -1-yl, spiro [ pyrrolidine-3, 1 ' - (3 ', 4 ' -dihydronaphthalene) ] -1-yl, spiro [ piperidine-4, 4 ' -dihydronaphthalene) ] -1-yl, spiro [ indan-4, spiro [ piperidine-1, 1 ' -indan-yl, Spiro [ piperidine-4, 1 ' - (3 ', 4 ' -dihydronaphthalene) ] -1-yl, spiro [ imidazolidine-4, 2 ' -indan ] -1-yl, spiro [ piperidine-4, 1 ' -indene ] -1-yl, and the like.

The term "aryl-C_1-6-alkoxycarbonyl ", as used herein, refers to the radical aryl-C_1-6-alkoxy-C (═ O) -. Representative examples are benzyloxycarbonyl, phenylethoxycarbonyl (e.g., (2-phenylethoxy) carbonyl and (1-phenylethoxy) carbonyl), and the like.

The term "arylcarbonyl", as used herein, refers to the group aryl-C (═ O) -. Representative examples are benzoyl, naphthylcarbonyl, 4-phenylbenzoyl, anthracylcarbonyl, phenanthrylcarbonyl and the like.

The term "arylcarbonylamino", as used herein, refers to the group aryl-C (═ O) -NH-. Representative examples are benzoylamino, naphthylcarbonylamino, 4-phenylbenzoylamino and the like.

The term "arylcarbonylamino-C_1-6-alkyl ", as used herein, means C substituted on any carbon atom by arylcarbonylamino_1-6-an alkyl group. A representative example is benzoylaminomethylNaphthyl carbonylaminomethyl, 2- (4-phenylbenzoylamino) ethyl and the like.

The term "arylsulfonyl", as used herein, refers to the group aryl-S (═ O)₂-. Representative examples are phenylsulfonyl, (4-methylphenyl) sulfonyl, (4-chlorophenyl) sulfonyl, naphthylsulfonyl and the like.

The term "cyano-C _1-6-alkyl ", as used herein, means C substituted on any carbon atom by cyano_1-6-an alkyl group. Representative examples are cyanomethyl, 2-cyanoethyl and the like.

The term "C_3-8-cycloalkenyl ", as used herein, represents a partially saturated monocyclic carbocyclic ring having 3 to 8 carbon atoms and at least one double bond. Representative examples are cyclopropylene, cyclobutylene, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohex-1, 3-dienyl and the like.

Obviously, the term "C_3-8-cycloalkenyl-C_1-3-alkyl "is C_3-8Cycloalkenyl radical and C_1-3-a combination of alkyl groups. Representative examples are cyclopenten-1-ylmethyl, 3- (cyclohexen-1-yl) propyl, and the like.

The term "C_3-8Cycloalkyl ", as used herein, represents a saturated monocyclic carbocyclic ring having 3 to 8 carbon atoms, such as C_3-6Alkyl groups and the like. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. C_3-8-cycloalkyl is also intended to represent a saturated bicyclic carbocyclic ring having 4 to 8 carbon atoms. Representative examples are decahydronaphthyl, bicyclo [3.3.0]Octyl, and the like. C_3-8Cycloalkyl is also intended to represent a saturated carbocyclic ring having from 3 to 8 carbon atoms and containing one or two carbon bridges. Representative examples are adamantyl, norbornyl, nortricyclyl, bicyclo [3.2.1 ]Octyl, bicyclo [2.2.2]Octyl, tricyclo [5.2.1.0/2, 6]Decyl, bicyclo [2.2.1]Heptyl, and the like. C_3-8Cycloalkyl is also intended to represent a saturated carbocyclic ring having from 3 to 8 carbon atoms and containing one or more spiro atoms. A representative example is spiro [2.5 ]]Octyl, spiro [4.5 ]]Decyl groups, and the like.

Obviously, the term "C_3-8-cycloalkyl-C_1-3-alkyl "is C_3-8-cycloalkyl and C_1-3-a combination of alkyl groups. Representative examples are cyclopropylmethyl, 2-cyclohexylethyl, 3-cyclopentylprop-1-yl, 1-cyclohexylethyl, adamantylmethyl and the like.

“C_3-8-cycloalkylcarbonylamino-C_1-6Representative examples of-alkyl ", as used herein, are cyclopentylcarbonylamino-methyl, 3- (cyclohexylcarbonylamino) propyl and the like.

The term "halo-C_1-6-alkyl ", as used herein, means C substituted one or more times on any carbon atom by any halogen atom_1-6-an alkyl group. Representative examples are trifluoromethyl, 2, 2, 2-trifluoroethyl, and the like.

The term "halo-C_1-6-alkoxy ", as used herein, means C substituted one or more times on any carbon atom by any halogen atom_1-6-alkoxy groups. Representative examples are trifluoromethoxy and 2, 2, 2-trifluoroethoxy and the like.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

The term "heteroaryl", as used herein, is intended to include a compound containing one or more members selected from the group consisting of nitrogen, oxygen, sulfur, SO and S (═ O)₂The heteroatom of (a) is a monocyclic heterocyclic aromatic ring. Representative examples are pyrrolyl (e.g. pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl), furyl (e.g. furan-2-yl and furan-3-yl), thienyl (e.g. thiophen-2-yl and thiophen-3-yl),Azolyl (e.g. ofAn oxazol-2-yl group,Oxazole-4-A base andoxazol-5-yl), thiazolyl (e.g. thiazol-2-yl, thiazol-4-yl and thiazol-5-yl), imidazolyl (e.g. imidazol-2-yl, imidazol-4-yl and imidazol-5-yl), pyrazolyl (e.g. pyrazol-1-yl, pyrazol-3-yl and pyrazol-5-yl), iso-pyrazolylAzolyl (e.g. iso-hexyl)Azolyl-3-yl, isoAzolyl-4-yl and isoAzolyl-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), 1, 2, 3-triazolyl (e.g., 1, 2, 3-triazol-1-yl, 1, 2, 3-triazol-4-yl, and 1, 2, 3-triazol-5-yl), 1, 2, 4-triazolyl (e.g., 1, 2, 4-triazol-1-yl, 1, 2, 4-triazol-3-yl, and 1, 2, 4-triazol-5-yl), 1, 2, 3-Oxadiazolyl (e.g. 1, 2, 3-Oxadiazol-4-yl and 1, 2, 3-Oxadiazol-5-yl), 1, 2, 4-Oxadiazolyl (e.g. 1, 2, 4- Oxadiazol-3-yl and 1, 2, 4-Oxadiazol-5-yl), 1, 2, 5-Oxadiazolyl (e.g. 1, 2, 5-Oxadiazol-3-yl and 1, 2, 5-Oxadiazol-4-yl), 1, 3, 4-Oxadiazolyl (e.g. 1, 3, 4-Oxadiazol-2-yl and 1, 3, 4-Oxadiazol-5-yl), 1, 2, 3-thiadiazolyl (e.g. 1, 2, 3-thiadiazol-4-yl and 1, 2, 3-thiadiazol-5-yl), 1, 2, 4-thiadiazolyl (e.g. 1, 2, 4-thiadiazol-3-yl and 1, 2, 4-thiadiazol-5-yl), 1, 2, 5-thiadiazolyl (e.g. 1, 2, 5-thiadiazol-3-yl and 1, 2, 5-thiadiazol-4-yl), 1, 3, 4-thiadiazolyl (e.g. 1, 3, 4-thiadiazol-2-yl and 1, 3, 4-thiadiazol-5-yl), tetrazolyl (e.g. tetrazol-1-yl and tetrazol-5-yl), tetrazolyl, Pyranyl (e.g. pyran-2-yl), pyridyl (e.g. pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), pyridazinyl (e.g. pyridazin-2-yl and pyridazin-3-yl), pyrimidinyl (e.g. pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl), pyrazinyl, 1, 2, 3-triazinyl, 1, 2, 4-triazinyl, 1, 3, 5-triazinyl, thiadiazinyl, aza-asMesityl, azecinyl and the like. Heteroaryl is also meant to include those containing one or more members selected from nitrogen, oxygen, sulfur, S (═ O) and S (═ O)₂The heteroatom bicyclic heterocyclic aromatic ring of (a). Representative examples are indolyl (e.g. indol-1-yl, indolyl, Indol-2-yl, indol-3-yl and indol-5-yl), isoindolyl, benzofuranyl (e.g. benzo [ b)]Furan-2-yl, benzo [ b ]]Furan-3-yl, benzo [ b ]]Furan-5-yl, benzo [ c ]]Furan-2-yl, benzo [ c ]]Furan-3-yl and benzo [ c]Furan-5-yl), benzothienyl (e.g. benzo [ b)]Thiophen-2-yl, benzo [ b ]]Thiophen-3-yl, benzo [ b ]]Thiophen-5-yl, benzo [ c)]Thiophen-2-yl, benzo [ c)]Thiophen-3-yl and benzo [ c]Thiophen-5-yl), indazolyl (e.g., indazol-1-yl, indazol-3-yl, and indazol-5-yl), indolizinyl (e.g., indolizin-1-yl and indolizin-3-yl), benzopyranyl (e.g., benzo [ b ] c)]Pyran-3-yl, benzo [ b ]]Pyran-6-yl, benzo [ c)]-pyran-1-yl and benzo [ c]Pyran-7-yl), benzimidazolyl (e.g. benzimidazol-1-yl, benzimidazol-2-yl, and benzimidazol-5-yl), benzothiazolyl (e.g. benzothiazol-2-yl, and benzothiazol-5-yl), benzisothiazolyl, benzoin-7-yl), benzoinAzolyl, benzisoylAzolyl, benzoAzinyl, benzotriazolyl, naphthyridinyl (e.g., 1, 8-naphthyridin-2-yl, 1, 7-naphthyridin-2-yl, and 1, 6-naphthyridin-2-yl), 2, 3-naphthyridinyl (e.g., 2, 3-naphthyridin-1-yl, and 2, 3-naphthyridin-5-yl), pteridinyl, purinyl (e.g., purin-2-yl, purin-6-yl, purin-7-yl, purin-8-yl, and purin-9-yl), quinazolinyl (e.g., quinazolin-2-yl, quinazolin-4-yl, and quinazolin-6-yl), cinnolinyl, quinolinyl (e.g., quinolin-2-yl, quinolin-3-yl, quinolyl, cinnolinyl, and the like, Quinolin-4-yl and quinolin-6-yl), isoquinolinyl (e.g., isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl), quinoxalinyl (e.g., quinoxalin-2-yl and quinoxalin-5-yl), pyrrolopyridyl (e.g., pyrrolo [2, 3-b ] group ]Pyridyl, pyrrolo [2, 3-c]Pyridyl and pyrrolo [3, 2-c]Pyridyl), furopyridyl (e.g. furo [2, 3-b ]]Pyridyl, furo [2, 3-c ]]Pyridyl and furo [3, 2-c ]]Pyridyl group (a),Thienopyridyl (e.g. thieno [2, 3-b ]]Pyridyl, thieno [2, 3-c ]]Pyridyl and thieno [3, 2-c]Pyridyl), imidazopyridyl (e.g. imidazo [4, 5-b)]Pyridyl, imidazo [4, 5-c)]Pyridyl, imidazo [1, 5-a ]]Pyridyl and imidazo [1, 2-a ]]Pyridyl), imidazopyrimidinyl (e.g. imidazo [1, 2-a)]Pyrimidinyl and imidazo [3, 4-a]Pyrimidinyl), pyrazolopyridinyl (e.g. pyrazolo [3, 4-b)]Pyridyl, pyrazolo [3, 4-c]Pyridyl and pyrazolo [1, 5-a ]]Pyridyl), pyrazolopyrimidyl (e.g. pyrazolo [1, 5-a)]Pyrimidinyl and pyrazolo [3, 4-d]Pyrimidinyl), thiazolopyridinyl (e.g. thiazolo [3, 2-d)]Pyridyl), thiazolopyrimidinyl (e.g. thiazolo [5, 4-d)]Pyrimidinyl), imidazothiazolyl (e.g. imidazo [2, 1-b)]Thiazolyl), triazolopyridinyl (e.g. triazolo [4, 5-b)]Pyridyl), triazolopyrimidine group (e.g., 8-azapurinyl), and the like. Heteroaryl is also meant to include those containing one or more members selected from nitrogen, oxygen, sulfur, S (═ O) and S (═ O) ₂The polycyclic heterocyclic aromatic ring of (a). Representative examples are carbazolyl (e.g. carbazol-2-yl, carbazol-3-yl, carbazol-9-yl), thiophenOxazine radicals (e.g. thiophenes)Oxazin-10-yl), phenazinyl (e.g. phenazin-5-yl), acridinyl (e.g. acridin-9-yl and acridin-10-yl), phenothiazinyl (e.g. phenothiazin-10-yl), carbolinyl (e.g. pyrido [3, 4-b ]]Indol-1-yl, pyrido [3, 4-b ] s]Indol-3-yl), phenanthrolinyl (e.g., phenanthrolin-5-yl), and the like. Heteroaryl is also meant to include those containing one or more members selected from nitrogen, oxygen, sulfur, S (═ O) and S (═ O)₂The heteroatom of (a) is a partially saturated monocyclic, bicyclic or polycyclic heterocycle. Representative examples are pyrrolinyl, pyrazolinyl, imidazolinyl (e.g. 4, 5-dihydroimidazol-2-yl and 4, 5-dihydroimidazol-1-yl), indolinyl (e.g. 2, 3-dihydroindol-1-yl and 2, 3-dihydroindol-5-yl), dihydrobenzofuranyl (e.g. 2, 3-dihydrobenzo [ b ] b]Furan-2-yl and 2, 3-dihydrobenzo [ b ]]Furan-4-yl), dihydrobenzothienyl (e.g. 2, 3-diHydrobenzo [ b]Thien-2-yl and 2, 3-dihydrobenzo [ b]Thiophen-5-yl), 4, 5, 6, 7-tetrahydrobenzo [ b]Furan-5-yl), dihydrobenzopyranyl (e.g. 3, 4-dihydrobenzo [ b ]]Pyran-3-yl, 3, 4-dihydrobenzo [ b ] ]Pyran-6-yl, 3, 4-dihydrobenzo [ c ]]Pyran-1-yl and dihydrobenzo [ c]Pyran-7-yl),Oxazolinyl (e.g. 4, 5-dihydro)An oxazol-2-yl group,

4, 5-dihydroOxazol-4-yl and 4, 5-dihydroOxazol-5-yl), isoOxazolinyl, oxazaA group, 2, 4-dioxadihydropyrimidin-3-yl, tetrahydroindazolyl (e.g., 4, 5, 6, 7-tetrahydroindazol-1-yl, 4, 5, 6, 7-tetrahydroindazol-3-yl, 4, 5, 6, 7-tetrahydroindazol-4-yl, and 4, 5, 6, 7-tetrahydroindazol-6-yl), tetrahydrobenzimidazolyl (e.g., 4, 5, 6, 7-tetrahydrobenzimidazol-1-yl, and 4, 5, 6, 7-tetrahydrobenzimidazol-5-yl), tetrahydroimidazo [4, 5-c ] -l]Pyridyl (e.g. 4, 5, 6, 7-tetrahydroimidazo [4, 5-c)]Pyridin-1-yl,

4, 5, 6, 7-tetrahydroimidazo [4, 5-c ]]Pyridin-5-yl and 4, 5, 6, 7-tetrahydroimidazo [4, 5-c ]]Pyridin-6-yl), tetrahydroquinolinyl (e.g., 1, 2, 3, 4-tetrahydroquinolinyl and 5, 6, 7, 8-tetrahydroquinolinyl), tetrahydroisoquinolinyl (e.g., 1, 2, 3, 4-tetrahydroisoquinolinyl and 5, 6, 7, 8-tetrahydroisoquinolinyl), tetrahydroquinoxalinyl (e.g., 1, 2, 3, 4-tetrahydroquinoxalinyl and 5, 6, 7,8-tetrahydroquinoxalinyl), 2, 3-dihydrobenzo [1, 4 ]]II En-6-yl, 2, 3-dihydrobenzo [1, 4 ]]IIEn-5-yl, 2, 3-dihydrobenzo [1, 4 ]]IIEn-2-yl, benzo [1, 3 ]]Dioxol-4-yl, benzo [1, 3 ]]Dioxol-5-yl, benzo [1, 3 ]]Dioxol-2-yl, 3, 4-dihydro-2H-benzo [1, 4 ]]Oxazin-7-yl, 4-methyl-3, 4-dihydro-2H-benzo [1, 4]Oxazin-7-yl and the like. Heteroaryl is also meant to include partially saturated bicyclic or polycyclic heterocycles containing one or more spiro atoms. A representative example is spiro [ isoquinoline-3, 1' -cyclohexane]-1-yl, spiro [ piperidine-4, 1' -benzo [ c ]]Thiophene(s)]-1-yl, spiro [ piperidine-4, 1' -benzo [ c ]]Furan compounds]-1-yl, spiro [ piperidine-4, 3' -benzo [ b ]]Furan compounds]-1-yl, spiro [ piperidine-4, 3' -coumarin]-1-yl and the like.

The term "heteroarylcarbonyl", as used herein, refers to the group heteroaryl-C (═ O) -. Representative examples are pyridylcarbonyl (e.g., pyridin-2-ylcarbonyl and pyridin-4-ylcarbonyl), quinolinylcarbonyl (e.g., 2- (quinolin-2-yl) carbonyl and 1- (quinolin-2-yl) carbonyl), imidazolylcarbonyl (e.g., imidazol-2-ylcarbonyl and imidazol-5-ylcarbonyl), and the like.

The term "heteroarylcarbonylamino", as used herein, refers to the group heteroaryl-C (═ O) -NH-. Representative examples are pyridylcarbonylamino (e.g. pyridin-2-ylcarbonylamino and pyridin-4-ylcarbonylamino), quinolinylcarbonylamino (e.g. 2- (quinolin-2-yl) carbonylamino and 1- (quinolin-2-yl) carbonylamino) and the like.

The term "heteroarylcarbonylamino-C_1-6-alkyl ", as used herein, refers to C substituted on any carbon atom by heteroarylcarbonylamino_1-6-an alkyl group. Representative examples are pyridylcarbonylaminomethyl (e.g. pyridin-2-ylcarbonylaminomethyl and pyridin-4-ylcarbonylaminomethyl), 2- (quinolinylcarbonylamino) ethyl (e.g. 2- (2- (quinolin-2-yl) carbonylamino) ethyl and 2- (1- (quinolin-2-yl) carbonylamino) ethyl) and the like.

The term "heterocyclyl", as used herein, denotes a compound containing one or more members selected from nitrogen, oxygen, sulphur, SO and S (═ O)₂A saturated 3-8 membered monocyclic ring of heteroatoms of (a). Representative examples are aziridinyl (e.g. aziridin-1-yl), azetidinyl (e.g. azetidin-1-yl and azetidin-3-yl), oxetanyl, pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl), 2-oxo-pyrrolidin-1-yl, 2, 5-dioxo-pyrrolidin-1-yl, imidazolidinyl (e.g. imidazolidin-1-yl, imidazolidin-2-yl and imidazolidin-4-yl), 2, 4-dioxo-imidazolidin-3-yl, 2, 4-dioxo-1-methylimidazolidin-3-yl, azetidin-1-yl, azetidin-3-yl, azetidin-yl, and imidazolidin-1-yl, 2, 4-dioxo-1, 5, 5-trimethylimidazolidin-3-yl, 2, 4-dioxo-5, 5-dimethylimidazolidin-3-yl, Oxazolidinyl (e.g.Oxazolidin-2-yl,Oxazolidin-3-yl andoxazolidin-4-yl), 2-oxo-Oxazolidin-3-yl, thiazolidinyl (e.g. thiazolidin-2-yl, thiazolidin-3-yl and thiazolidin-4-yl), 2, 4-dioxo-thiazolidin-3-yl,isothiazolidinyl, 1-dioxo-isothiazolidin-2-yl, 1-dioxo- [1, 2, 5 [ ]]Thiadiazol-2-yl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), 2-oxo-piperidin-1-yl, 2, 6-dioxo-piperidin-1-yl, homopiperidinyl (e.g., homopiperidin-1-yl, homopiperidin-2-yl, homopiperidin-3-yl, and homopiperidin-4-yl), piperazinyl (e.g., piperazin-1-yl and piperazin-2-yl), morpholinyl (e.g., morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl), 2-oxo- [1, 3-yl]Oxazinane (oxazinan) -3-yl, thiomorpholinyl (e.g., thiomorpholin-2-yl, thiomorpholin-3-yl, and thiomorpholin-4-yl), 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl and tetrahydrofuran-3-yl), tetrahydrothienyl, tetrahydro-1, 1-dioxothienyl, tetrahydropyranyl (e.g., 2-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 2-tetrahydrothiopyranyl), 1, 4-bis Alkyl, 1, 3-diAlkyl groups, and the like. Heterocyclyl is also intended to represent a compound which contains one or more substituents selected from nitrogen, oxygen, sulphur, SO and S (═ O)₂Saturated 6-12 membered bicyclic rings. Representative examples are octahydroindolyl (e.g., octahydroindol-1-yl, octahydroindol-2-yl, octahydroindol-3-yl and octahydroindol-5-yl), decahydroquinolinyl (e.g., decahydroquinolin-1-yl, decahydroquinolin-2-yl, decahydroquinolin-3-yl, decahydroquinolin-4-yl and decahydroquinolin-6-yl), decahydroquinoxalinyl (e.g., decahydroquinoxalin-1-yl, decahydroquinoxalin-2-yl and decahydroquinoxalin-6-yl), and the like. Heterocyclyl is also intended to represent a compound which contains one or more substituents selected from nitrogen, oxygen, sulphur, SO and S (═ O)₂And a saturated 6-12 membered ring having one or two bridges. A representative example is 3-azabicyclo [3.2.2]Nonyl, 2-azabicyclo [2.2.1]Heptyl, 3-azabicyclo [3.1.0]Hexyl, 2, 5-diazabicyclo [2.2.1]Heptyl, atropine, and tropylTropyl, quinuclidinyl, 1, 4-diazabicyclo [2.2.2]Octyl, and the like. Heterocyclyl is also intended to represent a compound which contains one or more substituents selected from nitrogen, oxygen, sulphur, SO and S (═ O)₂And a 6-12 membered saturated ring containing one or more spiro atoms. A representative example is 1, 4-dioxaspiro [4.5 ] ]Decyl (e.g. 1, 4-dioxaspiro [4.5 ]]Decan-2-yl and 1, 4-dioxaspiro [4.5 ]]Decan-7-yl), 1, 4-dioxa-8-azaspiro [4.5]Decyl (e.g. 1, 4-dioxa-8-azaspiro [4.5 ]]Dec-2-yl and 1, 4-dioxa-8-azaspiro [4.5]Decan-8-yl), 8-azaspiro [4.5]Decyl (e.g. 8-azaspiro [4.5 ]]Decan-1-yl and 8-azaspiro [4.5 ]]Decan-8-yl), 2-azaspiro [5.5]Undecyl (e.g. 2-azaspiro [5.5 ]]Undecan-2-yl), 2, 8-diazaspiro [4.5]Decyl (e.g. 2, 8-diazaspiro [4.5 ]]Decan-2-yl and 2, 8-diazaspiro [4.5 ]]Decan-8-yl), 2, 8-diazaspiro [5.5]Undecyl (e.g. 2, 8-diazaspiro [5.5 ]]Undecan-2-yl), 1, 3, 8-triazaspiro [4.5]Decyl radicals (e.g. 1, 3, 8-triazaspiro [4.5 ]]Decan-1-yl and 1, 3, 8-triazaspiro [4.5]Decan-3-yl, 1, 3, 8-triazaspiro [4.5]Decan-8-yl), and the like.

The term "heterocyclyl-C_1-6-alkoxy ", as used herein, refers to the group heterocyclyl-C_1-6-alkoxy groups. Representative examples are piperidin-1-ylmethoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propan-3-oxy, piperazin-1-ylmethoxy, 2- (piperazin-1-yl) ethoxy, 3- (piperazin-1-yl) propan-3-oxy, morpholin-4-ylmethoxy, 2- (morpholin-4-yl) ethoxy, 3- (morpholin-4-yl) propan-3-oxy, and the like.

The term "heterocyclyl-C_1-6-alkyl ", as used herein, refers to the group heterocyclyl-C_1-6-an alkyl group. Representative examples are piperidin-1-ylmethyl, 2- (piperidin-1-yl) ethyl, 3-hydroxy-3- (piperidin-1-yl) propyl, piperazin-1-ylmethyl, 2- (piperazin-1-yl) ethyl, 3-hydroxy-3- (piperazin-1-yl) propyl, morpholin-4-ylmethyl, 2- (morpholin-4-yl) ethyl, 3-hydroxy-3- (morpholin-4-yl) propyl, and the like.

The term "heterocyclylcarbonyl", as used herein, refers to the group heterocyclyl-C (═ O) -. Representative examples are piperidinylcarbonyl (e.g., piperidin-2-ylcarbonyl, piperidin-3-ylcarbonyl, and piperidin-4-ylcarbonyl), piperazinylcarbonyl (e.g., piperazin-1-ylcarbonyl, and piperazin-2-ylcarbonyl), and the like.

The term "hydroxy-C_1-6-alkyl ", as used herein, means C substituted one or more times on any carbon atom by hydroxy_1-6-an alkyl group. Representative examples are hydroxymethyl, hydroxyethyl (e.g., 1-hydroxyethyl and 2-hydroxyethyl), and the like.

The term "N- (C)_1-6-alkylcarbonyl) -N- (C)_1-6-alkyl) amino ", as used herein, is substituted with two substituents, i.e. C_1-6-alkylcarbonyl and C_1-6-alkyl substituted amino. Similarly, the following terms include groups in which the amino group has two substituents: n- (C) _3-8-Cycloalkylcarbonyl) -N- (C)_1-6-alkyl) amino and N- (C)_3-8-cycloalkyl-C_1-6-alkylcarbonyl) -N- (C)_1-6-alkyl) amino. Similarly, the following terms include where in amino-C_1-6-a group with two substituents on the nitrogen atom in the alkyl moiety: n- (C)_1-6-alkylcarbonyl) -N- (C)_1-6-alkyl) amino-C_1-6Alkyl, N- (C)_3-8-Cycloalkylcarbonyl) -N- (C)_1-6-alkyl) amino-C_1-6Alkyl and N- (C)_3-8-cycloalkyl-C_1-6-alkylcarbonyl) -N- (C)_1-6-alkyl) amino-C_1-6-an alkyl group. Representative examples are N-cyclohexylcarbonyl-N-methylamino, 2- (N-cyclopentylcarbonyl-N-methylamino) ethyl and the like.

The term "bridge" as used herein denotes a connection between two atoms of a saturated or partially saturated ring, said two atoms not being adjacent, and said connection being made through a chain of 1 to 4 atoms selected from carbon, nitrogen, oxygen and sulfur. Representative example of such a connecting chain-CH₂-、-CH₂CH₂-、-CH₂NHCH₂-、-CH₂CH₂CH₂-、-CH₂OCH₂-and the like.

The term "spiro atom" as used hereinDenotes the carbon atom in a saturated or partially saturated ring, said carbon atom being linked to the two ends of a chain of 3 to 8 atoms chosen from carbon, nitrogen, oxygen and sulfur. A representative example is- (CH)₂)₅-、-(CH₂)₃-、-(CH₂)₄-、-CH₂NHCH₂CH₂-、-CH₂CH₂NHCH₂CH₂-、-CH₂NHCH₂CH₂CH₂-、-CH₂CH₂OCH₂-、-OCH₂CH₂O-, etc.

The term "optionally substituted", as used herein, means that the group is unsubstituted or substituted with one or more of the indicated substituents. If the gene is substituted with more than one substituent, the substituents may be the same or different.

Certain defined terms may appear more than once in a structural formula, with each term being defined independently of the other terms at each occurrence.

Certain defined terms may appear in combination, with the understanding that the first-mentioned group is a substituent on the later-mentioned group, wherein the substitution site, i.e., the point of attachment to another part of the molecule, is on the last-mentioned group.

The term "solvate" as used herein is a complex of defined stoichiometry formed by a solute (herein, a compound of the invention) and a solvent. The solvent is a solvent generally used in the field of pharmaceutical pharmacy, such as water, ethanol, acetic acid, and the like. The term "hydrate" refers to a complex in which the solvent molecule is water.

The term "treatment," as used herein, refers to the management and care of a patient for the purpose of combating a disease, disorder, or condition. The term is intended to include delaying the progression of the disease, disorder or condition, alleviating or alleviating 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.

The terms "disease," "condition," and "disorder," as used herein, are used interchangeably to describe a state of a patient that is not the normal physiological state of a human.

The term "drug", as used herein, means a pharmaceutical composition suitable for administration of a pharmaceutically active compound to a patient.

The term "prodrug", as used herein, includes biohydrolyzable amides and biohydrolyzable esters and also includes a) compounds wherein the biohydrolyzable functionality of the prodrug is contained in the compounds of the present invention, and b) compounds which can be biooxidized or reduced at a given functional group to produce the drug substance of the present invention. Examples of such functional groups include 1, 4-dihydropyridine, N-alkylcarbonyl-1, 4-dihydropyridine, 1, 4-cyclohexadiene, t-butyl, and the like.

The term "biohydrolyzable ester" as used herein is an ester of a drug substance (in the present invention, a compound of formula I) which either a) does not interfere with the biological activity of the parent substance but confers on the substance advantageous properties in vivo, such as duration of action, onset of action, etc., or b) is not biologically active but is readily converted in vivo by the individual to the biologically active substance. This has the advantage that, for example, the biohydrolyzable esters are absorbed orally from the intestine and converted into (I) in the plasma. Many examples of such esters are known in the art and include, for example, lower alkyl esters (e.g., C) _1-4) Lower acyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkylacylaminoalkyl esters and choline esters.

The term "biohydrolyzable amide" as used herein is an amide of a drug substance (in the present invention, a compound of formula I) which either a) does not interfere with the biological activity of the parent substance but confers on the substance advantageous properties in vivo, such as duration of action, onset of action, etc., or b) is not biologically active but is readily converted in vivo by the individual to the biologically active substance. This has the advantage that, for example, the biohydrolyzable amides are absorbed orally from the intestine and converted into (I) in the plasma. Many examples of such biohydrolyzable amides are known in the art and include, for example, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

The term "pharmaceutically acceptable", as used herein, means suitable for normal pharmaceutical use, i.e., without producing adverse events in a patient or the like.

The term "effective amount", as used herein, refers to a dosage sufficient to have a therapeutic effect on a patient as compared to no treatment.

The term "therapeutically effective amount", as used herein, refers to an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a particular disease and its complications. An amount sufficient to accomplish the stated purpose is defined as a "therapeutically effective amount". The effective amount for each purpose depends on the severity of the disease or injury, as well as the weight and general condition of the individual. It will be appreciated that determination of an appropriate dosage may be achieved by modeling the established values and testing the various points in the model using routine experimentation and is well within the ordinary skill of a trained physician or veterinarian.

The term "metabolite", as used herein, refers to an intermediate or product produced by metabolism.

The term "metabolism", as used herein, refers to the biotransformation of the drug substance (in the present invention, the compound of formula I) administered to the patient.

The representative examples set forth above are specific embodiments of the present invention.

In the examples below, the following terms are meant to have the following general meanings: d is day, g is g, h is hour, Hz is Hertz, kD is kilodaltons (kiloDalton (s)), L is liter, M is mole, mbar is mbar, mg is mg, min is minute, mL is mL, mM millimole, mmol is millimole, mol is mole, N is normal, ppm is parts per million, psi is pounds per square inch, APCI is atmospheric pressure chemical ionization, ESI is electrospray ionization, I.v. isIntravenous, m/z mass to charge ratio, Mp/Mp is melting point, MS is mass spectrometry, HPLC high performance liquid chromatography, RP is reverse phase, HPLC-MS is high pressure liquid chromatography-mass spectrometry, NMR nuclear magnetic resonance spectroscopy, p.o. is oral, R._fIs relative TLC flowability, rt is room temperature, s.c. subcutaneous, is thin layer chromatography, t_rRetention time, BOP is (1-benzotriazolyloxy) tris (dimethylamino) Hexafluorophosphate, CDI carbonyl diimidazole, DCM dichloromethane, CH₂Cl₂Is dichloromethane, DIBAL-H is diisobutylaluminum hydride, DBU is 1, 8-diazabicyclo [5.4.0]Undec-7-ene, DEAD is azodicarboxylic acid diethanoyl, DIC is 1, 3-diisopropylcarbodiimide, DIPEA is N, N-diisopropylethylamine, DMA is N, N-dimethylacetamide, DMF is N, N-dimethylformamide, DMPU is N, N' -dimethylpropyleneurea, 1, 3-dimethyl-2-oxohexahydropyrimidine, DMSO is dimethyl sulfoxide, EDAC is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, Et₂O is diethyl ether, EtOAc is ethyl acetate, HMPA hexamethylphosphoric triamide, HOAt is 1-hydroxy-7-azabenzotriazole, HOBt is 1-hydroxybenzotriazole, LAH is lithium aluminum hydride (LiAlH)₄) LDA is lithium diisopropylamide, MeCN is acetonitrile, MeOH is methanol, NMM is N-methylmorpholine (4-methylmorpholine), NMP is N-methylpyrrolidin-2-one, TEA is triethylamine, TFA is trifluoroacetic acid, THF is tetrahydrofuran, THP is tetrahydropyranyl, TTFH is fluoro-N, N, N ', N' -tetramethylformamidinium hexafluorophosphate, CDCl₃Is deuterium chloroform, CD₃OD is tetradeuteromethanol, and DMSO-d ₆Is hexadeuterium dimethyl sulfoxide.

Summary of The Invention

The present invention relates to compounds of the general formula I as specified in the claims below. The compounds of the present invention are structurally different from known compounds.

The invention also relates to the use of said compounds in therapy, and in particular to pharmaceutical compositions containing said compounds.

In another embodiment, the invention relates to a method of treatment comprising administering to a subject in need thereof an effective amount of one or more compounds of formula I.

In yet another embodiment, the invention relates to the use of a compound of formula I for the preparation of a medicament.

Detailed Description

Due to their interaction with the histamine H3 receptor, the compounds of the invention as defined in the claims below and in the present specification may be useful in the treatment of various diseases and conditions in which interaction with the histamine H3 receptor is beneficial. Thus, the compounds of the present invention may be used, for example, in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrine system.

In one embodiment, the present invention relates to compounds of formula I:

wherein W, X, Y, Z are independently of each other of the formula-C (R) ²) (ii) or-N ═ (i.e., nitrogen), provided that at least one of symbols W, X, Y or Z must be a moiety-N ═ N; r²Is hydrogen, halogen, cyano, C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkyl or halo-C_1-6-an alkoxy group;

R¹representing the following possibilities i) and ii): wherein the possibility i) is of the formula-NR³R⁴Wherein R is³Is hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl or C_3-8-a cycloalkyl group; and R is⁴Is C_1-6Alkyl radical, C_2-6-alkenyl or C_3-8-cycloalkyl, each of which is selected from-NR⁵R⁶And heterocyclyl group substitution; r⁵And R⁶Independently represent hydrogen or C_1-6-an alkyl group; and wherein the possibility II) is a group of one of the formulae II to VII:

wherein the asterisks indicate the position of the free bond (and not methyl), and wherein m is 0 (zero), 1, 2, or 3; n is 1, 2 or 3; o is 0 (zero), 1, 2, 3 or 4; p is 0 (zero), 1 or 2; q is 1 or 2; q represents-CH₂-, -O-, -S-or > NR³Wherein R is³As defined above; r⁷And R⁸Independently of one another are hydrogen or C_1-6-alkyl, or R⁷And R⁸May form a heterocyclic group together with the nitrogen to which it is attached; r⁹Is C_1-6-alkyl or C_3-8Cycloalkyl, both of which may be represented by the formula-NR⁷R⁸Wherein R is⁷And R⁸As defined above; r¹⁰Is hydrogen or C _1-6-an alkyl group; r¹¹Is hydrogen, C_1-8Alkyl radical, C_3-8-alkenyl, C_3-8-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-3-alkyl or C_3-8-cycloalkenyl-C_1-3-alkyl, or C_1-6-alkyl or C_3-8-cycloalkyl, both of which are substituted with at least one substituent selected from the group consisting of: hydroxy, C_1-6-alkoxy, C_1-6-alkylcarbonyl, cyano, -NR⁵R⁶，-C(＝O)NR⁵R⁶Arylcarbonyl, heteroarylcarbonyl, C_1-6-alkylsulfonyl, arylsulfonyl, heterocyclylcarbonyl, C_1-6Alkoxycarbonyl, aryl-C_1-6Alkoxycarbonyl, heteroaryl and heterocyclyl, which may be substituted by C where appropriate_1-6-alkyl substitution; r⁵And R⁶As defined above; a is aryl or heteroaryl, each of whichOptionally substituted by one or more groups independently selected from R¹²Substituted with the substituent(s); r¹²Is halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylsulfonyl, C_1-6-alkylsulfinyl, -V- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴，C_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, cyano-C_1-6-alkyl, hydroxy-C_1-6Alkyl radical, C_1-6-alkoxy-C_1-6Alkyl radical, C_1-6-alkylcarbonylamino, N- (C)_1-6-alkylcarbonyl) -N- (C)_1-6-alkyl) amino, C_1-6-alkylcarbonylamino-C_1-6Alkyl or N- (C) _1-6-alkylcarbonyl) -N- (C)_1-6-alkyl) amino-C_1-6-an alkyl group; or heterocyclyl-C_1-6-alkyl, heterocyclyl-C_1-6Alkoxy, heterocyclylcarbonyl, C_3-8-cycloalkylcarbonylamino, N- (C)_3-8-Cycloalkylcarbonyl) -N- (C)_1-6-alkyl) amino, C_3-8-cycloalkylcarbonylamino-C_1-6Alkyl or N- (C)_3-8-Cycloalkylcarbonyl) -N- (C)_1-6-alkyl) amino-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_1-6-alkylcarbonylamino, N- (C)_3-8-cycloalkyl-C_1-6-alkylcarbonyl) -N- (C)_1-6-alkyl) amino, C_3-8-cycloalkyl-C_1-6-alkylcarbonylamino-C_1-6Alkyl or N- (C)_3-8-cycloalkyl-C_1-6-alkylcarbonyl) -N- (C)_1-6-alkyl) amino-C_1-6Alkyl, arylcarbonylamino, aryl-C_1-6-alkylcarbonylamino, arylcarbonylamino-C_1-6Alkyl, aryl-C_1-6-alkylcarbonylamino-C_1-6-alkyl, heteroarylcarbonylamino or heteroarylcarbonylamino-C_1-6-alkyl, wherein said aryl, heteroaryl, C_3-8Cycloalkyl and heterocyclyl may each be optionally substituted by halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylsulfonyl, C_1-6-alkylsulfinyl, C_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, cyano-C_1-6-alkyl, hydroxy-C_1-6-alkyl or C_1-6-alkoxy-C_1-6-alkyl substitution; or aryl or heteroaryl, each of which may be substituted by halogen, hydroxy, carboxy, nitro, cyano, C _1-6Alkyl radical, C_3-8-cycloalkyl, C_1-6-alkoxy, C_1-6-alkylthio radical, C_1-6-alkylsulfonyl, C_1-6-alkylcarbonyl group, C_1-6-alkylcarbonylamino, C_1-6-alkylcarbonylamino-C_1-6Alkyl radical, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, hydroxy-C_1-6Alkyl radical, C_1-6-alkoxy-C_1-6Alkyl, aryl, arylcarbonylamino-C_1-6Alkyl, heteroaryl, heteroarylcarbonylamino-C_1-6-alkyl or- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Substitution; r is 0 (zero) or 1; s is 0 (zero), 1, 2 or 3; v represents a bond or a group of formula-O-, -S-or > NR³Wherein R is³As defined above; r¹³Is hydrogen, C_1-6Alkyl radical, C_3-8-cycloalkyl or C_1-6-an alkylcarbonyl group; r¹⁴Is hydrogen, C_1-6-alkyl or C_3-8-cycloalkyl, with the proviso that if R is¹³Is C_1-6-alkylcarbonyl, then R¹⁴Is hydrogen; or R¹³And R¹⁴May form a heterocyclic group together with the nitrogen to which it is attached; and pharmaceutically acceptable salts and solvates thereof; with the following limitations a) to g): a) if R is¹Is a group of formula VI; w is-N ═ N; x, Y and Z are each of the formula-C (R)²) A moiety; wherein R is²As defined above; then a cannot be imidazolyl; b) if R is¹Is a group of formula VI; q is 1; x is-C (R)²)＝；R¹¹Is a branched chain C_4-6Alkyl, branched C _4-6Alkenyl, branched C_4-6-alkynyl, C_3-5-cycloalkyl, C_3-7-cycloalkenyl radical, C_3-6-cycloalkyl-C_1-3-alkyl or C_3-6-cycloalkenyl-C_1-3-an alkyl group; and W, Y, Z are each of the formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then R¹²Not being halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula-V- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein V is a bond, wherein R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group; c) if R is¹A group of formula VII; m is 1, 2 or 3; x is of the formula-C (R)²) A moiety; and W, Y, Z are each of the formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then R¹²Not being halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula-V- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein V is a bond, R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group; d) if R is¹Is a group of formula VI; q is 1; r¹¹Is ethyl, n-propyl or isopropyl; y and Z are each-N ═ N; x is of the formula-C (R)²) And W is a moiety of formula-C (R)²) A moiety or-N ═ or; wherein R is ²As defined above; then R¹²Not being halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_16-Alkoxy radical, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group; e) if R is¹Is a group of formula VII; m is 1, 2 or 3; y and Z are each-N ═ N; x is of the formula-C (R)²) A moiety; and W is of the formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then R¹²Not being halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group; f) if R is¹Is of formula VI, q is 1, X and W are each of the formula-C (R)²) Wherein R is²As defined above, Y and Z are each-N ═ R¹¹Is isopropyl and A is phenyl, then R¹²Must not be fluorine, bromine, iodine, hydroxy, trifluoromethoxy, C_2-6-alkoxy, C_1-6Alkyl radical, C_2-6-alkylthio radical, C_2-6-alkylsulfinyl, C_2-6Alkylsulfonyl, cyano, aryl, heteroaryl, C _3-8-cycloalkyl or of formula- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group; and g) if X and Z are each-C (R)²) Is as follows; and one or both of W and Y is-N ═ N; then R¹Cannot be a radical of the formula II in which m is 2.

