TWI291958B - Pyrazinyl-piperazine compounds, their use in the treatment of serotonin related diseases, and their preparation - Google Patents

Description

1291958 A7 B7 V. INSTRUCTIONS (1) Field of the Invention (Please read the note on the back and then fill out this page) The present invention relates to a novel compound, a drug comprising the compound, a group, a preparation method thereof, and the use of the same The preparation of the compound acts on the central god, the systemic agent. BACKGROUND OF THE INVENTION Some pharmacological and genetic experiments involving receptors for hemoglobin are strong @暗1 indicating that the HT2C receptor subtype is involved in the regulation of food intake (〇bes. Res· 1 995, 3, Suppl. 4,449 S-462S). The 5-HT2C receptor subtype is printed and displayed by the Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative in the hypothalamic structure associated with appetite. It has been demonstrated that the non-specific 5 - Η T 2 c receptor agonist, chlorophenylpiperazine (m CPP ), which has a preference for 5- Η T 2 c, will show normal 5- Η T 2 The mice of the c-receptor lost weight, and the compound lacked activity in mice showing a mutant inactive form of the 5 - Τ Τ 2 c receptor (Nature 1 995, 374, 542-546). In recent clinical studies, there was a slight but persistent decrease in body weight after 2 weeks of treatment with mCPP in obese individuals (Psychopharmacology 1 997, 133, 309-312). Clinical studies with other, blood stasis sputum agents have also been reported to reduce body weight (see, for example, IDrugs 1 998, 1, 456-470). For example, 5 - Η T re-intake inhibitor fluphenoxypropylamine and 5- Η Τ release/re-ingesting inhibitor dexfenfluramine show weight loss in controlled individuals. However, the available drugs that can now increase the delivery of blood stasis can only be small and in some cases, short-lived effects. It has been shown that the 5 - Η T 2 c receptor subtype participates in the CNS disorder. For example, the paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm -) 4 - "" 1291958 A7 B7 Description of the invention (2) Depression and anxiety (Exp. 〇pin. Invest. Drugs 1 998, 7, 1587-1599; IDrugs, 1999, 2, 109-120). Further shows 5 - Η T 2 . Receptor subtypes participate in urinary tract disorders such as urinary incontinence (IDrugs, 1 999, 2, 109-1 20). Compounds that have a selective effect at the 5 - Η T 2 c receptor therefore have therapeutic potential in disorders as described above. This selectivity also has the potential to reduce the adverse effects of modulation by other hemoglobin receptors. 9 8 9 reveals the use of 111〇??

8 6 3 1 3 6 revealed as selective 5 - HT2C

U S - A - 3 appetite suppressant. E P — A 1 — The azetidine and pyrrolidine derivatives of the receptor agonist have antidepressant activity and are useful for the treatment or prevention of hemoglobin-related diseases, including eating disorders and anxiety. E P - A - 6 5 7 4 2 6 reveals that the tricyclic pyrrole derivative is active against the 5 - H T 2 C receptor and is useful for treating anorexia disorders. ΕΡ — Α — 6 5 5440 discloses that 1-amine ethyl hydrazine is active at the 5 -Η Τ 2 c receptor and can be used to treat foraging disorders. E P — A - 5 7 2 8 6 3 Reveals that pyrazine is also active in the Η T 2 c receptor and can be used to treat foraging disorders in the Ministry of Economic Affairs' Intellectual Property Office Staff Consumer Cooperative. J. Med. Chem. 1 978, 2 1,536-542 and US-A-4,08 1,542 disclose that a series of piperazinylpyrazines have activity similar to central hemoside. J. Med. Chem. 1981, 24, 93-101 reveals that a series of piperazinyl quinoxalines have similar central hemoglobin activity. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -5 - 1291958 A7 B7 V. INSTRUCTION DESCRIPTION (3) SUMMARY OF THE INVENTION In accordance with the present invention, a novel class of compounds is developed which is linked to 5 -Η T2c receptors and their use in the treatment of hemoglobin-related disorders. In one aspect, the invention provides a novel compound of formula (I):

Wherein A r is an aryl or heteroaryl group, one or more of which are via a lower fenestration group, a Cl - 6 - alkoxy group, a Cl-6 -

Column group substitution: C i - 6 thiol, C i - 6 - fluorenyl, hydroxy, C 2 6 - enemethyl, trifluoromethyl, difluoro, trifluoromethylthio, halogen, yl , arylthio, aryl-C

C-alkylsulfonyl, cyano, nitro, C 2 - 6 - alkynyl, fluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio __ N (R 2 ) (R 3 ) 'Aryl, aryloxy-4, aryl-C 2 - 4 - alkenyl (please read the back of the note before you fill out this page)

, aryl-C heterocyclyl-C 2-4 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 1 - 4 - fast-based base multiple positions on the selective basis, Cl-6 - courtyard oxygen, C 1 - 6 - a carboxylic acid group, a hydroxy group, an amine group, a ci group, a heterocyclic group, a heterocyclic oxy group, a heterocyclic thiol group, wherein one or more of the aryl and heterocyclic group residues Group substitution: halogen, C 1 - 6 - Institute Cl-6 -alkylthio, Cl-6-fluorenyl, nitro, trifluoromethyl, trifluoromethylthio, cyanide or

C 1 — 6 alkyl) Amine; A is (i)-〇S〇-N Η This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 > -6 - A7 1291958 ______B7__ V. Invention Description (4) (ii) a nitrogen atom substituted with a Cl-4 or a fluorenyl group, or (iii) a Ci-8-alkyl chain or a heteroalkyl group having 2 to 8 chain atoms a chain optionally comprising at least one unsaturated bond, wherein one or more of the C i-8 alkyl chain and the heteroalkyl group are respectively C i 4 -alkyl, trifluoromethyl or ketone a base substitution, and a side-by-side or spacer chain atom thereof on a C i-8 alkylene chain or a heteroalkyl group is selectively bonded via an alkylene bridge having 1 to 5 carbon atoms or having 2 to 5 carbon atoms Extending the base bridge connection, or forming a saturated or partially saturated or all-saturated 3 to 8 ring via a one-bond connection at a c 1 - 8 alkyl chain or a heterojunction base. Carbon ring or heterocyclic ring of an atom; B is a C (R4) (r5)-, a 〇C (r4) (R5) I, a N (R6) C (R4) (R5) -, - N (R6) -, one, one, one, S Or a S〇2—; R is a C3-8-cycloalkyl, aryl or heteroaryl group substituted at one or more positions by a group: C i - 6 -alkyl, C i - 6 - alkoxy, Ci-6-alkylthio, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, difluoromethylthio, trifluoromethoxy, trifluoromethane Base, halogen, thiol, nitro, cyano, trifluoromethylsulfonyloxy, methylamino, C2- 6-alkenyl, C2-6-alkynyl, 6-fluorenyl, Cb 6 — Alkylcarbonyl-C 1 - 6 -alkyl, C: i - 6 monoalkylthio, C 1 - 6 -alkylsulfonyl, Cl-6-alkylsulfonyloxy, Cl-6 alkoxy base-

Ci-6-alkyl, Ci-6-alkoxycarbonyl, Cl-6-alkoxycarbonyl-Cl-6-alkyl, Ci-6-decyloxy-Cl-6-alkyl, hydroxy-Cl -6—Alkyl, C3- 8 —cycloalkyl, aryl, aryloxy, aryl paper scales applicable to China National Standard (CNS) A4 specification (210 X 297 mm 3"""" Please read the notes on the back and fill out this page) -i^w· -------tr--------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 __B7___000^-- V. INSTRUCTIONS (5) (Please read the notes on the back and fill out this page.) Sulfur-based, aromatic fluorenyl, aryl-C 1-6 -fluorenyl, aryl-C 1 alkyl, aryl — C 2-6 - alkenyl, aryl - C 2 - 6 - alkyne, anthracenyl - C 1-6 -indolyl, heteroaryl - C 2 - 6 - alkenyl, heteroaryl C 2 - 6 - Alkynyl, heterocyclic, heterocyclooxy, heterocyclic thio, heterocyclic aryl, heterocyclic amino, heterocyclyl-C 1 - 6 -,

π (when R -N ( R 2 ) ( R 3 ), a C〇N(R7) (R8) or is a C 3 - 8 -cycloalkyl) ketone group, wherein any cycloalkyl, aryl, hydrazine The aryl group and the heterocyclic group residue may be substituted at one or more positions by the following groups: C 1 - 6 -alkyl, C 1 - 6 -alkoxy, methanesulfonylamino, C 1 -6 —院thio, C 1-6—homo-based fluorenyl, Cl-6ylaryl-C i — 6 —fluorenyl, heterocyclic oxy, heterocyclic thio, aryloxy, aryl Sulfur, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, halogen, hydroxy, nitro, cyano , N ( R 2 ) ( R 3 ) or (for cycloalkyl) ketone groups; Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printing R i is (i) a saturated or unsaturated nitrogen heterocyclic or amine nitrogen heterocycle, Or a saturated diaza heterocyclic ring or an aminodiaza heterocyclic ring having 4 to 7 ring atoms, or a saturated amino azabicyclo, azabicyclo or diazabicyclo ring (having a 7 to 10 ring atom), wherein - or one or more positions on the double ring can be single or double taken by the following groups, respectively :C i — 6 —alkyl, C 3 - 6 —alkenyl, C i — 6 —alkoxy, fluoromethyl, trifluoromethyl, difluoromethyl, keto, halogen, hydroxymethyl, Ci -6-alkoxymethyl, 2-hydroxyethyl (preferably attached to a nitrogen atom on the ring), 2-cyanoethyl (preferably attached to a nitrogen atom on the ring), or attached to a nitrogen atom on the ring, Ci -6 —Mercapto, aryl-Ci — 6 —fluorenyl, heteroaryl-Ci-6 —mercapto, arylamine This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) - 8- A7 1291958 B7___ V. INSTRUCTIONS (6) (Please read the note on the back and fill out this page) Mercapto, heteroarylamine thiol, C1-4 one-site oxycarbyl or tetrahydroanthracene a quaternary 2-yl group, wherein the saturated nitrogen heterocycle may contain another hetero atom; or (ii) a [C(R4)(R5)]XN(R2)(R3); R2 and R3 are respectively qi , Cl-6- ί 兀, Cl -6 — aryl, —CON ( R 7 ) ( R 8 ), aryl, heteroaryl, aryl-Cb 6-alkyl, heteroaryl-C1-6 —alkyl, aryl-C1-6-fluorenyl or heteroaryl-C 1-6 -fluorenyl, any of which The aryl and heteroaryl residues may be substituted at one or more positions in the following groups by halogen, C-6, one courtyard, Cl-6, alkoxy, Cl-6, thiol, Cl. — 6 —院基sulfonyl, C 1 - 6 -fluorenyl, methanesulfonylamino, nitro, cyano, thiol, trifluoromethyl, difluoromethoxy, difluoromethylthio, three Fluoromethoxy, dichloromethylthio, C2-4-sense, C2-4-fast or a N(R2)(R3); or R2 and R3 together with the attached nitrogen atom have 4 a saturated heterocyclic ring of 7 ring atoms and optionally another hetero atom which may be substituted by a C i 6 -alkyl or keto group; R 4 and R 5 are respectively hydrogen or C on the individual substituted carbon atom i - 6 -alkyl; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed R6 is hydrogen or Cl-6 - yard; R7 and Rs are gas, C 1-6 - yard, aryl, heteroaryl, Aryl-C 1 - 4 - one or heteroaryl - C 1 - 4 - a aryl group wherein the aryl and heteroaryl residues are substituted at one or more positions in turn by the following groups: halogen, Cl - 6 — yard base, Cl-6 — hospital oxygen, Cl − 6 — hospital Base, C 1 - 6 -yard base, C 1 - 6 - fluorenyl, methanesulfonamide, nitro, cyano, hydroxy, trifluoromethyl, difluoromethoxy, difluoromethane Base and three paper scales apply to China National Standard (CNS) A4 specification (210 X 297 mm) -9- Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1291958 A7 _ B7___ V. Description of invention (7) Fluoromethoxy , trifluoromethylthio, C2-4-alkenyl, C2-4-alkynyl or -N(R 2 ) ( R 3 ); or R7 and R8 together with the nitrogen atom to which they are attached form a 4-7 ring atom a saturated heterocyclic ring and optionally another hetero atom; η is 0 or 1 ' and X is 2, 3 or 4, but (i) when a Α - R is a phenoxy group or a phenylthio group, then A r is not Is a quinoxalinyl or pyridyl group, and (ii) when A is a vinyl group, Ar is not a sulfonyl group, and a pharmaceutically acceptable salt, hydrate, and prodrug thereof. Where the compound of formula (I) can be in the form of an optical isomer, the present invention comprises a racemic mixture as well as individual enantiomers. Where the compound of formula (I) is present in tautomeric form, the invention encompasses forms of tautomers and mixtures thereof. Where the compound of formula (I) can be in the form of a geometric isomer, the present invention encompasses geometric isomers and mixtures thereof. In another aspect, the compounds of formula (I) provided herein are useful in therapy. In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) as an active ingredient together with a pharmaceutically acceptable carrier, preferably, and, if desired, other pharmacologically active agents. In another aspect, the present invention provides a method of treating a blood stasis-related disease in a human or animal individual, the blood-related hormone-related disease, particularly an eating disorder (especially obesity), a memory disorder, a spirit The split paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) Binding-10-1291958 A7 B7 V. Invention Description (8) Symptoms, emotions Disorders, anxiety, pain, sexual dysfunction, and urinary system disorders. In another aspect, the invention provides the use of a compound of formula () as described above for the preparation of a medicament for the treatment of a blood stasis-related disease, in particular a food disorder (especially obesity), memory disorder, schizophrenia, Emotional disorders, anxiety disorders, pain, sexual desire dysfunction and urinary system disorders. In another aspect, the invention provides a process for the preparation of a compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION First, the various nouns used in the definition of formula (I) above will be explained individually or in combination. ''Hetero atomic hydrazine refers to nitrogen, oxygen, sulfur, and may also refer to selenium in a heterocyclic ring. The ''aryl fluorene ring') includes an aryl ring (monocyclic or bicyclic) having 6 to 10 carbon atoms, such as a phenyl group and a naphthyl group. &heteroaryl oxime refers to a monocyclic, bi- or tricyclic aryl ring system (only one ring needs to be an aryl group) having 5 to 14 ring atoms, preferably 5 to 1 ring atoms (single- or double ring) Where one or more of the ring atoms are not carbon, such as nitrogen, sulfur, oxygen, and selenium. Examples of such heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, diazole oxazole, isoxazole, oxadiazine, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole , tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, pyridazine, cinnoline, quinoxaline, D-d, D, D, D Introduce D-porphyrin, iso- D-derived D-porphyrin, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2, . Install i I (please read the notes on the back and fill out this page) Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Paper Scale Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) -11 - 1291958 A7 B7__ V. Invention Description (9) 1 ' 3 -Benzene Oxazole, benzothiazole, 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole, benzimidazole, carbazole, benzodiazepine (please read the notes on the back) On this page) Disgusting $兀, life full, 1, 2 ' 3 ' 4 — tetraammine, 3,4-dichloro-2H-1, 4-benzoxazine, 1,5-naphthyridine, 1 ,8 —naphthalene 11 定, acridine, phenazine, xanthene, coumarin, 2,3-dibenzopyrene, benzodioxane, 2,3 - two Hydrogen-1,4-benzodioxan, 1,3-benzodioxan, 3,4-dihydro-2H-pyrido[3'2-b]-1,4-choke and 2 , 3 - dihydro-1, 4 - benzoxanthene. The heteroaryl ring can be attached to the divalent group A in formula (I) via its upper carbon or nitrogen atom. The w-alkylene group refers to an alkylene group containing a terminal hetero atom (one or both ends) and/or one or more carbon chains which are inserted by a hetero atom selected from N, 0 and S. The number of heteroatoms is at least 1, and usually from 1 to 3, especially 1 or 2. When a heteroalkyl group is substituted, it is usually substituted on a carbon atom, but it may be substituted on or otherwise on a nitrogen or sulfur atom, if present. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives, ''Heterocyclyl" refers to mono- and di--containing 4 to 14 ring atoms (especially 4 to 10 ring atoms) which are unsaturated and partially and fully saturated. And a tricyclic group such as a heteroaryl group as described above and a corresponding partially saturated or fully saturated heterocyclic group. Examples of saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine. C i - 6 -alkyl (which may be straight or branched) is preferably C i - 4 - alkyl. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a second butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, and an isohexyl group. This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) -12- 1291958 A7 _____Β7 _ V. Invention description (10) (Please read the note on the back and fill out this page) C 1 - 6 The alkoxy group (which may be linear or branched) is preferably a C 1 - 4 monoalkoxy group. Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a second butoxy group, a third butoxy group, a pentyloxy group, an isopentyloxy group, and a hexyloxy group. Base and isohexyloxy. The C 2-6-alkenyl group (which may be linear or branched) is preferably a C 2 - 4 -alkenyl group such as a propylene group, a 2-propenyl group or a vinyl group. C 2 -6 -alkynyl (which may be straight or branched) is preferably a C 2 -4 -alkynyl group such as propynyl or ethynyl. The C 3 - 8 -cycloalkyl group is preferably a C 4 - 7 -cycloalkyl group. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

The Ci-6-mercapto group may be saturated or unsaturated, preferably Cl·- 4 fluorenyl. Examples of the fluorenyl group include a decyl group, an ethyl fluorenyl group, a propyl fluorenyl group, an isobutyl fluorenyl group, a pentyl group, an isovaleryl group, a butenyl group (such as a 3-butenyl group) 己 hexene fluorenyl group (such as 5). - hexene fluorenyl). The Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Consortium, prints C i - 8 -alkylene (wherein the 1-8 chain carbon number) and a heteroalkyl group having 2 to 8 chain atoms, which may contain one or more The saturated bond (double and/or triple bond) 'preferably, respectively, is a C 1 - 4 -extended base and a heteroalkyl group having 2 to 4 chain atoms. Examples of alkylene groups include methyl, extended & propyl, butyl, and isomers thereof (e.g., 1,3, butyl, 2, methyl-1, 3, propyl) . Examples of the heteroalkyl group include an oxygen-extended methyl group (and a methyloxy group), an oxygen-extended ethyl group (and an ethyloxy group), an oxygen-extended propyl group (and a propyloxy group), and an oxygen-butylene group. (and butyloxy), benzyldioxy, propyldioxy, butyldioxy, oxyallyl (and this paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -13- 1291958 A7 ___B7 V. Description of the invention (11) Allyloxy) and the like. The alkyl-substituted heteroalkyl group is a methyl-extended ethyldioxy group. (Please read the notes on the back and fill out this page.) Hydroxy-C i - 6 -alkyl (preferably hydroxy-C i - 4 - one base) can be straight or branched and have 1 or 2 hydroxyl groups ( If 2 is present in the base, it will not be attached to the same carbon atom). Hydroxyalkyl includes hydroxymethyl, 1-cycloethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl 2,3 -di-propylidene. Exemplary aryl-Ci-6-acid groups include the presently-branched, 1-benzhydryl, 2-naphthylmethyl, cinnamyl and phenylacetate groups. Demonstration of C 1-6 - the base of the base - C 1 - 6 - the base includes 2 - decyl butyl. Exemplary C 1-6 - alkoxy-C 1-6 - the hospital base includes 2-ethoxyethyl. Exemplary C l-6 -alkoxycarbonyl-C 1-6 -alkyl groups include ethoxycarbonyl butyl groups. Exemplary C 1 - 6 -ethoxyoxy-C 1-6 -yard groups include propyloxypropyl. Saturated and unsaturated (partial and complete) nitrogen heterocycles and saturated azabicyclocycles printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, including azetidine, pyrrolidine, piperidine, morpholine, hexahydroaza , tetrahydropyridine, pyridine and 1-azabicyclo[2 · 2 · 2] xinyuan. When η = 〇, the nitrogen heterocycle and the azabicyclo ring are coupled via a carbon atom on the ring. Exemplary saturated and unsaturated amino nitrogen heterocycles include aminopiperidines (such as 4-aminopiperidine) and amine azetidines (such as 3-aminoazepines). Standard (CNS) A4 specification (210 X 297 mm) -14- 1291958 A7 ___Β7__ V. Invention description (12) ▼-Install i (please read the notes on the back and fill in this page)), Aminopyrrolidine (such as 3-aminopyrrolidine) and aminopyridine (such as 4-aminopyrene). The amino nitrogen heterocycle is preferably coupled via a nitrogen atom of an aza or a nitrogen atom of an amine group. An example of a saturated aminoazabicyclo ring is 3-aminoazabicyclo[2·2·2]octane, and the coupling is preferably via a nitrogen atom on the 3-amino group. An example of a saturated aminodiazepine is 1-aminopiperazine, and the coupling is preferably via a nitrogen atom of a 4-aza atom or a nitrogen atom of an amine group. Exemplary saturated diazo heterocycles include piperazine and homopiperazine, and examples of the diazabicyclo ring are diazabicyclo[2.2.1]heptane. The diaza heterocycle and the diazabicyclo ring are preferably coupled via a nitrogen atom on the ring. -t C ( R 4 ) ( R 5 ) ] XN ( R 2 ) ( R 3 ) is preferably attached to A of formula (I) via a hetero atom (ie, when n = 1 and B is oxygen, nitrogen or sulfur) r. "Individual substituted carbon atoms" are in reference to the substituents R 4 and R 5 in which individual carbon atoms may be substituted differently on non-adjacent carbon atoms, The exemplary chain is (where X = 3) - C Η (CH3) - CH2 - C (C Η 3 ) (CH3) -. Halogen includes fluorine, chlorine, bromine and iodine. The aryl, heteroaryl and heterocyclic residues described above may be substituted by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs. This refers to the aryl, heteroaryl and heterocyclic groups and any aryl group-containing A combination group of a heteroaryl or heterocyclic residue such as an aryl-Ci-6-fluorenyl group, a heteroaryl-C 2 -4-alkenyl group, a heterocyclic thio group or the like. ''Prodrugs' refers to pharmaceutically acceptable derivatives, such as esters or guanamines, which are biologically converted in the body to form an active drug. References This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -15- A7 1291958 B7_ V. Invention description (13) (Please read the notes on the back and fill out this page)

Goodman and Gilman's, The Pharmacologicalbasis of Therapeutics, 8lhed., McGraw-Hill, Int. Ed. 1 992, "Biotransformation of Drugs, p. 13-15 o pharmaceutically acceptable guanidine means that it can be used to prepare a pharmaceutical composition, It is safe, non-toxic, and biologically and otherwise not bad and includes pharmaceutically acceptable salts, which are pharmaceutically acceptable as defined above. And having the desired pharmacological activity. Such salts include acid addition salts with organic and inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, Maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid, etc. in the formula (I) ' A 〃 is preferably the divalent group of formula (II):

R9 RH —— XE(C)〇——(Y)pE(C)——(Z)—— (II) I Γ R10 R12 Among them, the Ministry of Economic Affairs’ Intellectual Property Office employee consumption cooperative prints R 9 and R i Q, R ii and R i 2 are each independently hydrogen, Ci-4-alkyl, trifluoromethyl or keto on each of the substituted carbon atoms; X is a C(Rl3) (R 1 4 ), one, one, one S —, —S〇2 — or a N (Rl5)—; Y are —C(Ri6) ( R 1 7 ), 〇一,一 S —, —S〇2 — or N (Rl5)— This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -16- A7 1291958 B7 _ V. Invention description (14) Z is -C(Rl8) (R 1 9 ), one 分别One, one S -, - S 〇 2 - or one N (R 1 5 ) -; R ! 3 ' R 1 4 > R i 6, R i 7, R i 8 and R i 9 in individual substituted carbon Atom is hydrogen, C 1 -4 monoalkyl, trifluoromethyl or keto group; or 1^13, 1^14, 1^16, 1^17, 1118 and 1119 are mutually interconnected a bond or a stretched alkyl bridge of a 1 to 5 chain carbon atom or a heteroalkylene bridge of a 2 to 5 chain atom forming a ring structure having a 3-8 ring atom with the atom to which it is attached;

Rl5 is hydrogen, Cl-4 -yard or Cl-6-fluorenyl; 〇, p, Q and r are 0 to 3, respectively; and 4 dashed lines are selective carbon-carbon bonds; A on the open chain does not contain a diadlined heteroatom 0 or S, and (ii) ο, p, Q and r add up to no more than 8. ''Individual substituted carbon atom 〃 means that if the integer 〇 and / or P in the formula (I I ) is 2 or 3, individual carbon atoms will be substituted. Thus, in the case of R 9 and R 1 ,, for example, if 〇 is 2 or 3, for 2 or 3 carbon atoms, at 2 or 3 carbon atoms, R9 & Ri. The meaning can be different. For example, when ◦ is 2 and is linked to X via a single bond, R 9 and R i are each selected from the group consisting of hydrogen and methyl, and then, for example, on the first carbon, R 9 may be hydrogen and Ri. It is a methyl group, and it is 9 and 1^1 on the second carbon. It may be all hydrogen, such as 1-methylethyl. If R9 and Riq are both gas on the first carbon, R9 is hydrogen on the second carbon and R1 (} is methyl, then 2-methyl-extended ethyl is obtained. 0-2 and when 9 and 1 ^1. When selected from hydrogen, methyl and keto groups, respectively, the group obtained is 2-keto-1,3-, 3-butane, 1----------- I (please read the notes on the back and fill out this page)

tSJ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) -17- 1291958 A7 V. Description of invention (15 keto-2-methyl-3) Butyl diyl and 1-keto- 2 -methyl-anthracene can also be used in formula (II). YRZ is not an integer P and r is 2 or 3. ketone group -1,3 -~ This is of course 〇- or -S- and when formula (II) contains a carbon-carbon double bond and/or a triple bond, the - or di-substituent on the carbon atom to which it is present does not of course @(double bond) : R9 and Ri3 and/or RijDR are not left females respectively. ~ WK 1 6 is small, when the two bonds are: R9, Rl., Rh, Rl4 are not present, and r12, Rl6, R1 7 are not present). R in the formula (I) is preferably an aryl group or a heteroaryl group. When R is an aryl group, it is preferably a phenyl group (substituted or unsubstituted). When R is a substituted phenyl group, it is preferably a Substituted in the ortho position. When R is a heteroaryl group, it is preferably selected from the group consisting of quinolyl, quinolinolyl, isoquinolinyl, quinazolinyl and pyridyl. R i is preferably saturated. Nitrogen heterocycle (especially piperazine ), Or unsubstituted

Replaced by C-hospital (especially methyl) (please read the note on the back and fill out this page) Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs. The integer η is preferably 0. The integer 〇 is preferably 2. The integer Ρ is preferably 1. The integer Q is preferably 〇. The integer r is preferably zero. X, Y and Z are preferably oxygen. R 9 to R 1 2 are preferably hydrogen. In the compound of formula (I), when Α is a pyrazine ring, the compound: then is a formula----1---order _!丨i This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) Love).18- 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (16)

Where R2. And R21 are respectively hydrogen, C1-6-hospital, Cl-6-homoyloxy, Cl-6-yard thio, Cl-6-mercapto, Cl-6-yard sulfonyl, cyano, nitrate Base, hydroxyl group, c 2 - 6 monoalkenyl group, C 2 - 6 - alkynyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, difluoromethyl sulfide , trifluoromethylthio, halogen, an N(R2)(R3), aryl, aryloxy, arylthio, aryl-Cl-4 alkyl, aryl-C2-4-alkenyl , aryl-C 2-4 -alkynyl, heterozygous, heterocyclic oxy 'heterocyclic thio, heterocyclyl-C 1 -4 monoalkyl, wherein any aryl and heterocyclic residue It may be substituted at one or more positions by the following groups: halogen, Cl-6-hospital, Cl-6-homoyloxy, Cl-6-indolylthio, Ci-6-mercapto, Ci - 6 - alkylsulfonyl, nitro, cyano, trans, trifluoromethyl 'trifluoromethylthio, amine, Cl-4 monoalkylamino, di-(Cl-4-alkyl) An amine group; or R20 and R21 form a 5- or 6-membered aryl or heteroaryl ring with the attached carbon atom, which is selected at one or more positions Substituted by the following groups: halogen, C 1 - 6 a yard, C i - 6 - alkoxy ' C 1 - 6 - alkylthio, C 1 - 6 -alkylsulfonyl, nitro, Cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amine, -1------- ! Install i I (please read the notes on the back and fill out this page). Applicable to China National Standard (CNS) A4 specification (210 x 297 public) -19- A7 a 1291958 V. Description of invention (彳7) C 1 - 4 -alkylamino, di-(ci - 4 -alkyl) Amine; mi and m 2 are respectively 〇 or 1; and A, B, R, R丨, R 2, r 3 and n are as defined above. When R 2 Q and r 2 i in the formula (I a ) form a 5- or 6-membered aryl or heteroaryl ring with a carbon on the pyrazine ring, the ring may, for example, be selected from the group as described above. Base and heteroaryl ring. R 2 q and R 2 1 are preferably (respectively) hydrogen, halogen or methyl. When R 2 〇 and R 2 i form a ring with the carbon atom attached to the ring, the ring is preferably benzene or thiophene, which is especially unsubstituted or monosubstituted or (differently) double substituted by halogen or methyl. The integers m i and m 2 are preferably both 〇 (i.e., the nitrogen atom of pyrazine is not in the form of oxidation). A subgroup of compounds of formula (I a ) is a compound of formula (I b ):

R R25 (please read the notes on the back and fill out this page) ----订---I--I--^^1 · (R24)y & Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed in which v6 〇

