TW201225955A

TW201225955A - Glycine transporter inhibitory substance

Info

Publication number: TW201225955A
Application number: TW100133464A
Authority: TW
Inventors: Shuji Yamamoto; Hiroshi Ohta; Akito Yasuhara; Hiroki Urabe; Kumi Abe; Minoru Moriya; Kazunari Sakagami; Masato Hayashi; Yoshihisa Shirasaki
Original assignee: Taisho Pharmaceutical Co Ltd
Priority date: 2010-09-16
Filing date: 2011-09-16
Publication date: 2012-07-01
Also published as: WO2012036268A1; JP2013249257A

Abstract

Disclosed is a novel compound, and pharmaceutically acceptable salts thereof, useful in the treatment or prevention of diseases caused by inhibitory activity on glycine intake, such as schizophrenia, Alzheimer's disease, cognitive impairment, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post traumatic stress disorder, specific phobias, acute stress disorder etc.), depression, substance abuse, convulsions, tremors, pain, or sleep disorders. Disclosed are the compound represented by formula [I], and pharmaceutically acceptable salts thereof.

Description

201225955 六、發明說明：【發明所屬之技術領域】本發明係關於具有甘胺酸運輸體阻礙作用的化合物。 I 【先前技術】 '麩胺酸受體之一的NMDA受體存在於腦內神經細胞膜上，與神經的可塑性、認知、注意、記憶等種種神經生理學上的現象有關。於NMD A受體存在著複數異構性結合部位，甘胺酸結合部位亦爲其中一個（NMDA受體複合體甘胺酸結合部位）。NMDA受體複合體甘胺酸結合部位與 NMDA受體的活性化有關已被報告（非專利文獻1 )。甘胺酸活動性神經的突觸前末端上活動電位到達時，開始對突觸間隙釋出甘胺酸。釋出的甘胺酸與突觸後部的受體等結合後，藉由轉運子由突觸間隙去除。藉此甘胺酸的轉運子藉由調節在細胞外液的甘胺酸量，可能可調節 NMDA受體之功能。甘胺酸運輸體（GlyT)係爲與細胞外甘胺酸對細胞內之再吸收有關的蛋白質，至今已知存在GlyTl及GlyT2的兩種亞型。GlyT 1主要發現於大腦皮質、海馬及丘腦等，與精神分裂症、阿茲海默病、認知功能障礙、失智症、焦慮障礙（全般性焦慮障礙、恐慌障礙、強迫性障礙、社會焦慮障礙' 創傷後壓力心理障礙、特定恐懼症、急性壓力障礙等）、憂鬱症、藥物依存、痙攣、手震、疼痛、及睡眠障礙等疾病有關連已被報告（非專利文獻2〜4)。 -5- 201225955 具有GlyTl阻礙作用，且具有5員環雜芳基醯胺結構之化合物已揭示於以下文獻（專利文獻1〜3、非專利文獻 5 〜6 )。〔先行技術文獻〕〔專利文獻〕〔專利文獻 1〕W02005/037216 〔專利文獻 2〕W02006/1 06425 〔專利文獻 3〕W02008/065500 〔非專利文獻〕〔非專利文獻 1〕Molecular Psychiatry ( 2004) 9, 984-997 〔非專利文獻 2〕 Current Medicinal Chemistry, 2006, 13， 1017-1044 〔非專利文獻 3〕 Neuropsychopharmacology ( 2005 ) ，1-23 〔非專利文獻 4〕 Expert Opinion on Therapeutic Patents ( 2004 ) 1 4 ( 2 ) 201-214 〔非專利文獻 5〕Bioorganic & Medicinal Chemistry Letters ( 2009 ) 1 9 2974-2976 〔非專利文獻 6〕Bioorganic & Medicinal Chemistry Letters ( 201 0 ) 20 907-91 1 【發明內容】發明所要解決的課題201225955 VI. Description of the Invention: [Technical Field to Which the Invention Is Ascribed] The present invention relates to a compound having a hindrance effect of a glycine transporter. I [Prior Art] The NMDA receptor, one of the glutamate receptors, is present on the nerve cell membrane of the brain and is involved in various neurophysiological phenomena such as nerve plasticity, cognition, attention, and memory. There is a complex isomer binding site at the NMD A receptor, and the glycine acid binding site is also one of them (the NMDA receptor complex glycine binding site). The NMDA receptor complex glycine-binding site has been reported to be involved in the activation of the NMDA receptor (Non-Patent Document 1). When the activity potential on the presynaptic end of the glycine active nerve arrives, glycine is released from the synaptic cleft. The released glycine is bound to the receptor at the posterior synapse and the like, and is removed by the transporter from the synaptic cleft. Thereby, the glycine transporter may regulate the function of the NMDA receptor by regulating the amount of glycine in the extracellular fluid. The glycine transporter (GlyT) is a protein involved in intracellular resorption of extracellular glycine, and two subtypes of GlyTl and GlyT2 are known to date. GlyT 1 is mainly found in the cerebral cortex, hippocampus and thalamus, and schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (all-ordinary anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder). Related diseases such as post-traumatic stress disorder, specific phobia, acute stress disorder, and depression, drug dependence, convulsions, hand shocks, pain, and sleep disorders have been reported (Non-Patent Documents 2 to 4). -5-201225955 A compound having a GlyTl inhibitory action and having a 5-membered ring heteroarylamine structure is disclosed in the following documents (Patent Documents 1 to 3, Non-Patent Documents 5 to 6). [Prior Art Document] [Patent Document] [Patent Document 1] WO2005/037216 [Patent Document 2] W02006/1 06425 [Patent Document 3] W02008/065500 [Non-Patent Document] [Non-Patent Document 1] Molecular Psychiatry (2004) 9, 984-997 [Non-Patent Document 2] Current Medicinal Chemistry, 2006, 13, 1017-1044 [Non-Patent Document 3] Neuropsychopharmacology (2005), 1-23 [Non-Patent Document 4] Expert Opinion on Therapeutic Patents (2004) 1 4 ( 2 ) 201-214 [Non-Patent Document 5] Bioorganic & Medicinal Chemistry Letters (2009) 1 9 2974-2976 [Non-Patent Document 6] Bioorganic & Medicinal Chemistry Letters (201 0 ) 20 907-91 1 SUMMARY OF THE INVENTION Problems to be solved by the invention

S -6- 201225955 本發明係以提供以甘胺酸吸收阻礙作用爲準的精神分裂症、阿茲海默病、認知功能障礙、失智症、焦慮障礙（全般性焦慮障礙、恐慌障礙、強迫性障礙、社會焦慮障礙、創傷後壓力心理障礙、特定恐懼症、急性壓力障礙等）、憂鬱症、藥物依存、痙攣、手震、疼痛、或睡眠障礙等疾病的預防或治療爲有用之新穎化合物或其醫藥上可被許可的鹽爲目的。解決發明的手段本發明者們對於對GlyTl具有阻礙作用之新穎骨架的化合物進行詳細檢討結果，發現下述所示式表示的化合物爲優良GlyTl阻礙物質，進而完成本發明。以下詳細說明本發明。本發明的型態（以下稱爲「本發明化合物」）如以下所示者。 (1 )式〔I〕式〔I〕【化1】S -6- 201225955 The present invention provides schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder, panic disorder, forcing) which is based on the inhibition of glycine absorption Novel compounds that are useful for the prevention or treatment of diseases such as sexual disorders, social anxiety disorders, post-traumatic stress disorder, specific phobias, acute stress disorders, etc., depression, drug dependence, convulsions, hand shocks, pain, or sleep disorders Or a pharmaceutically acceptable salt for the purpose. MEANS FOR SOLVING THE INVENTION The inventors of the present invention conducted a detailed review of a compound having a novel skeleton which inhibits GlyTl, and found that the compound represented by the following formula is an excellent GlyTl inhibitor, and completed the present invention. The invention is described in detail below. The form of the present invention (hereinafter referred to as "the compound of the present invention") is as follows. (1) Formula [I] Formula [I] [Chemical 1]

(式中， R1表不氫原子或Cl.6院基， R2表示 a)可由選自由1〜5個鹵素原子所取代之苯基、Ci—6烷氧 201225955 基、鹵素原子、及C3.6環烷基所成群的1〜3個取代基所取代的烷基，或 b ) C3-6環烷基， Y表示氮原子或式CH，(wherein R1 represents a hydrogen atom or a Cl.6 group, and R2 represents a) may be selected from a phenyl group substituted with 1 to 5 halogen atoms, a Ci-6 alkoxy 201225955 group, a halogen atom, and C3.6. An alkyl group substituted with 1 to 3 substituents of a group of cycloalkyl groups, or b) a C3-6 cycloalkyl group, and Y represents a nitrogen atom or a formula CH,

Ar1表示選自以下式群〔Π〕的結構，【化2】 RbAr1 represents a structure selected from the group of the following formulas, [Chemical 2] Rb

113表不Cl-6院基、_化Cl-6院基、Ci.6院氧基、可由H比略院基所取代之鹵化Cl·6院氧基、氟原子、氯原子，或可由鹵化c!_6烷氧基所取代之苯氧基，。表示鹵素原子，113 indicates that the Cl-6-based, _-Cl-6-based, Ci.6-yard oxy, halogenated Cl.6-group oxy, fluorine atom, chlorine atom, or halogenated by H. The phenoxy group substituted by c!_6 alkoxy group. Represents a halogen atom,

Rb、RC、Rd、Re、Rg、Rh、及Ri表示相同或相異的氫原子，或鹵素原子）所示化合物或其醫藥上可被許可的鹽。 (2) R2表示 a) Cu烷氧基、及可由選自1〜5個鹵素原子所取代之苯基所成群的1〜3個取代基所取代之（^-6烷基，或 b ) C3-6環院基，Rb, RC, Rd, Re, Rg, Rh, and Ri represent the same or different hydrogen atom or a halogen atom) or a pharmaceutically acceptable salt thereof. (2) R2 represents a) alkoxy group, and 1 to 3 substituents which may be grouped by a phenyl group selected from 1 to 5 halogen atoms (^-6 alkyl group, or b) C3-6 ring yard base,

Ar1爲選自式群〔II〕的結構，Ar1 is a structure selected from the group [II].