In one embodiment, the present invention relates to compounds of general formula I within the possible scope of claim 1:

wherein W, X, Y, Z are independently of each other of the formula-C (R)²) or-N (i.e. nitrogen) moietiesProvided that at least one of the symbols W, X, Y or Z must be part-N ═ N; r²Is hydrogen, halogen, cyano, C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkyl or halo-C_1-6-an alkoxy group;

R¹representing the following possibilities i) and ii): wherein the possibility i) is of the formula-NR³R⁴Wherein R is³Is hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl or C_3-8-a cycloalkyl group; and R is⁴Is C_1-6Alkyl radical, C_2-6-alkenyl or C_3-8-cycloalkyl, each of which is selected from-NR⁵R⁶And heterocyclyl group substitution; r⁵And R⁶Independently represent hydrogen or C_1-6-an alkyl group; and possibility II) is a group of one of the formulae II to VII:

wherein the asterisks indicate the position of the free bond (and not methyl), and wherein m is 0 (zero), 1, 2, or 3; n is 1, 2 or 3; o is 0 (zero), 1, 2, 3 or 4; p is 0 (zero), 1 or 2; q is 1 or 2; q represents-CH ₂-, -O-, -S-or > NR³Wherein R is³As defined above; r⁷And R⁸Independently of one another are hydrogen or C_1-6-alkyl, or R⁷And R⁸May form a heterocyclic group together with the nitrogen to which it is attached; r⁹Is C_1-6-alkyl or C_3-8Cycloalkyl, both of which may be of the formula-NR⁷R⁸Wherein R is⁷And R⁸As defined above; r¹⁰Is hydrogen or C_1-6-an alkyl group; r¹¹Is hydrogen, C_1-8Alkyl radical, C_3-8-alkenyl, C_3-8-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-3-alkyl or C_3-8-cycloalkenyl-C_1-3-alkyl radicalOr C_1-6-alkyl or C_3-8-cycloalkyl, both of which are substituted with at least one substituent selected from the group consisting of: hydroxy, C_1-6-alkoxy, C_1-6-alkylcarbonyl, cyano, -NR⁵R⁶、-C(＝O)NR⁵R⁶Arylcarbonyl, heteroarylcarbonyl, C_1-6-alkylsulfonyl, arylsulfonyl, heterocyclylcarbonyl, C_1-6Alkoxycarbonyl, aryl-C_1-6Alkoxycarbonyl, heteroaryl and heterocyclyl, which may be substituted by C where appropriate_1-6-alkyl substitution; r⁵And R⁶As defined above; a is aryl or heteroaryl, each of which may be optionally substituted with one or more groups independently selected from R¹²Substituted with the substituent(s); r¹²Is halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C _1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylsulfonyl, C_1-6-alkylsulfinyl, - (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴、C_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, cyano-C_1-6-alkyl, hydroxy-C_1-6Alkyl radical, C_1-6-alkoxy-C_1-6Alkyl radical, C_1-6-alkylcarbonylamino or C_1-6-alkylcarbonylamino-C_1-6-an alkyl group; or heterocyclyl-C_1-6-alkyl, heterocyclyl-C_1-6Alkoxy, heterocyclylcarbonyl, arylcarbonylamino-C_1-6-alkyl, heteroarylcarbonylamino or heteroarylcarbonylamino-C_1-6-alkyl, wherein said aryl, heteroaryl and heterocyclyl may each be optionally substituted by halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylsulfonyl, C_1-6-alkylsulfinyl, C_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, cyano-C_1-6-alkyl, hydroxy-C_1-6-alkyl or C_1-6-alkoxy-C_1-6-alkyl substitution; or aryl or heteroaryl, each of which may be substituted by halogen, hydroxy, carboxy, nitro, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, C_1-6-alkoxy, C_1-6-alkylthio radical, C_1-6-alkylsulfonyl, C_1-6-alkylcarbonyl group, C_1-6-alkylcarbonylamino, C_1-6-alkylcarbonylamino-C_1-6Alkyl radical, C _1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, hydroxy-C_1-6Alkyl radical, C_1-6-alkoxy-C_1-6Alkyl, aryl, arylcarbonylamino-C_1-6Alkyl, heteroaryl, heteroarylcarbonylamino-C_1-6-alkyl or- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Substitution; r is 0 (zero) or 1; s is 0 (zero), 1, 2 or 3;

R¹³is hydrogen, C_1-6Alkyl radical, C_3-8-cycloalkyl or C_1-6-an alkylcarbonyl group; r¹⁴Is hydrogen, C_1-6-alkyl or C_3-8-cycloalkyl, with the proviso that if R is¹³Is C_1-6-alkylcarbonyl, then R¹⁴Is hydrogen; or R¹³And R¹⁴May form a heterocyclic group together with the nitrogen to which it is attached; and pharmaceutically acceptable salts and solvates thereof; with the following limitations a) to g): a) if R is¹Is a group of formula VI; w is-N ═ N;

x, Y and Z are each of the formula-C (R)²) A moiety; wherein R is²As defined above; then a cannot be imidazolyl; b) if R is¹Is a group of formula VI; q is 1; x is-C (R)²)＝；R¹¹Is a branched chain C_4-6Alkyl, branched C_4-6Alkenyl, branched C_4-6-alkynyl, C_3-5-cycloalkyl, C_3-7-cycloalkenyl radical, C_3-6-cycloalkyl-C_1-3-alkyl or C_3-6-cycloalkenyl-C_1-3-an alkyl group; and W, Y, Z are each of the formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then R¹²Not being halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group; c) if R is¹Is a group of formula VII; m is 1, 2 or 3; x is of the formula-C (R)²) A moiety; and W, Y, Z are each of the formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then R¹²Not being halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group; d) if R is¹Is a group of formula VI; q is 1; r¹¹Is ethyl, n-propyl or isopropyl; y and Z are each-N ═ N; x is of the formula-C (R)²) And W is a moiety of formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then R¹²Not being halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C _1-6-an alkyl group; e) if R is¹Is a group of formula VII; m is 1, 2 or 3; y and Z are each-N ═ N; x is of the formula-C (R)²) A moiety; and W is of the formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then R¹²Must not be halogenHydroxy, trifluoromethyl, trifluoromethoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group; f) if R is¹Is of formula VI, q is 1, X and W are each of the formula-C (R)²) Wherein R is²As defined above, Y and Z are each-N ═ R¹¹Is isopropyl and A is phenyl, then R¹²Not being fluorine, bromine, iodine, hydroxy, trifluoromethoxy, C_2-6-alkoxy, C_1-6Alkyl radical, C_2-6-alkylthio radical, C_2-6-alkylsulfinyl, C_2-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group; and g) if X and Z are each-C (R)²) Is as follows; and one or both of W and Y is-N ═ N; then R¹Cannot be a group of the formula II in which m is 2.

In one embodiment the invention relates to compounds wherein W is-N ═ N; and X, Y and Z are each of the formula-C (R) ²) Wherein R is²As defined herein; the compounds have the general formula I-2:

wherein A and R¹As defined herein, and three symbols R²Are the same or different and are each as defined herein.

In one embodiment of the present invention, the present invention relates to compounds wherein W and Y are each-N ═ N(ii) a And X and Z are each of the formula-C (R)²) Wherein R is²As defined herein; the compounds have the general formula I-3:

wherein A and R¹As defined herein, and two symbols R²Are the same or different and are each as defined herein.

In one embodiment of the present invention, the present invention relates to compounds wherein W and X are each-N ═ N; and Y and Z are each of the formula-C (R)²) Wherein R is²As defined herein; the compounds have the general formula I-4:

In one embodiment of the present invention, the present invention relates to compounds wherein W and Z are each-N ═ N; and X and Y are each of the formula-C (R)²) Wherein R is²As defined herein; the compounds have the general formula I-5:

wherein A and R¹As defined herein, and two symbols R ²Are the same or different and are each as defined herein.

In one embodiment of the present invention, the present invention relates to compounds having one of the general formulas I-6a, I-6b, or I-6 c:

wherein A, m, o, p, R⁷、R⁸、R⁹、R¹⁰Each of W, X, Y and Z is as defined herein.

In one embodiment of the invention, the invention relates to compounds having one of the general formulas I-7a or I-7 b:

wherein W, X, Y, Z, m, q, R¹¹And a are each as defined herein.

In one embodiment of the present invention, the present invention relates to compounds having the general formula I-8:

wherein q and R¹¹And a are each as defined herein.

In one embodiment of the present invention, the present invention relates to compounds having the general formula I-9:

wherein q and R¹¹And a are each as defined herein.

In one embodiment of the present invention, the present invention relates to compounds having the general formula I-10:

wherein q and R¹¹And a are each as defined herein.

In one embodiment of the present invention, the present invention relates to compounds having the general formula I-11:

wherein q and R¹¹And a are each as defined herein.

In one embodiment of the present invention, the present invention relates to compounds having the general formula I-12:

wherein Q, n, m and A are each as defined herein.

In one embodiment of the present invention, the present invention relates to compounds having the general formula I-13:

wherein Q, m, n and A are each as defined herein.

In one embodiment of the present invention, the present invention relates to compounds having the general formula I-14:

wherein m and R⁹、R¹⁰And a are each as defined herein.

In one embodiment of the invention, A is aryl, 2-pyridyl, 3-pyridyl or 4-pyridyl.

In one embodiment of the invention, A is phenyl, benzofuranyl, benzodiEnglish-based, benzodioxolyl, benzoAzinyl, dihydrobenzodiIndolyl, pyrazinyl, pyridyl,Oxadiazolyl, quinolinyl, or thienyl.

In one embodiment of the invention, Q is-CH₂-or-O-.

In one embodiment of the invention, W is nitrogen (-N ═).

In one embodiment of the invention, W is of the formula-C (R)²) A group of (i) wherein R²Is hydrogen, i.e., carbon (-CH ═ c).

In one embodiment of the invention, X is nitrogen.

In one embodiment of the invention, X is carbon (-CH ═ c).

In one embodiment of the invention, X is nitrogen (-N ═) or carbon (-CH ═ c).

In one embodiment of the invention, Y is nitrogen.

In one embodiment of the invention, Y is carbon (-CH ═ c).

In one embodiment of the invention, Y is nitrogen (-N ═) or carbon (-CH ═).

In one embodiment of the invention, Z is nitrogen.

In one embodiment of the invention, Z is carbon (-CH ═ c).

In one embodiment of the invention, Z is nitrogen (-N ═) or carbon (-CH ═ c).

In one embodiment of the invention, W and Y are each nitrogen.

In one embodiment of the invention, W and X are each nitrogen.

In one embodiment of the invention, W and Z are each nitrogen.

In one embodiment of the invention, one or both of symbols W, X, Y and Z are nitrogen (-N ═ and the remainder are of formula-C (R)²) A group of (i) wherein R²As defined herein.

In one embodiment of the invention, the aromatic, divalent, 6-membered ring containing symbols W, X, Y and Z is a pyridine, pyridazine, pyrimidine or pyrazine in which the hydrogen atoms (para with respect to each other) are removed from two opposing carbon atoms.

In one embodiment of the invention, R¹Is a radical of the formula II

Wherein m, n and Q are each as defined in the claims below.

In one embodiment of the invention, R¹Is a radical of the formula III

Wherein m, o, p, R⁷And R⁸Each as defined in the following claims.

In one embodiment of the invention, R¹Is a radical of the formula III, where m is 0, 1 or 2, o is 0, 1 or 2, p is 1 or 2, and R⁷And R⁸Each is hydrogen or R⁷And R⁸Together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group.

In one embodiment of the invention, R¹Is a radical of the formula IV

Wherein R is⁹As defined in the following claims.

In one embodiment of the invention, R¹Is a radical of the formula V

Wherein m and R⁹And R¹⁰Each as defined in the following claims.

In one embodiment of the invention, R¹Is a radical of the formula V, where m is 2, R⁹Is C_1-6-alkyl, and R¹⁰Is hydrogen.

In one embodiment of the invention, R¹Is a radical of the formula VI

Wherein q and R¹¹Each as defined in the following claims.

In one embodiment of the invention, R¹Is a radical of the formula VI in which R¹¹Is hydrogen, C_1-8Alkyl radical, C_3-8-alkenyl, C_3-8Cycloalkyl, heterocyclyl, C substituted by_1-8-an alkyl group: c_1-6-alkoxy, cyano or C_1-6-an alkylcarbonyl group or a piperidinyl group, said piperidinyl group being optionally substituted with: c_1-6-alkyl, R⁵R⁶N-wherein R⁵And R ⁶Each is 1-6-alkyl, or R⁵R⁶N-C (═ O) -wherein R⁵And R⁶Each is C_1-6-an alkyl group.

In one embodiment of the invention, the heterocyclyl group is tetrahydropyranyl.

In one embodiment of the invention, R¹Is a radical of the formula VI in which R¹¹Is hydrogen, methyl, isopropyl, propyl, cyclopentyl, cyclohexyl, propenyl, methoxyethyl, cyanoethyl, piperidinylpropyl, N-methylpiperidylmethyl, methylcarbonylmethyl, N-dimethyl-aminoethyl, N-dimethylaminopropyl, N-diethylaminoethyl, N-dimethylaminocarbonylmethyl or tetrahydropyranyl.

In one embodiment of the invention, R¹Is a group of formula VII:

wherein m is as defined in the claims below.

In one embodiment of the invention, R¹Is of the formula VIIA group wherein m is 2.

In one embodiment of the invention, R¹Is piperazinyl, piperidinyl, pyrrolidinyl, piperidinylamino or diazepanyl.

In one embodiment of the invention, R²Is hydrogen, C_1-6-alkyl or halogen.

In one embodiment of the invention, R²Is hydrogen, methyl or isopropyl.

In one embodiment of the invention, R ²Is hydrogen or C_1-6-an alkyl group.

In one embodiment of the invention, R⁷Is hydrogen or C_1-6-an alkyl group.

In one embodiment of the invention, R⁸Is hydrogen or C_1-6-an alkyl group.

In one embodiment of the invention, R⁷And R⁸Together with the nitrogen to which they are attached form a heterocyclic group.

In one embodiment of the invention, R⁹Is C_1-6-an alkyl group.

In one embodiment of the invention, R⁹Is pentyl, more preferably pent-3-yl.

In one embodiment of the invention, R¹⁰Is hydrogen or C_1-6-an alkyl group.

In one embodiment of the invention, R¹⁰Is hydrogen.

In one embodiment of the invention, R¹¹Is hydrogen, C_1-8Alkyl radical, C_3-8-alkenyl, C_3-8-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-3-alkyl or C_3-8-cycloalkenyl-C_1-3-an alkyl group.

In one embodiment of the invention, R¹¹Is C_1-8Alkyl radical, C_3-8-cycloalkyl or C_3-8-cycloalkyl-C_1-3-an alkyl group.

In one embodiment of the invention, R¹¹Is C_3-8Alkyl radical, C_3-8-cycloalkyl or C_3-8-cycloalkyl-C_1-3-an alkyl group.

In one embodiment of the invention, R¹¹Is C_1-6-alkyl or C_3-8-cycloalkyl, both of which are substituted by at least one substituent selected from the group consisting of: hydroxy, C_1-6-alkoxy, C_1-6-alkylcarbonyl, cyano, -NR ⁵R⁶、-C(＝O)NR⁵R⁶Arylcarbonyl, heteroarylcarbonyl, C_1-6-alkylsulfonyl, arylsulfonyl, heterocyclylcarbonyl, C_1-6Alkoxycarbonyl, aryl-C_1-6Alkoxycarbonyl, heteroaryl and heterocyclyl, which may be substituted by C where appropriate_1-6-alkyl substitution; and R is⁵And R⁶As defined herein.

In one embodiment of the invention, R¹¹And cannot be hydrogen.

In one embodiment of the invention, R¹¹Is hydrogen, C_1-8Alkyl radical, C_3-8-alkenyl or C_3-8-cycloalkyl or C substituted by at least one substituent selected from the group consisting of_1-6-an alkyl group: c_1-6-alkoxy, C_1-6-alkylcarbonyl, cyano, -NR⁵R⁶、-C(＝O)NR⁵R⁶And a heterocyclic group which may be substituted by C_1-6-alkyl substitution; and R is⁵And R⁶Each is C_1-6-an alkyl group.

In one embodiment of the invention, R¹¹Is piperidinylpropyl, N-dimethylaminopropyl, N-methylpiperidylmethyl, methyl, N-dimethylaminoethyl, tetrahydropyranyl, hydrogen, propyl, cyclohexyl, methylCarbonylmethyl, N-dimethylaminocarbonylmethyl, cyanoethyl; n, N-diethylaminoethyl, methoxyethyl, propenyl, cyclobutyl, cyclopentyl, cyclopropyl, cyclopropylmethyl, ethyl, hydrogen or isopropyl.

In one embodiment of the invention, heterocyclyl is piperidinyl.

In one embodiment of the invention, R¹²Is halogen, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylsulfonyl, C_1-6-alkylsulfinyl, - (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Heterocyclic radical-C_1-6-alkyl, heterocyclyl-C_1-6Alkoxy, heterocyclylcarbonyl, C_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, cyano-C_1-6Alkyl radical, C_1-6-alkylcarbonylamino, C_1-6-alkylcarbonylamino-C_1-6Alkyl, arylcarbonylamino-C_1-6-alkyl, heteroarylcarbonylamino or heteroarylcarbonylamino-C_1-6-an alkyl group.

In one embodiment of the invention, R¹²Is aryl or heteroaryl, each of which may be substituted by halogen, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, C_1-6-alkoxy, C_1-6-alkylthio radical, C_1-6-alkylsulfonyl, C_1-6-alkylcarbonyl group, C_1-6-alkylcarbonylamino, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, C_1-6-alkoxy-C_1-6-alkyl, aryl, arylcarbonylamino, heteroaryl, heteroarylcarbonylamino or- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴And (4) substitution.

In one embodiment of the invention, R¹²Is halogen Element, hydroxy, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylsulfonyl, C_1-6-alkylsulfinyl, - (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴，C_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, cyano-C_1-6-alkyl, hydroxy-C_1-6Alkyl radical, C_1-6-alkoxy-C_1-6Alkyl radical, C_1-6-alkylcarbonylamino or C_1-6-alkylcarbonylamino-C_1-6-an alkyl group.

In one embodiment of the invention, R¹²Is heterocyclyl-C_1-6-alkyl, heterocyclyl-C_1-6Alkoxy, heterocyclylcarbonyl, arylcarbonylamino-C_1-6-alkyl, heteroarylcarbonylamino or heteroarylcarbonylamino-C_1-6-alkyl, wherein said aryl, heteroaryl and heterocyclyl may each be optionally substituted by halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6- -alkyl, C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylsulfonyl, C_1-6-alkylsulfinyl, C_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, cyano-C_1-6-alkyl, hydroxy-C_1-6-alkyl or C_1-6-alkoxy-C_1-6-alkyl substitution.

In one embodiment of the invention, R¹²Is aryl or heteroaryl, each of which may be substituted by halogen, hydroxy, carboxy, nitro, cyano, C _1-6Alkyl radical, C_3-8-cycloalkyl, C_1-6-alkoxy, C_1-6- - -alkylthio radical, C_1-6-alkylsulfonyl, C_1-6-alkylcarbonyl group, C_1-6-alkylcarbonylamino, C_1-6-alkylcarbonylamino-C_1-6Alkyl radical, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, hydroxy-C_1-6Alkyl radical, C_1-6-alkoxy-C_1-6Alkyl, aryl, arylcarbonylamino-C_1-6Alkyl, heteroaryl, heteroarylcarbonylamino-C_1-6-alkyl or- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴And (4) substitution.

In one embodiment of the invention, R¹²Is halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylthio radical, C_1-6-alkylsulfonyl, C_1-6-an alkylsulfinyl group,

-V-(CH₂)_s-(C＝O)_r-NR¹³R¹⁴，C_1-6Alkoxycarbonyl, cyano-C_1-6Alkyl radical, C_1-6-alkylcarbonylamino, N- (C)_1-6- - -alkylcarbonyl) - -N- - (C)_1-6-alkyl) amino, C_1-6-alkylcarbonylamino-C_1-6-alkyl, or heterocyclyl, heterocyclyl-C_1-6Alkyl, heterocyclylcarbonyl, C_3-8-cycloalkylcarbonylamino, N- (C)_3-8-Cycloalkylcarbonyl) -N- (C)_1-6-alkyl) amino, C_3-8-cycloalkyl-C_1-6-alkylcarbonylamino or heterocyclylcarbonylamino, wherein the heterocyclyl and C_3-8Cycloalkyl optionally substituted by oxo,

C_1-6Alkyl radical, C_1-6-alkoxy or C_1-6-alkoxy-C_1-6-alkyl substitution; or phenyl or heteroaryl substituted with: cyano, halo-C_1-6Alkyl radical, C_1-6-alkyl, halo-C_1-6-alkyl or- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein s, R, R¹³And R¹⁴As defined above.

In one embodiment of the present invention, the substrate is,r is 0 or 1, s is 0 or 1, R¹³Is hydrogen or C_1-6-alkyl, and R¹⁴Is hydrogen or C_1-6-alkyl, or R¹³And R¹⁴Together with the adjacent nitrogen atom form a heterocyclyl group, for example, piperidinyl optionally substituted with aminocarbonyl, and V is a bond.

In one embodiment of the invention, the heterocyclyl is morpholinyl, piperazinyl, piperidinyl or tetrahydropyranyl.

In one embodiment of the invention, heteroaryl isA diazolyl group.

In one embodiment of the invention, R¹²Is methoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, acetyl, acetylamino, acetylaminomethyl, cyanomethyl, ethylthio, butylthio, methylsulfonyl, ethylsulfonyl, ethylsulfinyl, methylOxadiazolyl, cyclopropylcarbonylamino, cyclopropylmethylcarbonylamino, methoxycyclohexylcarbonylamino, morpholinyl-methyl, methylOxadiazolyl, chloromethylphenyl, cyanophenyl, cyclopropyl, piperidinylmethylphenyl, aminocarbonylpiperidinylmethylphenyl, N-acetyl-N-methylamino, amino, aminomethyl, cyclohexylcarbonylamino, N-cyclopropylcarbonyl-N-methylamino, cyclohexylcarbonylamino, dimethylaminomethyl, dimethylamino, dimethylaminocarbonyl, (2, 2-dimethylpropyl) carbonylaminomethyl, diisopropylaminocarbonyl, 4- (1, 1-dioxoisothiazolidinyl) phenyl, ethoxy, hydroxy, (4-hydroxymethylpiperidinyl) carbonyl, (4-hydroxymethylpiperidinyl) methyl, isopropylcarbonylaminomethyl, 4-isopropylpiperazinyl, (4-methylpiperazinyl) carbonyl, (4-methylpiperazinyl) methyl, piperidinylmethoxy, N-acetylamino, amino, aminomethyl, cyclohexylcarbonylamino, N-cyclopropylcarbonyl-N-methylamino, N-dimethylaminopropyl, dimethylamino, dimethylaminocarbonyl, N-dimethylaminopropyl, (4-methylpiperidinyl) carbonyl group, (4-methylpiperidinyl) carbonyl group 4-methoxymethylpiperidinyl) carbonyl, methyl, methylamino, morpholinyl, morpholinylcarbonyl, piperidinylmethyl, piperidinyl, piperidinylcarbonyl, piperidinylsulfonyl, tetrahydropyranylcarbonylamino, tert-butylcarbonylamino and tert-butylcarbonylaminomethyl.

In one embodiment of the invention, R¹³Is hydrogen or C_1-6-an alkyl group.

In one embodiment of the invention, R¹⁴Is hydrogen or C_1-6-an alkyl group.

In one embodiment of the invention, R¹³And R¹⁴Together with the attached nitrogen, form a heterocyclic group.

In one embodiment of the invention, m is 0, 1 or 2.

In one embodiment of the invention, m is 0.

In one embodiment of the invention, m is 1 or 2.

In one embodiment of the invention, n is 1 or 2.

In one embodiment of the invention, o is 1.

In one embodiment of the invention, p is 1 or 2.

In one embodiment of the invention, m is 0 and p is 2.

In one embodiment of the invention, m is 0, p is 2 and o is 1.

In one embodiment of the invention, q is 1.

In one embodiment of the invention, r is 0 or 1.

In one embodiment of the invention s is 0 or 1.

In one embodiment, the invention relates to compounds wherein A is aryl, 2-pyridyl, 3-pyridyl or4-pyridyl; and/or Q is-CH₂-or-O-; and/or W is nitrogen; and/or W is of the formula-C (R)²) A group of (i) wherein R²Is hydrogen; and/or X is nitrogen; and/or X is of the formula-C (R)²) A group of (i) wherein R²Is hydrogen; and/or Y is nitrogen; and/or Y is of the formula-C (R)²) A group of (i) wherein R²Is hydrogen; and/or Z is nitrogen; and/or Z is of the formula-C (R)²) A group of (i) wherein R²Is hydrogen; and/or W and Y are nitrogen; and/or W and X are nitrogen; and/or W and Z are nitrogen; and/or R¹Is a radical of the formula II

Wherein m, n and Q are each as defined in the claims below; and/or R¹Is a radical of the formula III

Wherein m, o, p, R⁷And R⁸Each as defined in the following claims; and/or R¹Is a radical of the formula IV

Wherein R is⁹As defined in the following claims; and/or R¹Is a radical of the formula V

Wherein m and R⁹And R¹⁰Each as defined in the following claims;and/or R¹Is a radical of the formula VI

Wherein q and R¹¹Each as defined in the following claims; and/or R¹Is a radical of the formula VII

Wherein m is as defined in the claims below; and/or R²Is hydrogen, C_1-6-alkyl or halogen; and/or R ⁷Is hydrogen or C_1-6-an alkyl group; and/or R⁸Is hydrogen or C_1-6-an alkyl group; and/or R⁷And R⁸Together with the nitrogen to which they are attached form a heterocyclic group; and/or R⁹Is C_1-6-an alkyl group; and/or R¹⁰Is hydrogen or C_1-6-an alkyl group; and/or R¹¹Is hydrogen, C_1-8Alkyl radical, C_3-8-alkenyl, C_3-8-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-3-alkyl or C_3-8-cycloalkenyl-C_1-3-an alkyl group; and/or R¹¹Is C_1-8Alkyl radical, C_3-8-cycloalkyl or C_3-8-cycloalkyl-C_1-3-an alkyl group; and/or R¹¹Is C_3-8Alkyl radical, C_3-8-cycloalkyl or C_3-8-cycloalkyl-C_1-3-an alkyl group; and/or R¹¹Is C_1-6-alkyl or C_3-8-cycloalkyl, said C_1-6-alkyl or C_3-8-cycloalkyl groups are each substituted by at least one substituent selected from the group consisting of: hydroxy, C_1-6-alkoxy, C_1-6-alkylcarbonyl, cyano, -NR⁵R⁶、-C(＝O)NR⁵R⁶Arylcarbonyl, heteroarylcarbonyl, C_1-6Alkylsulfonyl, arylsulfonyl, heterocyclylCarbonyl group, C_1-6Alkoxycarbonyl, aryl-C_1-6Alkoxycarbonyl, heteroaryl and heterocyclyl, which may be substituted by C where appropriate_1-6-alkyl substitution; and R is⁵And R⁶As defined herein; and/or R¹¹Cannot be hydrogen; and/or R¹²Is halogen, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylsulfonyl, C _1-6-alkylsulfinyl, - (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Heterocyclyl radical-C_1-6-alkyl, heterocyclyl-C_1-6Alkoxy, heterocyclylcarbonyl, C_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, cyano-C_1-6Alkyl radical, C_1-6-alkylcarbonylamino, C_1-6-alkylcarbonylamino-C_1-6Alkyl, arylcarbonylamino-C_1-6-alkyl, heteroarylcarbonylamino or heteroarylcarbonylamino-C_1-6-an alkyl group; and/or R¹²Is aryl or heteroaryl, each of which may be substituted by halogen, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, C_1-6-alkoxy, C_1-6-alkylthio radical, C_1-6-alkylsulfonyl, C_1-6-alkylcarbonyl group, C_1-6-alkylcarbonylamino, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, C_1-6-alkoxy-C_1-6-alkyl, aryl, arylcarbonylamino, heteroaryl, heteroarylcarbonylamino or- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Substitution; and/or R¹²Is halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylsulfonyl, C_1-6-alkylsulfinyl, - (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴，C_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, cyano-C_1-6-alkyl, hydroxy-C_1-6Alkyl radical, C_1-6-alkoxy-C_1-6Alkyl radical, C _1-6-alkylcarbonylamino or C_1-6-alkylcarbonylamino-C_1-6-an alkyl group; and/or R¹²Is heterocyclyl-C_1-6-alkyl, heterocyclyl-C_1-6Alkoxy, heterocyclylcarbonyl, arylcarbonylamino-C_1-6-alkyl, heteroarylcarbonylamino or heteroarylcarbonylamino-C_1-6-alkyl, wherein said aryl, heteroaryl and heterocyclyl may each be optionally substituted by halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkylsulfonyl, C_1-6-alkylsulfinyl, C_1-6-alkylcarbonyl group, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, cyano-C_1-6-alkyl, hydroxy-C_1-6-alkyl or C_1-6-alkoxy-C_1-6-alkyl substitution; and/or R¹²Is aryl or heteroaryl, each of which may be substituted by halogen, hydroxy, carboxy, nitro, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, C_1-6-alkoxy, C_1-6-alkylthio radical, C_1-6-alkylsulfonyl, C_1-6-alkylcarbonyl group, C_1-6-alkylcarbonylamino, C_1-6-alkylcarbonylamino-C_1-6Alkyl radical, C_1-6Alkoxycarbonyl, C_1-6-alkylcarboxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, hydroxy-C_1-6Alkyl radical, C_1-6-alkoxy-C_1-6Alkyl, aryl, arylcarbonylamino, aryl-carbonylamino-C _1-6Alkyl, heteroaryl, heteroarylcarbonylamino-C_1-6-alkyl or-V- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein V is a bond; and/or R¹³Is hydrogen or C_1-6-alkyl radical(ii) a And/or R¹⁴Is hydrogen or C_1-6-an alkyl group; and/or R¹³And R¹⁴Together with the attached nitrogen form a heterocyclic group; and/or m is 0, 1 or 2; and/or m is 0; and/or m is 1 or 2; and/or n is 1 or 2; and/or o is 1; and/or p is 1 or 2; and/or m is 0 and p is 2; and/or m is 0, p is 2 and o is 1; and/or q is 1; and/or r is 0 and 1; and/or s is 0 or 1.

In one embodiment of the invention, the moiety V is a bond.

In one embodiment, the present invention relates to any one of the following compounds: 1- [5- (4-chlorophenyl) pyridin-2-yl ] -4-isopropylpiperazine; 1-isopropyl-4- [5- (4-methoxyphenyl) pyridin-2-yl ] piperazine; 1-isopropyl-4- [5- (4-trifluoromethoxyphenyl) pyridin-2-yl ] piperazine; 1- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } ethanone; 1- [5- (2, 6-difluorophenyl) pyridin-2-yl ] -4-isopropylpiperazine; 1- [5- (4-fluorophenyl) pyridin-2-yl ] -4-isopropylpiperazine; 1- [5- (3-fluorophenyl) pyridin-2-yl ] -4-isopropylpiperazine; 1- [5- (2-fluorophenyl) pyridin-2-yl ] -4-isopropylpiperazine;

1- {4- [6- (4-cyclopentylpiperazin-1-yl) pyridin-3-yl ] phenyl } ethanone; 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzonitrile; (4- (2-pyrrolidin-1-ylethyl) piperidin-1-yl) -5- (4-trifluoromethylphenyl) pyridine; 1- (3-piperidin-1-ylpropyl) -4- [5- (4-trifluoromethylphenyl) pyridin-2-yl ] piperazine; 1 '- [6- (4-methanesulfonylphenyl) pyridazin-3-yl ] - [1, 4' ] bipiperidinyl; dimethyl- (3- {4- [6- (4-trifluoromethylphenyl) pyridazin-3-yl ] piperazin-1-yl } propyl) amine; 3- [4- (1-methylpiperidin-3-ylmethyl) piperazin-1-yl ] -6- (4-trifluoromethylphenyl) pyridazine; 3- [4- (1-methylpiperidin-4-ylmethyl) piperazin-1-yl ] -6- (4-trifluoromethylphenyl) pyridazine; 4- {6- [4- (1-methylpiperidin-4-ylmethyl) piperazin-1-yl ] pyridazin-3-yl } benzonitrile; 4- {6- [4- (1-methylpiperidin-3-ylmethyl) piperazin-1-yl ] pyridazin-3-yl } benzonitrile; (S) -3- (4-butylsulfanylphenyl) -6- (2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) pyridazine;

(S) -3- (4-ethanesulfonylphenyl) -6- (2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) pyridazine; (S) -3- (4-ethanesulfinylphenyl) -6- (2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) pyridazine; (S) -3- (4-ethylsulfanylphenyl) -6- (2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) pyridazine; 5- (4-chlorophenyl) -2- (4-isopropylpiperazin-1-yl) pyrimidine; 2- (4-isopropylpiperazin-1-yl) -5- (4-trifluoromethylphenyl) pyrimidine;

4- [2- (4-Isopropylpiperazin-1-yl) -pyrimidin-5-yl]A benzonitrile; 5- (4-fluorophenyl) -2- (4-isopropylpiperazin-1-yl) pyrimidine; 2- (4-isopropylpiperazin-1-yl) -5- (4-trifluoromethoxyphenyl) pyrimidine; 2- (4-isopropylpiperazin-1-yl) -5- (4-methoxyphenyl) pyrimidine; (S) -3- (2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) -6- (4-trifluoromethylphenyl) pyridazine; n- {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl]Phenyl } acetamide; [1- (1-ethylpropyl) piperidin-4-yl group]- [6- (3-fluoro-4-methoxyphenyl) pyridazin-3-yl]An amine; [1- (1-ethylpropyl) piperidin-4-yl group]- [6- (4-Methanesulfonylphenyl) pyridazin-3-yl]An amine; 1-isopropyl-4- [5- (4-trifluoromethylphenyl) pyridin-2-yl]Piperazine; 3- (2, 3-dihydrobenzo [1, 4 ]]IIEn-6-yl) -6- (4-isopropylpiperazin-1-yl) pyridazine; 4- {6- [1- (1-ethylpropyl) piperidin-4-ylamino ]Pyridazin-3-yl } benzonitrile; dimethyl- (2- {4- [5- (4-trifluoromethylphenyl) pyridin-2-yl)]Piperazin-1-yl } ethyl) amine; 1- (tetrahydropyran-4-yl) -4- [5- (4-trifluoromethylphenyl) pyridin-2-yl]Piperazine;

1- [6- (4-trifluoromethylphenyl) pyridazin-3-yl]Piperidin-3-ylamine; n- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl]Benzyl } acetamide; 1-isopropyl-4- {5- [4- (5-methyl [1, 2, 4 ]]Oxadiazol-3-yl) phenyl]Pyridin-2-yl } piperazine; 1- (5- (5- (4-chloromethylphenyl) [1, 2, 4 ]]Oxadiazol-3-yl) pyridin-2-yl) -4-isopropylpiperazine; 4- {3- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl][1，2，4]Oxadiazol-5-yl } benzonitrile; 1- [5- (5-cyclopropyl [1, 2, 4 ]]Oxadiazol-3-yl) pyridin-2-yl]-4-isopropylpiperazine; 1-isopropyl-4- {5- [5- (4-piperidin-1-ylmethyl) phenyl ] [1, 2, 4]Diazol-3-yl]Pyridin-2-yl } piperazine; 1- (4- {3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl][1，2，4]Oxadiazol-5-yl } benzyl) piperidine-4-carboxylic acid amide; 1-propyl-4- [5- (4-trifluoromethylphenyl) pyridin-2-yl]Piperazine; 1-cyclohexyl-4- [5- (4-trifluoromethylphenyl) pyridin-2-yl]Piperazine; 1- {4- [6- (4-Isopropylpiperazin-1-yl) pyridazin-3-yl]Phenyl } ethanone; 1- {4- [5- (4-trifluoromethylphenyl) pyridin-2-yl]Piperazin-1-yl } propan-2-one; n, N-dimethyl-2- {4- [5- (4-trifluoromethylphenyl) pyridin-2-yl ]Piperazin-1-yl } acetamide; 3- {4- [5- (4-trifluoromethylphenyl) pyridin-2-yl]Piperazin-1-yl } propionitrile; diethyl- (2- {4- [5- (4-trifluoromethylphenyl) pyridin-2-yl)]Piperazin-1-yl } ethyl) amine; 1- (2-methoxyethyl) -4- [5- (4-trifluoromethylphenyl) pyridin-2-yl]Piperazine; 1-allyl-4- [5- (4-trifluoromethylphenyl) pyridin-2-yl]Piperazine; 1-isopropyl-4- [6- (4-trifluoromethylphenyl) pyridazin-3-yl]-[1，4]Diazepane; n- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyrazinyl-5' -yl) phenyl]An acetamide; [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyrazinyl-5' -yl) -phenyl]Acetonitrile and 5- (4-ethanesulfonylphenyl) -4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyrazinyl, and salts thereof such as hydrochloride, dihydrochloride, trihydrochloride, trifluoroacetate and disulfonate.

In one embodiment, the present invention relates to any one of the following compounds: n- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } acetamide; cyclopropanecarboxylic acid [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] amide; 2-cyclopropyl-N- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] acetamide; 4-methoxycyclohexanecarboxylic acid [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] amide;

4- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } morpholine; 4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzonitrile and N- {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzyl } acetamide and salts thereof such as hydrochloride, dihydrochloride, trihydrochloride, trifluoroacetate and bismethanesulfonate.

In one embodiment, the present invention relates to any one of the following compounds: 4- [6- (4-cyclopropylpiperazin-1-yl) piperidin-3-yl ] -N, N-dimethylbenzamide and N- {4- [6- (4-cyclopropylpiperazin-1-yl) pyridazin-3-yl ] -2-methoxyphenyl } acetamide, and salts thereof such as hydrochloride, dihydrochloride, trihydrochloride, trifluoroacetate and disulfonate.