N Λ N (R23' (lb) z R a is an aryl or heteroaryl group, which is optionally substituted as defined in R above; the private paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT) 20- 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed V. Inventions (18) R 2 Q and R 2 1 are as defined above; R22 is hydrogen, Cl-4 — yard base, C3 — 4 — Alkenyl, Cl-4 - fluorenyl, aryl-Cl-4, fluorenyl, heteroaryl-Cl-4, aryl, arylaminomethyl, heteroarylamine, 1-4 - oxycarbonyl, 2-ethylidene, 2-cyanoethyl or tetrahydrofuran-2-yl; R23 and R24 are respectively hydrogen, Cl-4-homo, transmethyl,

Ci-4 alkoxymethyl, fluoromethyl or keto; R 2 5 and R 2 6 are each hydrogen or C i - 4 -alkyl; and y and z are 1 or 2, respectively. In the formula (I b), R22 is preferably hydrogen, and R23 and r24 are preferably C 1 - 4 - a group (particularly methyl) or hydrogen. Specifically, R 2 3 is a methyl group (particularly at a position of 2 in the piperazine ring), Z is 1 and R 2 4 is hydrogen. When y or Z is 2, R23 or R24 may be the same or different, respectively. R 2 5 and R 2 6 are preferably hydrogen. The above compound of the formula (I) is preferably: 2 -( 2 -phenoxy)ethyl 3 -( 1 -piperazinyl)- 2 -pyridazinyl ether 2 -(2-fluorophenoxy)ethyl 3 —(1-piperazinyl)-2-oxazinyl ether 2,3-dihydro-1,4-benzodioxanylmethyl-3-(1-oxazinyl)-2-pyridazinyl Ether 2 —(2-methoxyphenoxy)ethyl 3 —(1~noxazinyl)-2-pyridyl ether 2 —(2,5-fluorophenoxy)ethyl 3 — ( 1 - piperazinyl)_ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

ϋ ei ·ϋ ^OJ ϋ ϋ ϋ ϋ I -21 - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 _ B7_ V. Description of Invention (19) 2 —Pyrazinyl Ether 2 — (3,5-Dimethyl Oxyphenoxy)ethyl 3 - (1 piperazinyl)-2-pyrazinyl ether 2 - (1,3-benzo-p-oxo--5-yloxy)ethyl 3 - ( 1 monopiperazinyl)-2-pyrazinyl ether 2 —[ 3 —( 4 morpholinyl)phenoxy]ethyl 3 —( 1 -piperazinyl)-2-pyrazinyl ether 2 - ( 3-aminophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl 2-(3,4-dihydro-2H-pyrido[3,2-b]-1 4-oxazin-2-yloxy)-3-(1-piperazine)pyrazine 2 —(methyl)-1-[3-(2-phenoxyethoxy)-2-pyrazine Piperazine methyl- 1 -{3 -[2 -(3 - 吼u-oxy)ethoxy]-2-pyrazinyl}piperazine 2 -[ 2 — ( 3 —吼π-oxyl Ethoxy]3-(3-piperazinyl)-6,7-difluoroquinoxaline 2 -[ 2 -( 3 -decyloxy) Oxy]3 - (1 -piperidinyl)thieno[3,4-b]pyrazine 2-(3,4-dihydro-2H-1,4-benzoxazine-2-yl Oxy)) 3-(1-piperazinyl)pyridazine-2-(3,4-dihydro-2H-chromene-2-ylmethoxy)-3 mono(1-piperazinyl)pyridazine 2 -( 3 -pyridyloxy)ethyl 3 -( 1 -piperazinyl)-2-pyridyl paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -22- I---- -----装--- (Please read the notes on the back and fill out this page) 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (20) azine ether methyl one 1 {3 - [2 - (2 -Amino-8-quinolinyloxy)ethoxy]-2-pyridinyl}piperazine 1 - { 3 - [2 - (2 - methoxy - 3 - fluorene)卩 氧基 oxy) ethoxy] 2- oxazinyl} piperazinyl methyl 1- 1 {3 — [2-(2-methoxy-3-pyrene b-oxy) ethoxy]-2 - pyrazinyl}piperazine, or a pharmaceutically acceptable salt or solvate thereof. As described above, the compounds of the present invention are useful for treating hemoglobin-related disorders in humans or animals, such as eating disorders (especially obesity), memory disorders (such as Alzheimer's disease), schizophrenia, mood disorders. (including, but not limited to, major depression and bipolar depression, including, but not limited to, mild and manic bipolar disorder, seasonally affected disorder (SAD)), anxiety (including but not limited to , situational anxiety, generalized anxiety disorder, primary anxiety disorder (panic disorder, fear, obsessive-compulsive disorder, and post-traumatic stress disorder) and secondary anxiety disorder (eg, anxiety related to substance abuse) )), pain, libido dysfunction and urinary system disorders (such as urinary incontinence). Labeled forms of the compounds of the invention (e.g., isotopically labeled) can be used as diagnostic reagents. The above compound of the formula (I) can be produced by a similar method and, in particular, according to or similar methods. Method A: This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) I----------Installation --- ----booking i 丨! I (please read the notes on the back and fill out this page) 1291958

V. INSTRUCTION DESCRIPTION (21) The compound of formula (I) is attached to A r, and (i is a diaza heterocycle, a diazepine wherein A is via its upper oxime, S or N atom η = 0 and R i is a saturated amine a nitrogen heterocycle, an amine: or a diazabicyclic residue, or (ii) n=l and B are -N(R6)- or -N(R6)C(R4)(R5) as defined above And R 1 is a saturated or unsaturated nitrogen heterocyclic bicyclic residue, and the compound of formula (I) is prepared by formula (wherein Ar is as defined above, Ha 1 is halogen) Hal (III)

Reacts with compound R - A (wherein R 4 , R 5 and R 6 or saturated aza III ) X / - Η or its corresponding anion, wherein X' is mono-, s- or-N-(R15)-, - An alkyl group, wherein the carbon chain may be inserted into one or more heteroatoms, and may have a terminal hetero atom attached to R, the hetero atom selected from N, fluorene and S, and R 1 5 are as defined above, (IV) Compound: (Please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

X,——A, one-R σc.

Hal (IV) wherein Ar, X >, A >, R and Ha 1 are as defined above. Compound R — A — — X — — H by a base (such as triethylamine, 1,8-diazabicyclo[5 · 4 · 0] ~ [--^ carbon-7-ene, K2C〇3, Na〇H, NaH, K〇一t — Bu, diisopropyl guanidinium lithium This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -24- 1291958 A7 B7 V. Description of invention (22, etc.) treatment may be converted in whole or in part to its corresponding anion. The reaction is carried out in a solvent such as monooxane, tetrahydrofuran or N,N-dimethylformamide (DMF) at 0-20 ° C. Carry out 1 - 24 hours. The appropriate amine of formula (IV) with 1 to 1 molar equivalents in a solvent (such as acetonitrile, dioxane, tetrahydrofuran, n-butanol, DMF) or a solvent mixture (such as DMF / Dioxane) in the presence of a selective base (such as κ 2 C〇3, Na2C〇3, C S2C〇3, Na〇H, diethylamine, mouth ratio D, etc.) in the presence of 0 - 2 0 〇 ° The compound of the formula (I) can be obtained by reacting for 1 to 24 hours under c. The exemplary amine has the following structure: (Please read the notes on the back and fill out this page)

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperative of the Ministry of Commerce, in which R23, R24, y and z are as defined above, and Z has the definition of R22 in the above formula (Ib) or is a suitable protecting group such as third butoxycarbonyl or triphenyl Methyl or benzyl. A compound of formula (I) wherein η 二 1 and B are oxygen, sulfur or -〇C ( R 4 ) ( R 5 ), and R i is a saturated nitrogen heterocyclic or azabicyclic residue, or —[C(R4) (R5)]xN(R2)(R3) ' wherein R2, R3, R4, R5 and X are as defined above. The compound of formula (1) is prepared by reacting a compound of formula (IV) above with a thiol group The basic paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -25 - 1291958 A7 B7 5. Inventive Note (23) Substituted for the reaction of the corresponding nitrogen heterocycle or azabicyclo compound, or with the compound H〇 A Ri or HS-R reaction (wherein Ri is a [C(R4)(R5)] x N(R 2 ) (R 3 ). Exemplary compounds substituted with hydroxy and thiol groups have the following structure:

H0 where Z is as defined above. The reaction is in a solvent (such as toluene, DMF or dioxane) and a base (such as 1,8-diazabicyclo[5 · 4 · 0] undecyl-7-ene, hydrazine, hydrazine-t-Bu In the presence of NaH, etc., at 〇-200 °C for 1 to 24 hours. (Please read the notes on the back and fill out this page)

^1 I .1 ^1 iai .^1 ^1 1 Βϋ I Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printing Method C: Compound of formula (I) (wherein A is attached to R via an oxygen or sulfur atom) Preparation of a compound of formula (V)

(V) wherein A r, R 1 , B and η are as defined above, and A 〃 is a C 1 -8-extension base in which the carbon chain can be inserted into one or more heteroatoms and may have terminal heteroatoms. Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) _ 26 m A7 1291958 B7_ 1-5, invention description (24) (please read the note on the back and then fill out this page) Connect to A r , the miscellaneous The atomic system is selected from N, 0 and S, and L is a trans group or a decomposing group (such as halogen, toluenesulfonyloxy, methanesulfonyloxy, etc.) and reacts with the compound R-OH or R-SH (where R The compound of formula (I) is prepared as defined above. When L is a free hydroxyl group, the reaction is carried out in diethyl azodicarboxylate (DEAD) or 1,1/-azobis(N,N-dimethylformamide) (cf. Tetrahedron Lett. 1 995) , 36, 2789-3792) and triphenylphosphine are present in a solvent such as tetrahydrofuran or dichloromethane (Mitsunobu reaction; see 〇rg. React·1 992, 42, 335-656). When L is a leaving group, the reaction is carried out in a suitable base (eg, Na2C〇3, K2C〇3, 〇32〇〇3, 1^〇11, triethylamine, 1,8-diazabicyclo[5·4· In the presence of 0]undecyl-7-ene, etc., in a solvent such as acetonitrile or DMF at 0 - 2 0 ° C for 1 - 24 hours. In the case where the group of the formula (V) is printed by the Intellectual Property Office of the Ministry of Economic Affairs, (B) n R i contains a primary or secondary amine group, the nitrogen may be suitably protected by a protecting group, preferably a third butoxy group. Carbonyl, trityl or benzyl. The N-deprotection is then carried out by conventional methods (as described in Protective Groups in Organic Synthesis, John Wiley & Sons, 1991). Process D: A compound of formula (I) wherein A is attached to Ar via a ruthenium, S or N atom thereon, and wherein η 2 or n = 1 , and B is oxygen, nitrogen, sulfur, mono-C (R4) (R_5)—, This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -27- 1291958 A7 B7 V. Invention description (25) -N ( R 6 ) C ( R 4 ) (R5 Wherein, wherein the rule 4, the ruler 5 and the ruler 6 are as defined above, the compound of the formula (I) is prepared by reacting a compound of the above formula (III) with a suitable amine or a suitable compound substituted with a hydroxy group or a thiol group. Compound of formula (VI):

CT C, (Please read the notes on the back and fill out this page) /Hal (VI) where A r, Β, R i, H a 1 and η are as defined above. The reaction conditions may be as described above in the methods and preparations. The compound of the formula (VI) reacts with the compound R — A / — X / - Η or its corresponding anion (where X / is - 〇, S - or -N (R15) - A 'is Ci-8 - a group wherein the carbon chain may be inserted into one or more heteroatoms, and wherein the terminal hetero atom may be bonded to R, the hetero atom is selected from N, fluorene and S, and R and R15 are as defined above) I) a compound. The reaction conditions may be as described above in Method A. The amine, hydroxyl or thiol-substituted compounds printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs include those shown in Methods A and B above, and the compound Η〇-R 1 or HS — R i (where Ri is [C(R4) ( R 5 ) ] x N ( R 2 ) ( R a ) , R 2 , R 3 , R 4 , R 5 and x are as defined above). A compound of formula (I) wherein A r is a selectively substituted phenyl, naphthyl, pyridyl or quinolinyl ring, and (i) A is oxygen or (ii) A is attached to Ar via an oxygen atom thereon The compound of the formula (I) can be prepared by a conventional method as described in the art, as described in the following Examples 1 5 4 and -28- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291958 A7 B7 V. INSTRUCTION DESCRIPTION (26) 15 5 ° The compound of formula (I) can be converted to another compound of formula (I) by a method known in the art. The compounds of the invention in the form of a free base or acid addition salt can be prepared by the methods described above. A pharmaceutically acceptable acid addition salt can be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to a conventional procedure for preparing an acid addition salt from an alkali compound. Exemplary acids used to form acid addition salts are maleic acid, fumaric acid, succinic acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, oxalic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. . The compound of formula (I) may have one or more asymmetric carbon atoms' and thus it may be prepared in the form of optical isomers, such as pure enantiomers, or mixtures of enantiomers (exogenous Cyclone) or a mixture comprising diastereomers. Separation of a mixture of optical isomers to produce a pure enantiomer is well known in the art, for example, by fractional crystallization with optically active (asymmetric) acids or by asymmetric column Chromatographic separation to achieve the desired starting materials for the preparation of the compound of formula (I) may be known or prepared by analogous methods for preparing known compounds. For example, the aryloxy- or heteroaryloxyethanol used to prepare the novel compounds of formula (I) can be prepared by the method described in Scheme 1 below. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I----------S - (Please read the note on the back and fill out this page) Order - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1291958 A7 B7 V. Invention description (27 Flow chart preparation of some starting materials

(a) Q-OH 〇 AV_7 Q, K2C〇3, DMF, heat, 〇〆

.OH Q = aryl or heteroaryl (optionally substituted) Please read the back of the note first

Rx

(b) Q-OH -- K2C〇3, DMF or CH3CN heat Rx = Br or Cl Q, , 〇

.〇H (6)

Q-〇H 〇Ζλ Q = aryl or heteroaryl (selective substituted)

Q, 〇~〇H items Fill in this page

NaH, THF Q = aryl or heteroaryl (selectively substituted) (d) Q-Br hct .〇Ry Q,

.0H

Ry = Na or K Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Q = aryl or heteroaryl (selectively substituted) According to the invention, a free base or a physiologically acceptable acid addition salt (I The compound can be formulated into a suitable galenic form according to an acceptable pharmaceutical process, such as a composition for oral, injection, nasal spray administration, and the like. This pharmaceutical composition according to the invention comprises an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent which is compatible with the art. The carrier can be any inert substance, organic or inorganic, suitable for use on this paper scale. China National Standard (CNS) A4 specification (210 X 297 mm) -30- 1291958 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5 , invention instructions (28) enteral, epidermal, subcutaneous or parenteral administration, such as water, gelatin, gum (gumarabicum), lactose, microcrystalline cellulose, starch, sodium, calcium hydrogen phosphate, magnesium stearate, talc The colloidal dioxide composition may also comprise other pharmaceutically active agents and conventional addition agents, wetting agents, emulsifiers, odorants, buffers, and the like. The composition of the invention can be prepared into a solid or liquid tablet for oral administration, a medicine 9, a capsule, a powder, a syrup, an elixir, a cachet, a suppository, etc., and can be prepared for a non-sterile solution. , suspension or latex, can be made into a spray (such as nasal spray preparation (such as patch), etc. As described above, the compound of the present invention can be used for treating human or A7 B7 arabinic starch, ethanol, etc. This agent, such as a stable form (such as granules, fog in the stomach), blood stasis-related disorders in animals, such as eating disorders (especially obesity), memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, Sexual dysfunction and urinary dysfunction. The dose and frequency of a particular compound will vary depending on factors such as the particular compound used, its metabolic stability and duration of action, age, weight, health, sex, The condition of eating, the form and timing of the administration, the excretion rate, the combination of the drugs, the severity of the condition being treated, and the patient being treated. For example, from about 0. 0 0 1 mg to about 1 〇〇mg / kg body weight, single or multiple doses, for example, from about 0. 01 mg to about 25 mg each time. Usually oral. However, it is also possible to use parenteral administration. The invention is further illustrated by the following examples which are not intended to be limited. The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). This page-31 - 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Office Employees Consumption Cooperatives Printed V. Inventions (29) Examples Generally speaking, the structure of the prepared compounds is determined by standard spectroscopic methods, elemental analysis and/or high resolution. The NMR data was obtained from a JE〇L JNM-EX270, Bruker 400 or Bruker DRX500 spectrometer. The IR spectra were obtained from a Perkin Elmer SPECTRUM 1 000 FT-IR spectrometer. The high resolution MS was obtained from a Micromass LCT spectrometer. The analysis was performed by Mikro Kenn AB, Uppsala, Sweden. Melting points (when available) were obtained from the Buchi or G a 11 enkamp melting point apparatus and were uncorrected. Examples 1 to 8 were used in Method A. Example 4 9 to 5 3 using Method B, Example 5 4 to 9 6 using Method C, and Examples 9 7 to 1 5 3 using Method D. Example 1 2 - (2-Phenoxy)ethyl 3 — (1 - piperazinyl)-2-pyrazinyl ether, maleate Step 1: 2 -Chloro-3-(2-phenoxyethoxy)pyrene 嗦NaO-t-Bu (2.9 1gJ 3〇· 2 9 mm ο 1 ) added to 2,3-dichloropyrazine (4.75g, 31 · 88mm〇1) and 2-phenoxyethanol (4 · 18g, 30 · 29mmo 1) In a mixture of chews (25 mL). The reaction mixture was stirred at room temperature for 1.5 hours and then filtered. The filtrate was concentrated under reduced pressure, and the obtained crystals crystals crystals crystals crystalssssssssssssssssssssssssssssss -----π---------· (Please read the notes on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -32 - 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Invention Description (3Q) °mp55 — 54°C. Elemental analysis (ChHhC 1Ν2〇2 ) C, Η, N. Step 2: 2 -( 2 -phenoxy)ethyl 3 -( 1 -piperazinyl)-2-pyridyl ether, maleate salt Step 1 product (1.7 〇5, 6.8 〇 111111 〇 1), a mixture of oral azine (1 · 750g, 20 · 3mmo 1) and K2C 〇 3 (1 · 16g , 8 · 39mmo 1) in acetonitrile (i〇mL) is stirred at 50 °C 1 · 5 Hour and stir for another 3 hours at 80 °C. The reaction mixture was diluted with C Η 2 C 1 2 and subjected to furnace and concentration. The semi-solid residue was purified by chromatography on a silica gel using C H C 1 3 /M e 〇Η (9:1) to give a pale brown oil. This material was redissolved in diethyl ether / C H C 1 3 (9:1), dried over Κ 2 C 〇 3 and filtered through a short (3 c m) plug of alumina. The filtrate was concentrated in vacuo to give the title compound (1 g. The free base is converted to maleate and recrystallized from Me 〇Η /ether: mpl55 - 157 ° C; HRMS m / z For C16H2 〇 N4 〇 2 (Μ) + calculation 値 300 .1 586 The experiment is 3 0 0 · 1 5 7 3. Alizarin analysis (Cl6H2〇N4〇2*C4H4〇4) C,Η,N. Example 2. 2 — ( 2 —Furylmethoxy)- 3 —( 1 -piperazinyl)pyrazine, maleate This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT) I----------装-----订--------- (Please read the notes on the back and fill out this page) 1291958 A7 _______Β7___ V. Description of invention ( 31) Step 1: 2 -Chloro-3-(2-furylmethoxy)pyrazine (please read the back of the note before refilling this page) From 2-furyl methanol (4 · 18g, 42 · 7mmo 1 , 2'3-dichloropyrazine (2.05 g, 13.8 mm 〇l) and KO-t-Bu(R) (1 · 82 g, 16.2 mmo 1 ). The title compound was prepared according to the procedure described in Example 1 Step 1. The product obtained as a slightly yellow oil (yield 68%) was used directly in the next step. Step 2: 2 —( 2 —furanylmethoxy)-3-( 1 —piperazinyl)pyrazine, maleate from 2-chloro-3-(2-furylmethoxy)pyr Starting from the azine (1 · 4 7 g '7 · 〇mm ο 1 ), the title compound was prepared according to the procedure described in Example 1, Step 2. The yield of the free base obtained was 0.62 g (34%). Converting a portion of the free base to cis-butyrazine-acid salt: mpll8-12 〇 °C; HRMS m/z for Ci3Hi6N4〇2 (Μ) + is calculated as 〇26〇.1 2 7 3 > It is 2 6 0 · 1 2 7 0. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printed by Alizarin Analysis (Cl3Hl6N4〇2*C4H4〇4) C, Η, Ν. Example 3 2 - (2 -Phenoxyethoxy)- 3 -(1-pyridazinyl)d-queousin, hydrochloride salt, step 1: 2 -chloro-3-(2-phenoxy) Ethoxy)quinoline from 2-phenoxyethanol (3 · 7g, 26 · 8mm 〇, 2,3-dichloroquinoxaline (1.33 bogey, 6.7111 melon 0), this paper scale applies to Chinese national standard (CNS A4 size (210 X 297 mm) -34- 1291958 A7 --------^__ V. Description of invention (32) and K〇一t— Bu〇 (0 · 75g , 6 · 7mm〇1 Starting, the title compound was prepared according to the procedure described in Example 1, Step 1: Yield 〇· 74 g (37%): mP99 · 5- 101 · 5 ° C; HRMS m/z Calculation for Ci6h13C 1N2〇2 (Μ) + For 300 · 0666 'experimental 値 is 300 · 0672. Elemental analysis (C16H13C 1N2 〇 2) C, Η, N. Step 2: 2 — (2 — scholastic / ethoxylated) 1-3 — (1 — shouting Starting from quinoxaline, hydrochloride from 2-chloro-3-(2-phenoxyethoxy)quinoxaline (〇·6 5 g, 2 · 1 5 mm 〇1 ), according to Example 1 2 Preparation of the title compound by the process: yield 0.44 g (58%) in the form of free base Convert a portion of the free base to its hydrochloride salt: mpl23-126〇C; HRMS m/z For the calculation of C2〇H22N4〇2 (Μ) + 値 is 350.1 7 43, the experimental 値 is 3 5 0 · 1 7 4 8. Elemental analysis (〇2〇Η22Ν4〇2·1 · 7 5 HC 1 · 0 · 5 Η 2 〇) C, Η, Ν. Example 4 2 — ( 2 —Naphthyloxyethoxy) 3-(1 - piperazinyl)pyridazine, trifluoroacetate Step 1: 2 -Chloro-(2-naphthyloxyethoxy)pyrazine hydride (55% dispersion in mineral oil; 4 4 mg, this paper size is applicable to China National Standard (CNS) A4 specification (210 297 297 mm) (please read the notes on the back and fill out this page) Pack--------- --- f Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -35- 1291958 A7 B7 V. Description of Invention (33) lmmo 1) Add to 2 — (2 —naphthyloxy)ethanol (1 88mg , :Lmmo 1) And 2,3 -dichloropyrazine (149 mg, (please read the back of the note first and then fill out this page) 1 mm ο 1 ) in a mixture of two apes (〇 · 5 m L ). The reaction mixture was stirred at 40 ° C for 15 hours. The crude material obtained was used directly in step 2. Step 2: 2 -( 2 -naphthyloxyethoxy)- 3 -( 1 -piperazinyl)pyrazine, trifluoroacetate piperazine (4 3 0 mg, 5 mm ο 1 ) in dioxane ( A solution of a mixture of 〇· 5 m L ) and DMF (1 m L ) is added to the crude material of step 1. The reaction mixture was stirred at 60 ° C for 15 hours, then diluted with E t 0 A c, rinsed with water, and dried (Mg S 0 4 printed by the Ministry of Economic Intelligence, Staff Intelligence Co., Ltd.), and Concentrate under reduced pressure. The residue was subjected to elution on a silica gel eluting with Et?Ac/Me?H/H?Ac/H?? (20:3:3:2). The fractions containing the product were concentrated, and the residue was further purified using CH3CN/H2 〇/TFA (gradient: CHsCNO% to 100%, TFA0 · 1%) to give C 4 8 Η PLC to obtain 3 4 · 5 mg (1 〇%) ) title compound. HRMS m/z for C2〇H22N4〇2 (M) + is calculated as 3 50 · 1743, experimental 値 is 350 . 1742 〇 Example 5 - 2 1 in a similar manner from 2,3-dichloropyridinium ( lmmo 1 And the appropriate alcohol (lmmo 1 ) was prepared. This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -36 - 1291958 A7 _ B7__ V. Description of the invention (34) Example 5 2 —( 4 bromophenoxy)ethyl 3 — ( 1 piperazinyl)-2-pyrazinyl ether, trifluoroacetate salt The title compound was prepared from 2-(4-bromophenoxy)ethanol to give 46. 9 mg (12%), HRMS m/ z The calculated 値 for C16H19B rN4〇2 (Μ) + is 378.0691, and the experimental 値 is 378.0698. Example 6 2-(2-Chlorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, trifluoroacetic acid salt The title compound was prepared from 2-(2-chlorophenoxy) Starting from ethanol, 32.lmg (1〇%) °HRMS m/z was calculated for C16H19C 1 N4〇2 (Μ) + 334 334. 11 9 7 , experimental 値 334 · 1195. Example 7 2 -( 4 -Chlorophenoxy)ethyl 3 -( 1 -piperazinyl)-2-pyrazinyl ether, trifluoroacetic acid salt The title compound was obtained from 2-(4-chlorophenoxy) Starting with ethanol, 55. 9 mg (17%) °HRMS m/z was calculated for C16H19C 1 N4〇2 (Μ) + 334 334. 1197, experimental 値 334 · 1182. (Please read the notes on the back and fill out this page.) ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ CNS) A4 size (210 X 297 mm) -37- !291958 A7 B7 1. Invention description (35) Example 8 2 - (2,3 '6 - win-win oxy) ethyl 3 - (1 - Climb Preparation of the title compound of the fluorenyl)-pyridazinyl ether, trifluoroacetate salt starting from 2 -( 2,3,6-trifluorophenoxy)ethanol to give 2 4 · 2 mg ( 5 % ) . HRMS m/z for ChHhFsNaOs (Μ) + is calculated as 354. 1304, and experimental 値 is 354 · 1298. Example g 2 -Phenoxypropyl 3-( 1 -piperazinyl)-2-pyridazinyl ether, trifluoroacetate. The title compound was prepared starting from 2-phenoxypropanol to give 24 〇mg (6%) °HRMS m/z For C 1 7 Η 2 2 N 4 0 2 (Μ) + The calculated 値 is 3 1 4 · 1 7 4 3 , and the experimental 値 is 3 1 4 · 1 7 4 2 . Example 1〇2-Phenoxy-1 monomethylethyl 3-(1-piperazinyl)-2-yl-pyridazinyl ether, trifluoroacetate salt The title compound was prepared from 1-phenoxy-2 Starting from propanol, 2 9 · 4 mg ( 9 %) °HRMS m/z is calculated for C 1 7 Η 2 2 N 4 0 2 (Μ) + 3 is 3 1 4 · 1 7 43 , experimental 値For 3 1 4 · 1 7 3 2. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) mb mi· w η· Bacteria _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 _B7_ V. Inventive Note (36) Example 1 1 2 —(2-methoxyphenoxy)-1-methylethyl 3 — (1 piperazinyl) The preparation of the title compound of pyrazinyl ether, trifluoroacetate was started from 1-(2-methoxyphenoxy)-2-propanol to give 2 4 · 9 mg (5 %). The HRMS m/z is 344 · 1848 for C18H24N4〇3(Μ)+, and the experimental 値 is 344. 1852. Example 1 2 2 —(3-methoxyphenoxy)-monomethylethyl 3-(1-n-phenazinyl)-2-indolyl ether, the title compound of the trifluoroacetate salt was prepared from 1 Starting with mono(3-methoxyphenoxy)-2-propanol, 3 7 · 9 mg (11%) was obtained. The HRMS m/z is calculated for C18H24N4〇3(Μ)+ as 3 4 4 · 1 8 4 8 and the experimental 3 is 3 4 4 · 1 8 4 2 . Example 1 3 2 —(2-Methoxyphenoxy)-1-methylethyl 3 —(1-deoxazinyl)-2-pyrazinyl ether, trifluoroacetate salt The title compound was prepared from Starting with 1 -(2-methylphenoxy)-2-propanol, 5 9 · 5 mg (18%) was obtained. The HRMS m/z is 328 · 1899 for C18H24N4〇2(Μ)+, and the experimental 値 is 328 · 1898. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I----------Install-------Book--------^wi ( Please read the phonetic transcription on the back side. Please fill out this page again. -39- 1291958 A7 _B7_ V. INSTRUCTIONS (37) EXAMPLE 1 4 2 — (4 —Methylphenoxy)-1-methylethyl 3 — ( 1 - piperidinyl)-2-pyrazinyl ether, trifluoroacetate salt The title compound was prepared starting from 1 -( 4 -methylphenoxy) - 2 -propanol to give 1 2 · 3 mg ( 3 % ). HRMS m/z is calculated for C18H24N4〇2(Μ)+ as 328. 1899, and experimental 値 is 328. 1896. Example 1 5 2 —(phenylthio)ethyl 3 —( 1 —piperazinyl)-2-pyrazinyl ether, trifluoroacetate salt The title compound was prepared starting from 2-(phenylthio)ethanol. 3 〇 4 mg (10%) °HRMS m/z The calculated 値 for C 1 6 Η 2 〇N 4 0 S (Μ)+ is 316 · 1358, and the experimental 値 is 3 1 6 · 1 3 5 9 . I----------Install-------Book--------- (Please read the notes on the back and then fill out this page) Example Ministry of Economic Affairs Intellectual Property Bureau staff consumption Co-production of 2 3 yl-ethyl X) / amide 6 phenyl sulfanyl piperazinyl hydrazine I 2 to prepare the starting ethyl alcohol benzene - 2 from the preparation of the compound salt acidification B title fluorine standard three gm 6 7 4 % 6 m SΜ R Η Ζ 验 Η 验 16 test C Μ / IV 〇 5 Ν 9 9 2 6 4 7 lx 9 9 2 4 4 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 ) A4 size (210 X 297 mm) -40- 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (38) Example 1 7 2 —(N-ethylanilino)ethyl 3 — (1-Piperazinyl)-2-pyrazinyl ether, trifluoroacetate The title compound was prepared from 2-(N-ethylanilinyl)ethanol to give 7.2 mg (2%). H R M S m / ζ for c 1 8 Η 2 5 Ν 5 Ο (Μ) + The calculated 値 is 327 · 2059, and the experimental 値 is 3 2 7 · 2 〇 5 7. Example 1 8 2,3-dihydro-1,4-benzodioxan-2-ylmethyl-3-(1-piperazinyl)-2-pyrazinyl ether, trifluoroacetate title compound The preparation was started from 2 -hydroxymethyl-1,4-benzodioxane to give 2 1 · 6 mg (5 %). The HRMS m/z is calculated as 328 · 1 5 35 for Ci7H2〇N4〇3(Μ)+, and the experimental 値 is 328 · 1519. Example 1 9 3-Phenylpropyl 3-(1-piperazinyl)-2-pyrazinyl ether, trifluoroacetate The title compound was prepared starting from 3-phenyl-1-propanol. · 4mg (2%) °HRMS m/z for