Ra爲鹵化q.6烷基、可由吡咯烷基所取代之鹵化（：，_6燒氧基，或可由鹵化C^6烷氧基所取代之苯氧基，Ra is a halogenated q.6 alkyl group, a halogenated group which may be substituted by a pyrrolidinyl group, or a phenoxy group which may be substituted by a halogenated C1-6 alkoxy group,

Rf爲鹵素原子，Rf is a halogen atom,

Re ' Rd、及Rg爲相同或相異的氫原子或鹵素原子，Re ' Rd, and Rg are the same or different hydrogen or halogen atoms,

Rb、Re、Rh、及t爲氫原子之（1 )所記載的化合物或其 201225955 醫藥上可被許可的鹽。 (3) R1爲Ct.6烷基的（1)或（2)所記載的化合物或其醫藥上可被許可的鹽。 (4) R2爲可由】〜3個Cl_6烷氧基所取代的Ci6烷基，或C3_6環烷基之（1 )〜（3 )中任1所記載的化合物或其醫藥上可被許可的鹽。 (5) R2爲分支鏈狀的Cm烷基，或（：3-6環烷基之（1) 〜（3)中任1所記載的化合物或其醫藥上可被許可的鹽〇 (6 ) Y爲式C Η的（1 )〜（5 )中任1所記載之化合物或其醫藥上可被許可的鹽。 (7 ) Ar 1 爲式〔III〕【化3】 RbThe compound described in (1), wherein Rb, Re, Rh, and t are a hydrogen atom, or a pharmaceutically acceptable salt thereof in 201225955. (3) The compound of (1) or (2) wherein R1 is a Ct.6 alkyl group or a pharmaceutically acceptable salt thereof. (4) R2 is a compound of any one of (1) to (3) or a pharmaceutically acceptable salt thereof, which is a Ci6 alkyl group which may be substituted with ～3 of a Cl_6 alkoxy group, or a C3_6 cycloalkyl group. . (5) R2 is a branched Cm alkyl group, or a compound of any one of (1) to (3) of (3-6 cycloalkyl group) or a pharmaceutically acceptable salt thereof (6) Y is a compound of any one of (1) to (5), or a pharmaceutically acceptable salt thereof. (7) Ar 1 is a formula [III] [Chemical 3] Rb

I till]I till]

P 所示基，Base shown by P,

Ra爲鹵化C,.6烷氧基， RC：、及Rd爲相同或相異的氫原子或鹵素原子， R、及Re爲氫原子之（1)〜（6)中任1項所記載的化合物或其醫藥上可被許可的鹽。 (8 )含有上述（1 )〜（7 )中任1所記載的化合物或其醫藥上可被許可的鹽作爲有效成分的醫藥。 (9 )含有上述（1)〜（7 )中任1所記載的化合物或其醫藥上可被許可的鹽作爲有效成分的精神分裂症、阿茲海 201225955 默病、認知功能障礙、失智症、焦慮障礙、憂鬱症、藥物依存、痙攣、手震、疼痛或睡眠障礙的疾病之預防劑或治療劑。〔發明的效果〕本發明化合物具有甘胺酸運輸體（GlyTl )阻礙活性。又，本發明化合物如以下試驗例所示顯示高膜透過性，故期待具有優良的對於經口投與的醫藥而言爲重要的腸管吸收。且本發明化合物如以下試驗例所示，因被辨識爲控制藥物腦移行性之排出轉運子的Ρ-糖蛋白質之基質，期待其良好腦移行性。實施發明的型態本說明書中所使用的「Cx_y (X、及y表示自然數）」表示碳原子的數目爲X個至y個。本說明書中所使用的「CL6烷基」表示直鏈狀或分支鏈狀之碳數1〜6個的烷基之意思，例如可舉出甲基、乙基、丙基、異丙基、丁基、異丁基'第三丁基、戊基、異戊基、己基。本說明書中所使用的「c3.6環烷基」表示碳數3〜6 個之環烷基的意思，爲環丙基、環丁基、環戊基、環己基本說明書中所使用的「（^-6烷氧基」表示直鏈狀或分支鏈狀的碳數1〜6個之烷氧基的意思，例如可舉出甲氧 -10- 3 201225955 基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、戊氧基、異戊氧基、己氧基。本說明書中所使用的「鹵素原子」爲氟原子、氯原子、*溴原子、确原子。本說明書中所使用的「鹵化（^-6烷基」表示由鹵素原子所取代之直鏈狀或分支鏈狀的碳數1〜6個之烷基的意思，鹵素原子的較佳取代數爲1〜3個，例如可舉出氟甲基、二氟甲基、三氟甲基、三氯甲基。本說明書中所使用的「鹵化（^.6烷氧基」表示由鹵素原子所取代之直鏈狀或分支鏈狀的碳數1〜6個烷氧基之意思，鹵素原子的較佳取代數爲1〜3個，例如可舉出氟甲氧基、二氟甲氧基、三氟甲氧基。所謂本說明書中之「醫藥上可被許可的鹽」表示藥劑上可許可的酸加成鹽之意思，作爲所使用的酸，可舉出硫酸、鹽酸、氫溴酸、硝酸及磷酸等無機酸，或乙酸、草酸、乳酸、檸檬酸、蘋果酸、葡萄糖酸、酒石酸、富馬酸、馬來酸、甲磺酸、乙磺酸、苯磺酸及p-甲苯磺酸等有機酸。由游離體轉換爲該鹽時可進行過去方法。對於本發明化合物，較佳型態可舉出以下者。 R1爲C!.6烷基之化合物爲佳，爲甲基的化合物爲較佳。 R2爲可由1〜3個Ci-6院氧基所取代之（^_6院基或 C3·6環烷基之化合物爲佳，分支鏈狀的C3_6烷基或（：3_8環烷基之化合物爲較佳》 -11 - 201225955Ra is a halogenated C, .6 alkoxy group, RC: and Rd are the same or different hydrogen atoms or halogen atoms, and R and Re are hydrogen atoms as described in any one of (1) to (6). A compound or a pharmaceutically acceptable salt thereof. (8) A medicine containing the compound according to any one of the above (1) to (7) or a pharmaceutically acceptable salt thereof as an active ingredient. (9) Schizophrenia containing a compound according to any one of the above (1) to (7) or a pharmaceutically acceptable salt thereof as an active ingredient, Azhai 201225955, a simple disease, cognitive dysfunction, dementia A prophylactic or therapeutic agent for a disease of anxiety disorder, depression, drug dependence, paralysis, hand shake, pain or sleep disorders. [Effects of the Invention] The compound of the present invention has a glycine transporter (GlyTl) inhibitory activity. Further, since the compound of the present invention exhibits high membrane permeability as shown in the following test examples, it is expected to have excellent intestinal absorption which is important for oral administration. Further, as shown in the following test examples, the compound of the present invention is expected to have good brain transition property because it is recognized as a matrix of sputum-glycoprotein which controls the drug-transition-transporter. Mode for Carrying Out the Invention "Cx_y (X, and y represents a natural number)" used in the present specification means that the number of carbon atoms is from X to y. The "CL6 alkyl group" used in the present specification means a linear or branched chain alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group. Base, isobutyl 't-butyl, pentyl, isopentyl, hexyl. The "c3.6 cycloalkyl group" used in the present specification means a cycloalkyl group having 3 to 6 carbon atoms, and is used in the basic instructions of the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, and the cyclohexane. (^-6 alkoxy group) means a linear or branched chain alkoxy group having 1 to 6 carbon atoms, and examples thereof include methoxy-10-3 201225955 group, ethoxy group, and propoxy group. , isopropoxy group, butoxy group, isobutoxy group, pentyloxy group, isopentyloxy group, hexyloxy group. The "halogen atom" used in the present specification is a fluorine atom, a chlorine atom, a *bromine atom, and indeed The "halogenated (^-6 alkyl group) used in the present specification means a linear or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a halogen atom, and a preferred substitution of a halogen atom. The number is 1 to 3, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a trichloromethyl group. As used herein, "halogenated (^.6 alkoxy group) means a halogen atom. The substituted linear or branched chain has a carbon number of 1 to 6 alkoxy groups, and the number of halogen atoms is preferably 1 to 3, and examples thereof include a fluoromethoxy group. "Difluoromethoxy" or "trifluoromethoxy". The "pharmaceutically acceptable salt" in the present specification means a chemically acceptable acid addition salt to the drug, and as the acid to be used, sulfuric acid is exemplified. , mineral acid such as hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid, or acetic acid, oxalic acid, lactic acid, citric acid, malic acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonate An organic acid such as an acid or p-toluenesulfonic acid. The conventional method can be carried out when the free form is converted into the salt. The preferred form of the compound of the present invention is as follows: The compound having R1 is C!.6 alkyl is Preferably, a compound which is a methyl group is preferred. R2 is a compound which may be substituted by 1 to 3 Ci-6 molybdenic groups (^-6 or a C3·6 cycloalkyl group, preferably a branched C3_6 alkane). Base or (: 3-8 cycloalkyl compound is preferred) -11 - 201225955