In one embodiment, the present invention relates to any one of the following compounds: n- {3- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] phenyl } acetamide; n- {3- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridin-3-yl ] phenyl } acetamide; n- {4- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] phenyl } acetamide; n- {4- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridin-3-yl ] phenyl } acetamide; n- {4- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridazin-3-yl ] phenyl } acetamide; n- {3- [6- (4-cyclopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] phenyl } acetamide;

3- [6- (4-cyclopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] -N, N-dimethylbenzamide;

n- {4- [6- (4-Cyclopropylpiperazin-1-yl) -4-methylpyridin-3-yl]Phenyl } acetamide; 4- [6- (4-Cyclopropylpiperazin-1-yl) -4-methylpyridin-3-yl]-N, N-dimethylbenzamide; 5-1, 3-benzodioxol-5-yl-2- (4-cyclopropylpiperazin-1-yl) pyrimidine; n- {4- [6- (4-isopropylperhydro-1, 4-diaza)-1-yl) pyridazin-3-yl]Phenyl } acetamide; 4- [6- (4-isopropylperhydro-1, 4-diaza)-1-yl) pyridazin-3-yl]A phenylamine; n- {4- [6- (4-cyclopropyl- [1, 4 ]]Diazepan-1-yl) pyridazin-3-yl]Phenyl } acetamide; 7- [6- (4-Cyclopropylpiperazin-1-yl) -pyridazin-3-yl]-4-methyl-3, 4-dihydro-2H-1, 4-benzoAn oxazine; 3- (4-Cyclopropylpiperazin-1-yl) -6- (2, 3-dihydro-1, 4-benzodiOn-6-yl) pyridazine; 5- [6- (4-Cyclopropylpiperazin-1-yl) pyridazin-3-yl]-1H-indole;

{4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] phenyl } acetonitrile; n- {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] phenyl } acetamide; 1- {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] phenyl } ethanone; 2- (4-isopropylpiperazin-1-yl) -5-pyridin-3-ylpyrimidine; 2- (4-isopropylpiperazin-1-yl) -5-pyridin-4-ylpyrimidine; {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] phenyl } dimethylamine; 3- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] -N, N-dimethylbenzamide; n, N-diisopropyl-4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) benzamide;

[4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] - (4-methylpiperidin-1-yl) methanone; 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -N, N-dimethylbenzamide; [3- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] morpholin-4-yl methanone; n- {4- [5- (octahydropyrido [1, 2-a ] pyrazin-2-yl) pyrazin-2-yl ] phenyl } acetyl

An amine; 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenol; n- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] -N-methylamine; 4-isopropyl-5 '- (4-morpholin-4-ylphenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; 5 '-1, 3-benzodioxol-5-yl-4-isopropyl-3, 4, 5, 6-tetrahydro-2H-1, 2' -bipyrazinyl; 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -2-methoxyphenylamine; 2-chloro-4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -6-methoxyphenol; 5 '- (3, 4-dimethoxyphenyl) -4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; 4-isopropyl-5 '- (3, 4, 5-trimethoxyphenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; n- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) benzyl ] acetamide; 4, 4 ' "-diisopropyl-3, 4, 5, 6, 3 '", 4 ' ", 5 '", 6 ' "-octahydro-2H, 2 '" H- [1, 2 '; 5', 2 "; 5 ", 1'" ] tetrabipyrazinyl (quaterpyrazine); 4-isopropyl-5 '- (6-methoxypyridin-3-yl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; n, N-diisopropyl-4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzamide; {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } - (4-methylpiperidin-1-yl) methanone; 6 '- (4-isopropylpiperazin-1-yl) -6-methoxy- [3, 3' ] bipyridinyl; 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) benzonitrile; 4-isopropyl-5 '- (4-trifluoromethylphenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; 6 '- (4-isopropylpiperazin-1-yl) -5-trifluoromethyl- [2, 3' ] bipyridinyl; 4-isopropyl-5 '- [4- (piperidine-1-sulfonyl) phenyl ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; 4-isopropyl-5 '- (4- (piperidin-1-yl) phenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -2-methylphenyl ] dimethylamine; 5 '- (6-ethoxypyridin-3-yl) -4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; 5 '-benzofuran-2-yl-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; 5- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) thiophene-2-carbonitrile; 4-isopropyl-5 '- (2-methylpyridin-4-yl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; (R) -2- (6-1, 3-benzodioxol-5-ylpyridazin-3-yl) octahydropyrido [1, 2-a ] pyrazine; 4-isopropyl-5 '- (5-trifluoromethyl-pyridin-2-yl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; n- {4- [6- (4-cyclobutylpiperazin-1-yl) pyridin-3-yl ] phenyl } acetamide; 4- [6- (4-cyclobutylpiperazin-1-yl) pyridin-3-yl ] -N, N-dimethylbenzamide; n- {4- [6- (4-cyclobutylpiperazin-1-yl) pyridazin-3-yl ] -2-methoxyphenyl } acetamide; {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } piperidin-1-yl ketone; {4- [6- (4-cyclopropylmethylpiperazin-1-yl) pyridazin-3-yl ] phenyl } piperidin-1-yl ketone; {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } morpholin-4-ylmethanone; (4-hydroxymethylpiperidin-1-yl) - {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } -methanone; 4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] -N, N-dimethylbenzamide;

{4- [6- (4-cyclopentylpiperazin-1-yl) pyridazin-3-yl ] phenyl } piperidin-1-yl-methanone; {4- [6- (4-isopropyl) amino acid

Piperazin-1-yl) pyridazin-3-yl ] phenyl } - (4-methylpiperazin-1-yl) methanone; {4- [6- (4-Isopropylpiperazine)

Oxazin-1-yl) pyridin-3-yl ] phenyl } morpholin-4-yl methanone; 4- [6- (4-isopropylpiperazin-1-yl) pyridine-3-

-methyl ] -N, N-dimethyl-benzamide; {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } piperazine

Pyridin-1-yl methanone; (4-Hydroxymethylpiperidin-1-yl) - {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-

Phenyl } -methanone; {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } - (4-methylpiperazine)

-1-yl) methanone; {4- [6- (4-Cyclopropylmethylpiperazin-1-yl) pyridin-3-yl ] phenyl } piperidin-1-ylmethane

A ketone; {4- [6- (4-cyclopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } piperidin-1-yl-methanone; {4- [6- (4-

Cyclopentylpiperazin-1-yl) pyridin-3-yl ] phenyl } piperidin-1-yl methanone; {3- [6- (4-isopropylpiperazine-1-)

Yl) pyridin-3-yl ] phenyl } morpholin-4-yl methanone; {3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ]

Phenyl } piperidin-1-yl ketone; 3- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl ] -N, N-dimethylbenzene

Formamide; {4- [6- (4-cyclopentylpiperazin-1-yl) pyridin-3-yl ] phenyl } - (4-methylpiperazin-1-yl)

A ketone; {4- [6- (4-cyclopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } - (4-methylpiperazin-1-yl) methanone; {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } - (4-methoxymethylpiperidin-1-yl) -

An ethanone; 4- [6- (4-' cyclopentylpiperazin-1-yl) pyridin-3-yl ] -N, N-dimethylbenzamide;

{4- [6- (4-cyclopentylpiperazin-1-yl) pyridin-3-yl ] phenyl } morpholin-4-yl methanone; 3- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] -N, N-dimethylbenzamide; 3- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridin-3-yl ] -N, N-dimethylbenzamide; 4- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridin-3-yl ] -N, N-dimethylbenzamide; 4- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] -N, N-dimethylbenzamide; 4- [ 4-isopropyl-6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] -N, N-dimethylbenzamide; 1-cyclopropylmethyl-4- [5- (4-piperidin-1-ylmethyl) pyridin-2-yl ] piperazine; {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } dimethyl

An amine; 3- (4-cyclopentylpiperazin-1-yl) -6- (4-piperidin-1-ylmethylphenyl) pyridazine; 1- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } -4-methylpiperazine; (1- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } piperidin-4-yl) methanol; 1-isopropyl-4- [5- (4-piperidin-1-ylmethyl phenyl) pyridin-2-yl ] piperazine; {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] benzyl } dimethyl

An amine; 3- (4-isopropylpiperazin-1-yl) -6- (4-piperidin-1-ylmethylphenyl) pyridazine; 3- (4-isopropyl piperazine)

Oxazin-1-yl) -6- [4- (4-methylpiperazin-1-ylmethyl) phenyl ] pyridazine; (1- {4- [6- (4-Isopropylpiperazine)

-1-yl) pyridazin-3-yl ] benzyl } piperidin-4-yl) methanol; 4- {4- [6- (4-Isopropylpiperazin-1-yl) pyridazine

-3-yl ] benzyl } morpholine; 1-cyclopentyl-4- [5- (4-piperidin-1-ylmethyl) phenyl) pyridin-2-yl ] piperazine;

1-cyclopropyl-4- [5- (4-piperidin-1-ylmethyl-phenyl) pyridin-2-yl ] piperazine; 3- (4-Cyclopropylmethylpiperazine)

Oxazin-1-yl) -6- (4-piperidin-1-ylmethylphenyl) pyridazine; 3- (4-Cyclopropylpiperazin-1-yl) -6- (4-piperidine)

-1-ylmethyl phenyl) pyridazine; 4- {4- [2- (4-cyclopropylpiperazin-1-yl) pyrimidin-5-yl ] benzyl } morpholine;

n- {3- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl]Phenyl } acetamide; n- {3- [6- (4-Cyclopropylpiperazin-1-yl) pyridazin-3-yl]Phenyl } acetamide; cyclopropanecarboxylic acid {3- [6- (4-cyclopropylpiperazin-1-yl) pyridazin-3-yl]Phenyl } amide; n- {4- [6- (4-Cyclopropylpiperazin-1-yl) pyridazin-3-yl]Phenyl } acetamide; cyclopropanecarboxylic acid {4- [6- (4-cyclopropylpiperazin-1-yl) pyridazin-3-yl]Phenyl } amide; cyclopropanecarboxylic acid {4- [6- (4-cyclopropyl-perhydro-1, 4-diaza ] -1-yl) pyridazin-3-yl]-phenyl } amide;

n- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] -2, 2-dimethylpropionamide; tetrahydropyran-4-carboxylic acid [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] amide; n- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] -N-methylacetamide; cyclopropanecarboxylic acid [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] methylamide; n- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -2-methoxyphenyl ] acetamide; cyclohexanecarboxylic acid [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] amide; 2- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenoxy ] -N, N-dimethylacetamide; 5 '- [4- (1, 1-dioxoisothiazolidin-2-yl) phenyl ] -4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl; 6- (4-isopropylpiperazin-1-yl) - [3, 3' ] bipyridinyl; 6- (4-isopropylpiperazin-1-yl) - [3, 4' ] bipyridinyl; 6 '- (4-isopropylpiperazin-1-yl) - [2, 3' ] bipyridinyl; 6 '- (4-ethylpiperazin-1-yl) - [2, 3' ] bipyridinyl; 6 '- (4-isopropylpiperazin-1-yl) -6-methyl- [2, 3' ] bipyridinyl; 6 '- (4-ethylpiperazin-1-yl) -6-methyl- [2, 3' ] bipyridinyl; 2- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] quinoline; n- {3- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridazin-3-yl ] phenyl } acetamide; n- {3- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridazin-3-yl ] phenyl } acetamide; 3- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridazin-3-yl ] -N, N-dimethylbenzamide; 3- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridazin-3-yl ] -N, N-dimethylbenzamide; 4- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridazin-3-yl ] -N, N-dimethylbenzamide; 4- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridazin-3-yl ] -N, N-dimethylbenzamide; n- {4- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridazin-3-yl ] phenyl } acetamide; 1 '- (6-pyridin-4-ylpyridazin-3-yl) - [1, 4' ] bipiperidinyl; 3- (pyridin-3-yl) -6- [ (4-pyrrolidin-1-yl) piperidin-1-yl ] pyridazine; 1 '- (6-pyridin-3-ylpyridazin-3-yl) - [1, 4' ] bipiperidinyl; 3- (pyridin-4-yl) -6- [ (4-pyrrolidin-1-yl) piperidin-1-yl ] pyridazine; 4-pyrrolidin-1-yl-3, 4, 5, 6-tetrahydro-2H- [1, 2'; 5', 3 "] terpyridine; 1-isopropyl-4- (6-phenylpyridin-3-yl) piperazine; (R) -2- [6- (3, 4-dimethoxyphenyl) pyridazin-3-yl ] octahydropyrido [1, 2-a ] pyrazine;

N- {3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } acetamide; n- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } -3, 3-dimethylbutanamide; n- {3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } -3, 3-dimethylbutanamide; n- {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzyl } isobutyramide; n- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } -2, 2-dimethylpropanamide; n- {3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } -2, 2-dimethyl-propionamide; 4- [2- (4-cyclopropylpiperazin-1-yl) pyrimidin-5-yl ] benzylamine; n- {4- [2- (4-cyclopropylpiperazin-1-yl) pyrimidin-5-yl ] benzyl } acetamide; n- {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] acetamide; n- [4- (4-cyclopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] acetamide; 2- {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenoxy } -N, N-dimethylacetamide; cyclohexanecarboxylic acid {4- [6- (4-cyclopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } amide and N- {4- [ 4-isopropyl-6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } acetamide and salts thereof such as hydrochloride, dihydrochloride, trihydrochloride, trifluoroacetate and disulfonate.

Further embodiments may be produced by combining any of the above embodiments, and the invention relates to all possible combinations of the above embodiments and all possible combinations with the following claims.

The definition of the compounds of the formula I herein includes some limitations, which are expressed as limitations a) to g). These limitations are defined in the following claim 1.

In one embodiment of the present invention, the restriction condition a) is expressed as follows: "a) if R¹Is any one of the groups of formulae II to VII; w is-N ═ N; x, Y and Z are each of the formula-C (R)²) A moiety; wherein R is²As defined above; then a cannot be an optionally substituted imidazolyl ".

In a further embodiment of the present invention, the restriction conditions a) are expressed as follows: "a) if R¹Is any one of the groups of formulae II to VII; w is-N ═ N; x, Y and Z are each of the formula-C (R)²)＝A moiety of (a); wherein R is²As defined above; then a cannot be optionally substituted heteroaryl.

In one embodiment of the invention, the restriction b) is expressed as follows: "b) if R¹Is a group of formula VI; x is-C (R)²)＝；R¹¹Is C_1-8Alkyl radical, C_2-8-alkenyl, C_2-8-alkynyl, C_3-8-cycloalkyl, C _3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-3-alkyl or C_3-8-cycloalkenyl-C_1-3-an alkyl group; and W, Y, Z are each of the formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then A cannot be unsubstituted aryl or substituted heteroaryl, and, if A is substituted, then R is¹²Not being halogen, hydroxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula-V- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein V is a bond, R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group ".

In one embodiment of the present invention, the restriction condition c) is expressed as follows: "c) if R¹Is a group of formula VII; x is of the formula-C (R)²) A moiety; and W, Y, Z are each of the formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then R¹²Not being halogen, hydroxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula-V- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein V is a bond, R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group ".

In one embodiment of the present invention, the restriction d) is expressed as follows: "d) if R ¹Is a group of formula VI; r¹¹Is C_1-8-an alkyl group; y and Z are each-N ═ N; x is of the formula-C (R)²) And W is a moiety of formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then R¹²Not being halogen, hydroxy, halo-C_1-6-alkoxy, halo-C_1-6-alkoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula-V- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein V is a bond, R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group ".

In one embodiment of the present invention, the restriction condition e) is expressed as follows: "e) if R¹Is a group of formula VII; y and Z are each-N ═ N; x is of the formula-C (R)²) A moiety; and W is of the formula-C (R)²) A moiety or-N ═ or; wherein R is²As defined above; then R¹²Not being halogen, hydroxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula-V- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein V is a bond, R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group ".

In one embodiment of the invention, the restriction condition f) is expressed as follows: "f) if R¹Is of formula VI, q is 1, X and W are each of the formula-C (R) ²) Wherein R is²As defined above, Y and Z are each-N ═ R¹¹Is C_1-8-alkyl, and A is phenyl, then R¹²Not being halogen, hydroxy, halo-C_1-6-alkoxy, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6-alkylthio radical, C_1-6-alkylsulfinyl, C_1-6Alkylsulfonyl, cyano, aryl, heteroaryl, C_3-8-cycloalkyl or of formula-V- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein V is a bond, R and s are each 0 (zero), and R¹³And R¹⁴Each being hydrogen or C_1-6-an alkyl group ".

In one embodiment of the invention, the restriction condition g) is expressed as follows: "g) if X and Z are each-C (R)²) Is as follows; and one or both of W and Y is-N ═ N; then R¹Not a group of formula II ".

In one embodiment of the invention, if the ring containing W, X, Y and Z is a pyridazine ring, then R is¹Different from possibility ii), formula VII.

In one embodiment of the invention, if the ring containing W, X, Y and Z is a pyridazine ring, then R is¹Different from the likelihood i).

In one embodiment of the invention, if the ring containing W, X, Y and Z is a pyrimidine ring, then R is¹Different from the likelihood i).

In one embodiment of the invention, R¹Different from the possibility i), i.e. R¹Is possibility ii).

In one embodiment of the invention, R¹¹Unlike hydrogen.

In one embodiment of the invention, R¹¹Different from methyl.

In one embodiment of the invention, R¹¹Is different from C_1-8-an alkyl group.

In one embodiment of the invention, R²Unlike cyano groups.

In one embodiment of the invention, at least one of W, X, Y and ZAt least one is of the formula-C (R)²) Wherein R is²As defined herein.

In one embodiment of the invention, if the ring containing W, X, Y and Z is a pyridazine ring, then R is¹Is not a group of formula II.

In one embodiment of the invention, if W and Y are each-N ═ N; and X and Z are each-C (R)²) Wherein R is²As defined herein, then R¹Different from possibility II), formulae II and III.

In one embodiment of the invention, if W and Y are each-N ═ N; and X and Z are each-C (R)²) Wherein R is²As defined herein, then R¹Different from possibility II), formula II, wherein m is 2, n is 1 or 2, and Q is-O-.

In one embodiment of the invention, if W and Y are each-N ═ N; and X and Z are each-C (R)²) Wherein R is²As defined herein, then R¹Different from possibility ii), formula III, wherein p is 1, m is 2, o is 0 (zero), and-NR ⁷R⁸Is a heterocyclic group.

In one embodiment of the invention, if W and Y are each-N ═ N; and X and Z are each-C (R)²) Wherein R is²As defined herein, and if a is aryl or heteroaryl optionally substituted with: halogen, hydroxy, cyano, C_1-6Alkyl radical, C_3-8-cycloalkyl, halo-C_1-6Alkyl radical, C_1-6-alkoxy, halo-C_1-6-alkoxy or-V- (CH)₂)_s-(C＝O)_r-NR¹³R¹⁴Wherein V, s, R¹³And R¹⁴As defined herein, then R¹Different from possibility II), formulae II and III.

The compounds of the present invention interact with the histamine H3 receptor and are therefore particularly useful in the treatment of various diseases or conditions in which histamine H3 interaction is beneficial.

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

In a further aspect, the present invention provides the use of a compound of formula I as defined hereinbefore in the manufacture of a pharmaceutical composition for the treatment of a disease or condition in which inhibition of the H3 histamine receptor has a beneficial effect.

In another aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.

In another aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for weight loss.

In another aspect, the present invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the treatment of overweight or obesity.

In another aspect, there is provided, in part, the use of a compound of formula I for the manufacture of a medicament for suppressing appetite or for satiety induction.

In a further aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the prevention and/or treatment of conditions and diseases associated with overweight or obesity, such as dyslipidemia, coronary heart disease, cystic disease, osteoarthritis and various types of cancer, such as endometrial, breast, prostate and colon cancer.

In another aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia or binge eating.

In another aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of IGT (impaired glucose tolerance).

In another aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.

In another aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for delaying or preventing the progression of IGT to type 2 diabetes.

In another aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for delaying or preventing the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.

In another aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of diseases and conditions in which stimulation of the H3 histamine receptor has a beneficial effect.

In another aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition having histamine H3 agonistic activity.

In another aspect, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis, ulcer or anorexia.

In another aspect, the present invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the treatment of Alzheimer's disease, narcolepsy, attention deficit or reduced insomnia (reduced wakefulness) or for the modulation of sleep.

In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the treatment of airway disorders such as asthma, for the modulation of gastric acid secretion or for the treatment of diarrhoea.

In another aspect, the present invention provides a method of treating a condition or disease associated with the histamine H3 receptor, which method comprises administering to a subject in need thereof an effective amount of a compound of formula I as defined above, or a pharmaceutical composition comprising said compound.

In another aspect, the present invention provides a method of treatment as hereinbefore described wherein the effective amount of a compound of general formula I as hereinbefore defined is from about 0.05mg to about 2000mg, preferably from about 0.1mg to about 1000mg and more preferably from about 0.5mg to about 500mg per day.

In one aspect, the present invention relates to compounds that exhibit histamine H3 receptor antagonistic or inverse agonistic activity, and thus may be used to treat various diseases or conditions in which histamine H3 receptor blockade is beneficial.

In another aspect, the present invention provides a method of reducing body weight, which method comprises administering to a subject in need thereof an effective amount of a compound of formula I as hereinbefore defined.

In another aspect, the present invention provides a method of treatment of overweight or obesity, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.

In another aspect, the present invention provides a method of suppressing appetite or satiety induction comprising administering to a subject in need thereof an effective amount of a compound of formula I.

In another aspect, the present invention provides a method for the prevention and/or treatment of conditions or diseases associated with overweight or obesity, such as dyslipidemia, coronary heart disease, cystic disease, osteoarthritis and various cancers, such as endometrial, breast, prostate or colon cancer, comprising administering to a subject in need thereof an effective amount of a compound of formula I.

In another aspect, the present invention provides a method of preventing and/or treating eating disorders such as bulimia and binge drinking, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I.

In another aspect, the present invention provides a method of treating IGT (impaired glucose tolerance) comprising administering to a subject in need thereof an effective amount of a compound of formula I.

In another aspect, the present invention provides a method of treating type 2 diabetes, comprising administering to a subject in need thereof an effective amount of a compound of formula I.

In another aspect, the present invention provides a method of delaying or preventing the progression of IGT to type 2 diabetes, which method comprises administering to a subject in need thereof an effective amount of a compound of formula I.

In another aspect, the present invention provides a method of delaying or preventing the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes comprising administering to a subject in need thereof an effective amount of a compound of formula I.

In another aspect, the present invention relates to compounds that exhibit histamine H3 receptor agonistic activity and therefore may be used to treat conditions and disorders in which histamine H3 receptor activation is beneficial.

The compounds of the invention may be useful in the treatment of airway disorders (e.g. asthma), as antidiarrheal agents and for the modulation of gastric acid secretion.

Furthermore, the compounds of the present invention may be useful in the treatment and regulation of sleep and insomnia and in the treatment of narcolepsy and attention deficit disorders.

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

The compounds of the present invention may also be useful in the treatment of conditions associated with epilepsy. In addition, the compounds of the present invention may be used for the treatment of motion sickness and vertigo. Furthermore, the compounds of the present invention may be useful as modulators of hypothalamic-pituitary secretion, as antidepressants, as modulators of cerebral circulation and for 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 invention may also be useful in the treatment of migraine [ see, for example, McLeod et al, the journal of Pharmacology and Experimental Therapeutics287(1998), 43-50] and in the treatment of myocardial infarction [ see, for example, Mackins et al, Experimental on investigational Drugs9(2000), 2537-2542 ].

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

In another aspect of the invention, one or more compounds of the invention are administered in combination with one or more additional active agents in any suitable ratio. The additional active substance may for example be selected from anti-obesity agents, anti-diabetic agents, anti-dyslipidemic agents, anti-hypertensive agents, agents for the treatment of complications arising from or associated with diabetes, and agents for the treatment of complications and conditions arising from or associated with obesity.

Thus, in another aspect of the invention, one or more compounds of the present invention may be administered in combination with one or more anti-obesity or appetite regulating agents. Such a medicament may for example be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocontin 4) agonists, MC3 (melanocontin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, beta 3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MCH MSH (melanocyte-stimulating hormone) agonists, melanocyte-c aggregating hormone antagonists, CCK (cholecystokinin) agonists, serotonin up-regulation inhibitors such as fluralin, sardine or norcitalopram, serotonin and epinephrine up-regulation inhibitors, mixed serotonin and epinephrine up-regulation compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormones, growth factors such as prolactin or placental lactogen, growth factor hormone releasing compounds, TRH (thyrotropin releasing hormone) agonists, UCP2 or 3 (conjugated protein 2 or 3) modulators, leptin agonists, DA agonists (bromoergoline, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator activated receptor) modulators, RXR (retinoid A X receptor) modulators, TR β agonists, AGRP (Agouti-related protein) inhibitors, opioid antagonists (e.g., naltrexone), exendin-4, GLP-1, and ciliary neurotrophic factors.

In one embodiment of the invention, the anti-obesity agent administered in combination with one or more compounds of the present invention is leptin.

In another embodiment, the anti-obesity drug is dextroamphetamine and amphetamine.

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

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

In another embodiment, the anti-obesity drug is orlistat.

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

In yet another embodiment, the anti-obesity drug is trimetazidine, bupropion, fluoxetine, bupropion, topiramate, or ecopipam.

In yet another aspect of the invention, one or more compounds of the present invention may be administered in combination with one or more antidiabetic agents. Relevant anti-diabetic drugs include insulin, insulin analogues and derivatives, such as those disclosed in the following documents: EP0792290(Novo Nordisk A/S), e.g. N^εB29Tetradecanoyl des (B30) human insulin, EP0214826 and EP0705275(Novo Nordisk A/S), e.g. Asp ^B28Human insulin, US 5,504,188(Eli Lilly), e.g. Lys^R28Pro^B29Human insulin, EP0368187(Aventis), for exampleGLP-1 derivatives, which are incorporated herein by reference in their entirety, e.g. WO98/0887](Novo Nordisk A/S), incorporated herein by reference, and an orally active hypoglycemic agent.

Orally active hypoglycemic agents preferably comprise imidazolines, sulfonylureas, biguanides, meglitinides, oxazolididinediones, thiazolidinediones, insulin sensitizers, alpha-glucosidase inhibitors, agents acting on beta-cell ATP-dependent potassium channels, e.g. potassium channel openers, e.g. those disclosed in WO97/26265, WO99/03861 and WO00/37474(NoVo Nordisk a/S), which are incorporated herein by reference, or miglitide, or potassium channel blockers, e.g. BTS-67582, nateglinide, glucagon antagonists, e.g. those disclosed in WO99/01423and WO00/39088(NoVo disk a/S and doggouuron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1 agonists, e.g. those disclosed in WO00/42026(NoVo disk a/S Pharmaceuticals and S agents, inc.), which is incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, and inhibitors of liver enzymes involved in the stimulation of neogenesis of glucose and/or breakdown of hepatic glucose, glucose upregulation inhibitors, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds that modulate lipid metabolism such as hypolipidemic agents, compounds that reduce food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid A X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.

In one embodiment of the invention, one or more compounds of the invention may be combined with insulin or an insulin analogue or derivative, such as N^εB29-tetradecanoyl des (B30) human insulin, Asp^B28Human insulin, Lys^B28Pro^B29Human insulin,Or a mixed preparation combination containing one or more of the aboveThe drugs are administered together.

In another embodiment of the invention, one or more compounds of the invention may be combined with a sulfonylurea, for example tolbutamide, chlorparamide, tolazamide, glatirucamide, glipizide, glimepiride, gliclazide (gliazide) or glyburide.

In another embodiment of the invention, one or more compounds of the invention may be administered in combination with a biguanide, for example metformin.

In yet another embodiment of the invention, one or more compounds of the invention may be administered in combination with a meglitinide, e.g., repaglinide or nateglinide.

In yet another embodiment of the invention, one or more compounds of the invention may be administered in combination with a thiazolidinedione insulin sensitiser, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T174 or the compounds disclosed in WO97/41097, WO97/41119, WO97/41120, WO00/41121 and WO98/45292(Dr. Reddy's Research Foundation), all of which are incorporated herein by reference.

In yet another embodiment of the present invention, one or more compounds of the present invention may be combined with an insulin sensitizer such as GI

262570，YM-440，MCC-555，JTT-501，AR-H039242，KRP-297，GW-409544，CRE-16336，

AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516, or in

WO99/19313, WO00/50414, WO00/63191, WO00/63192 or WO00/63193(Dr. Reddy's)

Research Foundation) or in WO00/23425, WO00/23415, WO00/23451, WO00/23445, WO

00/23417, WO00/23416, WO00/63153, WO00/63196, WO00/63209, WO00/63190 or

The compounds disclosed in W000/63189(Novo Nordisk A/S), all of which are incorporated herein by reference, are administered in combination.

In yet another embodiment of the invention, one or more compounds of the invention may be administered in combination with an α -glucosidase inhibitor, e.g., voglibose, emiglitate, miglitol or acarbose.

In another embodiment of the invention, one or more compounds of the invention may be administered in combination with a drug that acts on the beta-cell ATP-dependent potassium channel, such as tolbutamide, glyburide, glipizide, gliclazide, BTS-67582, or repaglinide.

In yet another embodiment of the present invention, one or more compounds of the present invention may be administered in combination with nateglinide.

In yet another embodiment, one or more compounds of the present invention may be administered in combination with an antihyperlipidemic or antilipidemic agent such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or sodium thyroxine.

In yet another embodiment of the invention, one or more compounds of the invention may be administered in combination with an antilipidemic agent such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dexthyroxine sodium.

In another embodiment of the invention, one or more compounds of the invention may be administered in combination with one or more of the above compounds, for example with metformin and a sulfonyl urea such as glibenclamide; sulfonyl ureas and acarbose; nateglinide and a biguanide; acarbose and biguanide; sulfonyl ureas and troglitazones; insulin and sulfonylurea; insulin and metformin; insulin, metformin and sulfonylurea; insulin and troglitazone; insulin and lovastatin, etc.

In addition, one or more 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, guanazolazine and terazosin. Reference may be further made to Remington: the science and Practice of Pharmacy, 19 ^th Edition，Gennaro，Ed.，MackPublishingCo.，Easton，PA，1995。

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

The compounds of the invention may be chiral, and any enantiomer (isolated, pure or partially purified) or racemic compound thereof is intended to be included within the scope of the invention.

Furthermore, diastereomers may be formed if a double bond, or a fully or partially saturated ring system, or more than one asymmetric center, or a bond of restricted rotation, is present in the molecule. Any diastereomer, isolated, pure or partially purified diastereomer or mixture thereof is intended to be included within the scope of the present invention.

Furthermore, certain compounds of the present invention may exist in different tautomeric forms, and any tautomeric form which a compound of the present invention is capable of forming is intended to be included within the scope of the present invention.

The invention also includes pharmaceutically acceptable salts of the compounds of the invention. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, dimethylenesalicylic, ethanedisulfonic, gluconic, furoic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in j.pharm.sci.1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, calcium, magnesium salts, and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.

Hydrates which the compounds of the invention are able to form are also intended as pharmaceutically acceptable acid addition salts.

Acid addition salts may be obtained as the direct product of the synthesis of the compounds. Alternatively, the free acid may be dissolved in a suitable solvent containing the appropriate acid and the salt separated by evaporation of the solvent or the salt and solvent separated.

The compounds of the present invention may be solvated with standard low molecular weight solvents using methods well known to those skilled in the art. Such solvates should also be understood to be within the scope of the present invention.

The invention also includes prodrugs of the compounds of the invention which undergo chemical conversion to the active species by metabolic action upon administration. In general, such prodrugs are functional derivatives of the compounds of the present invention that are readily converted in vivo to the desired compounds of formula I. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of produgs", ed.h. bundgaard, Elsevier, 1985.

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

Pharmaceutical composition

The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients in single or multiple doses. The pharmaceutical compositions of the present invention may be formulated with pharmaceutically acceptable carriers or diluents and any other known adjuvants and excipients according to conventional techniques, such as those disclosed in Remington: the Science and Practice of Pharmacy, 19 ^thEdition, Gennaro, ed., Mack publishing co., Easton, PA, 1995. The pharmaceutical compositions may be specially formulated for administration by any suitable route, for example oral, rectal, nasal, pulmonary, topical (including oral and sublingual), transdermal, intracisternal, intraperitoneal, intravaginal or parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) administration, the oral route being preferred. It will be appreciated that the preferred route will depend upon the general condition and age of the individual being treated, the nature of the disease being treated and the active ingredient selected.

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

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

Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injection solutions, dispersions, suspensions and emulsions, as well as sterile powders for constitution with a sterile injectable solution or dispersion before use. Depot (Depot) injectable formulations are also understood to be within the scope of the present invention.

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

Typical oral dosages will be from about 0.001 to about l00mg/kg body weight/day, preferably from about 0.01 to about 50mg/kg body weight/day, and more preferably from about 0.05 to about 10mg/kg body weight/day, in one or more doses, e.g., 1 to 3 doses. The exact dosage will depend upon the frequency and manner of administration, the sex, age, weight and general condition of the individual being treated, the nature and severity of the condition being treated and any concomitant diseases being treated, as well as other factors which will be apparent to those skilled in the art.

The formulations may be conveniently presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration once or more times daily, e.g., 1 to 3 times daily, may contain from about 0.05 to about 1000mg, preferably from about 0.1 to about 500mg, and more preferably from about 0.5mg to about 200mg of a compound of the present invention (or a salt or other derivative thereof as defined above).

For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typical dosages are about half of those for oral administration.

The compounds of the invention are generally employed as the free substance or as a pharmaceutically acceptable salt thereof. An example is an acid addition salt of a compound having a free base functionality. If the compound of formula I contains a free base functionality, the salt is prepared in a conventional manner by treating a solution or suspension of the compound of formula I in its free base form with a stoichiometric equivalent (acid-base equivalent) of a pharmaceutically acceptable acid. Representative examples of inorganic and organic acids are described above. Pharmaceutically acceptable salts of the compounds of the invention having a hydroxyl group include those in which the anion of the compound is combined with a suitable cation, such as sodium or ammonium.

For parenteral administration, solutions of the novel compounds of formula I in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be used. The aqueous solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed is readily available by standard techniques known to those skilled in the art.

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

Formulations of the invention suitable for oral administration may be presented as discrete units such as capsules or tablets each containing a predetermined amount of the active ingredient and which may contain suitable excipients. These formulations may be in powder or granular form, as solutions or suspensions in aqueous or non-aqueous liquids, or as liquid emulsions of oil-in-water or water-in-oil.

If a solid carrier is used for oral administration, the preparation may be tableted, filled into hard gel capsules as a powder or pellets, or may be in the form of a candy or lozenge. The amount of solid carrier can vary widely, but is generally from about 25mg to about 1 g. If a liquid formulation is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable solution, such as an aqueous or non-aqueous liquid suspension or solution.

A typical tablet, which may be prepared by conventional tabletting techniques, may contain in the core 5.0mg of a compound of the invention, 67.8mg lactose Ph.Eur., 31.4mg cellulose, microcrystalline cellulose (Avicel), 1.0mgIRP88 (i.e., Polacrillin potassium NF, tablet disintegrant, Rohm and Haas) and magnesii stearas ph. eur. q.s., and a coating of about 9mg hydroxypropyl methylcellulose and about 0.9mg Mywacett9-40T (which is an acylated monoglyceride that acts as a plasticizer for film coatings).

If desired, the pharmaceutical compositions of the present invention may comprise a compound of formula I and one or more additional pharmaceutically active substances, for example selected from those described hereinbefore.

In short, the compounds of the present invention can be prepared by methods known per se or analogously to known methods.

Test of

The ability of the compounds of the present invention to interact with the histamine H3 receptor can be determined by the following in vitro binding assay.

Binding assays

The human H3 receptor was cloned by PCR and subcloned into the pcDNA3 expression vector. Cells stably expressing the H3 receptor were generated by transfecting the H3-expression vector into HEK293 cells and selecting the H3 clone using G418. Human H3-HEK293 clone was cloned in DMEM (GIBCO-BRL) at 37 ℃ and 5% CO₂Culturing in DMEM containing glutamax, 10% fetal bovine serum, 1% penicillin/streptavidin and 1mg/ml G418, the confluent cells were washed with phosphate buffered saline (hereinafter referred to as PBS) and cultured with Versene (protease, GIBCO-BRL) for about 5 minutes. The cells were washed with PBS and DMEM and the cell suspension was collected in tubes and centrifuged at 1500rpm for 5-10 minutes in Heraeus Sepatech Megafuge1.0. Centrifugal sinking of the handle The pellet was resuspended in 10-20 times Hepes buffer (20mM Hepes, 5mM MgCl)₂Ph7.1(KOH)), and homogenized using an Ultra-Turrax homogenizer for 10-20 seconds. The homogenate was centrifuged at 23,000g for 30 minutes. The centrifuged pellet was resuspended in 5-10ml hepes buffer, homogenized using an Ultra-Turrax for 5-10 seconds, and centrifuged at 23,000g for 10 minutes. After this centrifugation step, the cell membrane centrifugation pellet is resuspended in 2-4ml Hepes buffer, homogenized with a syringe or Teflon homogenizer, and the protein concentration is determined. The cell membranes were diluted in Hepes buffer to a protein concentration of 1-5mg/ml, aliquoted, and stored at-80 ℃ until use.

Mixing an aliquot of the cell membrane suspension with 30pM¹²⁵I]Iodoproxyfan, a compound known to have high affinity for the H3 receptor, was incubated with varying concentrations of the test compound at 25 ℃ for 60 minutes. The culture was stopped by dilution with ice-cold medium and then filtered rapidly through Whatman GF/B filters pretreated for 1 hour with 0.5% polyethyleneimine. Radioactivity retained on the filters was counted using a Cobra II auto gamma counter. The radioactivity of the filter is indirectly proportional to the binding affinity of the test compound. The results were analyzed by nonlinear regression analysis.

When tested, the compounds of formula (I) of the present invention typically exhibit high binding affinity to the histamine H3 receptor.

Preferably, the IC of the compounds of the invention is determined by one or more assays₅₀Values of less than 10. mu.M, more preferably less than 1. mu.M, even more preferably less than 500nM, for example less than 100 nM.

Functional analysis I

The ability of the compounds of the invention to interact with the histamine H3 receptor as agonists, inverse agonists and/or antagonists was determined in an in vitro functional assay using cell membranes from HEK293 cells expressing the human H3 receptor.

The human H3 receptor was cloned by PCR and subcloned into the pcDNA3 expression vector. By transfecting H3-expression vector into HEK293 cellsAnd H3 clone was selected using G418 to generate cells stably expressing the H3 receptor. Human H3-HEK293 clone was cloned in DMEM at 37 ℃ and 5% CO₂The culture was continued in DMEM containing glutamax, 10% fetal bovine serum, 1% penicillin/streptavidin and 1mg/ml G418.

H3 receptor expressing cells were washed once with PBS and harvested using versene (GIBCO-BRL). PBS was added and the cells were centrifuged at 188g for 5 minutes. Cell centrifugation pellet was resuspended in stimulation buffer to a concentration of 1X 10 ⁶Individual cells/ml. Using FlashcAMP assay(NEN^TMLife Science Products) determined cAMP accumulation. The analysis is typically performed as described by the manufacturer. Briefly, 50 μ l of cell suspension was added to each well of a Flashplate also containing 25 μ l of 40 μ M isoproterenol to stimulate cAMP production, and 25 μ l of test compound (agonist or inverse agonist alone or agonist and antagonist in combination). The assay can be run in "agonist mode," which refers to adding increasing concentrations of the test compound to the cells and measuring cAMP. If cAMP is increased, it is an inverse agonist; it is a neutral antagonist if cAMP is unchanged and an agonist if cAMP is reduced. The assay can be run in "antagonist mode," which refers to the addition of increasing concentrations of the test compound with increasing concentrations of a known H3 agonist (e.g., RAMHA). If the compound is an antagonist, increasing concentrations of the compound will cause a right shift in the H3-agonist dose-response curve. The final volume in each well was 100. mu.l. Test compounds were dissolved in DMSO and diluted in water. The mixture was shaken for 5 minutes and allowed to stand at room temperature for 25 minutes. The reaction was stopped with 100. mu.l "Detection Mix" in each well. The plates were then sealed with plastic, shaken for 30 minutes, allowed to stand overnight, and finally radioactivity was counted in a Cobra II automated gamma Top-counter. EC was calculated by nonlinear regression analysis of dose-response curves (minimum 6 points) using GraphPad Prism ₅₀The value is obtained. Calculation by Schild Curve analysisKb value.

Preferably, the IC of the antagonists and agonists of the invention₅₀/EC₅₀The value is less than 10. mu.M. More preferably less than 1 μ M, even more preferably less than 500nM, for example less than 100 nM.

Functional assay II

By the term³⁵S]Functional assays for GTP γ S assays the ability of the compounds of the present invention to interact with the histamine H3 receptor as agonists, inverse agonists, and/or antagonists is determined. This assay measures the activation of the G protein by catalyzing the exchange of guanosine 5 '-diphosphate (hereinafter GDP) with guanosine 5' -triphosphate (hereinafter GTP) on the alpha-subunit. Dissociation of GTP-bound G protein into two subunits, G_GTPAnd G, which in turn regulates intracellular enzymes and ion channels. GTP is rapidly hydrolyzed by G-subunits (GTPases), and the G protein is inactivated and ready to enter a new GTP exchange cycle. To investigate the function of ligand-induced activation of a G protein-coupled receptor (GPCR) by increasing guanine nucleotide exchange on the G protein, assay³⁵S]Guanosine-5' -O- (3-thio) triphosphate (hereinafter referred to as "2³⁵S]GTPS), a non-hydrolyzable analog of GTP. The method may be monitored as follows: contacting a cell membrane comprising a G protein-coupled receptor H3 with GDP and ³⁵S]GTP γ S was cultured together. The cell membrane was obtained from CHO cells stably expressing the human H3 receptor. Cells were washed twice in PBS, harvested with PBS +1mM EDTA, pH7.4, and centrifuged at 1000rpm for 5 minutes. The cells were pelleted by centrifugation in 10ml ice-cold Hepes buffer (20mM Hepes, 10mM EDTA, pH7.4(NaOH)), homogenized using an Ultra-Turrax for 30 seconds, and centrifuged at 20,000rpm for 15 minutes. After the centrifugation step, the cell membrane pellet was resuspended in 10ml ice-cold Hepes buffer (20mM Hepes, 0.1mM EDTA, pH7.4(NaOH)) and homogenized as described above. This procedure was repeated 2 times except for the final homogenization step, the protein concentration was determined, and the cell membranes were diluted to a protein concentration of 2mg/ml, divided into aliquots and stored at-80 ℃ until use.

To study trans-excitationPresence and efficacy of agonist/antagonist H3-receptor agonist ligand R-alpha-methyl histamine (hereinafter RAMHA) was added. The ability of the test compound to resist the action of RAMHA is determined. In studying the effect of agonists, RAMHA was not added to the assay medium. Test compounds were assayed in assay buffer (20mM HEPES, 120mM NaCl, 10mM MgCl)₂pH7.4(NaOH)) at different concentrations, and then 10 was added ^-8nM RAMHA (Trans agonist/antagonist is measured only in this case), 3. mu.M GDP, 2.5. mu.g cell membrane, 0.5mg SPA bead and 0.1nM³⁵S]GTP γ S, and incubated for 2 hours by gentle shaking at room temperature. The plates were centrifuged at 1500rpm for 10 minutes and radioactivity was measured using a Top-counter. Analyzing the results by non-linear regression, and determining IC₅₀The value is obtained.

Stimulation of RAMHA and other H3 agonists³⁵S]Binding of GTP γ S to cell membranes expressing the H3 receptor. Determination of the amount of test Compound inhibited by 10 in an antagonist/Trans-agonist assay^-8Increased M RAMHA [ 2 ]³⁵S]The ability of GTP γ S to bind, as a result, appears as a decrease in the radioactive signal. For antagonists, IC determined₅₀The value is that the compounds of the invention will be 10^-8The effect of MRAMHA was 50% inhibitory. In agonist assays, the ability to measure an increased amount of test compound is manifested as an increase in radioactive signal. For agonists, EC determined₅₀The value is that the compound will pass 10^-5The ability of M RAMHA to obtain a maximum signal increase of 50%.

Preferably, the IC of the antagonists and agonists of the invention₅₀/EC₅₀Values of less than 10. mu.M, more preferably less than 1. mu.M, even more preferably less than 500nM, for example less than 100 nM.

Test for food intake inhibition

In this type of test, rats are allowed to acclimate to the experimental environment for 1-2 weeks prior to the start of the experiment. Food intake is limited to 5-7 hours per day, about 7-10 days before food intake is recorded. Water remains freely available. On the day of testing, each group of animals (n-10) received a single administration of histamine H3 receptor antagonist just prior to food administration. Then, 3 hours of food consumption was recorded. Preferred compounds are those that result in a statistically significant reduction in the 3 hour cumulative food intake. More preferred compounds are those that reduce the 3 hour cumulative food intake by 10-20%, and most preferred compounds are those that reduce the 3 hour cumulative food intake by more than 20% without the animal sedating.

Testing weight loss

This test is performed in rats that have become obese due to excessive intake of dietary energy, i.e. sustained positive energy balance. Rats were administered the test compound for 7 days. Preferred compounds are those that produce a statistically significant reduction in body weight compared to control rats administered the vehicle. More preferred compounds are those that reduce body weight by at least 4% compared to vehicle control groups, and most preferred compounds are those that reduce body weight by more than 8% compared to vehicle control rats.

General discussion

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).

All headings and sub-headings are used herein for convenience only and should not be constructed as limiting the invention in any way.

