TW200831498A - Heterocyclic compound - Google Patents

Abstract

An object of the present invention is to provide a heterocyclic compound having a wide therapeutic spectrum, not causing adverse effects and having high safety. A heterocyclic compound according to the present invention is represented by a general formula, wherein A represents a lower alkylene group or a lower alkenylene group; Z represents O or S; R1 represents hydrogen or the like; and R2 represents hydrogen or the like.

Description

200831498 IX. Description of the Invention [Technical Field of the Invention] The present invention relates to a novel heterocyclic compound. [Prior Art] A drug has various pharmacological effects coexisting to perform as desired because bipolar disorders, mood disorders, and emotional schizophrenia are heterologous. WO 2004/026864 A1 discloses (A) φ number represented by the following formula, RAg may be substituted by a hydrogen atom and 1 to 3 fluorine atoms, etc.] The quinolone derivative represented by the above formula has a D2 receptor antagonist 2A (5- HT2A) acts as a receptor antagonist and can cause narrow schizophrenia and other central nervous system diseases. However, W02 004/0268 64A1 does not reveal that the f-norketone derivative has a D2 receptor partial agonist action, a 5. anti-agent action, an α ! receptor antagonist action, and a serotonin smear with broad-spectrum treatment. Effective treatment system disorders (including norgestrel derivatives

[wherein A' shows -(CH2)mCH2-, -(CH2)mO-, etc., m shows the total C 1 _ 4 yard base of 1 to 4: the action of the agent and the quinine π2Α described in the blood effect treatment spirit = Inhibition and inhibition -5-200831498 Furthermore, WO 2005/043 309 A1 discloses certain types of [1,8]naphthyridin-2-one derivatives. However, WO 2004/0433 09A1 also does not disclose the [1,8] naphthyridin-2-one derivative described in the document having a D2 receptor partial agonist action, a 5-HT2A receptor antagonist action, an ai receptor antagonist. Action and serotonin absorption inhibition and broad-spectrum treatment.

SUMMARY OF THE INVENTION The problem to be solved by the present invention is to provide an antipsychotic drug which has a more effective treatment and less side effects than the typical antipsychotic and atypical antipsychotic drugs which have been known in detail. Excellent Tolerance and Safety The present inventors have intensively studied the above problems and successfully synthesized a novel compound having serotonin absorption inhibition (or serotonin reuptake inhibition) and dopamine quinone 2 Receptor partial agonist action (D2 receptor partial agonist action), serotonin 5-HT2A receptor antagonist action (5-HT2a receptor antagonist action) and adrenergic receptor receptor antagonist (α 1 receptor antagonist action). The present invention has been completed on the basis of these findings. Item 1 The present invention provides a heterocyclic compound represented by the formula (1) or a salt thereof: 200831498

[wherein Q represents a group represented by the following formula (I): Z R12 , II I t R11 - Q - N - Af -

(wherein A1 represents lower alkylene; Z represents 0 or S; R11 represents (1-1) hydrogen, (1-2) lower alkyl, (1-3) is selected from phenyl, naphthyl, and dihydrogen An aryl group of an indenyl group, wherein the aryl group may be substituted with at least one group selected from the group consisting of the following substituents (i) to (xxxiii): z (1) lower-grade fluorene (ϋ) lower alkenyl group 9 (iii) substituted by halogen Lower alkyl, (iv) lower-grade alkoxy (v) lower-grade alkoxy substituted by halogen, (vi) nitro (vii) cyano, (viii) halogen, (ix) aryl, 200831498 (X) ( Xi) aryloxy, lower alkoxycarbonyl, (xii) hydroxy, (xiii) protected hydroxy, (xiv) lower alkyl fluorenyl, (xv) sulfonamide, (xvi) lower grade thio, ( Xvii) lower alkylsulfonyl, (xviii) hydroxysulfonyl, (xix) may have an amine group selected from the group consisting of lower alkyl, lower olefin (XX), and cyclic (C3-C8) alkane , aryl, and aryl hydrazino, morpholinylcarbonyl lower alkenyl, (xxi)morpholinylcarbonyl lower alkyl, (xxii) pyrrolyl, (xxiii) pyrazolyl, (xxiv) imidazolyl, (XXV ) Azyl, (xx vi) pyridyl, (xxvii) pyrrolidinyl which may have a keto group, (xxviii) morpholinyl, (xxix) thiomorpholinyl, (XX x ) lower alkynyl, (xxxi) ring C3-C8)alkyl, (xxxii) indenyl, and -8- 200831498 (xxxiii) dihydropyrazolyl group having a group selected from a keto group and a lower alkane, (1-4) heterocyclic group Wherein the heterocyclic group may be substituted with at least one group selected from the group consisting of the following substituents (i) to (xix): (i) lower alkyl, (fluorene) lower alkyl substituted by halogen, (Hi) lower alkane Oxylate,

(iv) a lower alkoxy group substituted by a halogen, (v) a halogen, (vi) an aryl group which may have a group selected from a halogen and a lower alkyl group which is halogenated by halogen, on the aryl group, (vii) An aryl lower alkyl group having a halogen atom, (viii) a lower fluorenyl group, (ix) an aryl fluorenyl group, (X) an amine having a lower alkyl fluorenyl group on the amine group _ ® @ ^ 醯 ,, (xi) Lower-grade thiol' (xii) pyrrolyl, (xiii) keto, (xiv) thioketo, (xv) amide, (xvi) hydroxy, (XVii) fluorenyl, (xviii) thiophenyl, And -9-200831498 (xix) furanyl, (1-5) an amine-based lower alkyl group which may have a group selected from the group consisting of a lower alkyl group, a lower alkyl alkene group, and an amine group and/or a lower alkyl group. a hydroxy lower alkyl group, a lower alkoxycarbonyl group, an amine methyl decyl lower alkyl group, a fluorenyl carbonyl group, an aryl group (the aryl group may have a group selected from a halogen and a lower alkoxy group), and an aryl lower alkane Oxycarbonyl, (1-6) lower alkoxy lower alkyl,

(1-7) an arylsulfonyl lower alkyl group, (1-8) may have an aryl lower alkyl group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen, and Nitro, (1-9) may have an aryloxy lower alkyl group selected from the group consisting of lower alkyl, lower alkoxy, halogen, and cyano on the aryl group, (1-10) adamantyl group Lower alkyl, (ι-ll) may have an aryl lower alkenyl group selected from the group consisting of lower alkyl, lower alkoxy, halogen-substituted lower alkyl, halogen-substituted lower alkyl on the aryl group. An oxy group, an amine group which may have a lower alkyl group, a halogen, and a nitro group, (1-12) may have a ring (C3-C8) alkyl group selected from the group consisting of an amine group which may have a lower alkyl group, An amino group lower alkyl group having a lower alkyl group, and an aryl group which may have a group selected from a halogen group and a lower alkyl group, (1-13) a ring (C3-C8) alkyl lower alkyl group, (1-14) An arylthio lower alkyl group, (1-15) is a lower alkyl group substituted with a heterocyclic group selected from the group consisting of piperidinyl, tetrahydropyranyl, pyridyl, thienyl, imidazolyl, tetrazolyl, benzene- 10- 200831498 And imidazolyl , isodecyl, thiazolidinyl, and fluorenyl (wherein the heterocyclic group may have a group selected from the group consisting of lower alkyl, lower alkoxy, halogen, keto, and thioketo), (1- 16) an aryl lower alkenyl group which may have an aryl group on the lower alkenyl group, (1-17) a lower alkenyl group substituted with a heterocyclic group selected from the group consisting of benzodioxolyl, pyridine Base, furanyl, and imidazolyl,

(1-18) benzodioxoloxy lower alkyl, (1-19) pyridylthio lower alkyl, or (1-20) amine group having lower alkyl; and R12 (2 -1) hydrogen, (2-2) lower alkyl, (2-3) lower alkyl substituted by halogen, (2-4) lower alkenyl, (2-5) lower alkynyl, (2- 6) lower alkyl fluorenyl, (2-7) hydroxy lower alkyl, (2-8) lower alkoxy lower alkyl, (2-9) cyclo(C3-C8) alkyl, (2-10) ring (C3-C8)alkyl lower alkyl, (2-11) aryl, (2-12) may have an aryl lower alkyl group selected from the group consisting of an amine group which may have a lower alkyl group on the aryl group And aryloxy, -11 - 200831498 (2-13) Tetrahydrofuranyl, furan (2-14) is a lower alkyl group substituted with a heterocyclic group as defined below and a pyridyl group, (2-15) tetrahydropyran a group, or (2-16) lower alkyl alkoxy lower alkyl), or Q is a group represented by the following formula (II): R21-A2-

(wherein -A2- is a lower alkylene group, a lower alkylene group, or a group -A21-0-A22-, wherein A21 and A22 are the same or different, and each represents a C1-C5 alkylene group (only the composition A2) 1 The total number of carbon atoms in the extended base and the A2 2 extended base does not exceed 6); and R21 represents an N-containing heterocyclic group, wherein the N-containing heterocyclic ring represented by R21 may be selected from the following (1) to (13) Substituting at least one group: (1) halogen substituted or unsubstituted lower alkyl, (2) lower alkenyl, (3) lower alkoxy, (4) hydroxy, (5) protected hydroxy, (6) Aryl, (7) lower alkyl fluorenyl, (8) carboxyl group, (9) lower alkoxycarbonyl group, -12 - 200831498 (1 〇) amine amidyl group which may have a lower alkyl group, (1 1) aryl A lower alkyl group which may have a lower alkoxy group on the aryl group, (12) a ketone group, and (1 3) a thioketone group). Item 2

The present invention provides a heterocyclic compound according to item 1, or a salt thereof, wherein Q represents a group represented by the following formula (I): Z R12 ,, 丨丨I , R11—Q—N—A1- (where A1 is a lower alkyl group; Z is Ο or S; R11 is (1-1) hydrogen, (1-2) lower alkyl, (l-3a) is selected from the group consisting of phenyl, naphthyl, and indanyl. An aryl group, wherein the aryl group may be selected from the group consisting of the following substituents (1) to (viii), (ix a), (xa), (xii), (xiii a), (xiv) to (xviii), (xix a) , (xx) to (xxvi), (xxviia), and (xxviii) to (xxxiii) one to three groups substituted (i) lower alkyl, (ϋ) lower alkenyl, (iii) substituted by halogen Lower alkyl, (iv) lower alkoxy, (v) lower alkoxy substituted by halogen, -13- 200831498 (Vi) nitro, (vii) cyano, (viii) halogen, (ixa) phenyl , (xa) phenoxy, (xi) lower-grade oxyalkyl, (xii) hydroxy,

(xiiia) a lower alkoxy group or a phenyl lower alkoxy group having one to three halogens on the phenyl group, (xiv) a lower sulfhydryl group, (XV) an amine sulfonyl group (xvi) a lower alkylthio group, (xvii) lower alkylsulfonyl, (xviii) hydroxysulfonyl, (xix a) may have an amine group from one to two groups: lower alkyl, lower alkyl fluorenyl, ring (C3) -C8) alkyl, phenyl, and benzoyl, (XX) morpholinylcarbonyl lower alkenyl, (xxi)morpholinylcarbonyl lower alkyl, (xxii) pyrrolyl, (xxiii) Base, (xxiv) imidazolyl, (XXV) tridecyl, (xxvi) 13⁄4卩, -14- 200831498 (xxvii a) pyrrolidinyl group having one to two keto groups, (xxviii) morpholinyl, Xxix) thiomorpholinyl, (XXX) lower alkynyl, (xxxi) cyclo(C3-C8)alkyl, (xxxii) fluorenyl, and (xxxiii) dihydrogen having one keto group and one lower alkyl group

Pyrazolyl,

(1-4 a) a heterocyclic group selected from the group consisting of pyridyl, piperidinyl, thiazole, tetrahydroindenyl, lactoyl, imidazolyl, fluorenyl, dihydrogen ratio Π-sitting group, fluorene ratio D-based group, dihydroindole ratio n-based group, tetrahydro-suppressing group, pyridazinyl group, thiazolyl group, oxazolyl group, isoxazolyl group, thienyl group, furyl group, fluorenyl group, hydrazine group噪 啉 基, isopipelinyl, benzimidazolyl, imidazopyridyl, quinolyl, dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, porphyrinyl, carbazolyl, quin Minoline, benzotriazolyl, dihydronaphthyridinyl, benzothiazolyl, dihydrobenzothiazolyl, dihydrobenzothiazinyl, thienoindazinyl, benzoxazolyl, Dihydrobenzoxazolyl, dihydrobenzoxazinyl, furopyrrolyl, benzodioxolyl, dihydrobenzodioxenyl, and benzothienyl, Wherein the heterocyclic group may be selected from the group consisting of the following substituents (1) to (v), (vi a), (vii a), (viii), (ix a), (X a), and (xi) to (xix) One to three groups are substituted: (i) lower-grade yards, (ii) replaced by halogen Lower alkyl, (iii) lower alkoxy, -15-200831498 (iv) lower alkoxy substituted by halogen, (v) halogen, (via) may have one or three bases selected from the group consisting of a phenyl group: a halogen and a halogen-substituted lower alkyl group, (vii a) a phenyl lower alkyl group having one to three halogens, (viii) a lower alkyl fluorenyl group, (ix a) a benzoic acid group,

(X a) Amino-lower alkyl fluorenyl group having one to two lower alkyl fluorenyl groups on the amine group, (xi) lower-grade thiol group, (xii) lysyl group, (xiii) keto group, (X i V ) thioketo, (xv) carbamoyl, (xvi) thiol, (xvii) pyranyl, (xviii) thienyl, and (xix) furanyl, (1-5 a) in the amine group and / Or a lower alkyl group may have one to two amine-based lower alkyl groups selected from the group consisting of lower alkyl, lower alkyl sulfonyl, hydroxy lower alkyl, lower alkoxycarbonyl, amine mercapto lower alkyl, a mercaptocarbonyl group, a phenyl group (the phenyl group may have one selected from the group consisting of halogen and lower alkoxy groups to three groups), and a phenyl lower decyloxy ore group 5 (1 - 6) Base '-16- 200831498 (l-7a) benzylidene-based lower alkyl, (l-8a) may have a phenyl lower alkyl group selected from one to three groups as follows on the phenyl group: lower alkyl, lower An alkoxy group, a hydroxyl group, a halogen, and a nitro group, (l-9a) may have a phenoxy lower alkyl group selected from the group consisting of one to three groups: a lower alkyl group, a lower alkoxy group, a halogen, And cyano

(1-10) adamantyl lower alkyl group, (1-11 a) may have a phenyl lower alkenyl group selected from the group consisting of one to three groups on the phenyl group: a lower alkyl group, a lower alkoxy group, a halogen group a substituted lower alkyl group, a halogen-substituted lower alkoxy group, an amine group having one to two lower alkyl groups, a halogen group, and a nitro group, (1-12 a) may have one or two groups selected from the group consisting of one or two groups below Ring (C3-C8) alkyl: an amine group which may have one to two lower alkyl groups, an amine lower alkyl group which may have one to two lower alkyl groups, and may have one selected from the group consisting of halogen and lower alkyl a group of phenyl, (1-13) cyclo(C3-C8)alkyl lower alkyl, (1-14 a) phenylthio lower alkyl, (1 -1 5 a) selected from the following heterocyclic ring Lower alkyl substituted: piperidinyl, tetrahydropyranyl, pyridyl, thienyl, imidazolyl, tetrazolyl, benzimidazolyl, isodecyl, thiazolidinyl, and fluorenyl, wherein The heterocyclic group may have one or three groups selected from the group consisting of lower alkyl, lower alkoxy, halogen, keto, and thioketo, (1 -1 6 a)phenyl lower alkenyl (in Lower alkenyl There are one to -17-200831498 two phenyl), (1-17) lower alkenyl substituted by a heterocyclic group selected from the group consisting of benzodioxolyl, pyridyl, furyl, and imidazolyl , (1-18) benzodioxoloxy lower alkyl, (1-19) pyridylthio lower alkyl, or (1-20 a) amine having one to two lower alkyl groups Base; and R12

(2-1) Hydrogen, (2-2) Lower alkyl, (2-3) Lower alkyl substituted by halogen, (2 - 4 ) Lower sulphur' (2-5) Lower alkynyl, (2- 6) lower alkyl fluorenyl, (2-7) hydroxy lower alkyl, (2-8) lower alkoxy lower alkyl, (2-9) cyclo(C3-C8) alkyl, (2-10) ring (C3-C8)alkyl lower alkyl, (2-1 1 a)phenyl, (2-12 a) may have a phenyl lower stage group selected from one to three groups as follows on the phenyl group: One to two lower-grade amine groups and phenoxy(2-13)tetrahydrofuranyl, (2-14) lower alkyl substituted by a heterocyclic group selected from furyl and pyridyl, -18-200831498 (2 -15) tetrahydropyranyl, or (2-16) lower alkyl alkoxy lower alkyl), or Q is a group represented by the following formula (Π): R21-A2- (wherein -A2- A lower alkylene group, a lower alkylene group, or a group -A21-0-A22-, wherein A21 and A22 are the same or different, and each exhibits a C1-C5 alkylene group (only φ constitutes an alkylene group and A2). The total number of carbon atoms of the alkyl group does not exceed 6); and R21 is represented by an N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidinyl, hexahydropyrimidinyl, and piperidin Alkyl, octahydroisodecyl, azepanyl, azocanyl, azaphthyl, azaspiro, diazaspiro, dihydropyrrolyl, imidazolyl , dihydroimidazolyl, triazolyl, dihydrotriazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazine , tetrazolyl, fluorenyl, isodecyl, porphyrin, isoindolyl, hexahydroisodecyl, octahydroisodecyl, benzimidazolyl, quinolyl, isoquine Lolinyl, oxazolyl, quinazolinyl, dihydroquinazolinyl, benzotriazolyl, oxazolyl, spiropentane porphyrin, oxazolyl, isoxazolyl, oxadiazolyl , oxazolidinyl, isoxazolidinyl, oxazinanyl, morpholinyl, benzoxazolyl, dihydrobenzoxazolyl, benzoxazinyl, dihydrobenzoxazine , benzoxazolyl, benzooxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinyl, benzothiazolyl, and benzo Thiadiazolyl, -19- 20083 The N-containing heterocyclic ring represented by 1498 R may be selected from the group consisting of (1) to (4), (5 a) (6 a), (7) to (9), (1〇a), (ua), Substituting one of (12) and (13) to three groups: (1) a halogen-substituted or unsubstituted lower alkyl group, (2) a lower alkenyl group, (3) a lower alkoxy group, (4) a hydroxyl group, 5 a) lower alkoxy or phenyl lower alkoxy, (6 a) phenyl, (7) lower alkyl fluorenyl, (8) carboxyl, (9) lower-grade azoxy ore, (10 a) may have One to two lower alkylamines, (11 a) phenyl lowers (which may have from one to two lower alkoxy groups on the phenyl group),

(12) A ketone group, and (13) a thiol group. Item 3 The present invention provides a heterocyclic compound according to item 2 or a salt thereof, wherein Q represents a group represented by the following formula (I): 2 R12 R11 c-- 1-A1——(wherein 'A1 shows lower alkylene; -20- 200831498 Z shows 0 or s; R11 shows (1 -1) hydrogen, (1-2) lower alkyl, (1-3 aa) a phenyl '(1-4 aa) having one to two halogen atoms is selected from a heterocyclic group of pyrazinyl and thienyl (wherein the heterocyclic group may be substituted by a lower alkyl group),

(1-5 aa) an amine-based lower alkyl group which may have one or two groups selected from the group consisting of lower alkyl, lower alkyl sulfonyl, hydroxy lower alkyl, lower alkane on the amine group and/or lower alkyl group An oxycarbonyl group, an amine carbaryl lower alkyl group, a fluorenyl carbonyl group, a phenyl group (the phenyl group may have a group selected from a halogen and a lower alkoxy group), and a phenyl lower alkoxycarbonyl group, or 1-20 a) an amine group which may have one to two lower alkyl groups; and R12 represents (2-1) hydrogen, (2-2) lower alkyl group, (2-4) lower alkenyl group, (2-6) Lower alkyl alkano group, (2-7) hydroxy lower alkyl group, (2-8) lower alkoxy lower alkyl group, or (2-9) cyclo(C3-C8) alkyl group). Item 4 The present invention provides a heterocyclic compound according to item 2 or a salt thereof, wherein the towel is represented by the following formula (II): R21-A2- (wherein -A2- indicates lower alkylene) Or a lower alkyl group; and R21 is an N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidinyl, azepanyl, oxazolidinyl, and oxazinyl (oxazinanyl ) wherein the N-containing heterocyclic ring represented by R21 may be substituted with one to three groups selected from the group consisting of (1), (12) and (13): (1) halogen-substituted or unsubstituted substituents , (12) keto groups, and (13) thioketo groups). Item 5 The present invention provides a heterocyclic compound of the formula (1) according to item 3 or a salt thereof selected from the group consisting of: & Ν-[5-(4-benzo[b]thiophen-4-yl-piperazine) )·pentyl]-acetamide, Ν-[5·(4-benzo[b]thiophen-4-yl-piperazine·buki)·pentyl]-2,4-difluoro-benzamide Amine, N-[4-(4-benzo[b]thiophen-4-yl-piperazine-bukibbutyl]-N-cyclopropyl-acetamide, 5-methylpyrazine-2-carboxylic acid [4-(4benzo[b]thiophene-4-yl]piperazine·^ kibbutyl]-ethyl-decylamine, thiazole-4-carboxylic acid [4-(4-benzo[b]thiophene-4 _piperazinyl butyl butyl ethyl decylamine, -22- 200831498 N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-N-ethyl -acetamide, Ν-[4·(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-N-isopropyl-acetamide, N-[4 -(4 - benzo[b] phenanthren-4-yl-dep-1-yl)-butyl]-N-ethyl-thioacetamide, N-allyl-N-[4-( 4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-B

Indoleamine, and N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-N-tert-butyl-formamide. Item 6 The present invention provides a heterocyclic compound of the formula (1) according to item 4 or a salt thereof selected from the group consisting of: 1-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) -pentyl]-imidazolidine-2-one

^[5-(4-Benzo[b]thiophen-4-ylpiperazin-1yl)-pentyl]_3-methyl-imidazol-2-one, ' 1-[5-(4 - Benzo[b]嚷-phen-4-yl-indome-1-yl)-pentyl]-Banluyuan-2-嗣1-[5-(4-benzo[b]nonin-4-yl - 脉 -1- yl)-pentyl]- 卩 略 院 - 2,5-dione, 1-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl )-butyl]-azapan-2-one, -23- 200831498 3-[6-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-hexyl] Oxazolidinone 3-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-4,4-dimethyl-oxazolidine-2- Ketone, 3-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-4-methyl-oxazolidin-2-one,

3-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-oxazolidin-2-one, [4-(4-benzo[b][b Thiophen-4-ylpiperazin-1-yl)-butyl]-pyrrolidin-2-one [4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) -butyl]-piperidin-2-one, [[E)-4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-but-2-enyl]- 3-methyl-imidazolidine-2-one, [4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-piperidine-2-thione, And 3-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-4-methyl-oxazole

Item 7 The present invention provides a pharmaceutical composition comprising the heterocyclic compound of the formula (1) according to any one of items 1 to 6 or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier. Item 8 The present invention provides a pharmaceutical composition for the treatment or prevention of a central nervous system disorder. -24- 200831498. Item 9

The present invention provides the pharmaceutical composition according to item 8, which is used for treating or preventing a central nervous system disorder selected from the following: schizophrenia; persistent, refractory or chronic schizophrenia; emotional disorder; psychiatric disorder; Affective disorder; type I depression; type II depression; depression; endogenous depression; major depression; depression and obsessive depression, mood disorders; circulatory affective disorder; Panic disorder; square phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; physical symptoms; transformed disorder; pain disorder; suspected disorder; fabricated disorder; Sexual disorders; sexual dysfunction; sexual desire disorders; sexual arousal disorders; erectile dysfunction; anorexia; satiation; sleep disorders; adaptation disorders; alcohol abuse; alcoholism; drug addiction; stimulant poisoning; anesthetic poisoning; Lack of pleasure in the original Physician; lack of pleasure in mental or psychological reasons; lack of pleasure associated with depression; Lack of pleasure associated with schizophrenia; insanity; cognitive impairment; cognitive impairment associated with Alzheimer's disease; Parkinson's disease and other neurodegenerative disorders; due to Alzheimer's disease, Parkinson's disease and related nerves Cognitive impairment caused by degenerative conditions; cognitive impairment of schizophrenia; cognitive impairment due to obligatory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; Autism: Tourette's disease; convulsions; attention deficit 7 hyperactivity disorder; behavioral disorders; and Down's syndrome. -25-200831498 Item 10 The present invention provides a method for producing a pharmaceutical composition comprising the heterocyclic compound of the formula (1) according to any one of claims 1 to 6 or a salt thereof, and a pharmaceutically acceptable carrier mixing. Item 11

The present invention provides the use of the heterocyclic compound of the formula (1) according to any one of items 1 to 6 or a salt thereof as a medicament. Item 12 The present invention relates to a heterocyclic compound of the formula (1) or a salt thereof according to any one of items 1 to 6 as a dopamine D2 receptor partial agonist and/or a serotonin 5-HT2 A receptor antagonist and Use of an adrenergic receptor antagonist and/or a serotonin absorption inhibitor and/or a serotonin reuptake inhibitor. Item 13 The present invention provides a method of treating or preventing a central nervous system disorder, which comprises The heterocyclic compound or a salt thereof of the formula (1) according to any one of items 1 to 6 is administered to a human or an animal. Specific compounds of the indole type/heterocyclic type are described in items 5 and 6. [Embodiment] • 26-200831498 BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a heterocyclic compound represented by the formula (1) or a salt thereof, preferably in the formula, represents Rn in the formula (I) of Q, R12 and A1 and R21 and A2 in the formula (II) of the formula (II) represent the following substituents: The heterocyclic compound represented by the formula (1) or a salt thereof is as follows:

[wherein Q represents a group represented by the following formula (I): Z R12 II I R11-C-N_ ... _ (wherein A1 represents a lower alkyl group; Z represents 0 or s; R11 (i -1) Hydrogen (1 -2) Lower alkyl 5 (l -3 a) is selected from the group consisting of phenyl, naphthyl, and indanyl, wherein the aryl group may be substituted as follows丨之--To three groups substituted: (1) to (viii), (ix a), (X a), (X ii), (xiii a), (xiv) to (xviii), (xix a ) , (XX) to (xxvi), -(xxvii a), (xxviii) to (xxxii), and (xxxiii a): (1) lower alkyl, (ii) lower alkenyl, -27- 200831498 (iii) halogen Substituted lower alkyl, (iv) lower alkoxy, (v) halogen-substituted lower decyloxy ' (vi) nitro, (vii) cyano, (viii) halogen, (ixa) phenyl,

(xa) phenoxy, (xi) lower-grade oxyalkyl, (xii) hydroxy, (xiiia) lower alkoxy or phenyl low-grade hydrazine with one to three halogens on the phenyl Base ' (xiv) lower alkyl fluorenyl, (xv) sulfonyl, (X vi) lower thiol, (χνϋ) lower alkyl sulfonyl, (xviii) hydroxy sulfonyl, (xixa) may have An amine group selected from one of the following groups to two groups: lower alkyl, lower alkyl fluorenyl, cyclo(C3-C8) alkyl, phenyl, and benzamidine (more preferably, N, N-di lower) Alkylamino, lower alkylalkylamino, N-lower alkino-N-cyclo(C3-C8)alkylamino, phenylamino, or benzhydrylamino) (XX: morpholine) Carbonyl lower alkenyl, morpholinylcarbonyl lower alkyl, -28- (xxi) 200831498

(xxii) (xxiii) (xx iv) (XXV) (xx vi) (xxviia) pyrrolidinyl, (xxviii) (xxix) (XXX) (xxxi) (xxxii) (xxxiiia) pyrrolyl, pyrazolyl, Imidazolyl, triazolyl, pyridyl, may have one to two (preferably one) ketomorpholinyl, thiomorphinyl lower alkynyl, cyclo(C3-C8)alkyl, fluorenyl, and a keto group and a lower alkyl dihydropyrazolyl group, (1 -4 a) selected from heterocyclic groups: pyrrolidinyl, piperidinyl,

Thiazolidinyl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, dihydrogen thiol, butyl B, dihydropyrrole, tetrahydrogen chelate, 11 decyl, fluorene exposure, thiazole Base, oxazolyl, isoxazolyl, thienyl, furyl, fluorenyl, fluorenyl, isoindolyl, benzimidazolyl, imidazopyridyl, quinolyl, dihydroquinoline , tetrahydroquinolyl, isoquinolyl, porphyrinyl, oxazolyl, quinoxalinyl, benzotriazolyl, dihydronaphthyridinyl, benzothiazolyl, dihydrobenzothiazolyl, Dihydrobenzothiazolyl, thienopyrazinyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, furopyrrolyl, benzodioxolyl , dihydrobenzodioxanyl, -29-200831498 and the present thiophenyl group, wherein the heterocyclic group may be substituted with one or two of the following substituents: (i) to (v), Vi a), (vii a), (viii), (ix a), (X a), and (xi) to (xix): (i) lower alkyl, (ii) lower alkyl substituted by halogen, (iii) lower alkoxy, (iv) substituted by halogen Lower alkoxy,

卤素) Halogen '(vi a) may have a phenyl group selected from one to three (preferably one) groups on the phenyl group: a halogen and a halogen-substituted lower alkyl group, (vii a) may have one to three (preferably one to two) a phenyl lower alkyl group of a halogen atom, (viii) a lower alkyl fluorenyl group, (ix a) a benzyl fluorenyl group, and (xa) may have one to two (preferably one) on the amine group. Lower alkyl alkane amine lower alkyl alkane ' (xi) lower alkylthio ' (xii) pyrrolyl, (xiii) keto, (xiv) thioketo, (xv) amine carbaryl, (XV i Permeation group, (xvii) indoleyl, (xviii) thienyl, and -30- 200831498 (xix) furanyl, (1-5 a) may have an alkyl group and/or a lower alkyl group selected from the group consisting of One to two groups of amino lower alkyl: lower alkyl, lower alkyl fluorenyl, hydroxy lower alkyl, lower alkoxycarbonyl, amine methyl decyl lower alkyl, fluorenyl carbonyl, phenyl (the The phenyl group may have one selected from the group consisting of halogen and lower alkoxy groups to three (preferably one) groups, and a phenyl lower alkoxycarbonyl group, (1-6) lower alkoxy lower alkyl group,

(1-7 a) benzhydryl-based lower alkyl group, (1-8 a) may have a phenyl lower alkyl group selected from the group consisting of one to three (preferably one to two): a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen, and a nitro group, (1-9 a) may have a phenoxy lower alkyl group selected from the group consisting of one to three groups: a lower alkyl group, a lower alkoxy group, Halogen, and cyano (1-10) adamantyl lower alkyl, (1-11 a) may have a phenyl lower alkenyl group selected from the group consisting of one to three (preferably one to two) groups below a lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkyl group, a halogen-substituted lower alkoxy group, an amine group having one to two lower alkyl groups (preferably N,N-di-lower alkylamine) (C), halogen, and nitro, (1-12 a) may have a ring (C3-C8) alkyl group selected from the group consisting of: an amine group having one to two lower alkyl groups (preferably N, N) a di-lower alkylamino group; an amine-based lower alkyl group having one to two lower alkyl groups (preferably N,N-di-lower alkylamino lower alkyl group); and may have a halogen-selective and low- 31- 200831498 One to three alkyl group (preferably one) phenyl group '(1-13) cycloalkyl (C3-C8) lower alkyl, (1 -1 4 a) lower phenylthio group homes'

(1 _ 1 5 a) Lower alkyl substituted with a heterocyclic group selected from the group consisting of piperidinyl, tetrahydropyranyl, pyridyl, thienyl, imidazolyl, tetrazolyl, benzimidazolyl, isoindole An anthracenyl group, a thiazolidinyl group, and a fluorenyl group, wherein the heterocyclic group may have one selected from the group consisting of lower alkyl, lower alkoxy, halogen, keto, and thioketo to three (preferably one to two) a group '(1 -1 6 a)phenyl lower alkenyl group which may have one to two (preferably one) phenyl group in the lower alkenyl group), (1-17) is a lower stage substituted with a heterocyclic group selected as follows Alkenyl: benzodioxolyl, pyridyl, furyl, and imidazolyl, (1-18) benzodioxoloxy lower alkyl, (1-19) pyridine a thio-based lower alkyl group, or (1-20 a) may have one to two lower alkyl groups, and more preferably, R11 is defined as (1 -1) hydrogen, (1 - 2) lower-grade, (1-5 aaa) an amine-based lower alkyl group having one group selected from the group consisting of a lower alkyl fluorenyl group and a lower alkoxycarbonyl group on an amine group and/or a lower alkyl group, or (l-20 aa) having one to two Amino group of lower alkyl; and R12 ( 2-1) Hydrogen, (2-2) lower alkyl, -32- 200831498 (2-3) lower alkyl substituted by halogen, (2 - 4 ) lower base ' (2-5) lower alkynyl, (2-6) lower alkyl fluorenyl, (2-7) hydroxy lower alkyl, (2-8) lower alkoxy lower alkyl, (2-9) cyclo(C3-C8) alkyl,

(2-10) a ring (C3-C8) alkyl lower alkyl group, (2-1 1 a) phenyl group, (2-12 a) may have one to three (preferably one) selected from the group consisting of the following ones. a phenyl lower alkyl group: an amine group having one to two lower alkyl groups (more preferably N,N-dilower alkylamino group) and a phenoxy group, (2-13) tetrahydrofuranyl group, (2 -14) a lower alkyl group substituted with a heterocyclic group selected from the group consisting of furyl and pyridyl, (2-15) tetrahydropyranyl, or (2-16) lower alkyl alkoxy lower alkyl, and Preferably, R12 is defined as: (2-1) hydrogen, (2-2) lower alkyl, (2 - 4) lower base ' (2-6) lower alkane, (2-7) lower hydroxy Alkyl, -33- 200831498 (2-8) lower alkoxy lower alkyl, or (2-9) cyclo(C3-C8)alkyl), or Q is a group represented by the following formula (π) : R21-A2 (where '-A2- indicates a lower alkyl group, a lower alkyl group, or a group Α2ι_〇_ A22-, wherein

A21 and A22 are the same or different and each exhibits a C1-C5 alkylene group (only the total number of carbon atoms constituting the A1 alkylene group and the A2 alkylene group does not exceed 6); and R21 is selected from the following N-containing heterocyclic groups. : pyrrolidinyl, imidazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindole, azepanyl, azocanyl, azaindole, nitrogen Heterosidinyl, diazaspyl, dihydropyrrolyl, imidazolyl, dihydroimidazolyl, triazolyl, dihydrotriazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, Dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, tetrazolyl, fluorenyl, isodecyl, porphyrinyl, isoindolyl, hexahydroisodecyl, Octahydroisoindolyl, benzimidazolyl, quinolyl, isoquinolinyl, oxazolyl, quinazolinyl, dihydroquinazolinyl, benzotriazolyl, oxazolyl, snail Pentane porphyrin group], oxazolyl, isoxazolyl, oxadiazolyl, oxazolidinyl, isoxazolidinyl, oxazinanyl, morpholinyl, benzoxazolyl Dihydrobenzoxazolyl, benzoic acid Azinyl, dihydrobenzoxazolyl, benzoxazolyl, benzooxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazyl, thiazolidinyl a benzothiazolyl group, and a benzothiadiazolyl group, wherein the N-containing heterocyclic ring represented by R21 may be substituted with one or three groups selected from the group consisting of: -34- 200831498 (1) to (4), (53), 61), (7) to (9), (10&), (11&), (12), and (13): (1) halogen-substituted or unsubstituted lower-grade courtyard (2) lower alkenyl y (3) lower-grade alkoxyj (4) hydroxy, (5 2 1) lower alkoxy or phenyl lower oxime 5 (6 2 t) phenyl (7) lower alkyl fluorenyl (8) carboxy ( 9) lower alkoxy group, (10 a) amine carbenyl group having one to two lower alkyl groups, (11 a) phenyl lower stage group (which may have one to two on: benzene: group)

a lower alkoxy group, a (12) ketone group, and (13) a thioketone group, and more preferably, the definition of R12 includes: an imidazolidinyl group having one or two groups selected from the group consisting of a lower alkyl group and a ketone group; a piperidinyl group having one or two groups selected from the group consisting of a lower alkyl group, a ketone group, and a thioketone group; an oxazolidinyl group having one selected from the group consisting of a lower alkyl group and a ketone group to three groups; One of the lower alkyl and keto groups to the two groups of oxazinanyl). Specifically, each group shown in the above formula is shown below. Examples of lower alkyl groups are straight or branched fluorenyl groups having from 1 to 6 carbon atoms, preferably from 1 to -35 to 200831498 4 carbon atoms. More specifically, it includes a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a third butyl group, a second butyl group, a n-pentyl group. , 1-ethylpropyl group, isopentyl group, neopentyl group, n-hexyl group, 1,2,2-trimethylpropyl group, 3,3-dimethylbutyl group, 2-B a butyl group, an isohexyl group, a 3-methylpentyl group, and the like.

Examples of lower alkylene groups are straight or branched alkyl groups having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. More specifically, it includes a methyl group, an ethyl group, a propyl group, a 2-methyl propyl group, a 2,2-dimethyl-ethyl group, and a 2,2-dimethyl group. a propyl group, a 1-methyl propyl group, a methyl group, a methyl group, a butyl group, a 1-methyl butyl group, a 1-ethyl butyl group, 2 - Methyl butyl group, 2-ethyl butyl group, pentyl group and hexyl group. Examples of lower alkenylene groups are straight or branched chain extension groups having 1 to 3 double bonds and 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. More specifically, it includes a vinyl group, a propylene group, a 1-methyl-1-propenyl group, a 2-methyl-1-propenyl group, a 2-extended propylene group, and 2 - a butenyl group, a 1-butenyl group, a 3-butenylene group, a 2-pentopentenyl group, a 1-pentenyl group, a 3-pentopentenyl group, a 4-strand Pentenyl group, 1,3 - extended butadiene group, 1,3-pentylene group, 2-pentene-4-extension group, 2-extended hexene group, 1-extension Alkenyl group, 5-extension group, 3-extrusion group, 4-extended hexenylene group, 3,3-dimethyl-1-extended propylene group, 2-ethyl-1- A propylene group, a 1,3,5-extension hexanyl group, a 1,3 hexanyl group, and a 1,4-extended hexadiene group are exemplified. -36- 200831498 An example of a C1-C5 alkylene group is a straight or branched alkylene group having 1 to 5 carbon atoms. More specifically, it includes a methyl group, an ethyl group, a propyl group, a 2-methyl propyl group, a 2,2-dimethyl-ethyl group, and a 2,2-dimethyl group. A propyl group, a 1-methyl propyl group, a methyl group, a methyl group, a butyl group, and a pentyl group. In the formula, an example of the -A^O-A2- group may be -CH2-0-CH2.