The calculation of Ci7H22N4〇(Μ) + is 298.1794, and the experimental 値 is 2 9 8 · 1 7 9 5 ° I. The paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public 1 _ 41 _ I- --------Install -------- Order --------- (Please read the notes on the back and fill out this page) 1291958 A7 B7 V. Inventions (40) C , Η ; N : Calculate 値 1 8 . 6 5 ; Experiment 値 1 8 · 0. (Please read the notes on the back and fill out this page) Example 2 3 2 , 3 - Dihydro - 1 , 4 - Benzo Oxanthene-2-ylmethyl-3-(3-amino-1-pyrrolidinyl)-2-pyrazinyl ether The title compound was prepared according to the procedure described in Example 4, Step 2 from 2-chloro-3-(2) , 3-dihydro-1,4-benzodioxan-2-ylmethoxy)pyridazine* (150 mg, 〇·54mmo 1) and 3-aminopyrrolidil (2 4 ◦ mg, 2 · Starting at 7 9 mm ο 1 ), 1 1 9 mg (67%) was obtained. Elemental analysis (CHH20N4O3) C, hydrazine, N.. Prepared according to step 1 of Example 4. Example 2 4 2 — (2-Chlorophenoxy Ethyl 3-ethyl 3-(3-amino-1-indolyl)- 2-indolyl-methyl ether-based title compound The process described in Example 2, Step 2, was printed from 2-chloro-Ministry of Commerce, Intellectual Property Office, Staff Consumer Cooperative, 3-[2-(2-chlorophenoxy)ethoxy]pyrazine* (1 50 mg , 〇· 5 3 Starting with mm〇1) and 3-aminopyrrolidine (2 5 2 mg , 2 · 9 2 mm ο 1 ), 1 〇〇mg (56%) was obtained. Elemental analysis (C16H19C 1N4〇2) C , Η ; N : Calculate 値 1 6 · 7 3 ; Experiment 値 1 6 · 0. + Prepare according to Example 4, Step 1. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -43- 1291958 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed A7 -----B7_________ V. Description of Invention (4彳) Example 2 5 2 — (4-Chlorophenoxy)ethyl 3 — (3-Amino-A-1 The title compound of the pyrrole group is a 2-chloro- 3 -[2-(4-chlorophenoxy)ethoxy]pyridinium* (1 5) according to the procedure described in Example 4, Step 2. Starting from 〇mg , 0 · 53mmo 1) and 3-aminopyrrolidine (247mg ' 2 · 8 7 mm ο 1 ), 1 2 3 mg ( 6 9 % ) ° elemental analysis (C16H19C 1Ν4〇2) Η, N ; C : Computation 値 5 7 · 4 Ο ; Experiment 値 5 6 · 9. $ Prepared according to step 4 of Example 4. Example 2 6 2 —(Phenoxy)ethyl 3 —(1 ,4-diazepine-1-yl)-2-pyrazinyl (2-(phenoxy)ethyl3-(l,4-diazepan -l-yl)-2-pyrazinylether) The title compound was obtained from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 〇·6 〇mm ◦ 1) according to the procedure described in Example 4, Step 2. Starting from Example 1 Step 1) and homopiperazine (250 mg, 2 · 5 mmo 1), 141 mg (75%) was obtained. Elemental analysis (CHH22N4 0 2) Η ; C : Computation 値 64 · 94 ; Experiment 値 6 3 · 3 ; Ν : Computation 値 1 7 · 8 2 ; Experiment 値 16.8° Example 2 7 This paper scale applies to Chinese national standards (CNS )A4 size (210 X 297 mm) -44- I---------Installation--------------- (Please read the notes on the back and fill in the form) Page) 1291958 A7 9a 11 οι B7 V. INSTRUCTIONS (42) 2 — (2-methoxyphenoxy)_1-methylethyl 3 — (3 —amino —1 —D 2-Pyridazinyl ether (please read the precautions on the back side and fill out this page) The title compound was prepared according to the procedure described in Example 4, Step 2 from 3-chloro-2-pyrazine-2-(2-methoxyphenoxy) ) 1 -1 methyl ethyl ether * ( 150 mg, 0 · 5 1 mm ο 1 ) and 3-aminopyrrolidine (237111 bogey, 2.76 111111 〇 1) began to produce 12 〇 111 bogey

(68%). Elemental analysis (C18H24N4〇3) C, H, N 〇 > was prepared according to Step 4 of Example 4. Example 2 8 2 , 3 - diar ar - 1 , 4 - benzodioxan "S - 2 -methyl 3 - (1,4-diazanonane-1-yl)-2-piazine The title compound was prepared according to the procedure described in Example 4, Step 2 from 2-chloro-3-(2,3-dihydro-1,4-benzodioxan-2-ylmethoxy)-pyridazine. * (1 50 mg, 0.54 mm ο 1 ) and high azine (2 6 6 mg, 2 · 6 6 mm ο 1 ) were started to prepare 105 mg (57%). Elemental Analysis (C18H22N4〇3) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives Η, N; C: Computation 値6 3 · 1 4; Experiment 値 6 2 . 7〇. $ Prepared according to step 4 of Example 4. Example 2 9 2 —(4-Chlorophenoxy)ethyl 3 - ( 1 ,4 -diaza-capane- 1 -yl)-2-pyrazinyl ether This paper scale applies to Chinese national standards (CNS A4 size (210X297 mm) -45 - 1291958 A7 B7 V. Description of the invention (43) The title compound was prepared according to the procedure described in Example 4, Step 2 from 2-chloro-3-[2-(4-chlorophenoxy). Starting with ethoxy]pyrazine* (150 mg, 〇·53mmo 1) and homopiperazine (287 mg, 2 · 8 7 mm ο 1 ), 1 28 mg (69%) was obtained. HRMS m/z is 349 · 1431 for ChHuC 1Ν4〇2 (Μ) + and 349 · 1431 for experiment. Elemental analysis (CHHsiC 1N4〇2) C, Η, N. + Prepared according to step 4 of Example 4. Example 3 2 -(phenoxy)ethyl 3 -(3-methyl-l-piperazinyl)- 2 - fluorenyl title compound was prepared according to the procedure described in Example 4, Step 2 from 3-chloro- 2 —Pirazinyl 2-(2-methoxyphenoxy)-1-methylethyl ether* (1 5 〇mg , 〇· 6 0 mm ο 1 ) and 2-methyl-trinazine (25 Starting at 〇mg, 2 · 5mmo 1), 138mg (73%) was obtained. Alizarin analysis (Cl7H22N4〇2) C ′ Η ’ N. + Prepared according to step 4 of Example 4. Example 3 1 2 —(4-Chlorophenoxy)ethyl 3 —(3-methyl-l-piperazinyl)-2-pyrazinyl ether The title compound was obtained according to the procedure of Example 4, Step 2 from 2 - Chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine* (1 50mg This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the back) Precautions and then fill out this page) 装-订--------- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 46- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1291958 A7 _B7_ V. Invention description (44 Starting with 0. 53mmo 1) and 2-methylpiperazine (256mg, 2 · 56mmo 1), 143mg (77%) was obtained. HRMS m/z is 349 · 1431 for CHHsiC 1 N4〇2 (M) + and 349 · 1448 for experimental experiments. Elemental analysis (CHHziC 1N4〇2) C, Η, N. + Prepared according to step 4 of Example 4. Example 3 2 2 —(2-methoxyphenoxy)-1-methylethyl 3 —(3-methyl-l-oxazinyl)- 2-nonyl ether title compound according to Example 4 Step 2 The process is from 2-chloro-3-(2-(2-methoxyphenoxy)-l-methylethoxy]pyrazine* (1 50 mg, 〇.5 1 mm〇1) Starting with 2 -methylpiperazine (26 〇 mg, 2 · 6 mmo 1), 118 mg (65%) was obtained. The HRMS m/z is 359.2 083 for C 1 9 Η 2 6 N 4 Ο 3 (Μ) + , and the experimental 値 is 3 5 9 · 2〇9 6 . Elemental analysis (C i 9 Η 2 6 N 4 〇 3 ) C, Η, N. + Prepared according to step 4 of Example 4. Example 3 3 2,3 -Dihydro-1,4-benzodioxan-2-ylmethyl-3 - (3-methyl-1, fluorenyl) - 2 - 嗦 嗦 base title compound According to the procedure in step 2 of Example 4, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applied from the 2-chloro-paper scale. I----------Installation----- --Book --------- (Please read the note on the back and then fill out this page) -47- 1291958 A7 _B7_ V. Description of invention (45) 3 — (2 , 3 - a hydrogen -1 , 4-benzodioxan-2-yloxypyrazine* (15〇mg, 〇·54mmo 1) and 2-methylpiperazine (2 9 3 mg, 2 · 9 2 mm ο 1 ), The calculated enthalpy of 118 mg (69%) °HRMS m/z for C 1 8 Η 2 2 N 4 0 a (Μ) + is 343 · 1 77 〇, and the experimental enthalpy is 3 4 3 · 1 7 5 6 . Elemental analysis (C 1 8 Η 2 2 N 4 〇 3 ) Η, N ; C ·· Computation 値 6 3 · 1 4 ; Experiment 値 6 2 · 3 0. + Prepared according to step 4 of Example 4. Example 3 4 2 -(phenoxy)ethyl 3-(4-ethyl-1-piperazinyl)-2-pyrazazinyl ether The title compound was obtained from 2-chloro-2 according to procedure - (phenoxyethoxy)pyrazine* (1 50 mg, 〇.60 mm ο 1 ; obtained from Example 1 Step 1) and N-ethylpiperazine (25 〇 mg, 2 · 19 mmo 1), 127 mg (64%) was obtained. Elemental analysis (Ci8H24N4〇2) C, Η, N. Example 3 5 2 —(2-Chlorophenoxy)ethyl 3 —(4-ethyl-1-piperazinyl)-2-pyrazinyl ether The title compound was obtained according to the procedure of Example 4, Step 2 from 2 - Chlorine - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the note on the back and fill out this page). Installed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed -48- 1291958 A7 R9a lu". B7 V. INSTRUCTION DESCRIPTION (46), 3 —[ 2 —( 2 —Chlorophenoxy)ethoxy]pyrazine* ( 150 mg, Ο · 5 3 mm 〇1 ) and N — Ethyl piperazine (2 2 1 mg, (please read the back note first and then fill out this page) 1. 9 3 mm ο 1 ) Start with 1 Ο 〇mg ( 5 2 % ). Elemental Analysis (C18H23C 1N4〇2) C, Η, N. 'Prepared according to Step 4 of Example 4. Example 3 6 2 —(4-Chlorophenoxy)ethyl 3 —(4-ethyl-1-phenylazinyl)-2 - pyrazinyl ether title compound according to the procedure described in Example 4, Step 2, from 2-chloro-3-(2-(4-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0. 5) 3 mm ο 1 ) and N-ethylpipe (2 2 1 mg, 1 · 9 3 mm ο 1 ), starting with 1 3 8 mg (72 %). HRMS m/z for C18H23ClN4〇2(M)+ is calculated as 3 63 : 1587, experiment値 is 363. 1604. Elemental analysis (C18H23C 1N4 〇 2) C, Η, N. > Prepared according to step 4 of Example 4. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example 3 7 2,3 —Dihydro- 1 , 4 - benzodioxan-2-ylmethyl 3 - (4 - ethyl - 1 -azinyl)-2-pyridazinyl ether The title compound was obtained according to the procedure of Example 4, Step 2 from 2 -Chloro-3 - (2,3-dihydro-1,4-benzodioxan-2-ylmethoxy) D-pyridyl* (1 5 〇mg, 〇· 5 4 mm ο 1 ) and Ν—B-paper scale applies to Chinese National Standard (CNS) A4 specification (210Χ 297 mm) -49 - 1291958 A7 _B7_ V. Description of invention (47) Piperazine (2 1 9 mg, 1 · 9 2 mm ο 1 At the beginning, 128 mg (66%) °HRMS m/z was calculated for C 1 9 Η 2 4 N 4 Ο 3 (Μ) + 357 357 · 1 926 , and the experimental 3 was 3 5 7 · 1 9 1 5 . Elemental analysis (C19H24N4〇3) C, Η, N. + Prepared according to step 4 of Example 4. Example 3 8 2 —(2-Methoxyphenoxy)-1-methylethyl 3 —(4-ethyl-1-monopiperazinyl)-2-pyrazinyl ether The title compound was obtained according to Example 4 2 The process is from 2-chloro-3-(2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (15〇mg, 〇·51mmo 1) and Ν-B Starting from piperazine (222 mg, 1 · 94 mmo 1), 127 mg (67%) °HRMS m/z was calculated for C2〇H28N4〇3 (M)+, which was 373.2239, and the experimental 値 was 3 7 3 · 2 2 5 2. Elemental analysis (C2 〇 H28N4 〇 3) C ′ Η ’ N. + Prepared according to step 4 of Example 4. Example 3 9 2 -(3-Bromophenoxy)ethyl 3 -(1 -piperazinyl)-2-pyrazinyl Ether Step 1 : 2 —( 3 —Bromophenoxy)ethyl 3 —Chlorol 2—The basic paper size of pyrazine is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) I n II —.1 I 一^1 1^— ϋ ϋ ·ϋ -ϋ 1 I - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -50- 1291958 A7 ___B7 _ V. Invention Description (48) Ether (please read the notes on the back and fill out this page) 3 - Desert本酉(1 · 73g ' lOninio 1), Epoxy Institute (〇· 4 4 g ' 1〇mm ο 1 ), triethylamine (3 drops) and dioxane (4 m L ) at 1 Q 〇 ◦ C was heated in a sealed tube for 2 days. The obtained Lok solution was cooled in an ice bath' and the B-house (1 m L) was followed by κ〇-t-Bu (1 · 〇7g, 9 · 5mm〇1) and 2, 3-dichloropyrazine. (1 · 3 4 g, 9 mm ο 1 ) Join. The resulting mixture was stirred at room temperature for 90 minutes, diluted with C Η 2 C 1 2 and filtered. The filtrate was concentrated and purified by chromatography (yield: isohexane to 25 %. EtOAc / hexane) to afford 2 · 2 1 g ( 7 5 % ) White solid product: mp 5 7 — 5 8 ° C. Elemental analysis (C12H1〇BrC 1N2〇2) C,Η,N. Step 2: 2 -(3 -indolyloxy)ethyl 3 - (1 -piperazinyl)-2-pyrazinyl ether Ministry of Economics Intellectual Property Office Staff Consumer Cooperative Printed Piperazine at room temperature (1 · 2 9 g, 1 5 mm ο 1 ) and K2C〇3 (〇·69g, 5mmo 1) added to 2-(3-bromophenoxy)ethyl 3-chloro-2-pyrazinyl ether (1 · 6 5 g, 5 mm ο 1) A solution in acetonitrile (25 mL). The resulting mixture was heated under reflux for 2 1 h, cooled, concentrated and the residue was partitioned from &lt The layers were separated and the organic phase was washed with water and brine and dried over MgSO. Purification by chromatography on sand (gradient:

PhMe to PhMe/Me〇H/Et3N , 8 : 1:1) 'Prepared 1 · 6 1 g ( 8 5 % ) of the title compound of light yellow oil 'its-51 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 B7 V. Description of invention (49) Slowly solidified when rested: m ρ 6 2 — 6 3 °C ° Elemental analysis ( Ci6Hi9BrN4〇2) C'H'N. Example 4 Ο 2 -[ 2 -( 2 -Chlorophenoxy)ethoxy]-3 -( 1 -piperazinyl)quinoxaline Step 1: 2 -Chloro-3-(2 - (2-chlorobenzene) Oxy)ethoxy] oxaline 2-(2-chlorophenoxy)ethanol (0.229 g, 1 · 3 3 mm ο 1 ) as Na a Η (5 5 % dispersion in mineral oil; 0 ·〇5 8 g ' 1 · 3 3 mm ο 1 ) Solution treatment in two hospitals (2 m L ). Stirring was carried out for 3 hours at room temperature. The mixture was added dropwise to a slurry of 2,3-dichloroquinoxaline (0. 320 g, 1 · 60 m m ο 1 ) in dioxane (1 m L). The resulting mixture was stirred at room temperature for 15 hours to give 2-chloro-3-(2-(2-chloro-phenoxy)ethoxy]quinoxaline which was used directly in the next step. Step 2: 2 —[ 2 —(2-Chlorophenoxy)ethoxy]- 3 —( 1 -piperazinyl)quinoxaline piperazine (0 · 5 80 g, 6 · 6 5 mm〇1 The crude material obtained from Step 1 and the resulting mixture were stirred at room temperature for 5 hours. The solvent was evaporated and the crude material was dissolved in D M S 0 and precipitated with water. The precipitate was purified by chromatography on Shishi gum (using E t〇A c / Η〇A c / M e〇Η / Η 2〇 (4 0 : 3 : 3 : 2 ) as the eluent) Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -1--------- Install i 1 (please read the notes on the back and fill out this page) · 1291958 A7 B7 5 BRIEF DESCRIPTION OF THE INVENTION (50) 0 · 100 g (22%) of the title compound as a yellow oil. HRMS m/z is 384. 135 3 for C2QH2iC lN4〇2 (M) + and 384. 1334 for experimental experiment. Example 4 1 - 4 7 was prepared according to the preparation of Example 40. Example 4 1 2 —[2-(4-Chlorophenoxy)ethoxy]-3-(1-piperidinyl)quinoxaline The title compound was prepared from 2-(4-chlorophenoxy)ethanol (0 · 229g, 1,33mmo 1) Start with 〇. 2 50g (56%) yellow solid: mpl〇8 — 1 1 2 °C ; HRMS m / ζ For C20H21C 1 Ν4〇2 (Μ) + The first ten is 384. 1353, and the experimental one is 3 8 4. 1347. Example 4 2 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative (please read the notes on the back and fill in this page) 2 —[ 2 —(phenylthio)ethoxy]—3 —( 1 piperazinyl) The title compound of quinoxaline was prepared from 2 _(phenylthio)ethanol (〇·205 g, 1, 33 mmo 1) to give 〇·045 g (9%) of a yellow oil. The HRMS m/z is 3 6 6 · 15 14 for the C20H22N4O S (M) + g, and the experimental 値 is 3 6 6 · 15 〇 9. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 _ V. Invention description (51) Example 4 3 2—(1-methyl Preparation of a 2-phenoxyethoxy)-3-(1-decyl)quinoxaline title compound from 1-methyl-2-phenoxyethanol (0.202 g, 1, 33 mm 〇1) ) At the beginning, 0 · 084 g (17%) of yellow oil was obtained. HRMS m/z is calculated for C21H24N4〇2 (M) + as 364 .1899, and experimental 3 is 3 6 4 · 1 9 0 8 . Example 4 4 2 —[ 1 -Methyl 2- 2 -(methylphenoxy)ethoxy]- 3 -( 1 -piperazinyl)quinoxaline The title compound was obtained from 1-methyl-2- Starting with (4-methylphenoxy)ethanol (〇· 2 2 1 g , 1 , 3 3 mm ο 1 ), 047·047 g (9%) of a yellow oil was obtained. Elemental analysis (C22H26 N4〇2) C ′ Η ’ N. Example 4 5 2 —[2-(2-methoxyphenoxy)-l-methylethoxy]-3-(1-piperazinyl)quinoxaline The title compound was prepared from 1-methyl Starting with 2-(2-methoxyphenoxy)ethanol (0 · 242 g, 1, 33 mmo 1), 72 g (14%) of a yellow oil was obtained. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -54- I----------Install-------Book-------- - (Please read the notes on the back and fill out this page) 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 5, Inventions (52) Elemental Analysis (C!7H21C 1N4〇2) C , Η, N : Calculate 値1 4 . 2〇; experiment 値 1 3 · 70. Example 4 6 2 —(2,3-dihydro-1,4-benzodioxan-2-ylmethoxy)-3-(1-piperazinyl)quinoxaline The title compound was prepared from 2 , 3 - dihydro-1,4-benzodioxan-2-ylethanol (〇.221g, 1 · 3 3 mm ο 1 ) began to produce 〇·1 8 g ( 3 5 % ) yellow oil . Elemental analysis (〇21Η22Ν4〇3) C,Η,N. Example 4 7 2 —[2 —(2-Naphthyloxy)ethoxy]-3-(1-piperazinyl)quinoxaline The title compound was prepared from 2-(2-naphthyloxy)ethanol (〇 · 2 5 〇 g , 1 · 3 3 mm ο 1 ) Starting, a 22 g (41%) yellow solid was obtained. The calculation of HRMS m/z for C24H24N4〇2 (M) + is 4〇0 · 1899, and the experimental value is 4 0〇·1 9〇2. Example 4 8 2 -( 2 -Phenoxyethylamino)- 3 - ( 1 -piperazyl)pyrazine Step 1: 2 -Chloro-3-(2-phenoxyethylamino)pyrazine 2 - Phenoxyethylamine (2 · 65g , 19 · 3mmo 1) (Please read the notes on the back and fill out this page) ϋ ---- 1 ----Book --- f This paper size applies China National Standard (CNS) A4 Specification (210 297 297 mm) -00 - 1291958 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (53), 2, 3 - Dichloroanthracene (2 · a mixture of 88g, 19 · 3mmo 1) and K2C〇3 (2 · 67g , 19 · 3mmo 1) in acetonitrile ( 8 m L ) in a sealed tube at room temperature for 12 hours at .8 0 ° C is allowed to stir for 9 · 5 hours. The reaction mixture was diluted with diethyl ether and filtered and concentrated. The residue was purified by chromatography on EtOAc (EtOAc/EtOAc (EtOAc) : mp51-53〇C; HRMS m/z The calculated 値 for C i 2 H i 2 C 1 N 3 〇( Μ ) + is 249 · 0669, and the experimental 値 is 249 · 0659. Elemental analysis (Cl2Hl 2ClN3 〇) C, H, N. Step 2: 2 -( 2 -Phenoxyethylamino)-3-( 1 -piperazinyl)pyrazine was obtained from the product from Step 1 (1 · 59 g, 6 · 37 mmo 1 ), and hydrazide (1.56 g, A mixture of 18.2 mmol) and K2C〇3 (〇·88g, 6 · 37mmo 1) in acetonitrile (10 mL) was stirred in a sealed tube at 140 ° C for 12 hours. After cooling, the reaction mixture was diluted with C Η 2 C 1 2 and filtered and concentrated. The semi-solid residue was chromatographed on silica gel (using C H C 1 3 / M e 〇Η (9:1) as eluent) to give a brown oil. This oil was dissolved in C H C 1 3 and filtered through a short (3 c m) plug of alumina coated with Κ 2 C〇3. The plug was washed with a few portions of CHC 1 3 and the filtrate was concentrated to give a title of 1 · 4 8 g (78%) of pale yellow oil. The paper size was applied to the Chinese National Standard (CNS) A4 specification (210 X 297). PCT) I---------Install--------Book--------- (Please read the notes on the back and fill out this page) 1291958 A7 B7 V. Description of the invention (54). H R M S m / ζ For C \ 6 η 2 丄 Ν 5 〇 ( Μ ) + The calculation 値 is 299 · 1746, and the experimental 値 is 299 · 1753. Alizarin analysis (Cl6H2lN5〇*l/3H2〇) C,Η,N. Example 4 9 2 -(phenoxy)ethyl 3 -( 3 -pyrrolidinyloxy)- 2 -pyrazinyl ether 2 -chloro-3-(2-phenoxyethoxy)pyridazine (15 〇mg, 〇·6mm〇1; obtained from Example 1, step 1) to 3 -pyrrolidinol (2 60 mg, 2 · 9 9 mm 〇1 ) and Na Η (5 5 % in mineral oil) Dispersion; 1 1 〇mg, 2 · 5 mmo 1 ) A mixture of dioxane (2 mL), and the mixture was stirred at room temperature for 2 hr. Et0 A c was added, the mixture was washed with water, dried (M g S 〇 4 ), and concentrated. The residue was chromatographed on silica gel (Et 〇A c/Me 〇H/H 〇A c/H 2 〇 (50: 4 〇:9:1) as an eluent) to give 38 mg (22%). Title compound. Elemental analysis (C16H19N3〇3) Η ; C : Computation 値 6 3 · 7 7 ; Experiment 値 6 2 · 2 0 ; N : Calculate 値 1 3 . 9 4 ; Experiment 値 1 3 . Example 5 0 2 -(phenoxy)ethyl 3 -[(3R)-pyrrolidinyloxy]-2-pyrazazinyl ether Step 1: 2 -(phenoxy)ethyl 3 -[Ν -third Butoxycarbonyl (This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) Pack----Book-------- -. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (55) 3 R) - approved academy oxy] 1-2 oxazinyl 酉 fans 2-Chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1 · 〇〇mm〇1; obtained from step 1 of Example 1) was added to N - B〇c - (R) - 3 - a mixture of pyrrolidinol (225 mg, 1 · 2mmo 1) and K〇-t-Bu (140mg, 1 · 25mmo 1) in toluene (5mL), the reaction is stirred at 95 ° C for 30 minutes . The reaction mixture was diluted with toluene, washed with water, dried (M??? The residue was chromatographed on EtOAc (EtOAc/EtOAc (EtOAc:EtOAc) Without measuring its nature. Step 2: 2-(Phenoxy)ethyl 3-[(3R)-pyrrolidinyloxy]-2-pyrazinyl ether is obtained from the product of Step 1 above as C Η 2 C 1 2 /trifluoroacetic acid / Η 2〇 (5 0 : 4 5 : 5, 4 m L ) for 3 〇 minutes. The resulting mixture was concentrated and the residue was partitioned between EtOAc EtOAc EtOAc. After separation, the organic layer was dried (M g S 〇 4 ) and concentrated. The residue was chromatographed on silica gel (using C Η 2 C 1 2 / μ e 〇Η (8 ·· 2 ) as the eluent) to give 4 4 mg (15 %) of the title product··[a] D = - 4.6 〇 (c0.017, Me 〇 H); HRMS m / z for C16H19N3 〇 3 (μ) + calculation 値 is 3 〇 2 · 15 〇 4, the experimental 値 is 302 · 1505. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -58 -I------ Pack ---!! --III (Please read the note on the back and fill out this page) 1291958 A7 _B7_ V. Invention description (56) Example 5 1 (Please read the note on the back and fill in this page) 2 —(phenoxy)B The title compound of 3-(4-pyrrolidinyloxy)-2-pyrazinyl ether was prepared according to the procedure described in Example 50 from 2-chloro-3-(2-phenoxyethoxy)pyridinium. (250 mg, 1 mmol; obtained from Step 1 of Example 1) and N-Boc-4-hydroxyl-piperidine (2 3 4 mg, 1 · 16 6 〇1) afforded 112 mg (35%) of title product. The HRMS m/z is calculated as C 1 7 Η 2 3 N 3 0 3 ( Μ ) + 3 3 1 6 · 1 6 6 1 , and the experimental 値 is 3 1 6 · 1 6 4 8 . Example 5 2 2 -(phenoxy)ethyl 3 -[ (2R)-pyrrolidinylmethoxy] 2- 2 -decyl ether Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print Step 1: 2 - (Benzene The preparation of the title compound of the oxy)ethyl 3-(N-tert-butoxycarbonyl(2R)-fluorenyl methoxy)-2-pyridazinyl ether is carried out according to the procedure described in Example 5, Step 1. From 2-chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1 mmol; obtained from Example 1 Step 1) and N-Boc-D-Proline (pro lino 1) (234 mg, 1 Starting from 1 6 mm 〇 1 ), 20 〇 mg ( 48 % ) of the title product: [a] D = 35.6 ° (c 〇 〇 2, Me 〇 H); HRMS m/z for C22H29N3 〇 5 The calculation of (M) + is 4 1 6 · 2 1 8 5, and the experimental value is 4 1 6 · 2 1 7 7. This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -59- 1291958 Α7 Β7 5. Inventive Note (59) Purification by gel chromatography (using toluene / E t 0 A c ( 1 : 1) As an eluent), 1 6 · 8 6 (85 %) of the title product was obtained. (Please read the note on the back and fill out this page.) HRMS m/z is 324· 1798 for Ci5H24N4〇4(M)+ and 324. 1784 for experiment. Step 3: 2 - (2-methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether 1,1>-azobis(N,N-dimethylmethyl) Indoleamine (TMAD; 60mg, 〇·35mmo 1) is dissolved in THF (1mL) and DMF (〇·5mL), and added to the product from step 2 (10〇mg, 〇· 31mml), 2-A A stirred solution of oxyphenyl alcohol (124 mg, lmmo 1) and triphenylphosphine (92 mg, 0 · 35 mmol) in THF (1 mL). The reaction mixture was stirred for 15 hours and then concentrated under reduced pressure. The residual stream is passed through a silicone bed (using toluene / E t〇A c /M e〇Η ( 4 5 : 4 5 : 1 0) as the eluent), the pure fraction is poured out, concentrated and CH2C12/TFA/ H2〇 (5〇:45:5, printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative 5 m L) for 30 minutes. The mixture was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The fraction containing the product was concentrated and partitioned between a 5 % aqueous solution of N a 与 and C Η 2 C 1 2 . The organic layer was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj HRMS m / ζ for -62- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291958 A7 B7 V. Invention description (60) C17H22N4〇3(M)+ calculation 値 is 330· 1692, the experimental 3 is 3 3 0 · 1 7 〇 7. Example 5 5 - 8 4 was prepared according to the procedure described in Example 5, Step 4, from 2 -[ 3 -( 4 -t-butoxycarbonyl-1-piperazinyl)-2-pyrazineoxy]ethanol and necessary The phenolic compound (1 mm ο 1 , unless otherwise indicated) begins. Example 5 5 2-(3-Methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether The title compound was prepared from 3-methoxyphenol to give 39 mg. (39%) °HRMS m/z for C 1 7 Η 2 4 N 4 0 3 (Μ) + is calculated as 330. 1 692 , the experimental 3 is 3 3 0 . 1 6 7 7. Example 5 6 2 _[(1,1/biphenyl)-3-yloxy]ethyl 3 —( 1 -piperazinyl)-2-pyrazinyl ether The title compound was prepared from 3-phenyl Starting from phenol, 16 mg (16%) °HRMS m/z was obtained. For C22H24N4〇2 (Μ) + , the calculated 値 was 37 6 · 1 89 9 and the experimental enthalpy was 3 7 6 · 1 8 8 8 . This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). Pack -------- Order -------- - , Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative Printed -63- 1291958 A7 _B7_ V. Invention Description (61) Example 5 7 (Please read the note on the back and fill out this page) 2 — (3 — n-Butoxy The title compound of phenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether was prepared starting from m-butoxyphenol to give 9 · 7 mg (8%) °HRMS m / z The calculated 値 for C2〇H28N4〇3(M)+ is 372 · 2161, and the experimental 値 is 3 7 2 . 2 1 4 9 . Example 5 8 2 —(4-n-Butoxyphenoxy)ethyl 3 -( 1 -piperazinyl)-2-pyrazinyl ether, trifluoroacetate salt The title compound was prepared from p-butoxy Starting from phenol, but without Na 〇 H extraction and without a third chromatography step, 92 mg (1 9%) of the title compound as trifluoroacetic acid salt was obtained. HRMS m/z is calculated for C 2 Ο Η 2 8 N 4〇3 ( Μ ) + 372 . 2161, experimental 値 372 . 216 2. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printing Example 5 9 -(2,3,4-Trifluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether Starting from 2,3,4-trifluorophenol, 62 mg (17%) °HRMS m/z was calculated for C16H17F3N4O2 (Μ) + 354 354. 13 〇 4, experimental 値 354. 1321. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -64- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1291958 A7 _B7_ V. Invention description (62) Example 6 0 2 —(2 — Preparation of the title compound of isopropoxyphenoxy)ethyl 3-(1 piperazinyl)-2-pyrazinyl ether starting from 2-isopropoxyphenol, 216 mg (60%) °HRMS m/z For C19H26N4〇3 (Μ) +, the calculation is 358 · 2005, and the experimental 値 is 3 5 8 · 2 0 0 6. Example 6 1 2 -(1-Naphthyloxy)ethyl 3 - (1 - oxazinyl)- 2 - decyl ether The title compound was prepared from 1-naphthol to give 142 mg (4%) °HRMS m/z is calculated for C2〇H22N4〇2 (Μ) + 〇 35〇.1 7 43, experimental 3 is 3 5〇· 1 7 5 8 . Example 6 2 2 -(2,3-dichlorophenoxy)ethyl 3-(1-oxazinyl)-2-pyrazinyl ether The title compound was prepared starting from 2,3-dichlorophenol. 8 〇mg (16%) 〇HRMS m/z For CieHisC I2N4O2 (Μ) + The calculated 値 is 368 · 〇 8 〇 7 , and the experimental 値 is 368 · 0 818 . This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) I----------Install--------Set--------- ( Please read the notes on the back and fill out this page.) -65- 1291958 A7 B7 V. INSTRUCTIONS (63) EXAMPLE 6 3 2 — (2 ,4 -Difluorophenoxy)ethyl 3 — (1-piperazine The preparation of the title compound of 2-pyridyl ether is started from 2,4-difluorophenol to obtain 3 〇mg (14%) °HRMS m/z. For C16H18F2N4〇2 (Μ) + 336 · 1398, the experimental 値 is 336 · 1392. Example 6 4 2 —(2 ,5-Difluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyridyl ether, the title compound of the trifluoroacetate salt was prepared from 2,5 - The fluorophenol was started, but without the Na 0 Η extraction and without the third chromatography step, 2 l mg ( 6%) of the title compound of the trifluoroacetic acid salt was obtained. The HRMS m/z is calculated for C16H18F2N4〇2 (M) + as 337 · 1476, and the experimental 値 is 337 · 1485. Example 6 5 2 —(3 ,5-Dimethoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether The title compound was prepared from 3,5-dimethoxy Starting from phenol, 52mg (14%) °HRMS m/z is calculated for C 1 8 Η 2 4 N 4 Ο 4 (Μ) + 360 360 · 1798, this paper scale is applicable to China National Standard (CNS) A4 specification (210 χ 297 mm) (Please read the notes on the back and fill out this page) Install n -1_ 1 1_ ϋ I · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 _B7 _ V. Invention Description (64) The experimental experiment is 3 6〇·1 8 0 8 . (Please read the notes on the back and then fill out this page) Example 6 δ 2 —(2 ,6-Dimethoxyphenoxy)ethyl 3 —(1-piperazinyl)-2-pyrazinyl ether, Preparation of the title compound of the trifluoroacetate salt starting from 2,6-dimethoxyphenol gave 142 mg (3%). H R M S m / ζ For C 1 8 Η 2 4 Ν 4 Ο 4 (Μ) + The calculation 値 is 360 · 1 798 and the experimental 3 is 3 6 0 · 1 7 9 7 . Example 6 7 2 -(2,3-Dimethoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether The title compound was prepared from 2,3-dimethoxy Starting with phenol, 1 10 mg (31%) was obtained. H R M S m / ζ For C18H24N4〇4(M)+, the calculation 値 is 36〇·1798, and the experimental 値 is 3 6 0 · 18 8〇〇. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printing Example 6 8 2 —(4-Ethylphenoxy)ethyl 3 —(1—decalizinyl)-2-pyridazinyl ether The title compound was prepared from 4 Starting with -ethylphenol, 13mg (4%) °HRMS m/z is calculated for C18H24N4〇2(M)+ is 328 · 1899, this paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 PCT) -67- A7 1291958 B7___ V. INSTRUCTIONS (65) The experimental 3 is 3 2 8 · 1 8 8 7. Example δ 9 2 -(1 ,3 -benzodioxan-5-yloxy)ethyl 3 -(1 -piperazinyl)-2-pyrazinyl ether The title compound was prepared from sesame meal (1 7 3 mg, 1 · 25mmo 1 ) and 2 - [3 - (4 - tert-butoxycarbonyl-1 piperazinyl)-2-pyrazinyloxy]ethanol (3 2 5 mg, 1 mm ο 1 ; From the beginning of Example 5 4 step 2), 7 8 mg (23%) °HRMS m/z was calculated for C 1 7 Η 2 〇N 4 Ο 4 (Μ) + 344 344 · 1485, the experimental 値3 4 4 · 1 4 7 4. Example 7〇2 —( 2 —Hydroxyphenoxy)ethyl 3 —( 1 —piperazinyl)-2-pyrazinyl ether, trifluoroacetate The title compound was prepared from catechol (2 7 5 mg , 2 · 5mmo 1 ) and 2 —[ 3—(4 —Tertoxycarbonyl-1 piperazinyl)-2-pyrazineoxy]ethanol (3 2 5 mg, 1 mm ο 1 ; Example 5 4 Step 2) Start, to obtain 50 mg (12%) °HRMS τη / z