Ar1 爲式〔III〕【化4】Ar1 is of the formula [III] [Chemical 4]

RbRb

Re^Y^RcRe^Y^Rc

Rd 所示基的化合物爲佳，且Ra爲鹵化（：，-6烷氧 Rd爲相同或相異的氫原子或鹵素原子，Rb、及子之化合物爲較佳。 Y爲式CH之化合物爲佳。本發明化合物可含有複數不對稱中心。因合物可存在其光學活性||亦可存在其外消旋體在複數非對映異構物。前述所有形態皆包含於圍內。各異構物可藉由公知方法，例如藉由光物質或中間體的使用 '中間體或最終生成物之學選擇性反應或非對映選擇性反應，或使用中生成物的製造中之層析法進行分離等而得。且合物形成水合物或溶劑合物時，這些皆包含於圍內。同樣地，本發明化合物的水合物或溶劑上可被許可的鹽亦包含於本發明的範圍內。有關本發明的化合物可經口或非經口性投劑型爲錠劑、膠囊劑、顆粒劑、散劑、粉劑、膏劑、乳液劑、乳劑、懸浮劑、塞劑、注射劑由慣用製劑技術（例如第1 5改正日本藥局方法等）而製造。這些投與劑型可配合患者症狀療目的而做適宜選擇。基，、及 Re爲氫原此，前述化，且亦可存本發明之範學活性啓始製造中的光間體或最終，本發明化本發明的範合物之醫藥與。該投與含錠劑、軟等，皆可藉所規定之方、年齡及治A compound represented by Rd is preferred, and Ra is halogenated (:, 6-alkoxy Rd is the same or a different hydrogen atom or a halogen atom, and a compound of Rb and a group is preferred. Y is a compound of the formula CH Preferably, the compound of the present invention may contain a plurality of asymmetric centers. The optically active compound may exist in the compound, and the racemate may be present in the plural diastereomers. All of the above forms are included in the range. The structure can be subjected to a known method, for example, by the use of a photo substance or an intermediate, an intermediate or a final product, a selective reaction or a diastereoselective reaction, or a chromatography in the production of a product. The separation or the like is carried out, and when the compound forms a hydrate or a solvate, these are included. Similarly, a hydrate or a solvent-permissible salt of the compound of the present invention is also included in the scope of the present invention. The compound of the present invention can be administered orally or parenterally into tablets, capsules, granules, powders, powders, ointments, lotions, emulsions, suspensions, suppositories, injections, etc. by conventional formulation techniques (for example The 15th change It is manufactured by the Japanese Pharmacy Method, etc. These dosage forms can be appropriately selected in accordance with the purpose of the patient's symptoms. The base, and Re are hydrogenogens, the above-mentioned, and can also be stored in the invention. In the light interstitial or in the end, the present invention can be used to formulate the formula of the present invention. The dosage of the lozenge, soft, etc. can be determined by the prescription, age and treatment.

S -12- 201225955 這些製劑可由含有本發明的化合物之組成物中添加藥理學上被許可的載體，即添加賦形劑（例如結晶纖維素、澱粉、乳糖、甘露醇）、結合劑（例如羥基丙基纖維素、聚乙烯吡咯烷酮）、滑澤劑（例如硬脂酸鎂、滑石）、崩壞劑（例如羧基甲基纖維素鈣）、其他藥理學上被許可之各種添加劑而製造。又，本發明的化合物可與1種以上的其他治療藥、種種抗精神病藥（antipsychotics)、抗憂戀藥、例如5HT3 拮抗劑、5HT2拮抗劑、血清素促進劑、NK-1拮抗劑、選擇性血清素再取入阻礙藥（SSRI )、血清素去甲腎上腺素再取入阻礙藥（SNRI)、三環系抗憂鬱藥、多巴胺活動性抗憂鬱藥、H3拮抗劑、5HT1A拮抗劑、5HT1B拮抗劑、 5HT1D拮抗劑、D1促進劑、Ml促進劑、抗痙攣藥、認知功能增強藥、及其他精神活性藥物（psychoactive drug) 共同使用。所謂可與本發明的化合物組合共同使用的其他治療藥，例如可舉出 ondansetron、格拉司瓊（.granisetron)、 metoclopramide、sumatriptan、rauwolscine、yohimbine、 metoclopramide、fluoxetine、citalopram、escital opram、 femoxetine 、 fluvoxamine 、 paroxetine 、 indalpine 、 sertraline 、 zimeldine 、 venlafaxine 、 rebox etine 、 Milnacipran 、 duloxetine 、 imipramine 、 amitriptiline、 chlomipramine、nortriptiline、bupropion、amineptine、 divalproex ' carbamazepine 、 diazepam 、 risperidone 、 -13- 201225955 olanzapine 、 ziprasidone 、 aripiprazole 、 quetiapine 、 perospirone 、 clozapine 、 haloperidol ' pimozide 、 droperidol、chi orpromazine、thioridazine 、 mesoridazine 、 trifluoperazine 、 perphenazine 、 fluphenazine 、 thiflupromazine 、 prochlorperazine 、 acetophenazine 、 thiothixene、 chlorprothixene、 lamotrigine、 loxapine、 molindone等。這些組合可同時（對於相同醫藥處方，或相異醫藥處方）、個別或連續地進行投與。藉由本發明的化合物之組合所達到的與使用及治療方法相關連的特別利點，可舉出在各成分比一般所使用的投與量還少的投與量下得到同等或經改善的效果。又，對於精神障礙的陽性症狀及/或陰性症狀及/或認知功能障礙之治療效果的進一步增強亦受到期待。藉由本發明的組合之使用及治療方法，在某種神經弛緩藥的治療下並未有充分效果，或對於該治療有耐性之患者的治療上亦提供利益。有關本發明的化合物之投與量，治療成人時1天爲1 〜20 OOmg ’將此可分爲1天1次或數次進行投與。該投與量可依據患者的年齡'體重及症狀做適宜增減。式〔I〕的化合物可藉由種種合成方法而製造。以下方法爲本發明化合物的製造法之例示，但並未限定於此等〇 —般製造法中’所謂「惰性溶劑」，例如可舉出甲醇、乙醇、異丙醇、η-丁醇' 乙二醇等醇類、二乙醚、t_ 丁基甲基醚、二異丙基醚、四氫呋喃、1,4-二噁烷、1,2 -二S -12- 201225955 These preparations may contain a pharmacologically acceptable carrier from the composition containing the compound of the present invention, that is, an excipient (for example, crystalline cellulose, starch, lactose, mannitol), a binding agent (for example, a hydroxyl group). It is produced by propylcellulose, polyvinylpyrrolidone, a slip agent (for example, magnesium stearate, talc), a breaker (for example, carboxymethylcellulose calcium), and other pharmacologically acceptable additives. Further, the compound of the present invention may be combined with one or more other therapeutic agents, various antipsychotics, anti-anxiety drugs, such as 5HT3 antagonists, 5HT2 antagonists, serotonin promoters, NK-1 antagonists, and selection. Serotonin re-intake inhibitor (SSRI), serotonin norepinephrine re-taken inhibitor (SNRI), tricyclic antidepressant, dopamine active antidepressant, H3 antagonist, 5HT1A antagonist, 5HT1B Antagonists, 5HT1D antagonists, D1 promoters, M1 promoters, anticonvulsants, cognitive function enhancing drugs, and other psychoactive drugs are used together. Other therapeutic agents which can be used in combination with the compound of the present invention include, for example, ondansetron, granisetron, metoclopramide, sumatriptan, rauwolscine, yohimbine, metoclopramide, fluoxetine, citalopram, escital opram, femoxetine, fluvoxamine, Paroxetine, indalpine, sertraline, zimeldine, venlafaxine, rebox etine, Milnacipran, duloxetine, imipramine, amitriptiline, chlomipramine, nortriptiline, bupropion, amineptine, divalproex 'carbamazepine, diazepam, risperidone, -13- 201225955 olanzapine, ziprasidone, aripiprazole, quetiapine, perospirone , clozapine, haloperidol 'pimozide, droperidol, chi orpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, acetophenazine, thiothixene, chlorprothixene, lamotrigine, loxapine, molindone, etc. These combinations can be administered simultaneously (for the same pharmaceutical prescription, or for a different medical prescription), individually or continuously. Particularly advantageous in connection with the use and treatment method achieved by the combination of the compounds of the present invention, it is possible to obtain an equivalent or improved effect when the amount of each component is less than the amount of administration generally used. . Further, further enhancement of the therapeutic effects of positive symptoms of mental disorders and/or negative symptoms and/or cognitive dysfunction is also expected. By the use and treatment of the combination of the present invention, it is not sufficiently effective to treat a certain neuroleptic drug, or to provide benefit to the treatment of a patient who is resistant to the treatment. The administration amount of the compound of the present invention is 1 to 20 OO mg per day for treating adults. This can be administered once or several times a day. The dose can be appropriately increased or decreased depending on the age of the patient's body weight and symptoms. The compound of the formula [I] can be produced by various synthetic methods. The following method is exemplified as a method for producing the compound of the present invention, but is not limited to the so-called "inert solvent" in the above-mentioned general production method, and examples thereof include methanol, ethanol, isopropanol, and η-butanol' Alcohols such as diols, diethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-di