, -ch2-o-(ch2)2-, -ch2-o-(ch2)3-, -ch2-o-(ch2)4-, -ch2-o-(ch2)5-, -(ch2)2 -o-(ch2)2·, -(ch2)3-o-(ch2)3-, and -ch(ch3)-ch2-o-ch(ch3)-ch2-. Examples of lower alkenyl groups are straight or branched alkenyl groups having 1 to 3 double bonds and 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms), and include trans and cis-configurations. . More specifically, it includes a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-methyl-1-propenyl group, a 2-methyl-1-propenyl group, and a 2-methyl-2 group. a propylene group, a 2-propenyl group, a 2-butene group, a 1-butene group, a 3-butene group, a 2-pentenyl group, a 1-pentenyl group, a 3-pentene group a group, a 4-pentenyl group, a 1,3-butadiene group, a 1,3-pentadienyl group, a 2-penten-4-ynyl group, a 2-hexenylene group, 1 Hexenyl group, 5-hexenyl group, 3-hexenyl group, 4-hexenyl group, 3,3-dimethyl-1-propene group, 2-ethyl-1-propenyl group 1, 1,3,5-hexatrienyl group, 1,3-hexadienyl group, and 1,4·hexamethylene group. Examples of lower alkyne groups are straight or branched alkyne groups having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. More specifically, it includes an acetylene group, a 2. propynyl group, a 2-butynyl group, a 3-butynyl group, a 1-methyl-2-propynyl group, a 2-pentynyl group, And 2-hexyne group and the like. -37- 200831498 Examples of halogen atoms are fluorine atoms, chlorine atoms, bromine atoms and bowl atoms.

An example of the halogen-substituted lower alkyl group is the above-mentioned lower alkyl group substituted with 1 to 7, preferably 1 to 3, halogen atoms. More specifically, it includes a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyl group. , dichlorofluoromethyl group, 2,2·difluoroethyl group, 2,2,2·trifluoroethyl group, pentafluoroethyl group, 2-fluoroethyl group, 2-chloro Ethyl group, 3,3,3-trifluoropropyl group, heptafluoropropyl group, 2,2,3,3,3-pentafluoropropyl group, heptafluoroisopropyl group, 3-chloropropyl group Group, 2-chloropropyl group, 3-bromopropyl group, 4,4,4-trifluorobutyl group, 4,4,4,3,3-pentafluorobutyl group, 4-chlorobutyl group , 4-bromobutyl group, 2-chlorobutyl group, 5,5,5-trifluoropentyl group, 5-chloropentyl group, 6,6,6-trifluorohexyl group, 6-chlorohexyl group And perfluorohexyl groups, and the like. Examples of lower alkoxy groups are straight or branched alkoxy groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. More specifically, 'including methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, third butoxy group, second An oxygen group, a n-pentyloxy group, an isopentyloxy group, a neopentyloxy group, a n-hexyloxy group, an isohexyloxy group, a 3-methylpentyloxy group, and the like. Examples of the aryl group are a phenyl group, a biphenyl group, a naphthyl group, a dihydrogenated benzyl group, and a 9H-fluorenyl group. Examples of the aryloxy group are a phenoxy group, a naphthyloxy group and the like. Examples of the arylthio group are a phenylthio group, a naphthylthio group and the like. Examples of the aryl fluorenyl group are a benzamidine group, a naphthylquinone group, and the like. -38- 200831498 An example of a lower alkylthio group is a straight or branched alkylthio group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. More specifically, it includes a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a n-butylthio group, a third butanethio group, a n-pentylthio group, and a hexylsulfide group. Group and so on.

An example of the lower alkoxy group substituted by halogen is a lower alkoxy group as described above which is substituted with 1 to 7, preferably 1 to 3, halogen atoms. More specifically, it includes a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a chloromethoxy group, a dichloromethoxy group, a trichloromethoxy group, a bromomethoxy group. Group, dibromomethoxy group, dichlorofluoromethoxy group, 2,2,2-trifluoroethoxy group, pentafluoroethoxy group, 2-chloroethoxy group, 3,3,3 -trifluoropropoxy group, heptafluoropropoxy group, heptafluoroisopropoxy group, 3-chloropropoxy group, 2-chloropropoxy group, 3-bromopropoxy group, 4,4 , 4-trifluorobutoxy group, 4,4,4,3,3-pentafluorobutoxy group, 4-chlorobutoxy group, 4-bromobutoxy group, 2-chlorobutoxy group 5,5,5-trifluoropentyloxy group, 5-chloropentyloxy group, 6,6,6-trifluorohexyloxy group, and 6-chlorohexyloxy group. The sinus of the lower alkane group is a straight or branched alkane group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. More specifically, it includes a formamidine group, an acetamyl group, a propyl group, a butyl group, an isobutyl group, a pentamidine group, a third butanyl group, and a hexanyl group. Examples of lower alkoxy groups are straight or branched alkoxy groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. More specifically, it includes a methyloxy group, an ethoxy group, a propoxy group, a butoxy group, an isobutoxy group, a pentyloxy group, a third butane group. And hexyloxy groups and the like. -39- 200831498 Examples of lower alkyl alkoxy lower alkyl groups are straight or branched alkyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) having 1 to 3 lower alkyl groups as exemplified above Alkoxy group (preferably one). More specifically, it includes a methyloxymethyl group, an ethoxylated propyl group, a propyloxyethyl group, a butoxymethyl group, a 2-isobutyloxyethyl group, and 3 - a pentyloxypropyl hydrazine, a tert-butoxycarbonylmethyl group, a hexanyloxymethyl group, and the like.

Examples of the protecting group for a hydroxyl group are a lower alkyl group (linear or branched alkyl group, preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms), and a lower alkyl alkane group (linear or branched alkyl group). a mercapto group, preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and a linear or branched alkyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) A phenyl lower alkyl group (which may have one to three, preferably one, such as a halogen atom or the like) on the phenyl group. Examples of the protecting group for a hydroxy group are a linear or branched alkyl group having 1 to 6 carbon atoms (preferably i to 4 carbon atoms), a lower alkyl fluorenyl group (linear or branched alkyl fluorenyl group, preferably having A phenyl lower alkyl group having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and a linear or branched alkyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). An example of a protected hydroxy group is a lower alkoxy group, a phenyl lower alkoxy group having a lower alkoxy group as described above (the lower alkoxy moiety is a lower alkoxy group as described above, and it is in a phenyl group) There may be one to three 'better ones, such as a substituent such as a halogen atom. More specifically, it includes a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a third butoxy group, and a second group. Oxygen group, n-pentyloxy-40-200831498 group, isopentyloxy group, neopentyloxy group, n-hexyloxy group, isohexyloxy group, 3-methylpentyloxy group, methoxy group , ethoxylated group, propoxy group, butyloxy group, isobutyloxy group, pentyloxy group, tert-butoxy group, hexyloxy group, benzyloxy group , 4-chloro-benzyloxy group, 2-phenylethoxy group, 1-phenylethoxy group, 3-phenylpropoxy group, 4-phenylbutoxy group, 5-phenyl group A pentyloxy group, a 6-phenylhexyloxy group, a 1,1-dimethyl-2-phenylethoxy group, a 2-methyl-3-phenylpropoxy group, or the like.

Examples of the hydroxy lower alkyl group are the lower alkyl groups exemplified above having 1 to 5, preferably 1 to 3, hydroxyl groups (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms) , a straight or branched alkyl group). More specifically, it includes a methylol group, a 2-hydroxyethyl group, a 1-hydroxyethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, a 4-hydroxybutyl group, and 3 , 4·dihydroxybutyl group, 1,1-dimethyl-2·hydroxyethyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, 3,3-dimethyl-3-hydroxypropane a group, a 2-methyl-3-hydroxypropyl group, a 2,3,4-trihydroxybutyl group, a perhydroxyhexyl group, and the like. Examples of the protecting group of the hydroxy lower alkyl group are a straight or branched alkyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), and a lower alkyl alkene group (preferably having 1 to 6) More preferably, having from 1 to 4 carbon atoms, a straight or branched alkane group, and a lower alkyl group of the phenyl group and having a lower alkyl moiety having from 1 to 6 carbon atoms (preferably a straight or branched alkyl group of 1 to 4 carbon atoms. Examples of protected hydroxy lower alkyl groups are 1 to 5, preferably 1 to 3, protected hydroxy groups as described above (preferably lower alkoxy groups -41 _ 200831498)

a lower alkyl alkoxide group or a phenyl lower alkoxy group (which may have 1 to 3, preferably 1 such as a substituent of a halogen atom) on the phenyl group, as described above for the lower alkyl group ( It is preferably a straight or branched alkyl group having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. More specifically, it includes a methoxymethyl group, a 2-methoxyethyl group, a 2-ethoxyethyl group, a 2-n-propoxyethyl group, a 2-isopropoxyethyl group. , 2-n-butoxyethyl group, 2-isobutoxyethyl group, 2-tert-butoxyethyl group, 2-second butoxyethyl group, 2-n-pentyloxy group a group, 2-isopentyloxyethyl group, 2-neopentyloxyethyl group, 2-n-hexyloxyethyl group, 2-isohexyloxyethyl group, 2-(3-methylpentyloxy group) Ethyl group, 2-methyloxyethyl group, 2-ethyloxyethyl group, 2-propoxyoxyethyl group, 2-butoxyethanol group, 2-isobutyl group a methoxyethyl group, a 2-pentyloxyethyl group, a 2-tert-butylcarbonyloxyethyl group, a 2-hexyloxyethyl group, a 2-benzyloxyethyl group, 2 -(2-phenylethoxy)ethyl group, 2-(1-phenylethoxy)ethyl group, 2-(3-phenylpropoxy)ethyl group, 2-(4-benzene Butyloxy)ethyl group, 2-(5-phenylpentyloxy)ethyl group, 2-(6-phenylhexyloxy)ethyl group, 2-(1,1--*methyl group -2 - Benzoethoxy)ethyl group, 2-(2-methyl-3-phenylpropoxy)ethyl group, 3-ethoxypropyl group Group, 2,3-diethoxypropyl group, 4-ethoxybutyl group, 3,4·diethoxybutyl group, 1,1-dimethyl-2-ethoxyethyl group a group, a 5-ethoxypentyl group, a 6-ethoxyhexyl group, a 3,3-dimethyl-3-ethoxypropyl group, a 2-methyl-3-ethoxypropyl group, And 2,3,4-triethoxybutyl group and the like. Examples of the lower alkoxycarbonyl group are those having a lower alkoxy group as the above-exemplified lower alkoxy group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 to 42 to 200831498 carbon atoms). Alkoxycarbonyl group of alkoxy group). More specifically, it includes a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group, an isopropoxycarbonyl group, a n-butoxycarbonyl group, an isobutylpropoxycarbonyl group, a third butoxycarbonyl group, and a An example of a lower alkyl sulfonyl group such as dibutoxycarbonyl, n-pentyloxycarbonyl, neopentyloxy, n-hexyloxycarbonyl, isohexyloxycarbonyl, and 3-methylpentyloxycarbonyl is a lower alkane. The base moiety is an alkylsulfonyl group of the lower alkyl group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkyl group) as exemplified above. More specifically, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonate Sulfhydryl, t-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, and 3-methylpentyl Kesulfonyl and the like. Examples of the cyclic C3-C8 alkyl group are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cycloφ-hexyl group, a cycloheptyl group, a cyclooctyl group and the like. An example of an amine group which may have a substituent selected from the group consisting of a lower alkyl group, a lower alkyl fluorenyl group, a cyclo C3-C8 alkyl group, an aryl group, and an aryl fluorenyl group is one or two selected from the group consisting of A lower alkyl group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkyl group), as exemplified above, preferably having 1 to 6 carbon atoms More preferably, it is 1 to 4 carbon atoms, a linear or branched alkyl fluorenyl group, a ring C 3-e 8 alkyl group as defined above, and an aryl group (preferably a phenyl group), and an aryl group as exemplified above (preferably, The phenyl group, and the group exemplified above as the aryl fluorenyl group (preferably benzoyl fluorenyl group) are a group of the substituent -43-200831498. More specifically, for example, an amine group, N-methylamino group, hydrazine, hydrazine-dimethylamino group, hydrazine-ethylamino group, hydrazine, hydrazine-diethylamino group, hydrazine-n-propylamine Base, Ν-isopropylamino group, fluorenyl-methylamino group, fluorenyl-ethylamino group, fluorenyl-phenylamino group, fluorenyl-benzhydrylamino group, and fluorenyl-ethenyl-fluorene a ring C3-C8 alkylamino group or the like.

An example of a morpholinylcarbonyl lower alkenyl group is a lower alkenyl group having a lower alkenyl group as exemplified above (preferably having 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, a linear or branched alkenyl group) A morpholinylcarbonyl lower alkenyl group. More specifically 3' includes 1-(or 2-) (4-cylinyl) anthracene, 1-(or 2- or 3-)(4morpholinylcarbonyl)1-(or 2-) Propylene based. An example of a morpholinylcarbonyl lower alkyl group is a lower alkenyl group having a lower alkenyl group as described above (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkenyl group) Morpholinylcarbonyl lower alkyl. More specifically, it includes 4-morpholinylcarbonylmethyl, 1-(or 2-)(4morpholinylcarbonyl)ethyl, 1-(or 2- or 3-)(4-morpholinylcarbonyl) An example of a pyrrolidinyl group in which the 1-(or 2-)propyl group may have a keto group is a pyrrolidinyl group which may have one to two ketone groups (preferably one). Specifically, it includes (1-, 2_, or 3-) pyrrolidinyl, (2_ or 3-) keto-1-pyrrolidinyl, (3-, 4-, or 5-) keto-2 - pyrrolidinyl, (2-, 4-, or 5-) keto-3-pyrrolidinyl. Examples of the dihydropyrazolyl group which may be selected from the group consisting of a ketone group and a lower alkyl group are dihydropyrazolyl groups which may have one to two groups selected from a ketone group and a lower alkyl group as exemplified above. An example of an aryl group which may have a -44 - 200831498 group selected from a halogen and a halogen-substituted lower alkyl group on the aryl group is as follows: the aryl moiety is a phenyl group, a naphthyl group or the like, and may have a aryl group on the aryl group One to five (preferably one to three, more preferably one) are exemplified above as a halogen and a halogen-substituted lower alkyl group as described above (a halogen-substituted linear or branched alkyl group, preferably having 1 to 6 carbon atoms, more preferably Good 1 to 4 carbon atoms.

Examples of the aryl lower alkyl group which may have a halogen atom are as follows: a lower alkyl group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkyl group) has one to Three, preferably one, aryl groups, the aryl moiety being a phenyl group, a naphthyl group or the like. The aryl group may be one to five, preferably one to three, more preferably one to two, and examples of the substituent of the halogen exemplified above are an amine lower alkyl fluorenyl group as follows: a lower alkyl fluorenyl group is exemplified as above (preferably having 1 to 6) One carbon atom, more preferably 1 to 4 carbon atoms, of a linear or branched alkane group has one to three amine groups, preferably one. More specifically, it includes an aminoethyl group, a 3-aminopropyl group, a 4-aminobutyl group, a 3,4-diaminobutanyl group, a 3,3-dimethyl-3-aminopropyl group, 4-aminobutyryl group, 5-aminopentyl group, and the like. Examples of the amine lower alkyl fluorenyl group which may have a lower alkyl fluorenyl group on the amine group are as follows: The above-exemplified amine lower alkyl fluorenyl group has one to two, preferably one, and the lower alkyl fluorenyl group is a substituent as exemplified above. More specifically, it includes N-methyl decylaminoethyl, N-ethyl decylamino acetyl, N-propyl decyl ethyl, 3-(N-ethyl fluorenyl) Propyl, 4-(N-ethylhydrazino)butanyl, 3,4-bis(N-ethylhydrazino)butanyl, 3,3-dimethyl-3-(N-propylamino) A propyl fluorenyl group, a 4-(N-methyl decylamino) butyl fluorenyl group, and a 5-(N-ethyl hydrazine-45-200831498 arylamino) pentyl group. An example of the amine-methyl indenyl lower alkyl group is one or three, as exemplified above, a lower alkyl group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkyl group). More preferably one to two amine mercapto groups.

Examples of the amine lower alkyl group are as follows: a lower alkyl group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkyl group) having one to five, preferably One, an amine group. More specific examples include aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, N,N-dimethylaminomethyl, N-methyl-N-ethylamino Methyl, N-methylaminomethyl, 2-(N-methylamino)ethyl, 1-methyl-2-(N,N-dimethylamino)ethyl, 1-methyl -2-(N,N-Diethylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, 2 -(N,N-Diisopropylamino)ethyl, 3-(N,N-dimethylamino)propyl, and 3-(N,N-diethylamino)propyl. It may have an alkyl group and/or a lower alkyl group selected from the group consisting of lower alkyl, lower alkyl sulfonyl, hydroxy lower alkyl, amine methyl decyl lower alkyl, fluorenyl carbonyl, aryl (on aryl) An example of an amine lower alkyl group having a group selected from a halogen and a lower alkoxy group, and an aryl lower alkoxycarbonyl group is a lower alkyl group as exemplified above (preferably having 1 to 6 carbon atoms) More preferably, one to four carbon atoms, a linear or branched alkyl group, has one to five, preferably one, an amine group. The amine group and/or the lower alkyl group may have one or two groups selected from the group consisting of lower alkyl groups (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, linear chain as defined above). Or branched alkyl), as above -46- 200831498

A lower alkyl alkane group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkyl fluorenyl group), exemplified as a hydroxy lower alkyl group (preferably having 1 to 6) More preferably, the carbon atom, more preferably 1 to 4 carbon atoms, of a straight or branched alkyl group has from one to three hydroxyl groups, as exemplified above, an amine methylidene lower alkyl group (preferably having 1 to 6 carbon atoms, more preferably 1) To 4 carbon atoms, the linear or branched alkyl group has one to three amine carbenyl groups, a mercaptocarbonyl group, an aryl group (which may have a group selected from the above-exemplified halogens and lower alkoxy groups) Preferably, the phenyl group has from one to five, more preferably one to three groups selected from the group consisting of halogen and a linear or branched alkoxy group (having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms). And an alkoxycarbonyl group having one to three (preferably one) exemplified above as an aryl group (the alkoxy moiety is a lower alkoxy group as exemplified above, that is, preferably having 1 to 6 carbon atoms, more preferably 1 to Examples of 4 carbon atoms, linear or branched alkoxy) lower alkoxy lower alkyl are: lower alkyl as exemplified above (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, of a linear or branched alkyl group) having one to three, preferably one, as exemplified above, a lower alkoxy group (preferably having 1 to 6 carbon atoms) More preferably, a straight or branched alkoxy group of 1 to 4 carbon atoms. More specifically, it includes methoxymethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 2-isobutyryloxyethyl, 2,2- Dimethoxyethyl, 2-methoxy-1-methylethyl, 2-methoxy=1=ethylethyl, 3-methoxypropyl, 3-ethoxypropyl, 2 -isopropoxyethyl, 3-isopropoxypropyl, 3-n-butoxypropyl, 4-n-propoxybutyl, 1-methyl-3-isobutoxypropyl 1,1-methyl-methyl-2-n-pentyloxyethyl, 5-n-hexyloxypentyl, 6-methoxyhexyl, 1-ethoxy-47-200831498 isopropyl, 2-methyl 3-methoxypropyl and the like. The arylsulfonyl lower alkyl group means a lower alkyl group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms 'more preferably 1 to 4 carbon atoms' as described above) having 1 to Five, preferably one, aryl fluorenyl (preferably benzamidine). More specific examples include benzhydrylmethyl, 2-benzylidenylethyl, 1-benzylideneethyl, 1-(or 2-)naphthylmethyl. The aryl group may have a lower alkyl group, a lower alkoxy group, a hydroxyl group,

The aryl lower-grade alkyl group of the halogen and nitro group means a linear or branched alkyl group of a lower sulfhydryl group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms) as described above. There are 1 to 3 (preferably 1) aryl groups in which the aryl moiety is a phenyl group, a naphthyl group or the like. The substituent on the aryl group may be 1 to 5, preferably 1 to 3, more preferably 1 to 2, which is selected from the group consisting of lower alkyl groups as described above (preferably having 1 to 6 carbon atoms 'better 1 to a linear or branched alkane of 4 carbon atoms, a linear or branched alkyl group, as described above, a lower alkoxy group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms) a group of an oxy), a hydroxyl group, a halogen, and a nitro group. An aryloxy lower-grade system group which may have a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen group and a cyano group on the aryl group means a lower stage group (preferably having 1 to 6 carbon atoms as described above) The linear or branched pendant s of 'better 1 to 4 carbon atoms' has 1 to 3 (preferably 1) aryl 'wherein the aryl moiety is phenyl, naphthyl or the like. The substituent on the aryl group may be 1 to 5, preferably 1 to 3, which is selected from the group consisting of lower alkyl groups as described above (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms). a chain or branched alkyl group, a lower alkoxy group as described above (preferably having 1 to 6 carbon atoms -48 to 200831498, more preferably 1 to 4 carbon atoms, a linear or branched alkyl group), halogen And a group of cyano groups. The aryl lower alkoxy group means a lower alkoxy group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkoxy group) having 1 to 3 as described above. One (more preferably one) aryl group, wherein the aryl moiety is a phenyl group, a naphthyl group or the like.

The amine group which may have a lower alkyl group means that it may have 1 to 2 lower alkyl groups as described above (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, linear or branched alkyl groups) The amino group of the group s). More specific examples include an amine group, N-methylamino group, N,N-dimethylamino group, N-ethylamino group, N,N-diethylamino group, N-n-propylamino group, N - Isopropylamino groups and the like. The aryl lower alkenyl group means that the lower alkenyl group (preferably having 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, a linear or branched alkenyl group) as described above has 1 to 3 (more) Preferably, the aryl group is a phenyl group, a naphthyl group or the like. The aryl group may have a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkyl group, a halogen-substituted lower alkoxy group, an amine group having a lower alkyl group, a halogen group, and a nitro group. The aryl lower alkenyl group means that an aryl lower alkenyl group (having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, a linear or branched alkenyl group) as described above has preferably a phenyl group. Substituent. The substituent on the aryl group may be 1 to 5, preferably 1 to 3, more preferably 1 to 2, which is selected from lower alkyl groups as described above (preferably having from 丨 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a straight or branched alkyl group, a lower alkoxy group as described above (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 -49 - 200831498)

a carbon atom, a linear or branched alkoxy group, a lower alkyl group substituted by a halogen as described above (a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms) Preferably, having 1 to 3 halogens, a lower alkoxy group substituted by a halogen as described above (having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, preferably a linear or branched alkoxy group) An amine group having 1 to 3 halogens, which may have a lower alkyl group as described above (the amine group may have one or two linear or branched alkyl groups (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms), halogen and nitro. The aryl group which may have a group selected from a halogen and a lower alkylaryl group means that the aryl moiety is a phenyl group, a naphthyl group or the like, and is in the aryl group. And having 1 to 5, preferably 1 to 3, more preferably 1 halogen and a lower alkyl group as described above (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, linear or a branched alkyl group. It may have an amine group lower alkyl group which may have a lower alkyl group, an amine group lower alkyl group which may have a lower alkyl group, and an aryl group (which may have a group selected from a halogen group and a lower alkyl group) The C3-C8 cycloalkyl group means that the C3-C8 cycloalkyl group as described above may have 1 to 3, preferably 1, a group selected from the group consisting of an amine group which may have a lower alkyl group as described above ( It may preferably have 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, which may have the above-described lower alkyl group as described above. a lower alkyl group (wherein the amino lower alkyl group preferably has 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and the linear or branched alkyl group preferably has 1 to 2 on the amine group. a straight or branched alkyl group (having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms), and an aryl group (aryl group) selected from the group consisting of a halogen as described above and a lower alkyl group as described above The aryl moiety is preferably phenyl, naphthyl or the like -50-200831498, and may have 1 to 5, preferably 1 to 3 in the aryl moiety, as described above for the halogen and the lower alkyl group as described above ( Preferably, it has from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, of a straight or branched chain. C 3 -C 8 cycloalkyl lower alkyl means: lower alkyl as described above ( Preferably having 1 to 6 Atoms, preferably 1 to 4 carbon atoms, the straight-chain or branched alkyl group) having from 1 to 3, preferably 1, described above, C3-C 8 cycloalkyl.

The arylthio lower alkyl group means that the lower alkyl group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkyl group) has 1 to 3 as described above. Preferably, one is an arylthio group as described above. The adamantyl lower alkyl group means that the lower alkyl group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkyl group) has 1 to 3 as described above. Preferably, one adamantyl group. Substituted by a heterocyclic group selected from piperidinyl, tetrahydropyranyl, pyridyl, thienyl, imidazolyl, tetrazolyl, benzimidazolyl, isodecyl, thiazolidinyl, and fluorenyl Lower alkyl (wherein the heterocyclic group may be substituted by a lower alkyl group, lower alkoxy group, halogen, keto group and thioketo group) means a lower alkyl group as described above (preferably having 1 to 6 carbons) The atom, more preferably 1 to 4 carbon atoms, of a straight or branched alkyl group, is selected from the group consisting of 1 to 3, preferably 1, substituted by a heterocyclic group: piperidinyl, tetrahydropyranyl, pyridine Base, thienyl, imidazolyl, tetrazolyl, benzimidazolyl, isodecyl, thiazolidinyl, and fluorenyl. The substituent on the heterocyclic group may be 1 to 5, preferably 1 to 3 groups selected from the group consisting of lower alkyl groups as described above (preferably having 1 to 6 carbon atoms, more preferably 1 to a lower alkoxy group (preferably having from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, straight chain or as described above), having four carbon atoms, a linear or branched chain, -51 - 200831498 Branched alkoxy), halogen, keto and thioketo.

The aryl lower alkenyl group which may have an aryl group on the lower alkenyl group means: an aryl lower alkenyl group as described above (preferably having 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms) A linear or branched alkenyl group is substituted with a phenyl group). The substituent of the lower alkenyl group may be 1 to 3, preferably 1 to 2, more preferably 1 aryl group as described above (preferably phenyl group). The lower alkenyl group substituted with a heterocyclic group selected from benzodioxolyl, pyridyl, furyl and imidazolyl means: lower alkenyl group as described above (preferably having 2 to 6 carbons) 1 to 3, preferably 1 or more, selected from benzodioxolyl, pyridyl, and imidazolyl, of the atom, more preferably 2 to 4 carbon atoms, of a straight or branched alkenyl group. The heterocyclic group is substituted. The benzodioxoloxy lower alkyl group means a lower alkyl group as described above (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkane) The base has 1 to 3, preferably 1, benzodioxoleoxy. The pyrithione lower alkyl group means that the lower alkyl group (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a linear or branched alkyl group) has 1 to 3 as described above. Preferably, it is a pyridylthio group. The aryl lower alkyl group which may have an amine group and an aryloxy group which may have a lower alkyl group on the aryl group means a lower alkyl group as described above (preferably having 1 to 6 carbon atoms, more preferably 1 to The 4 carbon atoms, which may be a linear or branched alkyl group, may have 1 to 3, preferably 1, an aryl group, of which an aryl moiety is a phenyl group, a -52-200831498 naphthyl group, and the like. The substituent on the aryl group may be up to 3, more preferably one selected from the group consisting of the above (which may have an alkyl group (preferably having 1 to 6 carbon atoms, a linear or branched alkane) Amino) group (preferably phenoxy). The heterocyclic group selected from the group consisting of furyl and pyridyl is: a lower alkyl group (preferably having 1 to 6 φ to 4 carbon atoms, a linear or branched alkyl group) as described above, selected from a furan group And a heterocyclic group-substituted heterocyclic group of pyridyl means: 1 to 4 (preferably saturated 3 to 8 members (preferably 5 to 8 members) monocyclic, imidazolidinyl, pyrazolidinyl, piperidinyl , hexahydrooctahydroisoindole, azepanyl azocanyl, etc.; comprising 1 to 2 (preferably to 3 (preferably 1 to 2) nitrogen atom saturated 3 to ^) monocyclic group (e.g., oxazolidinyl, isoxazolidine contains a saturated spiroheterocyclic group of 1 to 2 nitrogen atoms (e.g., 1-azaspiro[4,4]decyl, 2-azaspiro[4, spirofluorenyl ( For example, 1-azaspiro[4,5]fluorenyl, 2-|), diazaspiro (for example, 1,3-diazaspiro[1,4]fluorenyl), etc.; Containing 1 to 2 sulfur atoms and hydrazine to 3 8 members (more preferably 5 or 6 members) heteromonocyclic groups, for example • 3 to 1 to 5 saturated with 1 to 2 oxygen atoms, preferably 1 low The alkyl group of an alkyl group, more preferably 1 to 4, and the lower alkyl group of the aryloxy group as described above means a carbon atom. Preferably, 1 to 3, preferably 1 to 1 to 2) a nitrogen atom group (e.g., pyrrolidinylpyridyl, piperazinyl, ), azulaki (1) oxygen atom, and 18 members (preferably 5) To 6 benzyl, morpholinyl, etc.; for example, azaspiro-yl (4) fluorenyl, etc., aza-Spiro[4,5]fluorenyl, etc. [4, 4] fluorenyl, 1,4-di The saturation of the nitrogen atom is 3 to, thiazoridiny 1 ; : 8 members (more preferably 5 or 6 -53 - 200831498 Å) heteromonocyclic group, for example, tetrachloropyranyl, tetrachloropyranyl, oxyranyl , 恶x〇ranyl, di〇x〇ranyl, etc.; • contains 1 to 2 (preferably i) sulfur atoms saturated 3 to 8 members (more earth 5 or 6 members) heteromonocyclic groups, for example, tetrathienyl, tetrahydrothiopyranyl, etc.; • unsaturated 1 φ to 8 members containing 1 to 4 (preferably 1 to 3) nitrogen atoms (better 5) Or 6 members) a heteromonocyclic group, for example, a pyrrolyl group, a dihydropyrrolyl group (for example, '1 Η-2,5-dihydropyrrolyl group, etc.), an imidazolyl group (for example, '1 Η-m-D sitting base, etc.), A hydrogen imidazolyl group (for example, ιΗ_2, 3-diimidazolyl, etc.), a triazolyl group (for example, 4Η-1, 2, 4_) Azolyl, ιΗ-1,2,3_trimethyl, 2Η-1,2,3-triazolyl, etc.), dihydrothiazolyl (eg, 1Η-4,5-monohydro-1,2,4 - triazolyl, etc.), fluorene ratio D, dihydrofluorenyl (for example, 4,5-dihydropyrazolyl, etc.), pyridyl, dihydropyridyl (for example, 1,2-hydroquinone) More than thiol, etc., oxime, dihydropyrimidine (for example, 1,6-^dihydropyrimidinyl, etc.), tetrahydropyrimidinyl (for example, 1,2,3,4-tetrahydropyrimidinyl, etc.) , pyrazinyl, dihydropyrazinyl (for example, 1,2-dihydropyrazinyl, etc.), pyridazinyl, tetrazolyl (for example, 1 Η-tetrazolyl, 2 Η-tetrazolyl, etc.) ), etc.; • an unsaturated 3 to 8 member (more preferably 5 members) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, a thioxyl group or a dihydrothianylene group (for example) , 2,3 dihydrothiazolyl, etc.), isothiazolyl, thiadiazolyl (for example, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4 thiazide Erazolyl, 1,2,5-thiadiazolyl, etc., dihydrothiaridinyl, etc.; -54- 200831498 • Contains 1 to 2 (preferably 1) oxygen atoms and 1 to 3 (preferably 1 2) an unsaturated 3- to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group of a nitrogen atom, for example, an oxazolyl group, an isoxazolyl group or an oxadiazolyl group (for example, 1,2,4-oxadiyl) Azolyl, iota, 3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) • Unsaturated 3 to 8 members containing 1 to 2 sulfur atoms (more preferably 5 or 6 members) a heteromonocyclic group, for example, a thienyl group, a dihydrothienyl group, or the like;

• Unsaturated 3 to 8 member(more preferably 5 or 6 members) heteromonocyclic groups containing 1 to 2 oxygen atoms, for example, furyl, pyranyl, etc.; • 1 oxygen atom and 1 or 2 sulfur An atomic unsaturated 3 to 8 member (more preferably 5 or 6 members) heteromonocyclic group, for example, dihydrothinyl, etc.; • 1 to 4 (preferably 1 to 2) nitrogen atoms which are unsaturated, Fused heterocyclic group 'for example, fluorenyl, isodecyl, porphyrin, isoindolinyl, hexahydroisoindolyl (for example, 2,3,3a,4,7,7a- Hexahydroisoindolyl, etc.), benzimidazolyl, imidazopyridyl (eg 'imidazolyl, 2-a] pyridyl, etc.), quinolyl, dihydroquinolinyl (eg, 1, 2) -dichloroluolinyl, etc.), tetrahydroquinolyl (1,2,3,4-tetraquinolinyl, etc.), iso-oxalinyl, porphyrinyl, oxazolyl, quinolinol, dihydroquine Π 啉 啉 ( (3,3-dihydroquinazolinyl, etc.), benzotrienyl (such as 'benzo[d][1,2,3]triazolyl, etc.), naphthilidyl (naphthilidyl) ( For example, ^8-naphthylpyridinyl, etc.), dihydronaphthalene pyridine (for example, 1,2-dihydro-poline U-based, etc.), odorant, etc.) An unsaturated, hydrazine-containing group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, a benzothiazolyl group (for example, benzo[d]thiazolyl-55-200831498, etc.), Hydrobenzothiazolyl (eg, 2,3-dihydrobenzo[d]thiazolyl, etc.), benzothiadiazolyl, dihydrobenzothiazinyl (2H-3,4-dihydrobenzo[ b ] [ 1,4 ]thiazinyl, etc.), thienopyridyl (for example, thieno[3,2-b]pyridyl, etc.);

An unsaturated, fused heterocyclic group containing from 1 to 2 (preferably 1) oxygen atoms and up to 3 (preferably 1 to 2) nitrogen atoms, for example, a benzoxazolyl group (for example, benzene) And [d]oxazolyl, etc.), dihydrobenzoxazolyl (for example, 2,3-dihydrobenzo[d]oxazolyl, etc.), benzooxazinoyl (for example, benzo[b] [l,4]oxaalkyl, etc.), dihydrobenzoxanyl (for example, 2H-3,4-dihydrobenzo[b][l,4]oxyalkyl, etc.), benzoxanthyl , benzooxadiazolyl, furopyrrolyl (for example, 4H-furo[3,2-b]pyrrolyl, etc.); etc.; • unsaturated, fused spiroheterocyclic group containing 1 to 2 nitrogen atoms , for example, spiro [cyclopentane porphyrinyl] (for example, spiro [cyclopentane-1,3'-carbolinyl], etc.); • unsaturated, fused heterologous containing 1 to 4 oxygen atoms a cyclic group, for example, a benzofuranyl group, a dihydrobenzofuranyl group (for example, 2,3-dihydrobenzofuranyl group, etc.), a benzoxolyl group (for example, benzo[d][ 1,3]oxyheterocyclyl, etc., dihydrobenzodioxynyl (for example, 2,3 dihydrobenzo[b][l,4]dioxole And the like; and • an unsaturated, fused heterocyclic group containing 1 to 2 sulfur atoms, for example, a benzothienyl group or the like. The N-containing heterocyclic group means: a saturated 3- to 8-membered (preferably 5 to 8 membered) heterocyclic group containing 1 to 4 (preferably 1 to 2) -56 to 200831498 nitrogen atoms; containing 1 to 2 nitrogen a saturated spiroheterocyclic group of an atom; an unsaturated 3 to 8 member (preferably 5 or 6 membered) heteromonocyclic group containing 1 to 4 (preferably 1 to 3) nitrogen atoms; comprising 1 to 4 Preferably 1 to 2) an unsaturated, fused heterocyclic group of a nitrogen atom; an unsaturated spiroheterocyclic group containing 1 to 2 nitrogen atoms; containing 1 to 2 (preferably 1) of an oxygen atom and 1 to 3 (more) 1 to 2) an unsaturated 3 to 8 member (more preferably 5 or 6 members) heterocyclic ring group of a nitrogen atom; containing 0 1 to 2 (preferably 1) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atom saturated 3 to 8 members (more preferably 5 or 6 members) heteromonocyclic group; containing 1 to 2 (preferably 1) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms An unsaturated, fused heterocyclic group; an unsaturated 3 to 8 member member (preferably 5 members) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; containing 1 to 2 sulfur atoms and 1 a saturated monocyclic group of 3 to 8 members (more preferably 5 or 6 members) to 3 nitrogen atoms; and an unsaturated group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, Heterocyclic group.

A saturated 3 to 8 member (preferably 5 to 8 membered) heteromonocyclic group containing 1 to 4 (preferably 1 to 2) nitrogen atoms means, for example, pyrrolidinyl, imiphate, thiol Sulfhydryl, hexammine, piperadinyl, octahydroisophthalide, azepanyl, azocanyl, etc., saturated heterocyclic group containing 1 to 2 nitrogen atoms Means, for example, azaindole (for example, 1-azaspiro[4,4]fluorenyl, 2-azaspiro[4,4]fluorenyl, etc.), arotropy (for example, 1 · Azaspiro[4,5]decyl, 2-azaspiro[4,5]decyl, etc., diazaspiro (for example, iota, 3-diazaspiro[4, -57- 200831498 4] mercapto, 1,4-diazaspiro[4,4]fluorenyl, etc.). An unsaturated 3 to 8 member (preferably 5 or 6 membered) heteromonocyclic group containing 1 to 4 (preferably 1 to 3) nitrogen atoms means, for example, a lalistyl or a dihydropyrrolyl group (for example, 1Η-2,5-dihydropyrrolyl, etc.), imidazolyl (eg, 1H-imidazolyl, etc.), dihydroimidazolyl (eg, iH 2 , 3 -dihydroimidazolyl, etc.), triazolyl (eg, 4H) -1,2,4-triazolyl, ih-1, 2 3_triazolyl, 2H-1, 2, 3 triazolyl, etc.), dihydrotriazolyl (for example, 1H_^4,5,·2 Hydrogen-1,2,4.triazolyl, etc.), pyrazolyl, pyridyl, dihydropyridyl (eg '1,2-dihydropyridyl, etc.), pyrimidinyl, dihydropyrimidinyl (eg ' 1,6 - a hydrogen thiol, etc.), _ exposure base, dihydro azozinyl (such as ' 1,2 - a ^ 嗦 嗦 嗦 寺), 11⁄2 嗦 base, four 卩 sit (for example, 1 Η-tetrazolyl, 2Η-tetrazolyl, etc.). An unsaturated, fused heterocyclic group containing 1 to 4 (preferably 1 to 2) nitrogen atoms means, for example, anthracenyl, isodecyl, hydrazine, isoindolyl, or Hydroisoisoindolyl (for example, 2,3 5 3 a,4,7,7a-hexahydroiso 11 derivatizing group, etc.), octahydroisopropenyl, benzoxandinyl, porphyrinyl, A porphyrin group, a carbazolyl group, a quinazolinyl group, a dihydroquinazolinyl group (3,4-dihydroporphyrinyl group, etc.), a benzotriwayl group, a taste D, and the like. Unsaturated, fused spiroheterocyclyl which contains 1 to 2 nitrogen atoms refers to, for example, spiro [cyclopentane porphyrinyl] (for example, spiro[cyclopenta] 4,3,_ porphyrinyl ]Wait). An unsaturated 3 to 8 member member (preferably 5 or 6 members) heteromonocyclic group containing 1 to 2 (preferably 1) oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms, which means : for example, oxazolyl, isoxazolyl, B oxadiazolyl (eg -58-200831498, 1,2,4-oxadiazolyl, 13,4-oxadiazolyl, ι, 2,5 evil Diazolyl, etc.) contains 1 to 2 (preferably 1) oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms saturated 3 to 8 members (preferably 5 or 6 members) The monocyclic group means, for example, an oxazolidinyl group, an isoxazolidinyl group, a morpholinyl group or the like. An unsaturated, fused heterocyclic group containing 1 to 2 (preferably 1) oxygen atoms and 1 to 3 (preferably 1 to 2) gas atoms means, for example, a benzo oxazolyl group (for example, Benzo[d]oxazolyl, etc.), dihydrobenzoxazolyl (eg '2,3-dihydrobenzo[d]oxazolyl, etc.), benzoxidinyl (eg, benzo[b] [l,4]oxaridinyl, etc.), dihydrobenzoxazinyl (eg, 2H-3,4-dihydrobenzo[b][l,4]oxaridinyl, etc.), benzoxazole Base, benzoxoxadiazolyl and the like. An unsaturated 3 to 8 member (preferably 5 membered) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms means, for example, a thiazolyl group or a dihydrothiazolyl group (for example, 2, 3 - 2) Hydrothiazolyl), isothiazolyl, thiadiazolyl (φ, for example, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazide, etc.), dihydrothiaridinyl and the like. A saturated 3 to 8 member (preferably 5 or 6 membered) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms means, for example, a thiazolidinyl group or the like. The unsaturated, fused heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms means, for example, a benzothiazolyl group, a benzothiadiazolyl group or the like. The amine formyl group which may have a lower alkyl group means that it may have from i to 2 lower alkyl groups as described above (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, straight chain or branch) Aminoalkyl group of an alkyl group. More specifically, -59-200831498 For example, an amine carbenyl group which may have the lower alkyl group includes: an amine methyl group, an N-methyl amine methyl group, N, N - dimethylamine-methyl fluorenyl, N-methyl-N-ethylamine, decyl, N-ethylamine, decyl, and the like.