The purpose of Ci6H2〇N4〇3 (Μ) + is 3 1 6 .1 5 3 5' The experimental 3 is 3 1 6 · 1 5 4 9 . I----------Install-------Book--------- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives Printed paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -68- 1291958 A7 _B7_ V. Invention description (66) Example 7 1 (Please read the note on the back and fill out this page) 2-(3-Hydroxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, trifluoroacetate salt The title compound was prepared analogously from 1,3 -dihydroxybenzene (276 mg , 2 · Smmol) and 2 - [3 - (4 - 3 -butoxy ortho-l-piperazinyl) 2- 2 -oxazinyloxy]ethanol ( 3 2 5 mg , 1 mm 〇 1 ; Example 5 4 Step 2) Start, but without N a 0 Η extraction and without a third chromatography step, 159 mg (37%) of trifluoroacetate was obtained. The HRMS m/z is calculated for C16H20N4〇3 (M) + as 3 16 · 1535 and the experimental enthalpy is 3 1 6 · 1 5 4 6 . Example 7 2 2 —(2 —Ethylphenoxy)ethyl 3 —(1—piperazinyl)-2-pyrazinyl Ether, Trifluoroacetate Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Title Compound The preparation is similarly from 2-hydroxyacetophenone (17 〇 mg, 1 · 25 mmo 1) and 2 - [3 - (4 - second butoxy ortho-l-piperazinyl)- 2-indole Starting from oxy]ethanol (325 mg, lmmo 1 ; obtained from step 54 of Example 54), but without N a 0 Η extraction and without a third chromatography step, 17 〇 mg (37%) of trifluoroacetic acid salt was obtained. The HRMS m/z is 342 · 1692 for C18H22N4〇3 (Μ) + and the experimental 値 is 3 4 2 · 1 7〇4. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -69- 1291958 A7 _B7__ V. Invention description (67) Example 7 3 (Please read the note on the back and fill out this page) 2 — (2-Ethylamino-5-methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyridyl ether, the preparation of the title compound of the trifluoroacetate is similarly from 2-hydroxyl 4-methoxyacetophenone (2〇8mg, 1 · 25mm〇1) and 2-(3-(4-tritoxycarbonyl-1-monopiperazinyl)-2-pyrazineoxy] Ethanol (325 mg, lmmo 1 ; obtained from Step 54 of Example 54) was started, but without a Na0 Η extraction and without a third chromatography step, 128 mg (26%) of trifluoroacetic acid salt was obtained. HRMS. m/z For C i 9 Η 2 4 N 4〇4 ( Μ ) + The calculated 値 is 3 7 2 · 1 7 9 8 and the experimental 値 is 3 7 3 · 1 8 1 0. Example 7 4 2 —(2 —Ethyl-3,5-dimethoxyphenoxy)ethyl 3 —(1-piperazinyl)-2-pyrazinyl ether, Trifluoroacetate Ministry of Economics The preparation of the title compound printed by the Property Bureau Staff Consumer Cooperative is similarly derived from 2-hydroxy-4,6-dimethoxyacetophenone (245 mg, 1 · 25 mm 〇 1) and 2 - 〔3 - (4 - third Starting from butoxycarbonyl-1 -piperazinyl)-2-pyrazinyloxyethanol (325 mg, lmmo 1 ; obtained from step 54 of Example 54), but without extraction and no third chromatography step 216 mg (42%) of trifluoroacetate was obtained. The HRMS m/z is calculated for C2〇H26N4〇5(M)+ as 4〇2 · 19 0 3 , and the experimental 値 is 4〇2 · 1886. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -70- 1291958 B7 V. Inventive Note (68) Example 7 5 2 I(3-Ethylaminophenoxy)ethyl 3 - (1 piperazinyl)-2-pyrazinyl ether, trifluoroacetate salt The title compound was prepared analogously from 3-ethylaminophenol (I89mg, 1 · 25mmo 1) and 2 - [3 - ( 4 —T-butoxycarbonyl-l-oxazinyl)-2-pyrazinyloxy]ethanol (325 mg, lmm0 1 ; obtained from Example 54, step 2) begins 'but does not require Na a extraction and no A third chromatography step was performed to make 196 mg (42%) of trifluoroacetate. The HRMS m/z is calculated as 357 · 1801 for Ci8H23N5〇3 (Μ) + and the experimental 値 is 3 5 7 · 1 7 8 9 . Example 7 6 2 -(2-keto-1'3-benzothiazepine-5-yloxy)ethyl 3-(1-piperazinyl)-2-pyridyl ether, trifluoroacetate The title compound was prepared analogously from 1,3-benzothiazepine-2-ketone (21 〇mg, 1 · 25 mmo 1) and 2-[3 - (3 - 3 -butoxycarbonyl - 1 -1) Piperazinyl)-2-pyrazinyloxyethanol (3 2 5 mg, 1 mm ο 1 ; obtained from Example 5 4 Step 2), but without Na Ο Η extraction and without the third chromatography step, 147 mg (30%) of trifluoroacetate was obtained. The HRMS m/z is calculated for CHHHN4 0 4S (M) + 374 374· 1049, and the experimental 値 is 374. 1044. This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public). (Please read the notes on the back and fill out this page)

• I ϋ I Bn ϋ ϋ ϋ -ϋ II Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed -71 - 1291958 A7 B7 V. Description of Invention (69) Example 7 7 2 — ( 5 , 6 , 7 , 8 - Tetrahydrogen —2 —Naphthyloxy)ethyl 3 —( (Please read the back of this section and then fill out this page) 1 1-piperazinyl) 2-pyridyl ether, the preparation of the title compound of trifluoroacetate is similarly From 5,6,7,8-tetrahydro-2-naphthol (185 mg, 1.25 mmo 1) and 2 -[ 3 -(4 a second butoxy ortho-l-piperidinyl)-2 Starting from oxazinyloxy]ethanol (3 2 5 mg, 1 mm 〇1; obtained from Example 5, Step 2), but without the Na 〇Η extraction and without the third chromatography step, 155 mg (33%) was obtained. Trifluoroacetate. The HRMS m/z is 354 · 2056 for C2 〇 H26N4 〇 2 (M) + and 354. 206 8 for experimental 値. Example 7 8 2 -(4-Chloro-2-hydroxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Title Compound Preparation System Starting from 4-chloro-2-fluorophenol (217 mg, 1 · 48 mm 〇 1), 123 mg (35 %) of a yellow oil was obtained. H R M S m / ζ For CieHisC 1 FN4O2 (M) + The calculated 値 is 3 52 · 11 〇 2 , and the experimental 値 is 352 · 1098. Example 7 9 2—(2-Fluoro-6-methoxyphenoxy)ethyl 3 — (1 monopyridazinyl)-2-pyrazinyl ether This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -72- Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1291958 A7 _B7_ V. INSTRUCTIONS (70) The title compound was prepared from 2-fluoro-6-methoxyphenol (178)11 Avoid, 1.25111111 〇 1), the production of 23 〇 111 bogey (6 6%) yellow oil. The HRMS m/z is 348 · 1598 for C 1 7 Η 2 1 F N 4 0 a (Μ) + and the experimental 値 is 3 4 8 · 1 6 0 2 . Example 8〇2 — (2-methoxy-4-methylphenoxy)ethyl 3-(1-piperazinyl)-2-pyridyl ether The title compound was prepared from 2-methoxy- Starting with 4-methylphenol (162 mg, 1 · 25 mmo 1), 233 mg (67%) of a yellow oil was obtained. The HRMS m/z is 344 · 1 848 for C 1 a Η 2 4 N 4 0 a (Μ) + and the experimental 値 is 3 4 4 . 1 8 3 9 . Example 8 1 2 —(4-cyclopentylphenoxy)ethyl 3-(1-piperazinyl)-2-indolyl was prepared from 4-cyclopentylphenol (2 0 3 mg, 1 · 25mmo 1) Start with 3 〇mg (8%) yellow oil. H R M S m / ζ For C 2 i Η 2 8 Ν 4 〇 2 ( Μ ) + The calculation is 368 · 2212, and the experimental number is 368 · 2193. Example 8 3 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I-------装--------订--------- ( Please read the notes on the back and fill out this page.) -73- 1291958 A7 _B7_ V. INSTRUCTIONS (71) 2 — ( 2 —Chloro-3-pyridyloxy)ethyl 3 —( 1 —piperazinyl) 2 —pyridyl ether (please read the note on the back and fill out this page) The title compound was prepared from 2-chloro-3-hydroxypyridine (33〇mg, 2 · 55mm〇1) to make 58mg ( 8%) White solid: mp22 5 - 2 3 〇 ° C. HRMS m/z for C15H18C 1Ν5〇2 (Μ) + is calculated as 335. 1 149, the experimental 値 is 335 · 1 146. Example 8 4 2 —(2-Chloro-4-methoxyphenoxy)ethyl 3 —(1-—indolyl)-2-pyridazinyl ether The title compound was prepared from 2-chloro-4-methyl Starting with oxyphenol (103 mg, 〇·6 5 mm ο 1 ), the procedure described in Example 5, Step 3, but using diethyl azodicarboxylate (DEAD) instead of TMAD. The yield was 50 mg (21%). HRMS m/z is 364. 13 0 2 for ChHuC 1N4〇3 (M) + and 364· 1307 for experiment. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printing Example 8 5 2 —[ 3 —( 4 -morpholinyl)phenoxy]ethyl 3 —( 1 -piperazinyl)- 2 -nonylether 1 1 &gt; azobis(N,N-dimethylformamide) (TMAD; 256mg, 1 · 5mmo 1) is added to 2 - [3 - (3 - 3 -butoxycarbonyl - 1 - piperazinyl) ) 2 - pyrazinyloxy] This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -74- 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (72 Ethanol (400 mg, 1 · 24 mmo 1 ; obtained from Example 54 Step 2), 3-(4-morpholinyl)phenol (4 4 1 mg, 1 · 23 mm〇1) and triphenylphosphine (646 mg, 2 · 46 mmo 1) in a solution in THF (3 mL). The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated. The residue was purified by repeated chromatography on silica gel (using toluene / E t 〇 A c (8: 2) as eluent). The solvent and residue were evaporated at room temperature for <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; After concentration, 5 Μ N a 加入 was added, followed by extraction with C Η 2 C 1 2 . The organic layer was dried (Κ 2 C 〇 3 ), filtered and concentrated. The residue was purified by chromatography on EtOAc EtOAc (EtOAc) H R M S m / ζ for C2〇H27N5〇3 (Μ) + is calculated as 38 5 .2 1 1 4, and the experimental 3 is 3 8 5 · 2 1 0 0. The preparation of Example 8 6 - 9 3 was carried out according to the procedure of Example 8 5 starting from the necessary phenol compound. Example 8 6 2 -(3-Fluorophenoxy)ethyl 3 -(1 -piperazinyl)-2-yl-pyridazinyl ether The title compound was prepared from 3-fluorophenol (2 7 6 mg, 1 . 24mmo 1) Start, make 228mg (58%) half paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) I-----------Install----- ---Order--------- (Please read the notes on the back and fill out this page) -75- 1291958 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print A7 B7 V. Inventions (73) Solid . HRMS m/z for Ci6H19FN4〇2 (M) + is calculated as 3 1 8 · 1 4 9 2, and experimental 値 is 3 1 8.1 4 8 7. Example 8 7 2 -(1 ,3 -benzodioxan-4-yloxy)ethyl 3 -(1 piperazinyl)-2-pyrazinyl ether The title compound was prepared from 1,3 -benzene Starting with dioxin-4-alcohol* (3 4 0 mg, 1 · 2 4 mm ο 1 ), 125 mg (29%) of oil was obtained. HRMS m/z is calculated for CHH20N4O4 (Μ) + as 344.1485, and experimental 344 is 1487. * The preparation thereof is described in Chem. Pharm. Bull. 1 980, 28, 24 14-242 1. Example 8 8 2 —(2,3-dihydro-1,4-benzodioxan-5-yloxy)ethyl 3 —( 1 —piperazinyl)-2-pyrazine ether The preparation was started from 2,3-di- 1 ,4-benzodioxan-5-ol* (37 4 mg, 1.24 mmo 1 ) to obtain 2 60 mg (59%) solid: mp98-99 °C. HRMS m/z is calculated for C18H22N4〇4 (Μ) + 358 358 · 1641, experimental 値 358. 1648. * The preparation thereof is described in J. Am. Chem. Soc. 1 959, 81, 5 1 99-52 1 0. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -76- I----------Install--------Set------- -- (Please read the notes on the back and fill out this page) 1291958 A7 _B7_ V. Inventions (74) Example 8 9 (Please read the notes on the back and fill out this page) 2 — (2 — propyl benzene Preparation of the title compound of oxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether starting from 2-allylphenol (3 30 mg, 1 · 24 mmo 1) to give 200 mg ( 74%) oil. HRMS m/z is 340 · 1899 for C19H24N4〇2 (Μ) + and 34〇·1888 for experiment. EXAMPLES 2 - (3 -Aminophenoxy)ethyl 3 - (1 -piperazinyl)-2-pyrazinyl ether The title compound was prepared from 3-aminophenol (2 6 8 mg, 1 · 24mmo 1) Start with 49mg (13%) oil. The HRMS m/z is calculated for C16H21N5〇2 (Μ) + 3 3 1 5 · 1 6 9 5, and the experimental 値 is 3 1 5 · 1 7 0 5 . Example 9 1 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 2 — (3-Nitrophenoxy)ethyl 3 — (1 — 卩 嗉 ) 一 一 一 一 标题 标题 标题 标题 标题Starting with 3-nitrophenol (3 4 2 mg, 1 · 24mmo 1), 195mg (46%) solids were obtained: mpl71°C°HRMS m/z for C 1 6 Η 1 9 N 5 0 4 (Μ) + The calculation 値 is 345 · 1437, and the experimental 値 is 3 4 5 · 1 4 2 0. -77- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 ---------B7_ V. Invention Description (75 EXAMPLES 9 2 2 —(3 —Benzylmercaptophenoxy)ethyl 3 —(1-piperazinyl)-2-pyridinyl ether The title compound was prepared from 3-bensylphenol ( Starting at 488 mg '1 · 24mmo 1), 12 〇mg (24%) solids were obtained: mp69 - 70 °C °HRMS m/z For C 2 3 Η 2 4 N 4 Ο 3 ( μ ) + calculation 値 404 · 1848, the experimental 値 is 404 · 1835. Example 9 3 2 —(1 -ketoindan-4-yloxy)ethyl 3 -(1-piperazinyl)-2-pyridazinyl ether The title compound was prepared from 4-hydroxy-1 Starting with full ketone (365 mg, 1 · 24 mmo 1), 19 mg (4 %) of oil was obtained. H R M S m / ζ For C 1 9 Η 2 2 Ν 4 Ο 3 (Μ) + The calculated 値 is 354 · 1 692 and the experimental 3 is 3 5 4 · 1 7 0 5 . Example 9 4 2 -(3-trifluoromethylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether

The title compound was prepared according to the procedure of Example 8 5 from 3-terbene methylphenol (199 mg, 1 · 23 mmo 1), TMAD. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 297 297 mm) – — — — — — — — — ^wa ^ ills — ^-1111111 I (Please read the note on the back and fill out this page) 1291958 A7 B7 V. Description of invention (76) (129mg, 〇.75mmol), 2 — [3 - (4 - tert-butoxycarbonyl-1-piperazinyl)-2-pyrazineoxy]ethanol (20 mg, 〇 · 62 mmo 1 ; obtained from Example 54 Step 2) and diphenylphosphine ( 3 2 3mg, 1 · 23mmo 1) Start with 109nig (49%) oil. HRMS m/z is 368 · 1460 for C17H19F3N4〇2 (M) + and 368 · 1465 for experimental experiments. Example 9 5 2 —(2 ,6-Difluorophenoxy)ethyl 3 —(1 piperazinyl)-2-pyrazinyl ether. The title compound was prepared according to the procedure of Example 8 5 from 2, 6 -difluorophenol (239 mg, 1.84 mmo 1), TMAD (3 8 4 πί g ' 2 · 2 5 πί m ο 1 ), 2 —[3 — ( 4 — 3 -butoxycarbonyl-1 piperazinyl a 2-pyrazineoxy]ethanol (6 〇〇mg, 1 · 86 mm 〇1; obtained from Example 54, Step 2) and triphenylphosphine (969 mg, 3 · 69 mm 〇1) to prepare 2 79 mg ( 45%) Solid: mpl〇l - l〇2 °C. HRMS m/z is calculated for C16H18F2N4〇2 (Μ) + as 3 3 6 · 1398, and experimental 値 is 336 · 1403. Example 9 6 2 —(3 ,5 -Difluorophenoxy)ethyl 3 —(1—piperazinyl)-2-pyrazinyl ether This paper scale applies to China National Standard (CNS) A4 specification (210 X 297) _ 79 _ (Please read the note on the back and fill out this page) Installed _ 1 IJ · IB1 emmmmw i_i IBB 1 mMml mMmB I m Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 ___ B7___ V. DESCRIPTION OF THE INVENTION (77) The preparation of the title compound is based on the procedure of Example 8.5 from 3,5 - (please read the note on the back side and fill out this page). Fluorobenzoquinone (239 mg, 1 · 84 mmo 1), TMAD ( 3 8 4mg, 2.2 5mm〇l), 2-[3-(4-Tertiaryoxycarbonyl-1-1-carbazinyl)-2-pyrazinyloxy]ethanol (600 mg, 1 · 8, 6 Starting from Example 5 4 Step 2) and diphenylphosphine (969 mg '3 · 69mmo 1), 123 mg (20%) of solid was obtained: mgll9 - 121 °C. The HRMS is calculated on Ci6Hi8F2N4〇2 (Μ) + and the calculation is 336 · 1398, and the experimental number is 336 · 1409. EXAMPLE 9 7 3 -(Phenoxy)propyl 3-(1-piperazinyl)- 2-d-pyruyl acid, dihydrochloride Step 1: 2 -Chloro-3-(1-piperazinyl) a 2-d-pyrazine* 2,3-dichloropyrazine (1 · 3 5 g, 1 5 · 3 2 mm 〇1 ), piperazine (2 · 3 4 g , 27 · 2mmo 1) and K2C〇3 (1 · 25g , 9 · 04 Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed mmo 1) Mixture of acetonitrile (5 · 5 m L ) in a sealed test tube at 1 10 ° C for 1 · 25 hours . The reaction mixture is diluted with CH 2 C 1 2, filtered and concentrated to give a pale-yellow semi-solid residue which is purified by chromatography on silica gel (using CHC 1 3 / M e 〇Η ( 9 : 1 ) as eluent ). The solid obtained was redissolved in C Η C 1 3 and a short (3 cm) plug flowing through the alumina. It was eluted with diethyl ether/CHC13 (9:1) to give the title compound of 1 · 24 g (69 %) of white solid. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -80 - 1291958 A7 B7 V. INSTRUCTIONS (78) : mp47 — 53°C°HRMS m/z For CsHhC 1N4 (Μ) + calculation 値 is 98 .〇672, experimental 1 is 1 9 8 ·◦ 6 7 3 . * described in J. Med. Chem. 1978, 21, 536-542 〇Step 2: 3 -(phenoxy)propyl 3-(1-piperazinyl)-2-pyrazinyl ether, dihydrochloride 2-Chloro-3-(1-piperazinyl)pyridinium (6〇8 mg, 3 · lmmo 1 ; obtained from the above step i) and 3 monophenoxypropanol (57〇mg, 3 · 7mm〇1) ) dissolved in dioxane (i〇mL). K〇一t-Bu (87〇mg, 7 · 7mmo 1 ) was added, and the resulting mixture was stirred at 95 ° C for 6 hours. Evaporation of the solvent and the residue were purified by chromatography (jjjjjjjjjj The free base is converted to the dihydrochloride salt: yield 〇 380 g (32%); mpl 46 — 146 · 5 〇 C. Elemental analysis (Ci7H22N4〇2*2HC 1 ) C, Η, Ν. The preparation of Example 9 8 - 1 3 6 was carried out according to the procedure of Example 9 7 Step 2 starting from 2-chloro-3-(1-carbazinyl)pyrazine and the appropriate alcohol. The purification was performed on a silica gel column chromatography (using CHC l3 / MeOH (9: 1 ) - CHCl 3 / Me 〇 H / NH 4 〇 H (95: 5: 0 · 5) or a suitable solvent system as an eluent). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). Install the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Ministry of Printing, Ministry of Economy, Intellectual Property Office, Staff Consumption Co-op printing 1291958 A7 B7 V. Inventive Note (79) Example 9 8 2 -(2-Trifluoromethylphenoxy)ethyl 3 -(1 piperazinyl)-2-pyrazazinyl Ether Step 1: 2-(2-trifluoromethylphenoxy)ethanol

Trifluoromethylphenol (2 · 〇〇§ '12 · 3mmo 1 ), K2C〇3 (1.71g, l2.3mmo1) and ethyl carbonate (1 · 20g, 13 · 6mmo 1) in dry DMF (3 The mixture in 0 m L ) was stirred at 1 5 ° C for 1 hour. After cooling, the reaction was quenched by the addition of water (10 mL). The mixture was concentrated in vacuo and EtOAc EtOAc m. An aqueous solution phase was further added by adding E t 〇 A c ( 3 x 3 0 m L ). The combined organic layers were treated with charcoal, dried with MgSO4, and filtered through celite. The filtrate was concentrated under vacuum, and the residual oil was purified by chromatography on silica gel (using n-hexane/E t〇A c ( 8 0 : 2 0 ) as an eluent) to obtain 〇·50 g (20%) white. The title product of the crystal: mp74 - 77 〇C. Elemental analysis (C9H9F3〇.2) c,H ο Step 2: 2 —(2-trifluoromethylphenoxy)ethyl 3 —(1—piperazinyl)-2-pyrazinyl ether 48% yield ; mp79 — 8〇 °C. Elemental Analysis (CHH19F3N4 0 2) C ' Η ' N° Example 9 9 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -82 - I----------- Loading -------- Order --------- (Please read the note on the back and fill out this page) 1291958 A7 _B7_ V. Description of invention (8〇) 2 —( 2 —Methyl sulfide Phenoxy group) ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, maleate (please read the back note first and then fill out this page) Step 1: 2 —( 2 -Methylthiophenoxy)ethanol* The title compound was prepared according to the procedure described in Example 9, Step 1. Yield 63%; mp 47 - 4 9 ° C. Elemental analysis (C9H12〇2S) C, H. * described in U.S. Patent No. 3,932,498. Step 2: 2 -( 2 -Methylthiophenoxy)ethyl 3 -( 1 -piperazinyl)-2-pyrazinyl ether, maleic acid salt yield 6 8%; 111 / 160 - 162° (:. Elemental analysis (CHH22N4O2S.C4H4O4-0 · 1 THF) C, hydrazine, hydrazine. Example 1 0 0 2 - (2-methylphenoxy)ethyl 3 - (1-piperazinyl) 2 — Pyrazinyl ether, maleate Step 1 : 2 — ( 2 —Methylphenoxy)ethanol * Preparation of the title compound by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs is based on Example 9 8 The process of step 1. The yield of 59% °HRMS m/z is 152.〇8 37 for 〇91112〇2(1^)+, and the experimental enthalpy is 152.0 84〇. * described in Tetrahedron 1 996, 52, 1 77- 1 84. This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -83- 1291958 A7 _B7_ V. Invention description (81) Step 2 : 2 —( 2 -Methylphenoxy Ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, maleic acid salt yield 33%; mpl51 - 152 ° C. Elemental analysis (CHHssNdOs-CdHdOrO · 5 Η 2 0 ) C, Η, Ν. Example 1 0 1 2 — (2 5-Dimethylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether Step 1: 2 - (2,5-Dimethylphenoxy)ethanol* Preparation of the title compound According to the process described in Example 9 Step 1. The yield is 60%; mp45 - 48 C. Alizarin analysis (Cl〇Hl4〇2) C 'Η. * described in J. Chem. Soc. 1914, 2117- 2139. Step 2: 2-(2,5-Dimethylphenoxy)ethyl 3 -(1 -piperazinyl)-2-pyrazinyl ether oil; Yield 6 5 %. Elemental analysis i 8 Η 2 4 N 4〇2 ) C, Η, Ν. Example 1〇2 2 — (2-fluorophenoxy)ethyl 3 —(1-piperazinyl)-2-pyrazinyl ether, cis Butadiene salt step 1 ·· 2 —( 2 —Fluorophenoxy)ethanol* This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill in the form) This page is loaded with the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed -84- Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumer Cooperatives, Printing 1291958 A7 _B7_ V. Description of Invention (82) Preparation of the title compound is described in Example 9 8 Step 1 Process . Oily; yield 71%. MS m/zl 56.2 (M)+, 値 1 5 6 · 1 6 ( Μ ) +. * described in J. Indian Chem. Soc. 1 962, 39, 5-8. Step 2 ··· 2 —(2-Fluorophenoxy)ethyl 3 —(1-piperazinyl)-2-pyridyl ether, maleic acid salt Yield 46%; mp 71 - 173 ° C.