S -14 - 201225955 甲氧基乙烷等醚類、戊烷、己烷、庚烷、甲苯、苯、二甲苯等烴類、乙酸乙酯、甲酸乙酯等酯類、丙酮、甲基乙基酮等酮類、氯仿、二氯甲烷等鹵化碳系溶劑、二甲基甲醯胺、N-甲基吡咯烷酮等醯胺類、乙腈、二甲基亞颯、水或這些混合溶劑等。所謂「鹼」，例如可舉出氫化鋰、氫化鈉、氫化鉀、氫化鈣等鹼金屬或鹼土類金屬的氫化物；鋰醯胺、鈉醯胺、鋰二異丙基醯胺、鋰二環己基醯胺、鋰六甲基二矽基胺基、鈉六甲基二矽基胺基、鉀六甲基二矽基胺基等鹼金屬或鹼土類金屬的醯胺；甲氧化鈉、乙氧化鈉、第三丁氧化鉀等鹼金屬或鹼土類金屬的低級烷氧化物；丁基鋰、第二丁基鋰、第三丁基鋰、甲基鋰等烷基鋰；氫氧化鈉、氫氧化鉀、氫氧化鋰、氫氧化鋇等鹼金屬或鹼土類金屬的氫氧化物；碳酸鈉、碳酸鉀、碳酸鉋等鹼金屬或鹼土類金屬的碳酸鹽；碳酸氫鈉、碳酸氫鉀等鹼金屬或鹼土類金屬的碳酸氫鹽：三乙胺、N-甲基嗎啉、N，N-二異丙基乙胺、1,8-二氮雜雙環〔5.4.0〕十一碳-7-烯（DBU) 、1，5-二氮雜雙環〔4.3.0〕酮-5-烯（DBN ) 、Ν,Ν-二甲基苯胺等胺；吡啶、咪唑、2,6-二甲吡啶等鹼性雜環化合物等。這些鹼可配合對於斯業者爲公知之種種反應條件而適宜選擇。所謂「酸」，例如可舉出鹽酸、氫溴酸、硫酸、硝酸、磷酸等無機酸及Ρ-甲苯磺酸、甲磺酸、三氟乙酸、甲酸、乙酸、檸檬酸、草酸等有機酸。這些酸可配合對於斯業者爲公知之種種反應條件而適宜選擇。 -15- 201225955 作爲「路易氏酸」，例如可舉出三氟化硼、三氯化錦、四氯化鈦、三氯化鐵、氯化鋅、四氯化錫等。一般製造法1 【化5】S -14 - 201225955 Ethers such as methoxyethane, hydrocarbons such as pentane, hexane, heptane, toluene, benzene and xylene, esters such as ethyl acetate and ethyl formate, acetone and methyl ethyl A ketone such as a ketone, a halogenated carbon solvent such as chloroform or dichloromethane, a guanamine such as dimethylformamide or N-methylpyrrolidone, acetonitrile, dimethylhydrazine, water or a mixed solvent thereof. Examples of the "base" include a hydrogenated product of an alkali metal or an alkaline earth metal such as lithium hydride, sodium hydride, potassium hydride or calcium hydride; lithium decylamine, sodium decylamine, lithium diisopropyl decylamine, and lithium bicyclo An alkali metal or alkaline earth metal guanamine such as hexyl decylamine, lithium hexamethyldidecylamino group, sodium hexamethyldidecylamino group or potassium hexamethyldidecylamino group; sodium methoxide, ethoxylated a lower alkoxide of an alkali metal or an alkaline earth metal such as sodium or potassium tributoxide; an alkyl lithium such as butyl lithium, a second butyl lithium, a third butyl lithium or a methyl lithium; sodium hydroxide or hydroxide Alkali metal or alkaline earth metal hydroxide such as potassium, lithium hydroxide or barium hydroxide; alkali metal or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate or carbonic acid; alkali metal such as sodium hydrogencarbonate or potassium hydrogencarbonate Or alkaline earth metal hydrogencarbonate: triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7- Alkene (DBU), 1,5-diazabicyclo[4.3.0] keto-5-ene (DBN), anthracene, fluorene-dimethylaniline and other amines; pyridine, imidazole, 2,6-dimethylpyridine, etc. A basic heterocyclic compound or the like. These bases are suitably selected in accordance with various reaction conditions known to those skilled in the art. Examples of the "acid" include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as hydrazine-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, citric acid, and oxalic acid. These acids are suitably selected in accordance with various reaction conditions well known to those skilled in the art. -15- 201225955 Examples of the "Lie's acid" include boron trifluoride, zinc trichloride, titanium tetrachloride, ferric chloride, zinc chloride, and tin tetrachloride. General Manufacturing Method 1 [Chemical 5]

式中，X1表示鹵素原子或羥基，L1表示鹵素原子、甲烷磺醯氧基、三氟甲烷磺醯氧基或P-甲苯磺醯氧基等脫離基，其他記號與前述同義。步驟1 :惰性溶劑中，鹼存在下或非存在下，將化合物（1)與XI爲鹵素原子之化合物（2)進行反應，可得到化合物（3 )。或將化合物（1 )與XI爲羥基之化合物 (2 )藉由斯業者所公知之種種醯胺化反應，可得到化合物（3 )。此所謂的醯胺化反應爲，例如有惰性溶劑中，鹼存在下或非存在下，經由使用〇-(7-氮雜苯並三唑-1-基）-氺沐：^’川’-四甲基脲六氫磷酸（HATU ) 、Ο-(苯並三唑-1 -基）-N，N，N ’，N’-四甲基脲六氫磷酸（HBTU)In the formula, X1 represents a halogen atom or a hydroxyl group, and L1 represents a leaving group such as a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a P-toluenesulfoxy group, and the other symbols are synonymous with the above. Step 1: Compound (3) is obtained by reacting compound (1) with compound (2) wherein XI is a halogen atom in an inert solvent in the presence or absence of a base. Alternatively, the compound (1) and the compound wherein XI is a hydroxyl group (2) can be obtained by a amide amination reaction known to those skilled in the art. This so-called hydrazide reaction is, for example, in an inert solvent, in the presence or absence of a base, via the use of 〇-(7-azabenzotriazol-1-yl)-氺沐:^'川'- Tetramethylurea hexahydrophosphate (HATU), Ο-(benzotriazol-1-yl)-N,N,N ',N'-tetramethyluronium hexahydrophosphate (HBTU)

、N，N’-二環己基碳二亞胺（DCC) 、1-乙基-3- (3-二甲基胺基丙基）碳二亞胺鹽酸鹽（EDC.HCl)、4·(4,6-二甲氧基-1,3,5 -三曉-2 -基）-4 -甲基嗎福啉氯化物（DMT-MM)、二苯基磷醯基疊氮（DPPA)或羰基二咪唑（CDI, N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), 4· (4,6-Dimethoxy-1,3,5-tris-2-yl)-4-methylmorpholine chloride (DMT-MM), diphenylphosphonium azide (DPPA) Or carbonyl diimidazole (CDI

S -16- 201225955 )等縮合劑的醯胺化反應、使用氯碳酸乙基、氯碳酸異丁基或三甲基乙醯基氯化物等混合酸酐的醯胺化反應等。於此使用縮合劑的醯胺化反應時，視必要可使用1 -羥基苯並三唑（HOBt)、羥基琥珀醯亞胺（HOSu)等添加劑。步驟2:惰性溶劑中，鹼存在下或非存在下，藉由將化合物（3 )與化合物（4 )進行反應，可得到本發明化合物（I)。一般製造法2 【化(5】S-16-201225955) A hydrazide reaction of a condensing agent, a hydrazide reaction using a mixed acid anhydride such as ethyl chlorocarbonate, isobutyl chlorocarbonate or trimethylethenyl chloride. When a hydrazide reaction using a condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt) or hydroxy amber succinimide (HOSu) may be used as necessary. Step 2: The compound (I) of the present invention can be obtained by reacting the compound (3) with the compound (4) in an inert solvent in the presence or absence of a base. General Manufacturing Method 2 [Chemical (5)

步驟3:惰性溶劑中，酸存在下或非存在下，使用還原劑，將化合物（5)與化合物（6)藉由進行還原性胺基化反應，可得到化合物（7 )。於此所謂還原劑，例如爲氣化三乙酿氧基硼鈉、氫化氰硼鈉、氫化砸鈉等。步驟4:使用化合物（7)與化合物（2)，藉由一般製造法1之步驟1的方法，可得到本發明化合物（I)。一般製造法3 -17- 201225955 【化7】Step 3: Compound (7) can be obtained by subjecting compound (5) to compound (6) by a reductive amination reaction in an inert solvent in the presence or absence of an acid using a reducing agent. The reducing agent herein is, for example, vaporized triethyl borohydride sodium, sodium cyanoborohydride, sodium hydride or the like. Step 4: Using the compound (7) and the compound (2), the compound (I) of the present invention can be obtained by the method of the general method 1 of Process 1. General Manufacturing Law 3 -17- 201225955 【化7】

Ra Rb (7a) 式中厌3及Rb獨立表示可由選自氫原子、Cl_6烷氧基、鹵素原子、C3·6環烷基、及可由1〜5個鹵素原子所取代之苯基的1〜3個取代基所取代的烷基、c3-6環烷基’或可由1〜5個鹵素原子所取代之苯基，或與Rb 與所結合的碳原子共同形成C3-6環院基環。步驟5:使用化合物（8)與化合物（1)，藉由一般製造法2的步驟3之方法，可得到化合物（7a)。化合物 (7a)含於上述化合物（？）所示化合物中。一般製造法4 【化8】Ra Rb (7a) wherein anamorphic 3 and Rb independently represent 1 to 1 which may be selected from a hydrogen atom, a Cl 6 alkoxy group, a halogen atom, a C 3 · 6 cycloalkyl group, and a phenyl group which may be substituted by 1 to 5 halogen atoms. An alkyl group substituted with 3 substituents, a c3-6 cycloalkyl group or a phenyl group which may be substituted by 1 to 5 halogen atoms, or a combination of Rb and a carbon atom to be bonded to form a C3-6 ring-based ring. Step 5: Using the compound (8) and the compound (1), the compound (7a) can be obtained by the method of the general method 2, step 3. The compound (7a) is contained in the compound represented by the above compound (?). General Manufacturing Method 4 [Chemical 8]