The aryl lower alkyl group (which may have a lower alkoxy group on the aryl group) means a lower alkyl group as described above (preferably having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, a straight chain) Or a branched alkyl group) has 1 to 3 (preferably 1) aryl groups as described above. Here, the aryl group may be substituted with 1 to 7, preferably 1 to 5, more preferably 1 to 2, as described above for the lower alkoxy group. Specific examples of the aryl lower alkyl group (which may have a lower alkoxy group on the aryl group) include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, and a 1-methyl-1-phenylethyl group. 1,1_1-Methyl-2-phenylethyl, 1,1·dimethyl-3-phenylpropyl, (2-,3- or 4-)methoxybenzyl, 2-[( 2-, 3- or 4-) methoxyphenyl]ethyl, 1-[(2-,3- or 4-)methoxyphenyl]ethyl, 3· or 4-) methoxybenzene Propyl, (2-, 3- or 4-)ethoxy nodal, (2,4-,3,4- or 3,5-)-dimethoxybenzyl, 2-[(3 ,5- or 3,4·)dimethoxyphenyl]ethyl, 2-(2-ethoxyphenyl)ethyl, 1-(4-methoxyphenyl)butyl, naphthyl Base. The heterocyclic compound represented by the above formula (1) (herein referred to as "compound (1)") can be described in various methods, for example, as described in the following reaction formula - 丨 to 4, 7, 8, 12 or 13 The method was prepared. -60 - 200831498 Reaction-1 (2> A1·

[wherein R11, R12, A1 and Z are as defined above; and Xn is a halogen atom or a group which causes the same reaction as the substitution in the halogen atom. ]

Here, examples of the group which causes the same substitution reaction as in the halogen atom, for example, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group, and the like. The halogen atom represented by the formula (2) is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Specifically, examples of the lower alkanesulfonyloxy group represented by Xm include: a straight or branched alkanesulfonyloxy group having 1 to 6 carbon atoms, such as a methanesulfonic acid group, and an ethyl sulfonate oxygen group. a group, an isopropylidene oxide group, a n-propanesulfonyloxy group, a n-butylsulfonyloxy group, a third butanesulfonyloxy group, a n-pentanesulfonyloxy group, and a hexylsulfonyloxy group. group. Examples of the arylsulfonyloxy group represented by Χιι are a benzenesulfonyloxy group, a naphthosulfonyloxy group, etc., which may have 1 to 3 carbon atoms of 1 to 6 on the phenyl ring. a straight or branched alkyl group, a straight or branched alkoxy group having up to 6 carbon atoms, a nitro group, and a substituent in a halogen atom. Specific examples of the benzenesulfonyloxy group which may have the above substituent include: benzenesulfonyloxy group, 4-methylbenzenesulfonyloxy group, 2-methylbenzenesulfonyloxy group, 4-nitro group Phenylsulfonyloxy group, 4-methoxybenzenesulfonyloxy group, 2-nitrobenzenesulfonyl-61 - 200831498 oxygen group, and 3-chlorophenylsulfonyloxy group. Specific examples of the naphthosulfonyloxy group include an α-naphthalenesulfoxy group and/or a 3-naphthalenesulfoxy group. Examples of the aralkyl sulfonyloxy group represented by X η are, for example, a straight or branched alkanesulfonyloxy group having 1 to 6 carbon atoms and substituted with a phenyl group; and having 1 to 6 carbon atoms and a straight or branched alkanesulfonyloxy group substituted with a naphthyl group; both of which may have from 1 to 3 straight or branched alkyl groups having from 1 to 6 carbon atoms in the phenyl ring, a straight or branched alkoxy group having 1 to 6 carbon atoms, a nitro group, and a substituent in a halogen atom. Specific examples of the alkanesulfonyloxy group substituted by the above phenyl group include: benzylsulfonyloxy group, 2-phenylethylsulfonyloxy group, 4-phenylbutylsulfonyloxy group, 2-methyl group a benzylsulfonyloxy group, a 4-methoxyloxysulfonyloxy group, a 4-n-octylsulfonyloxy group, a 3-chlorobenzylsulfonyloxy group, or the like. Specific examples of the sulfonyloxy group substituted by the above naphthyl group include α-naphthylmethylsulfonyloxy group, /5-naphthylmethylsulfonyloxy group and the like. The compound (la) can be obtained by a compound represented by the formula (2) (hereinafter referred to as φ as the compound (2)) and a compound represented by the formula (3) (hereinafter referred to as the compound (3)). Produced by reaction. This reaction is usually carried out in a conventional solvent which does not affect the reaction, such as water; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; etc.; a ketone solvent such as acetone And methyl ethyl ketone and the like; ether solvents such as tetrahydrofuran, dioxane, diethyl ether and diethylene glycol dimethyl ether; ester solvents such as methyl acetate and ethyl acetate; and aprotic polar solvents such as acetonitrile, N , N-dimethylformamide, dimethyl hydrazine, etc.; halogenated hydrocarbon solvents such as dichloromethane and dichloroethane; or other organic solvents. Further, the reaction can be carried out in a mixed solvent of these conventional solvents. This reaction is usually carried out on inorganic bases such as alkali metals (such as sodium and bromine, etc.), alkali metal hydrogencarbonates (such as lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), metal hydroxides (such as lithium hydroxide, Sodium hydroxide, barium hydroxide, and hydroxide), alkali metal carbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, and carbonic acid planing), alkali metal lower alcoholates (such as sodium methoxide and sodium ethoxide), And hydrides (such as sodium hydride and potassium hydride, etc.); and in organic bases such as trialkylamines (such as trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, N-A Piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4·3·0]non-5-ene ( DBN), 1,4-diazabicyclo[2·2·2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), etc. In the presence of it. Also. When these bases are in liquid form, they can be used as a solvent. These basic compounds may be used singly or in combination with one or more of the basic φ compounds. The basic compound may be used in an amount of usually 0.5 to 10 times, preferably 0.5 to 6 times the molar amount of the compound (2). If necessary, the above reaction may be carried out by adding an alkali metal iodide such as potassium iodide or sodium iodide as a promoter. The molar ratio of the compound (2) to the compound (3) used in the above Reaction Formula-1 is at least 0.5 times, preferably about 5-1 5 times, that of the latter. The reaction temperature is not particularly limited and is usually carried out under cold or heating conditions, and is preferably carried out at a temperature of from about room temperature to about 150 ° C for 1 to 30 hours -63 to 200831498.

[wherein R11, R12, A1 and Z are as defined above; and 乂12 is a radical, a halogen atom or a group which causes the same substitution reaction with a halogen atom. Here, in the formula (4), a group which causes the same substitution reaction as in the halogen atom and the halogen atom shown by Xi2 can be used in the same group as Xn. The compound (1) can be reacted with a compound represented by the formula (4) (hereinafter referred to as the compound (4)) and a compound represented by the formula (5) (hereinafter referred to as the compound (5)). And made. This reaction can be carried out under the same reaction conditions as in the above reaction formula. When the compound (4) has a hydroxyl group represented by X12, the reaction can be achieved by subjecting the compound (5) to the compound (4) in a general mercapto bond formation reaction. It is known that a guanamine bond forming reaction can be widely applied to this guanamine bond forming reaction. Specifically, the following methods may be used: (a) a method of mixing an anhydride, even if the compound (4) is reacted with an alkyl halide of a halogenate to prepare a mixed acid anhydride, and then the mixed acid anhydride is reacted with the compound (5); (b) The active ester method is a compound (4) which is active guanamine and an active ester (such as phenyl ester, p-nitrophenyl ester, N-hydroxy amber imidate, and hydroxybenzotriazole) , or reactive guanamine is reacted with benzoxazoline-2-thione, and then the resulting product is further reacted with -64 - 200831498 compound (5); (〇 carbodiimide method, even compound (5) and compound (4) a condensation reaction carried out in the presence of an activator such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), and Carbonyldiimidazole or the like; (1) other methods, for example, by using a dehydrating agent such as acetic anhydride or the like to prepare a compound (4) carboxylic anhydride, then reacting the resultant with the compound (5), and allowing the compound (4) And an ester and a lower alcohol are reacted with the compound (5).

The mixed acid anhydride used in the above mixed anhydride method (a) is obtained by subjecting a general Schotten-Baumann reaction, and the resultant is reacted with the compound (5) without isolation to obtain the compound of the formula (ia) of the present invention. The above Schotten-Baumann reaction is carried out in the presence of a basic compound. Basic compounds for Schotten-Baumann, for example, inorganic bases such as alkali metals (such as sodium and potassium), alkali metal hydrogencarbonates (such as lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal hydrogen Oxide (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and hydroxide planer, etc.) 'alkaline earth metal hydroxide (such as calcium hydroxide, etc.), alkali metal carbonate (such as lithium carbonate, sodium carbonate 'potassium carbonate And carbonic acid planing, etc., alkali metal lower alcoholates (such as sodium methoxide and sodium ethoxide), hydrides (such as sodium hydride and potassium hydride, etc.), and sodium amination, and organic bases such as trialkylamine (such as top three Amine, triethylamine, N-ethyldiisopropylamine, etc., pyridine, quinoline, N-methylpiperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methyl Porphyrin, 15-diazabicyclo[4·3·0]non-5-ene (DBN) '1,4-diazabicyclo[2·2·2]octane (DABCO), and 1, 8-diaza-65- 200831498 Bicyclo[5·4·0]undecene-7 (DBU) and the like. These basic compounds can be used singly or in combination with one or more of the basic compounds. The reaction is generally carried out at a temperature of from about -20 to 10 ° C, preferably from about 〇 to 50 ° C, for about 5 minutes to 10 hours, preferably from about 5 minutes to 2 hours. The reaction of the obtained mixed acid anhydride with the compound (5) is usually about -20 to 150 ° C, preferably about 10 to 50 ° C, and the reaction is carried out for about 5 minutes to 1 hour, preferably about 5 minutes to 5 hours.

The mixed anhydride method is usually carried out in a solvent. Specifically, the solvent used in the mixed anhydride method includes: water; a halogenated hydrocarbon solvent such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride, etc.; an aryl hydrocarbon solvent such as benzene, toluene, And xylene, etc., ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; ester solvents such as methyl acetate, ethyl acetate, and isopropyl acetate And aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethyl hydrazine, and trimethylamine hexamethylphosphate, or a mixed solvent thereof. The alkyl carboxylic acid ester used in the mixed anhydride method includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate. The amount of the compound (4), the alkyl fluorocarboxylate and the compound (5) in the mixed anhydride method is generally preferably at least equimolar, but the amount of the alkyl halide and the compound (4) may be about The method (c) of the condensation reaction of the compound (5) in the presence of the activator in the presence of an activator is carried out in a suitable solvent in the presence or absence of a basic compound. Here -66 - 200831498 The solvent and basic compound used in the reaction formula-1 can be used as the solvent and the basic compound. The amount of the activator to be used is generally at least a molar amount with respect to the compound (4), preferably 5 times the molar amount of the compound (4). WSC is used as an activator, and the reaction can be efficiently carried out by adding an acid such as 1-hydroxybenzotriazole and/or hydrochloric acid to the reaction system. The reaction is generally carried out at a temperature of from about -20 to 180 ° C, preferably from about 0 to 150 ° C, and usually from about 5 minutes to 90 hours.

Further, the guanamine bond forming reaction can also be carried out by a reaction of the compound (4) with the compound (5) in the presence of a condensing agent of a phosphorus compound such as triphenylphosphine or diphenylphosphonium chloride. (diphenylphosphinylchloride), phenyl-N-phenylphosphonium chloride, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoryl azide, and bis(2-keto) -3-B oxo base) is a secondary acid chloride (bis(2-oxo-3-oxazolidinyl)phosphinic chloride). The condensing agent may be used singly or in combination with one or more of the condensing agents. The reaction is generally carried out in a solvent and a basic compound of the above Reaction Scheme-1 at from about -2 to 150 ° C, preferably from about 0 to 100 ° C, and the reaction is usually from about 5 minutes to 30 hours. carry out. The condensing agent and the compound (5) are used in an amount of at least about a molar amount, preferably from the molar amount of the compound (4) to 3 times by mole, the compound (4), the starting compound of the compound of the present invention, It is a known compound or can be easily prepared via known compounds. -67- 200831498 Reaction-3

(!〇) [where R1 2 and A1 are as defined above. R14 means hydrogen or lower alkyl. ]

The compound of the formula (lb) (hereinafter referred to as the compound (lb)) can be produced by reacting a compound of the formula (10) (hereinafter referred to as the compound (10)) with the compound (5). This reaction is carried out in various solvents which do not affect the reaction. The solvent used is, for example, an ether such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and cyclopentyl methyl ether; and a halogenated hydrocarbon such as chloroform, dichloromethane, And dichloroethane, etc.; esters such as methyl acetate, ethyl acetate, and n-butyl acetate; and other organic solvents such as acetonitrile, and N,N-dimethylformamide, etc., or the like mixture. Again. When the compound (10) or (5) is in a liquid state, it can also be used as a solvent. The compound (5) is usually used in an amount of from 1 to 10 times the molar amount of the compound (10), preferably from 1 to 3 times the molar amount. The reaction can be carried out at any temperature which is cooled to heat. Preferably, a temperature of -10 ° C to 150 ° C is employed. The reaction is completed at about 10 minutes to 10 hours at this temperature. This reaction can be carried out in the presence of a base. Preferred bases such as organic bases, such as tri(lower)alkylamines (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethyl Aminopyridine 'dimethylaniline, N-(lower)alkylmorpholine (eg N-methylmorpholine, etc.), 1,5-diazabicyclo[4·3·0]non-5-ene (DBN), 1,8·diaza-68- 200831498 heterobicyclo[5.4·〇]undecene-7 (DBU), and 1,4·diazabicyclo[2·2·2] half Hospital (daBCO) and so on. Reaction-4

The compound of the formula (1d) (hereinafter referred to as the compound (?d)) can be produced by reacting a compound of the formula (1c) (hereinafter referred to as a compound (丨c)) with a thioketone. Here, preferred examples of the thioketone agent which is generally used to change a ketone group to a thioketone group are, for example, phosphorus pentasulfide, and Lawesson's reagent (2,4·bis(4-methoxyphenyl)-1 , 3-dithia-2,4-di-li ((11卩11〇8卩1161&116)- 2,4-disulfide), etc. The solvent used in this reaction does not affect the various solvents of the reaction, For example, a halogenated hydrocarbon solvent such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; an aromatic hydrocarbon solvent such as benzene, toluene, and xylene; and an ether solvent such as diethyl ether, Diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.; or a mixed solvent thereof, etc. The reaction is carried out conventionally, but the reaction temperature is not particularly limited to a heating state, preferably 65 to 150 ° C, The reaction time is about 30 minutes to 10 hours, preferably about 30 minutes to 5 hours. The proportion of the compound and the thiol agent used in the reaction is generally in the range of from mole to very large molar amount, preferably compound ( The molar amount of lc) is 1.3 times the molar amount. -69- 200831498 Furthermore, the compound (5), the initial compound of the compound of the present invention , # Novel compounds and may be prepared comprising a variety of methods, but the following reaction formula; The process of -6 to reaction scheme is an example of the reaction formula described -5 ❿

[wherein R12, Xn, and Α1 are as defined above; and R13 represents hydrogen or a lower-grade oxyiron group. Here, in the general formula (6), the above-exemplified groups which cause the same reaction with XM as the halogen atom and the halogen atom shown may be used. Preferred specific examples of the lower alkoxycarbonyl group represented by R13 are a methoxycarbonyl group, an ethoxycarbonyl group, a third butoxycarbonyl group and the like. A more preferred example of the lower alkoxycarbonyl group is (CrCd alkoxycarbonyl group. Among them, particularly preferred is a third butoxycarbonyl group. The compound (5a) can be represented by a compound of the formula (6) (hereinafter referred to as a compound) (6)) is carried out by reacting a compound of the formula (3) (hereinafter referred to as the compound (3)) to -70-200831498. This reaction is carried out under the same reaction conditions as in the reaction formula-1. (3) and (6), the starting compound of the compound of the present invention is a known compound, or can be easily prepared from a known compound. If R13 of the compound (5a) is a lower alkoxycarbonyl group, the formula (5) The compound (hereinafter referred to as the compound (5)) can be produced by subjecting the compound to a lower-stage electroless base removal reaction. This removal reaction is carried out according to a general method such as hydrolysis. The hydrolysis is preferably carried out in the presence of a Lewis acid containing an acid. Preferred acids are: organic acids (for example, formic acid, acetic acid, propionic acid, trichloroacetic acid, and trifluoroacetic acid, etc.), and inorganic acids (for example, Hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). In the presence of, e.g., trichloroacetic acid and the like, such as trichloroacetic acid, trifluoroacetic acid and the like, preferably a cation scavenger (e.g., anisole and phenol, etc.).

This hydrolysis reaction is carried out in various solvents which do not affect the reaction, for example, water; alcohols such as methanol, ethanol, trifluoroethanol, and ethylene glycol; ketones, such as acetonitrile, ugly, such as an ugly, a glimpse a stagnation, tetraammine, 1,2-dimethoxyethane, and cyclopentyl methyl ether; halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane; esters, such as Methyl acetate, ethyl acetate, n-butyl acetate, etc.; and other, organic solvents such as acetonitrile, and N,N-dimethylformamide, or the like, or mixtures thereof. Further, if the acid used is a liquid acid, it can also be used as a solvent. The reaction can be carried out under any temperature conditions of cooling to heating. -71 - 200831498 Preferably, a temperature condition of 〇 ° c to room temperature can be employed. The reaction is completed at about 0.5 to 10 hours at this temperature.

[wherein Xh and A1 are as defined above. Here, in the general formula (7), the above-exemplified groups which cause the same substitution reaction with the halogen atom and the halogen atom shown may be used.

The compound (8) can be produced by reacting a compound of the formula (7) (hereinafter referred to as the compound (7)) with a compound of the formula (3) (hereinafter referred to as the compound (3)). This reaction is carried out under the same reaction conditions as in Reaction Scheme-1. Here, the compounds (7) and (3), the starting compound of the compound of the present invention, are known compounds, or can be easily prepared from known compounds. The compound (5b) can be obtained by the compound of the formula (8) Hereinafter, it is obtained by reacting a compound (8)) with a compound of the formula (9) (hereinafter referred to as the compound (9)). This reaction is carried out in various solvents which do not affect the reaction, for example, water; -72-

200831498 Alcohol 'acetone such as methanol, ethanol, trifluoroethanol, and ethylene glycol; ethers such as diethyl ether, dioxane, tetrahydrofuranyloxy, and cyclopentyl methyl ether; halogenated hydrocarbons, such as two Methyl chloride, and dichloroethane; esters, such as methyl acetate, and n-butyl acetate; and others, organic solvents, N, N-dimethylformamide, etc., or mixtures thereof . The other acid is a liquid acid' which can also be used as a solvent. The reaction can be carried out under cooling conditions. Preferably, a temperature condition of 50X: to 1 〇 0 °C can be employed. Under the condition of about 〇 · 5 to 1 〇 hours to complete. : a ketone such as 1,2-dimethyltrichloromethane, ethyl acetate acetonitrile, and, if used, to be heated at the reaction reaction temperature-7

[wherein R21 and A2 are as defined above; and X21 is a group in which a halogen reacts with the same substitution in a halogen atom. Here, the same radical group which causes the same substitution reaction with a halogen atom is caused. This reaction is carried out in the same manner as in Reaction Scheme-1. Here, the compound (1 1 ), the starting of the compound of the present invention, includes a novel compound, and can be produced by various methods and is prepared by the method shown in the following Reaction Scheme-9. The atom or the agglomerate is a material compound as described above, for example, using -73-200831498 and, in the compound (1), hereinafter referred to as a compound (If), wherein A21 and A22 have the same definitions as above, wherein -A2 is for example For _a2i_〇-A22-, it can be produced by the method shown in the following Reaction Scheme-8. Reaction-8

[wherein R21, A21 and A22 are as defined above; and X22 represents a hydroxyl group, a halogen atom or a group which causes a reaction with the same substitution in a halogen atom. Here, in the formula (12), an example of a halogen atom of X22 and a group which causes the same substitution reaction with a halogen atom are the same as those described above. The compound (1f) can be produced by reacting a compound of the formula (1 2) (hereinafter referred to as the compound (12)) with a compound of the formula (13) (hereinafter referred to as the compound (13)). . This reaction is carried out under the same reaction conditions as in Reaction Scheme-1. When X22 of the compound (12) represents a hydroxyl group, the reaction can be carried out in the presence of a suitable solvent in the presence of a condensing agent.

The reaction is usually carried out in a general solvent which does not affect the reaction, for example, water; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, fluorofluoroethanol, ethylene glycol; a ketone solvent such as acetone, methyl ethyl Ketone; ether solvent, such as tetrahydrofuran, dioxane, diethyl ether, bis(2-methoxyethyl)-; ester solvent, such as methyl acetate, ethyl acetate; aprotic polar solvent, II-74-200831498 For example, acetonitrile, hydrazine, hydrazine dimethylformamide, dimethyl hydrazine; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane; or other organic solvents, or a mixture thereof. Further, the solvent used herein may include a mixture of conventional solvents. The condensing agent includes an azide dicarboxylate such as diethyl azide dicarboxylate and a phosphorus compound such as triphenylphosphine. The amount of the condensing agent used for the compound (12) is at least the molar amount, preferably

2 times the amount of Mo. The amount of the compounds (12) and (13) in the above Reaction Scheme-2, which is usually at least the same as the former, is preferably 2 times the molar amount of the former. The reaction temperature is not precisely controlled, and the reaction is usually carried out under cooling or heating. Preferably, the reaction is carried out at 〇 ° C to 150 ° C for 1 to 1 Torr. Here, the compound (1 2 ), the starting compound of the compound of the present invention, is a known compound or can be easily prepared from a known compound. And 'compound (1 3 ), the starting material compound ' of the compound of the present invention includes a compound, and can be produced by various methods, for example, by the following reaction formula or the reaction formula-1. Reaction formula-9 R2t-H --^ R«-A2 a & (14) (tt) [wherein R21, X21 and A2 are as defined above, and X23 represents a halogen atom or is caused to be the same as a halogen atom Substituting the reactive group. Here, in the general formula (15), an example of a halogen atom of ruthenium 23 and a group which causes the same substitution reaction with a halogen atom of -75-200831498 are the same as those described above. The compound (1 1) can be produced by reacting a compound of the formula (14) (hereinafter referred to as the compound (14)) with a compound of the formula (15) (hereinafter referred to as the compound (15)). This reaction is carried out under the same reaction conditions as in Reaction Scheme-1. Here, the starting compounds of the compounds (14) and (15) are known compounds or can be easily prepared from known compounds.

Reaction formula - 〇

[wherein A22 is as defined above; and χ24 represents a halogen atom or a group which causes the same substitution reaction with a halogen atom. ]

Here, in the formula (16), an example of a halogen atom of ruthenium 24 and a group which causes the same substitution reaction with a halogen atom are the same as those described above. Compound (13) can be produced by reacting compound (3) with a compound of the formula (16) (hereinafter referred to as compound (16)). This reaction is carried out under the same reaction conditions as in Reaction Scheme-1. Here, the compound (16), which is a starting compound of the compound of the present invention, is a known compound or can be easily prepared from a known compound. -76- 200831498 Reaction-η f^-O-A22-^

Depurination reaction

[wherein A22 is as defined above; and R23 represents a lower alkyl fluorenyl group, and X24 represents a halogen atom or a group which causes a reaction with the same substitution in a halogen atom. Here, the examples of the lower-grade brewing base of 'r23 in the general formulae (17) and (18) are the same as described above. Further, in the formula (17), examples of the halogen which is a halogen of χ24 and a group which causes the same substitution reaction with a halogen atom are the same as the above groups. The compound (18) (hereinafter referred to as the compound (18)) can be produced by reacting the compound (3) with a compound of the formula (17). This reaction is carried out under the same reaction conditions as in Reaction Scheme-1. Here, the compound (17), which is a starting compound of the compound of the present invention, is a known compound or can be easily prepared from a known compound. Thereafter, the compound (18) is subjected to a deuteration reaction to obtain a compound (13). A preferred method for the reaction is a conventional method such as hydrolysis. The water horn reaction is preferably carried out in the presence of a base or an acid including Lewis acid. Suitable _ including inorganic bases, such as alkali metals (such as sodium, potassium, etc.), alkali metal carbon _ -77-

200831498 Hydrogen salts (such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate are hydroxides (such as lithium hydroxide, sodium hydroxide, hydroxide oxidizer, etc.), alkali metal carbonates (such as lithium carbonate, potassium carbonate) And carbonic acid planing, etc.), alkali metal lower alcoholates (such as sodium methoxide, etc.), hydrides (such as sodium hydride, potassium hydride, etc.), such as trialkylamines (such as trimethylamine, triethylamine, N-ethyl II) ), pyridine, quinoline, piperidine, imidazole, picoline, dimethylamine dimethylaniline, N-methylmorpholine, DBN, DABCO, and when the acid includes organic acids (eg, formic acid, acetic acid, propionic acid) , tris, and trifluoroacetic acid, etc., and inorganic acids (for example, hydrochloric acid, hydrobromine, hydrogen chloride, hydrogen bromide, etc.) are mono- ligated by an acid such as a trihaloacetate (acetic acid, trifluoroacetic acid, etc.) It is carried out in the presence of cationic auxyl ether and phenol). The reaction is usually carried out in a conventional solvent which does not affect the reaction, for example, water; an alcohol solvent such as methanol, ethanol, isopropanol, trifluoroethanol, ethylene glycol; a ketone solvent such as acetone, methyl ethyl solvent such as tetrahydrofuran. , dioxane, diethyl ether, bis(2-yl)ether; ester solvent such as methyl acetate, ethyl acetate; non-solvent such as acetonitrile, N,N-dimethylformamide, dimethylene hydrocarbon solvent , such as dichloromethane, dichloroethane; or other organic mixtures. The preferred one is ethanol. The reaction temperature is controlled and usually carried out under cooling and heating conditions. Preferably, from room temperature to about the boiling point of the solvent used, 〇·5 to 75), gold, potassium, sodium hydrogencarbonate, sodium carbonate, and pyridine, such as an organic base, isopropylamine, DBU. Suitable for chloroacetic acid, acid, sulfuric acid such as trichloric acid (such as the conventional solvent n-butanol, ketone; ether methoxyethyl proton polar oxime; halogenated solvent, and not precisely reacted at about hour. -78- 200831498 reaction formula -12

[Where A is as defined above. R21 means the N-heterocyclic group in which the (8) carboxyl group is substituted with at least one of the groups indicated by the above R21. R21b means that the (10) aminomethyl group (8) is substituted with at least one of the groups indicated by the above R21, and the N-containing heterocyclic group may have (1〇) as a lower alkyl group. R22 and R23 may be the same or different and refer to a hydrogen atom or a lower-grade courtyard group. The reaction between the compound (lg) and the compound (19) is such that the amine of the compound (19) and the carboxylic acid of the compound (lg) are reacted by a general mercapto bond formation reaction. It is known that a guanamine bond forming reaction can be widely applied to this type of guanamine bond forming reaction. Specific examples include: (a) a mixed acid anhydride method, that is, a reaction of an alkyl halide of a halocarboxylate with a carboxylic acid (1 g) to provide a mixed acid anhydride, the resultant is then reacted with an amine (19), and (b) an activated ester method, that is, a carboxyl group. Acid (lg) and activated ester (such as phenyl ester, p-nitrophenyl ester, N-hydroxy succinimide, 1-hydroxybenzotriazole, or benzoxazoline-2-thione) Reacting to produce activated guanamine, the resulting product is then reacted with an amine (19), (c) a carbodiimide process in which the amine (11) is condensed with a carboxylic acid (lb) in the presence of an activator, the activation Agents such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropylethylcarbodiimide (WSC), carbonyldiimidazole, (d) other methods, for example, carboxylic acid (1 g) Reaction with a dehydrating agent such as acetic anhydride to produce a carboxylic anhydride which is then reacted with an amine (19); an ester of an amine (19) with a carboxylic acid (1 g) and a lower alcohol, and a halide of a carboxylic acid The reaction method, that is, the method of reacting amine-79-200831498 (19) with hydrazine halide. The mixed anhydride used in the above mixed anhydride method (a) is provided by the Schotten-Baumann reaction. The fine reacts with the amine (19) and is usually not isolated to give the compound of the invention of the formula (1 h). The above Schotten-Baumann reaction is carried out in the presence of a basic compound. The base used in the Schotten-Baumann reaction Sex compounds include:

For example, inorganic bases such as alkali metals (such as sodium, potassium, etc.), alkali metal hydrogencarbonates (such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate, etc.), alkali metal hydroxides (such as lithium hydroxide, hydrogen) Sodium oxide, potassium hydroxide, and hydroxide, etc.), alkaline earth metal hydroxides (such as calcium hydroxide, etc.), alkali metal carbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, and carbonic acid planing, etc.), alkali metals Lower alcoholates (such as sodium methoxide, sodium ethoxide, etc.), hydrides (such as sodium hydride, potassium hydride, etc.), and sodium amination, etc., and organic bases such as trialkylamines (eg, trimethylamine, triethylamine, N_) Ethyl diisopropylamine, etc., pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, diazabicyclo[4.3.0]壬-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5·4·0]undecene _7 (dBU) and so on. These basic compounds may be used singly or as a mixture of two or more. The reaction is generally about -20 to 1 Torr. (3, preferably about 〇 to 5〇t:, the reaction is about 5 minutes to 1 hour, preferably about 5 minutes to 2 hours. The reaction system of the mixed anhydride with the amine (19) is usually about -20. 15 〇 〇 ' preferably from about 1 Torr to 50 ° C, for about 5 minutes to 1 hour, preferably about 5 - 80 - 200831498 minutes to 5 hours.

The mixed acid anhydride method is usually carried out in a solvent. Any solvent can be used for the mixed anhydride method, and clear examples include: water; halogenated hydrocarbon solvent such as trichloromethane, dichloromethane, dichloroacetic acid, carbon tetrachloride; aromatic hydrocarbon solvent such as benzene, toluene, xylene Ether solvent, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane; ester solvent, such as methyl acetate, ethyl acetate, isopropyl acetate; aprotic polar solvent, such as acetonitrile, N,. Dimethylformamide, dimethyl amide, trimethylamine hexamethylphosphate, or a mixture thereof. The alkyl halocarboxylate used in the mixed acid anhydride method includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. The carboxylic acid (1 g), the alkyl carboxylic acid ester and the amine (19) are usually used in a mixed acid anhydride method in an amount of at least the same molar amount, but the alkyl halocarboxylate and the carboxylic acid (lg) are relative to the amine (19). It can be in the range of a molar amount to 6 times the molar amount. The method (c) of carrying out the condensation reaction in the presence of an activator is carried out in a suitable solvent in the presence or absence of a basic compound. The solvent and the basic compound used herein may be a solvent and a basic compound used in the method of reacting the amine (19) with a hydrazine halide in the other method (d) described hereinafter. The amount of the activator is usually equal to the molar amount of the compound (11), preferably in the range of from the molar amount to the molar amount of 5 times the molar amount. When WSC is used as the activator, 1-hydroxybenzotriazine and/or an acid such as hydrochloric acid may be added to the reaction to accelerate the reaction. The reaction is usually from -20 to 180 ° C, preferably from 0 to 150. (:, usually takes about 5 minutes to 90 hours to complete. -81 - 200831498

When the method of reacting the amine (19) with a hydrazine halide in the above other method (d) is carried out, the reaction is carried out in a suitable solvent in the presence of a basic compound. As the basic compound, a known compound can be widely used, and for example, any of the test compounds used in the above Schotten-Baumann reaction can be used. The solvent, for example, other solvents used in the above mixed acid anhydride method, includes: an alcohol solvent such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, 2-methoxyl Ethanol, 2-ethoxyethanol, and acetonitrile, pyridine, acetone, and water. The ratio of the amount of amine (19) and hydrazine is not controlled, and can be selected in a wide range of places, but it is recommended to be at least the molar amount, preferably the molar amount to 5 times the molar. the amount. The reaction is usually carried out at about -2 to 180 ° C, preferably about 0 to 150 ° C, for about 5 minutes to 50 hours. Further, the indole bond formation reaction represented by the above Reaction Formula-6 may be carried out by reacting a carboxylic acid (lg) with an amine (19) in the presence of a phosphorus compound such as triphenylphosphine or diphenylphosphine. Diphenylphosphinylchloride, phenyl-N-phenyl uranyl chloride, diethyl chlorophosphate, diethyl phosphorocyanidate, diphe ny 1 phosphorazidate, and Bis(2-keto-3-D oxazolidinyl)phosphinic chloride. The above condensing agents may be used singly or in combination of two or more. The reaction is carried out in a solvent and a basic compound used in the method for reacting the above amine (19) with a hydrazine halide, and is carried out at about -20 to 150 ° C, preferably 〇 to 10 ° C, for about 5 minutes to 30 hours. . The amount of the condensing agent and the amine (19) is preferably -82- 200831498. The amount is equivalent to the molar amount of the carboxylic acid (lg), preferably from the molar amount to 3 times the molar amount. Reaction formula-1 3

R21d shows the following groups;

(〇Η2)Λβ

φ R21e represents the following groups;

X25 and x26 each represent a halogen atom or a group which causes the same substitution reaction with a halogen atom. R24 represents the same group of the substituents (1) to (13) in R21. Ρ is 4 or 5. The reaction between the compound (1 i) and the compound (20) is carried out in the presence of a basic compound in a suitable inert solvent. -83 - 200831498 Basic compounds used herein include, for example, sodium metal, potassium metal, magnesium metal, sodium hydride, sodium amination, metal alkoxides (such as sodium methoxide, sodium ethoxide, potassium t-butoxide), alkyl Lithium aryl or lithium amide, such as (methyllithium, n-butyllithium, phenyllithium, lithium isopropylamide), sylilamide, such as lithium hexamethylphosphonium azide (lithium) Hexamethyldisilazide). These basic compounds may be used singly or in combination of two or more.

The basic compound is usually at least an equimolar amount with respect to the compound (1 i), preferably from the molar amount to 5 times the molar amount. The inert solvent includes, for example, an aromatic hydrocarbon solvent such as benzene, toluene, monomethylbenzene; an ether solvent such as diethyl ether, tetrahydrofuran, dioxins, mono(2-methoxyethyl)ether, bis(2-methoxy Ethyl ethyl ether; aliphatic hydrocarbon solvent such as n-hexane, heptane, cyclohexane; halogenated hydrocarbon solvent such as chloroform, dichloromethyl, dichloroethane, carbon tetrachloride; dimethyl Maple and N,N-dimethylformamide, or a mixture of them. The reaction is usually carried out at from -90 to 1501:, preferably from -90 to 120 °C, for about 10 minutes to 30 hours. The compound (20) may be at least an equimolar amount with respect to the compound, preferably a molar amount of 5 times the molar amount. (lj) The reaction to (lk) is carried out under the same conditions as the reaction of the compound to the compound (lj). The compound having the q group represented by the formula (2) in the compound (1) can be converted to various compounds by the following reactions A to G. -84 - 200831498

Reaction A In the compound (1), when the compound (12) is substituted with an N-heterocyclic group-containing heterocyclic ring represented by R21, the compound is deprotected to give a corresponding N-containing heterocyclic group. The ketone group on the heterocyclic ring is a compound (1) which is a deketo group.

The reducing agent used in the above reduction reaction includes, for example, a hydrogenation reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triethoxy borohydride and lithium aluminum hydride, or a mixture of hydrogenating reducing agents. The hydrogenated reducing agent is usually equal to 5 times the amount of the ear, preferably from the molar amount to 2 times the molar amount. The reduction reaction is usually carried out in a suitable solvent. Examples of the solvent are: an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, mono(2-methoxyethyl)ether, bis(2-methoxyethyl)ether; and an aromatic hydrocarbon solvent such as benzene. , toluene and xylene. The reaction temperature is usually from about 0 to 150 ° C, preferably from 0 to 10 ° C, for 30 minutes to 10 hours.

Reaction B In the compound (1), when the compound (5) is substituted with a protective hydroxy group on the heterocyclic ring containing the N heterocyclic group represented by R21, the compound is subjected to deprotection to produce a (4) hydroxy group. Compound (1) on a heterocyclic ring corresponding to an N-containing heterocyclic group. The above deprotection reaction is carried out in the presence of an acidic or basic compound in a suitable solvent or a non-solvent. The solvent used is, for example, water; a lower alcohol solvent such as methanol, B-85-200831498 alcohol, isopropanol, tert-butanol; a ketone solvent such as acetone, methyl ethyl ketone; an ether solvent such as diethyl ether, Dioxane, tetrahydrofuran, mono(2-methoxyethyl)ether, bis(2-methoxyethyl)ether; ester solvent such as methyl acetate, ethyl acetate; aliphatic acid solvent such as formic acid, Acetic acid; a rejuvenating hydrocarbon solvent such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; a guanamine solvent such as N,N-dimethylformamide, N,N-dimethyl B Indoleamine, N-methylpyrrolidone; dimethyl hydrazine, trimethylamine hexamethyl phosphate; or

mixture. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid. Also, examples of the basic compound include, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate; and metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide, and hydroxide. lithium. The acid and basic compound are used in an amount of at least 1 mole, preferably 1 to 10 moles, but the amount of the acid used as a reaction solvent may be an excess. The reaction is preferably carried out at a temperature of from about Torr to about 200 ° C, preferably from about 1,500 ° C, for from 10 minutes to 30 hours. When the protecting group is a lower alkyl group, the deprotection reaction can be carried out in the presence of a dealkylating agent in a suitable solvent. The above deprotection reaction can be carried out in any solvent. The dealkylating agent includes, for example, boron trihalide such as boron tribromide. The amount of dealkylating agent to be used is usually at least a molar amount relative to the starting material, preferably from 1 mole to 1 mole per mole. The reaction is carried out at a temperature of from 1 to 50 ° C, preferably from about room temperature to 100 ° C, for about 1 to 50 hours. When the protecting group is a lower alkyl group, the deprotection can be carried out under reducing conditions.