Elemental analysis (C16H19FN4〇2*C4H4〇4) C.,Η,N Example 1 0 3 2 —(2-Cyanophenoxy)ethyl 3 —(1-piperazinyl)-2-pyrazinyl ether , Maleate Step 1 : 2 - ( 2 -Cyanophenoxy)ethanol + The title compound was prepared according to the procedure described in Example 9, Step 1. Oily; yield 26%. MS m/zl63.2(M)+, 値 1 6 3 · 1 8 ( Μ ) +. * described in J. Chem. Soc. 1914, 2117-2139. Step 2: 2-(2-cyanophenoxy)ethyl 3-(1-oxazinyl)-2-pyridyl ether, maleic acid salt yield 40%; mp 1 6 5 — 1 6 6 ° C. Elemental analysis (CHHHNsOa-CdHdOd) C, Η, N. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I-----------Install--------Set--------- (Please read the precautions on the back and fill out this page) -85- 1291958 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7_ V. Invention Description (83) Example 1〇4 2 —[ (1,1 &gt; Phenyl)-2-yloxy]ethyl 3 - (1 piperazinyl)-2-pyrazinyl ether Step 1: 2 -[(1,1 'biphenyl)-2-yloxy] The preparation of the ethanol * title compound was carried out according to the procedure described in Example 9, Step 1. Yield 52%; mp 71 - 75 ° C. Elemental analysis (C14H14〇2) C, H. * described in J. Med. Chem. 1 987, 30, 939-943. Step 2: 2 -[( 1,1 /biphenyl)-2-yloxy]ethyl 3 -( 1 -piperazinyl)-2-pyrazinyl ether yield 53%; mpl〇l-1 〇 3 ° C. Elemental analysis (C22H24N4〇2) C, Η, N. Example 1 〇5 4 -(phenoxy)butyl 3 -( 1 -oxazinyl)- 2 -pyridazinyl ether, dihydrochloride salt Yield 49%; mp 29 - 131 °C. Elemental analysis (C18H24N4〇2*2HC1) C, H, N. * Preparation of starting material 4 - phenoxybutanol is described in 〇. rg. Chem. 1965, 30, 2441-2447. Example 1〇6 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I----------Install-------Book------- -- (Please read the notes on the back and fill out this page) -86- 1291958 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Inventions (84) 4 I (benzofuran-2-ylmethoxy) Base 3 - (1 - piperazinyl) pyrazine, hydrochloride * yield 39%; mpl 6 〇 -161 ° C. Elemental analysis (C17H18N4〇2*HC 1 ) C, ’ 'N° * Starting material 2,3-dihydrobenzofuran-2-ylmethanol was obtained from benzofuran-2-aldehyde reduced with sodium borohydride. Example 1 0 7 2 -(2 '3-dichlorobenzopyrano-2-ylmethoxy)-3-(1-piperazinyl)pyridinium, dihydrochloride salt yield 33%; mpl72-174 . (:. Elemental analysis (C17H2QN4〇2*2HC 1 ) C, Η, Ν. * Starting material 2,3-dihydrobenzofuran-2-yl-based methanol via benzofuran-2-aldehyde to sodium borohydride The reduction is followed by catalytic hydrogenation. Example 1〇8 2 —(1-piperidinyl)-3-(tetrahydro-2-pyranylmethoxy)pyrazine, hydrochloride salt yield 65%; mpl30 — 13 6 ° C. Elemental analysis (〇13Η2〇Ν4〇2·Η(:1·Η2〇)c,η,n ο Example 1 0 9 2 -( 1 piperazinyl)-3 -[ 3 — ( 2 —pyridyl)propoxy This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I-----------装-------订---- ----- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 _B7_ V. Description of Invention (85) 〕 Pyrazine, maleate yield 51%; mpl47 - 148 ° C. Elemental analysis (〇16Η21Ν5〇·1 · 〇5 C 4 Η 4 0 4 ) C , Η , Ν. Example 1 1 Ο 2 -( 1 -piperazinyl)-3 - 3-(3-pyridyl)propoxypyrazine, maleate 43%; mpl28 — 130° C. Elemental analysis (C16H21N5〇*C4H4〇4) C , Η, N. Example 1 1 1 2 — ( 1 —piperazinyl)-3 —[ 3 —( 4 —pyridyl) Propoxy]pyrazine, maleic acid salt yield 41%; mp90 - 91 ° C. Elemental analysis (〇16Η21Ν5〇·〇4Η4〇4·0 · 7 Η 2 0 ) C , Η, N. Examples 1 1 2 2 —[3 -(6-methyl- 2 -pyridyl)propoxy]- 3 -( 1 -piperazinyl)pyrazine, yield of maleic acid salt 3 %; mpl 34 - 136 ° C. Elemental Analysis (ChHuNsO-CaHaQa) C , Η, N. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I---------- Pack-- -----Order--------- (Please read the notes on the back and fill out this page) -88- 1291958 A7 B7 V. Inventions (86) Example 1 1 3 (Please read first Precautions on the back side of this page) 2 —[ (E) - 3 -Phenyl-2-propanyloxy]- 3 - (1 - piperazinyl)pyrazine oil; Yield 3 9 %. Analysis (ChHuN^OO · 2 Η 2 0 ) C, Η, Ν. Example 1 1 4 2 —(3,4-dihydro-2Η-1,4-benzoxazine-2-ylmethoxy)-3-(1-piperazinyl)pyrazine, dihydrochloride Yield 22%; mpl 71 - 175 °C. Elemental analysis (ChHuNsOsIHCI) C, H, N. Example 1 1 5 2 —(4-methyl-3,4-dihydro- 2H-1,4-benzoxoxazine-2-ylmethoxy)-3-(1-piperazinyl)pyrazine , hydrochloride * yield 4 9 %; mp 1 1 9 t: (decomposed). Elemental analysis (C18H23N5〇2*1 · 3 3 H C 1 ) C, Η, Ν. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. * The starting material 3 ' 4 - monochloro - 2 - 1 , 4 - benzoxazine - 2 - base methanol is described in J. Heterocycl. Chem. 1 996, 33, 191-196. Example 1 1 6 2 —(2 ,3 -Dihydro-1,4-benzothiazepine-2-ylmethoxy)-3-(1-piperazinyl)pyrazine, fumaric acid Salt* This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) -89- 1291958 A7 B7 V. Description of invention (88) Chromatography on silica gel (using E t 0 A c as eluent) The title compound was obtained in the form of an oil of 1 g. (g.). The experimental experiment is 1 8 9 · Ο 7 8 9. Elemental analysis (C11H11NO2) C, Η, N. Step 2: 2-(5-Isoquinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, maleic acid salt Yield 55%, as free base. The free base was converted to maleic acid salt: m p 1 7 8 - 1 8 0 · 5 ° C; HRMS m/z The calculated 値 for CuHsiNsOs (Μ) + was 351 · 1695, and the experimental 値 was 351 · 1694. Elemental analysis (CHHsiNsOs.CdHdOd) C, Η, N. Example 1 1 9 2 —( 5 —Quinolinyloxy)ethyl 3 —( 1 —piperazinyl)-2-pyrazinyl ether, maleic acid anhydride Ministry of Commerce Intellectual Property Bureau employee consumption cooperative printing steps 1 : 2 -( 5 -Quinolinyloxy)ethanol The title compound was prepared according to the procedure described in Example 1 1 Step 1 starting from 5-hydroxyquinoline (〇·9 3 g, 6 · 4 0 mm ο 1 ) . Yield 1.19 g (91%); mpl〇9 — lilt:; HRMS m/z for ChHhNOs(M)+ is 189 · 0790, and experimental 値 is 189 · 0786. Element-91 - (Please read the notes on the back and fill out this page) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291958 A7 B7 V. Invention description (89) Analysis (C11H11N〇 2) C, H, N. Step 2: 2 -( 5 -quinolineoxy)ethyl 3 - ( 1 -piperazinyl) - 2 -pyrazinyl ether, maleic acid salt yield 6 1 %, in free base form. The free base is converted to maleate: mpl32 - 135 ° C; HRMS m/z is calculated for C19H21N5〇2(M)+ 値 351 · 1695, experimental 値 3 5 1 · 1 6 8 1. Elemental analysis (〇19Η21Ν5〇2·1 · 8 C 4 Η 4 0 4 ) G , Η , Ν. Example 1 2〇2 — ( 6 —Quinolinyloxy)ethyl 3 — ( 1 嗦 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Yield 78%; mp68 — 7〇°C. Elemental analysis (C ! χ Η i ! Ν 〇2 ) C,Η,N. Step 2 : 2 —( 6 —Quinolinyloxy)ethyl 3 —( 1 piperazinyl)-2-pyrazinyl Ether, maleic acid salt yield 33%; mpl67 - 169 ° C. Elemental analysis (C19H21N5〇2*C4H4〇4) C , Η, N. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back and fill out this page) Pack----Book--------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Co-operative printing A7 B7 V. Inventive Note (90) Example 1 2 1 2 - ( 7 -Quinolinyloxy)ethyl 3 - ( 1 -piperazinyl)-2-pyrazinyl ether, maleic acid Salt Step 1: 2 - (7-Quinolinyloxy)ethanol The title compound was prepared according to the procedure described in Example 9 Step 1. Yield 76%; mp 93 - 95 ° C. Elemental Analysis (ChHhNOs) C, Η , N. Step 2: 2 - (7-quinolinyloxy)ethyl 3 - (1 -monoindolyl) 2- 2 -pyridyl ether, maleic acid salt yield 39%; mpl56 - 158 °C. Elemental analysis (C19H21N5〇2*C4H4〇4) C, Η, N. Example 1 2 2 2 — ( 8 —Quinolinyloxy)ethyl 3 —( 1 —piperidinyl)-2-pyridinium Basics Step 1 : 2-(8-Quinolinyloxy)ethanol* The title compound was prepared according to the procedure described in Example 9, Step 1. Yield 48%; mp 82 - 84 ° C. Elemental analysis (ChHhNOs) C, Η, N. * described in Pharm. Chem. J. 1 994, 28, 934-936. Step 2: 2 —(8 —wowenyloxy)ethyl 3 —(1—嗦嗦基) 1-2pyrazinyl ether This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -----------Install-------Book--------- (Please read the notes on the back and fill out this page) 1291958 A7 B7_ V. Invention Description ( 91) Yield 62%; mp 98 - 10 ° ° C. (Please read the notes on the back and fill out this page.) Elemental Analysis (〇19Η21Ν5〇2·〇·〇 5 E t 0 A c ) C , Η, N. Example 1 2 3 2 -(benzofuran-7-yloxy)ethyl 3-(1-piperazinyl)-2-oxazinyl ether, maleate Step 1: 2 - (Benzene The title compound was prepared starting from 7-hydroxybenzofuran* according to the procedure described in Example 9, Step 1, and was isolated as a semisolid. The yield was 7 9%. * Its preparation is described in J. Med. Chem. 1 987, 30, 62-67. Step 2: 2 -(benzopyrano-7-yloxy)ethyl 3 -(1 -piperazinyl)-2-pyrazinyl ether, maleic acid salt yield 42%, free Base form. A portion of the free base is converted to maleate·· m p 1 7 7 — 1 7 9 t:; MS m/z 341 (M + H) dec. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing element analysis (Cl8H2〇N4〇3*C4H4〇4) C ’ H ’ Ν. Example 1 2 4 2 -(7-Nitro-2,3-dihydro-1,4-benzodioxan-2-ylmethoxy)-3-(1-piperazinyl)pyrazine Step 1 : 7 —Nitro—2-hydroxymethyl—2,3—Dihydro-1' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -94- 1291958 Ministry of Economic Affairs Intellectual Property Office Employees' Consumption Cooperatives Printed A7 B7 V. Inventive Note (92) 4 Monobenzodioxole trifluoroacetic anhydride (2〇mL, 149mmo 1) is added dropwise to 2-aminomethyl-2,3—one A solution of hydrogen-1,4-benzodioxane (6·64 g, 40 mmo) and ΝΗ4Ν〇3 (84·8 g, 6〇mm〇1) in CH2C I2 (3〇〇mL). The reaction mixture was stirred at room temperature for 4 hr then concentrated under reduced pressure. The residue was chromatographed on silica gel (using E t 0 A c / isohexane (1:3 to 2:3) as the eluent) to obtain a small portion (〇·3 g, 4%) of pure C7 nitrate. The title compound and 6.5 g of the C6- and nitro derivative of the C7 structural isomer. The structural isomer mixture was used in the first step of Example 1 2 5 without being separated. Step 2: 2 —(7-Nitro-2'3-dihydro-1,4-benzodioxan-2-ylmethoxy)-3-(1-piperazinyl)pyrazine Yield 43%; mpl 33 - 135 °C. The HRMS m/z for CuHhNsOs (M) + is calculated as 3 7 3 · 1 3 8 6 and the experimental enthalpy is 3 7 3 · 1 3 6 7 . Example 1 2 5 2 — (7 —Ethylamino-2,3-dihydro-1,4-benzodioxan-2-ylmethoxy)-3(1-piperazinyl)pyridinium Pyrazine Step 1: 7 - Amino-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxime This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I-----------Install--------Set-------- (Please read the notes on the back and fill out this page) 1291958 A7

6 — with 7 —nitro-2-hydroxymethyl-2,3—diqi—1′ 4—one and one oxygen (6·3g, 30mmo 1; obtained from the real five, invention description (93) ( Please read the notes on the back and fill out this page. Example 1 2 4 Step 1), Ammonium formate (2 · 8 g, 4 5 mm ο 1 ) and 10% Pd/C (〇.4g) on Me〇H ( The mixture in 2 〇 0 m L ) was stirred at room temperature for 3 hours. The reaction mixture was filtered through a plug of stopper. The plug was washed with a few portions of Me 〇 η, and the filtrate was concentrated under vacuum. 6 - and 7 - amino-substituted 1 2,3-di- 1 - 4 -benzodioxan derivatives were chromatographed on silica gel (using E t〇AC / isohexane (1:3 to 2: 3) was the eluent) to give 2,8 g (5 8 %) of the title product as an oil. Step 2: 7 -Acetylamino-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxanic anhydride (0 · 2 4 g, 2.4 mm ο 1 ) plus From the above step 1 compound (0 · 30g, 1 · 66mm 〇 1) and Et3N (〇 · 7g, 6 · 9mmo 1) in CH2C 12 (Ministry of Commerce, Intellectual Property Bureau employee consumption cooperative printed 30 m L) It is stirred in the mixture. The reaction was stirred at room temperature for 15 hours. More acetic anhydride (0 · 1 g, 1 · 0 m m ο 1 ) was added, and the resulting mixture was stirred at room temperature for another 5 hours. The residue was purified by chromatography on EtOAc (EtOAc EtOAc (EtOAc) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -96- 1291958 A7 B7_ V. Invention description (94) Step 3: 2 — (7 —Acetylamine-2,3—2 Hydrogen-1,4-benzodioxan-2-ylmethoxy)-3-(1-piperazinyl)pyrazine oil; Yield 45%. H R M S m / ζ for C 1 9 Η 2 3 Ν 5 Ο 4 (Μ) + is calculated as 385 · 175 〇, and the experimental 3 is 3 8 5 . 1 7 4 1. Example 1 2 6 2 —[ (2S) — 2,3 -Dihydro-1,4-benzodioxan-2-ylmethoxy]-3-(1-piperazinyl)pyridinium salt Acid salt * m ρ 1 6 0 °C (decomposed). Elemental analysis (Cl7H2〇N4〇3*HC 1 ) C ′ Η ’ N. *Starting material (s) - 2 -Hydroxymethyl-2,3 -dihydro-1' 4 -benzodioxan is described in Tetrahedron Lett. 1 988,29, 3671-3674 ° Example 1 2 7 2 —[ (2R) — 2,3—Dihydro-1,4-benzodioxan-2-ylmethoxy]-3-(1-piperidinyl)pyrazine' hydrochloride* m ρ 1 6 5 °C (decomposition). Elemental analysis (Ci7H2〇N4〇3*HC 1 ) C ′ Η ’ N. * The starting material (R) - 2 - hydroxymethyl-2,3 -dihydro-1 1 '4-benzodioxan is described in Tetrahedron Lett. 1 9 8 8, 29, 3671-3674. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) ϋ ϋ 1 1 I ai ϋ tri------- Ministry of Economics Property Bureau Staff Consumer Cooperative Printed -97- 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (95) Example 1 2 8 2 —( 3 —pyridoxy)ethyl 3 — ( 1-Piperazinyl)-2-pyrazinyl ether, hydrochloride Step 1: 2 - (3 - pyridyloxy)ethanol 3 - via pyridyl (2 · 〇〇g, 2lmmo 1), 2 - chloro A mixture of ethanol (1·69 g, 21 mmo 1) and k2c〇3 (8·7g '63rnm〇1) in DMF (10 mL) was stirred at 130 ° C for 3 hours. After cooling, the black mixture was filtered through a short bed of alumina using acetone as an eluent to give a brown oil which was partitioned between water (3 0 πι) and C Η 2 C 1 2 ( 4 〇 m L ). The aqueous phase was extracted with C Η 2 C 1 2 (3 X 4 0 m L) and the combined organic extracts were dried with MgSO 4 and filtered. The filtrate was concentrated to give the title compound m. Elemental analysis (C7H9N〇2*0 · 2H2〇) c, H, N. Step 2: 2 -( 3 -pyridyloxy)ethyl 3 -( 1 -piperazinyl)-2-pyrazinyl ether, hydrochloride Yield 41%; mp 1 7 0 - 1 75 ° C. Elemental analysis (C15H19N5〇2*2HC 1·2Η2〇) C, Η, Ν. Example 1 2 9 2 —( 4 —pyridyloxy)ethyl 3 —( 1 —piperazinyl)- 2 -pyridyl I--------I----- ------- (Please read the notes on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -98- 1291958 A7 B7___ V. Description of invention ( 96) Pyrazinyl ether, hydrochloride Step 1 : 2 -( 4 -pyridyloxy)ethanol * The title compound was prepared according to the procedure described in Example 1 28 Step 1. Yield 19%; mpll9 - 121 °C. Elemental analysis (c 7 Η 9 N〇2 ) C, Η, N. * described in J. Chem. Soc., Perkin Trans 2 1987, 1867-1870. Step 2: 2 -( 4 -pyridyloxy)ethyl 3 -( 1 -piperazinyl)-2-pyrazinyl ether, hydrochloride Yield 5 8 %; m p 1 70 ° C (decomposition). Elemental analysis (Ci5Hi9N5〇2*2HC 1 · 2 Η 2 0 ) C Η Η , Ν. Example 1 3 0 2 - (6-methyl-3 - d-pyridyloxy)ethyl 3 - (1 -piperazyl)- 2-pyrazinyl ether, hydrochloride Step 1 : 2 - (6 The preparation of the title compound of methyl 3-pyridyloxy)ethanol was carried out according to the procedure described in Step 1 of Example 98. Yield 25%; mp49 - 5 1 °C. Elemental analysis (C8HHN0 2) C, Η ’ N. Step 2: 2-(6-methyl-3-pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, hydrochloride salt yield 5〇%; 1^_0 157° 〇 (decomposed). (Please read the notes on the back and fill out this page) · I 丨! ! Book! _ ! - . Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed on this paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -99 - 1291958 A7 B7 V. Description of invention (97) Elemental analysis (( :16Η21Ν5〇2·2 · 3 HC 1 ·〇.2Et2〇)C,H,N. Example 1 3 1 2 —( 2 —Methyl- 3 -pyridyloxy)ethyl 3 -( 1 -piperazinyl - 2 - pyrazinyl ether, hydrochloride Step 1: 2 - (2-methyl-3-pyridinyloxy)ethanol The title compound was prepared according to the procedure described in Example 1 28 Step 1. Yield 36% ;mp75 — 80°C. Elemental Analysis (C8HHN0 2) C,Η,N. Step 2: 2 — (2 —Methyl—3 —N-butyloxy”ethyl 3 —(1-piperazinyl) 2-pyrazinyl ether, hydrochloride yield 36%; mp 5 〇 ° C (decomposition) Elemental analysis (Cl6H2lN5〇2*3 · 1 HC 1 · 〇.2Et2〇) C, H, N. Example Γ 3 2 2 — ( 5 —Chloro-3-pyridyloxy)ethyl 3 —( 1 —piperazinyl)-2-pyridyl ether, hydrochloride Step 1 : 2 —( 5 —Chloro-3-pyridinium Preparation of alkoxy)ethanol title compound According to the procedure described in Example 1 2 8 Step 1. Yield 25%; mp38 — 4〇°C°HRMS m/z For C7H8C 1N〇2 (Μ) + calculation 値 is 173.0 2 2 4 4 (please Read the notes on the back and fill out this page) _·Binding-------- Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) -100- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 _B7__ V. Invention Description (98), the experiment is 1 7 3 · 0 2 4 4. Step 2: 2 —(5 — Chlorine 3 – 吼卩Alkoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, hydrochloride salt yield 65%; mpl 〇 4 ° C (decomposition) Elemental analysis (C15H18C 1 N 5 0 2 · 1 · 9HC 1·〇.3Et2〇)C,H,N. Example 1 3 3 2 —( 3 —Thienyloxy)ethyl 3 —( 1 -piperazinyl)-2-pyrazine ether, hydrochloric acid Salt # yield 39%; mp75 - 85 ° C. Elemental analysis (CHHHNdOsSj · 1HC 1 ) C , Η, Ν. * Preparation of starting material 2 — ( 3 -thienyloxy)ethanol described in Synth. Met. 1 9 8 8,26,1 5 3 - 1 68. Example 1 3 4 2 —(2 ,3 -Dihydro-2,2-dimethyl-7-benzofuranyloxy)ethyl 3 -( 1 -piperazinyl)-2-pyrazinyl ether, cis Butenedioic acid 2,3-dihydro-2,2-dimethyl-7-benzofuranol (〇.82g, 5mm〇l), ethylene oxide (0.22g, 5 mm ο 1 ), Triethylamine (3 drops) and dioxane (4 m L) are applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) on this paper scale. I----------- ------Set--------- (Please read the notes on the back and fill out this page) -101 - 1291958 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives Α7 Β7 V. Inventions ( 99) Heating at 1 0 0 °C for 3 days. The resulting solution was cooled in an ice bath and successively added K〇-t-Bu (〇·56g, 5mm〇1) and 2-chloro-3-(1-oxazinyl)pyrazine (〇· 7 9 g, 4 mm ο 1 ; From Example 9 7 Step 1). The mixture was stirred at room temperature for 30 minutes, stirred at 100 ° C for 4 hours, cooled, diluted with C Η 2 C 1 2 and filtered. The filtrate was concentrated and purified by chromatography on silica gel (gradient: PhMe to PhMe/Me〇H/Et3N, 8:1:1) to obtain 146 g of a gray-brown viscous oil. Add maleic acid (〇.46忌, 4111111〇1) and cognac 6〇11 (1〇1111). The mixture was heated until a clear solution was formed. The resulting maleic acid salt of the title compound was crystallized to give a pale brown solid. Yield 1.40 g (7.2%); mpl56-157 t:. Elemental analysis (C2〇H26N4〇3*C4H4〇4) C , Η, N. Example 1 3 5 2 —(1 ' 3 -benzoxanthoquinone-4-yloxy)ethyl 3 -(1 -piperazinyl)-2-pyrazinyl ether, maleate Step 1 : 2 — ( 1,3 -benzoxazole-4-yloxy)ethanol Κ 2 C〇3 ( 2 5 4 mg, at room temperature