The use of any and all example exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

The citation and citation of patent documents herein is for convenience only and does not reflect the validity, patentability and/or enforceability of such patent documents. The references mentioned herein are not an admission that they constitute prior art.

In this context, the term "comprising" should be interpreted in a broad sense and is intended to mean "including", "containing" or "containing" (EPO guide C4.13).

This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

General Experimental methods

NMR spectra were recorded at 300 and 400MHz on a Bruker DRX300, Avance300, DRX400 or AV400 apparatus equipped with a 5mm Selectivity-inversion (SEI, CsI,¹h and¹³C) 5mm broadband inverse (BBI,¹H. Broadband) and 5mm quadrupole nuclear magnetic (QNP,¹H，¹³C) a probe. The shift (δ) is given in parts per million (ppm) relative to tetramethylsilane low field as an internal standard.

HPLC method A. RP-analytes analysis was performed on a Merck-Hitachi series 7000 system (Merck-Hitachi pump L-7100 and Merck-Hitachi autosampler L-7200 or Rheodyne sample injector) using a Hibar^TM RT250-4，Lichrosorb^TMRP-18, 5.0 μm, 4.0X250 mm; gradient elution, 20% -80% mixture of solvent B (0.1% TFA in acetonitrile) in solvent A (0.1% TFA in water) over 30min at 1.0ml/min, detection at 210nm, 30 ℃.

HPLC method B.RP-purification was performed on a Gilson System (3Gilson306 pump, Gilson170DAD detector and Gilson215 liquid processor) using Waters PrepRP₁₈(10 μm, 30mm x150mm), gradient elution, 5% -95% solvent B (acetonitrile) in solvent a (0.05% TFA in water) mixture, over 15min, 40mL/min, detection at 210nm, room temperature. The pooled fractions were evaporated to dryness in vacuo or evaporated in vacuo until acetonitrile was removed, then Freezing, and drying the frozen product.

HPLC method C.RP-analysis was performed on Shimadzu LC-20 using YMC-ODS, 5.0 μm, 4.6X50 mm; gradient elution, mixture of 0% -30% solvent B (0.1% TFA in acetonitrile) in solvent A (0.1% TFA in water) over 6min, then 2min, 2.5mL/min, detection at 220nm, 30 ℃.

HPLC method D.RP-analysis was performed on Shimadzu LC-20 using YMC-ODS, 5.0 μm, 4.6X50 mm; gradient elution, mixture of 0% -60% solvent B (0.1% TFA in acetonitrile) in solvent A (0.1% TFA in water) over 8min, then 2min, 2.5mL/min, detection at 220nm, 30 ℃.

HPLC method E.RP-analysis was performed on Shimadzu using YMC-ODS, 5.0 μm, 4.6X50 mm; gradient elution, 10% -80% mixture of solvent B (0.1% TFA in acetonitrile) in solvent A (0.1% TFA in water) over 6min, then 2min, 2.5mL/min, detection at 220nm, 30 ℃.

HPLC method f.rp-purification was performed on a Gilson Nebula Series system using Luna, 5 μm, 21.2mm x250mm, gradient elution, 5% -30% solvent B (0.1% TFA in acetonitrile) in solvent a (0.1% TFA in water) mixture, 15min, 80mL/min, detection at 220nm, temperature 25 ℃, injection volume 30mL. pooled fractions were evaporated to dryness in vacuo or evaporated in vacuo until acetonitrile was removed, then frozen and the frozen was dried.

HPLC-MS method g.: waters Xterra MSC-18X3mm id buffer: linear gradient 5% -95%, 4min, acetonitrile, 0.01% TFA, flow rate 1.0ml/min detection at 210nm (similar output from diode array detector), MS-detection ionization mode API-ES, scan 100-1000amu steps 0.1 amu.

Microwave Synthesis when synthesized in a microwave oven, Expfrom in the Single mode Emrys OptimizerThe reaction is heated by microwave radiation in a sealed microwave container.

The following examples and general methods described herein refer to intermediate compounds and final products of formula I identified in the specification and synthetic schemes. The preparation of the compounds of the general formula I according to the invention is described in detail using the following examples. The reaction may sometimes not be applicable to every compound included within the scope of the present disclosure. The compounds in which this occurs can be readily recognized by those skilled in the art. In these cases, the reaction can be successfully carried out by conventional modifications known to those skilled in the art, i.e., by appropriate protection of interfering groups, by changing other conventional reagents, or by making routine adjustments to the reaction conditions. Alternatively, other reactions disclosed herein or other conventional reactions will be suitable for preparing the corresponding compounds of the invention. In all preparative methods, all starting materials are known or can be prepared by one skilled in the art in analogy to the preparation of similarly known compounds or by the general methods a to N described herein. The following examples are given for the purpose of illustration and are not intended to be limiting.

General method A

Wherein Y and/or W is-N ═ and A, X, Z and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula Ia, may be prepared as follows:

wherein R may be¹An amine of formula a-1 as defined herein is reacted with a halo-substituted heteroaryl compound of formula a-2 wherein A, X, Y, Z and W are each as defined herein and Hal represents chloro or bromo to produce a compound of formula Ia. The reaction may be carried out in a suitable solvent such as dimethylsulfoxide, at a temperature up to reflux. Formula (II)The A-2 compounds can be prepared according to known methods, for example as described in WO03/066604A2, Tetrahedron2000, 56, 9655-9662, and Tetrahedron Lett.2001, 42, 2779-2781.

General method B

Wherein a is aryl or heteroaryl optionally substituted with R- (C ═ O) NHCH2-, and X, Y, Z, W and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula Ib, may be prepared as follows:

x, Y, Z, W and R therein¹An amine of formula B-2, respectively as defined herein, and a represents aryl or heteroaryl, is acylated with an activated carboxylic acid derivative to produce a compound of formula Ib. Such activated carboxylic acid derivatives may be acid chlorides or anhydrides of formula B-4 or B-3, respectively. The reaction may be carried out in a suitable solvent such as dichloromethane or acetic acid at temperatures up to reflux. The carboxylic acid of formula B-5 can also be reacted with an amine of formula B-2 to form an amide of formula Ib. The reaction can be carried out by activating the carboxylic acid with, for example, HOBt/EDAC in a suitable solvent such as THF at a temperature up to reflux. The compound of formula B-2 can be prepared by reacting X, Y, Z, W and R therein ¹Respectively as defined herein, and A represents aryl or heteroaryl, respectively, by hydrogenation of a nitrile of formula B-1. The reaction can be carried out in a suitable solvent such as THF, at temperatures up to reflux, in a reducing agent such as LiAlH₄In the presence of oxygen. The compounds of formula B-1 may be prepared according to other general methods described herein.

General method C

Wherein A is aryl or heteroaryl, and X, Y, Z, W and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula Ic, can be prepared as follows:

x, Y, Z, W and R therein¹Hydroxyamidines of formula C-2, each as defined herein, and A represents aryl or heteroaryl, are reacted with an acyl chloride or carboxylic acid anhydride of formula C-3 to produce a compound of formula Ic. The reaction may be carried out in a suitable solvent such as N, N-dimethylacetamide or acetic acid at a temperature up to reflux. Compounds of formula C-2 may be prepared by reacting X, Y, Z, W and R therein¹Respectively as defined herein, and A represents aryl or heteroaryl, with hydroxylamine. The reaction may be carried out in a suitable solvent such as ethanol and water at a temperature up to reflux in the presence of a base such as potassium carbonate. The compounds of formula C-1 may be prepared according to other general methods described herein.

General method D

Wherein X, Y, Z, W and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula Id, may be prepared as follows:

x, Y, Z, W and R therein¹The hydroxyamidine of formula D-2, respectively as defined herein, is reacted with an acyl chloride or carboxylic acid anhydride of formula D-3 to produce the compound of formula Id. The reaction may be carried out in a suitable solvent such as N, N-dimethylacetamide or acetic acid at a temperature up to reflux. Compounds of formula D-2 may be prepared by reacting X, Y, Z, W and R therein¹Respectively, of formula D-1 as defined herein with hydroxylamine. The reaction may be carried out in a suitable solvent such as ethanol and water at a temperature up to reflux in the presence of a base such as potassium carbonate.

General method E

Wherein X, Y, Z, W and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula Ie, may be prepared as follows:

x, Y, Z, W and R therein¹Benzyl halides of formula E-1, respectively as defined herein, and Hal represents chlorine, bromine or iodine, are reacted with amines of formula E-2 to yield compounds of formula Ie. The reaction may be carried out in a suitable solvent such as ethanol at a temperature up to reflux and in the presence of a base such as triethylamine or an excess of an amine of formula E-2. Compounds of formula E-1 can be prepared according to general procedure D, described above.

General procedure F

Wherein R is¹¹From R^11a-CH-R^11bAnd q, A, X, Y, W and Z are each as defined for formula I, such compounds being referred to herein as compounds of formula If, and can be prepared as shown below:

wherein R may be^11aAnd R^11bReacting a carbonyl compound of formula F-1, each as defined herein, with an amine of formula F-2, wherein q, A, X, Y, Z and W are as defined herein, in the presence of a reducing agent, to produce a compound of formula If. The reaction may be carried out in a suitable solvent such as tetrahydrofuran or 1, 2-dichloro-ethane at temperatures up to reflux. The reducing agent may be, for example, NaCNBH₃Or NaBH (OAc)₃Eventually in the presence of an acidic catalyst such as acetic acid. The compounds of formula F-2 may be prepared according to other general methods described herein.

General method G

Wherein a is aryl or heteroaryl optionally substituted with R- (C ═ O) -, and R, X, Y, Z, W and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula Ig, may be prepared as follows:

x, Y, Z, W and R therein¹Cyano compounds of formula G-1, respectively as defined herein, and A represents aryl or heteroaryl, are reacted with organometallic compounds of formula G-2 or G-3, followed by acidic hydrolysis with, for example, hydrochloric acid, to yield compounds of formula Ig. The reaction may be carried out in a suitable solvent such as tetrahydrofuran or tetrahydrofuran/toluene at temperatures up to reflux. The compounds of formula G-1 may be prepared according to other general methods described herein.

General method H

Wherein R is¹¹Q, A, X, Y, W and Z are compounds of formula I, respectively, as defined for formula I, such compounds being referred to herein as compounds of formula Ih, and may be prepared as follows:

a compound of formula H-1 wherein Hal represents chlorine, bromine or iodine may be reacted with an amine of formula H-2 wherein q, a, X, Y, Z and W are as defined herein to produce a compound of formula Ih. The reaction can be carried out in a suitable solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile or 2-butanone at temperatures up to reflux. The reaction can be carried out in the presence of a base such as sodium hydride, potassium carbonate or N, N-diisopropylethylamine, and a catalyst such as potassium iodide. The compounds of formula H-2 may be prepared according to other general methods described herein.

General method I

Wherein A, X, Y, W, Z and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula Ii, may be prepared as follows:

x, Y, W, Z and R therein¹A compound of formula I-1, each as defined herein, and Hal represents chloro, bromo or iodo, is reacted with a boronic acid derivative of formula I-2, or a corresponding boronic ester derivative, wherein a is as defined herein, to produce a compound of formula Ii. The reaction may be carried out in a suitable solvent such as acetonitrile/water at a temperature of up to 150 ℃ in the presence of a suitable catalyst such as bis-triphenylphosphine palladium (II) dichloride and sodium carbonate. The reaction can also be initiated in other ways from reactants in which the halogen and boronic acid moieties have been interchanged. The reaction can be carried out under conditions similar to those described above.

General procedure J

Wherein a is aryl or heteroaryl optionally substituted by-C (═ O) -NR' R, and X, Y, Z, W and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula Ij, may be prepared as follows:

a, X, Y, Z, W and R therein¹A carboxylic acid of formula J-2, respectively as defined herein, is reacted with an amine of formula R' RNH to produce an amide of formula Ij. The reaction can be carried out by activating the carboxylic acid with, for example, HOBt/EDAC in a suitable solvent such as THF at a temperature up to reflux. The carboxylic acid of formula J-2 may be represented byPrepared by hydrolyzing a nitrile of formula J-1, wherein A, X, Y, Z, W and R¹Each as defined herein. The reaction can be carried out under strongly acidic conditions, for example in 6N hydrochloric acid, at temperatures up to reflux. The compounds of formula J-1 may be prepared according to other general methods described herein.

General method K

Wherein A is optionally substituted by-CH₂-NR' R substituted aryl or heteroaryl, and X, Y, Z, W and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula Ik, may be prepared as follows:

a, X, Y, Z, W and R therein¹An aldehyde of formula K-2, respectively as defined herein, is reacted with an amine of formula R' RNH under reducing conditions to produce an amine of formula Ik. The reaction may be carried out in a suitable solvent such as tetrahydrofuran or 1, 2-dichloroethane at temperatures up to reflux. The reducing agent may be, for example, NaCNBH ₃Or NaBH (OAc)₃Eventually in the presence of an acidic catalyst such as acetic acid. The aldehydes of the formula K-2 can be prepared from nitriles of the formula K-1, where A, X, Y, Z, W and R¹Each as defined herein. The reaction can be carried out in a reducing agent such as DIBAL-H or LiAlH₄In the presence of a suitable solvent such as THF, at a temperature of-40 deg.C up to reflux. The compounds of formula K-1 may be prepared according to other general methods described herein.

General procedure L

Wherein A is aryl or heteroaryl optionally substituted with R-C (═ O) NH-, and X, Y, Z, W and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula 11, can be prepared as follows:

x, Y, Z, W and R therein¹An aromatic amine of formula L-2, each as defined herein, and a represents aryl or heteroaryl, is acylated with an activated carboxylic acid derivative to produce a compound of formula Il. Such activated carboxylic acid derivatives may be acid chlorides or anhydrides of formula L-4 or L-3, respectively. The reaction may be carried out in a suitable solvent such as dichloromethane or acetic acid at temperatures up to reflux. The carboxylic acid of formula L-5 can also be reacted with an amine of formula L-2 to produce an amide of formula Il. The reaction can be carried out by activating the carboxylic acid with, for example, HOBt/EDAC in a suitable solvent such as THF at a temperature up to reflux. Compounds of formula L-2 may be prepared by reacting X, Y, Z, W and R therein ¹Respectively as defined herein, and A represents aryl or heteroaryl, by hydrogenation of a nitro compound of formula L-1. The reaction can be carried out in a suitable solvent such as ethanol and/or water at temperatures up to reflux in the presence of a reducing agent such as iron powder. Other reducing conditions may be hydrogenation using hydrogen in the presence of a suitable catalyst such as Pd/C at pressures up to 3000 psi. The compounds of formula L-1 may be prepared according to other general methods described herein.

General method M

Wherein A is optionally substituted with R- (CH)₂-O-substituted aryl or heteroaryl, and X, Y, Z, W and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula Im, may be prepared as follows:

x, Y, Z, W and R therein¹An aromatic alcohol of formula M-1, each as defined herein, and A represents aryl or heteroaryl, is alkylated with a compound of formula M-2, wherein LG represents a suitable leaving group such as halogen or mesylate. The reaction may be carried out in a suitable solvent such as DMF at temperatures up to reflux in the presence of a base such as sodium hydride. The compounds of formula M-1 may be prepared according to other general methods described herein.

General method N

Wherein A is aryl or heteroaryl optionally substituted with a cyclic sulfonamide, p is 1-4, and X, Y, Z, W and R¹Compounds of formula I, respectively as defined for formula I, such compounds being referred to herein as compounds of formula In, may be prepared as follows:

x, Y, Z, W and R therein¹An aromatic amine of formula N-1, each as defined herein, and A represents aryl or heteroaryl, is reacted with an activated sulfonic acid of formula N-2, wherein p is 1-4, and LG₁And LG₂Represents a suitable leaving group such as halogen to yield a compound of formula N-3. The reaction can be carried out in a suitable solvent such as DMF at temperatures up to reflux in the presence of a base such as TEA. The compound of formula N-3 may be ring closed to produce a compound of formula In. The reaction may be carried out in a suitable solvent such as DMF at temperatures up to reflux in the presence of a base such as NaH. The compounds of formula N-1 may be prepared according to other general methods described herein.

Example 1 (general method A)

1- [5- (4-chlorophenyl) pyridin-2-yl ] -4-isopropylpiperazine, dihydrochloride

2-chloro-5- (4-chlorophenyl) pyridine (500mg, 2.23mmol), DMSO (2.0mL), and 1-isopropylpiperazine (3mL, 23.4mmol) were stirred and heated in a 100 ℃ oil bath overnight. The reaction mixture was poured into water (75mL) and the solid was isolated by filtration, washed with water and dried. The crude product was purified by column chromatography on silica gel (Kiselegel 60, 0.040-0.63 mesh) and washed with a mixture of ethyl acetate and methanol (4: 1). The appropriate fractions were collected to yield 600mg (85%) of 1- [5- (4-chlorophenyl) -pyridin-2-yl ] -4-isopropylpiperazine.

¹H NMR(300MHz，CDCl₃) δ 1.10(d, 6H), 2.63-2.68(m, 4H), 2.75 (heptad, 1H), 3.59-3.66(m, 4H), 6.69(d, 1H), 7.35-7.45(m, 4H), 7.67(dd, 1H), 8.40(d, 1H).

The free base was dissolved in a mixture of 0.5N hydrochloric acid solution and ethanol. After dissolution, the mixture was evaporated and then re-evaporated with ethanol. The solid residue was recrystallized from ethanol (50mL) to yield 740mg (81%) of1- [5- (4-chlorophenyl) pyridin-2-yl ] -4-isopropylpiperazine, dihydrochloride.

¹H NMR(300MHz，DMSO-d₆)δ1.32(d，6H)，3.05-3.22(m，2H)，3.45-3.67(m，5H)，4.49-4.61(m，2H)，4.9(brs，6H)，7.23-7.31(m，1H)，7.52(d，2H)，7.73(d，2H)，8.13-8.19(m，1H)，8.42-8.46(m，1H)，11.4(brs，1H)。

C₁₈H₂₂ClN₃，2x HCl，2.5x H₂Microanalysis of O:

calculated values: c: 49.84 percent; h: 6.74 percent; n: 9.69 percent;

measured value: c: 49.82 percent; h: 6.66%, N: 9.36 percent.

Example 2 (general method A)

1-isopropyl-4- [5- (4-methoxyphenyl) pyridin-2-yl ] piperazine, dihydrochloride

2-chloro-5- (4-methoxyphenyl) pyridine (200mg, 0.91mmol), anhydrous DMSO (2.0mL), and 1-isopropylpiperazine (500mg, 3.9mmol) were stirred and heated in an oil bath at 130 ℃ overnight, then heated at 150 ℃ for 4 hours, left at room temperature for 2 days, and finally heated at 140 ℃ overnight. The reaction mixture was cooled and then poured into water (100 mL). The mixture was extracted with ethyl acetate (100mL) and the organic extracts were washed with water and dried (MgSO ₄). The solvent was evaporated to give a solid residue, which was dissolved in 0.5N hydrochloric acid (20 mL). A small amount of insoluble solid was removed by filtration and the aqueous solution was evaporated to give a residue which was re-evaporated with anhydrous ethanol. The resulting solid was recrystallized from absolute ethanol to yield 210mg (60%) of 1- [5- (4-methoxyphenyl) pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride.

¹H NMR(400MHz，CDCl₃)δ1.51(d，6H)，3.23-3.34(m，2H)，3.49-3.59(m，1H)，3.60-3.67(m，2H)，3.86(s，3H)，4.30-4.40(m，2H)，4.64-4.71(m，2H)，7.00(d，2H)，7.19(d，1H)，7.43(d，2H)，8.20(d，1H)，8.31(s，1H)，12.9(brs，1H)。

C₁₉H₂₅N₃O，2x HCl，3x H₂Microanalysis of O:

calculated values: c: 52.06 percent; h: 7.59 percent; n: 9.58 percent;

measured value: c: 51.99 percent; h: 7.47%, N: 9.21 percent.

Example 3 (general method A)

1-isopropyl-4- [5- (4-trifluoromethoxyphenyl) pyridin-2-yl ] piperazine, dihydrochloride

The title compound was prepared in a similar manner to that described in example 1 starting from 2-chloro-5- (4-trifluoromethoxyphenyl) pyridine and 1-isopropylpiperazine.

Mp＝271-273℃.

¹H NMR(300MHz，DMSO-d₆)δ1.32(d，6H)，3.05-3.21(m，2H)，3.45-3.67(m，5H)，4.50-4.61(m，2H)，7.28(d，1H)，7.46(d，2H)，7.82(d，2H)，8.17(d，1H)，8.46(s，1H)，11.4(brs，1H)。

C₁₉H₂₂F₃N₃Microanalysis of O, 2 × HCl:

calculated values: c: 52.06 percent; h: 5.52 percent; n: 9.59 percent;

measured value: c: 52.07 percent; h: 5.53%, N: 9.36 percent.

Example 4 (general method A)

1- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } ethanone, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1, starting from 2-chloro-5- (4-acetylphenyl) pyridine and 1-isopropylpiperazine.

Mp＝288-290℃.

¹H NMR(300MHz，DMSO-d₆)δ1.32(d，6H)，2.61(s，3H)，3.05-3.22(m，2H)，3.40-3.67(m，5H)，4.51-4.62(m，2H)，7.27(d，1H)，7.86(d，2H)，8.03(d，2H)，8.22(d，1H)，8.55(s，1H)，11.4(brs，1H)。

C₂₀H₂₅N₃O，2x HCl，1.25x H₂Microanalysis of O:

calculated values: c: 57.35 percent; h: 7.10 percent; n: 10.03 percent;

measured value: c: 57.06 percent; h: 7.05%, N: 9.78 percent.

Example 5 (general method A)

1- [5- (2, 6-difluorophenyl) pyridin-2-yl ] -4-isopropylpiperazine, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1, starting from 2-chloro-5- (2, 6-difluorophenyl) pyridine and 1-isopropylpiperazine.

¹H NMR(300MHz，DMSO-d₆)δ1.33(d，6H)，3.05-3.20(m，2H)，3.44-3.65(m，5H)，4.50-4.60(m，2H)，7.19-7.31(m，3H)，7.43-7.54(m，1H)，7.88(d，1H)，8.24(s，1H)，11.4(brs，1H)。

C₁₈H₂₁F₂N₃，2x HCl，0.5x H₂Microanalysis of O:

calculated values: c: 54.14 percent; h: 6.06 percent; n: 10.52 percent;

measured value: c: 54.02 percent; h: 6.04%, N: 10.25 percent.

Example 6 (general method A)

1- [5- (4-fluorophenyl) pyridin-2-yl ] -4-isopropylpiperazine, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1 starting from 2-chloro-5- (4-fluorophenyl) pyridine and 1-isopropylpiperazine.

¹H NMR(300MHz，DMSO-d₆)δ1.32(d，6H)，3.06-3.20(m，2H)，3.45-3.67(m，5H)，4.49-4.59(m，2H)，7.25-7.35(m，3H)，7.70-7.77(m，2H)，8.15(d，1H)，8.40(s，1H)，11.4(brs，1H)。

C₁₈H₂₂FN₃，2x HCl，3.5x H₂Microanalysis of O:

calculated values: c: 49.66 percent; h: 7.18 percent; n: 9.65 percent;

measured value: c: 50.01 percent; h: 7.05%, N: 9.47 percent.

Example 7 (general method A)

1- [5- (3-fluorophenyl) pyridin-2-yl ] -4-isopropylpiperazine, hydrochloride

The title compound was prepared in analogy to the procedure described for example 1 starting from 2-chloro-5- (3-fluorophenyl) pyridine and 1-isopropylpiperazine.

¹H NMR(300MHz，DMSO-d₆)δ1.32(d，6H)，2.99-3.14(m，2H)，3.36-3.67(m，5H)，4.45-4.55(m，2H)，7.06-7.19(m，2H)，7.43-7.57(m，3H)，8.02(d，1H)，8.55(s，1H)，11.0(brs，1H)。

C₁₈H₂₂FN₃，HCl，0.5x H₂Microanalysis of O:

calculated values: c: 62.69 percent; h: 7.01 percent; n: 12.18 percent;

measured value: c: 62.93 percent; h: 6.88%, N: 11.91 percent.

Example 8 (general method A)

1- [5- (2-fluorophenyl) pyridin-2-yl ] -4-isopropylpiperazine, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1 starting from 2-chloro-5- (2-fluorophenyl) pyridine and 1-isopropylpiperazine.

¹H NMR(300MHz，DMSO-d₆)δ1.33(d，6H)，3.06-3.22(m，2H)，3.44-3.69(m，5H)，4.50-4.61(m，2H)，7.25-7.48(m，4H)，7.59(t，1H)，7.82(d，2H)，8.03(d，1H)，8.31(s，1H)，11.4(brs，1H)。

C₁₈H₂₂FN₃Microanalysis of 2 × HCl:

calculated values: c: 58.07 percent; h: 6.50 percent; n: 11.29 percent;

measured value: c: 58.16 percent; h: 6.61%, N: 10.94 percent.

Example 9 (general method A)

1- {4- [6- (4-cyclopentylpiperazin-1-yl) pyridin-3-yl ] phenyl } ethanone, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1, starting from 2-chloro-5- (4-acetylphenyl) pyridine and 1-cyclopentylpiperazine.

¹H NMR(300MHz，DMSO-d₆)δ1.47-1.63(m，2H)，1.68-1.95(m，4H)，1.96-2.09(m，2H)，2.61(s，3H)，3.03-3.19(m，2H)，3.44-3.65(m，5H)，4.47-4.57(m，2H)，7.23(d，1H)，7.85(d，2H)，8.03(d，2H)，8.19(d，1H)，8.56(s，1H)，11.5(brs，1H)。

C₂₂H₂₇N₃O，2x HCl，2x H₂Microanalysis of O:

calculated values: c: 57.64 percent; h: 7.26 percent; n: 9.17 percent;

measured value: c: 58.06 percent; h: 7.23%, N: 9.10 percent.

Example 10 (general method A)

4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzonitrile, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1, starting from 2-chloro-5- (4-cyanophenyl) pyridine and 1-isopropylpiperazine.

¹H NMR(300MHz，DMSO-d₆)δ1.32(d，6H)，3.04-3.19(m，2H)，3.46-3.66(m，5H)，4.52-4.62(m，2H)，5.05(brs，6H)，7.24(d，1H)，7.91(s，4H)，8.19(dd，1H)，8.56(d，1H)，11.4(brs，1H)。

C₁₉H₂₂N₄，2x HCl，2.5x H₂Microanalysis of O:

calculated values: c: 53.78 percent; h; 6.89 percent; n: 13.20 percent;

measured value: c: 53.51 percent; h: 6.82%, N: 12.59 percent.

Example 11 (general method A)

(4- (2-pyrrolidin-1-ylethyl) piperidin-1-yl) -5- (4-trifluoromethylphenyl) pyridine, hydrochloride

The title compound was prepared in analogy to the procedure described for example 1, starting from 2-chloro-5- (4-trifluoromethylphenyl) pyridine and 4- (2-pyrrolidinylethyl) piperidine.

Mp＝166-168℃.

¹H NMR(300MHz，CDCl₃)δ1.35-2.31(m，11H)，2.76-2.97(m，2H)，3.10-3.26(m，2H)，3.38(t，2H)，3.69-3.87(m，2H)，4.48-4.67(m，2H)，7.15(d，1H)，7.64(d，2H)，7.73(d，2H)，8.09(d，1H)，8.41(s，1H)，12.2(brs，1H)，15.5(brs，1H)。

Example 12 (general method A)

1- (3-piperidin-1-ylpropyl) -4- [5- (4-trifluoromethylphenyl) pyridin-2-yl ] piperazine, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1, starting from 2-chloro-5- (4-trifluoromethylphenyl) pyridine and 1- (3-piperidinopropyl) piperazine.

HPLC (method a): t is t_r＝12.05min(100％)。

Example 13 (general method A)

1 '- [6- (4-methanesulfonylphenyl) pyridazin-3-yl ] - [1, 4' ] bipiperidinyl

The title compound was prepared in analogy to the procedure described for example 1, starting from 3-chloro-6- (4-methanesulfonylphenyl) pyridazine and 4- (piperidin-1-yl) piperidine.

¹H NMR(400MHz，CDCl3)δ1.24(t，J＝6.82Hz，1H)，1.38-1.51(m，2H)，1.52-1.69(m，5H，1.98(d，J＝12.63Hz，2H)，2.47-2.63(m，4H)，2.95-3.07(m，2H)，3.09(s，3H)，3.72(q，J＝7.07Hz，1H)，4.56(d，J＝13.14Hz，2H)，7.01(d，J＝9.60Hz，1H)，7.67(d，J＝9.60Hz，1H)，8.02(d，J＝8.59Hz，2H)，8.20(d，J＝8.59Hz，2H)。

C₂₁H₂₈N₄O₂S，0.25x H₂Microanalysis of O:

calculated values: c: 62.27 percent; h: 7.09%; n: 13.83 percent;

measured value: c: 61.85 percent; h: 6.84 percent; n: 13.49 percent.

Example 14 (general method A)

Dimethyl- (3- {4- [6- (4-trifluoromethylphenyl) pyridazin-3-yl ] piperazin-1-yl } propyl) amine, dihydrochloride

The title compound is obtained in analogy to the procedure described for example 1 starting from 3-chloro-6- (4-trifluoromethylphenyl) pyridazine and (3-dimethylaminoprop-1-yl) piperazine.

¹H NMR(400MHz，D₂O)δ2.06-2.35(m，2H)，2.85(s，5H)，3.13-3.23(m，2H)，3.23-3.32(m，2H)，3.49(s，3H)，4.70(s，7H)，7.68(d，J＝10.11Hz，1H)，7.78(d，J＝8.59Hz，2H)，7.90(d，J＝8.59Hz，2H)，8.08(d，J＝9.60Hz，1H)。

C₂₀H₂₆N₅F₃，2x HCl，2.75x H₂Microanalysis of O:

calculating a value; c: 46.56 percent; h: 6.54 percent; n: 13.57 percent;

measured value: c: 46.53%; h: 6.35 percent; n: 13.32 percent.

Example 15 (general method A)

3- [4- (1-methylpiperidin-3-ylmethyl) piperazin-1-yl ] -6- (4-trifluoromethylphenyl) pyridazine

The title compound is prepared in analogy to the procedure described for example 1 starting from 3-chloro-6- (4-trifluoromethylphenyl) pyridazine and (1-methylpiperidin-3-ylmethyl) piperazine.

¹H NMR(400MHz，DMSO-d₆)δ1.12-1.31(m，1H)，1.71-2.01(m，2H)，2.54-2.97(m，4H)，3.04-3.33(m，3H)，3.40(d，J＝10.61Hz，1H)，3.53-3.86(m，9H)，4.62(brs，1H)，7.78(d，J＝10.11Hz，1H)，7.91(d，J＝8.08Hz，2H)，8.23-8.37(m，3H)。

Example 16 (general method A)

3- [4- (1-methylpiperidin-4-ylmethyl) piperazin-1-yl ] -6- (4-trifluoromethylphenyl) pyridazine, dihydrochloride

The title compound is prepared in analogy to the procedure described for example 1 starting from 3-chloro-6- (4-trifluoromethylphenyl) pyridazine and (1-methylpiperidin-4-ylmethyl) piperazine.

¹H NMR(400MHz，DMSO-d₆)δ1.48-1.64(m，2H)，2.05-2.20(m，3H)，2.68-2.79(m，3H)，2.94(t，J＝11.87Hz，2H)3.06-3.25(m，4H)3.69(d，J＝12.13Hz，4H)4.58(d，J＝13.64Hz，2H)7.65(d，J＝9.60Hz，1H)7.89(d，J＝8.59Hz，2H)8.23(d，J＝9.60Hz，1H)8.29(d，J＝8.08Hz，2H)。

C₂₂H₂₈N₅F₃，2x HCl，2.75x H₂Microanalysis of O:

calculated values: c: 48.85 percent; h: 6.43 percent; n: 12.95 percent

Measured value: c: 49.00 percent; h: 6.23 percent; and (3) N12.80%.

Example 17 (general method A)

4- {6- [4- (1-methylpiperidin-4-ylmethyl) piperazin-1-yl ] pyridazin-3-yl } benzonitrile, hydrochloride

The title compound is prepared in analogy to the procedure described for example 1, starting from 3-chloro-6- (4-cyanophenyl) pyridazine and (1-methylpiperidin-4-ylmethyl) piperazine.

¹H NMR(400MHz，D₂O) δ 1.45-1.62(m, 2H), 2.06(d, J ═ 14.15Hz, 2H), 2.17-2.32(m, 1H), 2.74-2.84(m, 3H), 2.98(t, 1H), 3.19(d, J ═ 7.07Hz, 2H), 3.25-3.63(m, 7H), 3.80-4.30 (wide m, 3H), 7.66(d, 1H), 7.78(d, 2H), 7.87(d, 2H), 8.06(d, J ═ 10.11Hz, 1H).

Example 18 (general method A)

4- {6- [4- (1-methylpiperidin-3-ylmethyl) piperazin-1-yl ] pyridazin-3-yl } benzonitrile, trihydrochloride

The title compound is prepared in analogy to the procedure described for example 1, starting from 3-chloro-6- (4-cyanophenyl) pyridazine and (1-methylpiperidin-3-ylmethyl) piperazine.

¹H NMR(400MHz，D₂O)δ1.30(m，1H)，1.74(m，1H)，1.99(m，2H)，2.41(dd，J＝6.82，3.28Hz，1H)，2.84(m，5H)，3.21(d，J＝6.57Hz，2H)，3.49(m，6H)，4.03(m，4H)，7.81(m，3H)7.91(d，2H)，8.17(d，J＝9.60Hz，1H)。

C₂₂H₂₈N₆，3x HCl，3.75x H₂Microanalysis of O:

calculated values: c: 47.75%; h: 7.01 percent; n: 15.18 percent

Measured value: c: 47.99 percent; h: 6.96 percent; n: 15.01 percent.

Example 19 (general method A)

(S) -3- (4-butylsulfanylphenyl) -6- (2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) pyridazine, hydrochloride

The title compound was prepared in analogy to the procedure described for example 1 starting from 3-chloro-6- (4-butylsulfanylphenyl) pyridazine and (2S) - (pyrrolidin-1-ylmethyl) pyrrolidine.

¹H NMR(400MHz，D₂O)δ0.74(t，J＝7.33Hz，3H)，1.00(t，J＝7.07Hz，2H)，1.27(m，2H)，1.49(m，2H)，2.04(m，5H)2.88(t，J＝7.58Hz，2H)，3.24(m，6H)，3.62(m，3H)，4.46(m，J＝6.06Hz，1H)，7.28(d，J＝8.59Hz，2H)，7.47(d，J＝10.11Hz，1H)，7.55(d，J＝8.59Hz，2H)，8.00(d，J＝9.60Hz，1H)。

Example 20 (general method A)

(S) -3- (4-Ethanesulfonylphenyl) -6- (2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) pyridazine, hydrochloride

The title compound was prepared in analogy to the procedure described for example 1, starting from 3-chloro-6- (4-ethanesulfonylphenyl) pyridazine and (2S) - (pyrrolidin-1-ylmethyl) pyrrolidine.

¹H NMR(400MHz，D₂O)δ1.12(t，J＝7.33Hz，3H)，2.10(m，8H)，3.16(m，2H)，3.27(q，J＝7.58Hz，2H)，3.36(m，2H)，3.47(m，1H)，3.67(m，2H)，3.82(s，1H)，4.59(m，1H)，7.42(d，J＝9.60Hz，1H)，7.87(m，2H)，7.94(m，2H)，8.02(d，J＝9.60Hz，1H)。

Example 21 (general method A)

(S) -3- (4-Ethanesulphinylphenyl) -6- (2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) pyridazine, hydrochloride

The title compound was prepared in analogy to the procedure described for example 1 starting from 3-chloro-6- (4-ethanesulfinylphenyl) pyridazine and (2S) - (pyrrolidin-1-ylmethyl) pyrrolidine.

¹H NMR(400MHz，D₂O)δ1.03(t，J＝7.33Hz，3H)，2.04(m，8H)，2.89(m，1H)，3.02(m，3H)，3.31(m，3H)，3.57(m，2H)，3.79(m，1H)，4.50(q，J＝5.73Hz，1H)，7.33(d，J＝9.60Hz，1H)，7.65(d，J＝7.07Hz，2H)，7.89(d，J＝8.08Hz，2H)，7.97(d，J＝9.60Hz，1H)。

Example 22 (general method A)

(S) -3- (4-ethylsulfanylphenyl) -6- (2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) pyridazine, hydrochloride

The title compound is prepared in analogy to the procedure described for example 1 starting from 3-chloro-6- (4-ethylsulfanylphenyl) pyridazine and (2S) - (pyrrolidin-1-ylmethyl) pyrrolidine.

¹H NMR(400MHz，CD₃OD)δ1.37(t，J＝7.33Hz，3H)，2.20(m，7H)，3.10(q，J＝7.07Hz，2H)，3.47(m，6H)，3.84(brs，2H)，3.97(brs，1H)，4.73(brs，1H)，7.52(d，J＝7.58Hz，2H)，7.91(m，J＝7.58Hz，3H)，8.41(m，1H)。

Example 23 (general method A)

5- (4-chlorophenyl) -2- (4-isopropylpiperazin-1-yl) pyrimidine, dihydrochloride

The title compound was prepared in analogy to the procedure described in example 1, starting from 2-chloro-5- (4-chlorophenyl) pyrimidine and 1-isopropylpiperazine.

¹H NMR(300MHz，DMSO-d₆)δ1.33(d，J＝6.41Hz，6H)，3.08(m，2H)，3.53(m，5H)，4.82(d，J＝13.94Hz，2H)，7.54(d，J＝8.67Hz，2H)，7.74(d，J＝8.67Hz，2H)，8.82(s，2H)。

C₁₇H₂₁N₄Microanalysis of Cl, 2 × HCl:

calculated values: c: 52.39 percent; h: 5.95 percent; n: 14.37 percent;

measured value: c: 52.90 percent; h: 6.04 percent; n: 14.18 percent.

Example 24 (general method A)

2- (4-Isopropylpiperazin-1-yl) -5- (4-trifluoromethylphenyl) pyrimidine, hydrochloride

The title compound was prepared in analogy to the procedure described in example 1, starting from 2-chloro-5- (4-trifluoromethylphenyl) pyrimidine and 1-isopropylpiperazine.

¹H NMR(400MHz，DMSO-d₆)δ1.31(d，J＝6.57Hz，6H)，3.05(m，2H)，3.51(m，5H)，4.82(d，J＝14.65Hz，2H)，7.81(d，J＝8.08Hz，2H)，7.93(d，J＝8.08Hz，2H)，8.89(m，2H)，11.23(brs，1H)。

C₁₈H₂₁F₃N₄1.75 × HCl microanalysis:

calculated values: c: 52.20 percent; h: 5.54 percent; n: 13.53 percent;

measured value: c: 52.41 percent; h: 5.54 percent; n: 13.26 percent.

Example 25 (general method A)

4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzonitrile, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1, starting from 2-chloro-5- (4-cyanophenyl) pyrimidine and 1-isopropylpiperazine.

¹H NMR(400MHz，DMSO-d₆)δ1.31(d，J＝6.57Hz，6H)，3.07(m，2H)，3.52(m，5H)，4.81(d，J＝14.15Hz，2H)，7.93(s，4H)，8.91(s，2H)，11.34(brs，1H)。

C₁₈H₂₁N₅，2x HCl，0.75x H₂Microanalysis of O:

calculated values: c: 54.90 percent; h: 6.27 percent; n: 17.78%;

measured value: c: 55.23 percent; h: 6.45 percent; n: 17.54 percent.

Example 26 (general method A)

5- (4-fluorophenyl) -2- (4-isopropylpiperazin-1-yl) pyrimidine, bis (mesylate)

The title compound was prepared in analogy to the procedure described for example 1 starting from 2-chloro-5- (4-fluorophenyl) pyrimidine and 1-isopropylpiperazine.

¹H NMR(400MHz，DMSO-d₆+D₂O)δ1.29(d，J＝7.07Hz，6H)，2.39(s，6H)，3.10(m，2H)，3.32(t，J＝12.38Hz，2H)，3.55(m，3H)，7.31(t，J＝8.84Hz，2H)，7.73(dd，J＝8.84，5.31Hz，2H)，8.79(s，2H)，9.52(brs，1H)。

C₁₇H₂₁N₄F，2xCH₃SO₃Microanalysis of H:

calculated values: c: 46.33 percent; h: 5.93 percent; n: 11.37 percent;

measured value: c: 46.05 percent; h: 6.07 percent; n: 11.06 percent.

Example 27 (general method A)

2- (4-isopropylpiperazin-1-yl) -5- (4-trifluoromethoxyphenyl) pyrimidine, dimesylate

The title compound was prepared in analogy to the procedure described for example 1, starting from 2-chloro-5- (4-trifluoromethoxyphenyl) pyrimidine and 1-isopropylpiperazine.

¹H NMR(400MHz，DMSO-d₆+D₂O)δ1.31(d，J＝6.57Hz，6H)，2.41(s，6H)，3.12(m，2H)，3.34(t，J＝12.13Hz，2H)，3.56(m，3H)，4.86(d，J＝14.15Hz，2H)，7.48(d，J＝8.08Hz，2H)，7.83(d，J＝8.59Hz，2H)，8.84(s，2H)。

C₁₈H₂₁F₃N₄O，2xCH₃SO₃H，0.75x H₂Microanalysis of O:

calculated values: c: 41.99 percent; h: 5.37 percent; n: 9.79 percent;

measured value: c: 42.17 percent; h: 5.34 percent; n: 9.74 percent.

Example 28 (general method A)

2- (4-isopropylpiperazin-1-yl) -5- (4-methoxyphenyl) pyrimidine, dimesylate

The title compound was prepared in analogy to the procedure described for example 1, starting from 2-chloro-5- (4-methoxyphenyl) pyrimidine and 1-isopropylpiperazine.