200831498. This reduction reaction is carried out, for example, in a suitable solvent in the presence of a catalytic catalyst. The solvent used is, for example, water; an alcohol solvent such as methanol isopropanol; a hydrocarbon solvent such as n-hexane, cyclohexane; an ether solvent methane, tetrahydrofuran, diethyl ether, ethylene glycol, dimethyl ether; Ester, methyl acetate; aprotic polar solvent, meglumine, or a mixture thereof. Examples of the catalyst to be used include: palladium, palladium black, palladium carbon, platinum, copper oxybromide, Raney nickel, or a mixture thereof. The catalysis is 0.02 to 1 times relative to the starting material. The reaction temperature is from about -2 to about 10 ° C, preferably from about 〇 to 80 ° C, usually from 1 to 10 atm, for about 0.5 to 20 hours.

Reaction C In the compound (1), when the compound contains an unsaturated miscry group as indicated by R21, the compound is reduced to give a compound (1) which becomes saturated with a heterocyclic group. The above reduction reaction is carried out, for example, in the presence of a non-solvent or in the presence of a reducing agent. The solvent used in this reaction is, for example, water; lower alcohol solvent alcohol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; agents such as acetonitrile, formic acid, acetic acid; ether solvent such as diethylene furan, Dioxane, mono(2-methoxyethyl)ether, bis(2-methyl® ether; aromatic hydrocarbon solvent such as benzene, toluene, xylene; hydrogenation hydrogenation reaction, ethanol, such as diester solvent, such as The amount of dimethyl uranium, oxidizing agent, hydrogen pressure Ν heterocyclic group in the solvent, such as methyl aliphatic acid ether, tetrahydro I yl ethyl hydrocarbon solvent, -87- 200831498 such as dichloromethane, dichloro Ethane, chloroform, carbon tetrachloride; or a mixture thereof. Examples of the reducing agent to be used include: a catalytic hydrogenating reducing agent such as palladium black, palladium carbon, platinum, platinum oxide, platinum black, Raney nickel. The catalytic hydrogenation reducing agent is usually used in an amount of from 1 to 5 times, preferably from about 1 to 3 times the amount of the starting material.

The reaction is carried out at a chamber pressure of about 20 atmospheres, preferably at a pressure of about 10 atmospheres, at a hydrogen pressure of from about -30 to 100 ° C, preferably from 0 to 60 ° C. The reaction is completed in about 1 to 20 hours.

Reaction D In the compound (1), when the compound (9) lower alkoxycarbonyl group is substituted on the N-heterocyclic group-containing heterocyclic ring represented by R21, the compound is subjected to hydrolysis to produce (8) The carboxyl group is substituted with the compound (1) corresponding to the heterocyclic ring containing the N heterocyclic group. The above hydrolysis reaction is carried out in the presence of an acidic or basic compound in a suitable solvent or a non-solvent. The solvent used is, for example, water; a lower alcohol solvent such as methanol, ethanol, isopropanol, tert-butanol; a ketone solvent such as acetone, methyl ethyl ketone; an ether solvent such as diethyl ether, dioxane, tetrahydrofuran , mono(2-methoxyethyl)ether, bis(2-methoxyethyl)ether; aliphatic acid solvent such as acetic acid, formic acid; ester solvent such as methyl acetate, ethyl acetate; halogenated hydrocarbon solvent 'such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; guanamine solvent, such as dimethyl hydrazine, N,N-dimethylformamide, hexamethyl phosphate-88- 200831498 Triamcinamide, or a mixture of these. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid. These acids may be used singly or in combination of two or more. Examples of the test compound include: for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide . These basic compounds may be used singly or in combination of two or more. The above hydrolysis reaction is from about 0 to 200. (:, preferably from about 0 to 150 ° C, and usually takes about 1 至 to 80 hours to complete.

Reaction E

In the compound (1), when the compound (8) is substituted with a carboxyl group on the heterocyclic ring containing the N heterocyclic group, the compound is reacted with a lower alcohol such as methanol, ethanol 't-butanol' to produce Wherein (9) a lower alcohol oxycarbonyl group is substituted with a compound corresponding to a heterocyclic ring containing an N heterocyclic group (υ.

Any of the general ester reaction conditions can be used in the above reaction. For example, the reaction is carried out in the presence of a mineral acid and/or a halogenating agent. Examples of inorganic acids are: hydrochloric acid, sulfuric acid, and the like. Examples of the halogenating agent are: sulfinium chloride, phosphonium chloride, phosphorus pentachloride, phosphorus trichloride, and the like. An excess of lower alcohol was used as the starting material. The reaction is carried out at about ° to 150 ° C, preferably about 50 to 100 ° C, usually for about i to 1 〇 hours. Reaction F-89-200831498 In the compound (1), when the compound (1 1) lower alkyl (which may include a lower-order alkoxy group on the aryl group) is substituted with a heterocyclic ring containing an N heterocyclic group represented by R21 When the N atom is present, the compound is treated in the presence of an acid in a suitable solvent or a non-solvent to obtain a compound in which the lower aryl group of the corresponding N-containing heterocyclic group is removed (1) .

The solvent used in the above reaction is, for example, water; a lower alcohol solvent such as methanol, ethanol, isopropanol, butanol; a ketone solvent such as acetone, methyl ethyl ketone; an ether solvent such as diethyl ether or dioxane. , tetrahydrofuran, mono(2-methoxyethyl)ether, bis(2.methoxyethyl)ether; an aliphatic acid solvent such as acetic acid, formic acid; an ester solvent such as methyl acetate, ethyl acetate, Halogenated hydrocarbon solvent such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; guanamine solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone; dimethyl hydrazine, trimethylamine hexamethylphosphate, or a mixture thereof. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid. The acid is usually used in an amount of at least 1 mole, preferably 1 to 30 moles, and the acid may be used in excess as a reaction solvent. The reaction is preferably carried out at a temperature of from about 0 to 20 (TC, preferably from 0 to 150 ° C, usually from about 1 Torr to 30 hours).

Reaction G in the compound (1), wherein the compound of the (7) lower alkyl fluorenyl group substituted with the N atom on the heterocyclic ring containing the N heterocyclic group represented by R21 is the compound (1) -90-200831498 (at least The N atom containing one of the N heterocyclic groups is unsubstituted) and is obtained by reacting an alkylating agent in a suitable solvent or a nonsolvent in the presence or absence of a basic compound.

The inert solvent used in the above reaction is, for example, an aromatic hydrocarbon solvent such as benzene, toluene, xylene; an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, mono(2-methoxyethyl)ether, bis (2) -methoxyethyl)ether; halogenated hydrocarbon solvent 'such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride: lower alcohol solvent such as methanol, ethanol, isopropanol, butanol, third Butanol, ethylene glycol; aliphatic acid solvent, such as acetic acid; ester solvent, such as methyl acetate, ethyl acetate; ketone solvent, such as acetone, methyl ethyl ketone; acetonitrile, bismuth, dimethyl Anthraquinone, N,N-dimethylformamide, N-methylindole, trimethylamine hexamethylphosphate; or a mixture thereof. The basic compound includes, for example, an inorganic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydrogencarbonate (e.g., lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), an alkali metal hydroxide (e.g., hydroxide). Lithium, sodium hydroxide, potassium hydroxide, and hydroxide planers, etc., soil metal hydroxides (such as calcium hydroxide, etc.), alkali metal carbonates (such as lithium carbonate, sodium carbonate, barium carbonate, and carbonic acid planers, etc.) ), metal lower alcoholates (such as sodium methoxide, sodium ethoxide, etc.), hydrides (such as sodium hydride, potassium hydride, etc.), and sodium amination, etc., and organic bases such as trialkylamines (such as trimethylamine, triethylamine) , N_ethyl-isopropylamine, etc.) _ D, quinoline, piperazine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, hydrazine-methylmorpholine, 1,5·2 Azabicyclo[4·3·0]壬-5-ene (DBN), 1,4-diazabicyclo[2·2·2] Xinyuan (DABCO), and 1,8-diaza Bicyclo [5.4.0] undecene-7 (DBU) -91 - 200831498 or a mixture of these. When the inclusion reaction is carried out in the presence of a basic compound, the amount of the basic compound is at least the molar amount of the starting material, preferably from the molar amount to 5 times the molar amount. The alkylating agent includes, for example, a lower alkyl alkane halide such as ethyl hydrazine chloride and an aliphatic acid anhydride such as acetic anhydride.

The lower alkyl alkaneating agent is used in an amount of at least the molar amount of the starting material, preferably from the molar amount to 5 times the molar amount. The reaction is usually carried out at a temperature of from 200 ° C, preferably from about 0 to 150 ° C, for about 5 minutes to 5 hours. An alkali metal halogen compound such as sodium hydride or potassium iodide may be added to this reaction. The starting compound used in each of the above reaction formulas may preferably be a salt, and in addition, the final compound obtained by each reaction may preferably form a salt. Among these preferred salts, preferred salts of the compound (1) are exemplified below. Preferred salts of the compound (1) are pharmacologically acceptable salts, for example, metal salts such as alkali metal salts (e.g., sodium salts and potassium salts), alkaline earth metal salts (e.g., calcium salts, and magnesium salts, etc.), inorganic a salt of a base such as an ammonium salt, an alkali metal carbonate (for example, lithium carbonate, potassium carbonate, sodium carbonate, and carbonic acid planing, etc.), an alkali metal hydrogencarbonate (for example, lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.) An alkali metal hydroxide (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and oxyhydrin, etc.), a salt of an organic base such as a tri(lower)alkylamine (eg, trimethylamine, triethylamine, and Ν-ethyl diisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethyl-92-200831498 phenylamine, N-(lower) alkylmorpholine (eg N-methylmorpholine, etc., 1,5-diazabicyclo[4·3·0]壬-5-calcined (DBN), 1,8-diazabicyclo[5·4.0] eleven Carbene·7 (DBU), 1,4-diazabicyclo[2·2·2] Xinyuan

(DABCO) and the like; salts of inorganic acids such as hydrochlorides, hydrobromides, hydrosulfates, nitrates, and phosphates; and salts of organic acids such as formates, acetates, propionates, Oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate Pier ate), mesylate, ethanesulfonate, p-toluenesulfonate, and glutamate. Further, a compound obtained by adding a solvate (e.g., hydrate, ethanolate, etc.) to the raw material and the final compound shown in each reaction formula is included in each formula. An ideal solvate can be a hydrate. Each of the final compounds prepared in each of the above reaction formulas can be isolated and purified from the reaction mixture, for example, by cooling the reaction mixture, followed by isolation (eg, filtration, concentration, extraction, etc.) and general purification operations. (such as column chromatography and recrystallization, etc.) separate from the reaction product. The compound of the formula (1) of the present invention also includes isomers such as geometric isomers, stereoisomers, and optical isomers. The compound of the formula (1) and salts thereof can be used in the form of a general pharmaceutical formulation. The formulation may be prepared using a diluent or excipient such as a dip, an extender, a binder, a wetting agent, a disintegrant, a surfactant, a lubricant, and the like. In the case of pharmaceutical formulations, various forms can be used for medical purposes. Representative forms include tablets, nine doses, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions, etc.) -93- 200831498

Forming a tablet aspect A carrier known in the art of a wide variety of types can be used. For example, excipients such as lactose, sucrose, sodium chloride, dextrose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and citric acid; binding agents such as water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gel solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dried starch, sodium alginate, powdered agar, powder Laminaria, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, powder, and lactose; disintegration inhibitors, such as recommended sugar, three Glyceryl stearate, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium base and sodium lauryl sulfate; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal tannic acid; Agents such as refined talc, stearate, powdered boric acid, and polyethylene glycol. Further, if necessary, the tablets may be coated with a general coating agent such as a sugar-coated tablet, a gel-coated tablet, a film-coated tablet or a double-layer tablet, and a multilayer tablet. In terms of the formation of nine doses, a carrier known in the art of a wide variety of types can be used. For example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin and talc; binders such as powdered gum arabic, powdered tragacanth, gel and ethanol; and disintegrants, Such as laminaria and agar. As the suppository, a carrier known in the art of a wide variety of types can be used. For example, polyethylene glycol, cocoa butter, higher alcohols, higher alcohols -94-200831498 esters, gels, and semi-synthetic glycerides. The capsules are usually obtained by mixing the active ingredient compound with the various carriers exemplified above according to a conventional method, and then kneading the mixture into a hard gel capsule or a soft gel capsule or the like.

For the preparation of injections, the liquid, emulsion and suspension are preferably sterilized and are isotonic with the blood. When used as an injection, any diluent used in the art can be used, for example, water, ethanol, polyethylene glycol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, Polyoxyethylene sorbitan fatty acid ester and the like. Further, in this case, the pharmaceutical formulation may contain a sufficient amount of a salt, glucose or glycerin to prepare an isotonic solution, and a general solubilizing agent, a buffering agent or an analgesic agent may be added. In addition, if necessary, a pigment, a preservative, a fragrance, a fragrance, and a sweetener or other pharmaceutical substance may be added to the pharmaceutical formulation. The compound of the formula (1) contained in the pharmaceutical formulation according to the present invention is contained. Φ The amount of the salt thereof is not particularly limited and may be appropriately selected from a wide range; however, it is usually from about 1 to 70% by weight, preferably from about 1 to 30% by weight, based on the composition of the formulation. The method of administration of the pharmaceutical formulation of the present invention is not limited and can be administered by a method according to the dosage form, the age, sex and other conditions of the patient, and the severity of the disease. For example, if it is a tablet, a nine-dose, a liquid, a suspension, an emulsion, a granule, and a capsule, it is administered orally. In addition, if it is an injection, it can be administered alone or by intravenous injection with a general supplement such as glucose, amino acid, etc., and if necessary, by intramuscular-95 - 200831498, intradermal Subcutaneously or subperitoneally. In the case of a suppository, it is administered intrarectally. The dosage of the pharmaceutical formulation of the present invention is appropriately selected depending on the mode of use, the age, sex and other conditions of the patient, and the severity of the disease, etc. However, the dose of the active ingredient compound is usually and preferably set at about 0 per ton. · 1 to 10 mg / body weight (kg). Furthermore, it is expedient to formulate the active ingredient compound in the form of the dosage form in the range of about 1 to 200 mg.

Inside. The compounds of the present invention have a D2 receptor partial agonist effect, a 5·ΗΤ2Α receptor antagonist effect, and a serotonin absorption inhibitory effect. The D2 receptor partial agonist effect inhibits dopamine-induced (DA) nerve conduction when it is enhanced, and when it is lowered, it can stabilize dopamine-induced (DA) nerve conduction to a normal state ( Dopamine system stabilizers). According to this effect, excellent clinical improvement effects on symptoms of abnormal nerve conduction (enhancement and reduction) of DA, for example, improvement effects of positive and negative symptoms, improvement effects of cognitive impairment, and improvement effects of depressive symptoms, etc. Development (see Michio Toru,

Psychiatry, V ο 1. 46, page 855-864 (2 0 04); Tetsuro

Kikuchi and Hirose Takeshi : Nou-no-Kagaku ( Brain Science ) ? Vo 1. 25, pp. 5 7 9-5 83 (2003 ); and Harrison, TS and Perry, CM: Drugs 64: 1715-1736, 2004) . The 5-HT2A receptor antagonist effect means an effect of reducing extrapyramidal side effects and developing an excellent clinical response, and more particularly effective to ameliorate negative symptoms, improve cognitive impairment, improve depressive symptoms, and insomnia (see Jun-96-200831498)

Ishigooka and Ken Inada: Rinsho-Seishin-Yakuri (Japanese Journal of Clinical Psychopharmacology), vo 1. 4, pp. 1 6 5 3- 1 664 (200 1); Mitsuk uni Mu rasa ki: Rinsho-

Seishin-Y akuri (Japanese Journal of Clinical Psychopharmacology), vo 1. 1 ? pp. 5-22 (1 998), Puller, 1. A. et al., E ur. J. Pharmacol., 407:39-46 , 2000, and

Meltzer, HY et al.: Prog. Neuro-Psychopharmacol. Biol. Psychiatry 27: 1 1 59- 1 1 72, 2003 ) serotonin absorption inhibition effect (or serotonin reuptake inhibitory effect) is, for example, effective to improve Depressive symptoms (see Mitsukuni Murasaki:

Rinsho-Seishin-Yakuri (Japanese Journal of Clinical Psychopharmacology), vo 1. 1, page 5-22 (1 988)) ° The compounds of the present invention are excellent in all three effects, or one or two of them are remarkably excellent. Furthermore, in addition to the above effects, some of the compounds according to the present invention also have a receptor antagonist effect. The a i receptor antagonist effect is effective in ameliorating the positive symptoms of schizophrenia (see Svensson, Τ·H.: Prog.

Neuro-Psychopharmacol. Biol. Psychiatry 27: 1 1 45- 1 158, 2003) 〇 The compounds of the present invention are therefore broadly efficacious for the treatment of schizophrenia and other central nervous system disorders and have excellent clinical response. 'This 'the compound of the present invention is extremely effective for treating or preventing the following central nervous system disorders· schizophrenia; persistent, intractable or chronic schizophrenia; emotional disorders; psychiatric disorders; affective disorders; bipolar disorder -97 - 200831498

Symptoms (eg, type I depression and type II depression): depression; endogenous depression; major depression; depression and obsessive depression; mood disorders; circulatory affective disorders; anxiety disorders ( For example, panic attacks, panic attacks, square phobias, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.; body-form disorders (eg, hysteria, physical symptoms, transformation) Sexual condition, painful condition, suspected condition, etc.); fabricated condition; schizophrenic condition; sexually functional condition (eg, sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction, etc.); foraging disorder (eg, anorexia) , satiety disorders, etc.; sleep disorders; adaptation disorders; substance-related disorders (eg, alcohol abuse, alcoholism, drug addiction, stimulant poisoning, anesthetic poisoning, etc.); lack of pleasure (eg, physician lack of pleasure, spirit Or lack of pleasure in psychological reasons, lack of pleasure associated with depression, lack of pleasure associated with schizophrenia, etc.): spirit Cognitive impairment; cognitive impairment associated with Alzheimer's disease; Parkinson's disease and other neurodegenerative disorders; cognitive impairment due to Alzheimer's disease, Parkinson's disease and related neurodegenerative disorders; Cognitive impairment of schizophrenia; cognitive impairment due to obsessive, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental disorder; autism; Symptoms; Attention deficit/hyperactivity disorder; behavioral disorders; and Down's syndrome. Furthermore, the compounds of the present invention have only a few or no side effects and are excellent in safety and tolerability. Furthermore, the compounds of the present invention achieve the following effects which cannot be achieved by general treatment by using in combination with at least one agent conventionally used in clinical practice: such as -98-200831498, lowering the dose, reducing side effects, enhancing the therapeutic effect, etc., wherein the clinical practice is at least A pharmaceutical agent is selected from the group consisting of: (1) mood stabilizers, (2) serotonin reuptake inhibitors, (3) norepinephrine reuptake inhibitors, (4) serotonin and norepinephrine reuptake inhibitors, and 5) Anxiolytics. (1) Emotional stabilizer

As the mood stabilizer, a compound known in the art as a mood stabilizer can be widely used. Emotional stabilizers for use in the present invention include, but are not limited to, lithium, valproic acid, di vapro ex sodium, carb amazepine, oxcarbamazepine, zonisamide, 1 amotrigine, topiramate, gabap entin, le vetiracetam, clonazepam, phenitoin, thyroxine, tiagabine And omega-3-fatty acids. Preferred are Lamotrigine, zonisamide, topiramate, lithium, valproic acid, and carbamazepine o (2) Serotonin reuptake inhibitors As for serotonin reuptake inhibitors, known compounds which are inhibitors of hemoglobin reuptake are widely used. According to the standard pharmacological analysis proposed by Wong et al. (Neuropsychophamacology, 8, pp. 3 3 7-344 (1 993)), the preferred serotonin reuptake inhibitor is IC50値 (inhibition of serotonin reuptake 50%) The concentration of the agent is about nM or less. Such serotonin reuptake inhibitors include, for example, flavox amine (5-99-200831498 methoxy-trifluoromethyl)phenyl]-1-pentanone-oxime-(2aminoethyl)anthracene)

, fluoxetine (N-methyl-3-(p-difluoromethylphenoxy)-3-phenylpropylamine), paroxetine (trans-(-)-3-[(1,3-benzo) M-dioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine), sertraline (1S-cis-4_(3,4-dichlorophenyl)- 1,2,3,4·tetrahydromethyl-1-naphthylamine hydrochloride), venlafaxine (1-[2-(dimethylamino)-1-(4-methoxyphenyl)) Cyclohexanol, milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide), citalopram (1-[3·(dimethylamino)propyl) ]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuranonitrile), duloxetine (N-methyl-3-(1-naphthalenyloxy)-3-(2- Thienyl)propylamine), and escitalopram (S-(+)-l-[3·(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3·dihydro-5- Isobenzofuranonitrile oxalate. (3) Adrenalin reuptake inhibitors For the norepinephrine reuptake inhibitors, known compounds which function as φ-adrenergic reuptake inhibitors can be widely used. Adrenergic reuptake inhibitors include: levoxetine, atomoxetine and bup Ropion, preferably levoxetine and atomoxetine ° (4) serotonin and norepinephrine reuptake inhibitors for serotonin and norepinephrine reuptake inhibitors, widely used as serotonin and norepinephrine reuptake inhibitors Known compounds. Such serotonin and norepinephrine reuptake inhibitors include, for example, venlafaxine, duloxetine, and milnacipran®-100-200831498 (5) Anxiolytics The anti-anxiety agents used in the present invention include, but are not limited to, : benzodiazepine type drugs such as diazepam, chlordiazepoxide, cloxazolam, clotiazepam, alprazolam, etizolam and oxazolam, serotonin 5-HT1 A receptor agonist type anxiolytics such as tandospirone and buspirone.

For selected agents (1) mood stabilizers, (2) serotonin reuptake inhibitors, (3) norepinephrine reuptake inhibitors, (4) serotonin and norepinephrine reuptake inhibitors, and (5) An anxiolytic agent, which may be in the form of a free base or a salt (acid addition salt). These agents can be in the form of racemates or R and S pairs of shopping. These agents may be used singly or in combination of two or more. It is preferred to use it alone. These agents readily form acid addition salts with pharmaceutically acceptable salts. These acids include, for example, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, and organic acids such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, maleic acid, anti Butenedioic acid, malic acid, tartaric acid, and benzoic acid. These acid addition salts can also be used as the active ingredient compound of the present invention and as a drug in a free form. Salts can also be easily formed by reacting these compounds having an acid group in a drug with a pharmacologically acceptable basic compound. Basic compounds include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate , or bicarbonate; metal alkoxide, such as methyl-101 - 200831498 sodium alkoxide and potassium methoxide. Hereinafter, the present invention is further described by reference examples, examples, pharmacological experiments, and preparation examples. Reference Example 1 Synthesis of tert-butyl ethyl-(4-hydroxybutyl)carbamate

Add 9.32 g (43 mmol) of di-tert-butyl dicarbonate to 5.0 ml (39 mmol) of 4-ethylamino-1-butanol and 6.5 ml (47 mmol) of triethylamine under ice cooling. Methyl chloride solution (1 〇〇 mi). This mixture was stirred at room temperature for 21 hours. Water was added to the reaction solution for separation. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by hexane column chromatography (hexane: ethyl acetate = 2:1 to 1:1). The purified product was concentrated under reduced pressure to give EtOAc (yield: EtOAc) φ Reference Example 2 Synthesis of 4-(t-butoxycarbonyl-ethyl-amino)butyl sulfonate 2.5 ml (32 mmol) of methanesulfonyl chloride was added dropwise to 6.50 g (30 mmol) under ice cooling. A solution of tert-butyl ethyl-(4-hydroxybutyl)carbamate and 5.0 ml (36 mmol) of triethylamine in dichloromethane (130 ml), and the mixture was stirred at the same temperature for one hour. Water was added to the reaction solution for separation. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 2:1 to 1.5:1). The purified product was concentrated under reduced pressure to give 7.2 g (yield: 182 %) -102 - 200831498 4-(t-butoxycarbonyl-ethyl-amino)butyl ethanesulfonate as colorless oil . Reference Example 3 Synthesis of [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butyl]-ethyl-aminocarbamic acid tert-butyl ester hydrochloride 6.83 g (26.8 mmol) 4-Benzo[b]thiophen-4-yl-piperazine hydrochloride and 7.75 g (5.6·1 mmol) potassium carbonate were added to 7.20 g (24.4 mmol)

A solution of 4-(t-butoxycarbonylethylamino)butyl sulfonate in DMF (150 ml). This mixture was stirred at 80 ° C for 3.5 hours. The reaction solution was cooled to room temperature, water was added, and the reaction product was extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 2:1 to 1:2). The purified product was concentrated under reduced pressure to give 4. 4 g (yield: 48%) of [4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl] - tert-butyl ethyl carbamic acid. 3 40 mg of the concentrate thus obtained was dissolved in 2 ml of ethanol, and 0.9 ml of a 1 N HCl solution in ethanol was added. The precipitated crystals were filtered off and dried to give a white powder of [4_(4·benzo[b]thiophen-4-ylpiperazine-diyl)butyl]-ethyl-aminocarbamic acid tert-butyl ester. Hydrochloride. Melting point 230 to 23 2 ° C Reference Example 4 Synthesis of [4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-ethyl-amine dihydrochloride 7·8 Methyl trifluoroacetic acid was added to 4.20 g (10.1 mmol) [4-(4·benzo-103- 200831498)

[b] 嚷--4-yl-dimyl-yl)butyl]-ethyl-aminocarboxylic acid dibutyl vinegar in dichloromethane (80 ml). This mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and aqueous sodium hydrogen sulfate was evaporated. The reaction product was dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by basic column chromatography (dichloromethane:methanol = 1:0 to 9:1). The purified product was concentrated under reduced pressure to give (yield: </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; ] Ethyl-amine. The concentrate was taken out and 260 mg was dissolved in 2 ml of ethanol, and 1.8 ml of 1 NHC1 ethanol solution was added. The precipitated crystals were filtered off and dried to give [4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-ethyl-amine dihydrochloride as a white powder. . Melting point 265 to 267 ° C Reference Example 5 Synthesis of 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]isoindole-1,3-dione salt Acid salt 200 mg (0·71 mmol) 2-(4-bromobutyl)isoindole-1,3·dione, 200 mg (0·78 mmol) 1-benzo[b]thiophen-4-yl Piperazine hydrochloride, potassium carbonate (230 mg, 1.66 mmol) and sodium iodide (130 mg, 0.87 mmol) were added to dimethylformamide (DMF) (4 ml). This mixture was stirred at 80 ° C for 5 hours. The reaction solution was cooled to room temperature, water was added, and the reaction product was extracted with ethyl acetate. The resulting organic layer was washed with water and dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure. The residue obtained was purified by column chromatography (methylene chloride:methanol = 30:1). The purified product was concentrated under reduced pressure. -104- 200831498 The residue was dissolved in ethanol (2 ml) and concentrated hydrochloric acid (0.65 ml). This solution was concentrated under reduced pressure after addition of hydrochloric acid. The obtained residue was recrystallized from ethanol-ethyl acetate to give 210 mg (yield: 65 0) of pale yellow powder of 2-[4-(4-benzo[b]thiophen-4-yl-piperazine-1 -yl)butyl]isoindole-l,3-dione hydrochloride. Melting point 295 °C (decomposition)

Reference Example 6 Synthesis of 4-(4-benzo[b]thiophen-4-yl-piperazine-1-yl)butylamine 0.27 ml (5.6 mmol) of hydrazine monohydrate was added to 789 mg (1.89 mmol) 2-[ A solution of 4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butyl]isoindole-1,3-dione in ethanol (8 ml). The mixture was stirred and heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure and aq. The reaction product obtained was extracted with dichloromethane, washed and dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure to give 581 mg (yield) of 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butylamine as a yellow oil. Reference Example 7 N-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]propyn-2-ylamine 0.084 ml (1.14 mmol) propargyl bromide To a solution of 3 3 0 mg (1.14 mmol) of 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butylamine in dichloromethane. This mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the reaction product was extracted with methylene chloride and dried over anhydrous sodium sulfate - 105 - 200831498. The dried product was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) The purified product was concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& -propyn-2-ylamine. Reference Example 8

Synthesis of 1-benzo[b]thiophen-4-yl-piperazine from 14.4 g of 4-bromobenzo[b]thiophene, 29,8 g of piperazine anhydride, 9.3 g of sodium butoxide, 0.65 g a mixture of (R)-( + )-2,2,-bis(diphenylphosphine naphthalene (BINAP), 0.63 g of tris(dibenzylideneacetone)dipalladium (ruthenium) and 25 0 ml of toluene is heated to After refluxing for 1 hour, water was added to the reaction solution. The solution was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. :methanol: 2 5 % aqueous ammonia = 1 0 0 ·· 1 0 : 1) Purified to obtain 9.5 g of 1-benzo[b]thiophen-4-yl-piperazine as a yellow oil. 3.7 ml of concentrated hydrochloric acid To a solution of 9.5 g of 1-benzo[b]thiophen-4-yl-piperazine in methanol, and evaporating the solvent under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were filtered. The methanol was recrystallized to obtain a colorless needle crystal of 1-benzo[b]thiophen-4-ylpiperazine hydrochloride. Melting point: 2 7 6 to 2 80 ° C ^-NMR (DMSO-d6) ( 5 ppm :

3.25-3.3 5 ( 8H,m) ,6·94 ( 1H,d,J = 7.6Hz) , 7.30 ( 1H , dd , J = 7.8Hz , 7.8Hz ) , 7.51 ( 1H,d,J = 5.5Hz ) , 7.68 -106- 200831498

(1H, d, J = 8·1 Hz), 7.73 (1H, d, J = 5.5 Hz), 9·35 ( 2H , brs ) 〇 Reference Example 9 Synthesis of 1-benzo[b]thiophen-4-ylpiper The azine consists of 14.4 g of 4-bromobenzo[b]thiophene, 29.8 g of piperazine anhydride, 9.3 g.

Sodium tert-butoxide, 0.65 g (R)-( + )-2,2,-bis(diphenylphosphine h1,1'-binaphthyl (BINAP), 0.63 g of tris(dibenzylideneacetone)dipalladium (混合物) and a mixture of 25 〇 il of toluene were heated to reflux for 1 hour under a nitrogen atmosphere. Water was added to the reaction solution, which was extracted with ethyl acetate. The obtained organic layer was washed with water, dried over magnesium sulfate, and solvent Evaporation under reduced pressure. The obtained residue was purified mjjjjjlilililililililililililili b] thiophen-4-yl-piperazine. 3.7 ml of concentrated hydrochloric acid was added to a solution of 9.5 g of 1-benzo[b]thiophen-4-yl-piperazine in methanol, and the solvent was evaporated under reduced pressure. Ethyl ester was added to the residue obtained by φ, and the precipitated crystals were filtered off, and recrystallized from methanol to obtain a colorless needle crystal of 1-benzo[b]thiophene-enyl-piperazine hydrochloride.

Melting point: 2 7 6 to 2 80 ° C ^-NMR (DMSO-d6 ) 5 ppm : 3.2 5 - 3 · 3 5 ( 8 Η, m ) &gt; 6.94 (1Η, d, J = 7.6Hz ) , 7.30 ( 1H ' dd, J = 7.8 Hz, J = 7.8 Hz ), 7.51 ( 1H, d, J = 5.5 Hz ) ' 7.6 8 ( 1H,d,J = 8.1 Hz ) , 7.73 (lH,d,J = 5.5 Hz) , 9·35 (2H, brs) 〇 Reference Example 1 0 -107- 200831498 Synthesis of 4-Benzo[b]thiophen-4-yl-methylpiperazine-1-carboxylic acid tert-butyl ester According to the dream test, 3-methylindole-1-resin dibutyl butyl ester and 4-bromobenzo[b]thiophene were used as the reaction compound. ^-NMR ( DMSO-d6 ) δ ppm : 1. 8 5 - 1.9 5 ( 3 Η » m ) , 1.50 (9H, s) , 2·8-2·9 (1Η, πι) , 3.15-3.35 (2H , m), 3.4-3.5 ( 1H,m) , 3·5-3·65 ( 1H,m) , 3.65-3.7 ( 1H, m) , 3.7-3.9 ( 1H,m) ,6·98 ( 1H, d, J = 7.5Hz) » 7.29

(1H, dd, J = 8 Hz, J = 8 Hz), 7.38 (1H, d, J = 5.5 Hz), 7.61 ( 1 H » d, J = 8 H z ) ° Reference Example 1 1 Synthesis of 1-benzo[ b] thiophen-4-yl-2-methylpiperazine dihydrochloride 6 ml trifluoroacetic acid added to 1.22 g (3.7 mmol) 4 -benzo[1)]thiophene-4-yl-3-methylpipe A solution of the tert-butyl-carboxylic acid tert-butyl ester in dichloromethane (12 ml) was obtained and the mixture was stirred at room temperature for one hour. This reaction solution was concentrated under reduced φ pressure. A 5 % aqueous solution of potassium carbonate was added to the residue, which was extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. 6 ml of concentrated hydrochloric acid and 10 ml of methanol were added to the residue obtained, and the solution was concentrated under reduced pressure. The residue obtained was recrystallized from acetonitrile to give 1-benzo[b]thiophen-4-yl-2-methylpiperazine dihydrochloride as a pale brown powder. 1 Η - NMR ( DMS 0 - d 6 ) 5 ppm : 0.9 2 ( 3 Η, d, J = 6.5 Η z ), 2.8-3.6 ( 6H,m ) , 3 · 6 -4 · Ο ( 1 Η,m ) , 5 · 3 - 6 · 8 ( 1 Η, m ), 7·20 ( 1Η, br) , 7 · 3 8 ( 1Η, dd, J = 8Hz, J = 8Hz ), -108- 200831498 7.5-8.0 (3H,m), 9·4-10·1 (2Η, ιη). Reference Example 12 Synthesis of 1-benzo[b]thiophen-4-yl-3-methylpiperazine dihydrochloride The title compound was used according to Reference Example 9 using 2-methylpiperazine and 4-bromobenzo[b] The porphin is prepared as a reaction compound.

^-NMR ( DMSO-d6 ) δ ppm : 1·34 ( 3H,d,J = 6.5 Hz ), 2.85 -2.95 ( 1 H,m) , 3.05-3.15 ( 1H,m) , 3.2-3.6 ( 6H , m ), 6·97 ( 1H,d, = 7.5Hz ) , 7.31 ( 1H, dd, J: =8 Hz , J=8H2 :), 7·54 ( 1H, d, J = 5 .5 Hz ) ' 7.69 (1H, d, J=8Hz), 7·75 (1H, d, J = 5.5Hz) &gt; 9.2-9.3 ( 1H,m ), 9.64 ( 1H,br ).

Reference Example 13 Synthesis of 1-(4-chlorobutyl)-2-pyrrolidone Sodium hydroxide (60% oil) (2.47 g, 61·8 mmol) was added to 2-pyrrolidone (5.0 g, 5 8.7) under ice cooling. A solution of mmol of dimethylformamide (50 ml) and the resulting mixture were stirred at the same temperature for 1 hour. This reaction product was further stirred at room temperature for 1 hour. 1-Bromo-4-chlorobutane (13.5 ml, 1 17.3 mmol) was added, and the resulting mixture was stirred at 80 ° C for 2 hr. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: The purified product was concentrated under reduced pressure to dryness eluted elution elution elution W-NMR ( CDC13 ) 5 ppm : 1.65-1.90 ( 4H,m ) ^ 2.00-2.10 (2H,m ) , 2·39 ( 2H,t,J = 8.3Hz ) , 3.32 ( 2H,t, 1 = 7.1 Hz ) , 3.39 ( 2H, t, J = 7.1 Hz ) , 3.5 8 ( 2H, t, J = 6.4 Hz ) 化合物 The compounds of Reference Examples 14 to 40 were prepared according to Reference Examples 9 to 13 using the relevant reaction compounds.

-110 200831498 m i] Reference example ~n~

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Example 1 Synthesis of N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-N-ethyl-acetamide hydrochloride 0 · 1 0 m 1 (1 · 0 6 mm ο 1) Acetic anhydride added to 270 mg (0 · 8 5 mm ο 1)

39 40

N-[4-(4-benzo[b]nonin-4-yl-pyran-1-yl)butyl]ethyl-amine and 0.15 m 1 (1.0 8 mm ο 1) triethylamine Chlorinated solution (1 〇m 1). This mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the resulting mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography (dichloromethane:methanol = 30:1 to 9:1). The purified product was concentrated under reduced pressure. The residue obtained was dissolved in 2 ml of ethanol, and 0.85 ml of a 1 N HCl solution was added. The precipitated crystals were filtered off and dried to give 240 mg (yield: 71%) of white powder of N-[4-(4-benzo[b]thiophen-4-yl-piperazine-1-yl)butyl. ]-N-ethylacetamide

Hydrochloride. Melting point 198 to 200 ° C Example 2 -114- 200831498 Synthesis of N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]benzamide hydrochloride 〇·15 ml (1.3 mmol) of benzamidine chloride was added to 220 mg (0.76 mmol) 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butylamine under ice cooling And 15 ml (1·9 mmol) of pyridine in dichloromethane (5 ml), the resulting mixture

The mixture was stirred at the same temperature for two hours. Water was added to the reaction solution. The reaction solution was extracted with dichloromethane and washed with a sodium hydrogen carbonate aqueous solution. The extract was washed with anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (dichloromethane: methanol = 30:1). The purified product was concentrated under reduced pressure. The resulting residue was dissolved in 2 ml of ethanol, and 0.8 ml of a 1 N HCl 1 ethanol solution was added. The precipitated crystals were filtered off and dried to give 230 mg (yield: 70%) of white powder of bismuth-[4·(4-benzo[b]thiophen-4-yl-piperazin-1-yl) Base]-benzamide hydrochloride.

Melting point 2 0 9 to 2 1 0 °C Synthesis of 3-ethylhydrazino-N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-benzene Methionamine 0.15 ml (1.06 mmol) triethylamine and 0·1 ml (0.67 mmol) diethyl cyanophosphate (DEPC) was added to 150 mg (0·52 mmol) 4-(4-benzo[b] Thiophen-4-yl-piperazin-1-yl)butylamine and 110 mg (0. 61 mmol) of 3-ethylguanidinium benzoic acid in DMF (3 ml). This mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution. The reaction product was extracted with ethyl acetate and washed with water. The product was washed with anhydrous sodium sulfate and concentrated under reduced pressure -115-200831498. The residue obtained was purified by basic EtOAc EtOAc (EtOAc:EtOAc:EtOAc The purified product was concentrated under reduced pressure. The obtained residue was recrystallized from ethanol-hexane to obtain 170 mg (yield: 73%) of yellow needle crystals of 3-ethylaminoamino[4-(4-benzo[b]thiophen-4-yl. - piperazin-1-yl)butyl]benzamide.