式中Rla表不Ci·6院基，其他記號與前述同義。步驟6 :惰性溶劑中，鹼存在下或非存在下，藉由將 R爲氯原子之本發明化合物（1-1)與化合物（9)進行反應’可得到本發明化合物（1-2 )。一般製造法5Where Rla is not Ci6, and other marks are synonymous with the foregoing. Step 6: The compound (1-2) of the present invention can be obtained by reacting the compound (1-1) of the present invention wherein R is a chlorine atom with the compound (9) in an inert solvent in the presence or absence of a base. General manufacturing method 5

S -18- 201225955 【化9】S -18- 201225955 【化9】

(10) (I-3)(10) (I-3)

式中X2表示硼酸、硼酸酯或鹵素原子，Ar2表示可由鹵化C!_6烷氧基所取代之苯基，其他記號與前述同義。步驟7 :惰性溶劑中，鹼的存在下或非存在下，對於化合物（1 〇 )，將化合物（1 1 )在銅觸媒及視必要在胺配體存在下進行反應，可得到本發明化合物（1-3 )。此所謂的銅觸媒，例如可舉出氧化銅（I )、碘化銅（I )、溴化銅（I ) '溴化銅（11 )、乙酸銅（I )、乙酸銅（11 )等，所謂胺配體可舉出N，N’-二甲基伸乙基二胺、1>2-環己烷二胺、啡啉等。【實施方式】〔實施例〕其次，藉由製造例、實施例及試驗例更詳細說明本發明，但本發明並未受限於這些實施例。對於以下製造例及實施例，所使用之微波反應裝置爲 Biotage 公司的 Initiator。對於以下製造例及實施例，使用管柱層析法進行純化時的「NH矽膠匣」爲使用 Biotage (註冊商標） SNAPCartridge KP-NH，「矽膠匣」爲使用 Biotage (註冊商標）SNAPCartridge KP-Sil，「逆相矽膠匣」爲使用 201225955 MORITEX (註冊商標）Purif-Pack ODS。對於以下製造例及實施例，使用分取薄層層析法（ PTLC )進行純化時的「NH矽膠」爲使用和光純藥公司的 NH2 砂膠 60F254plate wako 20cmx20cm，「砂膠」爲使用 Merck 公司的砂膠 60F254，20cmx20cme 對於以下製造例及實施例，藉由分取高速液體層析法 (HPLC )的純化以以下條件進行。但於具有鹼性官能基的化合物之情況，在本操作使用三氟乙酸時，有時必須進行欲得到自由體的中和操作等。儀器：Gilson 公司 preparative HPLC system 管柱：資生堂 Capcelpak C18 MGII 5μιη 2〇xl50mm 溶劑：A液；含有0.1 %三氟乙酸之水、B液；含有0.1% 三氟乙酸之乙腈梯度：〇分鐘（人液/8液=90/10)、22分鐘（人液/8液 = 20/80) 、25 分鐘（A 液/B 液=10/90) 流速：20mL/min，檢測法：UV 254nm 對於以下製造例及實施例，質譜（MS )爲藉由以下條件進行測定。Wherein X2 represents a boronic acid, a boronic acid ester or a halogen atom, and Ar2 represents a phenyl group which may be substituted by a halogenated C!-6 alkoxy group, and other symbols are synonymous with the foregoing. Step 7: The compound of the present invention can be obtained by reacting the compound (1 1 ) with a copper catalyst and optionally in the presence of an amine ligand in the presence or absence of a base in an inert solvent for the compound (1 〇). (1-3). Examples of the copper catalyst include copper (I) oxide, copper (I) iodide, copper (I) bromide (II) copper bromide (11), copper (I) acetate, and copper acetate (11). The amine ligand may, for example, be N,N'-dimethylethylidene diamine, 1>2-cyclohexanediamine or phenanthroline. [Embodiment] [Embodiment] Next, the present invention will be described in more detail by way of Production Examples, Examples and Test Examples, but the present invention is not limited to these Examples. For the following production examples and examples, the microwave reaction apparatus used was an Initiator of Biotage Corporation. In the following production examples and examples, the "NH 矽匣" used in the purification by column chromatography was Biotage (registered trademark) SNAPCartridge KP-NH, and "Bio (" was used as Biotage (registered trademark) SNAPCartridge KP-Sil. , "Reverse phase gel" is the use of 201225955 MORITEX (registered trademark) Purif-Pack ODS. For the following production examples and examples, the "NH 矽 gel" used for purification by fractional thin layer chromatography ( PTLC ) was used as the NH 2 sand paste 60F254plate wako 20 cm x 20 cm from Wako Pure Chemical Industries Co., Ltd., and the "sand rubber" was used by Merck. Sand rubber 60F254, 20cmx20cme For the following production examples and examples, purification by fractional high-speed liquid chromatography (HPLC) was carried out under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in the present operation, it is sometimes necessary to carry out a neutralization operation for obtaining a free body. Instrument: Gilson preparative HPLC system Column: Shiseido Capcelpak C18 MGII 5μιη 2〇xl50mm Solvent: Liquid A; water containing 0.1% trifluoroacetic acid, solution B; acetonitrile gradient containing 0.1% trifluoroacetic acid: 〇 minute (human liquid /8 liquid = 90/10), 22 minutes (human liquid / 8 liquid = 20/80), 25 minutes (A liquid / B liquid = 10/90) Flow rate: 20 mL / min, detection method: UV 254 nm For the following manufacture In the examples and examples, the mass spectrum (MS) was measured by the following conditions.

MS 光譜：島津 LCMS-2010EV 或 micromass Platform LC 對於以下製造例及實施例，核磁共振光譜（NMR)爲藉由以下條件進行測定。 NMR 光譜：〔1H-NMR〕600MHz : JNM-ECA600 (日本電子）、500MHz : JNM-ECA500 (曰本電子）、300MHz : UNITYNOVA3 00 ( Varian Inc. ) 、200MHz : GEMINI2000/ s -20- 201225955 200 ( Varian Inc.) 對於以下製造例及實施例，化合物名藉由 ACD/Name (ACD/Labs 12.01, Advanced Chemistry Development Inc. )命名。製造例1 1-甲基-N-〔 3-(三氟甲氧基）苯甲基〕-1H-咪唑-4-胺甲醯【化1 0】MS spectrum: Shimadzu LCMS-2010EV or micromass Platform LC For the following production examples and examples, nuclear magnetic resonance spectroscopy (NMR) was measured by the following conditions. NMR spectrum: [1H-NMR] 600MHz: JNM-ECA600 (Japan Electronics), 500MHz: JNM-ECA500 (Sakamoto Electronics), 300MHz: UNITYNOVA3 00 (Varian Inc.), 200MHz: GEMINI2000/ s -20- 201225955 200 ( Varian Inc.) For the following production examples and examples, the compound names are named by ACD/Name (ACD/Labs 12.01, Advanced Chemistry Development Inc.). Production Example 1 1-Methyl-N-[3-(trifluoromethoxy)benzyl]-1H-imidazol-4-aminecaramidine [Chemical 1 0]

於 1-甲基-1H -咪唑-4 -羧酸（ 500mg) 、EDC.HC1( 920mg) 、HOBt · H20 ( 73 5mg )與乙腈（10mL )的混合物中加入3-三氟甲氧基苯甲基胺（84lmg)的乙腈（lOmL) 溶液，在室溫經一晚攪拌。減壓下將乙腈餾去，加入飽和碳酸氫鈉水溶液。以乙酸乙酯進行萃取，以無水硫酸鎂乾燥。過濾分離乾燥劑後，將濾液進行減壓濃縮，殘渣以管柱層析法（矽膠匣，氯仿/甲醇=1: 0〜9: 1)進行純化後得到標題化合物（1 . 1 8 g )。 1H NMR ( 600 MHz, CHLOROFORM-d ) d ppm 3.73 ( s, 3H )'4.62 ( d, J = 6.0 Hz, 2H ) ，7 · 0 8 - 7 · 1 4 ( m，1 H )， 7.18 ( s, 1H ) > 7.26-7.30 ( m, 1H ) > 7.3 1-7.37 ( m, 2H ) ，7.47 ( br. s·，1H) ，7.52-7.57 (m，1H) (ESI pos. ) m/z ： 300 ( 〔 M + H〕+ ) 201225955 製造例2 N-〔4_氟- 3-(三氟甲氧基）苯甲基〕丙烷-2-胺【化1 1】3-Trifluoromethoxybenzene was added to a mixture of 1-methyl-1H-imidazole-4-carboxylic acid (500 mg), EDC.HC1 (920 mg), HOBt·H20 (73 5 mg) and acetonitrile (10 mL) A solution of the amine (84 mg) in acetonitrile (10 mL) was stirred at room temperature overnight. The acetonitrile was distilled off under reduced pressure and a saturated aqueous solution of sodium hydrogen carbonate was added. Extraction with ethyl acetate and drying over anhydrous magnesium sulfate. After the desiccant was separated by filtration, the filtrate was concentrated under reduced pressure. 1H NMR ( 600 MHz, CHLOROFORM-d ) d ppm 3.73 ( s, 3H )'4.62 ( d, J = 6.0 Hz, 2H ) , 7 · 0 8 - 7 · 1 4 ( m,1 H ), 7.18 ( s , 1H ) > 7.26-7.30 ( m, 1H ) > 7.3 1-7.37 ( m, 2H ) , 7.47 ( br. s·, 1H) , 7.52 - 7.57 (m, 1H) (ESI pos. ) m/ z: 300 ( [ M + H]+ ) 201225955 Production Example 2 N-[4-fluoro-3-(trifluoromethoxy)benzyl]propan-2-amine [Chemical 1 1]