1.84 mmo 1) A stirred solution of 4-hydroxybenzoxazole* (248 mg, 1 · 84 mmo 1) in DMF (5 mL). The resulting mixture was stirred at 90 ° C for 15 minutes and ethylene carbonate (1 7 6 m g , 2 m m〇1 ) was added. The resulting mixture was stirred at 150 ° C and allowed to stand at room temperature. The mixture is water (2 m L ) and Me Ο Η This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) I---------- Pack! _!i 订-! __ί (Please read the note on the back and fill out this page) -102- 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 5, Invention Description (100) (2 m L ) Dilution, And concentrated. The residue is partitioned between water and C Η 2 C 1 2 . The aqueous layer was separated and extracted with C H 2 C 1 2 ( 2 X 1 0 m L ). The combined organic phases were decanted and rinsed with water and brine and dried with MgSO4. The filtrate was concentrated to give a brown oil product which crystallised slowly: yield 278 mg (84%); mp 47 - 49. Elemental analysis (C9H9N〇3) C, H, N. * The preparation thereof is described in Med. Chem. 1987, 30, 62-67. Step 2: 2 -( 1 ,3 -benzoxazole-4-yloxy)ethyl 3 -(1 -piperazinyl)-2-pyridinyl ether, maleate at room temperature K〇一t-Bu (146mg, 1 · 30 mmo 1 ) was added to 2 -( 1 ,3 -benzoxanthoin-4-yloxy)ethanol (223mg, 1 · 24mmo 1) in two B in a stirred solution in a hospital (5 m L ). After 1 5 minutes, 2-chloro-3-(1-piperazinyl)pyridinium (2 4 7 mg, 1 · 24 mm 〇1; obtained from Example 9 7 Step 1) was added in one portion followed by dioxane. (3 m L ). The resulting mixture was stirred at room temperature for 10 minutes, stirred at 100 Torr for 3 hrs, cooled and then diluted with C Η 2 C 1 2 and filtered through celite plastic. The filtrate was concentrated and purified by chromatography on EtOAc (t::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: The preparation of the maleic acid salt form is as described in Example 134: mpl9l - 193 〇C. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -103- I----------Install--------Set------- - (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1291958 A7 _B7_ V. Invention Description (101) Elemental Analysis (CHHHNsOs-CaHdOd) C, Η, Ν. Example 1 3 6 2 —(3,4-dihydro-2 Η-pyrido[3,2—b]-1,4-spiroazine-2-ylmethoxy)-3-(1-piperazinyl Pyridazine, maleate step 1 : 3 , 4 - 1 - hydrogen - 3 - fluorenyl - 2H - 吼 D and [3 ' 2 - b] - 1 , 4 - oxazine - 2 - carboxylic acid Ethyl ester added diethyl malonate (9 · 7 3 g, 5〇mm ◦ 1 ) to 3-hydroxy-2-aminopyridine (5 · 51g, 5〇mmo 1), triethyl at room temperature A stirred mixture of amine (6 · 9 7 mL, 5 〇 mm ο 1 ) and E t〇Η (1 〇〇m L ). The resulting mixture was heated under reflux for 17 hours and allowed to stand at room temperature. The precipitate formed was filtered off, washed with EtOAc, and dried to give a white solid product. Yield: 3.85 g (35%); mp. Elemental analysis (Cl〇Hl〇N2〇4) C ′ Η ’ N. Step 2: 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxan-2-yl-based methanol, 3,4-dihydro-3-keto group at 40 ° C - a solution of pyridyl[3,2-b]-1,4-oxazin-2-carboxylate (1. l〇g, 5mm〇1) in THF (5 mL) for 5 min Add to L i A 1 Η 4 ( 0 · 3 8 g, this paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------Package!丨—丨定! (Please first Read the notes on the back and fill out this page) -104- 1291958 A7 _____Β7_ V. Inventions (102) (Please read the notes on the back and fill out this page) 1 0 mm ο 1 ) with Ding HF ( 20 m L The mixture is stirred. The resulting mixture was stirred at 45 ° C for 30 minutes and at reflux for 4 hours. The mixture was allowed to stand at room temperature and L i A 1 Η 4 was decomposed with a 50% aqueous solution of N a 。 。. The mixture was filtered through celite plastic and the filtrate was concentrated. The residue (〇. 4 2 g) was extracted with C Η 2 C 1 2, and the extract was concentrated and purified by chromatography on silica gel (gradient: P h M e to P h M e / MeOH/EtsN, 8 : 1 : 1), a white solid product was obtained: yield 〇.llg (13%); mp. Alizarin analysis (C8H iqN2〇2) C'H'N. Step 3: 2-(3,4-dihydro-2H-pyrido[3'2-b]-1,4-oxan-2-ylmethoxy)-3-(1-piperazinyl)pyridinium The preparation of the title compound of the azine, maleate is similar to the procedure of Example 3 3 5 Step 2 from 3,4 - dihydro - 2H - D than D [3, 2 - b] - 1 ' 4 a Starting with the pyrazin-2-yl-methanol, the product was isolated as a brown solid. Yield 4 7 %; mpl 54 - 158 〇 C. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing element analysis (〇16Η2〇Ν6〇2·1 · 2 C 4 Η 4 0 4 ) C Η Η , Ν. Example 1 3 7 2 —[ 2 —( 3 —pyridyloxy)ethoxy]- 3 —( 1 -azazine)quinoxaline, maleate Step 1: 2 -Chloro-3-( 1 - piperazinyl) quinoxaline, cis-butene-105- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V , invention description (103) acid salt # 2,3 - dichlorooxalin (3 · 0 5 g, 1 5 · 3 2 mm ο 1 ), piperazine (2 · 6 4 g, 30 · 64mmol) and K2C A mixture of 〇3 (2 · 12 g , 1 5 · 3 mmo 1 ) in acetonitrile (20 mL) was stirred at 55 ° C for 1 hour. The reaction mixture was diluted with EtOAc (3 mL), filtered and concentrated to give a pale yellow solid which was purified on silica gel eluting with CHC 1 3 /M 〇Η (9:1) as a solid. Re-dissolved in CHC 1 3 and a short (4 cm) plug placed in alumina. The title compound was obtained as a free-yellow solid. Part of the free base is converted to maleate and recrystallized from Me Ο Η /ether: mpl65 - 166 ° C; HRMS m / z For C12H13C 1 Ν 4 (Μ) + Calculated 248 248. 0 8 2 9 The experimental enthalpy is 2 4 8 · 〇 8 3 0. Elemental analysis (C12H13C 1N4*C4H4 〇 4) C, Η, N. * The corresponding hydrochloride salt is described in Med. Chem. 1981, 24, 93-101. 2 : 2 —[2 —(3-pyridyloxy)ethoxy]- 3 —( 1 -piperazinyl)quinoxaline, maleate K〇-t-Bu (〇· 57g, 5 Lmmo 1) Stirring to 2-(3-pyridyloxy)ethanol (〇·97g, 7·0 mm 0 1 ; obtained from Example 1 2 8 Step 1) in dioxane (20 m L ) Solution, the resulting mixture was stirred at room temperature for 3 minutes. Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I---- II--- Pack-------Book|丨_! (Please read the notes on the back and fill in This page) -106- 1291958 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Print A7 B7 V. Inventive Note (104) Clock. Then add the free base from step 1 above (〇· 9 7g, 3. 8 9 mm ο 1), the resulting mixture is stirred at 80 ° C for 4 hours. The reaction mixture is diluted with C Η 2 C 1 2, filtered and concentrated to give a pale yellow oil, which is purified by chromatography on silica gel (using CHC 1 3 / M e〇Η ( 9 ·· 1 ) is the eluent). The obtained oil is redissolved in CHC 1 3 and placed on a short (4 cm) plug of alumina. It is eluted with CHC 13 to obtain 1 · 20 g (88%) light grayish brown as the title compound as free base. The free base is converted to the maleate and recrystallized from Me 〇Η / diethyl ether: m ρ 1 3 7 - 1 3 9 ° C ; The HRMS m / z is 351 · 1695 for C i 9 Η 2 ! N 5〇2 ( Μ ) + and the experimental 値 is 351.170 1 . Elemental analysis ((: 19Η21Ν5〇2·1 · 3 C 4 Η 4 0 4 ) C , Η , Ν ο Example 1 3 8 2 —[ 2 —( 3 —pyridyloxy)ethoxy]-3 — ( 1 - piperazinyl)-6,7-difluoroquinoxaline, maleate step 1 ·· 2 -Chloro-3-(1-piperazinyl)-6'-7-fluorofluoroquinoline Piperazine (0 · 8 6 g, 10 mm ο 1 ) was added to 6,7-difluoro-2,3-dichloroquinoxaline* (1 · 18 g, 5 mm ο 1 ) at room temperature a stirred suspension of t 〇Η (5 0 mm ο 1 ). The resulting mixture was heated at 75 ° C for 17 hours, allowed to cool until cooled and filtered to give a pale yellow solid: yield 〇······· g ( 2 8 % This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -107- I-----1----#装--------Set- ------· (Please read the notes on the back and fill out this page) 1291958 A7 _B7__ V. Invention description (105) ); mp294 — 297°C (decomposition) MS m/z285/287 (M+ l)+ (Please read the notes on the back and fill out this page) * described in J. Med. Chem. 1 990, 33, 2240-2254. Step 2: 2 — [2 (3-pyridyloxy)ethoxy]-3-(1-piperazinyl)-6,7-difluoroquinoxaline, maleate according to the procedure described in Example 1 3 7 Step 2 from 2 -Chloro-3-(1-piperazinyl)-6,7-difluoroquinoxaline (230 mg, 0 · 8 mmo 1 ) and 2 - (3 - 11 -stoxy)ethanol (1 4 〇mg ' 1 mm ο 1 ; The title compound was obtained from Example 1 2 8 Step 1) Yield 9 5 mg (3 1 %). The maleate salt was obtained as described in Example 134: mp 1 1 〇1 1 5 °C.

Elemental analysis (Cl9Hl9F2N5〇2*l · 5 C4H4O4) C , Η, N. Example 1 3 9 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative printed 2 —[ 2 —( 3 —pyridyloxy)ethoxy]—3 —( 1 piperazinyl)-6,7-dichloroquinoxaline, Maleate Step 1: 3 - (1 - piperazinyl)-2,6,7-trichloroquinoxaline Piperazine at room temperature (〇· 6 9 g , 8 · 0 6 mm ο 1 Add to a stirred suspension of 2,3,6,7-tetrachloro-quinoxaline (1 · 08 g, 4 · 〇 3 mm 〇 1) in Et 〇 H (125 mL). The resulting mixture was stirred at room temperature for 8 hours 'filtered' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -108- 1291958 A7 __B7 _ V. Invention description (106) Made of light yellow Solid: Yield 0.88 g (69%); mp &gt; 3 ° ° C ° MS m / Z 3l 6 / 318 (M) +. (Please read the precautions on the back and fill out this page) Step 2: 2 —[ 2 —( 3 —Pyridinyloxy)ethoxy]- 3 _( 1 -piperazinyl)~6 ,7-dichloroquine a porphyrin, maleate salt according to the procedure described in Example 1 3 7 Step 2 from 3-(1-piperazinyl)-2,6,7-trichloro D-quinoxaline (27 mg, immo 1 ) and 2-(3-Pyridinyloxy)ethanol (i7 〇 mg, 1 · 2 mm ο 1 ; The yield was 1 3 5 m g (32%). The maleate salt was prepared as described in Example 134: m p 1 8 7 - 1 8 9 °C. Elemental analysis (C19H19C 12Ν5〇2·〇4Η4〇4) C , Η , Ν . Example 1 4 0 2 —[ 2 —( 3 —pyridyloxy)ethoxy]-3 —( 1 —piperazinyl)thieno[3′ 4 —b]pyrazine, maleate anhydride Intellectual Property Bureau Staff Consumer Cooperative Print Step 1: 2,3 - Dichlorothieno[3,4-b]11-pyrazine 1,4-dihydro-thieno[3,4-b]pyrazine-2' 3-diketone* (1 · 26 g , 7 · 5 mmo 1) and P〇C13 (6 · 9 m L, 7 5 mm 〇 1 ) were stirred under reflux for 2 1 hour. The resulting dark mixture was poured into ice and extracted with C Η 2 C 1 2 ( 4 X 3 〇 m L ). The mixed yellow extract was decanted and concentrated to give a 〇·1 1 g (7%) product which was used in the next step without purification. The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X). 297 mm) -109- 1291958 A7 B7 V. Description of invention (107) * described in Bull. Soc. Chim. Fr. 1 9 8 3, 1 59- 1 63. (Please read the notes on the back and then fill out this page) Step 2: 2 -Chloro-3-(1 - piperazinyl)thieno[3,4 - b]pyrazine Piperazine at room temperature (9 2 Mg,1 · 〇7 mm 〇1 ) added to 2 ' 3 -dichlorothieno[3 ,4 - b ]pyrazine (1 1〇mg , 0 · 54mmo 1 ) in E t〇H (5mL) The suspension was stirred. The resulting mixture was stirred at reflux for 16 hours and filtered. The solid obtained was purified by chromatography on silica gel (gradient: &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& The obtained product was used in the next step without purification. Step 3: 2 - [ 2 - (3 - fluorene than n-oxyl) ethoxy] -3 - (1 -piperazinyl) thieno[3,4-b]pyrazine, maleate Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives, according to the procedure described in Example 1 3 7 Step 2, from 2-chloro-3-(1-piperazinyl)-thieno[3,4-b]pyrazine (40 mg) 〇·1 6 mm ο 1 ; The title compound was obtained from the above step 2) and 2-(3-pyridyloxy)ethanol (44 mg, 0·31 mmo1; obtained from Example 1 2 8 Step 1). The yield was 3 8 m g (6 6 %). The maleate salt was prepared as described in Example 134: mpl 52 - 1560C. Elemental analysis (Cl7Hl9N5〇2S*l · 8C4H4〇4) C ' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -110- 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Description of the invention (108) Η, N. Example 1 4 1 2 —[ 2 —( 5 —Pyrimidinyloxy)ethoxy]-3 —( 1 -piperazinyl)quinoxaline Step 1 : 2 —( 5 —pyryloxy)ethanol t—Bu (7 · 7g , 68 · 6mm〇1 ) Add to the stirring glycol (1〇· 45g 'l68mm〇1). The resulting mixture was gently heated to remove all K 0 -t - B u . 5-Bromopyridine (8 · 4 5 g , 5 3 · 1 m m〇1) was added to the resulting pale brown mixture. After stirring at 1 30 ° C for 8 hours, C Η 2 C 1 2 (50 m L ) was added to the light brown mixture to form a second layer. The CH2C 1 2 (5 OmL) layer was taken and the other layer was extracted with additional C H 2 C 1 2 . The mixed C Η 2 C 1 2 was concentrated under vacuum, and the residue was purified by chromatography on silica gel (using CHC 1 3 /M e 〇Η ( 9 : 1 ) as eluent) to obtain 0 · 4 5 g ( 6%) of the title compound as an oil which is sufficiently pure to be used in the next step. H R M S m / ζ for C6H8N2〇2 (Μ) + is calculated as ΐ4〇 · 0 586 , and the experimental 1 is 1 4 0 · 0 5 8 9 . Step 2: 2-[2-(5-pyrimidinyloxy)ethoxy]-3 mono(1-piperazinyl)quinoxaline according to the procedure described in Example 1 3 7 Step 2 from 2-chloro-3-( 1 — piperazinyl) quinoxaline (0 · 6 6 g , 2 · 6 5 mm 〇 1 ; the paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public ^ 7 ------ ------Install-------Book-------- (Please read the notes on the back and fill out this page) -111 - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 _B7_ V. Description of the invention (1G9) The title compound was prepared from Example 1 3 7 Step 1) and 2-(5-pyrimidinyloxy)ethanol ( 〇.45 g, 3 · 2 〇mmo 1). Yield 0. 5 5 g ( 5 9 % ) ; mpll5 — 117 ° C ; HRMS m / z for C18H2 〇 N6 〇 2 (Μ) + calculation 値 is 3 5 2 · 1 6 4 8, the experimental 値 is 3 5 2 · 1 6 5 4 Elemental analysis (C18H2〇N6〇2) C, H, N. Example 1 4 2 2 — (3 , 4 — Dihydro — 2H — 1 ' 4 — Benzoindole 2 -ylmethoxy) 3-(1-piperazinyl)quinoxaline, 〇·5 fumarate according to the procedure described in Example 1 3 7 Step 2 from 2-chloro- 3 -( 1 The title compound was prepared from the hydrazinyl) quinoxaline and 3,4-dihydro-2 hydrazine-1,4-benzoxazine-2-yl-methanol*. Yield 41%; mpl 25 - 134 ° C (decomposition) Elemental analysis (〇2ΐΗ23Ν4〇4·〇· 5 〇4Η4〇4*2Η2〇)C,Η,Ν. *See example 1 1 5 Example 1 4 3 2 — (3 ,4 —Dihydro-2Η—color storage —2 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — , 4 - Dihydrogen - 2 Η - chromene - 2 - based I--I-- 丨! Install i - ·! 丨丨 丨 丨 丨丨 丨丨 丨丨 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -112- 1291958 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 _ V. Description of Invention (111) Preparation of Hydrochloride Title Compound According to the procedure described in Example 2, Step 2, the process is from 1-(3-chloro-2-y-Q-exposed to the base)- 4-methylpiperazine and 2-aminomethyl-2,3-**-amino-1. 4 Benzene ^ Oxygen begins to bitter. Yield 87%; mpl60 - 167. . . Elemental analysis (C18H22N4〇3*2HC 1 ) Η, N ; C : Calculate 値 5 2 · 0 6, experiment 値 5 2 · 6. Example 1 4 5 2 —(phenoxy)ethyl-3-(4-methyl-l-piperazinyl)-2-pyrazinyl ether, hydrochloride The title compound was prepared according to Example 9 Step 2 The process starts from 1 (3-chloro-2-indolyl)-4-methylpiperidin and 2-phenoxyethanol, and the yield is 79%; m ρ 1 7 2 - 1 7 4 °C . Elemental analysis (ChHhNaO^HC 1 ) C , Η, N. Example 1 4 6 2 —( 2 -Phenoxy)ethyl 3 —( 2 —methyl- 1 -piperazinyl)-2-pyrazinyl ether, maleate Step 1 : 3 —Chlorol — 2 — ( 4 —benzyl- 2 -methyl- 1 -piperazinyl)pyrazine 2,3-dichloropyrazine (0 · 332g, 2 . 2 3 mm ο 1 ), 1 - fluorenyl 1 - Mouthazine* (〇· 423 g , 2 · 23mm〇1) and K2C〇3 (〇· 339g, I------Packed----I--book----- (please read first) Note on the back side of this page) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 114- 1291958 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (112) 2 . 4 5 mm ο 1 ) The mixture in acetonitrile (2 · 5 m L ) was stirred at 1 15 ° C in a sealed tube for 17 hours. The reaction mixture was diluted with ethyl ether and filtered and concentrated. The brown oily residue was purified by chromatography on silica gel eluting with hexane / EtOAc / EtOAc (7:3) as eluent, to give the title product of 0. 19 g (28%) of viscous oil. It is pure enough to be used in the next step. * described in J. Med. Chem. 1 996, 39, 2962-2970. Step 2. 2 - (2-Phenoxy)ethyl 3 - ( 4 - fluorenyl 2 - methyl - 1 - piperazinyl) - 2 - 1:1 ratio of pyrazinyl ether at room temperature One t-Bu (0 · 087g, 〇·77mmo 1 ) was added to the stirred solution of 2-phenoxyethanol (〇·164g, 1 · 19mmo 1) in the second hospital (5mL). Stir at 90 ° C for 5 minutes, add 3-chloro-2-(4-benzyl-2-methyl-1 -piperazinyl)pyrazine (0 · 18g, 0 · 59mmo 1) to dioxane Solution in (3 mL). The resulting mixture was stirred at room temperature for 10 minutes and at 85 ° C for 2 hours. The reaction mixture was diluted with ether, filtered and concentrated. The residual gray-brown oil was purified by chromatography on silica gel eluting with hexane / EtOAc (7:3) to afford the title product of 0.02 g (93%). H R M S m / ζ for C24H28N4〇2 (Μ) + is calculated as 4〇4.2212, and experimental 値 is 4〇4 · 2 2 3 2. (Please read the notes on the back and fill out this page.) 装•Μ·· am This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -115- 1291958 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printing A7 B7 V. INSTRUCTIONS (113) Step 3: 2 —(2 —Phenoxy)ethyl 3 —(2-methyl-1-monopiperazinyl)-2-pyrazinyl ether, cis-butene A solution of the diacid formate (0 · 18 g, 2 · 85 mm 〇 1 ) was added to the product from the above step 2 (〇 22 g, 0 · 54 mmol 1) in ethanol (5 m L). The resulting mixture was washed with nitrogen and added with 5 % Pd / C (0 · 15 g). The flask was sealed and the mixture was stirred at 90 ° C for 2.5 hours. The reaction mixture was filtered through celite and concentrated. The residue was chromatographed on silica gel (using CHC 1 3 / M e 〇Η (1 〇: 1 ) as the eluent) to obtain 0 · 1 2 g (72%) as an oily free base. Title compound. The free base is converted to maleate and recrystallized from Me 〇Η /ether: mpl 〇 2 - 1 〇 3 ° C; HRMS m / z For CHH22N4 0 2 (M) + 値 is 3 1 4 .1 743, the experimental experiment is 3 1 4 . 1 7 5 4. Elemental analysis C, Η, Ν. EXAMPLE 1 4 7 (2R)-Methyl-1—[3-(2-phenoxyethoxy)-2-pyrazinyl]piperazine, hydrochloride Step 1 : 4 —T-butoxycarbonyl- (2 R )-methylpiperazine was added glacial acetic acid (6 · 3 g , 1 〇 5 mm ο 1 ) and dibutyl succinate (23 · llg, l 〇 6mmo 1 ) at 0 °C. To (2R)-methylpiperazine (1 0 · 3 g, 103mmo 1) stirred in Me〇H (200mL) This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) I-----------Install-------Book-------- (Please read the notes on the back and fill out this page) 116 1291958 A7 B7 V. Invention Description (114) The solution was stirred for 1 hour. The reaction mixture was warmed to room temperature and stirred for 15 hours. An excess of triethylamine (20 m L, 1 40 m ο 1 ) was added and the mixture was concentrated under reduced pressure. The residue was suspended in C H C 1 3 and filtered through a fritted glass filter. The filtrate was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Naturally crystallized. The product was used directly in the next step without further testing of its properties. Step 2: 3-Chloro-2-(4-tetrabutoxycarbonyl-(2R)-methyl-l-piperazinyl]pyrazine 2,3-dichloropyrazine (22 · Og, 148mmo 1), 4 a mixture of tert-butoxycarbonyl-(2R)-methylpiperazine (2 1 g, l〇5mmol) and K2C〇3 (30.4g, 2 2 0 mm〇1) in DMF at 95 ° C Heat for 15 hours. The black reaction mixture was filtered through a bed of silica gel and the filtrate was concentrated. The residue was chromatographed on EtOAc (EtOAc: EtOAc (EtOAc) H R M S m / ζ for C 1 4 Η 2 1 C 1 N 4 0 2 ( M ) + The calculated 値 is 312 · 1353, and the experimental 値 is 312. 1358. Step 3: (2R) -Methyl-1 -[3-(2-phenoxyethoxy)-2-pyridyl]piperazine, hydrochloride This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the note on the back and fill out this page) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumer Cooperatives -117- 1291958 A 7 丨Β7 V. Inventions (115) K〇-t One Βυ (Ο · 52g, 4· 66mmo 1) Add to 2-phenoxyethanol (〇·42g, 3 · Ommo 1) at (please read the note on the back and fill out this page) Dioxane (1 5 The resulting mixture in m L ) was stirred at room temperature for 15 hours. 4-tert-butoxycarbonyl mono(2R)-methylpiperazine (0 · 73 g, 2 · 33 mmo 1 ; obtained from the above step 1) was added to the suspension, and the reaction was stirred at 85 ° C. 5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel eluting with CHC l3 /Me </ s>H/NH4 〇H (97:3:0:2) as eluent. The oil obtained was dissolved in CH 2 C 12 / T F A (1:1), and the mixture was stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure and the residual oil was partitioned from 1M NaHH/CHC. The organic phase was dried (M g S 0 4 ) and the solvent was evaporated. The oil obtained was purified by chromatography on silica gel (using CHC 1 3 /Me 〇H/NH 4 〇H (9 5 : 5 ··0.2) as an eluent) to give a free base. The title compound was obtained from the title compound: </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Printed by the Consumers’ Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

The calculation Ci of Ci7H22N4〇2(M)+ is 314. 1743, and the experimental 値 is 3 1 4 . 1 7 3 1. Elemental analysis (Cl7H22N4〇2*HCl) C, H, N. Example 1 4 8 - 1 5 2 was prepared according to the procedure described in Example .1. (2R)-methylpiperazine was replaced with (2S)-methylpiperazine in Examples 1 50 and 157. This paper scale applies to China National Standard (CNS) A4 specification (210X29*7 mm) * 118- A7 B7 1291958 V. Invention description (116) Example 1 4 8 (2R) - Methyl-1 1 {3 2 —(3 —pyridyloxy)B (please read the back of the note first and then fill out this page) oxy]-2-pyrazinyloxazine' hydrochloride The title compound was prepared from 2 — ( 3 — Pyridyloxy)ethanol (obtained from Example 1 2 8 Step 1) and 3-Chloro-2-iso[4-t-butoxycarbonyl-(2R)-methyl-l-piperazinyl]pyrazine (obtained from Example 1 4 7 Step 2) Start. The title compound was obtained as white crystals with a yield of 3 1 %; mp 1 8 0 - 1 8 3 ° C ^ HRMS m 〆z for . 〇 1611211 ^5〇2(^)+ is calculated as 315.1695, and the experimental is 3 1 5 · 1 6 8 9 ° Elemental analysis (〇ΐ6Η2ιΝ5〇2·1 · 33HC1) C, H, N. Example 1 4 9 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed (2R) - Methyl-1 1 (3 -[2 - (2 -Amino-8-quinolinyloxy)ethoxy]-2-pyridyl Pyrazinium oxazine, fumarate step 1 : 2 _( 2 -amino-8 quinolinyloxy)-ethanol 2 -amino-8 quinolinol (3 · 2 0 3 g, 2〇mm〇1), ethyl carbonate (1 · 76g ' 2〇mmo 1) and K〇-t-Bu (2 · 24g, 20mmo 1) in DMF (2〇mL) mixture at 9〇°c Stir for 15 hours. The mixture is poured into brine, extracted with E t〇A c, dried (M g S〇4 ), and concentrated under reduced pressure. The residue is used in the country of the country. Paper PCT 97 2 X - 10 2 9 1291958 A7 B7 V. INSTRUCTIONS (117) Purification by gel chromatography (using toluene / E t〇A c / M e〇Η ( 5 0 :5〇:2) Eluent), the title product of 1 · 134 g (28%) of solid was obtained. HRMS m/z was calculated for C 1 1 Η 1 2 N 2 0 2 (Μ) + 〇 2〇4· 0899 , experiment 値Is 2 0 4 ·〇9〇6. Step 2: (2R) —Methyl—1— {3—[2—(2—amine 8-8-quinolinyloxy)ethoxy]-2-pyrazinyl}piperazine, fumarate The title compound was prepared from 2-(2-amino-8-quinolinyloxy)ethanol And 3-chloro-2-(4-tetrabutoxycarbonyl-(2R)-methyl-piperidinyl]pyrazine (obtained from Example 1 4 7 Step 2). The free base obtained is its antibutene The acid salt precipitated to give the title compound as yellow, slightly wet, crystals: yield 5%; m ρ 1 6 0 - 1 6 3 ° C (decomposition); HRMS m / ζ for C2〇H24N6〇2 (Μ ) + The ten liters of the head is 38 0 .1 9 6 1' The experimental 値 is 3 8 〇 · 1 9 5 8. Example 1 5 〇(2 S )-Methyl-1—[3 — (2-phenoxy Ethyloxy)-2-pyrazinylpiperazine, hydrochloride yield 62%; mpl 62 - 163 ° C. Elemental analysis (Cl7H22N4〇2*HC 1 ) C ' Η 'N. This paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm) (Please read the note on the back and fill out this page) 1111111 11111111 ^^^1 . Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -120- 1291958 Ministry of Economic Affairs Intellectual Property Officer Consumer Cooperatives Printed A7 B7 V. INSTRUCTIONS (118) EXAMPLE 1 5 1 (2S)-Methyl-1—{3—[2 —(3—Pyridinyloxy)ethoxy]-2-pyrazinyl} Piperazine, hydrochloride yield 51%; mpl 70 - 172 °C. Elemental analysis (C i 6 Η 2 i N 5 〇 2 · 1 · 4 5 H C 1 ) c, H, N. Example 1 5 2 2 -[ 2 - ( 1 ,3 -benzoxyl)-ethoxymethyl]- 3 -( 2 -methyl- 1 -piperazinyl) quinine Phenanthine, hydrochloride step 1 : 4 - tert-butoxycarbonyl-2-methylpiperazine * The title compound was prepared according to the procedure described in Example 1 4 7 Step 2, except that using racemic 2-methylpiperazine Instead of (2R)-methylpiperazine. Yield 82% (free base). An analytical sample was prepared by converting it to the hydrochloride salt: m p 1 6 2 ° C (decomposed). Elemental analysis (Ci 〇 H2 〇 N2 〇 2 * HC 1·) C ′ Η ' N ° * is described in J. Med. Chem. 1 993, 36, 690-698. Step 2: 4-(3-Chloro-2-quinoxalinyl)-3-methyl-l-piperazinecarboxylic acid tert-butyl ester is obtained from the title product of Step 1 above (12 · 3g ' 61 · 4 mmo 1), 2,3-dichloroquine B oxaline (14 · 72.2 mmol) and K 2 C 〇 3 (13.8 g ' 1 〇 0 mm ο 1 ) in DMF (100 m L ) -----------AW- ^ · -------BOOK-------- (Please read the notes on the back and fill out this page) This paper size applies to China Standard (CNS) A4 specification (210 X 297 mm) -121 - 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (彳19) 8 5 ° c stirring for 15 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel (using petroleum ether / E t 〇A c ( 9 4 : 6 ) as eluent) to obtain 5 · 8 g ( 36 % ) of red oil which crystallized upon standing. :mp 9 3 - 9 7. C. Elemental analysis (C i 8 Η 2 3 C 1 N 4 〇 2 ) C, Η, N. Step 3: 2 - (1,3-benzodioxan-4-yloxy)ethanol 1,3 -benzodioxan-4-ol* (0 · 74g, 5. 3 6 mm ο 1 ) A mixture of ethyl carbonate (0.47g, 5.3 mmo 1 ) and k2C〇3 (〇·67g , 4 · 8mmo 1 ) in DMF ( 30 m L ) is at 150. Heat under C. After the carbon dioxide evolution was stopped (1 hour), the reaction mixture was filtered and concentrated. The crude product was purified by chromatography on EtOAc (EtOAc:EtOAc (EtOAc:EtOAc) : mp56 — 57°C. Elemental analysis (C9Hi〇〇4) C'H. $See example 8 7. Step 4: 2 -[2 -(1 ,3 -benzodioxan-4-yloxy)ethoxy]- 3 -( 2 -methyl- 1 -piperazinyl) hydroxyphenanthroline, salt The acid salt K〇-t-Bu (〇.41g, 3.7mmol) was added to 2-(1,3-benzodioxan-4-yloxy)ethanol (〇·3 3 g , 1 · 8 mm ο 1 ; From the above steps 3) Apply the Chinese National Standard (CNS) A4 specification (210 X 297 mm) to the standard of the second chew paper I----------- Pack------- -Book -------- (Please read the notes on the back and fill out this page) -122-

m L 5 , 6 (1 1291958 A? - B7 5. Inventive Description (12〇) A solution of alkane (15 m L). After stirring at room temperature for 15 minutes, add the title compound of the above step 2 (0 · 7 3g, 2 · Ommo 1 ), the resulting mixture was stirred at 95 ° C for 1.5 hours. The reaction mixture was filtered through a plug of celite, concentrated under vacuum, and the residue was purified by chromatography. The petroleum ether / E t〇A c (9:1) was used for elution, the oil obtained was dissolved in C Η 2 C 1 2 / TFA) and stirred at room temperature for 15 hours. The mixture was concentrated to obtain 2 MHC. 1 co-evaporation twice. The residue was recrystallized from water to give the title of 〇2 2 g (2 6%) white solid. Compound: mpi 3 3 _ 138 ° C; HRMS m/z for C22H24N4〇4 (Μ) The calculation of + is 4〇8 1 7 9 8 ^ The experimental value is 4 0 8 . 1 7 8 2. Elemental analysis (C22H24N4〇4*HCl.H, n, wide