Melting point 1 7 8 to 1 8 0 °C

Example 4 Synthesis of N_[4-(4-benzo[b]thiophen-4-ylpiperazine-l-yl)butyl]-N-propyl-acetamide hydrochloride 1 ml under ice cooling Formic acid methyl vinegar and 73 mg (1.3 mmol) propylene to 246 mg (0.85 mmol) 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butylamine in methanol (7 ml). This mixture was stirred at the same temperature for 5 minutes. 0.4 g (1.3 mmol) of MP-boron boron (3.18 mmol/g) was added to the resulting solution, and the mixture was stirred at room temperature for 1 hour. The resin was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was dissolved in 7 ml of dichloromethane. 0.12 ml (1.3 mmol) of acetic anhydride was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc m. The purified product was concentrated under reduced pressure. The resulting residue was dissolved in 2 ml of ethanol. 3·3 ml of 1 N HC1 ethanol solution was added to the prepared solution. The precipitated crystals were filtered off and dried to give [4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl] as a white powder (yield: 24%). -N-propyl-acetamide hydrochloride. -116- 200831498 Melting point 198 to 200 ° C Example 5 Synthesis of N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-N-methyl-acetamidine Amine hydrochloride

50 mg (1.04 mmol) of lithium aluminum hydride added to 166 mg (0.52 mmol) of N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-carboxamide THF solution (1 5 ml). The mixture was stirred and heated to reflux for 2 hours. The reaction solution was cooled to cool to room temperature. A small amount of water, methanol and seri plastic was added and the mixture was stirred for 5 minutes. This mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 15 mL dichloromethane. 0.074 ml (0.78 mmol) of acetic anhydride was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the reaction product was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) The purified product was concentrated under reduced pressure. The residue obtained was dissolved in 1 ml of ethanol, and 2 ml of a 1 N HCl solution in ethanol was added. The resulting solution was added to ether, and the precipitated crystal was allowed to stand. The crystals were filtered off and dried to give 58 mg (yield: 29%) of white powder of N-[4-(4-benzo[b]thiophen-4-yl-piperazine-1-yl)butyl] -N-methylacetamide hydrochloride. Melting point 2 16 to 2 1 7 ° C Example 6 Synthesis of N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-N-phenyl- -117 - 200831498 Acetamide hydrochloride

288 mg (1.13 mmol) 4-benzo[b]thiophen-4-yl-sodium hydrochloride and 468 mg (3.4 mmol) potassium carbonate added to 367 mg (1.35 mmol) N-(4-bromobutyl) A solution of D-phenyl-acetamide in DMF. This mixture was stirred at 80 ° C for 3 hours. The resulting reaction solution was cooled to room temperature. Water was added and the reaction product was extracted with ethyl acetate. The resulting organic layer was washed with water and dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) The purified product was concentrated under reduced pressure. The residue obtained was dissolved in 5 ml of ethanol, and a solution of 1.05 ml of 1 N HCl in ethanol was added. The precipitated crystals were filtered off and dried to give 153 mg (yield: 31%) of white powder of N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) Base]-N-phenyl-acetamide hydrochloride. Melting point 2 1 6.5 to 2 1 8.0 °C Example 7 Synthesis of N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-(R)-pyrrolidine- 2-Carboxyguanamine 10 ml of 4 N HCl solution in ethyl acetate was added to 2.01 g (4.13 mmol) of N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) A solution of the base]-(R)-l-(t-butoxycarbonyl)pyrrolidone-2-carboxamide in methanol (5 ml). This mixture was stirred at room temperature for 17 hours. Water and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction solution to make the reaction solution alkaline. The product was extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate (MgSO4). 4-yl-piperazinyl)butyl]-(R)-pyrrolidine-2-carboxamide. H-NMR (DMSO-d6) 5p pm : 1.45-1.63 ( 4H,m) 5 1.63- 1 . 8 0 ( 2 Η &gt; m ) , 1.84-1 ·94 ( 1H,m ) &gt; 2.02-2.26 ( 1 H ^ m ), 2.37-2.56 (2H, m) , 2.5 9-2.79 (4H, m) » 2.84- 3.06 (2H,m) , 3.09-3.23 (4H,m),3.23-3.37 (2H,m ),3·72 ( 1H,dd,J = 5.3,9.0Hz ) ' 6.90 ( 1H,d, J = 7.7Hz ) , 7.27 ( 1H,t,J = 7.8Hz ) ' 7 · 3 3 - 7 · 4 4 ( 2 H,m

), 7.55 (iH, d, J = 8.0), 7.59-7.81 (lH, brs). Example 8 Synthesis of N_[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-(R)-1-(2-acetamidoaminoethenyl) Pyrrolidine-2-carboxyguanamine 104 mg of N-ethinylglycine, 214 mg (1.11 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt Acid salt (WSC) and 170 mg (1.11 mmol) of 1-hydroxybenzotriazole (HOBT) added to 288 mg (0.745 mmol) N-[4-(4-benzo[b]thiophen-4-yl- A solution of piperazin-1-yl)butyl]-(R)-pyrrolidine-2-carboxamide in dichloromethane (7 ml). This mixture was stirred at room temperature for 18 hours. Water and a saturated aqueous solution of sodium hydrogencarbonate are added to the reaction solution to make the reaction solution alkaline. The product was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by column chromatography on ethylbenzene (ethyl acetate, methanol = 20:1). The purified product was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give 104 mg (yield: 29%) of N-[4-(4-benzo[b]thiophen-4-yl-piperazine-diyl)butyl. ]-(R)-1-(2-Ethylaminoethenyl)pyrrolidine-2-carboxy-119- 200831498 decylamine. Melting point 1 2 5 · 5 to 1 2 6.5 ° C Example 9 Synthesis of hydrazine-[4·(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-N-ethyl- Thioacetamide hydrochloride

3.01 g (7.44 mmol) Lawesson's reagent was added to 2.23 g (6·2 mmol) Ν-[4-(4·benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-oxime Ethyl-thioacetamide in THF (70 ml). The mixture was stirred and heated to reflux for 3 hours. The resulting reaction solution was cooled to room temperature and purified by basic column chromatography. The purified product was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of ethanol, and 4.6 ml of a 1 N HCl solution was added. The resulting solution was added to 15 ml of ether, and the precipitated crystals were allowed to stand. The crystals were filtered off and dried to give 1.47 g (yield: 58%) N-[4-(4-benzo[b]thiophen-4-yl-piped-1-yl)butyl]-N -ethyl-thioacetamide hydrochloride. Melting point 224.0 to 225.5 t: Example 10: 口-[4·(4-Ben[b] 嚷 -4--4-yl-indol-1-yl)butyl]-Ν - propyl-thio-ethyl The amine hydrochloride title compound was used according to Example 9 using Ν-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-isopropyl-acetamide. Made from the starting materials. White powder-120- 200831498 Melting point 217.5 to 223.5 ° C Example 11 Synthesis of [4-(4-benzo[b]thiophen-4-yl·piperidinyl)butyl]ethyl-3,3_dimethyl Urea hydrochloride

0.2 g (1·9 mmol) N,N-dimethylamine formazan to 〇·5 g (1.6 mmol) Ν-[4·(4-benzo[b]thiophen-4-yl-piperazine A solution of -1-yl)butyl]-ethylamine and 0.33 ml (2.4 mmol) of triethylamine in dichloromethane (20 ml). This mixture was stirred at room temperature for 3 days. Water was added to the reaction solution, and the reaction product was extracted with ethyl acetate. The resulting organic layer was washed with water and dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure. The obtained residue was purified by chromatography (methylene chloride:methanol = 15:1). The purified product was concentrated under reduced pressure. The residue obtained was dissolved in methanol and 2.5 ml of a 0.5 N HCl solution in methanol was added. The precipitated crystals were filtered off and dried to give 0.44 g (yield: 66%) of white powder of 1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) Ethyl]ethyl-3,3-dimethylurea hydrochloride. Melting point 1 8 4 to 1 8 6 ° C Example 1 2 Synthesis of 1-[2-(4-benzo[b]nonin-4.yl-indole-1-yl)ethyl]-3-ethyl Hydrochloride 0.125 ml (1.58 mmol) ethyl isocyanate was added to 319 mg (1.22 mmol) 2-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)ethylamine Methyl chloride solution (7 ml). This mixture was stirred at room temperature for 1 hour. This reaction dissolved in -121 - 200831498 and concentrated under reduced pressure. The residue obtained was purified by basic hydrazine gel column. The purified product was concentrated under reduced pressure. The residue obtained was alcohol, and 0.7 ml of a 1 N HCl solution in ethanol was added. This solution was centrifuged overnight to precipitate crystals. The crystals were filtered off and dried to give a white powder (yield: 28%) of 1-[2-(4-benzo[b]thiophen-pyridin-1-yl)ethyl]-3-ethylurea salt as a white powder. Acid salt. Melting point 19 0·5 to 191.5X: ί (Acetic acid dissolved in B, statically placed to give 126 4-yl-piperidine

Examples 1 3 to 1 4 4 8 The compounds of Examples 1 3 and 1548 S 1585 shown in the following Tables 1 to 8 9 and 1 0 8 to 1 1 2 can be prepared in the same manner as in Examples 1-12. In the following list, physical properties such as crystal, melting point, salt, W-NMR and MS (mass spectrometry) are actually obtained. To 1 448 using pairs, such as

-122- 200831498 tTable 6] - N,

N

Instance

Rt R2 R3 R4 R5 R6

T3 14 t5 16 t7 18 %9 20 2\ n 23 24

4i -H •H 41 -H 41 -Η -H -Η -H -H -OC -H -Cl -HO -Η -H -H -SO -H -H 4»

4i -H -H -H 41 -001⁄2 -OCHa -H •H 4 -F 41 -M 4 -NHCOCH^ -NHCOCeHs -OCH» -H -H •H -H 4 4 •OCkh 4i -CHa -H 4 • OCHS, -H -H -H 4 -scy^Hj -H -H 4 «Η -H octh •H 4 •H -H 4» 4 -a -H ·» 4 4 Form (recrystallization solvent) Melting point CO salt White powder 165-167 to win JlILR9LJnL yellow powder (Berlin monohydrochloride - · SSl.. JEEDL white powder (acetonitrile) trace 235 (decomposition) reftt tB£B salt white powder (acetonitrile &gt; t«MS2 ICtti ECtt* hydrochloride white powder (acetonitrile) 13M41 dihydrochloride white powder (acetonitrile) 14IM43 dihydrochloride white powder (acetonitrile) 212-216 (decomposition) hydrochloride white powder (acetonitrile) 212-214 hydrochloride White powder (acetonitrile) 196 Hydrochloride white powder (acetonitrile) 157-163 (decomposition) hydrochloride white powder (ethanol) 157-161 ΕΒύΚ monohydrochloride white powder (acetonitrile) 212-215 hydrochloride salt* 14 NMR data

^-NMR (DMSO-de) 5ppm: 1.50-1.70 (2H, m), 1.70-1.90 (2Hf m)f 3.10-3.50 (8H, m)f 3.50-3.65 (4H, m), 6.96 (1H, df J=7-5 Hz)f 7.31 (1H, t, J=7.9Hz), 7.48 (lHf df J=5.6 Hz), 7.69 (1H, d, J=8.1 Hz), 7.76 (1H, d, J= 5.5 Hz), 8.09 (2H, dd, J=2.0, 6·9 Hz), 8·32 (2H, dd, J=2.0, 6.9 Hz)f 8.9 (lHf m) f 10.2 (1H, br). 123- 200831498 [Table 7]

27 -» -« -€Μ 28 Ή -Η Phase-Η -Η -Η -Η 14&amp;-150 Bg|X&amp;BS Cocoon DSaX3Ci^EB&amp;X Transducing to XEZLP4X.JSL Heat-Η-NWOCNb - Η 30 -Μ -Η -Η 31 41 -Η -Η 32 -» -Η -Η 33 41 -Η -Η 34 Ή -Η -Η » -Η -Η 4 4 4 -Η -Η -Η -CH, -3⁄43⁄4 4 -Η C-CsHb 4 -Η -N{CHah -CaHs 4 OCHb -H -3⁄41⁄2 4 -Η -Η -Η 4 -Η White powder white powder (methanol·dichloromethane) white powder (acetic acid B Cool) White powder (ethyl acetate) White powder (ethyl acetate) White powder (ethyl acetate) White powder (ethyl acetate) White powder (ethyl acetate) White powder (acetonitrile) t3t-m Ι3θ-Ι3» 222226 (decomposition) chlorate hydrochloride hydrochloride rri^j jgftj hydrochloride hydrochloride nri.WPCTnl· hydrochloride* Example 28 NMR data ^-NMR (DMSO-de) δρριπ: 0.90-1.10 (3H, Br) , 1.40-1.70 (4H, br), 2.03 (3H, s), 3.00-3.70 (14Hf m), 6.9 (1H, br)f 7.28 (2H, d, J=8.3 Hz), 7.4 (2Hf br ), 7.61 (2H# d, J=8.6 Hz), 7.7 (2H, br), 10.06 (1H, brs)·

*Example 29 NMR data XH-NMR (DMSO-d6) 5 ppm: 1.00-1.20 (3H, br), 1.50-1.70 (4Hf br)f 2.03 (3Hf s), 2.50-3.60 (14Hf m), 6.80-7.00 ( 2Hf m)f 7.10-7.80 (7H, m)f 10.03 (1H, brs). -124 - [^8]200831498

White powder (acetonitrile) you ies two salt view

36 -» 37 -Η 38 ·« 39屮40 -CH 41 -Η 42 -〇C •H .24»YRIDYL -Η -Η 44 ^PYRIDYL -Η -Η -Η -Η -Η -Η •Η -NHCOO ^ -Η -Η 4Ί -Η -ΟΟΛ -Η -OCHj -Η -Η -Η -Η ·Η -Η -Η 4 -Η 4 -Η 5 5 -Η 5 -Η 5 -Η 5 White powder (acetonitrile) White powder white powder (dichloromethane-hexane) white powder (acetonitrile) white powder (acetonitrile) 202-206 dihydrochloride (decomposition) 19&amp;-1SB hydrochloride 182-185 ~ 205-208 dihydrochloride (decomposition) 192-195 dihydrochloride 1^-159 = salty white powder (acetonitrile) 43 -H -Η -Ν〇2 -Η -Η -Η 5 yellow powder (acetonitrile) 44 -0Η» -Η • Η -CHg t -Η -Η 5 White powder (acetonitrile) 45 44 •α -Η -OCHa -Η 5 White powder (acetonitrile) 40 -H -α -003⁄4 -Η -ch3 -Η 5 White powder (acetonitrile) 47 -α -Η -α -Η -Η -Η 5 White powder (acetonitrile) 202-204 Dihydrochloride 195499 Hydrochloride 207410 Hydrochloride 21 («13 face salt 1964200 hydrochloride

-125- 200831498 [Table 9]

Example R1 R2 R3 R4 R5 R6 n Crystal form (recrystallization solvent) Melting point Cc) Salt 48 -F -Η -F -H -H 5 White powder (acetonitrile) 195-198 Di-salt view 49 •Η -Η -OCH3 -OCHs -H -H 5 white powder (acetonitrile) vein 193 hydrochloride 50 -cf3 -Η -Η -H -H -H 5 white powder (acetonitrile) 198-203 (decomposed) dihydrochloride 51 -Η -Η - Η -CFa -H -H 5 white powder (acetonitrile) 179-181 dihydrochloride 52 -Η -Η •^hVTrtyl -H -H •H 5 white powder (acetonitrile) 204-210 (decomposition) hydrochloride 53 • Η -Η -SC^CHa -H -H -H 5 white powder (acetonitrile) 205-208 dihydrochloride 54 -α -Η -Cl -SO2NH2 -H -H 5 white powder (acetonitrile) 174-176 salt Acid salt 55 -CI -Η -F -SOiNHz -H -H 5 White powder (acetonitrile) 165-167 Dihydrochloride 56 -C! -Η -F _F -H •H 5 White powder (acetonitrile) 187-190 Hydrochloride 57 -CI -Η -Cl -F -H -H 5 White powder (acetonitrile) 192-196 Hydrochloride 58 &lt;3 -Η •H -ch3 -H -H 5 White powder (acetonitrile) 200- 203 hydrochloride 59 -C! -Η -003⁄4 -och3 -H -H 5 white powder (acetonitrile) 188-192 hydrochloride

-126- 200831498 m ι〇]

Example R1 R2 R3 R4 R5 R6 η Crystal form (recrystallization solvent) Melting point (βΟ salt 60 -α -Η -Η -Br •Η -Η 5 White powder (acetonitrile) 216-2» (decomposition) Di-salt _ 61 -α -Η -Η ·SCH, -Η -Η δ white powder (acetonitrile) 2(^207 hydrochloride 62 -SQiCHa -Η -Η -Η -Η -Η 5 white powder (acetonitrile) 180-182 salt noodles 63 - Η -Η -SO2KH2 -Η -Η •Η 5 White powder (acetonitrile) 201-204 Hydrochloride 64 -Η -F -Η -Η -CI -Η 5 White powder (acetonitrile) 185-197 Hydrochloride 65 - Η -SQzNH2 -Η -Η -OCHa -Η 5 Hydrochloride 66 -Η -F -CI -Η •Η -Η 5 White powder (acetonitrile) 207-210 Hydrochloride 67 -Η -OH -NHCOCHa •Η - Η •Η 5 White powder (ethanol) 197-201 Hydrochloride 68 -Η -Η -ch=ch2 -Η -Η -Η 5 White powder (acetonitrile) 179-102 Hydrochloride 69 -Η -Η -2- PYRIDYL -Η •Η -Η 5 White powder (acetonitrile) 175-180 (decomposed) Dihydrochloride 70 -Η -Η Each PYRIDYL -Η -Η -Η 5 White powder (acetonitrile) 160-163 Dihydrochloride 7 » -Η -Η -4-PYRIDYL -Η •Η 5 White powder (acetonitrile) 185-188 Dihydrochloride-127- 20 0831498 im li] R2 R1 R3- i

m 〇8 R5 Example Rt R2 R3 R4 R5 R6 n Crystal form (recrystallization solvent) Melting point (°c) Salt 72 -H -H 4i -H 44 5 White powder (acetonitrile) 201-204 Hydrochloride 73 -H -H -H -H -H 5 white powder (acetonitrile) 207-210 salt body 74 «Η 44 CN~ -H -H -H 5 yellow powder (acetonitrile > 180-184 two salt noodles 75 -H D- -H • H-H 5 yellow powder (acetonitrile &gt; 153-157 hydrochloride 76 -H -H -H -H -H 5 white powder (acetonitrile) 189-193 dihydrochloride

-128- 200831498 [ft 12] 's Example R1 R2 crystal form (recrystallization solvent) Melting point (. 〇 salt 77 -CH3 -H 2 white powder 223-225 salt ΜΜ 78 -CsH5 -H 2 white powder 268-270 salt wake up Η-ch3 2 white powder (ethanol·acetamidine 239-241 salt 雠80-H 2 white powder (ethanol) white powder (ethanol-acetonitrile 188·(Μ89.0 salt with 8t &quot;CHjOOfe-H 2 white powder 233.0 -235.0 hydrochloride 82 -CHzCHiOCHa -H 2 (ethanol) 203.0-205.0 hydrochloride 83 -ch3 -H 3 white powder 214-215 salt surface 84 -CeH5 -H 3 colorless needle crystal (ethanol · 乙院) 143 -145 85 86 -CHa -H -C2H5 -H 3 3 White powder white powder 235^237 Hydrochloride (ethyl acetate) White powder (ethanol-ethylidene) 119 87 -CHi -CH3 3 hydrochloride white powder (Ethanol·B SD 257-259 Hydrochloride 88 -CH2OCH3 -H 3 197.0-199.0 Hydrochloride m -ch3 -CH^CHzOCH^ 3 White powder 194.5-195.5 Salt 雠90 -H 4 White powder (ethanol) 212.0* 214.0 Hydrochloride 9t - C2H5 -H 4 White powder (ethanol) 196, (M9a hydrazine hydrochloride 92 - W &gt; YRIDYL 4i 4 light yellow powder (ethanol - Ethyl acetate) 167·(Μ69.0 dihydrochloride 93-H 41 4 white powder (ethanol-ethyl) 235.0-237.0 hydrochloride 94-ch3 4 white powder (ethanol · acetamidine 211.0-213 Λ salt 雠 white Powder 95 -CH3 -CH2CH(CH3)2 4 (Ethanol) 222.0^224.0 Salt White Powder 96 •CHa _____ -{CH2)2CH(CHa)2 4 (Ethanol 'B-Europe&amp;7.0-199.0 Hydrochloride & 7 -CH3 -CHrCydo-CeHn 4 white powder (ethanol) 194·&lt;Μ96 hydrochloride 98-CH3 -CHjCeWs 4 white powder (ethanol) 194·0496.0 salt 雠99 -ch3 -CH(CH^ 4 white powder (ethanol 215.0-217Λ mm too -ch3 4 white powder (ethanol) 246.0-248.0 hydrochloride 101 -ch3 -CHtCaHs^ 4 white powder (ethanol) 218,0-220.0 hydrochloride-129- 200831498 warm 13] :iw_&lt;

Example R1 R2 n crystal form (recrystallization solvent) melting point cc) salt

102 103 -CHj tM -CHa 1D5 -CHa toe for 107 -CHa 108 -CHj 109 -CHa110 -CHa -cydcMyis -cydo-CeHn -CHaCH^OH •CH2CH2OCH3-CHaCHiF •CH2CH=CH2

-CiCHaJa -CHaC-CH 4 4 4 4 4 4 4 4 4 nt 4 mmmms7mm0 like 232425 Ξ 仪 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩 佩5 5 White powder (ethanol) 237·£Κ239·0 Hydrochloride white powder (ethanol) 248.0^250.0 Salt white powder (ethanol) 22Ζ0·224·0 Hydrochloride JnLHXjnL. White powder (ethanol) 1710-173.0 Salt Acid salt white powder (ethanol-acetic acid) 160.5-162.0 hydrochloride white powder (ethanol-acetic acid) 189.0-191:0 hydrochloride white powder (ethanol·ethyl brew 207.0-209.0 hydrochloride white powder white powder (ethanol ·Yellow age 199.0-201.0 Hydrochloride 193ΛΜ94.5 Hydrochloride white powder (ethanol·water) 209.0-210.5 Salt awake white powder (ethanol-primary 262.5-264.5 hydrochloride white powder (ethyl acetate) t hope &lt; 192 Dihydrochloride white powder (ethyl acetate) NMRit dihydrochloride white powder (ethyl acetate) 182-186 hydrochloride white powder (ethyl acetate) NMR* hydrochloride white powder (ethyl acetate) m Your hydrochloride white powder (ethyl acetate) 16 &-169 hydrochloride white powder (ethyl acetate NMR» Salt White Powder (Ethanol) 185.0-185.0 Hydrochloride White Powder (Ethyl Acetate·Hangyuan) 85,0-87.0 A white powder (Ethanol-Ethyl 豳197.0-198Λ Hydrochloride White Powder (Ethanol·B) Age mm dihydrochloride white powder (ethanol·acetonitrile 160-163 re/tt ·*» 八rrw — salt salt white powder (ethanol·ethyl age micro-4-hydrochloride-130- 200831498 *example 114 NMR data ^-NMR (DMSO-d6) 5ppm: 1.00-1·20 (3Hf m), 1.50-1.80 (4H, m) , 3.00-3.70 (14Hf m)f 6.97 (lHf dr J=7.5 Hz)f 7.25-7 ·40 (3H, m), 7·48 (1H, t, J=5.9Hz), 7·69 (1H, d, J=8.0 Hz)f 7.75 (lHf df J=5-6 Hz)f 8.66 ( 2Hf d, J=5.9 Hz), 10.3 (lHf br). +Example 116 NMR data

h-NMR (DMSO-d6) 5 ppm: 1.19 (3Hf t, J=6.9 Hz), 1.60-1·75 (4H, m), 3·10-3·60 (14H, m), 6·97 (1H , d, J=7.4 Hz), 7·13 (1H, dd, J=3.7, 5·0 Hz), 7·30-7·35 (1H, m), 7.40-7.45 (lHf m)f 7.45- 7.50 (1H, m), 7.65-7.80 (3H, m), 10.3 (1H, br). Λ Example 117 NMR data 4-NMR (DMSO-de) 5 ppm: 1.12 (3Hf tf J=7.1 Hz ), 1.55- 1.75 (4Hf m), 3.00-3.60 (14H, m)f 6.66 (1H, ddf J=0.6, 1.7 Hz)f 6.96 (1H, d, J=7.7 Hz)f 7.30 (1H, t, J=7.9 Hz ) f 7.45-7-50 (1H, m)f 7.65-7.80 (3Hf m), 8.01 (lHf s) y 10.32 (1H, brs). *Example 119 NMR data rH-NMR (DMSO-dei δρρια: 1.02, 1 Γ〇9 (total 3H, t, J=7.0 Hz ), 1.50-1.80 (4H, m), 3.10-3.60 (17H, m), 4,06 (2H, s)f 6-95 (1H, d , J=7.5 Hz), 7.30 (1H, tf J=7.8 Hz)f 7.47 (1H, df J=5.6 Hz)f 7.69 (lHf d, J=8.0 Hz)f 7.75 (lHf d, J=5.5 Hz) , 10.5 (1H, br). -131 - 200831498 IS14]

Ο R1^ Factory Λ /Ν—(oyn—Ν Ν

R2' % U Example R1 R2 n Crystal form (recrystallization solvent) Melting point (. 〇 salt 126 -ch3 • ch2c=ch 5 white powder (ethanol·ethyl ether) 2115-213.0 salt surface 127 -ch3 -C(CH3)3 5 white Powder (Ethanol-Eb) 203.5-204.5 Hydrochloride 128 -ch3 -C0CH3 5 White powder (ethanol·B sleep) 183.5-184.5 Hydrochloride 129 •ch3 -H 6 White powder 182-184 mmm 130 -CeHs -H 6 white powder 201-203 salt 喔

Im is] instance FI1 R2 ο M-i / /Ν—(Οφη—Ν R2 , Ν

η crystal form (recrystallized lysate melting point Cc) salt 4 lllf 131 -CHa 164.0-166.0 hydrochloride

132 -CH$

4 t5Z0-155.0 salt _ 133 -CH3

-〇~Λ 4 22Z0-225.0 Salt _ 134 -CH3

4 white (t oysters 267.0-269 盐 hydrochloride t35 &quot; ° coffee

4 White powder (Ethanol-Eto) 132-134 Hydrochloride • 132- 200831498 im i6]

η 2 2 3 4 4 111 End 2, 7·5 — White powder White powder (acetonitrile) White powder (acetonitrile)

White powder (acetonitrile) White powder (acetonitrile) White powder (acetonitrile) White powder (acetonitrile) White powder (acetonitrile) NMf^215-218235-239 (decomposition) 247-253 (decomposition) 243-248 (decomposition) 200-202255 -260 (decomposition) 170-172 ethylene dihedral salt with dihydrochloride salt with hydrochloride salt hydrochloride salt dihydrochloride + example 138 NMR data 1H-NMR (DMSO-d6) Sppm: 1.78-1.80 (2Hf m) f 1.84 (3Hf -133- 200831498

Hz) f 1.86-2.10 (4Hf m), 2.80-3.01 (2Hf m) f 3.13-3.30 (15H m), 3.91 (2H, m), 4.20 (1H, dd, J=8.1f 3.5 Hz)r 6.95 ( 1H, d, J=7.6 Hz), 7·31 (1H, t, J=7.8 Hz), 7·46-7·50 (1H, m}, 7·68 (1H, d, J=8.0 Hz) , 7·75 (1H, dr J=5.5 7.98-8.07 (2Hf m).

-134- 200831498 [Table 17]

Vh-{c

Example Rt R2 ft Form (recrystallization solvent) Salt 146 -Η 4 White powder (acetonitrile) 28Θ-270 (decomposition) Salt 147

41 4 White powder (ethanol·acetic acid) 160-165 Salt (decomposed) 148 -H 4 White powder (ethanol-Emei) 162-166 Dihydrochloride 149 -Η 4

Q lilf 1S0 white powder (ethyl acetate) mm dihydrochloride tst

-Η 4 white powder (ethanol·ethyl 165-168 dihydrochloride t52-H 4 white powder (ethanol-b) 177-182 dihydrochloride t53 white powder (ethyl acetate) 178-180 dihydrochloric acid Salt 154 〇-\ 4 white powder (ethyl acetate)

CkfX 4 white powder (ethyl acetate) hydrochloride m 4 white powder (ethyl acetate) 182-t85 hydrochloride-135-200831498 *Example 150 NMR data h-NMR (DMSO-d6) 5 ppm: 1·03, 1· 12 (total 3Hf t, J=7.1 Hz )f 1.50-1^80 (4Hf m) f 3.00-3.60 (14Hf in) f 3.91 (2H, s), 6.90-7.00 (lHf m)f 7.20-7.50 (4Hf m)f 7.69 (1H, df J=8.0 Hz), 7.76 (1H, df J=5.6 Hz), 7.8 (lHf br), 8.52 (1H, brs), 10.2 (lHf br). *Example 155 NMR data

^-NMR (DMSO-de) δρρια: 1.10-1.20 (3H, m) f 1.40-1.80 (8H, m)f 2.80-3.50 {14H, m)r 3.50-3.60 (4H, m)f 4.30-4.60 ( lHf m), 6.95 (lHf df J=7.6 Hz), 7.25-7.45 (6H, m), 7.47 (1H, df J=5.6 Hz), 7.69 (lHf d, J=8.0 Hz)f 7.75 (1H, d , J=5.5 Hz), 10.2 (1H, br)·

-136- 200831498 im is] 〇 R2 instance R1 R2 n

White powder (ethanol) 215-219 salt sleep solution white powder 194497 hydrochloride (acetonitrile) white powder 160-164 hydrochloride (acetonitrile) white powder 154-158 dihydrochloride (acetonitrile) (decomposed) white powder (Ethanol-acetic acid ethyl acetate) 145-150 Dihydrochloride (decomposed) White powder 177-179 Trihydrochloride (acetonitrile-ethyl acetate) White powder (acetonitrile-ethyl acetate) 163^166 Hydrochloride white powder (acetonitrile) light brown powder (acetonitrile · acetonitrile f86»188 dihydrochloride 132-135 salt white powder 204·207 dihydrochloride (acetonitrile) (decomposition) white powder 177-179 dihydrochloride (acetonitrile) -137- 200831498 0 η R2 5555 55 5 5 5 -Η-Η-Η-Η-Η-Η-Η-Η-Η 5 5 -Η-Η Form (recrystallization solvent) White powder (acetonitrile) Salt 147- 151 Dihydrochloride white powder (ethanol·acetonitrile) white powder (acetonitrile) yellow powder (ethanol-acetonitrile) white powder (acetonitrile) white powder (ethanol) white powder (ethanol) yellow powder (acetonitrile)

Iflf white powder (acetonitrile) white powder (acetonitrile) 173-176 hydrochloride 157-160 di-salt surface 218-223 (decomposed) dihydrochloride 21" 218 solutions) 237-246 (decomposition) 265^277 (decomposition 236-240 汾) 178-181 Dihydrochloride salt hydrochloride salt dihydrate 181-486 dihydrochloride 148-154 trihydrochloride-138- 200831498 13⁄4 20] Example R1 R2 n (re-n agent) salt

-H 5 white powder (acetonitrile) 160-162 anti-butene two view 180

White powder (acetonitrile) 206-208 salt noodles

Ai 5 white powder 153-t57 dihydrochloride (acetonitrile) (decomposed) 5 white (! | produced 15CM54 hydrochloride T83

• H 5 white powder 173-175 hydrochloride (acetonitrile)

-H 5 white powder (acetonitrile) wins 186 hydrochloride -H 5 white powder (acetonitrile &gt; 181-183 hydrochloride

-H 5 Μ 5 -Η 5 Brown powder White powder (acetonitrile) White powder (acetonitrile) 128-130 Hydrochloride 187-189 Hydrochloride 204-210 Hydrochloride (decomposed) -139- 200831498 [ft 21]

-H 5 white powder (acetonitrile) 145-147 salt wake m m

-Η 5 white powder (acetonitrile) 217-221 salt

White powder (acetonitrile) white powder (acetonitrile) 182-185 two 172-175 hydrochloride

-H 5 white powder (acetonitrile) 172-176 hydrochloride

White powder (ethanol·acetic acid) white powder (ethanol·gyco) 187.0-190.0 hydrochloride 126.0-129.0 hydrochloride -140- _22]200831498

196 -CH3 anti-butene S 4 (DMSOcfe) 5ppm: 1.354.52 {3H,m), t.52-164 (1Ht mX 2.00-2.15 (3Ht m)t 2.39-2.46 (2H, m)t 2.59^ Z73 (4H, m), 3.01-3.15 (4H, m)T 3.30 (1H, t, J=6.8 te), 3.37 (1Hr t, &gt;7.6 Hz), 4.57 (1H, s). 4.S3 ( 1H, s), 6.61 (2H, s\ 6.90 (1H, d, J=7 J Hz), 7.17-7.35 (3H, 7.40 (1H, d, J=5.4 Hz), 7.63 {1H,d, &gt; 8·0

Hz&gt;, 7·70 (1H, d, &gt; 5.5 Hz&gt;, 7.78 (1H, 7J, 33.0), 8, 45-8.58 (1H, m&gt; _

-141- 200831498 im 23]

Example R1 R2 R3 R4 R5 R6 n MS(M+1) 197 -H 44 -H -H -H 4i 4 394 198 -H -H -CH3 -H -H •H 4 408 m -H -H -Cl - H -H 4 428 200 -H H H -F -H -H +1 4 412 201 -H -OCH3 -H -H 4 424 202 -H -NHCOCH3 -H -H 4 451 203 -H -NHCOCH3 _H -H -H -H 4 451 204 -H -a -Cf -H -H •4&quot;! 4 462 205 -H Buck l -CFa -H -H -H 4 462 206 -H -CF3 -H •H -H 4 480 207 •och3 -H -H -H -H 4 424 m -Cl -H -H •H -H 4 428 209 -CH3 -H •H -H -H -H 4 408 210 -N〇2 -H - H Ή -H 4 439 2lt -F -H -H •H •H -H 4 412 212 -CbHs -H -H -H •H 4 470 213 -N(CH3)2 -H •H -H -H 4 437 214 -NHCeHs -Ή -H -H 4 485 215 -OCH3 -H -H -OCH3 •H 4 454 215 -Cl -H -H •Cl •H 4 462 217 -CHS -H -H - H -ch3 - H 4 422 218 -C〇aC2H5 -H -H -H -H 4 466 21» -H -och3 -H -H 4 424 220 -H -Cl -H -H -H -H 4 428 221 -H -ch3 -H -H -H 4 408 222 -H -CM -H -H -H 4 419 223 -H -N〇2 -H -H -H -H 4 439 224 -H -F -H -H -H • H 4 412 225 -H -H -H -H -H 4 437 226 -H -OCeHs •H -H •Ή -H 4 486 227 -H -OCH 3 -H ^OCHj -H -H 4 454 228 -a 44 -Cl -H •H 4 462 229 -H -ch3 •H -ch3 -H -H 4 422 230 -OCH3 -0CH3 -H -H 4 454 231 -Cl -a •H +1 -H 4 462 232 -H -H -N(CH3&gt;2 -H •H -H 4 437 233 -H ^CN •H -H 44 4 419 234 -H -*N〇 2 Dance H - H - H 4 439 235 -H -H -C02CH3 -H -H 4 452 -142- 200831498 [Table 24]

hsH5F3WN £CFiCHHbCHCH -HHo(-a9-F-H4l-Hv-FHc-H94i&lt;?-HFFHFFFcFc!-F-cl§-H«H9-CI-cH-oc-H*Ho 23623?23823924024124224324424524e247248249250i252253254255256257258259i26t2$22632642652662672e8l27ai2722732742?5 H3 CH3H3F3Q2CF3CH3 -HHHHHH-oc-cFHHFH-CF-HH-«-co-HF-FN-H孑-H4i-HH.-H3F-oc-HHHHHH-oc 4i -ocl-a-CH-F-OCHS-CH3- F-CH-FF-H41-H·YANG-HHHHHHFHHHFF-cl-H^-ocrf+l-Hf-a-NH-NH-H Hs 452436454:43045442243043e448lil419452430430ll44B448422430446l49e478478478454462§§45848t543458 4 444444 44444444444444444444444 444 44 4444 4 -Η-Η -Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η-Η^-Η- Η-Η-Η-Η+Ι-Η-Η-Ηΐ-Η-Η-Η-Η Hs -HHHHHHH-.HHcF--HHHHHHHH:¥-FHHHH:?-HaHHH-H+l:?:?4i. HH-H H3h34f$*+lHHHHHHHHFHHHHHH-H4f-FH-FH--CH not-Ή-Η-Η-Η-Η七-oci?-*FH-H-«-H-ct H38H5i ,)coc -143 - 200831498 im 25] R2. R1 &lt;fy qing-00 R4 R5 Example R1 R2 R3 R4 R5 mn MS(M+1) 276 -a -OCH3 -H -CH3 -H 4 472 2 77 -H -H -Twrolyl -H •H 4 459 278 -H -H -H -H 41 4 472 279 -H -so2nh2 -Cf -H •ΌΙ •H 4 541 280 -H -so2nh2 -F -H - a • H 4 525 281 -Cl -H •F -F -H -H 4 464 282 -Cl •H -a -F -H -H 4 480 283 -Cl -H •H -OH3 -H -H 4 442 284 -Cl -H -och3 -OCH3 41 -H 4 488 285 -Cl -H -Br -HH 4 506 286 •H •H -N〇2 -H -Cl •H 4 473 287 -a -H -H - SCH3 -H •H 4 474 28B -no2 -H -H -Cl -H -H 4 473 289 4i〇2 -H -Cl •H +1 -H 4 473 290 -N〇2 -Cl -H -H • H -H 4 473 291 -N〇2 •CHj -H -H -H -H 4 453 292 -N〇2 -OCHa -H -H -H -H 4 468 293 -N〇2 -H -H -ch3 -H -H 4 453 294 -N〇2 -N〇2 -H -OCH3 +1 4 469 295 -H -OCH3 -OCH3 •H -H 4 499 296 -CH3 &gt;N〇2 -H -H -H -H 4 453 297 •H -N〇2 Ct -H -H 4 473 298 -H 4tOz -OCH3 -H -H -H 4 469 299 -H -N02 -H -CO2CH3 •H •H 4 497 300 -H -N〇2 -CHa -H •H -H 4 453 301 •H -NOa -H -H OH -H 4 455 302 -H -F -H -H -H 4 457 303 -H -N〇2 -H -H -C! 44 4 473 304 •H •no2 -H -H -F 44 4 457 305 -H -H •N〇2 -OH -H -H 4 455 306 -H -H -N〇2 •€H3 +1 -H 4 453 307 -N〇2 -H -cf3 -H -H -H 4 507 308 -N〇2 -H -H •H -ch3 - H 4 453 309 -N〇2 -HH -NHCOCH3 -H •H 4 496 310 -N〇2 -H -H -F -H -H 4 457 3!t -SO2CH3 -H •H 4i -H -H 4 472 312 41 -N02 -Cl -SQjH -H -H 4 553 313 -H -H -so2nh2 -H -H •H 4 473 -144 - 200831498 [ft 26]