¹H NMR(400MHz，DMSO-d₆)δ1.29(d，J＝6.57Hz，6H)，2.40(s，6H)，3.07(m，2H)，3.31(t，J＝12.13Hz，2H)，3.54(m，J＝11.37，11.37Hz，3H)，3.79(s，3H)，4.81(d，J＝14.15Hz，2H)，7.03(d，J＝8.59Hz，2H)，7.61(d，J＝9.10Hz，2H)，8.75(s，2H)，9.52(brs，1H)。

Example 29 (general method A)

(S) -3- (2-pyrrolidin-1-ylmethylpyrrolidin-1-yl) -6- (4-trifluoromethylphenyl) pyridazine, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1 starting from 3-chloro-6- (4-trifluoromethylphenyl) pyridazine and (2S) - (pyrrolidin-1-ylmethyl) pyrrolidine.

¹H NMR(400MHz，CD₃OD)δ2.20(m，8H)，3.31(m，2H)，3.48(m，2H)，3.62(m，1H)，3.86(m，3H)，4.80(m，1H)，7.91(m，J＝8.59Hz，3H)，8.20(d，J＝8.08Hz，2H)，8.45(d，J＝9.60Hz，1H)。

C₂₀H₂₃F₃N₄，2x HCl，3x H₂Microanalysis of O:

calculated values: c: 47.72 percent; h: 6.21 percent; n: 11.13 percent;

measured value: c: 47.95 percent; h: 6.35 percent; n: 10.92 percent.

Example 30 (general method A)

N- {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } acetamide

The title compound was prepared in analogy to the procedure described for example 1, starting from 3-chloro-6- (4-acetylaminophenyl) pyridazine and 1-isopropylpiperazine.

¹H NMR(400MHz，CDCl₃)δ1.10(d，6H)，2.20(m，3H)，2.68(m，4H)，2.75(m，1H)，3.73(m，4H)，6.97(d，J＝9.60Hz，1H)，7.38(s，1H)，7.61(dd，J＝9.10，5.05Hz，3H)，7.96(d，J＝8.59Hz，2H)。

Example 31 (general method A)

[1- (1-ethylpropyl) piperidin-4-yl ] - [6- (3-fluoro-4-methoxyphenyl) pyridazin-3-yl ] amine

The title compound was prepared in analogy to the procedure described for example 1 starting from 3-chloro-6- (4-methoxy-3-fluorophenyl) pyridazine and 4-amino-1- (1-ethylpropyl) piperidine.

¹H NMR(400MHz，CD₃OD)δ0.93(m，6H)，1.47(m，7H)，2.07(d，J＝11.62Hz，2H)，2.20(m，1H)，2.45(m，2H)，2.83(d，J＝12.13Hz，2H)，3.85(m，1H)，3.91(s，3H)，6.90(d，J＝9.10Hz，1H)，7.17(t，J＝8.59Hz，1H)，7.68(m，3H)。

Example 32 (general method A)

[1- (1-ethylpropyl) piperidin-4-yl ] - [6- (4-methanesulfonylphenyl) pyridazin-3-yl ] amine

The title compound was prepared in analogy to the procedure described for example 1 starting from 3-chloro-6- (4-methanesulfonylphenyl) pyridazine and 4-amino-1- (1-ethylpropyl) piperidine.

¹H NMR(400MHz，CD₃OD)δ0.93(m，6H)，1.49(m，7H)，2.08(d，J＝11.62Hz，1H)，2.23(m，1H)，2.48(m，2H)，2.85(d，J＝12.13Hz，2H)，3.16(s，3H)，3.90(m，1H)，6.96(d，J＝9.60Hz，1H)，7.83(d，J＝9.60Hz，1H)，8.03(d，J＝8.59Hz，2H)，8.19(d，J＝8.59Hz，2H)。

C₂₁H₃₀N₄O₂Microanalysis of S:

calculated values: c: 62.66 percent; h: 7.51 percent; n: 13.92 percent;

measured value: c: 62.38 percent; h: 7.58 percent; n: 13.31 percent.

Example 33 (general method A)

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

The title compound was prepared in analogy to the procedure described for example 1, starting from 2-chloro-5- (4-trifluoromethylphenyl) pyridine and 1-isopropylpiperazine.

¹H NMR(400MHz，DMSO-d₆)δ1.00(d，J＝6.57Hz，6H)，2.52(m，4H)，2.69(m，1H)，3.55(m，4H)，6.93(d，J＝9.09Hz，1H)，7.75(m，2H)，7.85(m，2H)，7.93(dd，J＝8.84，2.78Hz，1H)，8.53(d，J＝2.53Hz，1H)。

C₁₉H₂₂F₃N₃Microanalysis of (2):

calculated values: c: 65.31 percent; h: 3.35 percent; n: 12.03 percent;

measured value: c: 65.08 percent; h: 6.23 percent; n: 12.05 percent.

Example 34 (general method A)

3- (2, 3-dihydrobenzo [1, 4 ]]IIEn-6-yl) -6- (4-isopropylpiperazin-1-yl) pyridazine, dihydrochloride

From 3-chloro-6- (4- (2, 3-dihydrobenzo [1, 4 ]]IIEn-6-yl) -phenyl) pyridazine and 1-isopropyl-piperazine were prepared in analogy to the procedure described in example 1.

¹H NMR(400MHz，DMSO-d₆)δ1.32(d，J＝6.57Hz，6H)，3.18(m，2H)，3.53(m，J＝12.13Hz，3H)，3.75(t，J＝12.38Hz，2H)，4.32(s，4H)，4.60(d，J＝13.64Hz，2H)，7.05(d，J＝8.08Hz，1H)，7.59(m，2H)，7.95(d，J＝10.11Hz，1H)，8.37(d，J＝9.60Hz，1H)，11.68(brs，1H)。

C₁₉H₂₄N₄O₂Microanalysis of 2 × HCl:

calculated values: c: 55.21 percent; h: 6.34 percent; n: 13.55 percent;

measured value: c: 55.25 percent; h: 6.40 percent; n: 13.55 percent.

Example 35 (general method A)

4- {6- [1- (1-ethylpropyl) piperidin-4-ylamino ] pyridazin-3-yl } benzonitrile

The title compound is prepared in analogy to the procedure described for example 1 starting from 3-chloro-6- (4-cyanophenyl) pyridazine and 4-amino-1- (1-ethylpropyl) piperidine.

¹H NMR(400MHz，DMSO-d₆)δ0.87(t，J＝7.33Hz，6H)，1.35(m，7H)，1.98(m，2H)，2.17(m，1H)，2.36(t，J＝10.36Hz，2H)，2.71(m，J＝12.13Hz，2H)，6.89(d，J＝9.60Hz，1H)，7.09(d，J＝7.58Hz，1H)，7.91(m，3H)，8.17(d，J＝8.08Hz，2H)。

Example 36 (general method A)

Dimethyl- (2- {4- [5- (4-trifluoromethylphenyl) pyridin-2-yl ] piperazin-1-yl } ethyl) amine

Starting from 2-chloro-5- (4-trifluoromethylphenyl) pyridine and (2-dimethylaminoethyl) -piperazine,

the title compound was prepared in analogy to the procedure described in example 1.

¹H NMR(400MHz，CDCl₃)δ2.29(s，6H)，2.53(m，4H)，2.61(m，4H)，3.64(m，4H)，6.72(d，J＝9.10Hz，1H)，7.64(m，4H)，7.72(dd，J＝9.10，2.53Hz，1H)，8.45(d，J＝2.53Hz，1H)。

Example 37 (general method H)

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

The title compound was prepared in analogy to the procedure described for example 1, starting from 4- (5- (4-trifluoromethylphenyl) pyridin-2-yl) piperazine and 4-chloro-tetrahydropyran.

¹H NMR(400MHz，CDCl₃)δ1.63(m，2H)，1.82(m，2H)，2.50(m，1H)，2.70(m，4H)，3.40(t，J＝10.86Hz，2H)，3.64(m，4H)，4.05(dd，J＝11.12，4.04Hz，2H)，6.73(d，J＝9.10Hz，1H)，7.64(m，4H)，7.73(dd，J＝9.10，2.53Hz，1H)，8.46(d，J＝2.53Hz，1H)。

Example 38 (general method A)

1- [6- (4-trifluoromethylphenyl) pyridazin-3-yl ] piperidin-3-ylamine, hydrochloride

3-chloro-6- (4-trifluoromethylphenyl) pyridazine (0.2g, 0.77mmo1), 3-aminopiperidine dihydrochloride (0.27g, 1.54mmol) and potassium carbonate (0.53g, 3.87mmol) were combined in acetone (4mL) in a 20mL microwave tube. The reaction mixture was heated in a microwave oven at 120 ℃ for 2 hours. The reaction mixture was filtered and the precipitate was washed with MeOH. The combined organic phases were evaporated. The crude oil was purified on a silica gel column (0.04-0.063 mesh) using dichloromethane/MeOH (9: 1) as eluent. 110mg of oil was obtained, which was dissolved in MeOH and acidified with concentrated HCl (5 mL). The mixture was evaporated, the residue dissolved in MeOH (1mL), and diethyl ether (100mL) added with stirring. The mixture was evaporated to yield 76mg (25%) of the title compound as a yellow solid.

Mp＝97-135℃.

¹H NMR(400MHz，CD₃OD)δ1.74(m，2H)1.93(m，1H)2.16(m，1H)3.35(m，3H)3.44(m，1H)4.14(d，d，1H)4.45(d，d，1H)4.97(s，3H)7.39(d，1H)7.75(d，2H)7.78(s，2H)7.95(s，1H)8.13(d，2H)。

HPLC-MS (method G): m ten 1 ═ 323; t is t_r＝1.117min.

Example 39 (general method B)

N- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } acetamide, dihydrochloride

Step 1:

4- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzylamine

LiAlH₄A1M solution in THF (1.1mL, 1.1mmol) and dry THF (10mL) were placed under nitrogen. A solution of 4- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl) benzonitrile (306mg, 1.0mmol, prepared as described in example 10) in anhydrous THF (5mL) was added dropwise. The reaction mixture was then stirred at room temperature for 3 hours and quenched with 1N NaOH. The mixture was filtered and the volatiles were removed. The residue was re-evaporated with THF to yield 310mg (100%) of 4- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl]Benzylamine.

¹H NMR(300MHz，CDCl₃) δ 1.10(d, 6H), 2.63-2.68(m, 4H), 2.75 (heptad, 1H), 3.59-3.64(m, 4H), 3.90(s, 2H), 6.70(d, 1H), 7.37(d, 2H), 7.48(d, 2H), 7.71(dd, 1H), 8.44(d, 1H).

Step 2:

a mixture of the above benzylamine (310mg, 1.0mmol), glacial acetic acid (15mL), and acetic anhydride (0.2mL, 2.1mmol) was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness and the residue stirred with a mixture of ethyl acetate (200mL) and 2M sodium carbonate (50mL) And (4) stirring. The phases were separated and the organic phase was dried (MgSO₄). The solvent was evaporated to give a solid residue which was stirred with a small amount of acetonitrile. The solid was isolated and dried to yield 250mg (71%) of N- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl]Benzyl } acetamide.

Mp＝188-190℃.

¹H NMR(300MHz，CDCl₃) δ 1.10(d, 6H), 2.03(s, 3H), 2.64-2.68(m, 4H), 2.75 (heptad, 1H), 3.58-3.66(m, 4H), 4.46(d, 2H), 5.83(brs, 1H), 6.72(d, 1H), 7.33(d, 2H), 7.47(d, 2H), 7.68(dd, 1H), 8.43(d, 1H).

The free base (250mg) was dissolved in 0.5N hydrochloric acid solution. After dissolution, the mixture was evaporated and then re-evaporated with acetonitrile. The solid residue was stirred with ethyl acetate, filtered and dried to yield 270mg (69%) of the title compound.

¹H NMR(300MHz，DMSO-d₆)δ1.32(d，6H)，1.89(s，3H)，3.05-3.21(m，2H)，3.45-3.66(m，5H)，4.28(d，2H)，4.48-4.59(m，2H)，7.27(d，1H)，7.34(d，2H)，7.64(d，2H)，8.16(d，1H)，8.40(s，1H)，8.45(t，1H)，11.3(brs，1H)。

C₂₁H₂₈N₄O，2x HCl，1.5x H₂Microanalysis of O:

calculated values: c: 55.75 percent; h: 7.35 percent; n: 12.38 percent;

measured value: c: 55.53 percent; h: 7.38%, N: 12.17 percent.

Example 40 (general method C)

1-isopropyl-4- {5- [4- (5-methyl [1, 2, 4 ]]Oxadiazol-3-yl) phenyl]Pyridin-2-yl } piperazine, hydrochloride

Step 1:

n-hydroxy-4- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl) benzamidine

A mixture of 4- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl) benzonitrile (330mg, 1.1mmol, prepared as described in example 10), ethanol (15mL), hydroxylamine hydrochloride (225mg, 3.2mmo1), potassium carbonate (240mg, 1.7mmol) and water (1.5mL) was stirred at reflux temperature overnight. The reaction mixture was cooled to room temperature and the solid was isolated by filtration and dried. The solid was stirred with water (10mL) to remove the inorganic residue. The mixture was filtered and the solids were washed with water and a small portion of ethanol. Drying in vacuo gave 260mg (71%) of N-hydroxy-4- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl) benzamidine.

¹H NMR(300MHz，DMSO-d₆) δ 1.00(d, 6H), 2.50-2.55(m, 4H), 2.67 (heptad, 1H), 3.49-3.54(m, 4H), 5.81(brs, 2H), 6.88(d, 1H), 7.62(d, 2H), 7.73(d, 2H), 7.86(dd, 1H), 8.48(d, 1H), 9.65(s, 1H).

Step 2:

the above N-hydroxybenzamidine (260mg, 0.76mmol), glacial acetic acid (10mL) and acetic anhydride (0.56mL) were stirred at room temperature for 2 days. The reaction mixture was then heated at reflux temperature for 45 minutes. The mixture was evaporated to give an oily residue which was stirred with a mixture of ethyl acetate (100mL) and 2M sodium carbonate (25 mL). The phases were separated and the organic phase was dried (MgSO₄). The solvent was evaporated to give a residue which was boiled with acetonitrile. The mixture was cooled and the solid was isolated by filtration and dried to yield 110mg (28%) of 1-isopropyl alcohol4- {5- [4- (5-methyl [1, 2, 4 ] methyl ester]Oxadiazol-3-yl) phenyl]Pyridin-2-yl } piperazine.

¹H NMR(300MHz，CDCl₃) δ 1.11(d, 6H), 2.64-2.69(m, 4H), 2.67(s, 3H), 2.75 (heptad, 1H), 3.63-3.67(m, 4H), 6.73(d, 1H), 7.63(d, 2H), 7.76(dd, 1H), 8.10(d, 2H), 8.50(d, 1H).

The free base (110mg) was dissolved in a 0.5N hydrochloric acid solution. After dissolution, the mixture was evaporated and then re-evaporated with acetonitrile. The solid residue was recrystallized from absolute ethanol to obtain 120mg (28%) of the title compound.

¹H NMR(300MHz，DMSO-d₆)δ1.32(d，6H)，2.69(s，3H)，3.06-3.23(m，2H)，3.40-3.66(m，5H)，4.51-4.63(m，2H)，7.29(d，1H)，7.90(d，2H)，8.07(d，2H)，8.23(d，1H)，8.54(s，1H)，11.3(brs，1H)。

Example 41 (general method D)

1- (5- (5- (4-chloromethylphenyl) [1, 2, 4 ]]Oxadiazol-3-yl) pyridin-2-yl) -4-isopropylpiperazine

Step 1:

6- (4-Isopropylpiperazin-1-yl) nicotinonitrile, hydrochloride

2-chloropyridine-5-carbonitrile (5.0g, 36.1mmol), DMSO (10mL), and 1-isopropylpiperazine (10.7mL, 75.8mmol) were stirred under nitrogen and heated in an oil bath at 100 ℃ for 3 hours. The reaction mixture was cooled and then poured into cold water (500 mL). The solid was isolated by filtration, washed with water and dried to yield 6.8g (82%) of6- (4-isopropylpiperazin-1-yl) nicotinonitrile.

¹H NMR(400MHz，CDCl₃) δ 1.08(d, 6H), 2.59-2.64(m, 4H), 2.75 (heptad, 1H), 3.67-3.72(m, 4H), 6.59(d, 1H), 7.60(dd, 1H), 8.40(d, 1H).

The free base (500mg) was dissolved in methanol (50mL), and a 1N hydrochloric acid solution (3mL) was added. The mixture was evaporated and then re-evaporated with ethanol. The solid residue was stirred with 2-propanol, filtered and dried to yield 570mg (98%) 6- (4-isopropylpiperazin-1-yl) nicotinonitrile, hydrochloride.

¹H NMR(300MHz，DMSO-d₆)δ1.30(d，6H)，2.97-3.12(m，2H)，3.41-3.61(m，5H)，4.52-4.63(m，2H)，7.06(d，1H)，7.97(dd，1H)，8.56(d，1H)，11.5(brs，1H)。

Step 2:

n-hydroxy-6- (4-isopropylpiperazin-1-yl) nicotinamidines

A mixture of6- (4-isopropylpiperazin-1-yl) nicotinonitrile (2.3g, 10mmol), ethanol (25mL), hydroxylamine hydrochloride (2.1g, 30mmol), potassium carbonate (2.2g, 16mmol) and water (5mL) was stirred at room temperature for 30 minutes and then at reflux temperature for 3 hours. The reaction mixture was left at room temperature for 2 days, and then the formed solid was separated by filtration. The solid was dried, boiled with ethanol (200mL) and filtered hot to remove inorganic impurities. The filtrate was evaporated to give 2.0g (76%) of N-hydroxy-6- (4-isopropylpiperazin-1-yl) nicotinamidine.

¹H NMR(400MHz，DMSO-d₆) δ 0.98(d, 6H), 2.67 (heptad, 1H), 3.31-3.51(m, 8H), 5.74(brs, 2H), 6.79(d, 1H), 7.75(dd, 1H), 8.38(d, 1H), 9.4(brs, 1H).

And step 3:

the above N-hydroxynicotinamidine (263mg, 1.0mmol) was dissolved in N, N-dimethylacetamide (10mL), and 4-chloromethylbenzoyl chloride (190mg, 1.0mmol) was added. The reaction was stirred at room temperature for 1 hour and then heated at 105 ℃ for 2 hours. The mixture was cooled to room temperature and then filtered. The solid was washed with ethyl acetate and dried. 280mg (65%) of1- (5- (5- (4-chloromethylphenyl) [1, 2, 4 ] were obtained]Oxadiazol-3-yl) pyridin-2-yl) -4-isopropylpiperazine, hydrochloride. The hydrochloride salt (400mg) was stirred with water (30mL) and potassium carbonate was added until basic reaction. The mixture was extracted with several portions of ethyl acetate (100 mL total). The combined organic extracts were dried and evaporated to give 300mg of1- (5- (5- (4-chloromethylphenyl) [1, 2, 4 ]]Oxadiazol-3-yl) pyridin-2-yl) -4-isopropylpiperazine.

¹H NMR(300MHz，CDCl₃)δ1.09(d，6H)，2.59-2.67(m，4H)，2.68-2.80(m，1H)，3.66-3.72(m，4H)，4.66(s，2H)，6.71(d，1H)，7.57(d，2H)，8.16(dd，1H)，8.20(d，2H)，8.95(d，1H)。

Example 42 (general method D)

4- {3- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl][1，2，4]Oxadiazol-5-yl benzonitrile, hydrochloride

The title compound was prepared in analogy to the procedure described for example 41 starting from N-hydroxy-6- (4-isopropylpiperazin-1-yl) nicotinamidine and 4-cyanobenzoyl chloride.

¹H NMR(300MHz，CDCl₃)δ1.50(d，6H)，2.86-3.03(m，2H)，3.41-3.55(m，3H)，3.97-4.10(m，2H)，4.49-4.60(m，2H)，6.78(d，1H)，7.87(d，2H)，8.25(dd，1H)，8.33(d，2H)，8.96(d，1H)，12.9(brs，1H)。

Example 43 (general method D)

1- [5- (5-cyclopropyl [1, 2, 4 ]]Oxadiazol-3-yl) pyridin-2-yl]-4-isopropylpiperazine, dimesylate

The title compound was prepared in analogy to the procedure described for example 42, starting from N-hydroxy-6- (4-isopropylpiperazin-1-yl) nicotinamidine and cyclopropylcarbonyl chloride.

¹H NMR(300MHz，CDCl₃)δ1.26-1.32(m，4H)，1.45(d，6H)，2.20-2.28(m，1H)，2.80(s，6H)，3.29-3.45(m，2H)，3.54-3.69(m，3H)，4.02-4.16(m，2H)，4.59-4.70(m，2H)，7.31(d，1H)，8.42(dd，1H)，8.72(d，1H)，10.9(brs，1H)。

Example 44 (general method E)

1-isopropyl-4- {5- [5- (4-piperidin-1-ylmethyl) phenyl ] [1, 2, 4]Diazol-3-yl]Pyridin-2-yl } piperazine, dihydrochloride

1- (5- (5- (4-chloromethylphenyl) [1, 2, 4 ]]Oxadiazol-3-yl) pyridin-2-yl) -4-isopropyl-piperazine, hydrochloride (280mg, 0.65mmol, prepared as described in example 41), 96% ethanol (20mL) and piperidine (0.2mL, 2.1mmol) were heated at reflux temperature for 4 hours. The mixture was evaporated to give a solid residue which was purified by silica gel column chromatography (75g, kisegel 60, 0.040-0.63 mesh) eluting with a mixture of dichloromethane and methanol (7: 3). The appropriate fractions were collected to yield 310mg (100%) of 1-isopropyl-4- {5- [5- (4-piperidin-1-ylmethyl-phenyl) [1, 2, 4 ]]Diazol-3-yl]Pyridin-2-yl } piperazine. The free base (310mg) was dissolved in ethanol (20mL), and a 1N hydrochloric acid solution (1.5mL) was added. After dissolution, the mixture was evaporated and the residue was recrystallized from ethanol to yield 240mg (67%) of the title compound.

¹H NMR(300MHz，D₂O)δ1.42(d，6H)，1.61-1.94(m，6H)，3.12-3.50(m，8H)，3.55-3.69(m，1H)，3.82-4.05(m，4H)，4.37(s，2H)，7.02(d，1H)，7.73(d，2H)，8.12(d，1H)，8.18(d，2H)，8.64(s，1H)。

Example 45 (general method E)

1- (4- {3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl][1，2，4]Oxadiazol-5-yl } benzyl) piperidine-4-carboxylic acid amide, dihydrochloride

From 1- (5- (5- (4-chloromethylphenyl) [1, 2, 4 ]]Starting with oxadiazol-3-yl) pyridin-2-yl) -4-isopropyl-piperazine and isopiperidinecarboxamide (isonipecotamide), the title compound was prepared in analogy to the procedure described in example 44.

¹H NMR(300MHz，DMSO-d₆)δ1.32(d，6H)，1.85-1.97(m，3H)，2.26-2.40(m，1H)，2.87-3.24(m，4H)，3.29-3.62(m，6H)，4.36-4.48(m，2H)，4.53-4.65(m，2H)，6.88-7.04(2xbrs，1H)，7.17(d，1H)，7.38-7.52(2xbrs，1H)，7.90-8.00(m，2H)，8.19-8.28(m，3H)，8.84(s，1H)，11.0(brs，1H)，11.3(brs，1H)。

Example 46 (general method F)

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

The title compound was prepared in analogy to the procedure described for example 213, starting from 4- (5- (4-trifluoromethylphenyl) pyridin-2-yl) piperazine and propionaldehyde.

¹H NMR(400MHz，CDCl₃)δ0.95(t，3H)，1.57(m，2H)，2.37(m，2H)，2.58(m，4H)，3.64(m，4H)，6.73(d，J＝9.10Hz，1H)，7.64(m，4H)，7.72(dd，J＝9.10，2.53Hz，1H)，8.46(d，J＝2.53Hz，1H)。

Example 47 (general method F)

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

The title compound was prepared in analogy to the procedure described for example 213, starting from 4- (5- (4-trifluoromethylphenyl) pyridin-2-yl) piperazine and cyclohexanone.

¹H NMR(400MHz，DMSO-d₆)δ1.18(m，3H)，1.46(m，2H)，1.62(m，1H)，1.82(m，2H)，2.18(m，2H)，3.17(m，3H)，3.59(m，4H)，4.53(d，2H)，7.25(d，J＝9.09Hz，1H)，7.81(d，J＝8.08Hz，2H)，7.93(d，J＝8.59Hz，2H)，8.18(m，1H)，8.54(d，J＝2.53Hz，1H)，11.47(brs，1H)。

Example 48 (general method G)

1- {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } ethanone

To 4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl group]To a suspension of benzonitrile (0.36g, 1.17mmo1, prepared by a method similar to that described in example 1) in anhydrous THF (5mL) was added a 1.4M solution of methylmagnesium bromide in toluene/THF. The reaction mixture was stirred at room temperature for 24 hours, 1M hydrochloric acid (7mL) was added, and the solution was stirred for 1 hour. By adding excess NaHCO ₃The solution made the mixture basic and was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, the solvent was removed, and the solid was recrystallized from ethanol to yield the title compound, 163mg (43%).

¹H NMR(400MHz，DMSO-d₆)δ1.01(d，J＝6.57Hz，6H)，2.57(m，4H)，2.62(s，3H)，2.71(m，1H)，3.66(m，4H)，7.37(d，J＝9.60Hz，1H)，8.04(m，J＝9.10，9.10Hz，3H)，8.19(d，J＝8.59Hz，2H)。

C₁₉H₂₄N₄Microanalysis of O:

calculated values: c: 70.34 percent; h: 7.46 percent; n: 17.27 percent;

measured value: c: 70.07 percent; h: 7.37 percent; n: 17.18 percent.

Example 49 (general method H)

1- {4- [5- (4-trifluoromethylphenyl) pyridin-2-yl ] piperazin-1-yl } propan-2-one, hydrochloride

The title compound was prepared in analogy to the procedure described for example 55, starting from 4- (5- (4-trifluoromethylphenyl) pyridin-2-yl) piperazine and chloroacetone.

¹H NMR(400MHz，CD₃OD)δ2.29(s，3H)，3.79(m，8H)，4.49(s，2H)，7.59(d，J＝9.60Hz，1H)，7.82(m，2H)，7.89(m，2H)，8.42(m，1H)，8.50(dd，J＝9.35，2.27Hz，1H)。

Example 50 (general method H)

N, N-dimethyl-2- {4- [5- (4-trifluoromethylphenyl) pyridin-2-yl ] piperazin-1-yl } acetamide, hydrochloride

The title compound was prepared in analogy to the procedure described for example 55 starting from 4- (5- (4-trifluoromethylphenyl) pyridin-2-yl) piperazine and 2-chloro-N, N-dimethylacetamide.

₁H NMR(400MHz，DMSO-d₆)δ2.95(m，6H)，3.45(m，6H)，4.48(m，4H)，7.20(d，J＝9.10Hz，1H)，7.80(d，J＝8.08Hz，2H)，7.92(d，J＝8.08Hz，2H)，8.16(dd，J＝9.09，2.53Hz，1H)，8.57(d，J＝2.02Hz，1H)，10.37(brs，1H)。

Example 51 (general method H)

3- {4- [5- (4-trifluoromethylphenyl) pyridin-2-yl ] piperazin-1-yl } propionitrile

The title compound is prepared in analogy to the procedure described for example 55, starting from 4- (5- (4-trifluoromethylphenyl) pyridin-2-yl) piperazine and 3-bromopropionitrile.

¹H NMR(400MHz，DMSO-d₆)δ2.54(m，4H)，2.62(t，J＝6.57Hz，2H)，2.73(t，J＝6.32Hz，2H)，3.58(m，4H)，6.97(d，J＝8.59Hz，1H)，7.76(m，2H)，7.86(m，2H)，7.94(dd，J＝8.59，2.53Hz，1H)，8.54(d，J＝2.53Hz，1H)。

Example 52 (general method H)

Diethyl- (2- {4- [5- (4-trifluoromethylphenyl) pyridin-2-yl ] piperazin-1-yl } ethyl) amine

The title compound is prepared in analogy to the procedure described for example 55, starting from 4- (5- (4-trifluoromethylphenyl) pyridin-2-yl) piperazine and 2-diethylaminoethyl chloride.

¹H NMR(400MHz，CDCl₃)δ1.05(t，J＝7.07Hz，6H)，2.61(m，12H)，3.63(m，4H)，6.73(d，J＝9.10Hz，1H)，7.64(m，4H)，7.72(dd，J＝9.10，2.53Hz，1H)，8.46(d，J＝2.53Hz，1H)。

Example 53 (general method H)

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

The title compound was prepared in analogy to the procedure described for example 55, starting from 4- (5- (4-trifluoromethylphenyl) pyridin-2-yl) piperazine and 2-methoxyethyl bromide.

¹H NMR(400MHz，CDCl₃)δ2.65(m，6H)，3.39(s，3H)，3.57(t，J＝5.56Hz，2H)，3.66(m，4H)，6.73(d，J＝8.59Hz，1H)，7.64(m，4H)，7.72(dd，J＝8.59，2.53Hz，1H)，8.46(d，J＝2.53Hz，1H)。

Example 54 (general method H)

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

The title compound was prepared in analogy to the procedure described for example 55, starting from 4- (5- (4-trifluoromethylphenyl) pyridin-2-yl) piperazine and allyl iodide.

¹H NMR(400MHz，DMSO-d₆)δ3.08(d，＝9.10Hz，2H)，3.80(d，J＝3.54Hz，2H)，4.29(s，4H)，4.55(d，J＝14.15Hz，2H)，5.54(m，2H)，6.06(m，1H)，7.24(d，J＝9.09Hz，1H)，7.81(d，J＝8.08Hz，2H)，7.92(d，J＝8.08Hz，2H)，8.19(dd，J＝9.10，2.53Hz，1H)，8.55(d，J＝2.53Hz，1H)，11.77(brs，1H)。

Example 55 (general method H)

1-isopropyl-4- [6- (4-trifluoromethylphenyl) pyridazin-3-yl ] - [1, 4] diazepane, dihydrochloride

4- [6- (4-trifluoromethylphenyl) pyridazin-3-yl ] - [1, 4] diazepane, dihydrochloride (0.028g, 0.071mmol) was suspended in THF (4mL), and triethylamine (0.022g, 0.21mmol) was added. Sodium hydride (0.0085g, 0.35mmol) was added and the reaction mixture was stirred at room temperature for 20 min. Anhydrous N, N-dimethylformamide (1mL) and 2-chloropropane (0.056g, 0.71mmol) were added, and the reaction mixture was heated in a microwave oven at 160 ℃ for 30 minutes and at 180 ℃ for 30 minutes. The reaction mixture was purified on a silica gel column (0.04-0.063 mesh) using dichloromethane/MeOH (9: 1) as eluent. An oil containing several components was obtained, which was further purified by preparative HPLC using method B. 9mg of oil was obtained, which was dissolved in MeOH. A mixture of HCl in ether was added to give 6.5mg (21%) of the title compound as an oily dihydrochloride salt.

¹H NMR(400MHz，CD₃OD)δ1.38(d，J＝6.57Hz，6H)，2.23-2.46(m，2H)，3.32-3.52(m，2H)，3.53-3.85(m，4H)，3.88-4.15(m，2H)，4.26-4.55(m，1H)，7.60(d，J＝9.60Hz，1H)，7.84(d，J＝8.08Hz，2H)，8.05-8.28(m，3H)

LC-MS (method G): m +1 ═ 365; t is t_r＝1.178min.

Example 56 (general method I)

N- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] acetamide, trifluoroacetate salt

Step 1:

4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl:

chloropyrazine (2.3g, 20mmol) and triethylamine (3g, 30 mmol 1) were mixed in acetone (8mL) in a 20mL microwave tube. 1-isopropylpiperazine (2.8g, 22mmol) was added and the reaction mixture was heated in a microwave oven at 120 ℃ for 3300 seconds. The reaction mixture was evaporated and the residue was purified on silica gel column with dichloromethane/MeOH (9: 1) as eluent. Yield: 1.64g of solid 4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl.

¹H NMR(400MHz，CDCl₃)δ1.08(d，J＝6.57Hz，6H)2.61-2.65(m，4H)2.68-2.77(m，1H)3.58-3.62(m，J＝4.55Hz，4H)7.70-7.91(m，1H)8.03-8.08(m，1H)8.13(s，6H)。

¹³C NMR(400MHz，CDCl₃)δ18.82，45.16，48.66，54.94，77.17，77.48，77.80，131.30，133.10，142.00，155.30.

Step 2:

5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl:

reacting 4-isopropyl-3, 4, 5, 6-tetrahydro-2H-[1，2’]Bipyrazinyl (1.0g, 4.8mmo1) was dissolved in dichloromethane (30mL), the solution was placed in an ice bath and brominated in very low yield according to the method described in literature (Tetrahedron44, 10, 1988, 2977-2984). N-bromosuccinimide (3.45g, 19.4mmol) was added slowly at 0 ℃ and then left overnight at room temperature. No reaction was observed. 3.45g N-bromosuccinimide was further added over 8 hours, and the reaction mixture was left at room temperature for 2 days. Adding concentrated Na ₂CO₃Aqueous solution and the mixture was extracted with dichloromethane (3 × 75 mL). The combined organic extracts were dried (MgSO)₄) Filtered and evaporated. The oily residue was purified on a silica gel column with dichloromethane/MeOH (9: 1) as eluent. Yield: 196mg (28%) of 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyrazinyl as an oil.

¹H NMR(400MHz，CDCl₃)δ1.09(d，J＝6.57Hz，6H)2.55-2.67(m，4H)2.72-2.83(m，1H)3.44-3.65(m，4H)7.87(s，1H)8.12(s，1H)。

¹³C NMR(400MHz，CDCl₃)δ18.71，30.05，45.19，48.39，48.68，54.92，126.04，130.51，144.16，154.31.

And step 3:

5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 'in a 20mL microwave tube under nitrogen']Bipyrazinyl (0.196g, 0.68mmol), 4-acetamidophenylboronic acid (0.123g, 0.69 mmol 1), bis (triphenylphosphine) palladium (II) dichloride (0.015g, 0.021mmol) and Na₂CO₃(0.168g, 1.37mmol, dissolved in 2mL H₂O) was mixed in acetonitrile (16 mL). The reaction mixture was heated in a microwave tube at 150 ℃ for 400 seconds. Debromination of the reaction mixture was observed by LC-MS. The reaction mixture was evaporated and the residue was redissolved in dichloromethane and H₂And O in a mixture. The phases were separated and the aqueous phase was extracted with dichloromethane (3 × 50 mL). The combined organic extracts were evaporated, the residue dissolved in MeOH and purified according to preparative HPLC method B. 49mg (15%)) The title compound, was trifluoroacetate salt.

¹H NMR(400MHz，DMSO-d₆)δ1.30(d，J＝6.57Hz，6H)2.03-2.11(m，3H)3.09-3.20(m，2H)3.23-3.34(m，2H)3.56-3.66(m，5H)4.55(d，J＝11.62Hz，2H)7.69(d，J＝8.59Hz，2H)7.94(d，J＝8.59Hz，2H)8.49(s，1H)8.71(s，1H)10.13(brs，2H)。

¹³C NMR(400MHz，DMSO-d₆)δ16.78，24.38，42.00，47.27，57.62，119.49，125.98，131.08，131.36，138.06，139.79，141.19，152.67，168.76.

Example 57 (general method I)

[4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] acetonitrile, trifluoroacetic acid salt

4-cyanomethylphenylboronic acid (0.137g, 0.85mmo1), 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 'in a 5mL microwave tube under nitrogen']Bipyrazinyl (0.242g, 0.85mmo1), bis (triphenylphosphine) palladium dichloride (0.035g, 0.080mmol) and 1N Na₂CO₃At H₂The solution in O (1.7mL) was mixed in acetonitrile (2 mL). The reaction mixture was heated in a microwave tube at 120 ℃ for 600 seconds. The reaction mixture was evaporated and the residue was dissolved in H₂O and dichloromethane. The phases were separated and the aqueous phase was extracted with dichloromethane (3 × 25 mL). The combined organic extracts were combined and trifluoroacetic acid was added. The volatiles were evaporated and the residue was dissolved in MeOH and purified according to preparative HPLC method B to yield 35mg (10%) of the title compound.

¹H NMR(400MHz，CDCl₃)δ1.40(d，J＝6.57Hz，6H)2.92-3.03(m，2H)3.54-3.65(m，5H)3.81(s，2H)4.48(d，J＝13.64Hz，2H)7.42(d，J＝8.08Hz，2H)7.91(d，J＝8.08Hz，2H)8.24(s，1H)8.55(s，1H)12.43-13.00(m，1H)。¹³C NMR(400MHz，CDCl₃)δ16.96，23.78，42.43，47.56，58.32，118.13，126.86，128.92，130.44，130.50，136.78，139.24，142.57，152.99.

Example 58 (general method I)

5- (4-Ethanesulfonylphenyl) -4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, trifluoroacetate salt

4-Ethanesulfonylphenylboronic acid (0.182g, 0.85mmo1), 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 'were placed in a 5mL microwave tube under nitrogen' ]Bipyrazinyl (0.242g, 0.85mmo1), bis (triphenylphosphine) palladium dichloride (0.035g, 0.080mmol) and 1N Na₂CO₃At H₂The solution in O (1.7mL) was mixed in acetonitrile (2 mL). The reaction mixture was heated in a microwave tube at 120 ℃ for 400 seconds. The reaction mixture was evaporated and the residue was dissolved in H₂O and dichloromethane. The phases were separated and the aqueous phase was extracted with dichloromethane (3 × 25 mL).

The combined organic extracts were combined and trifluoroacetic acid was added. The volatiles were evaporated and the residue was dissolved in MeOH and purified according to preparative HPLC method B to afford 60mg (12%) of the title compound.

¹H NMR(400MHz，CD₃OD)δ1.24(t，J＝7.33Hz，3H)，1.42(d，J＝6.57Hz，6H)，3.20(q，J＝7.58Hz，2H)，3.28-3.39(m，4H)，3.56-3.68(m，3H)，4.60-4.79(m，2H)，4.86(brs，6H)，7.96(d，J＝8.59Hz，2H)，8.20(d，2H)，8.44(s，1H)，8.76(s，1H)。

¹³C NMR(400MHz，CD₃OD)δ8.04，17.47，43.47，51.67，60.46，127.68，130.30，132.37，139.42，141.14，141.74，143.74，155.02.

Example 59 (general method I)

N- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } acetamide, dihydrochloride

Starting from 1- (5-bromo-pyridin-2-yl) -4-isopropyl-piperazine and 4-acetamidophenylboronic acid,

the title compound was prepared in an analogous manner to that described in example 56.

¹H NMR(400MHz，DMSO-d₆)δ11.25(brs，1H)，10.18(s，1H)，8.38(s，1H)，8.16(d，1H)，7.70(d，2H)，7.62(d，2H)，7.28(d，1H)，4.53(d，2H)，3.65-3.45(m，5H)，3.20-3.08(m，2H)，2.06(s，3H)，1.33(d，6H)。

C₂₀H₂₆N₄O，2x HCl，1.5x H₂Microanalysis of O:

calculated values: c: 54.80 percent; h: 7.13 percent; n: 12.78 percent;

measured value: c: 54.55 percent; h: 6.84%, N: 12.42 percent.

Example 60 (general method L)

Cyclopropanecarboxylic acid [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] amide, dihydrochloride

The title compound is prepared in analogy to the procedure described in example 176, starting from 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenylamine and cyclopropanecarboxylic acid.

¹H NMR(400MHz，DMSO-d₆)δ11.24(brs，1H)，10.52(s，1H)，8.70(s，1H)，8.47(s，1H)，7.92(d，2H)，7.72(d，2H)，4.49(d，2H)，3.55-3.44(m，5H)，3.15-3.04(m，2H)，1.91-1.83(m，1H)，1.32(d，6H)，0.83-0.75(m，4H)。

C₂₁H₂₇N₅O，2x HCl，2.25x H₂Microanalysis of O:

calculated values: c: 52.67 percent; h: 7.05 percent; n: 14.62 percent;

measured value: c: 52.79 percent; h: 7.00%, N: 14.53 percent.

Example 61 (general method L)

2-cyclopropyl-N- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] acetamide, dihydrochloride

The title compound is prepared in an analogous manner to that described in example 176, starting from 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenylamine and cyclopropylacetic acid.

¹H NMR(400MHz，DMSO-d₆)δ11.00(brs，1H)，10.06(s，1H)，8.71(s，1H)，8.46(s，1H)，7.92(d，2H)，7.71(d，2H)，4.49(d，2H)，3.52-3.42(m，5H)，3.15-3.04(m，2H)，2.23(d，2H)，1.30(d，6H)，1.10-1.00(m，1H)，0.50-0.44(m，2H)，0.22-0.17(m，2H)。

C₂₂H₂₉N₅O，2x HCl，0.75x H₂Microanalysis of O:

calculated values: c: 56.71 percent; h: 7.03 percent; n: 15.05 percent;

measured value: c: 56.51 percent; h: 6.73%, N: 14.82 percent.

Example 62 (general method L)

4-Methoxycyclohexanecarboxylic acid [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] amide, dihydrochloride

From 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']The title compound was prepared by an analogous method to that described in example 176 starting with bipyrazinyl-5' -yl) phenylamine and 4-methoxycyclohexanecarboxylic acid. ¹H NMR(400MHz，DMSO-d₆)δ11.22(brs，1H)，10.08(d，1H)，8.71(s，1H)，8.48(s，1H)，7.93(d，2H)，7.71(d，2H)，4.51(d，2H)，3.55-3.38(m，5H)，3.25+3.22(2x s，3H)，3.16-3.04(m，2H)，2.47-2.29(m，1H)，2.11-1.06(m，14H)。

C₂₅H₃₅N₅O₂，2x HCl，1.25x H₂Microanalysis of O:

calculated values: c: 56.33 percent; h: 7.47%; n: 13.14 percent;

measured value: c: 56.27 percent; h: 7.38%, N: 12.61 percent.