2 〇) C , Η, N Example 1 5 3 · monomethyl-2 - (2-phenoxyethoxy)-piperazinyl)pyrazine, dihydrochloride Step 1: 2 - atmosphere one 5, 6-Dimethyl- 3~(1pyrazine title compound was prepared according to the procedure described in Example 197, step i from 2,3-monochloro-5,6-dimethyl d-pyridazine* (〇60g, 3 · 3 9 mm 〇1 ) and piperazine (〇· 8 8 g , 10.2 m mol). Yield vermiculite], 丨s 里υ · ΰ 1 g (θ 6 %). This paper scale applies to Chinese national standards. (CNS) Α4 Specifications (210X29*7 mm) -------- Clothing -- (Please read the note on the back and fill out this page) Order the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative to print a piperazine基) -123 ' 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (121)

Ms m/z 226 (M)+. * The preparation thereof is described in J. Am. Chem. Soc. 1 956, 78, 407 1 - 4077. Step 2: 5,6-Dimethyl-2-(2-phenoxyethoxy)-3-(1-piperazinyl)pyridinium, the dihydrochloride salt is obtained from the above step 1 product (50 6 mg , 2 · 2mmo 1 ) and 2-phenoxyethanol (370mg, 2 · 7mmo 1) are dissolved in dioxane (l〇mL). K〇-t-Bu (6 2 6 m g, 5 · 6 m m ο 1 ) was added, and the resulting mixture was at 95. Stir for 4 hours at C. The solvent was evaporated, and the residue was purified by chromatography on silica gel to afford free. The free base is converted to the dihydrochloride salt in the form of a monohydrate: yield 〇 46g (50%); m p 1 3 8 - 1 4 0 0 C. Elemental analysis (C18H24N4〇2.2HC 1 ·Η 2 0 ) C , Η, Ν 〇 Example 1 5 4 1 -[ 2 -( 2 -phenoxyethoxy)phenyl]piperazine, hydrochloride Step 1 : 4-(2-Hydroxyphenyl)-1-piperazincarboxylic acid tert-butyl ester triethylamine (8 · 23 mL, 59 · 5 mmo 1) was added to 2 (1 piperazinyl) phenol dihydrobromide (9 · 8 7 g, 2 9 mm ο 1 ) A stirred solution of a mixture of water and dioxane (1:1, 60 m L). The reaction mixture was cooled in an ice bath (0 ° C) and a second addition of dibutyl succinate (6 · 3 3 g, the standard of China National Standard (CNS) A4 (210 X 297 mm) was applied. 77] Round ~ I----------^-------Book------- (Please read the notes on the back and fill out this page) 1291958 A7 B7 V. Invention Description (122) 2 9 . 0 mm ο 1 ). The resulting mixture was allowed to warm to room temperature and stirred for 5 hours. The mixture was partially concentrated. Water (20 m L) was added, and the white crystals were filtered and dried (1 m mH g, 70 EtOAc) Elemental analysis (Ci5H22N2〇3) C, Η, N. Step 2: 1 -[ 2 -( 2 -phenoxyethoxy)phenyl]piperazine is obtained from the above step 1 product (〇·55g , 2 · 〇mm〇1 ) and added to Na〇-t-Bu ( Ο · 55g , 2 · Ommo 1 ) Stirred solution in D Μ E ( 5 m L ). After 5 minutes, (3-bromophenylethyl ether (〇·5 6 g, 2 · 8 mm ο 1 ) was added, and the reaction was stirred at 55 ° C for 15 hours. 2 Μ HC 1 was added and the reaction was stirred. The mixture was concentrated in vacuo, and the residue was crystallised eluted eluted eluting The residue was chromatographed on a silica gel (using CHC 1 3 /Me 〇H / Ν Η 4 Ο Η (90:10:0 · 4) as an eluent) to give the free base of the title compound. The base was treated with EtOAc / EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH CisH22N2〇2*HC 1·Η2〇)Η,N ; C : Computation 値6 1 · 2 7, Experiment 値6 1 · 9. Example 1 5 5 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back and fill out this page) Installed _ IJ , a i_i iHi _1 IB1 emmmm — Hi II · Printed by the Ministry of Economic Affairs Intellectual Property Bureau -125 1291958 Α7 Β7 V. Description of the invention (123) 1 —[ 3 —( 2 —Phenoxyethoxy)-2-pyridyl]piperazine, dihydrochloride (please read the precautions on the back) This page) Step 1: 2 -Chloro-3-(2-phenoxyethoxy)pyridine 2 -Chloro-3-hydroxypyridine (3 · 0 g ' 23 · lmmo 1) , β-Bromophenylethyl ether (4 · 66g, 23 · 2mmo 1) and K2C〇3 (8 · Og, 57 · 9mm〇1) The mixture in DMF (5〇mL) is heated at 100 ° C for 1 · 5 hours. Under reduced pressure The removal solution 'residue is partitioned between E t 〇A c and Η 2 。. The organic phase is dried (M g S 〇 4 ), filtered and the solvent is evaporated. The solid residue is triturated with a small amount of ether and dried (6 5 ° C, 1 mm H g ) 'Prepared 4 · 2 3 g (74%) of white crystal title product: mp77 - 78 ° C. Elemental analysis (CHHHClNOsjC'H'N. Step 2: 1 -[3 -( 2-Benzyloxyethoxy)-2-pyridyl-4-pyrazinepiperazine, dihydrochloride acid industry intellectual property bureau employee consumption cooperative printed from the above step 1 product (〇·84g, 3 · lmmo 1 ) and Offer Hydrate (5.3 bogey 27.3111111〇1) the mixture was heated in a sealed tube at 1 6 5 ° C 1 hour. After cooling, the mixture was diluted with water (10 mL) and extracted twice with EtOAc. The organic phase was mixed and dried (M g S 0 4 ), and concentrated under vacuum. The residue was purified on silica gel chromatography (using CHC 1 3 /M e 〇Η / ΝΗ4 〇Η (90 : 10 : 〇· 4 ) As the eluent), the free base of the title compound was obtained. The free base is treated with HC 1 /ether, and the obtained paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -126- 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; C. Elemental analysis (Ci7H2iN3〇2*2HC 1 ) C, H, N. Example 1 5 6 2 —(2,3-dihydrobenzofuran-7-yloxy)ethyl 3 —( 1 -piperazinyl)-2-pyrazinyl ether, maleate salt 1 2 3 The title compound (3 90 mg, 〇·············································· The reaction mixture was filtered through Celite and concentrated. The residue was purified by chromatography on EtOAc (EtOAc:EtOAc:EtOAc: The free base is converted to maleate and recrystallized from Me〇H/ether: mpl49 - 1 54 ° C; MS m/z 343 (M + H) + o Elemental analysis (Cl8H22N4〇3*l · 1 C 4 Η 4 Ο 4 * 0.6H2 〇) C, H, N. Example 1 5 7 6 -methoxy- 7-(2-{[3-(1-piperazinyl)-2-pyridinyloxy]ethoxy)- 2H-chromen-2-one, Dihydrochloride I---------- loaded! Order·!-----a^_w. (Please read the notes on the back and fill out this page) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) -127- 1291958 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Inventive Note (125) Add DEAD (〇.50mL, 3 · 2mmo 1 ) dropwise to 2—[ 3 -(4 —T-butoxycarbonyl) at room temperature 1-1 piperidinyl)-2-pyrazinyloxy]ethanol (1 · 〇〇g, 3 · 08mmo 1 ; obtained from step 54 of Example 54), sco 菪 ( scopoletin ) ( 0 · 60 g, 3 · 1 mm ο 1 ) and triphenylphosphine (〇·87g, 3 · 3mmo 1) in THF (10 mL) stirred mixture. After 1 hour, the reaction mixture was diluted with EtOAc and washed with water. The organic phase was dried (M g S 〇 4), concentrated, and the residue was purified by chromatography on EtOAc (EtOAc/EtOAc (EtOAc) The pure fractions were combined and treated with CH 2 C 1 2 / TFA / H.sub.2 (50: 45: 5, 5 mL) for 3 min. The mixture was diluted with a 0.2 H aqueous solution of H 2 1 and washed with E t 0 A c (X 3 ). The aqueous layer was concentrated to give 0.75 g (5%) of title product. P 〇 s — E I — MS shows that M + and 15 5 ions support the structure. Elemental analysis ((: 2〇Η22Ν4〇5·1 · 3HC 1 · 1 . 4 Η 2 0 ) C, Η, Ν. Example 1 5 8 7 —isoquinolinyl 2—{[3—(1—piperazine Preparation of the title compound of the bis-pyridyl}oxy)ethyl ether, difumarate salt according to the procedure described in Example 157 from 7-hydroxyisoquinoline (435 mg, 3 · OOmmo) 1) and 2 —[ 3 —( 4 —T-butoxycarbonyl-1-1,4-piperazinyl)-2-pyrazinyl This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) – — — — — — — — — ^--------^-1------- (Please read the notes on the back and fill out this page) -128- 1291958 Intellectual Property Office of the Ministry of Economic Affairs The consumer cooperative printed A7 B7__ V. Inventive Note (126) 〕 Ethanol (1 · 0 0 mm 0 1 ; obtained from Example 5 4 Step 2). The free base of the title compound is converted to its fumarate salt. Yield 4 5 m g ( 2 % ) ; m p 1 5 7 ° C (decomposition). H R M S m / z is calculated for C i 9 Η 2 i N 5〇2 ( Μ ) + 3 is 3 5 1 · 1 6 9 5, and the experimental 値 is 3 5 1 · 1 6 9 5 . Elemental analysis (C19H21N5〇2«2 · 3 C 4 Η 4 0 4 ). Example 1 5 9 2 —[2-(3-Cyanophenoxy)ethoxy]-3-(1-piperazinyl)pyridinium Step 1: 2 —(3—Cyanophenoxy)-1 - Ethanol* The title compound was prepared starting from 3-cyanophenol according to the procedure described in Example 9, Step 1. Oil; yield 63%. MS m/zl63 (M)+. Elemental analysis (C9H9N〇2) C ′ Η ’ N. * described in J. Chem. Soc. 1914, 2117-2139 and Pharmazie 1 975, 30, 353-357. Step 2: 2-(2-(3-cyanophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine The title compound was prepared according to the procedure described in Step 2, Step 2, from the above steps. 1 product and 2-chloro-3-(1-piperazinyl)pyrazine (obtained from Example 9 Step 1). Solid; yield 74%. MS m/z 326 (M + H) +. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I-----------Install--------Set--------- (Please read the notes on the back and fill out this page) -129- 1291958 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives Α7 Β7 V. Invention Description (127) Elemental Analysis (ChHhNsOz) C, Η 'N. Example 1 6〇2 —[2 —(3 —Butoxyphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, maleate Step 1 : 2 —(3 — Preparation of the title compound of butoxyphenoxy)ethanol from 3 - n-butoxyphenol (2 · 〇g, 12 mmo 1) and ethyl acetate (0 · 8 8 g) according to the procedure described in Example 9 Step 1. , 1 0 mm ο 1 ) begins. Oil; yield 85%. MS m/z 210 (M)+. Step 2: 2 -[ 2 -(3 -Butoxyphenoxy)ethoxy]- 3 -(1 -piperazinyl)pyrazine, the maleic acid salt of the title compound was prepared according to Example 9 7 The procedure described in Step 2 begins with the product from Step 1 above and 2-chloro-3-(1-piperidinyl)pyridazine (from Example 9 Step 1). The yield of the free base of the title compound was 7 7 %. Part of the free base is converted to maleate. MS m/z 373 (M + H)+. Alizarin analysis (C2〇H28N4〇3*C4H4〇4) C,Η,Ν. Example 1 6 1 2 —[ 3 —( 2 — {[ 3 —( 1 —piperazinyl)-2-oxazinyloxy]ethoxy)phenoxy]ethanol, maleate title The preparation of the compound was carried out according to the procedure described in Example 2, Step 2, from the paper scale to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 丨丨丨! ! ---- 丨定---HI--- (Please read the notes on the back and fill out this page) -130- 1291958 A7

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing, V. Inventions (128) 1,3 - bis(2-hydroxyethoxy)benzene and 2-chloro-3-(indolyl-piperazinyl)pyridazine (from Example 9 7 Step 1) Start. The yield of the free base of the title compound was 45%. The maleic acid salt was obtained: mplll-ll4〇C; MS m/z 36l (M + H) + halogen analysis (Cl8H24N4〇4*C4H4〇4.Q · 1 R 2 Ο ) C,Η, N. EXAMPLE 1 6 2 4 One (2 - { 〔3 -(1-Piperazinyl)-2-indolazine)oxy}ethoxy)-2- quinolinamine, trihydrochloride Step 1 : 2 —[(2—Amino- 4 quinolinyl)oxy]-l-ethanol Add 2-bromoethanol (〇·470g, 3·78mm〇1) to 2-amino-4-hydroxyquinoline ( Ο · 5 Ο 5 g, 3 · 1 5 mmo 1) and K2C〇3 (0. 87g, 6 · 3mmo 1) Mixture in DMF (10 m L ). The resulting mixture was stirred at 150 ° C for 7 hours. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel eluting with &lt;RTIgt;M&lt;/RTI&gt; The resulting brown oil (◦·30 g, 3 Ο %) was used directly in the next step, which contained 75% of the expected product and 25% of the unreacted starting material. MS m/z 205 (M+H)+. Step 2: 4 — ( 2 — {[ 3 — ( 1 — Piperazinyl) 2-Piazine I---------- Pack------- -- (Please read the note on the back and fill out this page.) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) -131 - Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1291958 Δ7 Α7 Β7 5, invention description (129) yloxy} ethoxy) 2- quinolinamine, trihydrochloride obtained from the above step 1 (0 · 30g, 1 · 5mmo 1 ) in DMF ( 4 m L ) The solution was treated with Na a Η (5 5 % suspension in mineral oil; 〇 · 1 2 g , 3 · 〇 mm ο 1 ). After stirring at room temperature for 5 minutes, '2-chloro-3-(1-oxazinyl)pyrazine (0 · 2 1 2 g , 1 · 〇7 m m 〇 1 ; obtained from Example 9 7 Step 1) was added. The reaction mixture was stirred at 70 ° C for 4 hours and at room temperature for 14 hours. Purification by chromatography on silica gel (using a solution of 20% MeOH in CHC 1 3 as eluent) to give the title compound as a free base, which was converted to the hydrochloride salt. : mpl56 ° C (decomposition) °HRMS m / z for C 1 9 Η 2 2 N 6 0 2 (Μ) + calculation 値 is 366 · 1804, the experimental 値 is 3 6 6 · 1 7 9 5 . Example 1 6 3 (2R) — 2 —Methyl-1—(3 — {2 —[(6-methyl-1,3-pyridyl)oxy]ethoxy}-2-pyrazinyl)piperazine, The preparation of the fumarate title compound was carried out according to the procedure described in Example 1 4 7 Step 3 from 2-(6-methyl-3-pyridyloxy)ethanol (obtained from Example 130, Step 1) and 3-chloro- 2-[4-Tertioxycarbonyl-(2R)-methyl-l-piperidinyl]d-pyrazine (obtained from Example 1 4 7 Step 2). The crude product was purified by chromatography on a pad of Celite (using &lt;RTI ID=0.0&gt;0&gt;&gt; This paper size applies to the National Standard (CNS) A4 specification (210 X 297 mm) ------- Binding! ----- (Please read the notes on the back and fill in this page) -132- 1291958 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives A7 B7 V. Invention Description (13Q)

The solvent of the pure portion of the mixture is evaporated. The resulting free base precipitated as its fumarate salt. Recrystallization from Me Ο Η / diethyl ether gave 4 6 % of the title product as an amorphous solid: m ρ 1 1 5 ^ C (decomposed). Elemental analysis (Cl7H23N5〇2*C4H4〇4 ) C , Η, N Ο Example 1 6 4 2 — { 2 —[ (2 —Methoxy-3 1:1 ratio steep)oxy]ethoxy} a 3-(1-piperazinyl)pyrazine, fumarate step 1 · 2 - desert 3 - (2 - thioglyoxy) hydrazine [(preparation of the title compound according to Example 9 8 The process described in Step 1 begins with 2-bromo-3-hydroxypyridine. Oil; yield 2. 3 3 g (76%) Step 2: 3 —( 2 —Pentylethoxy)-2-methoxy The mouth ratio D疋 was obtained from the above step 1 product (2.33g, 1〇· 7mm〇1) and Na〇Me (0 · 634mg , 1 1 · 8 mm 〇1 ) in Me 〇Η ( 50 m L ) The mixture was refluxed overnight. The reaction mixture was filtered and the solvent was removed. Purified by chromatography on silica gel (using CH2Cl2/Me〇H / heptane (4:1:5) as eluent) to give 0 · 8 1 g (45%) of the title compound as a colorless oil. Step 3: 2 - { 2 -[(2-methoxy-3-pyridyl)oxy----------^ &gt; — — — — — 1 — (Please read the notes on the back and fill out this page) Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) -133- 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (131) 〕 Ethoxy} 1 - (1) Piperazinyl)d-pyrazine, fumarate 2-chloro-3-(1-piperazinyl)d than hydrazine (〇· 4 5 4 g , 2 · 13mmo 1 ; obtained from Example 97, step 1) a mixture obtained from the above step 2 product (0 · 38 〇g, 2 · 25 mmo 1) and Na〇t-Bu (〇· 432 g , 4 · 50 mm 〇 1 ) in dioxane (25 m L ) The reaction was stirred at 90 ° C for 2 hours, then added with Me 〇Η ( 〇 · 6 m L, 1 3 · 3 mm ο 1 ) and quenched. Add the silicone gel, and the mixture was filtered through a silica gel in a vacuum. Concentration. The residue was purified by chromatography on silica gel (using CHC l3/Me〇H/heptane (4:1:5) containing 0. 2% aqueous NH3 as eluent) to obtain 〇· 2 5 7 g (40%) of the free base of the title compound as a colorless oil. The free base is dissolved in Me Ο Η ( 3 m L ), and by adding fumaric acid (0 · 104 g, 0 · 87 mmo 1 ) In Me〇H (3mL) The solution and the diethyl ether were used to convert the free base to the fumarate to give the title compound: mp 1 8 1 - 1 8 3 ° C; (C2〇H25N5〇7) C, Η, N. Example 1 6 5 (2R) — 1—(3 — {2 —[(2-methoxy-3-tripyridyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazin , fumarate I------------ loaded--------order·------- (please read the notes on the back and fill in this Page) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -134- Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1291958 A7 ___B7_____ V. Invention Description (132) Step 1: (R) — 3 —Methyl-1,3-triphenylmethylpiperazine Add (2 R )-methylpiperazine-L — ( + ) —tartrate* ( 3〇〇g , 1 · 2m〇l) to K〇 H (240 g, 4 · 3 m ο 1 ) was stirred in Η 2 〇 (.2 4 〇m L ). A two phase was formed, the mixture was cooled to room temperature, and extracted with C Η 2 C 1 2 ( 3 X 4 0 0 m L). The extract was dried with Κ 2 C 〇 3 and filtered. Trityl chloride (2 60 0, 0 · 9 3 m ο 1 ) was slowly added to (R ) 2 -methylpiperazine * at K 2 C〇3 ( 1 4 0 g , 1 · 0 Mix the solution in 0 m ο 1 ) and cool it while cooling. (Exothermic!). After 4 hours, the resulting solution was poured into a solution of K 2 C〇3 (1 40 g, 1 · 〇 〇 m ο 1 ) in water (500 ml). The resulting organic phase is separated and dried (K 2 C 〇 3 ), and the solvent is evaporated. The title product of 370 g of oil was obtained which was used directly without purification. * described in J. Med. Chem. 1 990, 33, 1 645- 1 656. Step 2: (2R)-1-(3-Chloro-2-pyrazazinyl)-2-methylpiperazine is obtained from the product of step 1 above, 2,3-dichloropyrazine (1 5 4 g, 1 · 0 0 m 0 1) and a mixture of K2C〇3 (160 g, 1 · 2 0 m ο 1 ) in DMF ( 1 L ) was heated at 110 ° C for 20 hours with vigorous stirring. (T L C monitoring system: C H C 1 3 : E t〇Η ( 2 Ο : 1 ); vermiculite). The mixture was cooled and poured slowly into water (6 L) with stirring. Collect solids, rinse with water, dry and dissolve in CHC 1 3 ( 1 L ). This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -135- I------ ----装-------Book--------- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291958 A7 _ _ B7 V. INSTRUCTIONS (133) Dilute with n-heptane (1 L) and filter through S i〇2. Evaporate the solvent. The resulting oil was dried under vacuum (3 m m / 50 ° C, 30 min) to remove D M F. The oil was dissolved in hot ethanol (1 L) and H C 1 (1% aqueous solution, 30 〇 m L ) was slowly added. After 10 minutes, tritylmethyl alcohol began to crystallize. After 30 minutes, the formed trityl methanol was filtered off and the ethanol was evaporated. The aqueous solution was extracted with diethyl ether (2 X 2 0 0 L), and K 2 C 0 3 was added to make the solution alkaline and ρ Η was 1 2 . The basic layer was extracted with C H C 1 3 (3 X 2 0 0 m L ). The organic layer was dried (K 2 C EtOAc). Step 3: (2 R) — 1—(3- {2 —[(2-methoxy-3-tripyridyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine The fumarate is added to the product of step 2 (0 · 494 g, 2 · 18 mmo 1) to a 3-(2-hydroxyethoxy)-2-methoxypyridine (0 · at 90 ° C). 41〇g , 2 · 42mm〇1; from Example 1 6 4 Step 2) and Na a 〇t - B u ( 〇· 3 4 9 g, 3 · 63mmo 1) in dioxane (25mL) . The reaction was stirred at 90 ° C for 2 hours and then quenched by the addition of Me 〇Η (0 · 6 m L, 1 3 · 3 m m ο 1 ). The mixture was added via a silica gel and concentrated under vacuum. The residue was chromatographed on silica gel (using CHC 1 3 / M e 〇Η / n-heptane (4:1:5) containing 0. 2 % N Η 3 aqueous solution as the eluent) to obtain I-- — — — — — —--AW- - 11 I----^« — — — — — 1 — —^^1 (Please read the notes on the back and fill out this page.) This paper scale applies to Chinese national standards. (CNS) A4 size (210 X 297 mm) -136- 1291958 A7 B7__ V. Description of invention (134) (Please read the notes on the back and fill out this page) ◦ · 38 2 g (4 5%) colorless oil The free base of the title compound. Part of the free base (0 · 150 g, 〇 · 48 mmo 1) was converted to its fumarate to give 〇 · 〇 6 1 g (28%) of the title compound: mpl 41 - 1430C. Elemental analysis (C21H27N5〇7.〇. 2 5 Η 2 0 ) C , Η, Ν. Example 1 6 6 2 — {2 —[(2-Chloro-3-indolyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, fumarate Step 1: Preparation of the title compound of 2-[(2-chloro-3-(3-pyridyl)oxy]ethanol was started according to the procedure described in Example 9 Step 1 from 2-chloro-3-hydroxypyridine. Oil; yield (7 7 %; purity of about 80% according to 1 Η N M R ). This material was used directly in the next synthetic step without further purification. H R M S m / ζ For 〇7: «8〇11^〇2(to)+ is calculated as 173.0 24〇, and the experimental 1 is 1 7 3 ·〇2 4 4 . Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printing Step 2: 2 — { 2 —[( 2 —Chloro-3-pyridyl)oxy]ethoxy} — 3 — ( 1 —piperazinyl)pyrazine, counter The title compound of the butenedioate was prepared according to the procedure described in Example 2, Step 2, from the product from Step 1 above and 2-chloro-3-(1-piperazinyl)pyridazine (from Example 9 7 Step 1). At the beginning, except for the reaction system, the paper size is applied at the room temperature. The Chinese National Standard (CNS) A4 specification (210 X 297 mm) _ 1- 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (135). The crude product was purified by chromatography on silica gel using c H c 1 3 /M e Ο Η / ΝΗ4 〇Η (95 : 5 : Ο · 25 , then 90 : 10 : Ο · 3 ) as an eluent). The free base of the title compound is converted to the reverse methic acid salt. Yield 41%; mp 200 °C. Elemental analysis (C15H18C 1 N 5 0 2 · C 4 Η 4 0 4 ) C ′ Η ’ Ν. Example 1 6 7 (2R) — 1—(3 — {2 —[(2-Chloro-3-pyridyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine The title compound of the butenedioate was prepared according to the procedure described in Example 1, Step 5, except that the reaction was carried out at room temperature and 2-[(2-chloro-3-pyridyl)oxy]ethanol ( From Example 1 6 6 Step 1) Instead of 3-(2-hydroxyethoxy)-2-methoxypyridine. The crude product was purified by chromatography on silica gel (using 〇11 (: 13/"6〇11/1^114〇^[(97:3:0.2, then 95:5:0.25) as the eluent). Conversion of free base to fumarate. Yield 2 5 %; mp 1 4 7 0 C. Elemental analysis (Cl6H2〇C 1 N5〇2*C4H4〇4) C , Η, Ν. Example 1 6 8 2 — {2 —[(2 —Bromo-3-pyridyl)oxy]ethoxy] A paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------- -----------Book-------φ (Please read the note on the back and fill out this page) -138 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5 Description of the invention (136) 3 - (1 - piperazinyl)pyrazine 'fumarate title compound was prepared according to the procedure described in Example 9, Step 2, from 2-bromo-3 (2-hydroxyethoxy) Pyridine (from Example 1 6 4 Step 1) and 2-Chloro-3-(1-piperazinyl)pyridinium (from Example 9 7 Step 1) began 'except that the reaction was carried out at room temperature. Rate 39%; mp202〇C. Elemental analysis (Cl5Hl8B Γ N5〇2*C4H4〇4) C ' Η ' Ν. Example 1 6 9 (2 R ) - 1 - ( 3 — { 2 —[ ( 2 —Bromo-3-pyridyl)oxy]ethoxy}-2-pyrazinyl)-2 - Methylpiperazine, fumarate The title compound was prepared according to the procedure described in Example 1 6 5 Step 3 from 2-bromo-3-(2-hydroxyethoxy)pyridine (from Example 164 Step 1) And (2R) - 1 - (3-chloro-2-pyrazazinyl)-2-methylpiperazine (obtained from Example 1 6 5 Step 2), except that the reaction is carried out at room temperature. Rate 2 3 % ; m ρ 1 5 4 t: Elemental analysis (Cl6H2〇B Γ Ν5〇2·〇4Η4〇4) C , Η , Ν. Example 1 7 Ο 2 —(2— { 〔2 —(A Sulfur-based)-3-D-pyridinyloxy}ethoxy)-3-(1-piperazinyl)pyrazine, fumarate This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 139- ------------ Pack------Book---I-- (Please read the notes on the back and fill out this page) 1291958 A7 B7 V. INSTRUCTIONS (137) Step 1 : 2 — { 〔2 —(Methylthio)-3 - d is more than u Ethyl alcohol 2 [(2-chloro-3-pyridyl)oxy]ethanol

7 · 82g , 45 · lmmo l , from Example 166 Step 1 ) Add to a suspension of thiomethanol (3 · 〇1 g ' 4 2 · 9 mm ο 1 ) in dry DMF ( 30 m L ), The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between brine / EtOAc EtOAc EtOAc. The aqueous phase was extracted with C H n C 1 3 , and the combined organic layers were dried (M g S 〇 4 ), and the forces n f,, and s. The residual red oil was chromatographed on silica gel (using toluene / E t M e 〇Η ( 9 6 : 2 : 2 ) as eluent) to give the title compound: m ρ 8 0 ° C Ν / • 0 g (Elemental analysis {base oxide salt 2 acetic acid C } II | olefin 2 oxybutane 2 step 2 3

/—^ Anti-base, steepazine ratio D D I ). 3 base I azine } piperidine-sulfur 1 A C I----- 丨丨丨丨-装·! ___! Order!丨·! *^1^· (Please read the notes on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print 2 From 1 Process Change to Basics 7 From 9 to 2 The physical step is self-contained. According to the beginning of the roots of the azines, the preparation of the piperazine, the production of a 1 step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the first step, the second step 7 IX Example 1 Ηο , 2 C Ρ ) m 4 〇4 % Η ^4 4-C rate S·

Separation element ο C

N This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) _ 14〇_ 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (138) (2R) — 2 — Methyl-1 -[3 -(2 - {[2-(methylthio)-3-pyridyl)oxy}ethoxy)-2-pyrazinyl]piperazine, fumarate title The preparation of the compound was carried out according to the procedure described in Example 1 6 5 Step 3 from (2R)-1(3-chloro-2-oxazinyl)-2-methylpiperazine (from Example 1 6 5 Step 2) And Example 1 70 Step 1 The product begins. Conversion of the free base of the title compound to its fumarate: yield 39%; mp.