Example R1 R2 R3 R4 R5 R6 n MS{W+1) 314 -H -H -H Cl •H 4 Qiu 6 315 -H +l -N02 -OCH3 -H -H 4 469 316 -OH -N〇2 - H -H -H 4 455 317 •H -N02 -CO2CH3 -H •H -H 4 497 318 -Cl -N02 -H -H -C! -H 4 507 3t9 -H -NQz -H -H -Br • H 4 517 320 -H -SOzNHa -H -H -OCHa -H 4 503 321 -N〇2 -H -H -OH -H -H 4 455 322 -Cl -H -H -F -H -H 4 446 323 •H -H ^〇2»s)2 -H 4 465 324 -H -C! •F -H -H 4 446 325 -H -F -Cl Surface H -H -H 4 326 -H -H - H -H -H 4 420 327 -H -H -2-PYRIDYL •H •H -H 4 471 328 -H -3-PYRIDYL -H -H -H 4 471 329 -H -H -4-PYRIDYL -H -H -H 4 471 330 -H •H •cycloCgH” -H -H -H 4 476 331 -H -H -H -H •H -C2H5 4 422 332 -H -H -ch3 -H 4 436 333 - H -H -Cl -H -H -C2H5 4 456 334 -H -H -F -H -C2H5 4 440 335 -H •H -och3 -H -H 4 452 336 -H -H -NHCOCH3 H -C2H5 4 479 337 -H -NHCOCH3 -H -H -H •CaHs 4 479 338 -H -Cl •Cl -H -H -C2H5 4 490 339 -M -H -CF3 •H -H Ό2Η5 4 490 340 -F -H -cf3 -H -H -CzHb 4 50β 341 -och3 -H •H -H •C2H5 4 452 342 -Cl -H -H -H -C^5 A 456 343 -H -H -H 4 436 344 -N〇2 •H -H -« -C2H5 4 467 345 -F -H -H -C2H5 4 440 346 CeHg - H -H -C2H5 4 m 347 -H -H -H •H -C2H5 4 465 348 -NHCOCH3 -H -H -H Ό2Η5 4 479 349 -NHCbHs -H -H -H -H 4 513 350 -OC>H -H -H -H -OCHa •C2H5 4 482 35t -Cl +1 -H -H -Cl -C2H5 4 490 -145- 200831498 im 27]

Example Rt R2 R3 R4 R5 R6 n MS(_ 352 -ch3 -H -H -H -CH|$ -C2H5 4 450 353 -CO2Q2H5 -H -H -H •H 4 494 354 -H -OCH3 -H -H -H «CgHs 4 452 355 •H -a -H -H -H 4 456 356 -H •CH3 -H -H -CaHs 4 436 357 -CN -H -H -C2H5 4 447 358 •H -N〇i -H -H 4i -〇2H5 4 467 359 •H -F -H •H -H -〇2«5 4 440 360 -H -N(CH3)2 +I -H -H -C2H5 4 465 3δ1 -H -OC^Hg -H 4 514 362 -H -OCH$ •H -OCH3 -H 4 482 363 -H -a 44 -a •H -CjHs 4 490 364 -H •ch3 -H -ch3 -H &quot;C2H5 4 450 365 -OCH3 -OCH3 •H 41 -H -QaHs 4 482 366 -Cl -Cl -H -H •H -CaHs 4 490 367 -ch3 -H -H -H -C2H5 4 450 368 -CH3 -F - H -H -H -C2H5 4 454 369 -H -H -N(CH3)2 •H -H -CzHs 4 465 370 -H -« -CN •H -H -GaHs 4 447 371 •H 44 -N02 • H -H -C2H5 4 467 372 -H -H -CO2CH3 -H -H «C2H5 4 480 373 OCOCH3 -H -H -H -H -Cz»5 4 480 374 -COCH3 -H -H -H 41 -C2H5 4 464 375 -H -COCH3 -H 4 464 376 -OCH3 -H -OCH3 -H -H 4 4B2 377 -Cl -H -a -H 4 490 378 -CH3 -H -ch3 -H -H -CaHs 4 450 370 -F •H •F -H - H -CaHs 4 458 380 -H •H -H •C^Hs 4 482 38f 4i -ch3 -ch3 -H ^Hs 4 450 382 -H -F -F -H •H •C2H5 4 458 383 -CH3 -H • H -ch3 -C2H5 4 464 384 -H -F -F -F •C2H5 4 476 385 -cf3 -H •H 44 -H -CzHs 4 490 386 +1 -cf3 -H •H •H -〇t^ k 4 490 387 -OO^Ig -H -H •H •C2H5 4 5t4 388 M -H -OCeHg -H Ai -C^Hs 4 514 389 -CN 4H 4i 44 -H -C2H5 4 447 -146 - 200831498 験28]

Example R1 R2 R3 R4 R5

390 -F 41 -H 4* -F 391 -F -F 44 -H -H 392 -H -F 4f -F -H 393 -F -F •H -H -F 394 -F -H -F -F -Η 395 -F -F -HF -H 396 -CH3 -H •H -CHS -H 397 -F -H -H •F -H 398 -Ci -H -F -H -H 399 -F -F • F +i -H 400 -OCFa -H 41 -H •H 401 -H -OCF3 -H -H -H 402 -H -H -ocf3 -H -H 403 -OCHa -H -H -och3 -H 404 - a -H -Ci -H 405 -CH3 -H -H -F -H 406 -OCH3 •H -a -H «Η 407 -H -OCHs -NHCOCH3 -H -H 408 -OCH3 -H -H -Cl • H m -H •a -och3 410 -tt -H -^-ttfrrolyl -H -H 411 «Η •H -SO^CHa -H 412 -Cl -H -H -ch3 -H 4t3 -Ci •H -OCH3 -OCH3 -H 414 -CI -H 41 -sch3 -H 415 -S〇2CH3 -H 4i -H -H 416 4i -H -so2nh2 -H -H 417 -a -H -H 418 -H -H -t4HONH (NH2) -H 419 -H -H -NiC2H5)2 •H -H 420 -H -H •H -H 421 -H •H -2-PYRIDYL -H -H 422 -H -3-PYRiDYL -H - H 423 4i -H -4-PYRIDYL -H -H 424 -H -H -cydo-CeHti -H -H 425 -H -4-PYRiDYL -H -H 426 -H FYRiDYL «Η •H -H 427 - 3-PYRIDYL •H -H -H -H -C2H5 -C2H5 -CjHs &quot;C2H5 •C2H5 •C2H5 -C2H5 ^2Hs -C2H5 -C2H5 -C2H5 •C2H5 C2Hs -C2H5 -C2H5 -C2H5 -C2H5 «CjHs C2H5 •C2H5 ^H5 -QaHs •C2H5 -C^Hs •0 Office-C^Hs -C2H5 R6 n MSiM+1) 4 458 4 458 4 458. 4 476 4 476 4 476 4 450 4 458 4 474 4 476 4 S06 4 506 4 506 4 482 4 4 490 454 4 486 4 509 4 486 4 500 4 487 4 500 4 470 4 516 4 502 4 500 4 50t 4 474 4 479 4 4S3 4 448 4 499 4 499 4 499 4 504 4 499 4 499 4 499 -147- 200831498 表Table 29]

Example 扪R2_R3_R4 R5 R6 n MS(M^1) Capture-H-CH.f If 44H4I-C1-CF-CF-HHHHHHHHHHHHHHHHHHHHH-HHHH*«-HN(C COCHak -0c-HH-H4l-H--H- NH-ci-HHHHHH^HHHHHH-+l-H&lt;)ca-CH-CNrna.r^-cf-CH-FH-HHH#-HHHH-H4l-F-oc-cl-CH-NO-Fl-N (c-NH-oc-a-CH-co-H-H4li-HHHHHH-oc-cl-CH instrument 4i 42842943043t432§434435§437§43944044l442443444444444464474484494504514524534544554564574584594604et4624634e446s466 CH3" -HH-&gt;HHHH-HaF-H-H4i-HHHHH* -HHHHH*+lH.HHHHH:fHH-0c-ci-CH:FHHHH-H 4 495 •H 5 408 -H -H 5 422 5 442 4i 44 5 42S -H 5 438 •H -H 5 465 -H 41 5 465 -H -H 5 476 -H 5 476 -H -H 5 494 -H -H 5 438 •H -H 5 442 -H -H -H 5 5 422 453 •H -H 5 426 -H •H 5 404 •H -H 5 451 -H 5 499 -och3 -H 5 468 •Cl -H 5 476 5 436 -H -H 5 480 •H -H 5 438 -H -H 5 442 -H -H 5 422 -HM -H -H 5 5 433 453 -H -H 5 426 -H -H -H -H 5 5 451 500 •H -H 5 468 -H 5 478 -H 5 436 -HM 5 468 -H -H 5 476 •H •H 5 436 -H -H 5 440 • H 5 451 -148 - 200831498

[Table 30] 469 -Η ·Η 470 -Η 44 47t -Η ·Η 472 -〇CHa -Η 473 -CI -Η 474 -CHs -Η 475 孑·Η 476 -Η -OCHa 477 -Η 478 -Η 479 -CH3 seven 480 ^ -Η

481 -Μ -F 482 -CFa -Η 483 -CF3 484 -OCJtis -Η 485 -Η -Η 486 -CN ·» 487 -Η Χ020Η3 488 -F 4i 489孑 490 -Η

4d1 -F

492 -F

493 -F 494 -CHa 495 -F 486

497 -F 498 Ό 499 -〇CF3

500 -H

50t -H 502 -〇CH3 503 504 -CHa

505 -H il:ml436:iE43346644424444624624e2436i510492492il484472 -149- [^31]200831498

509 OCH3 5t0 -H 511 -H 512 -H 513 -H 514 515 -Ci 516 d 517 -Ct 5t8 -Cf 519 -C« 520 -H 521 -Cl 522 ^N〇2 523捣524 ^N〇2 525 iron 526 -NOz 527 -N〇i 528 ^NQz 529 -N〇2 530 -H 531 -CH3 532 -H 533 -H 534 Ή 535 7536 Ή 537 Ή 538 -Η 539 -Η 540 -Η 54t ·Η 542 - Ν〇2 543 -Ν〇2 544顿-Η -α 4Ι -Η -S〇aNHz Name 2〇-Η •Η -Η -Η -Η -Η -Η -Η -Η -α -CH3 -och3 - Η -Η -Η -Ν〇2 -Ν〇2 -NQa -Ν〇2 ·Ν〇2 44〇2 -νο2 -Ν02 -Η -Η -41 -Η 4»

-Η -och3

4tMrolyI •«〇2〇^ -α

-F

-F -α -Η -och3 -Η -Ν〇2 -Η -Η -α -Η •Η -Η -Η 44 &lt;ch3

-OH -Η -α -och3 -CHs -Η

-F -Η -Η -Ν〇2 -Ν〇2 -CFa -Η -Η -α -Η -Η -Η -Η -Η

-F

• F -CHj -och3 -Βγ •Η -SCH3

-CI -Η -Η -Η -Η -CH3 -OCH3 -OCH3 -Η •Η +1 -Η -C02CH3 -Η •Η «Η Η •Η -ΟΗ -Η -Η -NHCOCH3 -Η -Η -CHa - Η -Η -Η -Η ·Η -CI -Η -CI -Η -Η ·Η -Η 41 •Η -Η -Η -Η -Η -Η •CI -Η -Η -Η -Η -Η -Η -Η -Η -Η -Η -Η -Η ·Η 44 ·Η 41 -Η -Η «Η -Η 屮-Η -Η -Η 4i -Η 44 -Η -Η -Η -Η -ΟΗ ·Η - Η -Η -Cf -Η -F Μ -Η ·Η -Η -Η -Η -Η -CH3 -Η -Η 4ί 5 472 5 486 5 473 5 486 5 555 5 539 5 476 5 494 5 456 5 502 5 520 5 487 5 488 5 487 5 487 5 487 5 467 5 483 δ 467 5 483 δ 513 5 469 5 467 5 487 5 483 5 511 5 467 5 469 5 471 5 487 5 47ί 5 469 5 467 5 521 5 467 5 510 -150- 200831498 [Table 32]

Example R1 R2 R3 R4 R5 R6 n MS(M+1) 545 -N〇2 -Η -Η -F -H -H 5 471 546 -SO2CH3 -Η -Η M -H -H 5 486 547 -Η -Η -S〇2NH2 -H -H 5 487 548 -Η -Η -SQzCHa -H -Cl -H 5 520 549 •Η -Η ·Ν〇2 -OCH3 -H -H 5 483 550 -ΟΗ -Ν02 •Η - H -H -HS 469 551 -Η -CO2CH3 -H -H -H 5 511 552 «α -Ν〇2 -Η -H •Cl -H 5 521 553 -Η ·Μ〇2 -Η -H -Br - H 5 531 554 -Η -so2nh2 »η -H -OCHd -H 5 517 555 -Ν〇2 -Η -Η -OH -H -H 5 469 556 -CI -Η -Η -F 41 5 460 557 -Η -N(C2Hs)2 •H -H -H 5 479 558 -Η -CI -F -H -H -H 5 460 559 -Η -F 4Ά -H 4i 5 460 560 +1 -Η -ch=ch2 • H •H -H 5 434 561 -Η -Η -2-PYRIDYL -Η •H -H 5 485 562 -Η -Η -3-PYRIDYL -Η -H -H 5 485 Vertical -Η •Η -4-PYRIDYL -Η -H -H 5 485 564 •Η -Η -cycto-CeHn 1 -H -H -H 5 490 565 -« •Η -Η -H -H -H 6 422 5S6 »Η -Η -CH^ - H -H -H 6 436 567 4i -Η -Cl -H •H •H 6 456 568 -Η -Η -F -H -H •H 6 440 569 -Η -Η -OCH3 •H -H -H 6 452 570 «Η -Η -NHCOCH3 -H -H -H 6 479 571 -Η - NHCOCHa -Η -H -H -H 6 479 572 Μ -α -a -H -H 6 490 573 •Η -Η -cf3 •H -H -H 6 490 574 -F -Η -CF3 •H -H • H 6 508 575 •OCHs -Η -H -H -H 6 452 576 -α -Η •H -H -H •H 6 456 577 -CH3 -Η -H -H -H -H 6 436 578 44〇2 •Η -H -H -H -H 6 467 579 -F -Η -H -H -H -H 6 440 580 -CsHs 41 -H -H •H -H 6 498 58t •N(CH^ -Η • H -H -H -H 6 465 582 -Η -H •H 6 513 583 •och3 -Η -H -H -OCH3 -H 6 482 -151 - 200831498 [Table 33]

586 &quot;CO2C2H5 -Η

587 -Η 588 -Η 589 -Η 590 -Η 591 -Η 592 -Η 593 -Η 594 -Η 595 -Η 596 -Η 597 -Η 598 -〇CH3 5β9 θΟΟ -ch3 601 -CH3 802 -Η 603 -Η 604 -Η 605 -Η

-OCH3 -CJ -ch3 -CN

-F -N(CH3)2 -OCgH5 -OCH3 -a -ch3 -0CH3 -ci -ch3 -F -H -H -H -H -H -HH •H «Η -H •H -H •H -H -H •H -H •H •H -N (called -CN -NO^ -C02CH3 •Η ·Η ·Η 6 •Η -Η -Η 6 -Η 44 -Η 6 -Η ·Η ·Η S ,Η -Η -Η 6 -Η 41 6 •Η -Η -Η 6 -Η «Η ·Η 6 ΗΗ ·Η ·Η 6 -OCH3 -Η -Η 6 ΟΙ ~Η -Η 6 -CH3 -Η -Η 6 -Η -Η 44 •Η -Η -Η -Η -Η -Η -Η -Η ·Η ·Η -Η •Η -Η 44 «Η -Η -Η -Η -Η -Η -Η 6 6 6 6 6 6 6 6 494 452 456 436 447 467 440 465 514 482 490 450 482 490 450 454 465 447 467 480 -152 - [_34] 200831498

-153- 200831498 im 35]

619 -Η -Η -Η -Η -C2H5 4 4δβ

620 -Η -Η 621 -Η -Η 622 -Η -Η 6- CN- *Η -Η -CiHs 4 489 Ή -Η &quot;Ό^Ηδ 4 488 -Η -Η -C2H5 4 489 623 -Η -Η .Η ·Η -C2H5 4 523

624 -Η -Η Ή -Η 4 507 625 -» -Μ $26 -Η -Η 627 -Η -Η ς:_ -Η -Η ^ 5 547 -Ή -Η -Η 5 491 -154- 200831498

[Table 36]

n MS(M-M) 5 474 5 475 5 474 δ 475 5 509 5 493 5 504 5 548 5 549 -155- 200831498 im 37] R4 R3 丫

R1 R6 ) \ Vs Example R1 R2 R3 R4 R5 R6 n MS(MM) 637 -H 44 -CHj -H -H -H 4 422 638 -H -H -a -H -H 4 442 639 -H •4f • F • H • H 4 426 640 -H -H -OCHb -H -H 4 438 641 -CHs -H -H -H -H -H 4 422 642 -Cl -H -H -H -H -H 4 442 643 -H -OCHb -H •H 4 438 644 -H -Cl -a -H -H -H 4 47« 645 -och3 41 -H -H 4 438 646 -N02 -H -H -H -H -H 4 453 647 •H -N〇2 -H •H -H -H 4 453 648 -tt -H ^1(3⁄4 -H -H -H 4 453 649 -H -ch3 -H -H -H -H 4 422 650 •H -Cl -H -H -H -H 4 442 651 -F -M -H -H -H 4 426 652 -H -F -H -H -H -H 4 426 653 654 -OOfe -H -a -H -H -a -OCHa -H 4i -Η -H 4 468 476 -α -η 4! «ΟΗ 41 -H -OCH3 44 -H 655 656 ¢57 -H 658 -H 659 -H 860 - H 661 -CH3 662 -Cl

-H 41 -H 4i -H -H

-a -F -OC -H -H

-OCHb -H-a -a ¢¢5 -Η -H 863 -H 664 41

m -» 偶 667 -H -Cl 688 -F -H 669 -H »F 670 -a -H 671 -Cl -H S72 -H -OH 673 -Η -H 674 -Η -H

-H -H -H -H •H : -H -H -H -Cl 4+ 4i -OCMb -H Pei -H -a -H

•H 41 -H •H

-Cl 4i -Η -H -H &quot;CjHg -H -C2M5 -Η -Ο^Ηδ -H -C2H5 -H -H -CaHs -H -C2H5 -H -C2H5 -H -C2H5 -H -CjHs -H -C2H5 -H -CzHs -H -C2H5 -H -C2H5 -Cl -CzHs -H -C2H5 •Η -H «Η -H 4 4 4 m 454 4S0 470 454 466 450 470 4 4$6 4 504 4 4 5 5 466 450 470 454 454 504 504 482 436 450 -156- [^38]200831498 R4

Example R1 R2 R3 R4 R5 R6 n MS(M+1) 675 -Η -F -H -H -H 5 440 676 -Η -H -OCH3 41 -H -H 5 452 677 -CH3 •H •H •H -H -H 5 436 678 -C! •H -H +1 -H -H 5 456 679 -Η -OCH3 -H -H -H -H 5 452 680 -Cl -Cl -H -H -H 5 490 681 -N〇2 -H -H -H -H -H 5 467 682 -H -N〇2 41 -H •H -H 5 467 683 -H -H -N02 -H -H 5 467 684 -CH3 - H -H -H 4i 5 436 685 -H -a -H -H -H •H 5 456 6&amp;6 -H -H -H •H -H 5 440 687 -F -H -H -H •H 5 440 688 -OCH3 -H 4i •OCHj -H 4i 5 482 68» -Cl -H -a -H -H -H 5 490 690 -Cl -H -H -H -a -H 5 490 691 -H -OH -och3 -H -H 5 468 692 -H -H -CH3 -H -H -H 6 450 693 -H -H -a -H -H •H 6 470 694 -H -H -F -H -H - H 6 454 695 -H -H -OCH3 -H -H •H 6 466 -157· 200831498

诵R6 R5 R4 R3 R2 R1 4t-H-0t-HH-cl-H4*H*4&lt;4i-M&lt;¥4i-0c-Hr-aHH-Hr-CF-Hr=f-0c-HHaHHFN (4i money H3£-HHHHHHHHHHHHHH-H4I-H-CI-H--HH-H4i-H-+l-He-«=f-«^-H-H4i-HHHH ii700701702703704705706707§7(»710711?127137147t57t6717ssg72lss724?25726727728g§73t732? 33734 -H94i-H-cl-HHFHHNHH-CK=?

AaHF-CK-HcHHHHaHH-cl-HHFH-HA-H % ^+141=^41=^4444-+14444^+1=-+1-84141414144^ Pei Pei Pei Pei Pai Pei Pei ^ Pei I02ΟΗ3ΧΪΗ35ΟΗ3丨F3丨略略4i-HHcHHFHHNHH:f9-oc-o(-H9-HFHHHHHcHHH-H9-HHFHHHo(-ot 420450450454454454438438438465465465463|480480480488|456456480434||488504448478478482482482466 shed 466491508508-158- 200831498 [Table 40] R1 Ο RS^RS R6 R4

&quot;8 Example R2 R3 R4 R5 R6 n MS(M^1) 735 -H -och3 -H -OCHa -H -0CH3 -C^i5 4 508 73$ -H -H -OCH3 -H 4 508 737 -Cl -H -H -H -C! If 4 516 738 -H -Cl -a -H 4 516 739 -F -H -H -H -F 4 484 740 -H -F -H -F -H 4 484 741 -H •ch3 -H -CaHs 4 462 742 -H -H 4i -cf3 -C2H5 4 516 743 -H -H -cf3 -H -H 4 516 744 •H -H -H 41 -cf3 &quot;C2H5 4 516 745 •H 44 •H -H -H 4i 5 434 746 -H -H -H •och3 -H -H 5 464 747 -H -H -OCH3 -H -H -H 5 464 748 749 -H 41 -Η -H -H -a -a •H -H -H 5 468 468 468 750 4» -H -cr -H -H -H 5 751 •H •H -H -H •F -H 5 452 752 •H -H 4i -F -H -H 5 452 753 -H -H •F 44 -H -H 5 452 754 -H -H -H -H -N〇2 5 479 755 -H +» •N〇2 - H -H 5 479 75$ -H -N〇2 -H -H *H 5 479 757 -H -H 4t(CH^2 -H -OCHa -H 5 477 758 -H 41 -H -OCH3 41 5 494 759 -H -OC»% -H -OCH3 5 494 760 -OCHj -h -H -OCHa -H 494 761 -Η -H -och3 -003⁄4 -H -H 5 494 762 -Cl -H -H -H - Cl 502 763 -H -H •Cl -Cl -H -H 5 502 764 -F •H -H -H -F -H 5 470 765 -H -F -H -F 41 -H 5 470 766 -H -001⁄2 -OCHa -H 4i 5 494 767 -H 4f «Ofe -H -H -H 5 448 768 -H -H -H -CFa -H -H 5 502 769 - H -H -cf3 -H -H -H 5 502 m -H 4i -W -H -cf3 41 5 502 ?7t -H -H -ocf3 -H -H -H 5 518 -159- 200831498 13⁄4 41]

Rt Ο

Re R5 w R3 R2 1 R 例贤-HH-H9 fr-HHa-Hr-HAe-H-Hfr-HH-cl-HH-Hil-oc-HHH-ia-H-oc-H-Hf-cl-Fr -H-He-HH-CNr-Hr-Fr-H-^-HHH^N-Hf-aF^cHHHHH-CN-oca H3£ -Η-Η-Η4ι-«-Η-Η4ι-Η-Η-Η -Η·&lt;χϊι-Η-Η-Η::ρ-Η3;:4ι-Η-Η-+ί-Η-Η-Η-+ι-Η·+τ-Η-Η-Η-Η- Η-Η-Η · Η · Η-οο-Η -HHHHH-H + fHHHHH - HHH - HHH-HM-H-HA-HHHHHHHHHHHHHHwHM 772773774775s777778s78078t782g784785786787788789g791s793794g796ggg800§802g804805l80 80sl8toi -HHHHH- 42443 &amp; 458442454438454454438458458l5t449245246e486470482466482482466486486477438452472456468452468l452472472i528506 4444444444444444444444444455555555555555 ΐ-Η-Ηΐ? -Η-Η-Η-Η-Η-Η-Η-Η-Η-ΗΑΑΑΑΑΑ^^ΘΑ^^-Ηΐ-Η-Η-Η-Ηί-Η-Η-Η-Η-Η-Η-Η • -H4l-HHHHH-OCH9-a-+l-H4i-cHHHHHHH-OCH-caHHHHHHHHH-&lt;)c9-c-160- 200831498 [Table 42]

Rt ΟR2 丫~〇νΛ

R3&quot;X^R5 R4 Example R1 R2 R3 R4 R5 R6 n 812 -H +t -H -H &quot;H -H 6 452 8t3 -H •H -CH3 -H •H -H 6 466 8t4 -H 4i - Cl -H -H •H 6 48$ 815 4{ -H -F -H •H -H 6 470 816 -H -H -OCHa -H 44 6 482 817 •H -H -H -cm 41 -H 6 460 818 -H -H -H -och3 -H -H 6 482

-161 200831498 13⁄4 43] Ο / R2 , &gt;-8 Instance R1

8t9 -(CH^CeHs 820 -(CHjfcOCeHs 821 -2-PYRrDYL 822 -3-PYRIDYL 823 -4-PYRIDYL 824 -2-FURYL 825 -2-THIENYL 82$ -3-FURYL 827 Winter THIENYL 828 -(C^CeHs 829 -{C^KCsHs 830 -C2H5 83t 832 -CH(CH3)2 833 -cyct〇&lt;Vi5 834 -cydcnCsH» 835 -cydo&lt;^Hti 836 -cydo-CTHts 837 -CH2-cydo-C3H5 838 -cyclo- Csm 839 «C^rCyckhCeHit 840 -cydo-CzH^ 84t 842 -CH2SCeH5 843 -CHzNKCCX^ 844 «C 明CHb)z 845 846 847 -CHaNiCH^ttOHJz 848 仰2&gt;2〇6«5 849 «(CH^aOCaHs 850 -2-PYRIDYL 85t -3-PYRIDYL 852 -4-PYRIDYL 853 -2-FURYL 854 Winter THIENYL 855 -34=URYL 85S Each THIENYL 857 -CCH2hCeH5 R2 n -H 4 -H 4 -H 4 4i 4 -H 4 - H 4 -H 4 -H 4 -H 4 -H 4 -H 4 -H 4 -H 4 -H 4 •H 4 -H 4 4 4i 4 -H 4 -H 4 -H 4 -H 4 -H 4 -H 4 •H -H 4 4 -H -H 4 4 4 -C^ 4 -C2H5 4 -C^s 4 •CaH5 4 -C2H5 4 -〇2Η5 4 -CaHs 4 4 4 422 438 395 395 395 384 400 384 400 436 360 358 386 400 414 372 400 414 428 362 440 389 375 403 417 435 450 466 423 423 423 4t2 428 412 428 464 -162 200831498 [Table 44]

Ο R1&lt; f xN-{CH^)n-N R2 v—example one rT

858 *(.&quot;2)4〇^5 &quot;Q2H5 859 -C2H5 -QzHs 860 -CsH? 861 ·0Μ(Ο^)2 »0我$62 -c^cto-C^ -C2H5 863 -cycto-CsHg -C^Hs 864 aa^yc^C$Hts -C2H5 865 -&lt;^&lt;Λ&gt;-〇7Ηΐ3 866 -CH2*cj^do^^l5 &quot;OzHs 867 -cydo^Hs -C2H5 868 &quot;CH2&quot ;〇ycto-CeHti &quot;CiHs 4 478 4 374 4 388 4 388 4 386 4 414 4 428 4 442 4 400 4 428 4 442

869 -cyclo-C7Ht3 870 -CH^OCHs 871 -CHiSCeHs 872 -CH2M(CH^)2 873来"2^叫874 &lt;CHzm〇^kh 875 -{CH^eHs 876 -{CHzJaOC^ 877 -2-PYRIDYl 878 -3-PYRIDYL 879 ^-PYRIDYL 880 -2-FURYL 88t -2-THIENYL 882 -3-FURYL 883 -3-THIENYL 884 -(CH2)3CeH5 885 -CiHs 886 -C3H7 887 -CH(CH3)2 888 889 890 -cydo-CeH^ 89t -cydo^THta -CHrcycto-Cal^ 893 -CHrCydo-CeHtt 894 -CH^CH3 895 -CHjSCeHs 896 ^OmOhh

-C2H5 -C2H5 -Q2H5 -C2H5•QiHs -C2H5 456 390 4 4 468 4 403 4 451 4 445 4i 5 436 -H 5 452 -H 5 409 -H 5 409 -H 5 409 -H 5 398 -H 5 414 -H 5 398 41 5 414 5 450 -H 5 360 -H 5 374 -H 5 374 -H 5 372 -H 5 400 -H 5 414 -H 5 428 -H 5 386 -H 5 428 -H 5 376 - H 5 454 •H 5 389 -163· 200831498 [S45]

2Ϊ2〇〇8^ miDYL -H 6 450 -H 6 466 -H 6 423 -H 6 423 -H 423 -H 6 412 -H 6 428 -H 6 412 -H 6 428 4i 6 464 •H 6 478 -H 6 374 -H 6 388 -H 6 388 -H 6 386 -H 6 4t4 +r 6 428 6 442 •H 6 400 -H 6 428 -H 6 442 •H 6 45e -H 6 390 Ο mH: / R2 \ Example Rt 897 *(〇Η2)2〇βΗ5

898 -CCH^C

899 -2-PYF

900 -W&gt;YR»DYL 90!砵 PYRtDYL

902 -2-FURYL

903 -2-THIENYL

904 -3-FURYL

905 -3-THENYL 906 -(CH^CeHs 907 -(〇Η2)4〇$Η5 908 -C2H5 909 ·〇3Η7 9t0 -CH(CHa)2 911 912 913 914 915 -CHrcydo-CaHs 916 -Cit^do- CsHs 917 -CHrcydo^eHtt 9t8 ^HrCyclo-CTHta »19 -C^OCHj -164 - 200831498 [^46]

-165- 200831498 im 47]

n MS(M+1) 4 444

4 4 4 438 477 463 429 457 425 455 464 421

-Η 4 421 -166 - 200831498 [Table 48] Ο /~\ , N-(Cmn~N N R2'"U*m ri 942

R2IT π MS(M+1) &quot;4 434

951 -H 4 468 -H 4 429 -H 4 429 -H 4 463 •H 4 441 -H 4 429 -H 4 441 -H 4 433

-H 4 433 952 -H 4 383 -167- [^49] 200831498

-168- 200831498 im 5〇]

-169- 200831498 im si]

977 -Η 4 4Μ α

978 -Η 4 421 919 °b^ 535 -Η 4 511

-Η 4 447 •Η 4 5t7 -Η 4 403 -Η 4 467 -Η 4 463 •170- [^52] 200831498 Ο RH f , one (Chyn-N, R2, - Bao R1 986 cX^~ -H 4 467 »87

HP

4 493 988

-H 4 481 Qing

-H 4 40t

-H 4 475 99t

^ 4 491 9»2

-H 4 479

township

-H 4 517 995

-H 4 557

-H -171 - &gt;-8 200831498 im 53] Ο m-i R2

-H 4

Ίί ch3

-H 4 •H 4 -H 4 -H 4 -H 4 -H 4 465 465 461 477 4St 461 525 448 -172 200831498 im 54]

1006 - Η 4 464 Η, σ

Too? •Η 4 468 1008 «Η 4 434

1009 ^ /toto «Η 4 559 -Η ton tai2 1013

1016

-Η 4 451 •Η 4 411 Η 4 429 -Η 4 419 -Η 4 445 Ή 4 423 -173· 200831498 im 55] Ο R1&lt; ,N -- Μ Ν

Example Rt ton R24f tots

-H

1021

-H

-H 1022 σ

-H

-H

-H

-H n MS(M+1) ^~429 4 40t 4 397 4 413 4 410 4 396 4 460 4 398 4 446 4 410 -174- [_56] 200831498

-175- 200831498

[Table 57] p R1-^ R2 Example R1 1038 4i 4 472

-H 4 434 -H 4 410 -H 4 452 -H 4 434 -H 4 434 4 436 -H 4 464 -H 4 436 -H 4 434 -H 4 433 -176- 200831498 [Table 58]

Rt

Wn- instance Rt m listen

fX 4i n MS(,1) 4

433 510 448 482

477 476 44S 467 435 452 -177- 200831498 [Table 59]

Gi MS{M^1) 4 446 4 399 4 401 4 461 4 413 4 446 4 474 4 452 4 465 4 45t 4 437 -178- 200831498 [Table 60]

1071 ^Hs 4 437 1072 437 Μ 1073 1074 0~\ο-Ο- -〇2Hs 4 442 -CzHs 4 488 1075 -C2H5 4 442 1076 1077 1078 1079 1080 1081 cxjy,Η&gt; %οσ -QiHs 4 533 471 4 504 «C2HS 4 472 472 -179- 200831498 [Table 61] Ο mi—(oyn

R2 n MS(_) -C2H5 4 466

-3⁄43⁄4 4

-C2H5 4

-Q2H5 A tOS7 1娜 1089 1090 109tmz

-CaHs 4 -CiHs 4 -CaHs 4

4 -C2H5 4 505 491 457 485 453 4S3 492 449 449 462 -180- [*62]200831498

1094 457

1096 t097 1098 1099

ζΤ α -s

1101 1102 1103 Q- -C2H5 4 491 4 457 469 4 461 -3⁄43⁄4 4 4$) -Cz»^ 4 411 -C2H5 4 463 •C^Hs 4 429 -181 - [*63] 200831498 Ο Rt4 Factory ^ Example R1 !t04 im 110$

〇λοσίτ n MS{M»t) 4 473 -C2H5 -C2H5 4 473 4 473 1107 1108 tm 1110

Tt11 ςσ cor Ocv ttt2

a 1113 1tt4 -Q2HB 4 473 Ό2Η5 4 473 4 473 -3⁄43⁄4 4 462 -C2H5 4 492 -C2H5 4 49t -C2H5 4 49t 4 491 -182- [^64]200831498

1117

Tt18

475 491 1121

1122 tt23 OTQ~\_ 1124 tt25

-023⁄4 4 495 -CaHs 4 479 -3⁄43⁄4 4 475 -〇2^ 4 478 -C2H5 4 449 4 475 -〇2«5 4 495 -183- _65] 200831498 y〇R1-^ yN-(CH,)n- R2 &gt;s

R2 n MS(M+1) -CiHs 4 491 4 495 1128

Tt29 tt32 a

509

-C2H5 4 489 1130 113t

5t9 507

-CaHs 4 507

493 493 489 184· 200831498 [Table 66] &gt;-8 Ο «Η r R2 , example R2 n mouth U36 1137 Ι13β

-C2H5 4 489 -C2H5 4 489 -C2H5 4 505 1t39 492 tt40 -C2H5 4 496 1141 4 462 1142 f s XX1143 j -C2H5 4 479 -3⁄43⁄4 4 4t7 ίΤ 1144

4 439 1145

-023⁄4 4 457 me -C^Hs 4 447 -185- 200831498 im 67]

1147 α HO 4 473

1148 4 45t »49 -3⁄43⁄4 4 457

T150 -〇2«5 4 429 1t51 •C2H5 4 425 1152

€2^ 4 455 1t53

4 441

-C2H5 4 438 •C2H5 4 424 4 488 -186 - 200831498 [Table 68] Ο Ri啵 r sound one (〇yn - N R2 v

N

1159

n unloading or

R2 n MS(M.1) -Ca^ 4~426 -C2H5 4 474 -^H5 4 438 -CjHs 4 456 -C2H5 4 428 -〇z^s 4 467 -CaHs 4 462 C2H5 4 430 -〇2^fe 4 444 -CiHg 4 429 -C2H5 4 440 -187- [^69]200831498

R2 n MS(M-H) -C2H5 4 49β -CzHs 4 462 1170

Tt71 1172 1173 〇T/- p-c«3d·7&quot;

t!75 tt76 1177

4 462 -C2H5 4 438 -C2H5 4 480 -C2H5 4 462 -C2H5 4 462 -C2H5 4 464 •C2H5 4 492

CaH6 4 464 1178

-CiHs 4 462 -188- 200831498 [*7〇]

It 79 -C2H5 4 46t

1t80 4 461 I18t

4 461 1182 4 538 1183

-QiHs 4 476 1t84 H, C 1185

-C2H5 4 5t〇 •C2H5 4 463 f186 t187 1188

9S -C2H5 4 -C2H5 4 505 -C2H5 4 504 -189- 200831498 [Table 71]

1190 • C2H5 4 505 &lt;xr

•C2H5 4 495

1197 1198 ttS9

-C2H5 4 474 •C2H5 4 427 -C2H5 4 429 -C2H5 4 489 •Cyts 4 441 -CiHs 4 474 4 502 -C2H5 4 4 190- 200831498 [Table 72] Ο R1-&lt; N-(CH,)n - R2

N

Nta

Tm

-C2H5 4 493 -Cj^ 4 489 -C2H5 4 493 -C2H5 4 493 -C2H5 4 478 -QfcHs 4 509 •C2H5 4 502 4 479

-C2H5 4 499 -Q2H5 4 533 -C2^ 4 483 -191 - [*73] 200831498 ,0R1&lt;,Ν-(α^η—N, R2 'mm m 1211

cS

R2 • C2H5 m2 D&gt;

n MS(M+1} 4 495 4 462 4 507 4 491

-C2H5 4 476 -〇2»^ 4 495

-C2H5 4 505 •C2H5 4 499 •C2H5 4 499 -192- 200831498

CQ 0 R2 I café 2425

2·

4 4 4 4 4 4 4 4

4 4994654801476476455413494492 -193 - _75]200831498 ΟRtH: f, one (oyn- R2, ~mm ri

1233 R2 - C2H5 • C2H5

T234 1235 t236 1237 1238 1239 1240

Ch3 CHaCH3 NO^CH3

-C2H5 -C2H5 •C2H5 n MS(铋.1) 4 508 4 502 4 502 4 426 4 426 4 426 4 427 -C2H5 4 427 -C2H5 4 462 -CiHs 4 478 -194- 200831498 [Table 76] Ο «Η Wide λ R2 sound - W - V / an example ~ 1241

R2 n MS(M+1) ^H5~4 478~

-C2H5 4 489 -C2H5 4 491 1245 1246 1247 t248 1249 1250 1251 0~\Qr\ C&gt;ao^y-

•Ή 5 437 Ή 5 423 &gt;H 5 423 -H 5 423 ~H 5 428 4H 5 474 -H 5 428 -195- 200831498 [Table 77]

1253 i254

T255

T258 125» or

-H 5 414 -H 5 442 -H 5 519 -H 5 457 -H 5 490 -H 5 458 -H 5 458 -H 5 452 -H 5 491 44 5 477 -196- [*78]200831498 Ο mi sound One (oyrv instance R1 R2 1263 O7&quot;

-H n MSjtJbi) 5 443

471

1268 44 5

-H 5 -H 5 -H 5 43d 46» 478 435 435 448 482 443 443 477 -197- 200831498 13⁄4 79]

Στ Cl

1282 t283 αχΟΧ •Η 5 455 •Η 5 447 1284

1285

-Η 5 447 -Η 5 397 -Η 5 449 -Η 5 459 -Η 5 459 •Η 5 459 -Η 5 459 -198- 200831498 imsoi

1286 -H 5 459

1287 1288 cor t289 Η^σ

1290 03⁄4 1291

T2d2 &amp; 1293 t295 1296 1294

-H 5 459 Ή 5 448 •H 5 478 -H 5 510 -H 5 477 «Η 5 477 -H 5 477 -H 5 482 -H 5 466 44 5 464 -199, 200831498 im si]

-Η 5 475

T304 -H 5 1305 1306 〇cvQ~\_ -H 5

481 465 4$1 480 464 508 435 549 -200 - [*82]200831498 Ο R1-^NL- R2

Example R1 R2 n im -H 5 525 1309 1310 1311

-H 5 461 -H 5 53t -H 5 477 1312

• H 5 481 tm

-H 5 477 1314 1315 !3te 1317 Χψ -Η δ 481 W 5 507 -H 5 495 -H 5 475 tata

41 5 489 -201 - 200831498 [ft 83] m-i R2:

T321 -H 5 531 1322

-H 5 503 1323

1324

-+» 5 493 -H 5 571 1325 1326

-H 5 503 -H 5 479 1327

-H 5 479 -202 - 200831498 [Table 84] Ο

Ri-i R2 instance R1 &quot;l328

-cS

R2IFF 5 475 1329

1333 1334 1335 1336 t33? 1330 1331 1332

-H -H -H

-H 5 491 5 475 5 475 5 53d PH, 屮

5 462 -H 5 478 -H 5 482 -H 5 448 -H 5 573 -203- [^85]200831498

5 516

1343 •Η 5 465 -Η 5 403 -Η 5 425 -Η 5 443 〇R~ ^ 5 433 1344 1345 ί34β 1347

Ϊ́34β

-Η 5 417 -Η 5 459 -Η 5 431 -Η 5 437 -Η 5 443 -204 - 200831498 [S86] R1 R2 μ 1349

R2TfT 1350

T351 1353 1354 1355 1356 1358 1352

1357

-H

-H

-H 41 5 415 5 449 5 4tt 5 427 5 424 5 410 5 474 5 412 5 460 «Η 5 424 -205- 200831498 ims7]

-Η 5 4t4 Ή 5 453 Ή 5 476 - Η 5 448 - Η 5 476 - Η 5 416 Ή 5 430 • Η 5 415 - Η S 426 -206- [*88] 200831498

Rl-^ R2 instance R1 R2 1370

-H 1371

-H 1372

C!- 1373 1374 1375 1375

-H

-H

-H

-H n 5 482 5 448 5 486 5 448 5 424 5 466 5 448 •H 5 448 -H 5 450 -H 5 478 -H 5 450 -207- 200831498 [Table 89]

&quot;Η 5 448 ccr

Ή 5 447

1383 1384 t385 ta86 1388 1389 13S0 mt

-Η 5 447 -Η 5 -Η 5 α- -Η 5 -Η 5

-Η 5 % -Η 5 -Η 5 44 5 447 524 462 496 449 466 49t 490 -208- [^90] 200831498

-209- 200831498 [Table 91] p m-i R2

Example R1tm R2 n ~5 479~ tm -H 6 45t

1405 im Q~\ -H 6 -H 6 437 437 mi -H 6 437 1408 1409

•H 6 442 442

1410

-H 6 533

-H 6 494 -H 6 471 -H 6 504 -210- 200831498 [Table 92]

1414 - Η 6 472 1415 ccr +1 6 472

-Η 6 466 -Η 6 505 •Η 6 491

44 6 457 -Η 6 485 -211 - 200831498 [Table 93 ]

Example R2 R3 rr Crystalline melting point salt (recrystallization solvent) Cc) -C2H5 4 White powder (ethanol·ethyl yeast) 147Μ49Λ Hydrochloride-Η 4 White powder (ethanol·acetic acid) lei.MOLO hydrochloride-〇Λ 4 White Powder (ethanol·acetamidine) 179.5-181.5 Hydrochloride-Η 4* 4 White powder (ethanol·ethyl) 195.(M96.5 - -C2H5 -Η 4 white powder (ethyl acetate·hex) 161.0 -163.Q Hydrochloride-Η-CaHs 4 White powder (ethanol·acetic acid) 196.W98.5 Hydrochloride-C2H5 -Η 3 White powder (ethanol·acetic acid) 188.5-189.5 Hydrochloride 1421 -Η 1422 - 3⁄4 t423 -(3⁄4 1424 -Η 1425 -Η 1426 -Η 1427 -Η 1428 -Η -C2H5 3 1429 -CzHs -〇2»5 -Η 3 1430 -&lt;y 1431 -Η 1432 -Η 1433 -« t434 - Ρ2Ι -Η -Η -Η -Μ t435 1436 -C2H5 *C^5-Η -Η 4i 1437 4* -Η 1438 -Η -Cy 1439 -Η -3⁄4 1440 -C^Hs -CJ 1441 -C2H5 1442 -Η -Η -Η -Η 3 3 32222 ί 5 5 5 5 5 White powder white powder (ethanol) White powder (ethanol) White powder (ethanol·acetic acid) White powder (ethanol·acetic acid) White powder (ethanol_ethyl ether) White powder (ethanol White amorphous solid white powder (ethanol-water) White powder (ethanol-diethyl ether) White powder (ethanol·acetic acid) White powder (ethanol·ethyl ether) White powder (ethanol·ethyl vine) White powder (ethanol-acetic acid) White powder (Ethanol-Ether) 176 each 178.5 165.CM67.0 205.5- 206.5 Hungry 04830 176 each 17&amp;5 212 each 214,0 180.0-190.0 NMER* 217.5- 219.5 194.M96.5 237.CV239.0 hunger CM63.0 178.W80.5 MMR* 234·5*235·5 Hydrochloride hydrochloride hydrochloride salt hydrochloride salt hydrochloride salt hydrochloride salt hydrochloride salt Hydrochloride hydrochloride hydrochloride-212- 200831498 *Example 1435 NMR data ^-NMR (DMSO-d6) δρριη: 1.07 (6H, t, d=7.0 Hz), 1.11 (3H, t, J=7.0 Hz ), 3.12-3.21 (8H, m), 3·28-3·41 (2H, m), 3.47-3.49 (2Hf m) r 3.54-3.57 (2Hr m) , 3.63-3.66 (2Hf m), 6· 98 (1H, d, J=7.6 Hz), 7·32 (1H, d, J=7.8 Hz), 7.48 (1H, df d=5.5 Hz), 7.70 (lHf dr d=8.0 Hz)f 7.77 (lHf d, d = 5.4 Hz).