Example 63 (general method K)

4- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } morpholine, trifluoroacetate salt

The title compound is prepared by an analogous method to that described in example 153 starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzaldehyde and morpholine.

¹H NMR(300MHz，D₂O)δ8.29(dd，1H)，8.21(d，1H)，7.65(d，2H)，7.52(d，2H)，7.34(d，1H)，4.36-4.32(m，4H)，4.02-3.98(m，2H)，3.71-3.50(m，7H)，3.37-3.12(m，6H)，1.28(d，6H)。

HPLC (method D): t is t_r＝2.45min(97％)。

Example 64 (general method A)

4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzonitrile

The title compound was prepared in analogy to the procedure described for example 1, starting from 1-isopropylpiperazine and 4- (2-chloro-pyrimidin-5-yl) benzonitrile.

¹H NMR(400MHz，DMSO-d₆)δ11.34(brs，1H)，8.91(s，2H)，7.92(s，4H)，4.81(d，2H)，3.63-3.43(m，5H)，3.12-3.01(m，2H)，1.31(d，6H)。

C₁₈H₂₁N₅，2x HCl，0.75x H₂Microanalysis of O:

calculated values: c: 54.90 percent; h: 6.27 percent; n: 17.78%;

measured value: c: 55.23 percent; h: 6.45%, N: 17.54 percent.

Example 65

N- {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzyl } acetamide dihydrochloride

The title compound is prepared in analogy to the procedure described for example 39, starting from 4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzonitrile.

¹H NMR(300MHz，CDCl₃)δ8.79(s，2H)，7.53(d，2H)，7.45(d，2H)，5.06(d，2H)，4.47(s，2H)，4.15-4.01(m，2H)，3.65-3.52(m，3H)，3.32-3.19(m，2H)，2.13(s，3H)，1.48(d，6H)。

HPLC (method a): t is t_r＝6.66min(100％)。

C₂₀H₂₇N₅O，2x HCl，4x H₂Microanalysis of O:

calculated values: c: 48.19 percent; h: 7.48 percent; n: 14.05 percent;

Measured value: c: 48.19 percent; h: 7.03%, N: 13.66 percent.

Example 66 (general method I)

4- [6- (4-Cyclopropylpiperazin-1-yl) -piperidin-3-yl ] -N, N-dimethylbenzamide, dihydrochloride

Step 1:

1- (5-bromopyridin-2-yl) -piperazine

A mixture of piperazine (107g, 1.24mol) and 2-chloro-5-bromopyridine (30g, 156mmol) in toluene (150mL) was heated at 130 ℃ for 2 hours. The reaction mixture was cooled to room temperature,

and toluene (400mL) and water (200mL) were added. The organic phase was separated and the aqueous phase was extracted once with toluene (100 mL). The combined organic phases were washed with water (150mL) and brine (100mL), dried over magnesium sulfate and evaporated to dryness in vacuo to yield 30.1g (80%) of 1- (5-bromopyridin-2-yl) -piperazine.

¹H NMR(400MHz，CDCl₃) Δ 8.19(d, 1H), 7.52(dd, 1H), 6.54(d, 1H), 3.47(m, 4H), 2.97(m, 4H), 1.77 (broad s, 1H)

Step 2:

1- (5-bromopyridin-2-yl) -4-cyclopropylpiperazine:

by reacting [ (1-ethoxy-cyclopropyl) oxy group]Trimethylsilane (26mL, 129.3mmo1) was added to a solution of 1- (5-bromopyridin-2-yl) -piperazine (15g, 62.0mmol) in THF (120 mL). Water (24mL), acetic acid (11mL) and 1M NaCNBH₃A mixture in THF (90mL, 90mmo1) was added to the reaction mixture, which was then heated at reflux temperature for 3 hours. The resulting solution was cooled to room temperature and evaporated to dryness in vacuo. The residue was dissolved in a mixture of dichloromethane (200mL) and water (50mL) and 4N sodium hydroxide (20mL) was added to a pH of 8-9. The organic phase was separated and the aqueous phase was further extracted with dichloromethane (100 mL). The combined organic phases were evaporated to dryness in vacuo and the residue was purified on a silica gel column (gradient: 5% mixture of ethyl acetate in heptane-100% ethyl acetate over 40 min.). 13.1g (75%) of 1- (5-bromopyridin-2-yl) -4-cyclopropylpiperazine were obtained.

¹H NMR(400MHz，CDCl₃)δ8.19(d，1H)，7.52(dd，1H)，6.54(d，1H)，3.47(m，4H)，2.70(m，4H)，1.64(m，1H)，0.48(m，4H)。

And step 3:

a mixture of 1- (5-bromopyridin-2-yl) -4-cyclopropylpiperazine (2.5g, 8.86mmol), 4- (N, N-dimethylaminocarbonyl) -phenylboronic acid (2.5g, 13.0mmol), tetrakis (triphenylphosphine) palladium (0) (300mg, 0.26mmol) and anhydrous sodium carbonate (2.0g, 18.9mmol) was purged with nitrogen. 1, 2-Dimethoxyethane (30mL) and water (7mL) were added and the reaction mixture was heated at 80 ℃ for 1.5 hours and filtered after cooling to 0-5 ℃. The crystals were washed with water (20mL), dried, and then dissolved in acetone (130 mL). Adding HCl_gMixture in methanol gave 1.41g (37%) of 4- [6- (4-cyclopropylpiperazin-1-yl) -piperidin-3-yl]-N, N-dimethylbenzamide, dihydrochloride.

¹H NMR(400MHz，DMSO-d₆)δ11.36(brs，1H)，8.50(d，1H)，8.18(dd，1H)7.75(d，2H)，7.50(d，2H)，7.26(d，1H)，4.51(d，2H)，3.56(m，4H)，3.53(brs，2H)，3.00(s，3H)，2.96(s，3H)，2.89(brs，1H)，1.20(m，2H)，0.82(m，2H)。

Example 67 (general method I)

N- {4- [6- (4-Cyclopropylpiperazin-1-yl) pyridazin-3-yl ] -2-methoxyphenyl } acetamide

The title compound was prepared from 3-chloro-6- (4-cyclopropyl-piperazin-1-yl) -pyridazine (4.6g, 19.3mmol), 1M sodium carbonate solution (50mL, 100, 5mmol), acetonitrile (50mL), bis (triphenylphosphine) palladium dichloride (0.68g, 0.96mmol) and N- [ 2-methoxy-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl ] acetamide (6.73g, 23.1mmol) in 3.39g (40%) yield.

¹H NMR(400MHz，CDCl₃)δ8.44(d，1H)，7.94(d，1H)，7.86(s，1H)，7.66(d，1H)，7.34(dd，1H)，6.98(d，1H)，3.98(s，3H)，3.69(m，4H)，2.77(m，4H)，2.23(s，3H)，1.67(m，1H)，0.49(m，4H)。

Example 68 (general method I)

N- {3- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] phenyl) acetamide

Step 1:

1- (5-bromo-4-methyl-pyridin-2-yl) -4-isopropyl-piperazine

To a solution of 2, 5-dibromo-4-methyl-pyridine (5.0g, 20mmol) and isopropyl-piperazine (25.6g, 200mmol) was added pyridine (2.06g, 206 mmol). The reaction mixture was refluxed under nitrogen for 5 hours. Brine was added and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine and 0.5N hydrochloric acid. With Na₂CO₃The acidic layer was made basic to pH8 and then treated with CH₂Cl₂And (4) extracting. The organic extract was dried (Na)₂SO₄) And concentrated to give 5.4g (90%) of 1- (5-bromo-4-methyl-pyridin-2-yl) -4-isopropyl-piperazine.

¹H NMR(300MHz，CDCl₃)δ8.15(s，1H)，6.51(s，1H)，3.50(t，4H)，2.81-2.65(m，1H)，2.61(t，4H)，2.29(s，3H)，1.08(d，6H)。

Step 2:

to a solution of 1- (5-bromo-4-methyl-pyridin-2-yl) -4-isopropyl-piperazine (0.59g, 2mmol) in 1, 4-bisTo a solution of alkane (12mL) and water (3mL) was added 3-acetylamino-phenylboronic acid (430mg, 2.4mmol), Pd (PPh)₃)₄(231mg, 0.2mmol) and TEA (404mg, 4 mmol). The resulting mixture was degassed and heated at 100 ℃ under nitrogen for 4 hours. The mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (Na)₂SO₄) Concentrated and purified by silica gel column chromatography using CH ₂CI₂MeOH (100: 1) elution. 138mg (15%) of the title compound are obtained.

¹H NMR(300MHz，CDCl₃)δ8.00(s，1H)，7.57-7.50(m，2H)，7.50-7.29(m，2H)，7.00(d，1H)，6.52(s，1H)，3.59(t，4H)，2.79-2.70(m，1H)，2.66(t，4H)，2.30(s，3H)，2.16(s，3H)，1.10(d，6H)。

HPLC (method D): t is t_r＝3.90min(96％)。

Example 69 (general method I)

N- {3- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridin-3-yl ] phenyl } acetamide

The title compound was prepared in analogy to the procedure described for example 68, starting from 1- (5-bromo-3-methyl-pyridin-2-yl) -4-isopropyl-piperazine and 3-acetylamino-phenylboronic acid.¹H NMR(300MHz，CDCl₃)δ8.35(d，1H)，7.77(s，1H)，7.58(d，1H)，7.46(d，2H)，7.35(t，1H)，3.32(t，4H)，2.92-2.75(m，5H)，2.30(s，3H)，2.19(s，3H)，1.14(d，6H)。

HPLC (method D): t is t_r＝4.49min(97％)。

Example 70 (general method I)

N- {4- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] phenyl } acetamide, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 68, starting from 1- (5-bromo-4-methyl-pyridin-2-yl) -4-isopropyl-piperazine and 4-acetylamino-phenylboronic acid.¹H NMR(300MHz，CD₃OD)δ7.91(s，1H)，7.67(d，2H)，7.28(d，2H)，7.18(s，1H)，4.75-3.35(m，9H)，2.35(s，3H)，2.14(s，3H)，1.41(d，6H)。

HPLC (method D): t is t_r＝2.93min(98％)。

Example 71 (general method I)

N- {4- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridin-3-yl ] phenyl } acetamide, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 68, starting from 1- (5-bromo-3-methyl-pyridin-2-yl) -4-isopropyl-piperazine and 4-acetylamino-phenylboronic acid.

¹H NMR(300MHz，CD₃OD)δ8.37(d，1H)，8.06(s，1H)，7.68(d，2H)，7.58(d，2H)，3.99-3.71(m，2H)，3.62-3.55(m，3H)，3.52-3.31(m，4H)，2.44(s，3H)，2.13(s，3H)，1.42(d，6H)。

HPLC (method E): t is t_r＝3.53min(98％)。

Example 72 (general method I)

N- {4- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridazin-3-yl ] phenyl) acetamide, trifluoroacetate salt

Step 1:

n- [4- (6-chloro-5-methyl-pyridazin-3-yl) -phenyl ] -acetamide and N- [4- (6-chloro-4-methyl-pyridazin-3-yl) -phenyl ] -acetamide

4-Acylaminophenylboronic acid (2.7g, 15mmol), 3, 6-dichloro-4-methyl-pyridazine (1.6g, 10mmol) and Pd (PPh)₃)₄A solution of (1.2g, 1mmol) in DMF (58mL, degassed) was stirred at room temperature for 1 hour. Sodium carbonate (3.9g solution in 15mL water, degassed) was then added and the mixture was heated at 80 ℃ overnight with stirring. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (30mL), washed with brine, dried (sodium sulfate) and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc/petroleum ether 1: 1). 1g (39%) of N- [4- (6-chloro-5-methyl-pyridazin-3-yl) -phenyl are obtained]-acetamide and N- [4- (6-chloro-4-methyl-pyridazin-3-yl) -phenyl]A mixture of acetamides, which is used directly in the next step.

Step 2:

a mixture of the isomer (0.85g, 3.2mmol) obtained in the previous step and 1-isopropyl-piperazine (2.1g, 16mmol) was heated at 200 ℃ under nitrogen for 1 hour. The mixture was cooled to room temperature and diluted with dichloromethane (15 mL). The mixture was washed with brine, dried (sodium sulfate) and concentrated to give the crude product, which was purified by preparative HPLC method F to afford 261mg (8%) of N- {4- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridazin-3-yl ] -phenyl } -acetamide and 74mg (2%) of N- {4- [6- (4-isopropyl-piperazin-1-yl) -5-methyl-pyridazin-3-yl ] -phenyl } -acetamide as TFA salt.

N- {4- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridazin-3-yl ] -phenyl } -acetamide:

¹H NMR(300MHz，CD₃OD)δ7.89(s，1H)，7.82(d，2H)，7.56(d，2H)，4.70-3.30(m，9H)，2.44(s，3H)，2.17(s，3H)，1.42(d，6H)。

HPLC (method D): t is t_r＝2.88min(99％)。

Example 73 (general method I)

N- {3- [6- (4-Cyclopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] phenyl } acetamide, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 68, starting from 1- (5-bromo-4-methyl-pyridin-2-yl) -4-cyclopropyl-piperazine and 3-acetylamino-phenylboronic acid.¹H NMR(300MHz，CD₃OD)δ7.92(s，1H)，7.72(d，1H)，7.53-7.40(m，2H)，7.34(s，1H)，7.10-7.05(m，1H)，4.05-3.92(m，4H)，3.68-3.58(m，4H)，2.95-2.85(m，1H)，2.39(s，3H)，2.13(s，3H)，1.15-0.95(m，4H)。

HPLC (method D): t is t_r＝2.99min(94％)。

Example 74 (general method I)

3- [6- (4-Cyclopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 68, starting from 1- (5-bromo-4-methyl-pyridin-2-yl) -4-cyclopropyl-piperazine and 3- (N, N-dimethylamino-carbonyl) -phenylboronic acid.¹H NMR(300MHz，CD₃OD)：δ7.96(s，1H)，7.62-7.52(m，1H)，7.52-7.45(m，2H)，7.45-7.38(m，1H)，4.05-3.88(m，4H)，3.68-3.55(m，4H)，3.11(s，3H)，3.03(s，3H)，2.95-2.85(m，1H)，2.37(s，3H)，1.15-0.95(m，4H)。

HPLC (method D): t is t_r＝3.04min(98％)。

Example 75 (general method I)

N- {4- [6- (4-Cyclopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] phenyl } acetamide, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 68, starting from 1- (5-bromo-4-methyl-pyridin-2-yl) -4-cyclopropyl-piperazine and 4-acetylamino-phenylboronic acid.¹HNMR(300MHz，CD₃OD)：δ7.90(s，1H)，7.67(d，2H)，7.35-7.22(m，3H)，4.05-3.88(m，4H)，3.68-3.55(m，4H)，2.95-2.82(m，1H)，2.37(s，3H)，2.14(s，3H)，1.15-0.95(m，4H)。

HPLC (method D): t is t_r＝2.68min(99％)。

Example 76 (general method I)

4- [6- (4-Cyclopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 68, starting from 1- (5-bromo-4-methyl-pyridin-2-yl) -4-cyclopropyl-piperazine and 4- (N, N-dimethylamino-carbonyl) -phenylboronic acid.¹H NMR(300MHz，CD₃OD)：δ7.95(s，1H)，7.55(d，2H)，7.46(d，2H)，7.34(s，1H)，4.05-3.88(m，4H)，3.68-3.55(m，4H)，3.12(s，3H)，3.04(s，3H)，2.97-2.85(m，1H)，2.39(s，3H)，1.18-0.95(m，4H)。

HPLC (method D): t is t_r＝3.04min(94％)。

Example 77 (general method I)

5-1, 3-benzodioxol-5-yl-2- (4-cyclopropylpiperazin-1-yl) pyrimidine, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 68 starting from 5-bromo-2- (4-cyclopropyl-piperazin-1-yl) -pyrimidine and 3, 4- (methylenedioxy) phenylboronic acid. Mp 275-.

¹H NMR(300MHz，DMSO-d₆)δ11.0(brs，1H)，8.73(s，2H)，7.30(s，1H)，7.14(d，1H)，7.01(d，1H)，6.06(s，2H)，4.76-4.71(m，2H)，3.58-3.18(m，6H)，2.91-2.80(m，1H)，1.20-1.12(m，2H)，0.86-0.78(m，2H)。

HPLC (method Rx): t is t_r＝11.49min(100％)。

Example 78 (general method I)

N- {4- [6- (4-isopropylperhydro-1, 4-diaza)-1-yl) pyridazin-3-yl]Phenyl } acetamide, dihydrochloride

From 1- (6-chloro-pyridazin-3-yl) -4-isopropyl-perhydro-1, 4-diazaAnd 4-Acylaminophenylboronic acid the title compound is prepared in an analogous manner to that described in example 68.¹HNMR(400MHz，CD₃OD)δ8.43(d，1H)，8.03(d，1H)，7.94(m，2H)，7.84(m，2H)，4.36(m，1H)，4.17(m，1H)，4.03(m，1H)，3.73(m，4H)，3.42(m，2H)，2.50(m，1H)，2.39(m，1H)，2.17(s，3H)，1.41(d，6H)。

HPLC-MS (method G): m +1 is 354; t is t_r＝0.73min.

Example 79 (general method I)

4- [6- (4-isopropyl-perhydro-1, 4-diaza)-1-yl) -pyridazin-3-yl ]-phenyl amines

From 1- (6-chloro-pyridazin-3-yl) -4-isopropyl-perhydro-1, 4-diazaAnd 4-Aminophenylboronic acid, pinacol cyclic ester by an analogous method to that described in example 68, the title compound was prepared.¹H NMR(400MHz，CDCl₃)δ7.82(d，2H)，7.53(d，1H)，6.76(m，3H)，3.86(t，2H)，3.77(m，4H)，2.93 (heptad et, 1H), 2.81(m, 2H), 2.58(m, 2H), 1.95(m, 2H), 1.00(d, 6H).

HPLC-MS (method G): m +1 ═ 312; t is t_r＝0.61min

Example 80 (general method I)

N- {4- [6- (4-cyclopropyl- [1, 4] diazepan-1-yl) pyridazin-3-yl ] phenyl } acetamide dihydrochloride

From 1- (6-chloro-pyridazin-3-yl) -4-cyclopropyl-perhydro-1, 4-diazaAnd 4-Acylaminophenylboronic acid the title compound is prepared in an analogous manner to that described in example 68.¹H NMR(400 MHz，CD₃OD) δ 8.47(d, 1H), 8.08(d, 1H), 7.94(d, 2H), 7.85(d, 2H), 4.33 (wide m, 1H), 4.12 (wide m, 1H), 3.91 (wide m, 4H), 3.62 (wide m, 2H), 2.97 (heptad, 1H), 2.55 ((wide m, 1H), 2.43 (wide m, 1H), 2.17(s, 3H), 1.24 (wide m, 2H), 1.01(d, 2H).

HPLC-MS (method G): m +1 ═ 352; t is t_r＝0.82min

Example 81 (general method I)

7- [6- (4-cyclopropyl-piperazin-1-yl) -pyridazin-3-yl]-4-methyl-3, 4-dihydro-2H-1, 4-benzoOxazines, dihydrochloride

From 3-chloro-6- (4-cyclopropyl-piperazin-1-yl) -pyridazine and 4-methyl-7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydro-2H-1, 4-benzoOxazine starting, the title compound was prepared in analogy to the procedure described for example 68.¹H NMR(400MHz，DMSO-d₆) δ 8.47(d, 1H), 8.04(d, 1H), 7.61(m, 1H), 7.49(m, 1H), 6.85(d, 1H), 4.50 (wide m, 2H), 4.26(m, 2H), 3.61 (wide m, 4H), 3.40(m, 4H), 2.97(s, 3H), 2.88 (wide m, 1H), 1.23(m, 2H), 0.82(m, 2H).

HPLC-MS (method G): m +1 ═ 352; t is t_r＝0.83min.

Example 82 (general method I)

3- (4-Cyclopropylpiperazin-1-yl) -6- (2, 3-dihydro-1, 4-benzodiEn-6-yl) pyridazine, dihydrochloride

From 3-chloro-6- (4-cyclopropyl-piperazin-1-yl) -pyridazine and 1, 4-benzodiStarting with alkane-6-boronic acid, the title compound was prepared in analogy to the procedure described for example 68.¹H NMR(400MHz，DMSO-d₆) δ 8.38(d, 1H), 7.95(d, 1H), 7.63(m, 1H), 7.58(m, 1H), 7.05(d, 1H), 4.57 (wide m, 2H), 4.32(m, 4H), 3.63 (wide m, 4H), 3.39 (wide m, 2H), 2.88 (wide m, 1H), 1.23(m, 2H), 0.82(m, 2H).

HPLC-MS (method G): m +1 ═ 339; t is t_r＝0.84min

Example 83 (general method I)

5- [6- (4-Cyclopropylpiperazin-1-yl) pyridazin-3-yl ] -1H-indole, dihydrochloride

The title compound is prepared in analogy to the procedure described for example 68 starting from 3-chloro-6- (4-cyclopropyl-piperazin-1-yl) -pyridazine and 5-indolboronic acid.¹H NMR(400MHz，DMSO-d₆)δ11.49(s，1H)，8.43(d，1H)，8.28(s，1H)，7.93(d，1H)，7.82(dd，1H)，7.57(d，1H)，7.48(t，1H)，6.58(s，1H)，4.54(d，2H)，3.70-3.45(m，4H)，3.45-3.30(m，2H)，2.88(m，1H)，1.21(m，2H)，0.83(m，2H)。

HPLC-MS (method G): m +1 ═ 320; t is t_r＝0.75min

Example 84 (general method I)

{4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] phenyl } acetonitrile, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-2- (4-isopropylpiperazin-1-yl) -pyrimidine and 4-cyanomethyl-phenylboronic acid.

Example 85 (general method I)

N- {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] phenyl } acetamide, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-2- (4-isopropylpiperazin-1-yl) -pyrimidine and 4-acetamidophenyl-boronic acid.

Mp＞275℃.

¹H-NMR(400MHz，CD₃OD)δ8.65(s，2H)，7.65(d，2H)，7.50(d，2H)，5.0(m，2H)，3.65-3.55(m，3H)，3.35-3.25(m，2H)，3.20-3.10(m，2H)，2.15(s，3H)，1.40(d，6H)。

HPLC-MS (method G): m +1 ═ 340; t is t_r＝0.919min.

Example 86 (general method I)

1- {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] phenyl } ethanone dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-2- (4-isopropylpiperazin-1-yl) -pyrimidine and 4-acetylphenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.75(s，2H)，8.10(d，2H)，7.70(d，2H)，5.10-5.00(m，2H)，3.65-3.55(m，3H)，3.40-3.30(m，2H)，3.25-3.15(m，2H)，2.65(s，3H)，1.40(d，6H)。

HPLC-MS (method G): m +1 ═ 322; t is t_r＝1.07min.

Example 87 (general method I)

2- (4-isopropylpiperazin-1-yl) -5-pyridin-3-ylpyrimidine, trihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-2- (4-isopropylpiperazin-1-yl) -pyrimidine and 3-pyridylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ9.15(s，1H)，8.85(s，2H)，8.80(m，2H)，8.05(m，1H)，5.15-5.05(m，2H)，3.65-3.55(m，3H)，3.45-3.35(m，2H)，3.25-3.10(m，2H)，1.40(d，6H)。

HPLC-MS (method G): 284 for M + 1; t is t_r＝0.38min.

Example 88 (general method I)

2- (4-isopropylpiperazin-1-yl) -5-pyridin-4-ylpyrimidine, trihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-2- (4-isopropylpiperazin-1-yl) -pyrimidine and 4-pyridylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ9.10(s，2H)，8.80(d，2H)，8.30(d，2H)，5.25-5.05(m，2H)，3.70-3.55(m，3H)，3.55-3.35(m，2H)，3.35-3.15(m，2H)，1.40(d，6H)。

HPLC-MS (method G): 284 for M + 1; t is t_r＝0.337min.

Example 89 (general method I)

{4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] phenyl } dimethylamine, trihydrochloride

The title compound was prepared in analogy to the procedure described for example 57 starting from 5-bromo-2- (4-isopropylpiperazin-1-yl) -pyrimidine and N, N-dimethylamino-phenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.70(s，2H)，7.75(d，2H)，7.55(d，2H)，5.10-5.00(m，2H)，3.65-3.55(m，3H)，3.40-3.30(m，2H)，3.25(s，6H)，3.22-3.10(m，2H)，1.40(d，6H)。

HPLC-MS (method G): m +1 ═ 326; t is t_r＝0.729min.

Example 90 (general method I)

3- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] -N, N-dimethylbenzamide, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57 starting from 5-bromo-2- (4-isopropylpiperazin-1-yl) -pyrimidine and 3- (dimethylamino-carbonyl) phenylboronic acid.

Mp＝217-220℃.

¹H-NMR(400MHz，CD₃OD)δ8.70(s，2H)，7.70(d，1H)，7.65(s，1H)，7.55(d，d，1H)，7.40(d，1H)，5.05-4.95(m，2H)，3.65-3.55(m，3H)，3.35-3.25(m，2H)，3.20-3.10(m，2H)，3.12(s，3H)，3.05(s，3H)，1.40(d，6H)。

HPLC-MS (method G): m +1 is 354; tr is 0.938min.

Example 91 (general method I)

N, N-diisopropyl-4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) benzamide, hydrochloride

The title compound was prepared in analogy to the procedure described for example 57 starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 4-diisopropylaminocarbonylphenylboronic acid.

¹H NMR(400MHz，DMSO-d₆)δ8.63(s，1H)，8.32(s，1H)，8.00(d，1H)，7.91(s，1H)，7.55(dd，1H)；7.33(d，1H)，4.60-4.50(m，2H)，3.95-3.85(m，1H)，3.70-3.60(m，1H)，3.65-3.55(m，3H)，3.25-3.10(m，4H)，1.60-1.50(brs，6H)，1.25-1.10(brs，6H)。

HPLC-MS (method G): m +1 ═ 410; t is t_r＝1.32min.

Example 92 (general method I)

[4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] - (4-methylpiperidin-1-yl) methanone, hydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and (4-methylpiperidin-1-yl) carbonylphenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.65(s，1H)，8.35(s，1H)，8.02(d，2H)，7.50(d，2H)，4.65-4.55(m，3H)，3.80-3.70(m，1H)，3.65-3.55(m，3H)，1.85-1.75(m，1H)，1.75-1.60(m，2H)，1.40(d，6H)，1.25-1.05(m，2H)，0.95(d，3H)。

HPLC-MS (method G): m +1 ═ 408; t is t_r＝1.31min.

Example 93 (general method I)

4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -N, N-dimethylbenzamide, hydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 4-dimethylaminocarbonylphenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.65(s，1H)，8.35(s，1H)，8.02(d，2H)，7.53(d，2H)，4.65-4.55(m，2H)，3.65-3.55(m，3H)，3.35-3.15(m，4H)，3.13(s，3H)，3.04(s，3H)，1.40(d，6H)。

HPLC-MS (method G): m +1 is 354; t is t_r＝0.93min.

Example 94 (general method I)

[3- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] morpholin-4-yl methanone, hydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and N- (morpholin-4-yl) 3-borono (borono) benzamide.

¹H-NMR(400MHz，CD₃OD)δ8.70(s，1H)，8.45(s，1H)，8.07(d，1H)，8.01(s，1H)，7.58(dd，1H)，7.45(d，1H)，4.75-4.65(m，2H)，3.85-3.43(m，11H)，3.40-3.20(m，4H)，1.40(d，6H)。

Example 95 (general method I)

N- {4- [5- (octahydropyrido [1, 2-a ] pyrazin-2-yl) pyrazin-2-yl ] phenyl } acetamide, hydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 2- (5-bromopiperazin-2-yl) octahydropyrido [1, 2-a ] pyrazine and 4-acetamidophenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.95(s，1H)，8.47(s，1H)，7.85(d，2H)，7.80(d，2H)，4.80-4.60(m，2H)，3.60-3.50(m，3H)，3.45-3.29(m，3H)，3.15-3.00(m，1H)，2.15(s，3H)，2.10-2.05(m，1H)，2.02-1.90(m，3H)，1.79-1.62(m，2H)。

HPLC-MS (method G): m +1 ═ 352; t is t_r＝0.92min.

Example 96 (general method I)

4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenol, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 4-hydroxyphenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ9.08(s，1H)，8.45(s，1H)，7.75(d，2H)，7.0(d，2H)，4.72(d，2H)，3.7-3.5(m，4H)，3.3(m，3H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 299; t is t_r＝1.045min.

Example 97 (general method I)

N- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] -N-methylamines, tris-trifluoroacetate salt

Step 1:

[4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] methyl carbamic acid tert-butyl ester, trifluoroacetic acid salt

Tert-butyl [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 ' ] bipyrazinyl-5 ' -yl) phenyl ] methylcarbamate, trifluoroacetic acid was prepared in analogy to the procedure described in example 59, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 ' ] bipyrazinyl and tert-butyl-N-methyl-N- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -carbamate.

¹H-NMR(400MHz，CDCl₃) δ 8.5(s, 1H), 8.15(s, 1H), 7.85(d, 2H), 7.25(d, 2H), 3.65(m, 4H), 3.45(s, 3H), 2.7 (heptad, 1H), 2.6(m, 4H), 1.45(s, 9H), 1.1(d, 6H).

HPLC-MS (method G): m +1 ═ 412; t is t_r＝1.60mm.

Step 2:

tert-butyl [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] methylcarbamate (0.38g, 0.92mmol) was dissolved in DCM (10mL) and TFA (10 mL).

The reaction mixture was stirred at room temperature for 2 hours and then evaporated in vacuo. The solid residue (20mg) was purified by preparative HPLC (method B).

¹H-NMR(400MHz，CDCl₃) δ 8.5(s, 1H), 8.2(s, 1H), 8.0(brs, 1H), 7.8(d, 2H), 7.35(d, 2H), 4.45(d, 2H), 3.7(m, 2H), 3.65 (heptad, 1H), 3.45(m, 4H), 3.1(s, 3H), 3.0(m, 2H), 1.4(d, 6H).

HPLC-MS (method G): m +1 ═ 312; t is t_r＝0.909min.

Example 98 (general method I)

4-isopropyl-5 '- (4-morpholin-4-ylphenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, trihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 4-morpholino-phenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.90(s，1H)，8.68(s，1H)，8.18(d，2H)，8.01(d，2H)，4.81-4.75(m，2H)，4.20(m，4H)，3.80(m，4H)，3.76-3.65(m，5H)，3.44-3.32(m，2H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 368; t is t_r＝1.021min.

Example 99 (general method I)

5 '-1, 3-benzodioxol-5-yl-4-isopropyl-3, 4, 5, 6-tetrahydro-2H-1, 2' -bipyrazinyl, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57 starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 3, 4-methylenedioxyphenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.70(s，1H)，8.47(s，1H)，7.40(m，2H)，6.95(d，1H)，6.03(s，2H)，4.70-4.62(m，2H)，3.67-3.57(m，3H)，3.42-3.32(m，2H)，3.31-3.21(m，2H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 327; t is t_r＝1.115min.

Example 100 (general method I)

4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -2-methoxyphenylamine, trihydrochloride

The title compound was prepared in analogy to the procedure described for example 57 starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 4-amino-3-methoxyphenylboronic acid pinacol ester.

¹H-NMR(400MHz，CD₃OD)δ8.80(s，1H)，8.50(s，1H)，7.80(s，1H)，7.65(d，1H)，7.50(s，1H)，4.75-4.65(m，2H)，4.10(s，3H)，3.70-3.60(m，3H)，3.55-3.45(m，2H)，3.35-3.25(m，2H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 328; t is t_r＝0.676min.

Example 101 (general method I)

2-chloro-4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -6-methoxyphenol, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 3-chloro-4-hydroxy-5-methoxyphenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.85(s，1H)，8.38(s，1H)，7.48(s，1H)，7.43(s，1H)，4.73-4.65(m，2H)，4.00(s，3H)，3.70-3.60(m，3H)，3.58-3.46(m，2H)，3.35-3.25(m，2H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 363, r_t＝1.066min.

Example 102 (general method I)

5 '- (3, 4-Dimethoxyphenyl) -4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 3, 4-dimethoxyphenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.65(s，1H)，8.3(s，1H)，7.55(brs，1H)，7.45(dd，1H)，7.05(dd，1H)，4.6(d，2H)，3.9(s，3H)，3.85(s，3H)，3.6(m，3H)，3.35(m，2H)，3.2(m，2H)，1.45(d，6H)。

¹³C-NMR(400MHz，CD₃OD)δ154.38，151.64，151.25，143.61，140.62，130.88，130.66，120.21，113.47，111.03，60.43，56.92，48.79，43.77，17.53.

HPLC-MS (method G): m +1 ═ 343; t is t_r＝1.051min.

Example 103 (general method I)

4-isopropyl-5 '- (3, 4, 5-trimethoxyphenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 3, 4, 5-trimethoxyphenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.93(s，1H)，8.40(s，1H)，7.20(s，2H)，4.73-4.68(m，2H)，3.95(s，6H)，3.81(s，3H)，3.70-3.60(m，3H)，3.57-3.47(m，2H)，3.35-3.25(m，2H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 373; t is t_r＝1.106min.

Example 104 (general method I)

N- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) benzyl ] acetamide, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57 starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 4- (N-acetylamino-methyl) phenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.65(s，1H)，8.45(s，1H)，7.85(d，2H)，7.35(d，2H)，4.6(d，2H)，4.4(s，2H)，3.6(m，3H)，3.1-3.4(m，4H)，2.05(s，3H)，1.45(d，6H)。

HPLC-MS (method G): m +1 is 354; t is t_r＝0.867min.

Example 105 (general method I)

4, 4 ' "-diisopropyl-3, 4, 5, 6, 3 '", 4 ' ", 5 '", 6 ' "-octahydro-2H, 2 '" H- [1, 2 '; 5', 2 "; 5 ', 1' ] Tetramethylpyrazine (quaterpyrazine), bis-trifluoroacetate salt

The title compound was isolated as a by-product of example 104.

¹H-NMR(400MHz，CD₃OD)δ8.9(s，1H)，8.35(s，1H)，4.65(d，2H)，3.65(m，3H)，3.15-3.4(m，5H)，1.4(d，6H)。

¹³C-NMR(400MHz，CD₃OD)δ155.04，141.60，140.50，131.63，60.40，48.62，43.62，17.45.

Example 106 (general method I)

4-isopropyl-5 '- (6-methoxypyridin-3-yl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 2-methoxy-5-pyridineboronic acid.

¹H NMR(400MHz，CDCl₃)δ8.75(dd，1H)，8.46(dd，1H)，8.22(s，1H)，8.2(dd，1H)，7.42(brs，3H)，6.93(d，1H)，4.49(d，2H)，4.08(s，3H)，3.72-3.41(m，5H)，3.20-2.79(m，2H)，1.39(d，6H)。

¹³C-NMR(400MHz，CDCl₃)δ161.82，150.81，141.04，137.90，136.58，136.12，128.39，124.52，109.14，56.50，52.87，48.49，45.57，40.21，14.72.

HPLC-MS (method G): m +1 ═ 314; t is t_r＝0.965min.

Example 107 (general method I)

N, N-diisopropyl-4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzamide, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 1- (5-bromo-pyridin-2-yl) -4-isopropyl-piperazine and 4- ((N, N-diisopropylamino) carbonyl) phenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.5(dd，1H)，8.45(d，1H)，7.75(d，2H)，7.15(d，1H)，7.45(d，2H)，4.55(d，2H)，3.6-3.9(m，7H)，3.4(t，2H)，1.55(m，6H)，1.45(d，6H)，1.15(m，6H)。

HPLC-MS (method G): m +1 ═ 409; t is t_r＝1.229min.

Example 108 (general method I)

{4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } - (4-methylpiperidin-1-yl) methanone, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 1- (5-bromo-pyridin-2-yl) -4-isopropyl-piperazine and 4- ((4-methylpiperidin-1-yl) -carbonyl) phenylboronic acid.

¹H NMR(400MHz，CDCl₃) δ (d, 1H), 7.75(dd, 2H), 7.55(d, 2H), 7.45(d, 2H), 6.7(d, 1H), 4.65(brs, 1H), 3.75(brs, 1H), 3.6(t, 4H), 3.0(brs, 1H), 2.75 (heptad, 1H), 2.7(t, 4H), 1.85-1.6(m, 3H), 1.4-1.15(m, 2H), 1.1(d, 6H), 0.95(d, 3H).

¹³C-NMR(400MHz，CDCl₃)δ170.10，158.82，147.90，146.18，139.50，135.96，134.57，132.00，128.42，127.61，125.91，125.06，106.74，54.64，54.55，48.47，48.37，48.16，45.38，44.88，42.56，34.71，33.87，31.15，21.75，18.50，18.43.

HPLC-MS (method G): m +1 ═ 407; t is t_r＝1.20min.

Example 109 (general method I)

6 '- (4-Isopropylpiperazin-1-yl) -6-methoxy- [3, 3' ] bipyridinyl, trifluoroacetate salt

¹H-NMR(400MHz，CD₃OD)δ8.5(d，1H)，8.37(m，2H)，8.15(d，1H)，7.55(d，1H)，7.05(d，1H)，4.5(m，2H)，4.05(s，3H)，3.4-3.9(m，6H)，1.45(d，6H)。

¹³C-NMR(400MHz，CD₃OD)δ165.51，154.05，144.56，143.82，140.69，137.18，126.29，125.93，114.58，112.86，60.68，55.97，48.93，45.24，17.74.

Example 110 (general method I)

4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) benzonitrile, bis-trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 4-cyanophenyl-boronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.75(s，1H)，8.45(s，1H)，8.1(d，2H)，7.75(d，2H)，4，7(m，2H)，3.6(m，3H)，3.2-3.5(m，4H)，1.4(d，6H)。

Example 111 (general method I)

4-isopropyl-5 '- (4-trifluoromethylphenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, trifluoroacetate

The title compound was prepared in analogy to the procedure described for example 57 starting from 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 4- (trifluoromethyl) phenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.75(s，1H)，8.45(s，1H)，8.15(d，2H)，7.75(d，2H)，4.7(m，2H)，3.7-3.55(m，3H)，3.4-3.15(m，4H)，1.4(d，6H)。

¹³C-NMR(400MHz，CD₃OD)δ169.07，154.98，142.12，140.85，132.28，127.54，127.19，60.417，43.55，17.45.

HPLC-MS (method G): m +1 ═ 351; t is t_r＝1.523min.

Example 112 (general method I)

6 '- (4-Isopropylpiperazin-1-yl) -5-trifluoromethyl- [2, 3' ] bipyridinyl, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 1- [5- (5, 5-dimethyl-1, 3, 2-dioxaborolan (dioxabornanin) -2-yl) -pyridin-2-yl ] -4-isopropyl-piperazine and 2-bromo-5-trifluoromethylpyridine.

¹H-NMR(400MHz，CDCl₃) δ 8.85(d, 1H), 8.8(d, 1H), 8.2(dd, 1H), 7.9(dd, 1H), 7.7(d, 1H), 6.65(d, 1H), 3.65(m, 4H), 2.75 (heptad, 1H), 2.6(m, 4H), 1.1(d, 6H).

HPLC-MS (method G): m +1 ═ 351; t is t_r＝1.203min.

Example 113 (general method I)

4-isopropyl-5 '- [4- (piperidine-1-sulfonyl) phenyl ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, hydrochloride

From 5-bromo-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2']The title compound was prepared by an analogous method to that described in example 57 starting from bipyrazine and 4- (piperidine-1-sulfonyl) phenylboronic acid.¹H-NMR(400MHz，CD₃OD)δ8.75(s，1H)，8.45(s，1H)，8.18(d，2H)，7.82(d，2H)，4.75-4.68(m，2H)，3.80-3.55(m，4H)，3.45-3.22(m，4H)，3.00(m，4H)，1.68-1.60(m，4H)，1.45(m，7H)。

Example 114 (general method I)

4-isopropyl-5 '- (4- (piperidin-1-yl) phenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, trihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 4- (piperidin-1-yl) phenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.80(s，1H)，8.52(s，1H)，8.18(d，2H)，7.89(d，2H)，4.77-4.68(m，2H)，3.74-3.60(m，7H)，3.58-3.46(m，2H)，3.35-3.25(m，2H)，2.17-2.08(m，4H)，1.90-1.80(m，2H)，1.45(d，6H)。

HPLC-MS (method G): 366; t is t_r＝0.798min.

Example 115 (general method I)

[4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -2-methylphenyl ] dimethylamine, trihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 4- (dimethylamino) -3-methylphenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.80(s，1H)，8.50(s，1H)，8.05(m，2H)，7.87(d，1H)，4.75-4.68(m，2H)，3.70-3.58(m，3H)，3.54-3.43(m，2H)，3.37(s，6H)，3.33-3.22(m，2H)，2.65(s，3H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 340; t is t_r＝0.718min.

Example 116 (general method I)

5 '- (6-ethoxypyridin-3-yl) -4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, trihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 2-ethoxy-5-pyridineboronic acid.

¹H-NMR(400MHz，CDCl₃)δ8.62(s，1H)，8.45(s，1H)，8.19(s，1H)，8.10(d，1H)，6.80(d，1H)，4.40(q，4H)，3.65(m，4H)，2.75(m，1H)，2.65(m，4H)，1.42(t，3H)，1.10(d，6H)。

HPLC-MS (method G): m +1 ═ 328; t is t_r＝1.122min.

Example 117 (general method I)

5 '-benzofuran-2-yl-4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 2-benzofuranboronic acid.

¹H-NMR(400MHz，DMSO-d₆)δ8.70(s，1H)，8.55(s，1H)，7.70-7.60(m，2H)，7.47(s，1H)，7.46-7.25(m，2H)，4.63-4.55(m，2H)，3.60-3.45(m，5H)，3.18-3.06(m，2H)，1.32(d，6H)。

HPLC-MS (method G): m +1 ═ 323; and tr is 1.354min.