Elemental analysis (Cl7H23N5〇2S*C4H4〇4) C ,Η,N Ο Example 1 7 2 2 — { 2 —[ (2 —Ethoxy-3-tripyridyl)oxy]ethoxy} — 3 — ( 1 monopiperazinyl)pyrazine, fumarate Step 1 : 2 -Bromo-3-(2-{[t-butyl(dimethyl)methylglycine)oxy}ethoxy吼 将 将 将 将 将 将 将 将 将 将 将 将 将 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? Hydroxyethoxy)pyridine (1 5 · 3 g, 70 mm ο 1 ; obtained from Example 1 6 4 Step 1) and a suspension of imidazole (10·〇g, 147 mm〇1) in DMF (30 mL). The reaction mixture was stirred at room temperature for 2 hours, diluted with aq. EtOAc (EtOAc) (EtOAc) The mixed organic phase is washed once with water, dried (M g S〇4 ) and the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) _ 141 I--------- -装--------Book--------- (Please read the note on the back and fill out this page) 1291958 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (139) Concentrate. The oil obtained was treated with a mixture of petroleum ether and ethyl acetate (9 5 : 5; 50 mL), and an analytical sample of white crystals was collected. The remaining crystals were mixed with the filtrate, and the solvent was evaporated, and the obtained crude product was used directly to the next step. Solid; yield 18 · 3g (78%); mp8 1 °C. Elemental analysis (C i 3 Η 2 2 B r N 0 2 S i ) C, Η, N. Step 2: 2 - [(2-Ethyl-3-pyridyl)oxy]ethanol is obtained from the above step 1 product (1 3 · 2 g, 3 9 · 7 mm ο 1 ) added to sodium ethoxide to E t Ο Η [Prepared from N.a (1〇·5g, 457mmo 1) and Et〇H (200mL)]. The resulting mixture was heated at 70 ° C overnight. After cooling to room temperature, the reaction mixture was diluted with ice water (0·8 L) and extracted with E t 〇A c ( X 4 ). The combined organic phases were washed twice with brine, dried (MgSO4) and concentrated. The obtained dark red oil was purified by chromatography on silica gel (using toluene / E t 3 N (( 9 5 : 5 ) followed by ( 9 0 : 1 0 )) as an eluent) to obtain 3 · 〇g ( 4 1 % ) The title product of red oil. H R M S m / ζ for C 9 Η 1 a Ν Ο 3 (Μ) + The calculation 値 is 183 · 0896 , and the experiment is 8 1 8 3 · 0 8 9 5 . Step 3: 2 - {2 -[(2-Ethyl-3-indenyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine 'fumarate title The compound was prepared from 2-chloro by the procedure described in Step 2 of Example 9 7 (please read the back of this section and fill out this page). 0 H ϋ ϋ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT 1 142 1291958 A7 B7 V. INSTRUCTION DESCRIPTION (140) A 3-(1-piperazinyl)pyridazine (from step 9 of Example 9 7) and starting from the product of step 2 above. The free base of the title compound was converted to its methionate: yield 30%; mp l 86 °. Alizarin analysis (Cl7H23N5〇3*C4H4〇4) C, Η, Ν. EXAMPLE 1 7 3 (2R) — 1—(3 — {2 —[(2-Ethyloxy-3-pyridyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine , the fumarate title compound is according to the procedure described in Example 1 6 5 Step 3 from ( 2 R ) — 1 — ( 3 —chloro-2-pyrazinyl)-2-methylpiperazine (from the example 165 Step 2) and 2 -[(2-ethoxy-3-tripyridyl)oxy]ethanol (obtained from Example 1 7 2 Step 2). Title Conversion of the free base of the compound to its fumarate: Yield 7%; m ρ 1 7 9 0 C. Elemental analysis (C18H25N5〇3*C4H4〇4) C, Η, Ν. EXAMPLE 1 7 4 2 — {2 —[3 —(2-Fluoroethoxy)phenoxy]ethoxyindole-3-(1-piperazinyl)oxazin, trifluoroacetate Step 1 · 4 { 3 -[2 - (3 - mercaptophenoxy)ethyl] -2 -pyrazinyl}-1-butylpyrazinecarboxylic acid tert-butyl ester in ~0〇C (ice bath) in Ns Add NaH (3 · 90S , 0 · 1 6 3 m ο 1 ) - part to 2 - ( 3 - according to the paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ( Please read the notes on the back and fill out this page. Pack----Book---------^1^· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed-143- Ministry of Economic Affairs Intellectual Property Bureau Consumer Cooperatives Printed 1291958 A7 ---------B7___ V. Description of Invention (彳41) Phenyloxy) Ethanol (7 · 71 transport, 〇·〇 5m〇1) in dry DMF ( 1 〇〇 The stirred solution in ml). When the Η 2 is stopped, ' 2 -chloro - 3 - ( 4 - 3 - butyloxy - 1 - 1 - 1 - 11 - 11 - yl ) pyridazine (〇 · 0 5 m ο 1 , 1 4 · 9 g ; 5 4Step 1) Add the solution in 阜B DMF (7 〇m L ) once. The resulting mixture was spoiled at 65 C for 1 · 7 5 hours. After cooling, the solution was quenched by adding a solution of Η2〇 in D M F. The reaction was filtered and concentrated under vacuum. The residue was dissolved in E t 〇A c , dried (N a 2 S 0 4 + N 〇rit ) with 1 Μ KHS 〇 4 and water ', and concentrated under vacuum to obtain the title of gray-brown viscous oil. Compound. The yield was 94%. This product was used in the next step without further purification. Step 2: 2 - {2 -[3 - (2-fluoroethoxy)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine, trifluoroacetate obtained from the above step 1 ( 8 3 mg , 0 · 2〇mm ο 1 ) The solution dissolved in C Η 2 C 1 2 ( 8 · 0 m L ) is first supported by polymer-supported triphenylphosphine (3. 〇mmol/g) ( 133 mg; 0. 4 mmo 1 ) , 2 - fluoroethanol (26 mg, Ο · 40 mm 〇 1 ) and then treated with diethyl azodicarboxylate (DEAD; 7 〇 mg, Ο · 40 mm ο 1 ). The reaction mixture was shaken at room temperature for 18 hours and then the support was removed. The filtrate was concentrated under reduced pressure, then diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc)洗!丨! -装!!丨定·! !! - (Please read the notes on the back and fill out this page) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 144 1291958 A7 _____B7 _ V. Invention Description (142) (Please read the precautions on the back and fill out this page) Liquid to prepare the intermediate protected by B 0 c. This material was not isolated, but was directly treated with a solution of 0 · 2 5 % T F A in C Η 2 C 1 2 for 30 minutes, and then concentrated under reduced pressure to give 2 4 m g (25%) of the title compound. MS m/z 363 (M + H)+. Example 1 7 5 2 —(1—Piperazinyl)-3 — {2 —[3—(tetrahydro-2H-methylpyranyl-4-yloxy)phenoxy]ethoxy}pyridazine, three The fluoroacetate salt was obtained from the product of Example 174, Step 1 (208 mg, 〇. 50 mm ο 1 ), dissolved in C Η 2 C 1 2 ( 8 · 〇m L ), and supported by a polymer-supported triphenylphosphine (3 · 〇mm ο 1 / g ) ( 2〇〇mg ; 〇 · 6mmo 1), tetrahydro- 4H-pyran-4-ol (51mg, 0 · 5mmo 1) and then diethyl azodicarboxylate (87mg , 0 · 50mmo 1) Processing. The reaction mixture was shaken at room temperature for 18 hours and then the support was removed. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (using C Η 2 CI 2 / E t 2 〇 (1 0 : 1 ) as eluent) An intermediate protected by B 〇c was prepared, which was further purified by preparative C - 18 Η PLC (using CH3CN/H2 〇/TFA (gradient: CH3CN 60% to 90%, TFA 0 · 1 %) for elution liquid). This material was not isolated, but was directly treated with a solution of 0 · 2 5 % T F A in C Η 2 C 1 2 for 30 minutes, and then concentrated under reduced pressure to give the title compound (10.0 g). MS m/z 401 (M + H) +. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -145- 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7__ V. Invention description (143) Example 1 7 6 2 - 〔2 —(3 —Ethylphenoxy)ethoxy]-3-(1-piperazinyl)pyridinium Step 1: 2 — (3 —Ethylphenoxy)-1-ethanol* The title compound The preparation was started from 3-hydroxyethyl benzene according to the procedure described in Example 9, Step 1. Oil; yield 82%. MS m/zl8〇(M+H)+°HRMSm/z is calculated for C 1 〇Η 1 2 Ο 3 (Μ) + 〇 is 18〇· 0786 , and the experimental 値 is 1 8〇· 0 7 8 7 * At Helv. Chim Acta 1 989, 72, 1 2 1 6- 1 224. Step 2: 2-(2-(3-Ethylphenoxy)ethoxy]- 3-(1-piperazinyl)pyrazine, maleic acid salt, title compound, according to Example 9 7 The procedure described in Step 2 begins with the product from Step 1 above and 2-chloro-3-(1-piperazinyl)pyrazine (Step 1 from Example 9 7). The free base yield was 68%. Part of the free base is converted to maleate. M S m / z 3 4 3 ( Μ + H) +. Elemental analysis (Cl8H 22N4〇3·C4H4〇4) C ′ Η, N. Example 1 7 7 8 — ( 2 — {[ 3 — ( 1 —piperidyl)-2-pyridinyloxy]ethoxy)quinazoline, maleate salt, the title compound is prepared according to Example 1 5 7 The process is from 8 - This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) I-----1---'装-------- order ---------Φ (Please read the note on the back and fill out this page) -146- 1291958 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Description of Invention (144) Quinazoline And 2-[3-(4-tert-butoxycarbonyl-i-piperazinyl)-2-pyrazinyloxy]ethanol (obtained from Example 5, Step 2). The free base of the title compound is converted to its maleate salt. Yield 3 7 %

; P 〇 s — E I - M S shows that Μ + and 9 ions support the structure. Elemental analysis ((3ΐ8Η2〇Ν6〇2·1 . 3 C 4 Η 4 0 4 ) C , H , N. * Starting material 8 - Preparation of quinazolinol is described in Chem. Soc. 1 952, 4985-4993 Example 1 7 8 4 A ( 2 — { 〔 3 — ( 1 —piperazinyl)-2-pyrazazinyloxy}ethoxy)- 2,1,3-benzothiadiazole, di-salt The title compound of the acid salt was prepared according to the procedure described in Example 157 from 4-hydroxy-2,1,3-benzothiadiazole* and 2-[3-(4-t-butoxycarbonyl- 1 piperazine). Starting from pyrazinyl-2-pyrazinyloxyethanol (obtained from Example 5, Step 2). P 〇s - EI - MS shows that Μ + and 7 ions support the structure; HRMS m / ζ for C 1 6 Η 1 8 Ν 6 Ο 2 S (Μ) + The calculation 値 is 358 · 12 12 , and the experimental 値 is 3 5 8 · 1 2 0 7. Elemental analysis (C16H18N6〇2S-2HC 1·Η2〇)C ' Η , Ν. *Starting material 4 Preparation of monohydroxy- 2,1 '3-benzothiadiazole is described in Khim. Geterotsikl. Soedin 1 973,7,926-9 〇本纸标准Applicable to China National Standard (CNS)A4 Specifications (210 X 297 mm) I----------Package--------Book----- --- (Please read the notes on the back and fill out this page) -147- 1291958 A7 B7 V. INSTRUCTIONS (145) Preparation of Pharmaceutical Composition: Preparation of tablets in g / tablet! I 1. Active ingredient 10·0 2. Cellulose, microcrystalline 57.0 3. Calcium hydrogen phosphate 15.0 4. Sodium starch glycolate 5.0 5. Ceria, colloidal 〇 ·25 6. Magnesium stearate 0.75 (Please read the back Precautions Please fill out this page} Installed the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed active ingredient 1 and mixed with ingredients 2, 3, 4 and 5 for about 10 minutes, then added magnesium stearate, and the mixture was mixed for about 5 minutes. And compressed into tablets, with or without a film coating. The biological activity of the compounds prepared in the pharmacological test examples was tested using different tests.Affinity analysis 5 - Η Τ 2 of the compounds in the examples were measured in a competition test. Receptor Affinity, in which each compound is substituted for a 3 Η-labeled 5- ΗΤ in a serial dilution (binding to a transgenic Η Κ 2 9 3 cell line that stably displays the human 5-HT2C receptor protein) Membrane) by Scintillation Proximi Ty Assay technology detection. Use mianserin to define non-specific combinations. The results obtained for the exemplary compounds of the present invention are shown in Table 1 below. —订-------- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 148- 1291958 A7 V. Description of invention (146) Typically, 5 Η T 2 c receptor Affinity 値 (in the range of κ 5〇〇ηΜ. η Μ ) in 1 至 to Table 1 Example 65 Example 106 Example 142 Example 153 Example 1 2 8 Example 1 2 9 Example 148

Ki(nM) 24 45 34 10 50 185 16 (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed Effect Analysis Example 5 - Η T 2 c Receptor The efficacy of the agonist is determined by using a calcium chelate fluorescent dye FLU 0 - 3 to measure each compound in a cell that transfects Η Ε Κ 2 9 3 cells (stably displaying human 5 - Η Τ 2 c receptor protein) Measured by the ability of calcium to move (Sigma, St. Louis, M〇, USA). Typically, the maximum reaction of the 5 - Η Τ 2 c activator is in the range of 30 - 10 〇 % of the maximum reaction of 5-HT (hematocrit) at a concentration of ΙμΜ. Toxicity test This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -149- 1291958 A7 _B7__ V. Description of invention (147) Acute toxicity in rats After several compounds in oral examples The cause of death usually occurs at a dose of about 20 〇mg/kg body weight to sm 〇5 4 about the weight of the body gk (please read the back note first and then fill out this page) Order --------. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -150- This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

1291958 A8 B8 C8 D8 Public Port VI. Scope of Application Patent Attachment 2A: R Patent Application No. 891 09775 Replacement of Chinese Patent Application Area October 3, 1996 Correction of the following compounds of formula (I b ): a z (lb) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Χι as -Ο - or one N (R27) -; Yl is 〇, S, NH, N - Et, OCH2, C Η 2 C Η 2〇 or Ci - 4 alkylene; R a is selected from the group consisting of phenyl, benzyl, naphthyl, tetrahydronaphthyl, pyridyl, pyrimidinyl, 1-oxodihydroindenyl, quinolinyl, isoquinoline , quinazolinyl, thienyl, 3,4-dihydro-2H-chromenyl, 2-oxo-2H-chromenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzene And oxazolyl, 3,4-dihydro-2-indole-benzoxazinyl, 3,4-dihydro-2H-pyrido[3,2-b]-l,4-oxazinyl, benzo a group consisting of dioxin, 2,3-dihydromonobenzodioxan, 2,3-dihydro-1,4-benzoxanthene and benzothiadiazolyl, Or more positions are replaced by the following groups: C i 6 -alkyl, C i This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm)-1 - I ϋ nnn ϋ ϋ i^vi ^ I n ϋ I n ϋ ϋ n (Please read-«Precautions on the back page and fill in this page) 1291958 A8 B8 C8 D8 VI. Patent application scope (please Read the precautions on the back of the page and fill in this page.) -6 —Ethylene, C 1 — 6 — Institute of thio, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, fluoroethyl Oxyl, difluoromethylthio, trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano, C2 6-alkenyl, Cl-6-branched, Cl 6 -yard based ore基—Cl—6—hospital, Cl -6_theoremium_C 1-6—hospital, C 1 —6 —oxyl end group, via —C 1 —6 —, phenyl, Phenoxy, phenylthio, via a C 1 4 alkoxy, morpholinyl, benzhydryl, tetrahydro-2H-pyran-4-yloxy, a N(R2)(R3) or a C〇N(R7) ( R 8 ), wherein R 2 and R 3 are each independently hydrogen, Ch 6 alkyl or Ch 6 fluorenyl; R 7 and R 8 are each independently hydrogen or C i -6 alkyl; R 2 Q And R21 are, independently of each other, hydrogen or Ci-6-alkyl; or R20 and R21 form a phenyl or thienyl ring with the attached carbon atom, and when the ring is a phenyl group, one or more positions thereof Optionally substituted with a halogen; R 2 2 is hydrogen, hydroxy, C i - 4 -alkyl, C 3 I 4 -alkenyl, Ci - 4 - anthracenyl, Ci-4 alkoxycarbonyl, 2-hydroxyethyl, 2-cyanoethyl or tetrahydropyran-2-yl; Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs R 2 3 And R 2 4 are independently of each other hydrogen, C i 1 monoalkyl, hydroxymethyl, Ci-4-monoalkoxymethyl or fluoromethyl; R25 is hydrogen or Cl 4 —yard; R 2 6 is Hydrogen, C i 4 monoalkyl or together with R a and Y i B-methane, benzofuranyl, dihydrobenzofuranyl, tetrahydro-based paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) · 2 - 1291958 A8 B8 C8 D8 Patent application scope (ΓΥ° &quot; furan, Η "ΝγΝ, Η, dihydrobenzothiazepine, tetrahydrobenzopyran, or, alternatively, taken by methyl, nitro or acetamidine #R 2 7 Ammonia or C-hospital; and y and ζ are independently 1 or 2, and a pharmaceutically acceptable salt thereof. 2 · A compound of claim 1 wherein R methyl or ethyl. For example, the compound of claim 1 wherein R 2 is and R 21 is independently hydrogen or C-alkyl. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, 4 · Compounds as claimed in claim 1 R R21 forms a ring with a carbon atom attached to the ring. 5. A compound according to claim 4, wherein R 2 and R 21 together with the carbon atom to which they are attached form a quinoline to form a quinazoline ring or form a thiophene. It becomes thieno[3,4-b]pyrazine, its selectivity Or a single or a two-in-one substitution. 6 · A compound of claim 1 wherein R 2 2 is hydrogen and 7 is a compound of claim 1 or 6 wherein R 2 3 is methyl and hydrazine is 1 and R24 are hydrogen. 8 · For the compound of the scope of patent application, the R 2 6 is the standard for the paper. The Chinese National Standard (CNS) Α4 specification (210Χ297 mm)-3 - Φ--- --------- ^Please read the notes on the back of the section and then fill in this page) 1291958 A8 B8 C8 D8 X, the scope of application for patents (please first smell - «Precautions on the back and fill this page) 3,4-Dihydro-2Η-chromenyl, 3,4-dihydro-211-benzoxazinyl, 3,4_~hydro-2Η-pyrido[3,2-b]-l,4- Oxazinyl, 2,3·dihydro-1,4-benzoxanthene, 2,3-dihydrobenzodioxan, 2,3-dihydrobenzofuranyl and benzofuranyl 9. A compound of claim 1 or 6 wherein R 2 5 is hydrogen and R 2 6 is methyl. 1 0. A compound according to claim 1 or 6 wherein R 2 5 and R 2 6 is hydrogen. 1 1 · The compound of claim 1 is Is 2-(2-phenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, 2-(2-fluorophenoxy)ethyl 3-(1-piperazine) a pyrazinyl ether, 2'3-dihydro-1,4-benzodioxan-2-ylmethyl-3-(1-piperazinyl)-2-pyrazinyl ether, 2-(2-methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, 2 —(2 ' 5 -Difluoro Phenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, 2-(3,5-dimethoxyphenoxy)ethyl 3-(1-piperazinyl)- 2 —pyrazinyl ether, 2 -( 1 ,3 -benzodioxan-5-yloxy)ethyl 3 - ( 1 -piperazinyl)-2-pyrazinyl ether, 2 -[3 - (4 monomorpholinyl)phenoxy]ethyl 3 — (1 - piperazine paper size applicable to China National Standard (CNS) A4 specification (210X297 mm)-4 - 1291958 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative A8 Β8 C8 D8 VI. The scope of the patent application)) 2-pyrazinyl ether, 2 —(3 —Aminophenoxy)ethyl 3 —(1-piperazinyl)- 2-pyrazinyl ether, 2 —(3,4 dihydro-2H-pyrido[3,2—b] — 1 ' 4 嗦 嗦 2 2 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — 2 卩 嗪 嗪 基 〕 哌 ,, (2R) - methyl -1- 1 {3 - [2 - (3 - pyridinoxy) ethoxy] -2-pyrazinyl} piperazine, 2 - [ 2 —(3-pyridyloxy)ethoxy]-3-(1-piperazinyl)-6,7-dioxaline, 2-[2-(3-Rttn-oxy)ethoxy] 3 — ( 1 - piperyl) thieno[3,4 -b]pyrazine, 2 -(3,4 -monohydro-2H-1, 4-benzoindolein-2-ylmethoxy) a 3-(1-piperazinyl)pyrazine, 2-(3,4-dihydro-2H-chromene-2-ylmethoxy)-1,3-(1-piperazinyl)pyrazine, 2 — (3-pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, (2R)-methyl-1—{3—[2—(2—Amino-8-嗤Phenyloxy)ethoxy]-2-oxazinyl}piperazine, 1 -{ 3 -[2-(2-methoxy-3-pyranoxy)ethoxy]-2-pyrazine }}piperazine, 6-methoxy-7-(2-{2-[3-(1-piperazinyl)-2] (please read the «Precautions on the back page and fill out this page) This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) · 5 - 1291958 A8 B8 C8 D8 VI. Patent application range 嗦 〕 oxy] ethoxy) 1 2H - color burn one 2 - reward, 7 - different Quinolyl 2 — { 〔3 —(1-piperidinyl)]-2-indolazine (please read the back of the note first and then fill out this page) base oxy) ethyl ether, 2 —[2 -(3-cyanophenoxy)ethoxy]-3-(1-oxazinyl)pyrazine, 2-[2-(3-butoxyphenoxy)ethoxy]- 3 - ( 1-piperazinyl)pyrazine, 2-[3 - (2 - { 〔3 - (1 - piperazinyl)-2 - RH: pyrinyl)oxy} ethoxy)phenoxy]ethanol, 4 One (2 - { 〔3 -(1-piperazinyl)-2-phenylpyrazine)oxy}B (2-) porphyrin, (2R)-2-methyl- 1 -(3-{2-[(6-methyl-1,3-pyridyl)oxy]ethoxy}-2-pyrazine Piperazine, 2 — { 2 —[(2-methoxy-3-tripyridyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, (2R)-1- ( 3-(2-(2-methoxy-3-pyridyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 2-(2-[(2-Chloro-3-pyridyl)oxy]ethoxy}- 3 —( 1 -piperazinyl)pyrazine, (2R) — 1— (3—{2 -[ ( 2-Chloro-3-pyridyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, 2 — { 2 —[ (2-bromo-3-indolyl) Ethyloxy} -3 -( 1 -pyrazine)pyridazine, (2R) — 1— (3 - {2 —[ (2 —Bromo-3 - Rttn-based) This paper scale applies to Chinese national operations Quasi (CNS) A4 size (210X297 mm) · 6 - 1291958 (methylthiopyrazinyl) piperazine A 8 B8 C8 D8, the scope of patent application Liki] ethoxylated oxa-2-pyrazinyl)-2-methylpiperazine, 2 (1 -{[1 -(methylthio)-3-pyridyl)oxy Ethyloxy)~3 - (1 piperazinyl)pyrazine, (211)-2-methyl-l-[3-(2-{[2-yl]-3-pyridyl)oxy} Ethoxy)- 2 2 丨 1 -[(2-ethoxy-3-tripyridyl)oxy]ethoxy}- 3 - (1 piperazinyl)pyrazine, (2R)-1 - ( 3-{2-((2-ethoxy-3-pyridyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, 2 a {2_[3—(2 -Fluoroethoxy)phenoxy]ethoxy}- 3 -( 1 piperazinyl)pyrazine, ------IT------ (Please read the notes on the back and fill in This page) 8 (2 — {[(1-piperazinyl)-2-pyrazinyloxy) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed} Ethoxy)quinazoline 4 I (2 — { 〔 3-(1-piperazinyl)-2-pyrazinyloxy}ethoxy)- 2,1,3-benzothiadiazole, or a pharmaceutically thereof thereof Acceptable salt thereof. 1 2 · A compound according to claim 1, 2, 3, 4, 5, 6, 8, or 1 1 for the treatment of a serotonin associated with a 5-HT2c receptor in humans or animals disease. This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm)-7 - 1 -(1 piperazinyl)-3 - {2 - [3 - (tetrahydro-2H-pyran-4-yl) Oxy)phenoxy]ethoxy}pyrazine, 2-[2-(3-ethoxyphenoxy)ethoxy]- 3 - (1 - fluorene) D. Xiao, 1291958 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed A8 B8 C8 D8 VI. Application for Patent Range 1 3 · For example, the compound of the patent application category 12, wherein the serotonin-related disease is selected from eating disorders, especially obesity. A compound according to claim 12, wherein the serotonin-related disease is selected from the group consisting of memory disorders. 1 5 · A compound of claim 12, wherein the serotonin-related disease is selected from the group consisting of an affective disorder comprising major depression and bipolar depression (including mild and bipolar disorder) and seasonal emotions Sexual disorders (SAD). 1 6 The compound of claim 12, wherein the serotonin-related disease is selected from the group consisting of anxiety disorders, including situational anxiety disorder, generalized anxiety disorder, primary anxiety disorder, and secondary anxiety disorder. 1 7 . The compound of claim 12, wherein the serotonin-related disease is selected from the group consisting of sexual dysfunction and urinary system disorders. 1 8 · A compound of claim 12, wherein the serotonin-related disease is pain. 1 9 · A compound of claim 12, wherein the serotonin-related disease is schizophrenia. The use of a compound according to any one of claims 1 to 1 for the preparation of a medicament for the treatment or prevention of a serotonin-related disease, the serotonin-related disease From: eating disorders (especially obesity), memory disorders, schizophrenia, affective disorders, anxiety disorders, pain, sexual dysfunction and urinary disorders. 2 1 · A pharmaceutical composition for treating a serotonin-related disease in a human or an animal, wherein the serotonin-related disease is selected from the group consisting of eating and eating, and the paper is applicable to the Chinese national standard ( CNS ) A4 size (210X297 mm) -8 · 1291958 A8 B8 C8 D8 Sixth, apply for patent coverage disorders (including obesity), memory disorders, schizophrenia, affective disorders, anxiety disorders, pain, sexual dysfunction and urinary disorders, including the scope of patent applications No. 1 to 1 A compound as an active ingredient, a pharmaceutically or pharmaceutically acceptable carrier. 2 2. A method of preparing a compound of the formula (lb) according to any one of claims 1, 2, 3, 4, 6 and 1 1 which comprises: a compound of the formula (Ilia) and a formula ( Mb) compound·· Hal wherein R 2 〇 and R 21 are as defined in formula (lb), and Hal is halogen As defined in formula (lb), in the presence of a base selected from the group consisting of: third butoxide-sodium or potassium, sodium hydride or hydrazine hydride, in a suitable solvent selected from the group consisting of: THF, dioxane or DMF Reaction to produce a compound of formula (IIIc): ------IT----- (please read the first note on the back of the page and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm)-9 - 1291958 (lild) where R23, R24, y and raw (lb) compounds; and Z system is R22 in formula (lb) The definition is either an appropriate protecting group selected from the group consisting of: a third butoxymethyl group, a trityl group or a benzyl group. 23 · Preparation of patent application scope 1, 2, 3, 4, 6 and! The method of the compound of the formula (lb), wherein the oxime is selected from the group consisting of oxygen or, the method comprises: A8 B8 C8 D8 夂, the patent application scope of which R20, R2 1, R25, R26, Hal, X , Y and Ra are as defined above, and then the compound of formula (IIIc) is reacted with a suitable formula ( Illd) piperazine derivative: ^24) y HN NZ 〜) 2 is as defined (lb In the definition of sulphur---t-- (please read the first note on the back of the page), π Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed the compound of the formula (Ille): 0H (Hie) wherein X! is oxygen, R20, R2I, R23, R24, y and z are as defined in formula (lb), R25 and R26 are hydrogen or Cn alkyl, and Z is as Rn in formula (lb) The definition is either selected from: Ξ 者 执 执 执 纸张 纸张 纸张 纸张 纸张 纸张 纸张 纸张 纸张 纸张 纸张 纸张 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 规格 六 六 六 六 六 六 六 六 六 六 六 六 六 六 六Suitable protecting group for benzyl; under Mitsunobu conditions, and in diethyl azocarboxylate (DEAD) or 1,1'-azobis(N,N-dimethylformamide) (TMAD) •, in the presence of triphenylphosphine or tri-n-butylphosphine, in a suitable solvent selected from tetrahydrofuran (THF), reacting with the appropriate phenol or thiophenol corresponding to Ra in formula (lb) To produce a compound of formula (lb). A method of preparing a compound of the formula (lb) according to any one of claims 1, 2, 3, 4, 6 and 1 1 of the patent application, which comprises the compound of (IIla) and the formula (nid) The piperazine derivative phase reaction: 丫aiRAN^Hal (where R2Q and R21 are as defined in formula (lb), and Hal is halogen Η-Μ (R24) y N -Z ρ '^23) ζ ( Llld) (Please read the note on the back and fill out this page.) The Ministry of Economic Affairs, Intellectual Property Office, and the Consumer Cooperatives, printed in it, R23, R24, y, and ζ are defined in the formula (lb), and the Z system is The one defined by R2 2 in (lb) may be an appropriate protecting group selected from the group consisting of: a third butoxycarbonyl group, a benzyl group or a benzyl group; to produce a compound of the formula (Illf) R ^24)y VZ (Illf) This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)-11 · 1291958 A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing VI. Hal, Z, R 2 〇, R 21 , R 23 , R 24 , y and z are as defined above' and then a compound of the formula (Illf) and a compound of the formula (IIIb): FL As defined in formula (lb), in the presence of a base selected from the group consisting of: third butoxide-sodium or potassium or sodium hydride or potassium hydride, in a suitable solvent selected from the group consisting of: THF, dioxane or DMF The phase reacts to produce a compound of formula (lb). A method of preparing a compound of the formula (lb) according to any one of claims 1, 2, 3, 4, 6 and 1 1 of the patent application, by any one of the following: (a) Converting a compound of formula (lb) to another compound of formula (lb); (b) separating an isomer of a compound of formula (lb) from a mixture thereof (eg, a racemic mixture); or (c) (lb) The free base of the compound is converted to its salt. The method of preparing the compound of the formula (lb) of claim 1 in any one of claims 2 to 2, wherein r22 is η, wherein Ζ is in the corresponding formula (Hid) The intermediate product of (Ille) or (nif) is a protecting group selected from the group consisting of a third butoxycarbonyl group (tB〇C), a benzyl group or a trityl group. 2 7 · If you apply for the method of Article 26 of the patent scope, the basic paper size of the protection shall be applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)-12 - I 11 -I-IT- (please Read the precautions on the back and fill out this page.) 1291958 A8 B8 C8 D8 VI. The scope of the patent is removed to produce a compound of formula (lb). 2 8. The method according to claim 23, wherein the intermediate product of the formula (Ille) is 2-[3-(4-t-butoxycarbonyl-1-piperazinyl)-2·piperazine Base] ethanol. ---------- (Please read the notes on the back and fill out this page.) The Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Paper Size Applicable to China National Standard (CNS) Α4 Specifications (210X297) PCT)-13 -