*Example 1441 NMR data ^-NMR (DMSO-de) 5 ppm: 1.00-1.10 (9H, m), 1.27-1.29 (2H, m), 1·48-1·50 (2H, m), 1·70- 1·75 (2H, m), 3·04-3·20 (8H, m)f 3.20-3.25 (4H, m), 3.30-3.34 (2Hf m) f 3.50-3.60 (4H, m) f 6.97 ( 1H, d, J=8.1 Hz), 7.32 (1H, t, J=6.6 Hz), 7.48-7.49 (1H, m)f 7.70 (lHf d, J=7.1 Hz)f 7.74-7.80 (1H, m) , 10.36 (lH,brs)·

-213- [*94]200831498

Do N-(zero-

Example R1 R2 η Crystal form (recrystallization solvent) Melting point CO salt 1443 CN~ -H 2 White powder 206-208 Hydrochloride 1444 〇*- -H 3 White powder 181-183 Hydrochloride t445 CN_ 4 White powder 171-173 Hydrochloride 1446 CN~ AHs 4 White powder 182-184 Hydrochloride 1447 〇- -Η 5 White powder 162-164 Hydrochloride 1448 CN - -Η 6 White powder 174-176 rr^sr Hydrochloride-214- 200831498 Example 1449 Synthesis of 1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-2-pyrrolidone dihydrochloride

1-(4-Chlorobutyl)-2-pyrrolidone (150 mg, 0.85 mmol), 1-benzo[b]thiophen-4-yl-piperazine hydrochloride (240 mg, 0 · 94 mmol), carbonic acid Potassium (290 mg, 2·10 mmol) and sodium iodide (170 mg, 1.13 mmol) were added to dimethylformamide (DMF) (3 ml), and the mixture was stirred at 80 ° C for 6 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure. The residue obtained was purified by column chromatography (dichloromethane:methanol = 30:1 to 15:1). The purified product was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (2 ml) and concentrated hydrochloric acid (0.15 ml). The resulting solution was concentrated under reduced pressure. The obtained residue was recrystallized from ethanol ethyl acetate to give 1-[4-(4-benzo[b]thiophen-4-yl-piperazine-1-yl)butyl]-2pyrrolidinone as a pale brown powder. Hydrochloride (220 mg).

Melting points: 1 8 3.0 to 1 8 5.0 °C Examples 1462 to 1480, 1483, 1486 to 1490, 1493 to 1513, 1515 to 1518, 1520, 1522 to 1544 and 1586 to 1593 are used in the manner of Example 1 449. The material compounds are synthesized. Example 1 4 5 0 Synthesis of 4-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-6-methoxy- 3,4-dihydro-2H -Benzo[1,4]oxazine hydrochloride-215- 200831498 Lithium aluminum hydride (3 4 mg, 0·90 mm ο 1) was suspended in tetrahydrofuran (THF) (2 ml), and 4-[ 4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one (0.34 g , 0.75 mmol) in THF (5 ml). The reaction solution was heated to reflux for 1 hour and then cooled to room temperature. So far, the reaction solution was sequentially added with water (50 μM), 15% aqueous sodium hydroxide solution (50 μM) and water (150 μM), and the mixture was stirred at room temperature for 30 minutes. The resulting solution was filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (n-hexane: ethyl acetate = 5:1 to 2:1). The purified product was concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate (5 ml), and 1N EtOAc (0.11 ml). The insoluble matter produced is filtered off and dried to obtain a white powder of 4-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-6-methoxy Base - 3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride (39 mg).

Melting point: 218.7 to 219.8 °C φ Example 1 4 5 1 Synthesis of 3-[4-(4-benzo[b]thiophen-4-yl-piperazine-1-yl)butyl]_6-hydroxy-3H-quinine Oxazolin-4-one·1.5 hydrobromide 3-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]_6_hydroxy-3 Η-嗤哩Porphyrin-4-one (0.4 1 g, 0 · 9 1 mm ο 1) was dissolved in dichloromethane (1 5 m 1), and a solution of 2 Μ boron tribromide in dichloromethane (1.37 ml, 2.74 mmol). The resulting reaction solution was stirred at room temperature for 2 days, water was added, and the resulting mixture was stirred for 3 G minutes. The purified insoluble material was filtered off, and the filtered material was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 to -216 - 200831498 10:1). The purified product was concentrated and dried under reduced pressure to give 3-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-6-hydroxy- as a white powder. 3H-quinazolin-4-one·1.5 hydrobromide (0.16 g). Melting point: 249.0 to 250.2 °C Example 1 4 5 2

Synthesis of 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl] octahydroisoindol-1-one hydrochloride 0.2 g of 10% Pd/C Add to 2-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butyl]-2,3,3 a,4,7,7 a-hexahydroisoindol A solution of ketone (〇.1〇g, 0.24 mmol) in ethanol was added and the mixture was stirred at room temperature for 16 hours under hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (5 ml). The resulting insoluble matter was filtered off and dried to give 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl] octahydroisoindole as a white powder. 1-ketone hydrochloride (50 mg). Melting point: 219.7 to 221.0 ° C Example 1 4 5 3 Synthesis of 1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-3-(4-iodo) Pyrrolidin-2-one hydrochloride 1-[4-(4-benzo[1)]thiophen-4-yl-piperazin-1-yl)butyl]pyrrolidin-2-one (500 mg , 1.40 mmol) and 1,4-dioxinine (0.35 ml, 2.65 mmol) in THF were cooled in ice and added dropwise under nitrogen atmosphere 217-200831498

1.1 THF hexamethyl hexamethyl disilazide (3.2 ml, 3.52 mmol) in THF. This solution was stirred at room temperature for 20 hours. An aqueous solution of ammonium chloride was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography (hexane: ethyl acetate = 2:1). The purified product was concentrated under reduced pressure. The residue obtained was dissolved in ethanol (2 ml) and concentrated hydrochloric acid (0.15 ml). The resulting solution was concentrated under reduced pressure. The obtained residue was recrystallized from ethanol-ethyl acetate to give 1-[4-(4-benzo[1^]thiophen-4-yl-piperazin-1-yl)butyl]-3- (4-Iodobutyl)pyrrolidin-2-one hydrochloride (170 mg). Melting point: 1 18.0 to 120.0 ° C Example 1454 Synthesis of 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-2-azaspiro[4,4 ] decane-1-one dihydrochloride 1-[4-(4-benzo[1&gt;]thiophen-4-yl-piperazin-1-yl)butyl]pyrrol-2-one (500 THF solution of mg, 1.40 mmol) and 1,4-diiodobutane (0.35 ml, 2.65 mmol) was cooled in an ice-methanol bath, and 1.1 Μ hexamethyl ruthenium hydride was added dropwise in a nitrogen atmosphere. (1.9 ml, 2.09 mmol) in THF. The resulting reaction solution was stirred at room temperature for 22 hours. The reaction solution was cooled in an ice-methanol bath, and a solution of 1.1 Μ hexamethyl bis-sulphate (1 · 9 m 1, 2 · 0 9 mm ο 1 ) in THF was added dropwise, and the mixture was obtained in the room. Stir for 1 hour under temperature. An aqueous solution of ammonium chloride was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate - 218 - 200831498 and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (yield: ethyl acetate = 4:1). The purified product was concentrated under reduced pressure. The residue obtained was dissolved in ethanol (2 m 1 ), and a solution of 1 N hydrochloric acid (e. The insoluble matter produced was filtered off and dried to give a white powder of 2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-2-aza Spirogen [4,4]decane-1-one dihydrochloride (20 mg).

Melting point: 217.0 to 219.0 °C

Example 1 4 5 5 Synthesis of 1-[4-(4·benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]piperazin-2-one dihydrochloride trifluoroacetic acid (1.0 Ml, 13 mmol) added to 4-[4-(4-benzo[b]thiophene-

a solution of 4-butyl-piperazin-1-yl)butyl]-3-keto-piperazine-1-carboxylic acid tert-butyl ester (280 mg, 0.5 9 mm ο 1) in dichloromethane (1 0 m 1), and the resulting mixture was stirred at room temperature for 14 hours. An aqueous solution of sodium hydrogencarbonate was added to the reaction solution to make the reaction solution alkaline with φ. This solution was extracted with dichloromethane. The obtained organic layer was washed with sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by basic column chromatography (dichloromethane:methanol = 30:1). The purified product was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (2 ml), and 1N hydrochloric acid (1 ml). The insoluble matter produced is filtered off and dried to obtain a white powder of 1-[4-(4-benzo[b]thiophen-4-yl-piperazine)-butyl]piperazin-2-one di-salt Acid salt (210 mg). Melting point: 258.0 to 260.0 °C -219-200831498 Example 1456 Synthesis of 4-ethenyl-l-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butyl]piperazine 2-ketohydrochloride diethylamine (0.15 ml, 1.08 mmol) was added to 1-[4-(4-benzo[b]thiophenate

A solution of phen-4-yl-piperazin-1-yl)butyl]piperazin-2-one (260 mg 5 0. 70 mmol) in dichloromethane (5 mL). Acetic anhydride (0.1 mi, 1.06 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the resulting mixture was stirred for 30 minutes. Aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with dichloromethane. The obtained organic layer was washed with aqueous sodium hydrogen sulfate and dried over anhydrous sodium sulfate. The obtained residue was purified with EtOAc EtOAc EtOAc. The purified product was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (2 ml), and 1N hydrochloric acid in ethanol (0.6 ml). The insoluble matter produced was filtered off and dried to give a white powder of 4-ethylindol-1-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butyl]piperidin Pyrazin-2-one hydrochloride (220

Melting point: 2 1 5.0 to 2 1 7.0 °C Example 1457 Synthesis of 1-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propyl]imidazol-2-one Fluoroacetic acid (1.0 ml, 13 mmol) was added to 1-[3-(4benzo[b]thiophen-4-yl-piperazin-1-yl)propyl]-3-(2,4 dimethoxy) A solution of benzyl)imidazol-2-one (0 · 3 2 g, 0.6 5 mm ο 1 ) in dichloromethane (1〇1111), and the resulting mixture -220·200831498 was stirred at room temperature overnight. An aqueous sodium hydroxide solution is added to the reaction solution to make the reaction solution alkaline. This solution was extracted with dichloromethane. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated. The residue obtained was purified by column chromatography (dichloromethane:methanol = 30:1 to 10:1). The purified product was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-diethyl ether to give 1-[3-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)propyl]imidazolidine as a white powder. -2-ketone (0·10)

g). 1H-NMR ( DMSO-d6 ) 5 ppm : 1.60- 1.70 ( 2H,m ) , 2.30- 2.40 (2H,m) , 2.61 (4H,brs) , 3.00-3.15 (6H,m) ,3.15-3.50 (4H , m), 6.23 (lH, s), 6.90 (lH, d, J = 7.6 Hz), 7.27 (1H, dd, J = 7.8 Hz, J = 7.8 Hz), 7.40 (

1H, d, J = 5.5 Hz), 7.61 (1H, d, J = 7 · 9 Hz), 7.69 (1H, d, J = 5.5 Hz). The compounds of Examples 1514 and 1521 were prepared by the synthesis of the relevant material compound in the manner of Example 1457. Example 1 4 5 8 · Synthesis of 1-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propyl]-6-one-1,6-dihydropyridine- 3-carboxylic acid hydrochloride 6 N aqueous sodium hydroxide (1 ml) was added to 1-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propyl]-6 A solution of ethyl keto-1,6-dihydropyridine-3-carboxylate (0.31 g, 0.73 mmol) in ethanol (3 ml), and the mixture was stirred at room temperature for 3 days. 6 N hydrochloric acid was added to the reaction solution -221 - 200831498 under ice cooling. The insoluble matter produced was filtered off and dried to give a white powder of 1-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propyl]-6-butan-1 , 6-Dihydropyridine-3-carboxylic acid hydrochloride (181 mg). Melting point: 265.0 ° C (decomposition) Example 1 4 5 9

Synthesis of 1-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propyl]-6-one-1,6-dihydropyridine-3-carboxylic acid ethyl The guanamine hydrochloride monohydrate was added to 1-[3-(4-benzo[b], triethylamine (0.14 ml, 1.04 mmol) and isobutyl chlorocarbonate (0.07 ml, 0.52 mmol). a solution of thiophen-4-yl-piperazin-1-yl)propyl]-6-one-1,6-dihydropyridine-3-carboxylic acid (0.15 g, 0.35 mmol) in EtOAc (3 mL) The mixture was stirred for 30 minutes. A 70% aqueous solution of ethylamine (〇·〇 8 ml, 0·1 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, and the solution was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure. The residue was purified by basic EtOAc EtOAc (EtOAc:EtOAc:EtOAc The purified product was concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate and a solution of 4N hydrochloric acid ethyl acetate. The insoluble matter produced was filtered off and dried to give a white powder of 1-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propyl]-6-keto-oxime. , 6-Dihydropyridine-3-carboxylic acid ethyl decylamine hydrochloride monohydrate (71 mg). Melting point: 1 3 5 · 0 to 1 4 1.5 °C Example 1460 - 222 - 200831498 Synthesis of 1-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propyl; μ6 -keto-1,6-dihydropyridine-3-carboxylic acid dimethyl decylamine hydrochloride

Diethylamine (〇·24 ml, 1.7 mmol), dimethylamine hydrochloride (〇·〇9 g5 1.04 mmoi) and diethyl cyanophosphate (0.07 ml, 0.42 mmol) were added under ice cooling to a solution of 1-[3·(4benzo[b]thiophen-4-yl-piperazine-1·yl)propyl]-6-one-1,6-dihydropyridine-3-carboxylic acid in DMF ( 3 ml), and the resulting mixture was stirred at room temperature overnight. Additional triethylamine (0.24 ml, 1.7 mmol), dimethylamine hydrochloride (0.09 g, 1.04 mmol) and diethyl cyanophosphate (DEPC) (0.07 ml, 0.42 mmol) were added to the reaction solution And the resulting mixture was stirred at room temperature for 26 hours. Water was added to the reaction solution, and the solution was extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure. The residue obtained was purified by column chromatography on EtOAc (hexane: ethyl acetate = 3:1 to 0:1). The purified product was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and a solution of 4N hydrochloric acid ethyl acetate was added. The insoluble matter produced was filtered off and dried to give a white powder of 1-[3-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)propyl]-6-one-1 , 6-Dihydropyridine-3-carboxylic acid dimethyl decylamine hydrochloride (43 mg).

Melting point: 2 0 1 . 5 to 2 0 6 · 0 °C Example 1 4 8 4, 1 4 8 5 and 15 19 The synthesis was carried out in the manner of Example 1 460 using the relevant material compound. Example 1461 Synthesis of 3-[4-(4·benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-2-keto--223-

200831498 2.3-Dihydrothiazole-4-carboxylic acid methyl decylamine hydrochloride 40% aqueous methylamine solution (3 ml) was added to 3-[4-(4·piperazin-1-yl)butyl]-2- A solution of keto-2,3-dihydrothiazole-(0.25 g, 0.5 2 mmol) in methanol (3 ml). This solution was cooled to room temperature. Water is added to the reaction ester extraction. The obtained organic layer was washed with water and concentrated under reduced pressure with a solvent mixture. The residue obtained was purified (y-hexane: ethyl acetate = 5:1 to 0:1). concentrate. The resulting residue was dissolved in ethyl acetate and ethyl acetate. The resulting insoluble material was filtered off and the final 3-[4-(4-benzo[b]thiophen-4-ylpiperazine-1 2.3-dihydrothiazole-4carboxylic acid methyl decylamine hydrochloride 137.0 143.5 °C (decomposition) Examples 1481, 1482, 1491 and 1492 1 46 1 The chemical properties of the compounds prepared using the relevant material compounds in Examples 1 462 to 1 544 are shown in the following table. • Benzo[b] Thiophen-4-yl-4-carboxylic acid ethyl ester hydrochloride and heated to reflux 7 small solution, and dried with magnesium sulfate in ethyl acetate. The purified product was purified by basic column chromatography to 4N hydrochloric acid under reduced pressure. The acetic acid was dried to give a white powder: phenyl) butyl]-2- keto- (181 mg). Melting point: The compound is obtained by the example '. Chemical Structure and Physics and •224- 200831498 [Table 95]

1462

1464 1465 14Θ6 1467

1468 CH, »3^01, iN, ό- ό- ό- 4 white powder 207.0^209.0 hydrochloride (ethanol) 4 white (certificate 212.0-214,0 hydrochloride white powder (ethyl acetate-201- 205 Dihydrochloride diethyl ether) β Light yellow powder 4CM Λ 4〇£5 Π 碰陆弥5 (ethanol _ 184 Λ·186·0 hydrochloride ethyl acetate) 6 white powder 19t. (M93O hydrochloride (ethanol) White, color powder, (M94.0 hydrochloride (ethanol) 8 white fiber Nile hydrochloride -225- 200831498 [Table 96]

4 117-119 1469 1470 5 Light yellow powder (ethanol · ethyl acetate) Achromatic crystal needle crystal (ethanol · ethyl acetate) 2» shot 58.0 hydrochloride

White powder 177.0-179.0 Hydrochloride XD2. JQQ3L (Ethanol) White powder (ethanol) 223-224 issK&amp;tai White powder (ethanol) 204-205 Hydrochloride white powder (ethanol·ethyl acetate) 178-180 Hydrochloric acid salt

Yellow powder (ethanol) 179481 hydrochloride -226- 200831498 [Table 97]

Hydrochloride jrn.ptx.iTn. t478

1477 1478 t479 1480 3 Light yellow powder 21 &amp; 218 (ethanol-ethyl acetate) 4 Light yellow powder 2600 (ethanol·ethyl acetate) (^) rcr^ rr^g·-hydrochloride 5 (ethyl acetoacetate) ?&amp;) Age 169. 6 White powder (ethanol) 4 White powder (ethyl acetate) Dihydrochloride m〇-188· Hydrochloride 2&lt;».CW!12. Hydrochloride

T48t

4 White powder (ethyl acetate) Hydrochloride 1482 4 White powder (ethyl acetate) 173.0*180. Hydrochloride -227- 200831498 _98]

(recrystallization solvent) (°C) (||S 2 lake 7.5 earning salt m m

(!S) fine mo hydrochloride vm white powder (ethyl acetate) 130.0-133.0 hydrochloride I486 1487 m

m dr light yellow powder (ethanol-ethyl acetate) 204-206 hydrochloride 5 (ephthyl alcohol yellow vinegar) young 222.0 hydrochloride (ethyl 13⁄43⁄43⁄4 ester) 2 dirty 37·0 hydrochloride-228- 200831498 [ Table 99]

(recrystallization solvent) m m

1492 1493 m 1485

White powder 157.5-158.5 (methanol) White powder 225.0-228.0 Hydrochloride (ethyl acetate) (decomposition) White powder 226.5-233.0 Hydrochloride (ethyl acetate) (decomposition) White powder 234*236 Hydrochloride (ethanol White powder 157-159 hydrochloride (ethanol) (I11S) 246·^248·2 hydrochloride 1496

I486 m &amp; 0, ci-d- 4 white powder 217.0*219.0 hydrochloride (ethanol-ethyl acetate) 5 white powder 200.0-211.0 hydrochloride (ethanol-ethyl acetate) 4 white powder 214. (W15 .D hydrochloride (ethanol) 5 white syndrome followed by 30 hydrochloride -229- 200831498 im loo]

259·0·261·0 hydrochloride 15Ε» m

5 light yellow powder (ethanol) 4 light yellow powder (ethanol ethyl acetate) 168-170 hydrochloride

Light yellow powder (ethanol·ethyl acetate) colorless squamous crystal (ethanol) white powder (ethyl acetate) purple powder (ethanol) light yellow powder (ethanol) light yellow powder (dichloromethane-methanol) 295 hydrochloride Decomposition) 242-244 Hydrochloride 201.9-203.3 Hydrochloride 249*251 Hydrochloride 242-244 Hydrochloride 73-74 - -230- 200831498 im ion

(recrystallization solvent) 1508

4 white powder (ethyl acetate) 244.6-246.2 (decomposed)

1510 K11

4 (3⁄43⁄4 230 woven 0 hydrochloride 4 white powder 228,5&quot;2 grade 0 dihydrochloride (methanol-acetic acid ethyl acetate) 4 white powder 24&amp;1-247.9 _$salt (ethyl acetate)

-231 - 200831498 im 102]

1512 1513

tSt4 t5t5 1516

15t7 4 ^-NMR (DMSO-de) 5ppm: 1 J-1.8 &lt;4Hf m), 3.11-335~ Dihydrochloride~ (6H, m), 3.51-3.60 (4H, m), 4.05 (2H, m), 6.95 {1H, dt J=7.8 Hz), 7.31 (1H, ύά9 J=7.8, 7.8 Hz), 7.47 (1Hr d, J=5.5 Hz)t 7^6 (1Ht m), 7.6S-7.70 (2H, m), 7J5 (1Ht d, J=5.5 Hz), 7.84 (1H, m), β, 17 (1H, cW, J=8.0, 1.4 Hz), β.4θ (1Ht d, t.4 Uzl 10.37 (1H, i&gt;rs) 4 ^-NMR (DWSO-{fe) 1.4CM.60 (12H, m) (hydrochloride 1.1(Κ1.80 (2H, m)f 2.13 (2H, s ), 3J2 (2H, s)r 3.10-3.35 (8H, m)t 3.46-3.60 (4H# m)f 6.96 (1Ht d, J=7.5 Hz), 7.32 (1Ht cW, &gt;7.8, ?.8 Hz), 7.50 (1Ht d, J=5, $ Hz), 7.70 (1H, d, J*8.0 Hz), 7.77 (1H, d, J=5.5 Hz), 11.24 (IH^brs). 4 Ή- NMR (DMSOKfe) 5 ppm: t.40-150 (4H.m). A 2.30-2.45 (2H, m)f 2.50-2.60 (4Hf m&gt;, 3.0CK3.10 (6H, m), 3.15-3^5 (4H. m)t 6^1 (1Ht s)f β.90 (1Hf d, J=7.6 Hz), 7JZ7 (1Hr d4 J=7.8t 7.8 Hz), 7.39 (1H, dt J=5.5 Hz), 7.61 (1Ht d, &gt;8.a Hz), 7.69 (tH, d, J=5.5 Hz). 4 1H-NMR (CDC%) 6ppm: 1,48-1.63 (4H, m), Z36-2.52 Fumarate (2H, m), 2J&1-2T7 (4H, m)t 2.79 (3H, s), 3.K W.33 (10H, m&gt;, 6.80 (1H, d, J = 7.6 Hz), 7^2-7.32 (1H, m)r 7.34-7.43 (2H. m), 7.54 (1H, &lt;i, J = 8.0 Hz). 4 ^-NMR (CDCb) δρρτη: 1.11 (3H, t, J * 7.3Hz), fumarate 1.48-1.68 (AH, m). 2.37-2.55 (2H. m), Z5&-2 J8 (4H, m), 3.0S-3.38 (12H, m), 6.89 (1H, d. J = 7.7 Hz), 7.1S-729 (1H, m&gt;, 7.31-7.42 (2H, m ), 7.54 (1Hr d, J = 8.0 Hz). t5t9 o &lt; t (CDCy ^m: 1.11 (6Hr (f, J « 6.8 Hz), 1.48-1.63 (4H, m&gt;, 2.40*2.52 (2H, m), 2.57-2.73⁄4 (AHt m), 3.07^.34 (tOH, m)t ΑΛ4 {1H, quint, J = 6.8 Hz), 5.89 (1Hr d, J = 7.6 ItcX 7.21-7.30 (1H, nn ), 7.34-7.43 (2H. 7.54 (t H, = 0.1 Hz). 4 (DM^de) δρρτη: t.4$*1.64 {4Ht m&gt;r Fumarate 2.40-Z52 (2H, m ), 2.6S-2 J7 (4H. m), 2.97-3.2® {6Hf m)» 3.42-3.50 (2H, m), 3.76-3.85 (2Ht m)t 6.60 (2H, s), 6.90 (1H, 4 J=7.7 te), 6.9β (tH, dt, J=7.4t 0.9 Hz)t 7 25-7.34 (3H, m), 7.40 (1H, d, J=5.5 Hz), 7.55-7.» m ), 7·βΊ (tH, 甙J=8-0 Hz&gt;, 7^69 (1H, d, deduction 5.5 Hz>. 4 5ppm: 1,354,50 fumarate 1.70^1.80, 2.10-2.30 { 4H , m), 2.60-2.80 (4H, in% 2.83 (3H, s), 3.01 (3H, s), 3.06-3.15 (4H, m), 3.30-3.50 (4H, m), 4.65-4.70 (1H, m), 6.59 (2H, s), 6.89 (1H, df &gt; 7.5 Hz), 7J26 (tHcW, 0=7.8, 7.8 Hz), 7.39 (1H,d, &gt;5.5 Hz)t 7.61 (1H, d , J=8.0 Hz)f 7.68 (1H, d, J=5.5 Hz). 4 fumarate-232- 200831498

Ο ^NMR (solvent) salt

T522 ί524 4 (DM«Me) 5ppm: t.45-1.55 (2Η, m\ t.65-1.75 (2H, m), I. 9W.05 (1H* m), Z20*2.35 (2H· m) , 2·8Μ·00 (1H. m&gt;, 3.0W.30 0H, mX ^45-3*55 {6H, m), 3.71 (3H, s)f 4.3M.40 (1H, m)r6.86 (1H, dt J=7.5 te), 7.32 (1H, dd, J=7.0.7.8 Hz), 7.49 (1H, d, J=5.5 Hz), 7.70 {1H, d, &gt;8.1 Ht)t 7.77 ( 1Hf d, &gt; 5.5 Hz), II. 18(1«^). 5 fH-NMR (DMSOKfc) Cppm: 1.20-1.35 (2H, m) (t.36-1.50 (4Hr m)f 2.34 (2H, t J=7.2 lfe)r 2.45-2.60 (4Ht m), 2.95-3.10 (6H, m), 3.15-3.35 (4H, m&gt;, 6.18 (1H, s), 6.87 (1Ht d, J-7.6 Hz) , T.25 (1H, Mt J=7.8, 7.8 Hz), 7.37 (1H, d. J=5.6 Hz), T.59 (1H, c!, &gt; 8.0 Hz)r 7.ββ (1H, n 5 %HmR {bMSOdi) δρ|»η: 1JMV1.30 (2H, m), 1.40-1.65 (4H, m), 2.40-2.50 {6H, mX 2.61 (3H, s)t 3.00-3.10 (6H, m&gt ;, a.15-3.25 (4Ht UJ m), 6.59 (2H, s), e.8a (1Ht dt &gt; 7.5 Hz), 7.26 (1H, dd, J=7:9, 7.9 Hfe), 7.3» (1H, d, J=5.4 Hz), 7.60 (1Hf dt J=eO H2)t 7.68 (tH, d, J=5.5Hz). ί (DMSO&lt;fe) 5ppm: 1.00 (3Ht t, J*7.2 Hz ), 1;2t-t.62 (6H, in), 2.63-2.82 (4H, m), 2.96-3.33 (tOH, m), 6 .8D (2H, s), 6.90 (1H, d, J=7.6 Hz), 7.28 (1Ht cW, J=8,1t 7.β te)), 7.41 (1H, dd, J=5.5t 0.9 Hz) , 7.62 (1^4 &gt; 8.1 Hz), 7.70 (1H, d, J = 5.5 Hz). ;1H-NMR (CDC^) 5ppm: 1.57-1.76 {6H, m), 2.43-2.50 (2H, 2.60 -Z79 (4Ht m&gt;. 3.09-5.26 (4H, m), 3J»^.36 (2H. m), 3.44-3.53 (2H, 3 J3-3.38 (2H, m), 6.W (1H, &lt;;1, J = 7.6 H2), 7.01-7.W (1H, m). 7.24-7.44 (5Hf m), 7.52-7.60 (3H, m). Hydrochloride anti-butene two t523

Fumarate anti-butene s 1525

tH-NMR (CDOb) e^ppm: 1.50-1.74 (12H, m), Z42-2.51 (2Hr m), Z60-2.76 (4H, m). 3.08-3^6 (4H, m), 3.64 (^ ΗΛ J =5 7.2 Hz), 6.$9 (1H, d, i = 11 Hz), 7.23^7.31 (m, tH), 7.34-7.43 (2Hf m)t 7.54 (1H,d,J*79teX Ether 2526

S 3 tH-NMR (DMSO^fe) δ^ρτη: 1.6-Z0 (4H, m )9 2.6-3.7 ( 13H, m ), hydrochloride 4.16 (2H, I, J = 5.61⁄2 ), 6.96 {1H , &lt;t, J = 7.6Hz), 7.32 (ΙΗ,όά^ =7.6,8.0te), 7.49 (1Ht d, J = 6.5Hz), 7 JO (1H, dr J - 8.0I*), T. T6 (1H, d#J = 5.5Hz).

-233- 200831498 i〇4]

Example R1 ΈΙΖ Form (recrystallization solvent) Melting point CC) Salt 1527 (V Ζ White powder (ethanol) 229-231 Hydrochloride 1528 i- Ε White powder (ethanol) Sheng · Hydrochloride 1529 〇v Ζ White powder (ethanol ) 213-215 hydrochloride 1530 〇V VJ Ε white powder (ethanol) 185-187 hydrochloride 1531 2 white powder (ethanol) 219-221 hydrochloride 1532 Ε light yellow powder (ethanol) 205.0-207.0 KCCtt CttB salt

E White powder 223*225 Hydrochloride (ethanol)

Ι53β

E

E colorless scales 253*255 crystals (ethanol > white powder 2 246 (ethanol) hydrochloride rfn.p^pc ΓΓΠ. hydrochloride

Ε white powder 220·0»222·0 hydrochloride (ethanol) -234- 200831498 im ι〇5ΐ

1537

〇V white powder (ethanol-acetic acid) 144-146 hydrochloride [Table 106]

Ch3 Example R1 η Crystalline melting point salt (recrystallization solvent) (°c) 1538 6- 4 Light yellow powder (ethyl acetate) 184.5-188.0 CCZ38 B3C8 hydrochloride 1539 ό- 4 Light yellow powder (ethyl acetate) 196 each Gene 5 hydrochloride -235 - 200831498 13⁄4 107]

3 TH&gt; NMR (CD(%)eppm: 1J&amp;^9〇(2H,m}, 2-5(K2.6d(2H, — m), Z70-Z80 {4H, m)t 3.1CW.40 ( 6H, m), 3.83 (3Hf s), 3.84 (3H, 咏4·39 (2H, 咏6.45-6.55 {2H, r〇X 6.93 (1H, d, &gt;7.6 Hl% 7.20*7.35 {2H, m ), 7.4(^7.50 (2H, m), 7.58 (1H, cl, J=8.0Hz). 4 tH4^(CDCW5PPnri: 15CM.60(4lim), 2.4a*2.55{2li — m), 2.60-2.75 (4H, m), 3.1CW.30 (10H, m), 3.79 (3Hr $), 3.θ0 (3Ht s)f 434 (2Ht s). 6.4(«.50 (2Ht m), 6.89 (1Ht d , J=7.4 Hz), 7.15-7.30 (3H, m), 7.35-7.45 (2H, m), 7.54 (1H. (J,J=8.0H2). 5 fH-NMR (CDQa) δρρτη: 1.30-1.45 (2H, m\ 1.45-1.65 (4 H,-m), 2.40-Z50 (2H, m), 2.65-2 J5 (4H, m), 3.10-3.30 (10H, m)t 3.79 (3H, s) , 3.80 {3H, s), 4.34 (2H, s), 6.4 (^6.50 (2Hf m), 6.89 (1H, cJ, &gt; 7.6 Hz), 7.15-7.30 (2H, m), 7.35-7.45 (2H , m), 7.54 (1H, 4 J=8,0 Hz). 4 ^-NMR (CDCb) δρρτη: 1.47 (9H, sX 1.55-170 (4H, m), a 2.48 (2H. t J=7.2 Hz ), 2.60^2.75 (4H. mX 3.1CW.25 (4H, m), 3.3⁄4 (2H, t, J=5.$ H2), 3.46 (2Ht t J=7.0 Hz)t 3.65 (2H, t ^=5.6 Hz). 4.07 (2H, s), 6:90 (1H, d, J«7.6 Hz), 7^7 (1 Η&gt; dd, J^7.9t 7.8 Hz&gt;, 7.38 (1Ht d, J=5.6 Hz)r 7.41 (1H, d, J==5.6 Hz), 7.55 (1H, df J=8.1 Hz). 3 '« «NMR (CDCW 2%>pm: 1.40(3«, U=7.0Hz)· 1.98»2.10(2H, m)9 Z45(2H( t, J=6.3Hz), 2.57-2J5(4Ht m), 3.07-3.24(4H, m)t 4.09(2«, I, ^e.Wz}9 4.43(2Ht q, a J=7.OTz), 6.88(1Ht dt ^TC^Iz), 7.22-7.31(2 «, m), 7.39(2H, $), 7,56(1Ht d&gt; J=8.0Hz), S.33imt d, J=0.5Hz&gt;.