Example 118 (general method I)

5- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) thiophene-2-carbonitrile, bis-trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 57 starting from 5-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 5-cyano-2-thiopheneboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.70(s，1H)，8.33(s，1H)，7.72(d，1H)，7.61(d，1H)，4.75-4.65(m，2H)，3.70-3.55(m，3H)，3.40-3.20(m，4H)，1.42(d，6H)。

HPLC-MS (method G): m +1 ═ 314; t is t_r＝1.147min.

Example 119 (general method I)

4-isopropyl-5 '- (2-methylpyridin-4-yl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, trihydrochloride

The title compound was prepared in analogy to the procedure described for example 57, starting from 5-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl and 2-methyl-4-pyridineboronic acid.

¹H-NMR(400MHz，CD₃OD)δ9.05(s，1H)，8.65(d，1H)，8.60(s，1H)，8.50(s，1H)，8.45(d，1H)，4.90-4.82(m，2H)，3.70-3.50(m，5H)，3.35-3.24(m，2H)，2.83(s，3H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 298; t is t_r＝0.413min.

Example 120 (general method I)

(R) -2- (6-1, 3-benzodioxol-5-ylpyridazin-3-yl) octahydropyrido [1, 2-a ] pyrazine, dihydrochloride

From (R) -2- (6-chloropyridazin-3-yl) octahydropyrido [1, 2-a)]The title compound was prepared by an analogous method to that described in example 57 starting from pyrazine and 3, 4-methylenedioxyphenylboronic acid.¹H-NMR(400MHz，CD₃OD)δ8.45(brs，1H)，8.20(brs，1H)，7.50(d，1H)，7.47(s，1H)，7.10(d，1H)，6.15(s，2H)，4.75-4.55(m，2H)，3.80-3.30(m，6H)，3.20-3.05(m，1H)，2.15-1.92(m，4H)，1.85-1.65(m，2H)。

HPLC-MS (method G): m +1 ═ 339; t is t_r＝0.827min.

Example 121 (general method I)

4-isopropyl-5 '- (5-trifluoromethyl-pyridin-2-yl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, trifluoroacetate salt

5-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl (0.50g, 1.75mmo1) was dissolved in anhydrous THF under nitrogen and cooled to-78 ℃. A solution of 1.6N N-butyllithium in hexane (0.124g, 1.93mmol) was added while maintaining the temperature below-60 ℃. Tributyltin chloride (0.628g, 1.93mmol) was added and the reaction mixture was allowed to reach room temperature. The reaction mixture was transferred to a 5mL microwave tube and charged with 2-bromo-5-trifluoromethylpyridine (0.33g, 1.93mmo1),

Triphenylphosphine palladium (II) dichloride (0.088g, 0.0615mmol), cesium fluoride (0.581g, 3.85mm0l) and TEA (0.389g, 0.385 mmol). The reaction mixture was heated in a microwave oven at 100 ℃ for 1.6 hours. The reaction mixture was evaporated in vacuo and the oily residue was purified on silica gel column with DCM/MeOH (9: 1) as eluent. The isolated product was treated with a mixture of HCl in ether, followed by evaporation to yield 49mg (9%) of the title compound.

HPLC-MS (method G): m +1 ═ 352; t is t_r＝1.29min.

Example 122 (general method I)

N- {4- [6- (4-Cyclobutylpiperazin-1-yl) pyridin-3-yl ] phenyl } acetamide trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 59, starting from 1- (5-bromo-pyridin-2-yl) -4-cyclobutyl-piperazine and 4-acetamidophenylboronic acid.

¹H-NMR(400MHz，DMSO-d₆)δ8.48(d，1H)，7.92(dd，1H)，7.65(d，2H)，7.55(d，2H)，7.05(d，1H)，4.5(d，2H)，3.75(pent，1H)，3.45(d，2H)，3.15(m，2H)，2.9(m，2H)，2，2(m，4H)，2.05(s，3H)，1.75(m，2H)。

HPLC-MS (method G): m +1 ═ 351; t is t_r＝0.74min.

Example 123 (general method I)

4- [6- (4-cyclobutyl-piperazin-1-yl) -pyridin-3-yl ] -N, N-dimethyl-benzamide, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 57 starting from 1- (5-bromo-pyridin-2-yl) -4-cyclobutyl-piperazine and 4- (dimethylaminocarbonyl) -phenylboronic acid.

¹H-NMR(400MHz，CD₃OD)δ8.45(d，1H)，8.1(dd，1H)，7.65(d，2H)，7.5(dd，2H)，7.18(d，1H)，3.2-4.5(m，8H)，3.1(s，3H)，3.0(s，3H)，2.3(m，4H)，1.8-1.95(m，2H)。

HPLC-MS (method G): m +1 ═ 365; t is t_r＝0.931min.

Example 124 (general method I)

N- {4- [6- (4-Cyclobutylpiperazin-1-yl) pyridazin-3-yl ] -2-methoxyphenyl } acetamide, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 57 starting from 3-chloro-6- (4-cyclobutyl-piperazin-1-yl) -pyridazine and N- [ 2-methoxy-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetamide.

¹H-NMR(400MHz，CD₃OD)δ8.57(d，1H)，8.42(d，1H)，8.20(d，1H)，7.62(s，1H)，7.54(d，1H)，4.70-4.60(m，2H)，4.05(s，3H)，3.86-3.75(m，1H)，3.74-3.60(m，4H)，3.20-3.10(m，2H)，2.50-2.32(m，4H)，2.23(s，3H)，2.00-1.81(m，2H)。

HPLC-MS (method G): m +1 ═ 382; t is t_r＝0.787min.

Example 125 (general method J)

{4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } piperidin-1-yl-methanone, trifluoroacetate salt

Step 1:

4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzonitrile

To a solution of 4- (6-chloro-pyridazin-3-yl) -benzonitrile (20g, 92.8mmol) in 1-butanol (150mL) was added 1-isopropyl-piperazine hydrochloride (29.8g, 148.5mmol) and NH₄Cl (4.96g, 92.8 mmol). The reaction mixture was heated at reflux for 48 hours and then concentrated under reduced pressure. The residue was dissolved in a 10% solution of citric acid in water and filtered. A solid K₂CO₃Added to the filtrate until the pH is 9. The precipitate was separated and washed with waterObtaining 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl]Benzonitrile (20g, 70%).

Step 2:

4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzoic acid, hydrochloride

4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzonitrile (10g, 32.6mmo1) was dissolved in 6N hydrochloric acid (100 mL). The reaction mixture was heated at reflux for 6 hours and concentrated under reduced pressure to give 10.3g (79%) of 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzoic acid, hydrochloride.

And step 3:

to 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl group]Benzoic acid, hydrochloride (2g, 5mmol) in CH₂Cl₂To the solution in (1.91g, 10mmol) was added EDAC (1.91g, 6mmol) and HOBt (0.81g, 6mmol), followed by piperidine (2.56g, 30 mmol). The reaction mixture was stirred at room temperature for 60 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH₂Cl₂Elution afforded the crude product, which was further purified by HPLC (method F) to afford 850mg (43%) of the title compound as a TFA salt.

¹H NMR(300MHz，D₂O)δ8.25(d，1H)，7.90(d，1H)，7.84(d，2H)，7.50(d，2H)，4.51-4.48(m，2H)，3.59-3.42(m，7H)，3.40-3.16(m，4H)，1.57-1.49(m，4H)，1.45-1.34(m，2H)，1.34(d，6H)。

HPLC (method D): t is t_r＝2.94min(98％)。

Example 126 (general method J)

{4- [6- (4-Cyclopropylmethylpiperazin-1-yl) pyridazin-3-yl ] phenyl } piperidin-1-yl-methanone, trifluoroacetate salt

Starting from 4- [6- (4-cyclopropylmethyl-piperazin-1-yl) -pyridazin-3-yl ] -benzoic acid, hydrochloride and piperidine, the title compound was prepared in analogy to the procedure described for example 125.

¹H NMR(300MHz，CDCl3)δ8.24(d，1H)，7.91-7.81(m，3H)，7.48(d，2H)，4.48-4.43(m，2H)，3.76-3.69(m，2H)，3.53-3.43(m，4H)，3.30-3.09(m，4H)，3.02(d，2H)，1.53-1.39(m，6H)，1.07-0.92(m，1H)，0.63(d，2H)，0.27(d，2H)。

HPLC (method D): t is t_r＝3.04min(98％)。

Example 127 (general method J)

{4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } morpholin-4-yl methanone, trifluoroacetate

To 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl group]Benzoic acid, hydrochloride (2g, 5mmo1) in CH₂Cl₂To the solution in (1.91g, 10mmol) was added EDAC (1.91g, 6mmol) and HOBt (0.81g, 6 mmol). Morpholine (2.61g, 30mmol) was then added. The reaction mixture was stirred at room temperature for 60 hours and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography gave the product which was further purified by HPLC method F to give 600mg (30%) of the title compound as TFA salt.

¹H NMR(300MHz，D₂O)δ8.26(d，1H)，7.91(d，1H)，7.84(d，2H)，7.53(d，2H)，4.56-4.46(m，2H)，3.76-3.63(m，4H)，3.57-3.41(m，7H)，3.36-3.35(m，2H)，3.22-3.14(m，2H)，1.20(d，6H)。

HPLC (method E): t is t_r＝2.28min(95％)。

Example 128 (general method J)

(4-Hydroxymethylpiperidin-1-yl) - {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } -methanone, trifluoroacetate salt

To 4- [6- (4-isopropylpiperazin-1-yl) -pyridazin-3-yl group]Benzoic acid, hydrochloride (2.0g, 5.0mmol) in CH₂Cl₂To the solution in (1.91g, 10mmol) was added EDAC (1.91g, 6mmol) and HOBt (0.81g, 6 mmol). Then 4-hydroxymethyl-piperidine (2.56g, 30mmol) in CH was added₂Cl₂(10 ml). The reaction mixture was stirred at room temperature for 60 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH ₂Cl₂Elution provided the crude product, which was further purified by HPLC (method F). 580mg (28%) of the title compound are obtained as TFA salt.

HPLC (method D): t is t_r＝2.32min(95％)。

Example 129 (general method J)

4- [6- (4-Isopropylpiperazin-1-yl) pyridazin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate

To 4- [6- (4-isopropylpiperazin-1-yl) -pyridazin-3-yl group]Benzoic acid, hydrochloride (2g, 5mmol) in CH₂Cl₂To the solution in (1.91g, 10mmol) was added EDAC (1.91g, 6mmol), HOBt (0.81g, 6mmol) and TEA (4.04g, 40 mmol). Then addDimethylamine, hydrochloride (1.63g, 20mmol) were added. The reaction mixture was stirred at room temperature for 60 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH₂Cl₂Elution provided the crude product, which was further purified by HPLC (method F). 800mg (45%) of the title compound are obtained as TFA salt.

¹H NMR(300MHz，D₂O)δ8.26(d，1H)，7.90(d，1H)，7.82(d，2H)，7.50(d，2H)，4.56-4.47(m，2H)，3.57-3.40(m，5H)，3.22-3.09(m，2H)，2.96(m，3H)，2.85(m，3H)，1.23(d，6H)。

HPLC (method E): t is t_r＝2.25min(97％)。

Example 130 (general method J)

{4- [6- (4-Cyclopentylpiperazin-1-yl) pyridazin-3-yl ] phenyl } piperidin-1-yl-methanone, trifluoroacetate salt

To 4- [6- (4-cyclopentyl-piperazin-1-yl) -pyridazin-3-yl group]Benzoic acid, hydrochloride (2g, 5mmol) in CH₂Cl₂EDAC (1.91g, 10mmol) and HOBt (0.81g, 6mm0l) were added to the solution in (1). Piperidine (2.52g, 30mmol) was then added. The reaction mixture was stirred at room temperature for 60 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH ₂Cl₂Elution afforded the crude product, which was further purified by HPLC (method F) to afford 600mg (29%) of the title compound as a TFA salt.

¹H NMR(300MHz，D₂O)δ8.18(d，1H)，7.80-7.83(m，3H)，7.47(d，2H)，4.44(m，2H)，3.1-3.7(m，11H)，2.03(m，2H)，1.39-1.64(m，12H)。

HPLC (method D): t is t_r＝3.27min(95％)。

Example 131 (general method J)

{4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } - (4-methylpiperazin-1-yl) methanone, trifluoroacetate salt

To 4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl group]Benzoic acid, hydrochloride (2g, 5mmo1) in CH₂Cl₂To the solution in (1.91g, 10mmol) was added EDAC (1.91g, 6mmol) and HOBt (0.81g, 6 mmol). 1-methyl-piperazine (2.0g, 20mmol) was then added. The reaction mixture was stirred at room temperature for 60 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH₂Cl₂Elution provided the crude product, which was further purified by HPLC (method F). 300mg (15%) of the title compound was obtained as TFA salt.

¹H NMR(300MHz，D₂O)δ8.01(d，1H)，7.85(d，2H)，7.59-7.49(m，3H)，4.47-4.43(m，2H)，3.90-3.84(m，1H)，3.50-3.05(m，14H)，2.81(m，3H)，1.23(d，6H)。

HPLC (method D): t is t_r＝3.04min(96％)。

Example 132 (general method J)

{4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } morpholin-4-yl methanone, trifluoroacetate

The title compound was prepared by an analogous method to that described in example 125 starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid, hydrochloride and morpholine.

¹H NMR(300MHz，D₂O)δ8.27(dd，J＝2.4Hz，J＝9.6Hz，1H)8.20(d，J＝2.4Hz，1H)，7.62(d，J＝8.4Hz，2H)，7.44(d，J＝8.1Hz，2H)，7.32(d，J＝9.6Hz，1H)，4.34-4.30(m，2H)，3.73-3.50(m，11H)，3.46-3.41(m，2H)，3.25(m，2H)，1.29(d，J＝6.6Hz，6H)。

HPLC (method D): t is t _r＝3.75min(93％)。

Example 133 (general method J)

4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl ] -N, N-Dimethylbenzamide, trifluoroacetate

The title compound was prepared starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid, hydrochloride and dimethylamine, hydrochloride, in analogy to the procedure described for example 125.

¹H NMR(300MHz，D₂O)δ8.28(dd，J＝2.1Hz，J＝9.3Hz，1H)，8.20(d，J＝2.1Hz，1H)，7.6(d，J＝8.4Hz，2H)，7.44(d，J＝8.1Hz，2H)，7.33(d，J＝9.3Hz，1H)，4.35-4.30(m，2H)，3.64-3.51(m，5H)，3.29-3.26(m，2H)，3.02(s，3H)，2.91(s，3H)，1.23(d，J＝7.2Hz，6H)。

HPLC (method D): t is t_r＝3.73min(96％)。

Example 134 (general method J)

{4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } piperidin-1-yl methanone, trifluoroacetate

The title compound was prepared by an analogous method to that described in example 125 starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid, hydrochloride and piperidine.

¹H NMR(300MHz，D₂O)δ8.29(dd，J＝2.4Hz，J＝9.6Hz，1H)，8.15(d，J＝1.8Hz，1H)，7.58(d，J＝8.7Hz，2H)，7.38(d，J＝8.7Hz，2H)，7.34(d，J＝9.6Hz，1H)，4.32-4.27(m，2H)，3.62-3.48(m，7H)，3.28-3.19(m，4H)，1.53(m，4H)，1.38(m，2H)，1.26(d，J＝6.6Hz，6H)。

HPLC (method D): t is t_r＝4.43min(95％)。

Example 135 (general method J)

(4-Hydroxymethylpiperidin-1-yl) - {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } -methanone, trifluoroacetate salt

From 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl]Starting with benzoic acid, hydrochloride and 4-hydroxymethyl-piperidine, the title compound was prepared in analogy to the procedure described in example 125.¹H NMR(300MHz，D₂O)δ8.29(dd，J＝2.4Hz，J＝9.6Hz，1H)，8.22(d，J＝2.1Hz，1H)，7.64(d，J＝8.4Hz，2H)，7.43(d，J＝8.4Hz，2H)，7.34(d，J＝9.6Hz，1H)，4.45-4.32(m，3H)，3.65-3.51(m，6H)，3.4-3.38(m，2H)，3.30-3.27(m，2H)，3.11-3.07(m，1H)，2.90-2.85(m，1H)，1.80-1.76(m，1H)，1.29(d，J＝6.6Hz，6H)，1.19-1.09(m，2H)。

HPLC (method D): t is t_r＝3.79min(97％)。

Example 136 (general method J)

{4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } - (4-methylpiperazin-1-yl) methanone, trifluoroacetate salt

The title compound was prepared starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid, hydrochloride and 1-methylpiperazine using a method analogous to that described in example 125.

¹H NMR(300MHz，D₂O)δ8.29(dd，J＝2.4，J＝9.6Hz，1H)，8.16(d，J＝2.4Hz，1H)，7.61(d，J＝8.4Hz，2H)，7.45(d，J＝8.4Hz，2H)，7.34(d，J＝9.3Hz，1H)，4.32-4.27(m，2H)，3.92-3.84(m，1H)，3.61-3.44(m，8H)，3.32-3.01(m，6H)，2.80(s，3H)，1.24(d，J＝6.6Hz，6H)。

Example 137 (general method J)

{4- [6- (4-Cyclopropylmethylpiperazin-1-yl) pyridin-3-yl ] phenyl } piperidin-1-yl-methanone, trifluoroacetate salt

The title compound was prepared by an analogous method to that described in example 125 starting from 4- [6- (4- (cyclopropylmethyl) -piperazin-1-yl) -pyridin-3-yl ] -benzoic acid, hydrochloride and piperidine.

¹H NMR(300MHz，D₂O)δ8.45(d，1H)，8.08(d，1H)，7.68(d，2H)，7.47(d，2H)，7.16(d，1H)，4.72-3.34(m，12H)，3.12(d，2H)，1.77-1.49(m，6H)，1.22-1.11(m，1H)，0.80(q，2H)，0.47(q，2H)。

HPLC (method E): t is t_r＝3.39min(96％)。

Example 138 (general method J)

{4- [6- (4-Cyclopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } piperidin-1-yl-methanone, trifluoroacetate salt

The title compound was prepared by an analogous method to that described in example 125 starting from 4- [6- (4-cyclopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid, hydrochloride and piperidine.

¹H NMR(300MHz，CD₃OD)δ8.38-8.28(m，2H)，7.73(d，2H)，7.51(d，2H)，7.46-7.41(m，1H)，4.03-3.95(m，2H)，3.78-3.55(m，6H)，3.51-3.35(m，4H)，2.93-2.96(m，1H)，1.79-1.48(m，7H)，1.06-1.04(m，3H)。

HPLC (method D): t is t_r＝4.43min(96％)。

Example 139 (general method J)

{4- [6- (4-Cyclopentylpiperazin-1-yl) pyridin-3-yl ] phenyl } piperidin-1-yl-methanone, trifluoroacetate salt

The title compound was prepared by an analogous method to that described in example 125 starting from 4- [6- (4-cyclopentyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid, hydrochloride and piperidine.

¹H NMR(300MHz，CD₃OD)δ8.46(d，1H)，8.06(dd，1H)，7.68(d，2H)，7.47(d，2H)，7.13(dd，1H)，4.70-4.09(m，2H)，4.09-3.35(m，10H)，3.35-3.28(m，1H)，2.35-2.23(m，2H)，1.95-1.55(m，12H)。

HPLC (method E): t is t_r＝3.46min(98％)。

Example 140 (general method J)

{3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } morpholin-4-yl methanone, trifluoroacetate

The title compound was prepared by an analogous method to that described in example 125 starting from 3- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid and morpholine.

¹H NMR(300MHz，D₂O) delta 8.23(s, 1H), 8.15(d, 1H), 7.55-7.52(t, 2H), 7.37(d, 1H), 7.66-7.21(d, 1H), 4.36-4.26(m, 2H), 3.78-3.40(m, 13H), 3.30-3.17(s, 2H), 1.29(d, 6H). HPLC (method C): t is t_r＝3.95min(96％)。

Example 141 (general method J)

{3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } piperidin-1-yl methanone, trifluoroacetate

The title compound was prepared by an analogous method to that described in example 125 starting from 3- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid and piperidine.

¹H NMR(300MHz，D₂O)δ8.31(d，1H)，8.17(s，1H)，7.64(d，2H)，7.52(t，2H)，7.37(d，2H)，3.65-3.55(m，7H)，3.34(d，2H)，3.29(t，4H)，1.60-1.42(d，6H)，1.29(d，6H)。

HPLC (method D): t is t_r＝4.03min(97％)。

Example 142 (general method J)

3- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl ] -N, N-Dimethylbenzamide, trifluoroacetate

The title compound was prepared by an analogous method to that described in example 125 starting from 3- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid and dimethylamine, hydrochloride.

¹H NMR(300MHz，D₂O)δ8.26(d，2H)，8.20(s，1H)，7.56-7.51(dd，2H)，7.65(d，1H)，7.41-7.33(dd，2H)，4.33(d，2H)，3.64-3.54(m，5H)，3.29(t，2H)，3.02(s，3H)，2.92(s，3H)，1.29(d，6H)。

HPLC (method D): t is t_r＝2.52min(97％)。

Example 143 (general method J)

{4- [6- (4-Cyclopentylpiperazin-1-yl) pyridin-3-yl ] phenyl } - (4-methylpiperazin-1-yl) methanone, trifluoroacetate salt

The title compound was prepared starting from 3- [6- (4-cyclopentyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid, hydrochloride and 1-methylpiperazine using a method analogous to that described in example 125.

¹H NMR(300MHz，CD₃OD)δ8.41-8.32(m，2H)，7.77(d，2H)，7.62(d，2H)，7.47(d，1H)，4.62-4.21(m，2H)，4.01-3.35(m，11H)，3.25-3.05(m，2H)，3.05-2.78(m，3H)，2.52-2.12(m，2H)，2.12-1.98(m，4H)，1.98-1.51(m，6H)。

HPLC (method C): t is t_r＝4.29min(96％)。

Example 144 (general method J)

{4- [6- (4-Cyclopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } - (4-methylpiperazin-1-yl) methanone, trifluoroacetate salt

The title compound was prepared starting from 3- [6- (4-cyclopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid, hydrochloride and 1-methylpiperazine using a method analogous to that described in example 125.

¹H NMR(300MHz，CD₃OD)δ8.41(s，1H)，8.12-8.15(m，1H)，7.73(d，2H)，7.58(d，2H)，7.21-7.24(m，1H)，4.03-3.95(m，5H)，3.78-3.31(m，9H)，3.09-3.30(m，2H)，2.84-2.96(m，4H)，0.92-1.14(m，4H)。

HPLC (method D): t is t_r＝4.43min(96％)。

Example 145 (general method J)

{4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] phenyl } - (4-methoxymethylpiperidin-1-yl) -methanone, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 125, starting from 3- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid, hydrochloride and 4-methoxymethyl-piperidine, hydrochloride.

¹H NMR(300MHz，CD₃OD)δ8.45(d，1H)，8.10(dd，1H)，7.70(d，2H)，7.48(d，2H)，7.16(d，1H)，4.72-4.45(m，2H)，4.22-3.35(m，8H)，3.32(s，3H)，3.29-3.27(m，2H)，3.21-2.95(m，2H)，2.95-2.75(m，1H)，1.95-1.82(m，2H)，1.75-1.62(m，1H)，1.42(d，6H)，1.41-1.15(m，2H)。

HPLC (method D): t is t_r＝4.34min(97％)。

Example 146 (general method J)

4- [6- (4-Cyclopentylpiperazin-1-yl) pyridin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate salt

The title compound was prepared by an analogous method to that described in example 125 starting from 3- [6- (4-cyclopentyl-piperazin-1-yl) -pyridin-3-yl ] -benzoic acid and dimethylamine.

¹H NMR(300MHz，CD₃OD) delta 8.50(s, 1H), 8.00(dd, 1H)7.68(d, 2H), 7.50(d, 2H), 7.05(d, 1H), 4.75-4.50(m, 2H), 3.85-3.45(m, 4H), 3.25-3.17(m, 3H), 3.15-3.02(m, 6H), 2.33-2.15(m, 2H), 1.90-1.65(m, 6H). HPLC (method D): t is t_r＝4.83min(97％)。

Example 147 (general method J)

{4- [6- (4-Cyclopentylpiperazin-1-yl) pyridin-3-yl ] phenyl } morpholin-4-yl methanone, trifluoroacetate

From 3- [6- (4-cyclopentyl-piperazin-1-yl) -pyridin-3-yl]Prepared by a method analogous to that described in example 125, starting with benzoic acid and morpholineA compound (I) is provided.¹H NMR(300MHz，CD₃OD)δ8.50(s，1H)，8.05(d，1H)7.68(d，2H)，7.50(d，2H)，7.10(d，1H)，4.80-3.30(m，17H)，2.30-2.15(m，2H)，1.90-1.55(m，6H)。

HPLC (method D): t is t_r＝4.77min(96％)。

Example 148 (general method J)

3- [6- (4-Isopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate salt

From 3- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridin-3-yl]Benzoic acid and dimethylamine, hydrochloride salt starting, the title compound was prepared in a similar manner to that described in example 125.¹H NMR(300MHz，CD₃OD)δ7.98(s，1H)，7.58(t，1H)，7.48(t，2H)，7.41(s，1H)，7.20(s，1H)，4.81-3.35(m，9H)，3.12(s，3H)，3.04(s，3H)，2.36(s，3H)，1.42(d，6H)。

HPLC (method D): t is t_r＝3.95min(97％)。

Example 149 (general method J)

3- [6- (4-Isopropylpiperazin-1-yl) -5-methylpyridin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate salt

From 3- [6- (4-isopropyl-piperazin-1-yl) -5-methyl-pyridin-3-yl]Benzoic acid and dimethylamine, hydrochloride salt starting, the title compound was prepared in a similar manner to that described in example 125.¹H NMR(300MHz，CD₃OD)δ8.42(s，1H)，7.97(s，1H)，7.73(d，1H)，7.67(s，1H)，7.56(t，1H)，7.43(d，1H)，3.88-3.70(m，2H)，3.70-3.51(m，3H)，3.47-3.32(m，3H)，3.28-3.15(m，4H)，3.03(s，3H)，2.42(s，3H)，1.43(d，6H)。

HPLC (method D): t is t_r＝4.14min(98％)。

Example 150 (general method J)

4- [6- (4-Isopropylpiperazin-1-yl) -5-methylpyridin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate salt

From 4- [6- (4-isopropyl-piperazin-1-yl) -5-methyl-pyridin-3-yl]Benzoic acid and dimethylamine, hydrochloride salt starting, the title compound was prepared in a similar manner to that described in example 125.¹H NMR(300MHz，CD₃OD)δ8.43(d，1H)，8.01(d，1H)，7.72(d，2H)，7.53(d，2H)，3.91-3.72(m，2H)，3.70-3.51(m，3H)，3.47-3.32(m，3H)，3.21-3.09(m，4H)，3.04(s，3H)，2.38(s，3H)，1.43(d，6H)。

HPLC (method D): t is t_r＝4.11min(95％)。

Example 151 (general method J)

4- [6- (4-Isopropylpiperazin-1-yl) -4-methylpyridin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate salt

From 4- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridin-3-yl]Benzoic acid and dimethylamine, hydrochloride salt starting, the title compound was prepared in a similar manner to that described in example 125.¹H NMR(300MHz，CD₃OD)δ7.95(s，1H)，7.55(d，2H)，7.47(d，2H)，7.35(s，1H)，4.73-3.35(m，9H)，3.13(s，3H)，3.04(s，3H)，2.39(s，3H)，1.42(d，6H)。

HPLC (method D): t is t_r＝3.93min(98％)。

Example 152 (general method J)

4- [ 4-isopropyl-6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate

The title compound was prepared by an analogous method to that described in example 125 starting from 4- [ 4-isopropyl-6- (4-isopropylpiperazin-1-yl) -pyridazin-3-yl ] -benzoic acid and dimethylamine, hydrochloride.

¹H NMR(400MHz，CD₃OD)δ7.87(s，1H)，7.67(t，4H)，4.90-3.31(m，9H)，3.15(s，3H)，3.08-3.05(m，4H)，1.44(d，6H)，1.27(d，6H)。

HPLC (method D): t is t_r＝3.46min(99％)。

Example 153 (general method K)

1-Cyclopropylmethyl-4- [5- (4-piperidin-1-ylmethylphenyl) pyridin-2-yl ] piperazine, trifluoroacetate salt

Step 1:

4- [6- (4-cyclopropylmethyl-piperazin-1-yl) -pyridin-3-yl ] -benzonitrile

1-Cyclopropylmethyl-piperazine (13g, 94mmol) was combined with 4- (6-chloro-pyridin-3-yl) -benzonitrile (5g, 23mmo 1). The mixture was heated at 140 ℃ for 1.5 hours. The reaction mixture was cooled to room temperature and then purified by silica gel column chromatography (EtOAc: petroleum ether ═ 1: 1) to give 2.7g (43%) of4- [6- (4-cyclopropylmethyl-piperazin-1-yl) -pyridin-3-yl ] -benzonitrile.

Step 2:

4- [6- (4-cyclopropylmethyl-piperazin-1-yl) -pyridin-3-yl ] -benzaldehyde

To 4- [6- (4-cyclopropylmethyl-piperazin-1-yl) -pyridin-3-yl]-benzonitrile (2.0g, 6.3mmo1) dissolved in THF (40mL) DIBAL-H (25mL, 1N) was added at-40 ℃. The reaction mixture was stirred at-40 ℃ for 2 hours, then CH was added at-40 ℃₃OH (15mL), water (100mL) and 1N NaOH (15 mL). The mixture was extracted with EtOAc (3 × 300 mL).

The combined organic extracts were washed with water (3 × 50mL) and dried (Na)₂SO₄) And concentrated under reduced pressure to give 1.7g (51%) of4- [6- (4-cyclopropylmethyl-piperazin-1-yl) -pyridin-3-yl ]-benzaldehyde.

And step 3:

to 4- [6- (4-cyclopropylmethyl-piperazin-1-yl) -pyridin-3-yl]-benzaldehyde (1.7g, 3.18mmo1) dissolved in THF (15mL) Water (0.05mL), piperidine (0.33g, 3.8mmo1), acetic acid (0.01mL) and NaCNBH₃(400mg, 6.4 mmol). The mixture was stirred at 60 ℃ overnight and then concentrated to give the crude product, which was further purified by HPLC (method F) to afford 540mg (26%) of the title compound as TFA salt.

¹H NM[R(300MHz，D₂O)δ8.28(d，1H)，8.20(d，1H)，7.56(d，2H)，7.45(d，2H)，7.31(d，1H)，4.27-4.21(m，2H)，4.13(m，2H)，3.77-3.72(m，2H)，3.59-3.51(m，2H)，3.20-3.13(m，4H)，3.00(d，2H)，2.82-2.75(m，2H)，1.77-1.42(m，5H)，1.29-1.25(m，1H)，1.00-0.95(m，1H)，0.62-0.58(m，2H)，0.26-0.24(m，2H)。

HPLC (method D): t is t_r＝3.76min(96％)。

Example 154 (general method K)

{4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } dimethylamine, trifluoroacetate salt

The title compound was prepared by an analogous method to that described in example 153 starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzaldehyde and dimethylamine, hydrochloride.

¹H NMR(300MHz，D₂O)δ8.30(d，1H)，8.26(d，1H)，7.62(d，2H)，7.48(d，2H)，7.33(d，1H)，4.33-4.29(m，2H)，4.23(m，2H)，3.62-3.48(m，5H)，3.28-3.15(m，2H)，2.73(s，6H)，1.26(d，6H)。

HPLC (method D): t is t_r＝2.69min(98％)。

Example 155 (general method K)

3- (4-Cyclopentylpiperazin-1-yl) -6- (4-piperidin-1-ylmethylphenyl) pyridazine, trifluoroacetate salt

Starting from 4- [6- (4-cyclopentyl-piperazin-1-yl) -pyridazin-3-yl ] -benzaldehyde and piperidine, the title compound was prepared in analogy to the procedure described for example 153.

¹H NMR(300MHz，D₂O)δ8.06(d，J＝9.9Hz，1H)，7.80(d，J＝8.1Hz，2H)，7.67(d，J＝9.6Hz，1H)，7.50(d，J＝8.4Hz，2H)，4.44-4.38(m，2H)，4.18(m，2H)，3.65-3.61(m，2H)，3.51-3.30(m，5H)，3.16-3.07(m，2H)，2.85-2.78(m，2H)，2.03-1.96(m，2H)，1.77-1.73(m，2H)，1.61-1.52(m，9H)，1.34-4.22(m，1H)。

HPLC (method D): t is t_r＝3.69min(86％)。

Example 156 (general method K)

1- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } -4-methylpiperazine, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 153, starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzaldehyde and 1-methylpiperazine.

¹H NMR(300MHz，D₂O)δ8.33(d，1H)，8.30(d，1H)，7.66(d，2H)，7.53(d，2H)，7.35(d，1H)，4.57-4.31(m，4H)，3.65-3.53(m，13H)，3.31-3.23(m，2H)，2.90(s，3H)，1.28(d，6H)。

HPLC (method C): t is t_r＝2.59min(93％)。

Example 157 (general method K)

(1- {4- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } piperidin-4-yl) methanol, trifluoroacetate salt

The title compound was prepared by an analogous method to that described in example 153 starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzaldehyde and 4-hydroxymethylpiperidine.

¹H NMR(300MHz，D₂O)δ8.32(d，1H)，8.18(d，1H)，7.61(d，2H)，7.48(d，2H)，7.35(d，1H)，4.34-4.29(m，2H)，4.21(m，2H)，3.62-3.22(m，11H)，2.94-2.86(m，2H)，1.87-1.67(m，3H)，1.29-1.25(m，8H)。

HPLC (method C): t is t_r＝2.82min(97％)。

Example 158 (general method K)

1-isopropyl-4- [5- (4-piperidin-1-ylmethyl-phenyl) -pyridin-2-yl ] -piperazine, trifluoroacetate salt

The title compound is prepared by an analogous method to that described in example 153 starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzaldehyde and piperidine.

¹H NMR(300MHz，D₂O)δ8.27(d，1H)，8.16(d，1H)，7.59(d，2H)，7.45(d，2H)，7.31(d，1H)，4.31-4.26(m，2H)，4.17(m，2H)，3.56-3.45(m，4H)，3.31-3.17(m，4H)，2.84-2.76(m，2H)，1.82-1.44(m，6H)，1.24(d，6H)。

HPLC (method D): t is t_r＝4.45min(87％)。

Example 159 (general method K)

{4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] benzyl } dimethylamine, trifluoroacetate

The title compound was prepared by an analogous method to that described in example 153 starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzaldehyde and dimethylamine, hydrochloride.

¹H NMR(300MHz，CD₃OD)δ8.13-8.06(m，3H)，7.67-7.61(m，3H)，4.38(s，2H)，3.89-3.32(m，6H)，2.88(s，6H)，1.41(d，6H)。

HPLC (method C): t is t_r＝3.79min(96％)。

Example 160 (general method K)

3- (4-Isopropylpiperazin-1-yl) -6- (4-piperidin-1-ylmethylphenyl) pyridazine, trifluoroacetic acid salt

Starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzaldehyde and piperidine, the title compound was prepared in analogy to the methods described for example 153.

¹H NMR(300MHz，CD₃OD)δ8.12-8.05(m，3H)，7.67-7.60(m，3H)，4.35(s，2H)，3.89-3.35(m，8H)，2.98(t，2H)，1.95-1.64(m，5H)，1.62-1.48(m，1H)，1.41(d，6H)。

Example 161 (general method K)

3- (4-Isopropylpiperazin-1-yl) -6- [4- (4-methylpiperazin-1-ylmethyl) phenyl ] pyridazine, trifluoroacetate salt

Starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzaldehyde and 1-methyl-piperazine using a method analogous to that described in example 153, the title compound was prepared.

¹H NMR(300MHz，CD₃OD)δ8.19(d，1H)，7.98(d，1H)，7.76(d，1H)，7.62(d，1H)，4.01(s，2H)，3.78-3.32(m，10H)，3.19-3.02(m，4H)，2.90(s，3H)，1.95-1.64(m，5H)，1.62-1.48(m，1H)，1.41(d，6H)。

HPLC (method C): t is t_r＝3.74min(97％)。

Example 162 (general method K)

(1- {4- [6- (4-Isopropylpiperazin-1-yl) pyridazin-3-yl ] benzyl } piperidin-4-yl) methanol, trifluoroacetate salt

Starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzaldehyde and 4-hydroxymethylpiperidine, the title compound was prepared in analogy to the procedure described for example 153.

¹H NMR(300MHz，CD₃OD)δ8.05-8.11(m，3H)，7.58-7.67(m，3H)，4.36(s，2H)，3.78-3.38(m，10H)，2.99-3.12(m，4H)，1.46-2.05(m，5H)，1.41(d，6H)。

HPLC (method C): t is t_r＝3.94min(96％)。

Example 163 (general method K)

4- {4- [6- (4-Isopropylpiperazin-1-yl) pyridazin-3-yl ] benzyl } morpholine, trifluoroacetate salt

Starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzaldehyde and morpholine, the title compound was prepared in analogy to the methods described for example 153.

¹H NMR(300MHz，CD₃OD)δ8.12-8.06(m，3H)，7.70-7.59(m，3H)，4.43(s，2H)，4.33-3.23(m，14H)，1.41(d，6H)。

Example 164 (general method K)

1-cyclopentyl-4- [5- (4-piperidin-1-ylmethyl) phenyl ] pyridin-2-yl ] piperazine, trifluoroacetate salt

The title compound is prepared by an analogous method to that described in example 153 starting from 4- [6- (4-cyclopentyl-piperazin-1-yl) -pyridin-3-yl ] -benzaldehyde and piperidine.

¹H NMR(300MHz，D₂O)δ8.26-8.22(m，2H)，7.62(d，2H)，7.47(d，2H)，7.27(d，1H)，4.27(d，2H)，4.20(s，2H)，3.71(d，2H)，3.55-3.42(m，3H)，3.36(d，2H)，3.20(t，2H)，2.86(t，2H)，2.08(d，2H)，1.85-1.51(m，11H)，1.41-1.30(m，1H)。

HPLC (method D): t is t_r＝2.43min(98％)。

Example 165 (general method K)

1-cyclopropyl-4- [5- (4-piperidin-1-ylmethyl-phenyl) -pyridin-2-yl ] -piperazine, trifluoroacetate salt

The title compound is prepared by an analogous method to that described in example 153 starting from 4- [6- (4-cyclopropyl-piperazin-1-yl) -pyridin-3-yl ] -benzaldehyde and piperidine.

¹H NMR(300MHz，CD₃OD)δ8.46(s，1H)，8.05(d，1H)，7.71(d，2H)，7.57(d，2H)，7.18-7.13(m，1H)，4.87(s，2H)，4.18-3.72(m，4H)，3.65-3.35(m，6H)，3.08-2.82(m，3H)，1.99-1.62(m，5H)，1.39-1.61(m，1H)，1.05-1.15(m，2H)，1.05-0.89(m，2H)。

HPLC (method C): t is t_r＝4.43min(99％)。

Example 166 (general method K)

3- (4-Cyclopropylmethylpiperazin-1-yl) -6- (4-piperidin-1-ylmethylphenyl) pyridazine, trifluoroacetate salt

Starting from 4- [6- (4-cyclopropylmethyl-piperazin-1-yl) -pyridazin-3-yl ] -benzaldehyde and piperidine, the title compound was prepared in analogy to the procedure described for example 153.

¹H NMR(300MHz，CD₃OD)δ8.24(d，1H)，8.08(d，2H)7.80(d，1H)，7.70(d，2H)，4.89-2.85(m，12H)，3.22-2.92(m，4H)，2.05-1.89(m，2H)，1.89-1.75(m，3H)，1.65-1.45(m，1H)，1.25-1.06(m，1H)，0.83-0.78(m，2H)，0.52-0.40(m，2H)。

HPLC (method D): t is t_r＝3.04min(98％)。

Example 167 (general method K)

3- (4-Cyclopropylpiperazin-1-yl) -6- (4-piperidin-1-ylmethylphenyl) pyridazine, trifluoroacetate salt

Starting from 4- [6- (4-cyclopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzaldehyde and piperidine, the title compound was prepared in analogy to the methods described for example 153.

¹H NMR(300MHz，CDCl₃): δ 12.00(s, 1H), 8.08(d, 2H), 7.81(d, 1H), 7.62(d, 2H), 7.15(d, 1H), 4.25-4.00(m, 4H), 3.65-3.40(m, 5H), 2.85-2.40(m, 6H), 2.15-1.95(m, 3H), 1.95-1.85(m, 3H), 1.52-1.31(m, 2H), 0.91(d, 2H). HPLC (method D):_tr＝4.01min(96％)。

example 168 (general method K)

4- {4- [2- (4-cyclopropylpiperazin-1-yl) pyrimidin-5-yl ] benzyl } morpholine, dihydrochloride

The title compound is prepared by an analogous method to that described in example 153 starting from 4- [2- (4-cyclopropyl-piperazin-1-yl) -pyrimidin-5-yl ] -benzaldehyde and morpholine.

¹H NMR(300MHz，DMSO-d₆)δ11.6(brs，1H)，11.3(brs，1H)，8.85(s，2H)，7.81-7.71(m，4H)，4.82-4.69(m，2H)，4.40-4.30(m，2H)，4.00-3.77(m，4H)，3.61-3.42(m，4H)，3.34-3.00(m，6H)，2.92-2.79(m，1H)，1.25-1.15(m，2H)，0.86-0.77(m，2H)。

HPLC (method Rx): t is t_r＝3.88min(98％)。

Example 169 (general method L)

N- {3- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } acetamide trifluoroacetate

From 3- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl]Starting with phenylamine and acetyl chloride, the title compound is prepared in analogy to the procedure described in example 170.¹H NMR(300MHz，DMSO-d₆)10.08(s，1H)，9.78(s，1H)，8.33(s，1H)，7.97(d，1H)，7.62(t，2H)，7.53(d，1H)，7.40(t，1H)，4.60(d，2H)，3.61-3.50(m，3H)，3.34-3.25(m，2H)，3.16-3.13(m，2H)，2.05(s，3H)，1.28(d，6H)。

HPLC (method D): t is t_r＝2.28min(96％)。

Example 170 (general method L)

N- {3- [6- (4-cyclopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } acetamide

Step 1:

3- (4-cyclopropyl-piperazin-1-yl) -6- (3-nitro-phenyl) -pyridazine

To a solution of 3-chloro-6- (3-nitro-phenyl) -pyridazine (10.0g, 424mmol) in n-BuOH (150mL) was added 1-cyclopropyl-piperazine (8.55g, 678mmol) and NH ₄Cl (2.27g, 424mmol) and the mixture was stirred at 80 ℃ for 48 hThen (c) is performed. The solvent was removed under reduced pressure and the residue was diluted with water. After basification with ammonia, the mixture was extracted with ethyl acetate. The extract was dried (Na)₂8O₄) And concentrated to yield 7.2g of crude 3- (4-cyclopropyl-piperazin-1-yl) -6- (3-nitro-phenyl) -pyridazine.