於4 -氟-3-三氟甲氧基苯甲醛（ 500mg)的氯仿（5mL )溶液中加入2 -胺基丙烷（l4〇mg)，在室溫進行30分鐘攪拌。加入氫化三乙醯氧基硼鈉（61 Omg )，在室溫進行1小時攪拌。加入飽和碳酸氫鈉水溶液，以氯仿萃取。將溶劑減壓下餾去，殘渣以管柱層析法（NH匣，己烷/乙酸乙酯=9 : 1〜3 : 1 )進行純化後得到標題化合物（ 6 6 0 m g ) ° 1 H NMR ( 200 MHz, C HLOROFORM-d ) d ppm 1.09 ( d, J = 6.2 Hz, 6H ) - 2.74-2.9 1 ( m, 1H ) ，3.76 ( s，2H)， 7.07- 7.3 5 ( m, 3H ) (ESI pos. ) m/z ： 252 ( ( M + H ] +) 同樣地合成以下化合物。 (1-{ 〔 3-(三氟甲氧基）苯甲基〕胺基}環戊基）甲醇 (ESI pos. ) m/z : 290 ( ( M + H ) +) Ν-(3·溴-4-氟苯甲基）丙烷-2-胺 (ESI pos. ) m/z : 246，248 (〔 M + H〇 + ) N- ( 3-溴-4-氟苯甲基）環己烷胺 (ESI pos. ) m/z ： 286，28 8 ( 〔M + H〕+) N-〔 3-氯-5-(三氟甲氧基）苯甲基〕環己烷胺 1H NMR ( 200 MHz, CHLOROFORM-d ) d ppm 0.96- 1.99 ( m，10 Η) - 2.36-2.5 3 ( m, 1H ) > 3.8 1 ( s, 2H ) > 7.07- -22- s 201225955 7.1 6 ( m, 2H ) > 7.2 7-7.3 4 ( m, 1 H ) N-〔 3-氯5-(三氟甲氧基）苯甲基〕丙烷-2-胺 1H NMR ( 200 MHz, CHLOROFORM-d ) d ppm 1.09 ( d, J = 6.2 Hz, 6H ) > 2.75-2.91 ( m, 1H ) > 3.78 ( s, 2H ) > 7.07-7.15 ( m, 2H) > 7.28-7.32 ( m, 1H) N-〔 3-氯-5-(三氟甲氧基）苯甲基〕環戊烷胺 (ESI ρ 〇 s. ) m/z ： 294 ( [ M + H ) + ) N-〔（2 -漠卩比II疋-4 -基）甲基〕丙院-2-胺 (ESI ρ 〇 !i. ) m/z ： 229, 23 1 (〔 M + H〕+ ) N-〔（ 6-溴吡啶-2-基）甲基〕丙烷-2-胺 (ESI ρ 〇 s. ) m/z ： 229, 23 1 (〔M + H〕+ ) N-〔（6 -漠-5-氣D比卩定-2-基）甲基〕丙垸-2-胺 (ESI pos. ) m/z ： 247, 249 (〔M + H〕+ ) N-〔（ 2-溴吡啶-4-基）甲基〕環丁烷胺 (ESI pos. ) m/z ： 24 1, 243 ( 〔M + H〕+) N-〔 4-氟- 3-(三氟甲氧基）苯甲基〕環丁烷胺 1H NMR ( 200 MHz, CHLOROFORM-d) d ppm 1.56- 1.82 ( m, 4H ) - 2.12-2.3 1 ( m, 2H ) > 3.18-3.33 ( m, 1H ) > 3.68 ( s, 2H ) - 7.05-7.3 3 ( m, 3H ) (ESI pos. ) m/z ： 264 ( 〔M + H〕+ ) N-〔 4-氟- 3-(三氟甲氧基）苯甲基〕四氫-2H-吡喃-4-胺 (ESI pos. ) m/z ： 294 ( 〔M + H〕+) N- ( 4-氟苯甲基）丙烷-2-胺 (ESI pos. ) m/z : 168 ( 〔M + H〕+)To a solution of 4-fluoro-3-trifluoromethoxybenzaldehyde (500 mg) in chloroform (5 mL) was added 2-aminopropane (14 g) and stirred at room temperature for 30 minutes. Sodium triethoxyborohydride (61 Omg) was added and stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added and extracted with chloroform. The solvent was evaporated under reduced pressure. EtOAc mjjjjjjjjj ( 200 MHz, C HLOROFORM-d ) d ppm 1.09 ( d, J = 6.2 Hz, 6H ) - 2.74-2.9 1 ( m, 1H ) , 3.76 ( s, 2H), 7.07- 7.3 5 ( m, 3H ) ( ESI pos.) m/z : 252 ( ( M + H ) +) The following compound was synthesized. (1-{ 〔 3-(trifluoromethoxy)benzyl]amino}cyclopentyl)methanol ( ESI pos.) m/z : 290 ( ( M + H ) +) Ν-(3·bromo-4-fluorobenzyl)propan-2-amine (ESI pos. ) m/z : 246,248 ( M + H〇+ ) N-( 3-bromo-4-fluorobenzyl)cyclohexaneamine (ESI pos. ) m/z : 286,28 8 ( [M + H]+) N-[ 3- Chloro-5-(trifluoromethoxy)benzyl]cyclohexaneamine 1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.96- 1.99 (m,10 Η) - 2.36-2.5 3 ( m, 1H ) > 3.8 1 ( s, 2H ) > 7.07- -22- s 201225955 7.1 6 ( m, 2H ) > 7.2 7-7.3 4 ( m, 1 H ) N-[ 3-chloro-5-(trifluoromethyl) Oxy)benzyl)propan-2-amine 1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.09 ( d, J = 6.2 Hz, 6H ) > 2.75-2.91 ( m, 1H ) > 3.78 ( s, 2H ) > 7.07-7.15 ( m, 2H) > 7.28-7.32 ( m, 1H) N-[ 3-chloro-5-(trifluoro Methoxy)benzyl]cyclopentanamine (ESI ρ 〇s. ) m/z : 294 ( [ M + H ) + ) N-[ (2 - Desert 疋 II疋-4 -yl)methyl 〕乙-2-amine (ESI ρ 〇! i. ) m / z : 229, 23 1 ([ M + H] + ) N-[(6-bromopyridin-2-yl)methyl]propane-2 -amine (ESI ρ 〇s. ) m/z : 229, 23 1 ([M + H]+ ) N-[ (6 - -5-5-气 D比卩定-2-yl)methyl] propyl hydrazine 2-Amine (ESI pos.) m/z : 247, 249 ([M + H] + ) N-[(2-bromopyridin-4-yl)methyl]cyclobutaneamine (ESI pos.) m /z: 24 1, 243 ([M + H]+) N-[4-Fluoro-3-(trifluoromethoxy)benzyl]cyclobutaneamine 1H NMR (200 MHz, CHLOROFORM-d) d Ppm 1.56- 1.82 ( m, 4H ) - 2.12-2.3 1 ( m, 2H ) > 3.18-3.33 ( m, 1H ) > 3.68 ( s, 2H ) - 7.05-7.3 3 ( m, 3H ) (ESI pos m/z : 264 ( [M + H] + ) N-[ 4-fluoro-3-(trifluoromethoxy)benzyl]tetrahydro-2H-pyran-4-amine (ESI pos. m/z : 294 ( [M + H]+) N-(4-fluorobenzyl)propane 2-amine (. ESI pos) m / z: 168 ([M + H] +)

-23- 201225955 1-(4-氟苯基）-N-〔3-(三氟甲基）苯甲基〕甲烷胺製造例3 Ν·〔3-(三氟甲氧基）苯甲基〕丙烷-2-胺【化1 2】-23- 201225955 1-(4-Fluorophenyl)-N-[3-(trifluoromethyl)benzyl]methaneamine Production Example 3 Ν·[3-(Trifluoromethoxy)phenylmethyl] Propane-2-amine [1 2]

於丙酮（〇.38mL)與3-三氟甲氧基苯甲基胺（l.Og) 的氯仿（1 0 m L )溶液中加入氫化三乙醯氧基硼鈉（2 · 2 g ) ，在室溫進行45分鐘攪拌。加入飽和碳酸氫鈉水溶液’ 以氯仿萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥。過濾分離乾燥劑後，將濾液在減壓下濃縮，殘渣以管柱層析法（矽膠匣，氯仿/甲醇=1: 〇〜9: 1)進行純化後得到標題化合物（〇.68g)。 1 H NMR ( 600 MHz, CHLOROFORM-d ) d ppm 1.10 ( d, J = 6.4 Hz, 6H ) > 2.84 ( spt, J = 6.3 Hz, 1H ) ，3.80 ( s, 2H ) - 7.09 ( d, J = 7.3 Hz, 1H ) - 7.20 ( s, 1H ) > 7.30-7.36 ( m，1 H ) (ESI pos. ) m/z ： 234 ( 〔M + H〕+) 同樣地合成以下化合物。 N-〔 3-(三氟甲氧基）苯甲基〕環己烷胺 (ESI pos. ) m/z ： 274 (〔M + H〕+) 製造例4N-(丙烷-2-基）-N-〔 3-(三氟甲氧基）苯甲基〕-1H-1，2,4-三唑基-3-胺甲醯 -24- 201225955 【化1 3】To a solution of acetone (〇.38mL) and 3-trifluoromethoxybenzylamine (1.0 g) in chloroform (10 m L) was added sodium triethylphosphonium hydride (2 · 2 g). Stir at room temperature for 45 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added, and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After the desiccant was separated by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified to mjjjjjlilililililililililililililili 1 H NMR ( 600 MHz, CHLOROFORM-d ) d ppm 1.10 ( d, J = 6.4 Hz, 6H ) > 2.84 ( spt, J = 6.3 Hz, 1H ) , 3.80 ( s, 2H ) - 7.09 ( d, J = 7.3 Hz, 1H ) - 7.20 ( s, 1H ) > 7.30-7.36 ( m,1 H ) (ESI pos. ) m/z : 234 ( [M + H]+) The following compounds were synthesized in the same manner. N-[3-(Trifluoromethoxy)benzyl]cyclohexaneamine (ESI pos.) m/z: 274 ([M + H]+) Manufactured Example 4N-(propan-2-yl)- N-[ 3-(trifluoromethoxy)benzyl]-1H-1,2,4-triazolyl-3-aminecarbam-24- 201225955 [Chem. 1 3]