-236 200831498 Example 1545 Synthesis of 1-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butyl]piperazine-2-thione hydrochloride 1.30 g (3.2 Methyl) Lawesson's reagent is added to 995 mg of 1-[4·(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-2-piperidone (2·7 mmol) THF solution (3 5 ml), the resulting mixture was stirred for 3 hours and hot

To reflux. The reaction solution was cooled to room temperature, and purified by basic hexane column chromatography (hexane: ethyl acetate = 1··2 to 〇: 1). The purified product was concentrated under reduced pressure. The residue thus obtained was dissolved in ethanol, and 2.0 ml of an IN HC1 ethanol solution was added to the resulting solution, which was allowed to stand. The precipitated body was filtered off and dried to give 648 mg (yield: 57%) of white powder of 1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl). Butyl] piperazine-2-thione hydrochloride. Melting point: 2 5 8.0 to 2 6 0.0 °C Example 1 5 4 6 Synthesis of [4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]pyrrolidine-2- The title compound was synthesized using 1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]pyrrolidone as described in Example 1 5 45. Melting point: 122.0 to 124.0 ° C Example 1 5 4 7 Synthesis of 1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-4-benzylpiperazine- 2,5-Dione hydrochloride-237- 200831498 Using 1-benzyl-4-(4-chlorobutyl)-piperazine-2,5-dione and 1-benzo[,] b] Thiophen-4-yl-piperazine hydrochloride The title compound was synthesized. White powder (ethanol-diethyl ether)

Melting point: 2 2 0 to 2 3 0 °C

^-NMR (DMSO-de) δ ppm: 1.50-1.80 (4Η, m), 3.00-3.60 (12H, m), 3·87 (2H, s), 4·07 (2H, s), 4·52 (2H, s)r 6.95 (1H, d, J = 7.5 Hz), 7.20-7.40 (6H, m), 7·47 (1H, d, J == 5.5 Hz), 7.69 (1H, df J = 8.0 Hz) f 7.75 (1H, df J = 5.5 Hz), 10.93 (1H, brs) [Table 108]

O R1-f / , one (Chyn_N R2 , example R1 R2 n crystal form (recrystallization solvent) melting point CC) salt 1548 -ch3 -〇(〇Η3)3 5 white powder (ethanol·ethyl ether) 203.5-204.5 hydrochloride 1549 -CH3 -C2H5 δ white powder (ethanol·ethyl) 102-110 oxalate 1550 -ch3 -ch2ch=ch2 δ white powder (ethanol·ethyl ether) 104-109 oxalate 1551 -ch3 -CH(CH3 ) 2 5 white powder (ethanol · ethyl charm) 98-102 oxalate 1552 -ch3 -cyclo-CaHs 5 white powder (ethanol-acetic acid) 102-105 oxalate 1553 -CH2NHCOCH3 -C(CH3)S 4 1554 KCH2)2NHCOCH3 -〇(〇Η3)3 4 1555 -(CHsJaNHCOCHs -〇(〇Η3&gt;3 4 1556 -CHzNHCOsCHa -C(CH3)3 4 1557 -(ch2&gt;2nhco2ch3 -C(CH3)3 4 1558 -{ CHs^NHCOaCHa -〇(〇Η3)3 4 -238- 200831498 im ι〇9ΐ

Example R1 R2 R3 Crystalline melting point salt (recrystallization solvent) CC) 1559 -ch3 -H -CH3 White powder (ethyl acetate / methanol) 200-202 Hydrochloride 1560 -CH(CH3)2 -CH3 White powder (ethyl acetate Ester/methanol) 211-213 hydrochloride JI〇.PCX»XHL 1561 -CHa -H -C2H5 white powder (ethyl acetate / ethanol) 133-135 - 1562 -ch3 -CH(CH3)2 -c2h5 white powder ( Ethyl acetate / methanol) 238-240 hydrochloride 1563 -ch3 -CH3 -CH3 white powder (ethyl acetate / methanol) 232-234 hydrochloride. onxttX· JHI. 1564 -ch3 -C(〇H3)a - Ch3 white powder (ethyl acetate / methanol) 196-198 acid 1565 • ΌΗ3 -CH3 -CaHs white powder (ethyl acetate / methanol) 211-213 1566 -ch3 -ch3 white powder (ethyl acetate, methanol) 204-206 Hydrochloride 1567 -ch3 -C2M5 -CzHs White powder (ethyl acetate / methanol) 189-193 Hydrochloride 1568 -CHa -C(CH3)3 -C2H5 239- 200831498 im no]

R1 O : Nl R2 N-(CH,)n-R3 -o-δ Example R1 R2 R3 n Crystal form (recrystallization solvent) Melting point CO salt 1569 ~ ΈΓΖ • ch3 4-1 white powder (ethyl acetate) 198-202 ~ ~ hydrochloride 1570 -H -CH3 4 white powder (ethyl acetate) 177-180 hydrochloride 1571 -CH(CH3)2 -ch(ch3)2 •CH3 4 white powder (ethyl acetate) 207-212 Hydrochloride 1572 -ch3 捣-CH3 5 white powder (ethyl acetate) 114H16 oxalate 1573 -CH(CH3)2 -CH(CH3)2 -ch3 5 white powder (ethyl acetate / methanol) 211-213 A 1574 -H -ch3 -ch3 5 white powder (ethyl acetate) 58-61 oxalate 1575 -CH(CH3)2 •ch(ch3)2 -C2Hs 2 white powder (ethanol/ethyl acetate) 171- 173 Dihydrochloride 1576 -CH{CH3)2 -CH(CH3)2 -c2h5 3 White powder (ethanol/ethyl acetate) 202-206 - hydrochloride 1577 -H -ch3 -C2H5 4 White powder (ethanol / Ethyl Acetate) 140-143 Dihydrochloride 1578 -CH3 -H 5 White Powder (Ethanol / Acetate) 155-157 Hydrochloride

-240- 200831498 [Table 111]

Example Rt R2 R3 n Form (recrystallization solvent) Melting point (°c) Salt t579 • CH (called 2 light yellow powder (ethyl acetate / isopropyl) Hydrochloride 15» -〇H (CHafe 3 white powder (acetic acid) Ethyl acetate / isopropanol 180-101 rrrftt wrv rr*a hydrochloride 15δ1 -CHtCHsfe -CH (C^ 2 white powder (ethyl acetate / isotonic m.0-207.5 hydrochloride 1582 -CHiCHafe 3 white powder ( Ethyl acetate / t91i)-192L5 salt isopropyl acid) [m 112]

R1. O /~Λ }=(Η2 R3N^)n~NwN-Q Example R1 R2 R3 1583 -CH3 -ch3 -ch3 1584 -CH3 -CH3 -CHa

1585 -CH(CH3)2 -CH(CH^)2 -CH3 n_NMR_ 2 ^H-NMR (DMSO-de) 6ppm: 2J6 (6H, s), 2.82 (3H, s), 3.00-3.70 (12H, m), 6.55 (1H, d, J=7.4 Hz), 7.30 (1H, t J=7.9Hz), 7.47 (1H, dy J=5.5 Hz), 7.68 (1H, d, J=8.0 Hz), 7.75 (1H, d, J=5.5 Hz), 10.9 (1H, br). 3 1H-NMR (DMSO-de) δρρηη: 1.80-2.00 (2H, m), 2.72 (6H, s)t 3.00-aj〇( 12H, m), 6.96 (1H, d, J=7J Hz), 7.30 (1Hft, J=7.9Hz), 7.48 (1H, d, J=5.6Hz), 7.69 (1H,d, J=8.1 Hz) , 7.75 (1H, d, J=5.5 Hz), 10 J (1H, br). 3 1H-NMR (DMSO-de) 5ppm: 1.20 (6H, d, J=6.6 Hz), 1.21 (6H, d, J=6.1 Hz), 1,90-2.00 (2H, m), 2.68 (3Ht s), 2.90^,80 (14H, m), 6.95(1H(d, &gt;7.5Ηζ), 7.30 (1H, t J=7.8 Hz), 7.48 (1Ht d, J=5.6 Hz), 7.69 (1H, d, J=8.1 Hz), 7J5 (1H, d, J=5.5 Hz}, 10.9 (1H,br}· salt&quot ;i5s dihydrochloride dihydrochloride-241 - 200831498 13⁄4 113]

(recrystallization solvent) (°c) 1586 Ο

4 White powder 90-92 (ethyl acetate / isopropyl acid) 4 White powder 202-205 Hydrochloride (ethyl acetate) 4 White powder 212-216 Dihydrochloride (ethyl acetate)

-242- 200831498 m ii4]

Example R1 EJZ crystal form (recrystallization solvent) Melting point (°c) Salt 1590 6^ E White powder (ethanol/ethyl acetate) 92-94 Oxalate 1591 0 〇V E

Crystal form (recrystallization solvent)

White powder (ethanol/acetic acid) 236.5-238.0 salt hydrochloride 1593

White powder (ethanol/diethyl ether) -243- 200831498 Pharmacological test 1 1) Dopamine d2 receptor binding assay This analysis was performed by Kohler et al. (Kohier C, Hall H,

Ogre n SO and Gaweli L? Specific in vitro and in vivo binding of 3 H - rac 1 opride . A potent substituted benzamide drug with high affinity for dopamine D - 2 receptors in the rat brain. B iochem . Pharmacol·, 1 985; 3 4 : 225 1 -225 9 ) proceed.

The W i star male mouse was decapitated, the brain was immediately taken out, and the striatum was removed. Homogenize it in a 50 mM hydroxymethylaminomethane (Tris)-HCl buffer (pH 7.4) using a homogenizer with high-speed rotating blades. Centrifuge at 48,000 xg for 1 minute at 4 °C. The resulting precipitate was again suspended in the above buffer in an amount of 50 times the weight of the tissue, and incubated at 37 ° C for 10 minutes, and then centrifuged under the above conditions. The resulting precipitate was suspended in 25 mM (Tris) hydrochloric acid buffer (containing 120 mM sodium chloride, 5 mM potassium chloride, 2 mM chlorinated chloride, 1 mM magnesium chloride, pH 7.4). In the case, it was stored frozen at -85 ° C until it was used for the binding analysis as a film sample. The combined assay system used 40 microliters of membrane sample, 20 microliters of [3H]-racopride (final concentration 1 to 2 nM), 20 microliters of test drug and 50 mM (Tris)-hydrochloric acid buffer ( It was carried out with 1 20 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium chloride, pH 7.4) so that the total amount was 200 μl (final dimethyl sulfoxide concentration was 丨%). The reaction was further carried out at room temperature for 1 hour, and was terminated by suction filtration (using a cell harvester on a glass fiber -244 - 200831498 filter plate). The filter plate made of glass fiber was washed with 50 mM (Tris)-hydrochloric acid buffer (pH 7.4), and after drying, the micro-disc liquid scintillator was added to measure the radioactivity by a micro-disc liquid scintillation counter. The radioactivity in the presence of 1〇/ζΜ(+)-butaclamol hydrochloride was set to non-specific binding. The ICm値 system was calculated from the concentration-dependent reaction using a nonlinear analysis program. Ki値 uses the Cheng-Prussoff type from IC5. Calculated in 値. The results are shown in the table below.

[Table 116] Polytryptamine D2 Receptor Binding Assay Test Compound Ki (nM) Example 1 Compound 4 2 Example 9 Compound 2 0 Example 1 4 Compound 1 8 Example 1 6 Compound 2 4 Example 4 3 Compound 0 9 Example 4 8 Compound 2 4 Example 4 9 Compound 3 2 Example 104 Compound 2 7 Example 107 Compound 2 4 Example 1 1 6 Compound 1 0 Example 1 1 7 Compound 1 6 Example 1 1 9 Compound 3 2 Example 120 Compound 8 3 Example 154 Compound 5 0 Example 164 Compound 1 2 Example 1421 Compound 1 1 Example 1 435 Compound 12 • 9 Example 1 43 8 Compound 2 1 Example 1 4 5 1 Compound 0 5 Example 1 4 9 8 Compound 0_ .5 Example 1 5 1 7 Compound 0, .8 -245- 200831498 2) Serotonin 5_111'24 Receptor Binding Assay This analysis was performed by Leysen et al. (Leysen JE,

Niemegeers CJE, V an Nueten JM and Ladur on P M. [3 H]

Ketanserin (R 4 1 4 68), a selective 3 H-ligand for serotonin 2 receptor binding sites. Mol. Pharmacol·, 1982, 21: 301-3 14).

The Wistar male mouse was decapitated, the brain was immediately taken out, and the frontal cortex was taken out. Using a Teflon glass homogenizer, it was homogenized in 0.2 5 M sucrose at a weight of 1 〇 and then centrifuged at 1 000 x g for 1 〇 minutes at 4 °C. The resulting supernatant was transferred to another centrifuge tube, suspended in 0.25 M sucrose in an amount of 5 times the weight of the tissue, and the precipitate was centrifuged under the above conditions. The resulting supernatant was then combined with the supernatant obtained above, adjusted to 40-fold tissue weight using 50 mM Tris-HCl buffer (pH 7.4), and centrifuged at 3 5,000 x g for 10 minutes at 4 °C. . The resulting precipitate was again suspended in the above buffer in an amount of 40 times the tissue weight, and then centrifuged under the above conditions. The resulting precipitate was suspended in the above buffer in an amount of 20 times the weight of the tissue, and then frozen at -85 °C until it was used for the binding analysis as a membrane sample. Combining assays using 40 microliters of membrane sample, 20 microliters of [3H]-ketosinin (final concentration 1 to 3 nM), 20 microliters of test drug and 50 mM Tris-HCl buffer (pH 7· 4) Carry out so that the total amount is 200 μl (final dimethyl sulfoxide concentration is 1%). The reaction was further carried out at 37 ° C for 20 minutes and terminated by suction filtration (using a cell harvester on a glass fiber filter plate). -246 - 200831498 The filter plate made of glass fiber was washed with 50 mM Tris-HCl buffer (pH 7.4). After drying, the micro-disc liquid scintillator was added, and the radioactivity was measured by a micro-disc liquid scintillation counter. The radioactivity in the presence of 10 μΜ spiperone was set to non-specific binding. The IC5 oxime system was calculated from the concentration-dependent reaction I in a nonlinear analysis program. Ki値 is calculated from IC5 0値 using cheng-Prussoff. The results are shown in the table below. m 117] serotonin 5-HT2A receptor binding assay test compound Ki (qM) Example 1 Compound 3 0 Example 9 Compound 2 4 Example 1 4 Compound 4 0 Example 1 6 Compound 8 2 Example 43 Compound 6 4 Example 4 8 Compound 6 0 Example 4 9 Compound 1 8 Example 104 Compound 4 1 Example 107 Compound 3 3 Example 1 1 6 Compound 1 3 Example 1 1 7 Compound 1 3 Example 1 1 9 Compound 5 8 Example 120 Compound 4 0 Example 154 Compound 2 3 Example 164 Compound 2 5 Example 1421 Compound 1 8 Example 1 43 5 Compound 2 6 Example 1 43 8 Compound 5 2 Example 1451 Compound 3 1 Example 1 480 Compound 0 • 8 Example 1 5 1 3 Compound 0 • 8 -247 - 200831498

Human recombinant dopamine D2 receptor expressing Chinese hamster ovary/DHFR(-) cells in culture medium (Iscove's modified Duss ((11^6&lt;:〇〇'3) medium (11^014 medium), 10% fetal bovine serum , 50 IU·/ml penicillin, 50 μg/ml streptomycin, 200 μg/ml statin, 〇· 1 m 嘌 嘌 嘌 ,, 16 μ Μ Μ 苷 ), at 3 7 ° C and 5% Cultivate under carbon dioxide conditions. The cells were seeded in a 96-well microtiter plate coated with poly-L-lysine at a dose of 1 4 cells/well, and allowed to grow for 2 days under the same conditions. Each well was washed in 1 〇〇 microliter of medium (IMDM medium, 0.1 mM hypoxanthine, 16 μΜ thymidine). The medium was then replaced with 50 microliters of medium (IMDM medium, 0.1% sodium ascorbate, 0.1 mM hypoxanthine sodium, 16 μΜ thymidine) in which 3 μΜ of the test compound was dissolved. After incubating for 20 minutes at 37 ° C and 5% carbon dioxide, the medium was dissolved in 100 μl of forsk〇lin stimulating medium (IMDM medium) in which 3 μ Μ of the test compound was dissolved. , 0.1% sodium ascorbate, 〇.1 mM hypoxanthine, 16 μΜ thymidine, 10 μΜ forskolin, 500 μΜ 3-isobutyl-1-methylxanthine), then Incubate for 10 minutes at 37 ° C and 5% carbon dioxide. After the medium was removed, 200 μl of Lysis 1B aqueous solution (Amersham Bioscience, reagent attached to the AMP biotrack enzyme immunoassay system) was dispensed and shaken for another 10 minutes. An aqueous solution of each well was used as a sample for measurement. The four-fold diluted sample for measurement was subjected to measurement of the amount of cyclic AMP using the enzyme immunoassay system described above. The inhibition ratio of the individual compounds was calculated again, and the amount of the cyclic AMP which was not added to the pores in the test compound was set to 1% by weight. In the empirical test system of -248-200831498, dopamine, which is used as a control drug, inhibits the activity of cyclic AMP to about 1%, which is the maximum activity. As a result, it was confirmed that the test compound had partial agonistic activity against the dopamine D 2 receptor in the above test.

Since the test compounds have partial agonistic activity on the dopamine D2 receptor, they can stabilize the dopaminergic neurotransmission in patients with schizophrenia; to normal conditions, the results show (for example) positive and negative improvement effects, cognitive impairment improvement effects And other symptom-improving effects without causing side effects. Preparation Example 100 g of the compound of the present invention, 40 g of A Vi cel (trade name, product of Asahi Chemical Industry Co., Ltd.), 30 g of corn starch and 2 g of magnesium stearate Mix and polish, and then use a glucoside (glycocalyx) RIOmm to make tablets. Using a gram of TC-5 (trade name 'product of Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose)' 3 g of polyethylene glycol 6000, 40 g of castor oil and an appropriate amount of ethanol The film was coated on the obtained tablet to prepare a film-coated tablet having the above-mentioned components. -249-

Claims (1)

200831498 X. Patent application scope 1. A heterocyclic compound represented by the formula (η) or a salt thereof: [wherein Q represents a group represented by the following formula (I): Z R12 R11—C—N—A1 (wherein A1 represents lower alkylene; Z represents Ο or S; R1 1 shows (1-1) hydrogen, (1-2) lower alkyl, (1-3) An aryl group derived from phenyl, naphthyl, and indanyl, wherein the aryl group may be substituted with at least one group selected from the group consisting of the following substituents (i) to (xxxiii): z (1) lower alkane (ϋ) Alkene (iii) via halogen (iv) lower grade (v) via halogen (vi) nitro 5 (vii) cyano group 5, group, substituted lower alkyl, oxy, substituted lower alkoxy, -250 - 200831498 (viii) Halogen, (ix) aryl, (x) aryloxy, (xi) lower alkoxycarbonyl, (xii), (xiii) protected hydroxy, (xiv) lower alkyl fluorenyl , (xv) amidoxime, (xvi) lower-grade thiol, (X vii) lower fluorenylsulfonyl, (xviii) hydroxysulfonyl, (xix) may have an amine group selected from the group consisting of: Alkyl, lower alkyl fluorenyl, cyclo(C 3-C 8)alkyl, aryl, and aryl fluorenyl, (XX) morphinyl fluorenyl lower alkenyl, (xxi) morpholinyl fluorenyl lower fluorenyl , (xxii) pyrrolyl (xxiii) pyrazolyl, (xxiv) imidazolyl j (XXV) oxazolyl (xx vi) pyridinyl d (jvii) pyrrolidinyl (xxviii) morpholine capable of having a keto group Base r (xxix) thiomorpholinyl 5 (XXX) lower alkynyl-251 - 200831498 (xxxi) ring (C3-C8) alkyl, (xxxii) fluorenyl, and (xxxiii) may have one selected from keto groups and a dihydropyrazolyl group of a lower alkyl group, (1-4) a heterocyclic group, wherein the heterocyclic group may be substituted with at least one group selected from the group consisting of the following substituents (i) to (xix): (1) lower alkyl group, (fluorene) lower alkyl group substituted by halogen And (iii) a lower alkoxy group, (iv) a halogen-substituted lower alkoxy group, (v) a halogen, (vi) having a group selected from a halogen and a halogen-substituted lower alkyl group on the aryl group. An aryl group, (vii) an aryl lower alkyl group which may have a halogen atom, (viii) a lower alkyl fluorenyl group, (ix) an aryl fluorenyl group, (χ) an amine group lower stage which may have a lower alkyl fluorenyl group on the amine group Stuffed base ' (xi) lower alkylthio, (xii) pyrrolyl, (xiii) keto, 200831498 (xvii) pyranyl, (xviii) thienyl, and (xix) furanyl, (1-5) The amine group and/or the lower alkyl group may have an amine group lower alkyl group, a lower alkyl group, a lower alkyl alkene group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, and an amine methyl sulfonate group having a group selected from the group consisting of An alkyl group, a mercaptocarbonyl group, an aryl group (the aryl group may have a group selected from a halogen and a lower alkoxy group), and an aryl lower alkoxycarbonyl group, (1 - 6 ) Lower-grade alkoxy lower-grade '(1-7) arylsulfonyl lower alkyl, (1-8) may have an aryl group lower than the following group on the aryl group. An alkyl group, a lower alkoxy group, a hydroxyl group, a halogen, and a nitro group, (1-9) may have an aryloxy lower alkyl group selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a halogen group. And cyano, (1-10) adamantyl lower alkyl, (1-11) An aryl lower alkenyl group which may be selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkyl group, a halogen-substituted lower alkoxy group, and the like. An amine group having a lower alkyl group, a halogen, and a nitro group, (1-12) may have a ring (C3-C8) alkyl group selected from the group consisting of an amine group which may have a lower alkyl group and may have a lower alkyl group. An amino-based lower alkyl group, and an aryl group which may have a group selected from a halogen and a lower alkyl group, (1-13) a ring (C3-C8) alkyl lower alkyl group, (1-14) an arylthio group Affiliation, -253 - 200831498 (1-15) Lower alkyl substituted by a heterocyclic group selected from the group consisting of piperidinyl, tetrahydropyranyl, pyridyl, thienyl, imidazolyl, tetrazolyl, benzo Imidazolyl, isodecyl, thiazolidinyl, and fluorenyl (wherein the heterocyclic group may have a group selected from the group consisting of lower alkyl, lower alkoxy, halogen, keto, and thioketo) (1) -16) aryl lower alkenyl group which may have an aryl group (1-17) on a lower alkenyl group, a lower alkenyl group substituted with a heterocyclic group as follows: benzodioxole , pyridyl, furyl, and imidazolyl, (1-18) benzodioxolyl lower alkyl, (1-19) pyridylthio lower alkyl, or (1-20) R12 An amine group which may have a lower alkyl group; and (2-1) hydrogen, (2-2) lower alkyl group, (2-3) lower alkyl group substituted by halogen, (2-4) lower alkenyl group, ( 2-5) lower alkynyl group, (2-6) lower grade broth base '(2-7) hydroxy lower alkyl group, (2-8) lower alkoxy lower alkyl group, (2-9) ring (C3- C8) alkyl, (2-10) cyclo(C3-C8)alkyl lower alkyl, (2-11) aryl, -254- 200831498 (2-12) may have a group selected from the group consisting of the following groups An aryl lower alkyl group: an amine group which may have a lower alkyl group, and an aryloxy group, (2-13) tetrahydrofuranyl group, (2 = 14) a lower alkyl group substituted with a heterocyclic group selected from the group consisting of a furyl group And pyridyl, (2-15) Tetrahydropyranyl, or (2-16) lower alkyl alkoxy lower alkyl), or Q is not a group represented by the following formula (II): R21-A2-(wherein - A2- is a lower alkylene group, a lower alkylene group, or a group. A22-, wherein A21 and A22 are the same or different, and each exhibits a C1-C5 alkylene group (except for the composition of A21 and a22 alkyl) The total number of carbon atoms does not exceed 6); and r21 represents an N-containing heterocyclic group, wherein the N-containing heterocyclic ring represented by R may be substituted with at least one group selected from the following (1) to (13): (1) Halogen substituted or unsubstituted lower alkyl, (2) lower alkenyl, (3) lower alkoxy, (4) hydroxy, (5) protected hydroxy, (6) aryl, (7) lower alkane醯基, -255- 200831498 (8) Carboxy ' (9) lower-grade oxyalkylene group, (1 0) amine-methyl fluorenyl group having lower alkyl group, (1 1 ) aryl lower alkyl group (which is in aromatic The group may have a lower alkoxy group (1 2 ) ketone group, and (1 3) a thioketone group). 2. A heterocyclic compound or a salt thereof according to the first aspect of the invention, wherein Q is a group represented by the following formula (1): Z R12 r11-q--A1- (wherein A1 represents a lower alkyl group; 0 or S: , R11 represents (1-1) hydrogen, (1-2) lower alkyl, (1-3 a) an aryl group selected from the group consisting of phenyl, naphthyl, and indanyl, the aryl group It may be selected from the following substituents (i) to (viii), (ix w Vx a), (xii), (xiii a), (xi v) to (x viii), (xix a), to (Χχ · (xxviia), and (xxviii) to (xxxiii) one to three groups substituted. (i) lower-grade base, (ii) lower-grade base, (iii) halogen-substituted lower alkyl, -256- 200831498 (iv) lower alkoxy, (v) halogen-substituted lower alkoxy, (Vi) nitro, (vii) amino 9 (viii) halogen, (ix a) phenyl, (xa) phenoxy, (xi) lower alkoxycarbonyl, (xii) hydroxy, (xiiia) lower alkyl alkoxy or phenyl lower alkoxy having one to one halogen on the phenyl group, (xiv) lower alkyl fluorenyl, (XV) Aminesulfonyl, (xvi) lower alkylthio, (xvii) lower alkylsulfonyl, (xviii) hydroxysulfonyl, (xix a) may have a lower amine group selected from one to two of the following groups Alkyl, lower alkylalkyl, cyclo(C3-C8)alkyl, phenyl, and benzamidine, (XX) morpholinyl montene-based lower alkenyl, (xxi) Alkyl, (xxii) pyrrolyl, (xxiii) pyrazolyl, (xxiv) imidazolyl 5-257 200831498 (XXV) triterpene, (xxvi) deuterium D, (xxvii a) may have one to two ketones Base of the base, (xxviii) morpholinyl, (XXix) thiomorpholinyl, (XXX) lower alkynyl, (xxxi) ring (C3-C8) alkyl, (xxxii) fluorenyl, and (xxxiii) a dihydropyrazolyl group having a keto group and a lower substituent, (1-4a) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, Thiazolidinyl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, dihydroportazolyl, pyridyl, dihydropyridyl, tetrahydropyrimidinyl, pyrazinyl, thiazolyl, oxazolyl , isoxazolyl, thienyl, furyl, fluorenyl, oxalinyl, isoindolyl, benzimidazolyl, imidazopyridyl, quinolyl, dihydroquinolinyl, tetrahydroquin Polinyl, isoquinolyl, porphyrinyl, oxazolyl, quinoxalinyl, benzotriazolyl, dihydronaphthyridinyl, benzothiazolyl, dihydrobenzothiazolyl, dihydrobenzo Thiazinyl, thienopyrazinyl, benzoxoxazolyl, dihydrobenzospirobenyl, dihydrobenzoximeoxy, furanoindole, benzodioxole a dihydrobenzodioxanyl group, and a benzothienyl group, wherein the heterocyclic group may be selected from the group consisting of the following substituents (1) to (v), (vi a), (vii a), (viii) Substituting one to three groups of (ix a), (X a), and (xi) to (xix): (i) lower sulfhydryl ' -258- 200831498 (ϋ) lower alkyl substituted by halogen , (iii) lower alkoxy, · (iv) Halogen-substituted lower alkoxy (V) Halogen 5 (vi a) may have a phenyl group selected from one or three of the following groups on the phenyl group: a halogen and a halogen-substituted lower alkyl group, (vii a) a phenyl lower alkyl group having one to three halogens, (viii) a lower alkyl fluorenyl group, (ix a) benzhydryl group, (X a) an amine lower alkyl alkano group having one to two lower alkyl fluorenyl groups on the amine group, (xi) a lower alkylthio group, (xii) pyrrolyl, (xiii) keto, (xiv) thioketo, (xv) Aminomethyl, (xv i), (xvii) fluorenyl, (xviii) thiophenyl, and (xix) methoxy, (1-5 a) in amine and/or lower The alkyl group may have one to two amine-based lower alkyl groups selected from the group consisting of lower alkyl, lower alkyl sulfonyl, hydroxy lower alkyl, lower alkoxycarbonyl, amine mercapto lower alkyl, hydrazine a carbonyl group, a phenyl group (the phenyl group may have one selected from the group consisting of halogen and lower alkoxy groups -259 to 200831498 to three groups), and a phenyl lower alkoxycarbonyl group, (1-6) lower alkoxy group Lower alkyl, (1-7 a) benzhydryl lower alkyl, (1-8 a) may have a phenyl lower alkyl group selected from one to three groups below the lower alkyl group: lower alkyl, lower Alkoxy, hydroxy, halogen, and nitro, (1-9 a) A phenoxy lower alkyl group having at least one group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen group, and a cyano (1-10) adamantyl group on the phenyl group. The lower alkyl group, (1-11 a) may have a phenyl lower alkenyl group selected from the group consisting of one to three groups on the phenyl group: a lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkyl group, and a halogen-substituted one. a lower alkoxy group, an amine group having one to two lower alkyl groups, a halogen, and a nitro group, (1-12 a) may have a ring (C3-C8) alkyl group selected from one to two groups as follows: An amine group having one to two lower alkyl groups, an amine group lower alkyl group having one to two lower alkyl groups, and a phenyl group which may have one selected from the group consisting of halogen and lower alkyl groups to three groups, (1-13) a cyclic (C3-C8)alkyl lower alkyl group, (1-14 a) phenylthio lower alkyl group, (1 -1 5 a) is a lower alkyl group substituted with a heterocyclic group selected from the group consisting of piperidinyl, Tetrahydropyranyl, pyridyl, thienyl, imidazolyl, tetrazolyl, benzimidazolyl, isodecyl, thiazolidinyl, and fluorenyl, wherein the heterocyclic group may have a One to three groups: lower alkyl, lower alkoxy-260 - 200831498, halogen, keto, and thioketo, (1-16 a) phenyl lower alkenyl, which may have one to two in the lower alkenyl group a phenyl group, (1 = 17) a lower alkenyl group substituted with a heterocyclic group selected from the group consisting of benzodioxolyl, pyridyl, furyl, and imidazolyl, (1-18) benzo An iso-dioxolyl lower alkyl group, (1-19) pyridylthio-based lower alkyl, or (1-20 a) an amine group which may have one to two lower alkyl groups; and (2-1) hydrogen, (2 - 2 ) lower-grade phenyl group (2-3) lower alkyl group substituted by halogen, (2 -4) lower alkenyl, (2-5) lower alkynyl, (2-6) lower alkyl fluorenyl, (2-7) hydroxy lower alkyl, (2-8) lower alkoxy lower alkyl, ( 2-9) Cyclo(C3-C8)alkyl, (2-10) cyclo(C3-C8)alkyl lower alkyl, (2-1 1 a)phenyl, (2-12 a) on phenyl A phenyl lower alkyl group having one to three groups selected from the group consisting of an amine group having one to two lower alkyl groups and a phenoxy (2-13) tetrahydrofuranyl group, -261 - 200831498 (2-14) a heterocyclic group selected from a furyl group and a pyridyl group, # &amp; {alkylalkyl, (2-15) tetrahydropyranyl, or (2-16) lower alkyl alkoxy lower alkyl), or Q A group represented by the following formula (Π): R21-Α2- (wherein -Α2- is a lower alkylene group, a lower alkylene group, or a group -Α2ι_〇_ A22·, wherein A21 and A22 are the same or different, and each represents a C1-C5 alkyl group (only composition A1) The alkyl group and the alkyl group of the A2 alkyl group have a total number of carbon atoms not exceeding 6); and R2 1 is selected from the group consisting of the following N-containing heterocyclic group: pyrrolidinyl group, imidazolidinyl group, piperidinyl group, hexahydropyrimidine D group, and piperazine. Azinyl, octahydroisoindole, azepanyl, azocanyl, azaphthyl, azaspiro, diazaspyl, dihydropyrrolyl, Imidazolyl, dihydro Φ imidazolyl, triazolyl, dihydrotriazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, anthracene Azinyl, tetrazolyl, fluorenyl, isodecyl, porphyrin, isoindolyl, hexahydroisodecyl, octahydroisodecyl, benzimidazolyl, quinolyl, Isoquinolyl, oxazolyl, quinazolinyl, dihydroquinazolinyl, benzotriazolyl, oxazolyl, spiropentane porphyrin, oxazolyl, isoxazolyl, oxadi Azolyl, oxazolidinyl, heterosexual Alkyl, oxazinanyl, morpholinyl, benzoxazolyl, dihydrobenzoxazolyl, benzoxazinyl, dihydrobenzoxazinyl, benzoxazolyl, benzene And oxadiazolyl, thiazolyl, -262-200831498 monohydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinyl, benzothiazolyl, and benzothiadiazolyl, Wherein the N-containing heterocyclic ring which R21 does not have may be selected from the group consisting of (1) to (4), (5 a), (6 a), (7) to (9), (1〇a), (1) a), Substituting one of the 12) and (13) to three groups: (1) a halogen-substituted or unsubstituted lower alkyl group, (2) a lower alkenyl group, (3) lower alkoxy, (4) hydroxy, (5 a) lower alkoxy or phenyl lower alkoxy, (6 a) phenyl, (7) lower alkyl fluorenyl, (8) carboxy, (9) a lower-grade oxyalkylene group, (10 a) an amine carbenyl group having one to two lower alkyl groups, (11 a) a phenyl lower alkyl group (which may have one to two lower alkyl groups on the phenyl group) Oxy), (12) keto, and (13) thioketo). 3. A heterocyclic compound or a salt thereof according to claim 2, wherein Q is a group represented by the following formula (I): z R12 R"-I--N-A1- wherein A 1 represents a low-level extension Ordinary; -263- 200831498 Z Ο or S; R11 shows (1 -1) hydrogen, (1-2) lower alkyl, (1 - 3 aa) phenyl which may have one to two halogen atoms, (l -4aa) a heterocyclic group selected from pyrazinyl and thienyl (wherein the heterocyclic group may be substituted by a lower alkyl group), (l-5aa) An amine-based lower alkyl group having one or two groups selected from the group consisting of a lower alkyl group, a lower alkyl sulfonyl group, a lower hydroxy group lower alkyl group, and a lower alkoxy group on the amine group and/or the lower alkyl group. a carbonyl group, an amine carbaryl lower alkyl group, a fluorenyl carbonyl group, a phenyl group (the phenyl group may have a group selected from a halogen and a lower alkoxy group), and a phenyl lower alkoxycarbonyl group, or (l -20a) an amine group having one to two lower alkyl groups; and R12 (2-1) hydrogen, (2-4) lower alkenyl, (2-6) lower alkyl fluorenyl, (2-7) hydroxy lower alkyl, (2-8) lower alkoxy lower alkyl, or (2-9) ring ( C3-C8) alkyl. 4. The heterocyclic compound or a salt thereof according to item 2 of the patent application, wherein Q is a group represented by the following formula (II): R21-A2--264-200831498 (wherein -A2·lower lower alkylene Or an alkenyl group; and R2 1 is an N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidinyl, azepanyl, oxazolidinyl, and oxazine. An ox azinanyi wherein the N-containing heterocyclic ring represented by R21 may be substituted with one or three groups selected from one of the following (1), (12) and (13): (1) a halogen-substituted or unsubstituted alkane base, (12) a ketone group, and (13) a thioketone group). 5. A heterocyclic compound of the formula (1) of claim 3, which is selected from the group consisting of: N-[ 5-(4-benzo[b]thiophen-4-yl-piperazine-yl)·penta Benzalamine, N-[5-(4-benzo[b]thiophen-4-yl-piperazine-y-ylpentyl]_2,4-difluoro-benzamide, N-[4 -(4-Benzo[b]thiophen-4-ylpiperazinylbutyl b-N-cyclopropyl-B 5-methyl-pyrazine-2-carboxylic acid [4-(4benzo[b]thiophenan-4yl-piperazin-1-yl)-butyl]-ethyl decylamine, thiazole-4- Carboxylic acid [4-(4-benzo[b]thiophene-4-ylpiperazin-4-ylbutyl]-ethyl-decylamine, Ν-[4·(4-benzo[b]thiophene-4- Benzyl-piperazin-1-yl)-butyl]-ethyl-acetamide, N-[4-(4-benzo[b]thiophen-4-yl-piperazine _;!•)) Keb N-isopropyl-acetamide, -265- 200831498 N-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-N-B -thioethylamine, N-allyl-N-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-acetamide 5 and N- [4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-N-tert-butyl-formamide. 6. A heterocyclic compound of the formula (1) according to claim 4, which is selected from the group consisting of: 1-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)- Amyl]-imidazolidine-2-one 1-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-pentyl]-3-methyl-imidazolidine-2 -keto, 1-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-pentyl]-pyrrolidin-2-one 1-[5-(4-benzo [b]Thiophen-4-yl-piperazin-1-yl)-pentyl]-pyrrolidine-2,5- [4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-azapan-2-one, 3-[6-(4- Benzo[b]thiophen-4-yl-piperazin-1-yl)-hexyl]-oxazolidin-2-one 3-[4-(4-benzo[13]thiophen-4-yl-piperazine -1-yl)-butyl]-4,4-dimethyl-oxazolidin-2-one, 3-[4-(4-benzo[b]thiophen-4-yl-piperazin-1- ))-butyl]-4-methyl-oxazolidin-2-one, -266- 200831498 3-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl) _ Butyl]-oxazolidin-2-one&gt; 1 - [4-(4-Benzo[b]thiophen-4-yl-piperazinyl)-butylpyrrolidine-2«one 1-[ 4-(4-benzo[b]-phen-4-yl-indole-1-yl)-butyl]- mai g-butan-2-one, 1-[(Ε)-4-(4-benzene And [b]thiophen-4-yl-piperazin-1-ylbutan-2-alkenyl]-3-methyl-imidazolidine-2-one, 1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butyl]-piperidin-2-thione, and 3-[4-(4-benzophenone [b]Thiophen-4-yl-piperazin-1-yl)-butyl]_4_methyl-oxan-2-one. A pharmaceutically acceptable composition comprising the heterocyclic compound of the formula (1) or a salt thereof according to any one of claims 1 to 6 as an active ingredient and a pharmaceutically acceptable carrier. 8. A pharmaceutical composition according to claim 7 for use in the treatment or prevention of a central nervous system disorder. 9. A pharmaceutical composition according to claim 8 which is for use in the treatment or prevention of a central nervous system disorder selected from the group consisting of schizophrenia; persistent, refractory or chronic schizophrenia; emotional disorders; Sexually transmitted disease; affective disorder; type I depression; type II depression; depression; endogenous depression; major depression; depression and obsessive depression: mood disorders; circulatory affective disorder; Attack; panic disorder; square phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatic symptoms; turn-267- 200831498 Condition; painful condition; suspected condition; fabricated condition; schizophrenic condition; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia; satiation; sleep disorder; adaptation disorder; alcohol abuse; Drug addiction; stimulant poisoning; anesthetic poisoning; lack of pleasure; lack of physician's original pleasure; lack of pleasure of mental or psychological reasons; lack of pleasure associated with depression; lack of pleasure associated with schizophrenia; insanity; Damage; cognitive impairment associated with Alzheimer's disease; Parkinson's disease and other neurodegenerative disorders; cognitive impairment due to Alzheimer's disease, Parkinson's disease and related neurodegenerative disorders; schizophrenia Cognitive impairment; cognitive impairment due to obsessive, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental disorder; autism; torren's disease; convulsions; Lack of power/hyperactivity; behavioral disorders; and Down's syndrome. A method of preparing a pharmaceutical composition, which comprises mixing a heterocyclic compound of the formula (1) or a salt thereof according to any one of claims 1 to 6 with a pharmaceutically acceptable carrier. A use of the heterocyclic compound of the formula (1) or a salt thereof according to any one of claims 1 to 6 as a medicament. 12. Use of a heterocyclic compound or a salt thereof according to any one of claims 1 to 6 of the patent application, as a partial agonist of dopamine D2 receptor and/or a serotonin 5-HT2A receptor Antagonists and/or adrenergic alpha 1 receptor antagonists and/or serotonin absorption inhibitors and/or serotonin reuptake inhibitors. 1 3 · A method for treating or preventing central nervous system disorders, the package thereof -268- 200831498 A heterocyclic compound of the formula (1) or a salt thereof according to any one of claims 1 to 6 is administered to a human or an animal. Mm -269- 200831498 无···················———————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Please reveal the chemical formula that best shows the characteristics of the invention: Equation 1 -4-