¹H NMR(300MHz，DMSO-d₆)δ8.85(s，1H)，8.45(d，1H)，8.22(d，1H)，8.11(d，1H)，7.89-7.66(m，1H)，7.39(d，1H)，3.69-3.65(m，4H)，2.80-2.76(m，4H)，1.78-1.65(m，1H)，0.54-0.38(m，4H)。

Step 2:

3- [6- (4-cyclopropyl-piperazin-1-yl) -pyridazin-3-yl ] -phenylamine

A solution of3- (4-cyclopropyl-piperazin-1-yl) -6- (3-nitro-phenyl) -pyridazine (3.60g, 11mmol) in ethanol (18mL) was added to water (30mL) and powdered Fe (1.86g, 33 mmol). The mixture was stirred at 80 ℃ for 3 hours. The resulting mixture was filtered and the filtrate was taken up with CH₂Cl₂And (4) extracting. The organic phase was washed with brine and dried (Na)₂SO₄) And concentrated to give 2.32g (71%) of3- [6- (4-cyclopropyl-piperazin-1-yl) -pyridazin-3-yl]-a phenylamine.

And step 3:

to 3- [6- (4-cyclopropyl-piperazin-1-yl) -pyridazin-3-yl group]Phenyl amine (400mg, 1.36mmol) in CH₂Cl₂To a solution in (25mL) was added triethylamine (275mg, 2.72 mmol). Acetyl chloride (171mg, 2.18mmol) was then added dropwise and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (15mL) and the phases separated. The organic phase was washed with brine and dried (Na) ₂SO₄) And concentrated to give the crude product, which was recrystallized from MeOH to yield 201mg (48%) of the title compound.

¹H NMR(300MHz，CD₃OD)δ8.09(s，1H)，7.82(d，1H)，7.66-7.62(m，2H)，7.44-7.39(m，1H)，7.33(d，1H)，3.69-3.65(m，4H)，2.80-2.76(m，4H)，2.15(s，3H)，1.74-1.71(m，1H)，0.54-0.49(m，4H)。

HPLC (method D): t is t_r＝2.82min(95％)。

Example 171 (general method L)

Cyclopropanecarboxylic acid {3- [6- (4-cyclopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } amide

From 3- [6- (4-cyclopropyl-piperazin-1-yl) -pyridazin-3-yl]Starting with phenylamine and cyclopropanecarbonyl chloride, the title compound was prepared in analogy to the procedure described in example 170.¹H NMR(300MHz，CD₃OD)δ8.08(d，1H)，7.82(d，1H)，7.66-7.62(m，2H)，7.44-7.39(m，1H)，7.33(d，1H)，3.69-3.65(m，4H)，2.80-2.77(m，4H)，1.79-1.71(m，2H)，0.97-0.94(m，2H)，0.89-0.85(m，2H)，0.55-0.49(m，4H)。

HPLC (method D): t is t_r＝3.18min(97％)。

Example 172 (general method L)

N- {4- [6- (4-Cyclopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } acetamide trifluoroacetate salt

From 4- [6- (4-cyclopropyl-piperazin-1-yl) -pyridazin-3-yl]Starting with phenylamine and acetyl chloride, the title compound is prepared in analogy to the procedure described in example 170.¹H NMR(300MHz，CD₃OD) delta 8.31(d, 1H), 7.96-7.88(m, 3H), 7.81(d, 2H), 4.20-3.95(m, 4H), 3.70-3.58(m, 4H), 2.94-2.86(m, 1H), 2.16(s, 3H), 1.14-0.96(m, 4H). HPLC (method D): t is t_r＝2.74min(98％)。

Example 173 (general method L)

Cyclopropanecarboxylic acid {4- [6- (4-cyclopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } amide

From 4- [6- (4-cyclopropyl-piperazin-1-yl) -pyridazin-3-yl]Starting with phenylamine and cyclopropanecarbonyl chloride, the title compound was prepared in analogy to the procedure described in example 170. ¹H NMR(300MHz，DMSO-d₆)δ10.30(s，1H)，7.93(d，2H)，7.86(d，1H)，7.67(d，2H)，7.30(d，1H)，3.57-3.54(m，4H)，2.64-2.62(m，4H)，1.79-1.74(m，1H)，1.65-1.62(m，1H)，0.78(d，4H)，0.43-0.41(m，2H)，0.35-0.30(m，2H)。

HPLC (method D): t is t_r＝2.52min(93％)。

Example 174 (general method L)

Cyclopropanecarboxylic acid {4- [6- (4-cyclopropyl-perhydro-1, 4-diaza ]-1-yl) pyridazin-3-yl]-phenyl } amide, dihydrochloride

From 4- [6- (4-isopropyl-perhydro-1, 4-diaza)-1-yl) -pyridazin-3-yl]Starting with phenylamine and cyclopropanecarboxylic acid, the title compound was prepared in analogy to the procedure described in example 176.

¹H NMR(400MHz，CD₃OD) δ 8.44(d, 1H), 8.03(d, 1H), 7.94(m, 2H), 7.85(m, 2H), 4.22 (m, 2H wide), 3.89(t, 2H), 3.71 (m, 4H wide), 3.30(m, 1H), 2.48 (m, 2H wide), 1.82(m, 1H), 1.22(m, 2H), 1.00(m, 4H), 0.91(m, 2H).

HPLC-MS (method G): m +1 ═ 378; t is t_r＝0.96min.

Example 175 (general method L)

N- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] -2, 2-dimethylpropionamide, hydrochloride

The title compound was prepared by an analogous method to that described in example 176 starting from 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenylamine and tert-butylcarboxylic acid.

HPLC-MS (method G): m ten 1 ═ 382; t is t_r＝1.23min.

Example 176 (general method L)

Tetrahydropyran-4-carboxylic acid [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] amide, dihydrochloride

A mixture of tetrahydro-2H-pyran-4-carboxylic acid (0.313g, 2.19mmol), HOBt (0.368g, 2.40mmol), EDAC (0.46g, 2.40mmol) and TEA (0.243g, 2.40mmol) in DMF (5mL) was stirred at room temperature for 5 minutes. A solution of 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenylamine (0.65g, 2.19mmol) in DMF (5mL) was added. The reaction mixture was stirred for an additional 48 hours. The reaction mixture was purified by preparative HPLC (method B) to yield 240mg of TFA salt. The TFA salt was dissolved in MeOH, and a mixture of HCl in ether was added. The volatiles were evaporated in vacuo to yield 186mg (18%) of the title compound.

¹H-NMR(400MHz，CD₃OD)δ8.90(s，1H)，8.49(s，1H)，7.95(d，2H)，7.70(d，2H)，4.55-4.45(m，2H)，3.95-3.87(m，2H)，3.55-3.45(m，5H)，3.40-3.30(m，2H)，3.15-3.05(m，2H)，2.70-2.60(m，1H)，1.75-1.60(m，4H)，1.30(d，6H)。

HPLC-MS (method G): m +1 ═ 410; t is t_r＝1.037min.

Example 177 (general method L)

N- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] -N-methylacetamide, dihydrochloride

The title compound is prepared in analogy to the procedure described for example 170, starting from N- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] -N-methylamine and acetic anhydride.

¹H-NMR(400MHz，CD₃OD)δ8.95(s，1H)，8.60(s，1H)，8.04(d，2H)，7.35(d，2H)，4.80-4.72(m，2H)，3.73-3.62(m，5H)，3.40-3.28(m，5H)，1.95(brs，3H)，1.45(d，6H)。

HPLC-MS (method G): m +1 is 354; t is t_r＝1.27min.

Example 178 (general method L)

Cyclopropanecarboxylic acid [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] methylamide, dihydrochloride

The title compound is prepared in an analogous manner to that described in example 176 starting from N- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] -N-methylamine and cyclopropanecarboxylic acid.

¹H-NMR(400MHz，CD₃OD)δ8.90(s，1H)，8.55(s，1H)，8.05(d，2H)，7.55(d，2H)，4.80-4.70(m，2H)，3.72-3.55(m，5H)，3.40-3.25(m，5H)，1.57-1.50(m，1H)，1.45(d，6H)，0.95(m，2H)，0.72(m，2H)。

HPLC-MS (method G): m +1 ═ 380; t is t_r＝1.10min.

Example 179 (general method L)

N- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -2-methoxyphenyl ] acetamide, dihydrochloride

The title compound is prepared in analogy to the procedure described for example 170, starting from 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -2-methoxyphenyl-amine and acetic anhydride.

¹H-NMR(400MHz，CD₃OD)δ8.75(s，1H)，8.40(s，1H)，8.15(d，1H)，7.60(s，1H)，7.45(d，1H)，4.72-4.65(m，2H)，4.00(s，3H)，3.68-3.58(m，3H)，3.40-3.22(m，4H)，2.20(s，3H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 370; t is t_r＝1.004min.

Example 180 (general method L)

Cyclohexanecarboxylic acid [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] amide, hydrochloride

The title compound was prepared by an analogous method to that described in example 176 starting from cyclohexanecarboxylic acid and 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl amine.

HPLC-MS (method G): m +1 ═ 408; t is t_r＝1.34min.

Example 181 (general method M)

2- [4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenoxy ] -N, N-dimethylacetamide, dihydrochloride

4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenol (0.15g, 0.404mmol) was dissolved in DMF (4mL) in a 5mL microwave tube. NaH (0.039g, 1.62mmol) was added slowly and the mixture was stirred at room temperature for 30 min. chloro-N, N-dimethyl acetamide (0.147g, 1.21mmol) was added and the reaction mixture was heated in a microwave oven at 130 ℃ for 2.5 hours. The reaction mixture was evaporated in vacuo and the residue was redissolved in a mixture of DCM and water. The phases were separated and the aqueous phase was extracted with DCM (2 × 25 mL). The combined organic extracts were evaporated, redissolved in MeOH and purified by preparative HPLC (method B). An oil was obtained, which was treated with a mixture of HCl in ether to obtain a solid material. Recrystallization from acetone and MeOH yielded 75mg (41%) of the title compound.

¹H-NMR(400MHz，CD₃OD)δ8.75(s，1H)，8.35(s，1H)，7.85(d，2H)，7.1(d，2H)，4.65(d，2H)，3.65(m，3H)，3.2-3.5(m，6H)，3.1(s，3H)，2.95(s，3H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 384; t is t_r＝0.995min.

Example 182 (general method N)

5 '- [4- (1, 1-dioxoisothiazolidin-2-yl) phenyl ] -4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyrazinyl, dihydrochloride

A mixture of 4- (4-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenylamine (0.34g, 1.14mmol), 3-chloro-1-propanesulfonyl chloride (0.20g, 1.14mmol) and TEA (0.12g, 1.14mmol) in DMF was stirred at room temperature for 1 hour. NaH (0.055g, 2.29mmol) was added and stirring was continued for 5 h. The reaction mixture was transferred to a microwave tube (20mL) and heated in a microwave oven at 80 ℃ for 1000 seconds. The reaction mixture was evaporated in vacuo and redissolved in a mixture of DCM and water. The phases were separated and the aqueous phase was extracted with DCM (2 × 25 mL). The combined organic extracts were evaporated in vacuo, redissolved in MeOH and purified by preparative HPLC (method B). 220mg of solid are obtained, which is redissolved in MeOH and treated with a mixture of HCl in ether. The volatiles were evaporated to yield 126mg (22%) of the title compound.

¹H-NMR(400MHz，CD₃OD)δ9.05(s，1H)，8.5(s，1H)，7.86(d，2H)，7.4(d，2H)，4.75(d，2H)，3.85(t，2H)，3.65(m，7H)，3.5(t，2H)，2.55(m，2H)，1.45(d，6H)。

HPLC-MS (method G): m +1 ═ 402; t is t_r＝1.114min.

Example 183 (general method A)

6- (4-Isopropylpiperazin-1-yl) - [3, 3' ] bipyridinyl, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described in example 1, starting from 1-isopropylpiperazine and 6-chloro- [3, 3' ] bipyridinyl.

¹H NMR(300MHz，CD₃OD)δ1.25(d，6H)，2.19(t，2H)，3.40-3.59(m，5H)，4.37(d，2H)，7.26(d，1H)，8.01(t，1H)，8.19(d，1H)，8.34(s，1H)，8.71-8.64(m，2H)，8.93(s，1H)。

HPLC (method D): t is t_r＝2.51min(98％)。

Example 184 (general method A)

6- (4-Isopropylpiperazin-1-yl) - [3, 4' ] bipyridinyl, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described in example 1, starting from 1-isopropylpiperazine and 6-chloro- [3, 4' ] bipyridinyl.

¹H NMR(300MHz，D₂O)δ1.09(d，6H)，3.15(t，2H)，3.36(t，2H)，3.56-3.46(m，3H)，4.57(d，2H)，7.10(d，1H)，8.16(dd，3H)，8.58(d，3H)。

HPLC (method D): t is t_r＝2.53min(99％)。

Example 185 (general method A)

6 '- (4-Isopropylpiperazin-1-yl) - [2, 3' ] bipyridinyl, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described in example 1, starting from 1-isopropylpiperazine and 6 '-chloro- [2, 3' ] bipyridinyl.

¹H NMR(300MHz，D₂O)δ8.75-8.63(m，2H)，8.58-8.47(m，1H)，8.28-15(m，2H)，7.87(t，J＝6.3，7.2Hz，1H)，7.17(d，J＝9.3Hz，1H)，4.61(d，J＝14.1Hz，2H)，3.75-3.52(m，3H)，3.44-3.53(m，2H)，3.20-3.43(m，2H)，1.39(d，J＝6.9Hz，6H)。

HPLC (method C): t is t_r＝2.45min(97％)。

Example 186 (general method A)

6 '- (4-ethylpiperazin-1-yl) - [2, 3' ] bipyridinyl

The title compound was prepared in analogy to the procedure described in example 1, starting from 1-ethylpiperazine and 6 '-chloro- [2, 3' ] bipyridinyl.

¹H NMR(300MHz，D₂O)δ8.70(d，J＝2.1Hz，1H)，8.54(d，J＝4.2Hz，1H)，8.13(dd，J＝9.0，2.7Hz，1H)，7.90-7.70(m，2H)，7.35-7.24(m，1H)，6.92(d，J＝9Hz，1H)，3.66(t，J＝5.1Hz，4H)，2.63(t，J＝5.1Hz，4H)，2.52(q，J＝7.2Hz，2H)，1.16(t，J＝7.2Hz，3H)。

HPLC (method C): t is t_r＝2.23min(97％)。

Example 187 (general method A)

6 '- (4-Isopropylpiperazin-1-yl) -6-methyl- [2, 3' ] bipyridinyl, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 1, starting from 1-isopropyl-piperazine and 6 '-chloro-6-methyl- [2, 3' ] bipyridinyl.

¹H NMR(300MHz，D₂O)δ8.44(d，1H)，8.26(t，1H)，8.01(dd，1H)，7.83(d，1H)，7.60(d，1H)，7.05(d，1H)，4.45(d，2H)，3.60-3.40(m，3H)，3.31(t，2H)，3.13(t，2H)，2.67(s，3H)，1.25(d，6H)。

HPLC (method C): t is t_r＝2.70min(100％)。

Example 188 (general method A)

6 '- (4-ethylpiperazin-1-yl) -6-methyl- [2, 3' ] bipyridinyl

The title compound was prepared in analogy to the procedure described for example 1, starting from 1-ethyl-piperazine and 6 '-chloro-6-methyl- [2, 3' ] bipyridinyl.

¹H NMR(300MHz，CD₃OD)δ8.66(d，1H)，8.11(dd，1H)，7.70(t，1H)，7.51(d，1H)，7.14(d，1H)，6.90(d，1H)，3.63(d，4H)，2.65-2.40(m，9H)，1.15(t，3H)。

HPLC (method C): t is t_r＝2.42min(98％)。

Example 189 (general method A)

2- [6- (4-Isopropylpiperazin-1-yl) pyridin-3-yl ] quinoline, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 1, starting from 2- (6-chloro-pyridin-3-yl) -quinoline and 1-isopropyl-piperazine.

¹H NMR(300MHz，CD₃OD)δ8.87(s，1H)，8.40-8.25(m，2H)，8.04(d，1H)，7.95-7.85(m，2H)，7.80-7.60(m，1H)，7.58-7.48(m，1H)，6.96(d，1H)，3.67(t，4H)，2.80-2.65(m，5H)，1.13(d，6H)。

HPLC (method D): t is t_r＝3.40min(97％)。

Example 190 (general method A)

N- {3- [6- (4-isopropylpiperazin-1-yl) -4-methylpyridazin-3-yl ] phenyl } acetamide, trifluoroacetate salt

Step 1:

n- [3- (6-chloro-5-methyl-pyridazin-3-yl) -phenyl ] -acetamide and N- [3- (6-chloro-4-methyl-pyridazin-3-yl) phenyl ] acetamide

3-Acylaminophenylboronic acid (6.6g, 37mmol), 3, 6-dichloro-4-methyl-pyridazine (5g, 31mmol) and Pd (PPh)₃)₄A solution of (3.5g, 3mmol) in DMF (180mL, degassed) was stirred at room temperature for 1 hour. Sodium carbonate (12.3g solution in 45mL water, degassed) was then added. The mixture was heated at 80 ℃ overnight with stirring. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (100mL), washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether 1: 1) to give 3g (38%) of N- [3- (6-chloro-5-methyl-pyridazin-3-yl) -phenyl ]-acetamide and N- [3- (6-chloro-4-methyl-pyridazin-3-yl) -phenyl]A mixture of acetamides, which is used directly in the next step.

Step 2:

the mixture of isomer (1.5g, 5.9mmol) from the previous step and 1-isopropyl-piperazine (3.7g, 28.5mmol) was heated at 200 ℃ for 1 hour under nitrogen. The mixture was cooled to room temperature and then diluted with dichloromethane (30 mL). The mixture was washed with brine, dried (sodium sulfate) and concentrated to give the crude product, which was further purified by HPLC (method F) to afford 358mg (11%) of N- {3- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridazin-3-yl ] -phenyl } -acetamide and 195mg (6%) of N- {3- [6- (4-isopropyl-piperazin-1-yl) -5-methyl-pyridazin-3-yl ] -phenyl } -acetamide as TFA salt.

N- {3- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridazin-3-yl ] -phenyl } -acetamide, trifluoroacetate salt:

¹H NMR(300MHz，D₂O)δ7.90(s，1H)，7.76(d，1H)，7.63-7.55(m，2H)，7.43-7.35(m，1H)，4.61(dd，2H)，3.72-3.56(m，3H)，3.56-3.45(m，2H)，3.35-3.20(m，2H)，2.42(s，3H)，2.17(s，3H)，1.37(d，6H)。

HPLC (method D): t is t_r＝2.85min(96％)。

Example 191 (general method A)

N- {3- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridazin-3-yl ] phenyl } acetamide, trifluoroacetate salt

The title compound was prepared as described in example 195.

¹H NMR(300MHz，D₂O)δ8.23(s，1H)，7.98(t，1H)，7.68-7.55(m，3H)，4.12-3.98(m，2H)，3.70-3.54(m，3H)，3.50-3.30(m，4H)，2.58(s，3H)，2.18(s，3H)，1.39(d，6H)。

HPLC (method D): t is t_r＝3.30min(97％)。

Example 192 (general method A)

3- [6- (4-Isopropylpiperazin-1-yl) -4-methylpyridazin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate salt

Step 1:

3- (6-chloro-5-methyl-pyridazin-3-yl) -N, N-dimethyl-benzamide and 3- (6-chloro-4-methyl-pyridazin-3-yl) -N, N-dimethyl-benzamide

N, N-Dimethylbenzamide-3-boronic acid (7g, 36.5mmol), 3, 6-dichloro-4-methyl-pyridazine (5g, 30.5mmol) and Pd (PPh)₃)₄A solution of (1.7g, 1.5mmol) in DMF (180mL, degassed) was stirred at room temperature for 1 hour. Sodium carbonate (12.1g solution in 45mL water, degassed) was then added and the mixture was heated at 80 ℃ overnight with stirring. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (100mL), washed with brine, dried (sodium sulfate) and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc/petroleum ether 1: 1). A mixture of 2.8g (32%) 3- (6-chloro-5-methyl-pyridazin-3-yl) -N, N-dimethyl-benzamide and 3- (6-chloro-4-methyl-pyridazin-3-yl) -N, N-dimethyl-benzamide was obtained and used directly in the next step.

Step 2:

the mixture of isomer (1.5g, 5.9mmol) from the previous step and 1-isopropyl-piperazine (3.7g, 28.5mmol) was heated at 200 ℃ for 1 hour under nitrogen. The mixture was cooled to room temperature and diluted with dichloromethane (30 mL). The mixture was washed with brine, dried (sodium sulfate) and concentrated to give the crude product, which was purified by preparative HPLC (method F) to yield 185mg (6%) of 3- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridazin-3-yl ] -N, N-dimethyl-benzamide and 373mg (12%) of 3- [6- (4-isopropyl-piperazin-1-yl) -5-methyl-pyridazin-3-yl ] -N, N-dimethyl-benzamide as TFA salt.

3- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridazin-3-yl ] -N, N-dimethyl-benzamide, trifluoroacetate salt:

¹H NMR(400MHz，D₂O)δ7.83(s，1H)，7.69-7.56(m，3H)，7.56(s，1H)，4.53(d，2H)，3.63-3.50(m，3H)，3.50-3.39(m，2H)，3.30-3.15(m，2H)，3.01(s，3H)，2.92(s，3H)，2.33(s，3H)，1.29(d，6H)。

HPLC (method D): t is t_r＝3.02min(99％)。

Example 193 (general method A)

3- [6- (4-Isopropylpiperazin-1-yl) -5-methylpyridazin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate salt

The title compound was prepared as described in example 197.

¹H NMR(400MHz，D₂O)δ8.24(s，1H)，7.90(d，1H)，7.81(s，1H)，7.70-7.58(m，2H)，4.02(d，2H)，3.63-3.48(m，3H)，3.48-3.27(m，4H)，3.03(s，3H)，2.92(s，3H)，2.53(s，3H)，1.31(d，6H)。

HPLC (method D): t is t_r＝3.49min(98％)。

Example 194 (general method A)

4- [6- (4-Isopropylpiperazin-1-yl) -4-methylpyridazin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate

Step 1:

4- (6-chloro-5-methyl-pyridazin-3-yl) -N, N-dimethyl-benzamide and 4- (6-chloro-4-methyl-pyridazin-3-yl) -N, N-dimethyl-benzamide.

N, N-Dimethylbenzamide-4-boronic acid (7g, 36.5mmol), 3, 6-dichloro-4-methyl-pyridazine (5g, 31mmol) and Pd (PPh)₃)₄A solution of (1.7g, 1.5mmol) in DMF (180mL, degassed) was stirred at room temperature for 1 hour. Sodium carbonate (12.3g solution in 45mL water, degassed) was then added and the mixture was stirredThe mixture was heated at 80 ℃ overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (100mL), washed with brine, dried (sodium sulfate) and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc/petroleum ether 1: 1). A mixture of 2.5g (28%) 4- (6-chloro-5-methyl-pyridazin-3-yl) -N, N-dimethyl-benzamide and 4- (6-chloro-4-methyl-pyridazin-3-yl) -N, N-dimethyl-benzamide was obtained and used directly in the next step.

Step 2:

the mixture of isomer (15g, 5.9mmol) from the previous step and 1-isopropyl-piperazine (3.7g, 28.5mmol) was heated at 200 ℃ for 1 hour under nitrogen. The mixture was cooled to room temperature and diluted with dichloromethane (30 mL). The mixture was washed with brine, dried (sodium sulfate) and concentrated to give the crude product, which was purified by preparative HPLC (method F) to yield 256mg (8%) of4- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridazin-3-yl ] -N, N-dimethyl-benzamide and 278mg (9%) of4- [6- (4-isopropyl-piperazin-1-yl) -5-methyl-pyridazin-3-yl ] -N, N-dimethyl-benzamide as TFA salt.

4- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-pyridazin-3-yl ] -N, N-dimethyl-benzamide:

¹H NMR(300MHz，CD₃OD)δ7.76(s，1H)，7.70-7.60(m，4H)，4.70-3.35(m，9H)，3.13(s，3H)，3.03(s，3H)，2.40(s，3H)，1.42(d，6H)。

HPLC (method D): t is t_r＝2.89min(92％)。

Example 195 (general method A)

4- [6- (4-Isopropylpiperazin-1-yl) -5-methylpyridazin-3-yl ] -N, N-dimethylbenzamide, trifluoroacetate

The title compound was prepared as described in example 194.

¹H NMR(300MHz，CD3OD)δ8.14(s，1H)，8.07(d，2H)，7.61(d，2H)，4.10-3.90(m，2H)，3.70-3.55(m，3H)，3.55-3.32(m，4H)，3.13(s，3H)，3.03(s，3H)，2.53(s，3H)，1.43(d，6H)。

HPLC (method D): t is t_r＝3.38min(91％)。

Example 196 (general method A)

N- {4- [6- (4-isopropylpiperazin-1-yl) -5-methylpyridazin-3-yl ] phenyl } acetamide, trifluoroacetate salt

The title compound was prepared as described in example 72.

¹H NMR(300MHz，D₂O)δ8.10(s，1H)，7.95(dd，2H)，7.78(d，2H)，4.02-3.85(m，2H)，3.70-3.50(m，3H)，3.50-3.32(m，4H)，2.52(s，3H)，2.16(s，3H)，1.44(d，6H)。

HPLC (method D): t is t_r＝3.26min(94％)。

Example 197 (general method A)

1 '- (6-pyridin-4-yl-pyridazin-3-yl) - [1, 4' ] bipiperidinyl

The title compound was prepared in analogy to the procedure described for example 1, starting from 3-chloro-6-pyridin-4-yl-pyridazine and 4-piperidinopiperidine.¹H NMR(400MHz，DMSO-d₆)δ8.67(dd，2H)，8.04(m，3H)，7.40(d，1H)，4.53(d，2H)，2.95(t，2H)，2.56(m，1H)，2.45(m，4H)，1.82(d，2H)，1.48(m，6H)1.38(m，2H)。

HPLC-MS (method G): m +1 ═ 324; t is t_r＝0.54min.

Example 198 (general method A)

3- (pyridin-3-yl) -6- [ (4-pyrrolidin-1-yl) piperidin-1-yl ] pyridazine

Starting from 3-chloro-6- (pyridin-3-yl) -pyridazine and 4- (1-pyrrolidinyl) piperidine, the title compound was prepared in analogy to the methods described in example 1.¹H NMR(400MHz，DMSO-d₆)δ9.22(d，1H)，8.61(dd，1H)，8.39(dt，1H)，8.01(d，1H)，7.51(m，1H)，7.40(d，1H)，4.34(dt，2H)，3.09(m，2H)，2.56(s，4H)，2.33(m，1H)，1.95(m，2H)，1.69(m，4H)，1.44(m，2H)。

HPLC-MS (method G): m +1 ═ 310; t is t_r＝0.38min.

Example 199 (general method A)

1 '- (6-pyridin-3-yl-pyridazin-3-yl) - [1, 4' ] bipiperidinyl

The title compound was prepared in analogy to the procedure described for example 1, starting from 3-chloro-6- (pyridin-3-yl) -pyridazine and 4-piperidinopiperidine.¹H NMR(400MHz，CD₃0D)δ9.47(d，1H)，9.11(dt，1H)，8.93(d，1H)，8.40(d，1H)，8.15(q，1H)，7.94(d，1H)，4.66(d，2H)，3.66(m，1H)，3.58(d，2H)，3.36(t，2H)，3.08(t，2H)，2.38(d，2H)，1.80-2.00(m，7H)，1.54(m，1H)。

HPLC-MS (method G): m +1 ═ 324; t is t_r＝0.55min.

Example 200 (general method A)

3- (pyridin-4-yl) -6- [ (4-pyrrolidin-1-yl) piperidin-1-yl ] pyridazine

Starting from 3-chloro-6- (pyridin-4-yl) -pyridazine and 4- (1-pyrrolidinyl) piperidine, the title compound was prepared in analogy to the methods described in example 1.¹H NMR(400MHz，CDCl₃)δ8.69(d，2H)，7.90(d，2H)，7.67(d，1H)，7.01(d，1H)，4.47(d，2H)，3.12(m，2H)，2.67(s，4H)，2.40(m，1H)，2.07(d，2H)，1.83(s，4H)，1.67(m，2H)。

HPLC-MS (method G): m +1 ═ 310; t is t _r＝0.46min.

Example 201 (general method A)

4-pyrrolidin-1-yl-3, 4, 5, 6-tetrahydro-2H- [1, 2'; 5', 3 "] terpyridyl

From 6-chloro- [3, 3']The title compound was prepared by an analogous method to that described in example 1 starting with bipyridine and 4- (1-pyrrolidinyl) piperidine.¹H NMR(400MHz，CD₃OD)δ8.74(d，1H)，8.46(dd，1H)，8.39(d，1H)，8.03(dt，1H)，7.86(dd，1H)，7.49(q，1H)，6.95(d，1H)，4.40(d，2H)，2.92(m，2H)，2.67(t，4H)，2.35(m，1H)，2.05(d，2H)，1.82(m，4H)，1.51(m，2H)。

HPLC-MS (method G): m +1 ═ 309; t is t_r＝0.28min.

Example 202 (general method A)

1-isopropyl-4- (6-phenylpyridin-3-yl) piperazine dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1 starting from 5-bromo-2-phenylpyridine and 1-isopropylpiperazine.¹H NMR(400MHz，CD₃OD)δ8.41(m，1H)，8.13(m，2H)，7.90-7.85(m，2H)，7.63-7.55(m，3H)，4.3-4.1(m，2H)，3.75-3.55(m，3H)，3.50-3.30(m，4H)，1.45(d，J＝6.8Hz，6H)。

HPLC-MS (method G): m +1 ═ 282; t is t_r＝0.76min.

Example 203 (general method A)

(R) -2- [6- (3, 4-dimethoxyphenyl) pyridazin-3-yl ] octahydropyrido [1, 2-a ] pyrazine, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 1, starting from 3-chloro-6- (3, 4-dimethoxy-phenyl) -pyridazine and (R) -octahydro-pyrido [1, 2-a ] pyrazine, dihydrochloride.

¹H-NMR(400MHz，CD₃OD)δ8.55(d，1H)，8.22(d，1H)，7.60-7.54(m，2H)，7.21(d，1H)，4.73-4.58(m，2H)，3.98(s，3H)，3.95(s，3H)，3.72-3.52(m，3H)，3.50-3.35(m，3H)，3.15-3.05(m，1H)，2.12-2.05(m，1H)，2.02-1.93(m，3H)，1.81-1.63(m，2H)。

HPLC-MS (method G): m +1 ═ 355; t is t_r＝0.955min.

Example 204 (general method B)

N- {3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl) acetamide trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 39, starting from 3- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzylamine and acetyl chloride.

¹H NMR(300MHz，D₂O)δ8.27(d，1H)，8.10(s，1H)，7.40-7.24(m，5H)，4.32-4.28(d，4H)，3.64-3.53(m，5H)，3.25(t，2H)，1.92(s，2H)，1.27(d，6H)。

HPLC (method D): t is t_r＝2.40min(97％)。

Example 205 (general method B)

N- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } -3, 3-dimethylbutanamide, trifluoroacetate salt

The title compound was prepared starting from 4- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzylamine and 3, 3-dimethyl-butyryl chloride using a method analogous to that described in example 39.

¹H NMR(400MHz，D₂O)δ8.29(dd，1H)，8.14(d，1H)，7.51(d，2H)，7.40-7.30(m，3H)，4.40-4.25(m，4H)，3.70-3.48(m，5H)，3.34-3.15(m，2H)，2.06(s，1H)，1.28(dd，6H)，0.86(s，9H)。

HPLC (method D): t is t_r＝3.38min(97％)。

Example 206 (general method B)

N- {3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } -3, 3-dimethylbutanamide, trifluoroacetate salt

The title compound was prepared starting from 3- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzylamine and 3, 3-dimethyl-butyryl chloride using a method analogous to that described in example 39.

¹H NMR(300M[Hz，D₂O)δ8.27(d，1H)，8.12(s，1H)，7.46-7.28(m，5H)，4.32-4.28(d，4H)，3.64-3.53(m，5H)，3.25(t，2H)，2.06(s，2H)，1.27(d，6H)，0.85(s，9H)。

HPLC (method D): t is t_r＝3.39min(90％)。

Example 207 (general method B)

N- {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzyl } isobutyramide, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 39, starting from 4- (6- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzonitrile.

Mp＝287-289℃.

¹H NMR(300MHz，CDCl₃)δ13.06(brs，1H)，8.68(s，2H)，7.47-7.38(m，4H)，6.07(brs，1H)，5.12(d，2H)，4.52-4.47(m，2H)，4.25-4.12(m，2H)，3.60-3.44(m，3H)，3.11-2.76(m，2H)，2.52-2.38(m，1H)，1.49(d，6H)，1.21(d，6H)。

Example 208 (general method B)

N- {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } -2, 2-dimethylpropanamide, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 39, starting from 4- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzylamine and 2, 2-dimethyl-propionyl chloride.

¹H NMR(300MHz，D₂O)δ8.29(dd，1H)，8.13(d，1H)，7.50(d，2H)，7.35-7.25(m，3H)，4.45-4.25(m，4H)，3.65-3.45(m，5H)，3.34-3.15(m，2H)，1.28(d，6H)，1.07(s，9H)。

HPLC (method D): t is t_r＝2.84min(98％)。

Example 209 (general method B)

N- {3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzyl } -2, 2-dimethylpropanamide, trifluoroacetate salt

The title compound was prepared in analogy to the procedure described for example 39, starting from 3- (6- (4-isopropylpiperazin-1-yl) pyridin-3-yl ] benzylamine and 2, 2-dimethyl-propionyl chloride.

¹H NMR(300MHz，CDCl₃)δ8.41(d，1H)，7.02(t，1H)，7.43-7.27(m, 3H), 7.21-7.18(m, 1H), 6.72(t, 1H), 6.95-6.93(m, 1H), 4.49-4.46(m, 2H), 3.78-3.62(m, 4H), 2.90-2.65(m, 5H), 1.17-1.10(m, 15H). HPLC (method D): t is t_r＝3.10min(98％)。

Example 210 (general method B)

4- [2- (4-Cyclopropylpiperazin-1-yl) pyrimidin-5-yl ] benzylamine

The title compound is prepared in analogy to the procedure described for example 39, starting from 4- [2- (4-cyclopropyl-piperazin-1-yl) -pyrimidin-5-yl ] -benzonitrile.

Mp＝150-152℃.

¹H NMR(300MHz，CDCl₃)δ8.55(s，2H)，7.45(d，2H)，7.39(d，2H)，3.91(s，2H)，3.86-3.83(m，4H)，2.72-2.68(m，4H)，1.69-1.61(m，1H)，1.5(brs，2H)，0.52-0.46(m，4H)。

HPLC (method Rx): t is t_r＝3.29min(99％)。

Example 211 (general method B)

N- {4- [2- (4-cyclopropylpiperazin-1-yl) pyrimidin-5-yl ] benzyl } acetamide, dihydrochloride

The title compound was prepared in analogy to the procedure described for example 39, starting from 4- [2- (4-cyclopropyl-piperazin-1-yl) -pyrimidin-5-yl ] -benzylamine and acetic anhydride.

Mp＝235-236℃.

HPLC (method)Rx)：t_r＝7.11min(100％)。

Example 212 (general method B)

N N- {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] acetamide, bis-trifluoroacetate salt

Starting from 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -benzonitrile the title compound is prepared in analogy to the procedure described for example 39.

¹H NMR(400MHz，CD₃OD) Δ 8.24(d, 1H), 7.91(d, 2H), 7.84(d, 1H), 7.50(d, 2H), 4.44(s, 2H), 3.63 (heptad et, 1H), 3.70-3.30 (broad m, 8H), 2.02(s, 3H), 1.42(d, 6H).

HPLC-MS (method G): m +1 is 354; t is t_r＝0.66min.

Example 213 (general method F)

N- [4- (4-cyclopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) phenyl ] acetamide, hydrochloride

N- [4- (3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyrazinyl-5' -yl) -phenyl ] -acetamide (125mg, 0.42mmol) was dissolved in methanol (2mL) and ethoxycyclopropoxy) trimethylsilane (0.11g, 0.63mmol) and acetic acid (0.076g, 1.26mmol) were added. The mixture was stirred for 5 minutes and,

sodium cyanoborohydride (0.04g, 0.63mmol) and water (1mL) were then added. The reaction mixture was heated at 65 ℃ for 1 hour, then an additional equivalent of sodium cyanoborohydride was added and stirring was continued at 65 ℃ for 1 hour. The reaction mixture was evaporated in vacuo and the crystalline mixture was washed with methanol. The volatiles were evaporated to give a residue which, after treatment with a mixture of HCl in ether, gave 72mg (46%) of the title compound.

¹H-NMR(400MHz，CD₃OD)δ8.85(s，1H)，8.45(s，1H)，7.85(d，2H)，7.75(d，2H)，4.6(d，2H)，3.7(m，2H)，3.5(m，4H)，2.95(m，1H)，2.15(s，3H)，1.2(brs，2H)，1.05(dd，2H)。

HPLC-MS (method G): m +1 ═ 338; t is t_r＝1.51min.

Example 214 (general method M)

2- {4- [6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenoxy } -N, N-dimethylacetamide, dihydrochloride

Step 1:

4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -phenol

Starting from 3-chloro-6- (4-isopropyl-piperazin-1-yl) -pyridazine and (4-hydroxyphenyl) boronic acid, through a similar process to that described in example 71, 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl ] -phenol was prepared.

Step 2:

reacting 4- [6- (4-isopropyl-piperazin-1-yl) -pyridazin-3-yl]A mixture of phenol (110mg, 0.37 mmol 1) and 60% sodium hydride (58mg, 1.45mmol) in anhydrous DMF (5mL) was heated at 60 ℃ for 30 min. 2-chloro-N, N-dimethylacetamide (54mg, 0) was added.44mmol) and heating is continued at 60 ℃ for a further 20 hours. The reaction mixture was evaporated to dryness and partitioned between water (10mL) and DCM (10 mL). The organic phase was separated, washed with brine (5mL), dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. The residue was dissolved in hot ethyl acetate and then HClg in Et was added₂O to obtain the title compound.

¹H NMR(400MHz，DMSO-d₆) δ 11.29 (wide s, 1H), 8.30(d, 1H), 8.00(d, 2H), 7.86(d, 1H), 7.08(d, 1H), 4.93(s, 2H), 4.58(d, 2H), 3.65(t, 2H), 3.51(m, 3H), 3.16(m, 2H), 3.02(s, 3H), 2.85(s, 3H), 1.32(d, 6H).

HPLC-MS (method G): m +1 ═ 384; t is t_r＝0.72min.

Example 215 (general method L)

Cyclohexanecarboxylic acid {4- [6- (4-cyclopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } amide, trifluoroacetic acid salt

Starting from 4- [6- (4-cyclopropyl-piperazin-1-yl) -pyridazin-3-yl ] -phenylamine and cyclohexylcarbonyl chloride, the title compound was prepared in analogy to the procedure described for example 170.

¹H NMR(300MHz，CD₃OD)δ8.34(d，1H)，7.98-7.82(m，5H)，4.05-3.95(m，4H)，3.69-3.55(m，4H)，2.96-2.85(m，1H)，2.44-2.37(m，1H)，1.91-1.82(m，4H)，1.73(d，1H)，1.59-1.19(m，5H)，1.09-0.99(m，4H)。

HPLC (method D): t is t_r＝3.90min(98％)。

Example 216

N- {4- [ 4-isopropyl-6- (4-isopropylpiperazin-1-yl) pyridazin-3-yl ] phenyl } acetamide trifluoroacetate salt

3- (4-bromophenyl) -4-isopropyl-6- (4-isopropyl-piperazin-1-yl) -pyridazine (500mg, 1.24mmo1), acetamide (87.8mg, 1.49mmol), Pd (OAc)₂(13.9mg，0.062mmol)、Cs₂CO₃(606mg, 1.86mmol) and Xantphos (53.8mg, 0.093mmol) in 1, 4-bisThe mixture in alkane (10mL) was heated at reflux for 12 hours. Water (5mL) was then added. After filtration, the mixture was extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine and dried (Na)₂SO₄) And concentrated. The residue was purified by HPLC (method F) to yield 196mg (38%) of the title compound.

¹H NMR(300MHz，CD₃OD)δ7.96(s，1H)，7.89(d，2H)，7.57(d，2H)，4.90-3.314(m，9H)，3.19-3.15(m，1H)，2.20(s，3H)，1.46(d，6H)，1.31(d，6H)。

HPLC (method D): t is t_r＝3.35min(100％)。

Claims

1. A compound selected from the group consisting of:

n- {4- [6- (4-isopropylpiperazin-1-yl) piperidin-3-yl ] benzyl } acetamide, and

n- {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzyl } isobutyramide.

2. The compound of claim 1 wherein said compound is N- {4- [6- (4-isopropylpiperazin-1-yl) piperidin-3-yl ] benzyl } acetamide or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein said compound is N- {4- [2- (4-isopropylpiperazin-1-yl) pyrimidin-5-yl ] benzyl } isobutyramide or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 3 and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.