異丙胺（450mg) 、HATU ( 1 .1 g)，進行一晚攪拌。加入水，以〃 ^晴（5mL )的混合物在室溫 &乙酸乙酯萃取後，將溶劑在減匣、己烷/乙酸乙酯=Isopropylamine (450 mg), HATU (1.1 g), stirred overnight. Water was added, and the mixture was extracted with EtOAc (5 mL) at room temperature & ethyl acetate.

壓下餾去。殘渣以管柱層析法（NH 1 : 1〜ΟΠ、氯仿/甲醇=1 : 0〜丨9 : 1 )進行純化後得到標題化合物（500mg)。 1H NMR ( 600 MHz, CHLOROFORM-d ) d ppm 1.19-1.30 ( m, 6H ) ，4.57-6.01 ( m，3H ) > 7.08-7.13 ( m, 2H )， 7.15-7.22 ( m, 1H) - 7.3 0-7.3 8 (m, 1H) - 7.97-8.21 ( m, 1H) (ESI pos.) m/z: 3 2 9 (〔M + H〕+) 同樣地合成以下化合物。 N- ( 3-溴-4-氟苯甲基）-N-(丙烷-2-基）-1H-1,2,4-三唑基-3-胺甲醯 (ESI pos.) m/z ： 3 3 9，341 (〔 M + H〕·）心（3-溴-4-氟苯甲基）-1^-環己基-^-1，2,4-三唑基-3-胺甲醯 (ESI pos. ) m/z ： 379,381 ( [ M + H ]') N-〔 3-氯-5-(三氟甲氧基）苯甲基〕-N-(丙烷-2-基）-1H-1，2,4-三唑基-3-胺甲醯 201225955 (ESI pos. ) m/z ： 3 63 ( 〔 M + H〕+) N-〔3-氯- 5-(三氟甲氧基）苯甲基〕-N-環戊基-1H-1,2,4- 三唑基-3-胺甲醯 (ESI pos. ) m/z ： 3 89 ( 〔M + H〕+ ). N-〔4-氟-3-(三氟甲氧基）苯甲基〕-N-(丙烷-2-基）-1H-1，2,4-三唑基-3-胺甲醯 (ESI pos. ) m/z ： 347 ( 〔M + H〕+) 製造例5N-(4-氟-3-羥基苯甲基）-1-甲基-N-(丙烷-2-基 )-1H -咪唑-4-胺甲醯【化1 4】Press down and distill off. The residue was purified by column chromatography (NH1: EtOAc (EtOAc) 1H NMR ( 600 MHz, CHLOROFORM-d ) d ppm 1.19-1.30 ( m, 6H ) , 4.57-6.01 ( m,3H ) > 7.08-7.13 ( m, 2H ), 7.15-7.22 ( m, 1H) - 7.3 0-7.3 8 (m, 1H) - 7.97-8.21 (m, 1H) (ESI pos.) m/z: 3 2 9 ([M + H]+) The following compounds were synthesized in the same manner. N-(3-Bromo-4-fluorobenzyl)-N-(propan-2-yl)-1H-1,2,4-triazolyl-3-aminecarboxamide (ESI pos.) m/z : 3 3 9,341 ([ M + H]·) Heart (3-bromo-4-fluorobenzyl)-1^-cyclohexyl-^-1,2,4-triazolyl-3-amine A ESI (ESI pos. ) m/z : 379,381 ( [ M + H ]') N-[ 3-chloro-5-(trifluoromethoxy)benzyl]-N-(propan-2-yl)- 1H-1,2,4-triazolyl-3-aminecarbamidine 201225955 (ESI pos.) m/z : 3 63 ( [ M + H]+) N-[3-chloro-5-(trifluoromethyl) Oxy)benzyl]-N-cyclopentyl-1H-1,2,4-triazolyl-3-aminecarboxamide (ESI pos.) m/z : 3 89 ( [M + H]+ ) N-[4-Fluoro-3-(trifluoromethoxy)benzyl]-N-(propan-2-yl)-1H-1,2,4-triazolyl-3-aminecarboxamide ESI pos.) m/z : 347 ([M + H]+). Production Example 5 N-(4-fluoro-3-hydroxybenzyl)-1-methyl-N-(propan-2-yl)-1H -Imidazole-4-amine formazan [Chemical 1 4]

(1)將4-氟-3·羥基安息香酸甲基酯（5g)、第三丁基二甲基矽基氯化物（13.2g)、咪唑（10g)的二甲基甲醯胺（50mL )溶液在室溫進行1小時攪拌。加入水，以二乙醚萃取，將溶劑在減壓下餾去。殘渣以管柱層析法（矽膠匣，己烷/乙酸乙酯=1 : 〇〜19 : 1 )進行純化，得到3-{〔第三丁基（二甲基）矽基〕氧基} _4_氟安息香酸甲基(1) 4-fluoro-3.hydroxybenzoic acid methyl ester (5 g), tert-butyldimethylammonium chloride (13.2 g), imidazole (10 g) in dimethylformamide (50 mL) The solution was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with diethyl ether. The residue was purified by column chromatography (hexanes, ethyl acetate = 1 : 〇~19:1) to give 3-{[t-butyl(dimethyl)decyl)oxy} _4 _Fluorobenzoic acid methyl

S -26- 201225955 (7.2g)。 1H NMR ( 200 MHz, CHLOROFORM-d) d ppm 0.21 ( s, 6H )，1.01 (s, 9 H) ，3.89(s，3H) > 7.03-7.1 6 ( m, 1H ) '7.54-7.69 ( m, 2H ) (2 )以乾冰-丙酮浴冷卻的3- {〔第三丁基（二甲基 )矽基〕氧基} -4-氟安息香酸甲基（2g )的四氫呋喃（ 20mL )溶液中，滴入二異丁基鋁氫化物（1.0M己烷溶液，7.7mL)，並進行1小時攪拌進一步追加二異丁基鋁氫化物（7.7mL)，再進行1小時攪拌。加入酒石酸鉀鈉水溶液，並進行1小時攪拌後，以乙酸乙酯萃取。減壓下將溶劑餾去，得到（3 - {〔第三丁基（二甲基）矽基〕氧基 } -4-氟苯基）甲醇（1.7g)。 1H NMR ( 200 MHz, CHLOROFORM-d) d ppm 0.19 ( s, 6H )，1.00 ( s，9 H) ，4.60 ( s，2H) * 6.82-7.08 ( m, 3H ) (3)於（3- {〔第三丁基（二甲基）矽基〕氧基}-4-氟苯基）甲醇（ 900mg)的氯仿（2〇mL)溶液中加入二氧化鍤（9.2g)，在室溫進行一晚攪拌。過去除去不溶物後’將爐液在減壓下濃縮，得到3 - {〔第三丁基（二甲基 )矽基〕氧基} -4-氟苯甲醛（ 93 5mg)。 (4 )藉由與製造例2之同樣方法，由3_ {〔第三丁基（一甲基）矽基〕氧基} _4·氟苯甲醛（l 7g)與2_胺基丙烷（435mg)得到N- ( 3- {〔第三丁基（二甲基）砍基〕氧基}-4-氟苯甲基）丙烷-2-胺（2.〇g)。 (ESI pos. ) m/z ： 298 ( 〔 M + H〕+ ) -27- 201225955 (5) 藉由與製造例4之同樣方法，由N-(3-{〔第三丁基（二甲基）矽基〕氧基} -4-氟苯甲基）丙烷·2-胺 (2.0g)與1-甲基·1Η-咪唑-4-羧酸（840mg)得到N- ( 3-{〔第三丁基（二甲基）矽基〕氧基} ·4·氟苯甲基）-^ 甲基-Ν·(丙烷-2-基）-1Η-咪唑·4-胺甲醯（1.19g)。 (ESI pos.) m/z : 406 ( 〔 M + H〕+) (6) 於N-(3-{〔第三丁基（二甲基）矽基〕氧基 } -4-氟苯甲基）-1-甲基-N-(丙烷-2-基）-1H-咪唑-4-胺甲醯（l_19g)的THF(2 0mL)溶液中加入四丁基銨氟化物（1M四氫呋喃溶液，2.9mL)，在室溫進行10分鐘攪拌。加入水，以氯仿萃取。減壓下將溶劑餾去後，殘渣以管柱層析法（矽膠匣，氯仿/甲醇=1: 0〜19: 1)進行純化後得到標題化合物（ 750mg)。 1H NMR ( 600 MHz, CHLOROFORM-d ) d ppm 1.11-1.23 ( m，6H) * 3.70 ( br. s., 3H ) ，4.47-5.75 (m，3H) - 6.70- 7.55 ( m, 5H) (ESI pos. ) m/z ： 292 (〔M + H〕+) 製造例6 6-溴-5-氟吡啶-2-甲醛【化1 5】S -26- 201225955 (7.2g). 1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.21 ( s, 6H ), 1.01 (s, 9 H) , 3.89 (s, 3H) > 7.03-7.1 6 ( m, 1H ) '7.54-7.69 ( m , 2H) (2) 3-{[Tertobutyl(dimethyl)indenyl]oxy}-4-fluorobenzoic acid methyl (2g) in tetrahydrofuran (20 mL) cooled in dry ice-acetone bath Diisobutylaluminum hydride (1.0 M hexane solution, 7.7 mL) was added dropwise thereto, and the mixture was stirred for 1 hour, and further diisobutylaluminum hydride (7.7 mL) was added thereto, followed by stirring for 1 hour. A potassium potassium tartrate solution was added, and the mixture was stirred for 1 hour, and then extracted with ethyl acetate. The solvent was distilled off under reduced pressure to give (3 -{[t-butyl(dimethyl)decyl)oxy}-4-fluorophenyl)methanol (1.7 g). 1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.19 ( s, 6H ), 1.00 ( s, 9 H) , 4.60 ( s, 2H) * 6.82-7.08 ( m, 3H ) (3) at (3- { [T-butyl(dimethyl)indenyl]oxy}-4-fluorophenyl)methanol (900 mg) in chloroform (2 mL) was added cerium oxide (9.2 g). Stir at night. After removing the insoluble matter in the past, the furnace liquid was concentrated under reduced pressure to give 3 -{[t-butyl(dimethyl)indenyloxy}-4-fluorobenzaldehyde (93 5 mg). (4) By the same procedure as in Production Example 2, 3_{[t-butyl(monomethyl)indenyl]oxy}_4·fluorobenzaldehyde (17 g) and 2-aminopropane (435 mg) N-(3-{[Terbutyl(dimethyl)decyl)oxy}-4-fluorobenzyl)propan-2-amine (2. g) was obtained. (ESI pos.) m/z : 298 ( [ M + H] + ) -27 - 201225955 (5) By the same method as in Production Example 4, from N-(3-{[T-butyl (dimethyl) N-( 3-{[,]- methoxy]-4-fluorobenzyl)propane-2-amine (2.0 g) with 1-methyl·1Η-imidazole-4-carboxylic acid (840 mg) Tert-butyl(dimethyl)indolyloxy}·4·fluorobenzyl)-^methyl-indole·(propan-2-yl)-1Η-imidazole·4-amineformamidine (1.19g) ). (ESI pos.) m/z : 406 ( [ M + H]+) (6) on N-(3-{[T-butyl(dimethyl)indenyl)oxy}-4-fluorobenz Tetrabutylammonium fluoride (1M tetrahydrofuran solution) was added to a solution of 1-methyl-N-(propan-2-yl)-1H-imidazol-4-aminecarboxamide (1-19 g) in THF (20 mL). 2.9 mL), stirred at room temperature for 10 minutes. Water was added and extracted with chloroform. After the solvent was evaporated under reduced pressure, the residue was purified mjjjjlililililililililililililililililili 1H NMR ( 600 MHz, CHLOROFORM-d ) d ppm 1.11-1.23 ( m,6H) * 3.70 ( br. s., 3H ) , 4.47-5.75 (m,3H) - 6.70- 7.55 ( m, 5H) (ESI Pos.) m/z : 292 ([M + H]+) Production Example 6 6-Bromo-5-fluoropyridine-2-carbaldehyde [Chemical 1 5]

(1 )於2-溴-3-氟-6-甲吡啶（500mg )的四氯化碳（ 10mL )溶液中力卩入N-溴琥珀醯亞胺（940mg)及過氧化苯甲醯基（102mg)，在80°C進行5小時加熱攪拌。在室溫 201225955 進行16.5小時攪拌後，追加N-溴琥珀醯亞胺（90mg)及過氧化苯甲醯基（2〇mg)，在80°C進行5小時加熱攪拌。在室溫進行1 8小時攪拌後，過濾分離不溶物，以氯仿洗淨。減壓下將溶劑餾去，將所得之殘渣以管柱層析法（矽膠匣，己烷：乙酸乙酯= 98: 2〜82: 18)與（矽膠匣與 NH矽膠匣，己烷：乙酸乙酯=98 : 2〜82 : 18 )進行純化後得到2 ·_溴-6 -(二溴甲基）-3 -氟耻D定（6 6 3 m g )。 (ESI p o s. ) m/z ： 346，348，3 50，3 52 ( 〔 M + H〕+ ) (2 )將2-溴-6-(二溴甲基）-3-氟吡啶（615mg)及碳酸鈣（391mg)的二甲基亞颯（6.5mL)溶液在150°C進行4.5小時加熱攪拌後恢復至室溫，並進行15.5小時攪拌。加入水並攪拌後，以乙酸乙酯萃取。將有機相以水及飽和食鹽水進行洗淨後，在減壓下將溶劑餾去。將所得之殘渣以管柱層析法（矽膠匣，己烷：乙酸乙酯= 98: 2〜82 :18)進行純化後得到標題化合物（ 240mg)。 1H NMR ( 600 MHz, CHLOROFORM-d ) d ppm 7.55-7.64 ( m，lH) - 7.95-8.03 ( m, 1H ) ，9.99(s，lH) (ESI pos. ) m/z ： 204，206 ( 〔M + H〕+ ) 實施例1 N，l-二甲基-N-〔 3-(三氟甲氧基）苯甲基〕-1H-咪唑-4-胺甲醯【化1 6】(1) Into a solution of 2-bromo-3-fluoro-6-methylpyridine (500 mg) in carbon tetrachloride (10 mL), N-bromosuccinimide (940 mg) and benzamidine peroxide ( 102 mg), heating and stirring at 80 ° C for 5 hours. After stirring at room temperature 201225955 for 16.5 hours, N-bromosuccinimide (90 mg) and benzammonium peroxide (2 mg) were added, and the mixture was heated and stirred at 80 ° C for 5 hours. After stirring at room temperature for 18 hours, the insoluble material was separated by filtration and washed with chloroform. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 98: 2 to 82: 18) and (yellow gum and NH oxime, hexane: acetic acid Ethyl ester = 98: 2 to 82: 18) After purification, 2·_bromo-6-(dibromomethyl)-3-fluorodisdodine (6 6 3 mg) was obtained. (ESI po s. ) m/z : 346,348,3 50,3 52 ( [ M + H]+ ) (2 ) 2-bromo-6-(dibromomethyl)-3-fluoropyridine (615 mg A solution of calcium carbonate (391 mg) in dimethyl hydrazine (6.5 mL) was heated and stirred at 150 ° C for 4.5 hours, then returned to room temperature, and stirred for 15.5 hours. After adding water and stirring, it was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography eluting elut elut elut elut elut elut elut 1H NMR ( 600 MHz, CHLOROFORM-d ) d ppm 7.55-7.64 ( m,lH) - 7.95-8.03 ( m, 1H ) , 9.99 (s,lH) (ESI pos. ) m/z : 204,206 ( M + H]+ ) Example 1 N,l-Dimethyl-N-[3-(trifluoromethoxy)benzyl]-1H-imidazol-4-aminecaramidine [Chem. 1 6]

-29- 201225955 氮環境下’於1-甲基-N-〔3-(三氟甲氧基）苯甲基〕-1H-咪唑-4-胺甲醯的二甲基甲醯胺（imL)溶液中加入氫化鈉（8mg)，在室溫進行1〇分鐘攪拌。加入碘化甲基 (12μ〇，在室溫進行30分鐘攪拌。加入飽和碳酸氫鈉水溶液並以乙酸乙酯萃取後，將有機層以水、飽和食鹽水的順序洗淨，以無水硫酸鎂乾燥。過濾分離乾燥劑後，將濾液在減壓下濃縮，殘渣以管柱層析法（矽膠匣，氯仿/ 甲醇=1 : 0〜49 : 1 )進行純化後得到標題化合物（42mg 實施例2 N-〔 3-氯- 5-(三氟甲氧基）苯甲基〕-1-甲基-N-(丙烷-2-基）-1H-1，2,4-三唑基-3-胺甲醯鹽酸鹽-29- 201225955 dimethylformamide (imL) of 1-methyl-N-[3-(trifluoromethoxy)benzyl]-1H-imidazol-4-aminecarboxamide under nitrogen atmosphere Sodium hydride (8 mg) was added to the solution, and the mixture was stirred at room temperature for 1 minute. Add methyl iodide (12 μM, and stir for 30 minutes at room temperature. After adding saturated aqueous sodium hydrogencarbonate solution and extracting with ethyl acetate, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After the separation of the desiccant by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography eluted eluted elut elut elut elut elut -[ 3-chloro-5-(trifluoromethoxy)benzyl]-1-methyl-N-(propan-2-yl)-1H-1,2,4-triazolyl-3-amine Formamidine hydrochloride

將N-〔 3-氯- 5-(三氟甲氧基）苯甲基〕丙烷-2-胺（ 23 2mg ) 、1-甲基·1Η-咪唑-4-羧酸（99mg) 、EDC.HC1( 1 96mg ) 、HOBT · H20 ( 144mg )與二甲基甲醯胺（6mL)N-[3-chloro-5-(trifluoromethoxy)benzyl]propan-2-amine (23 2 mg), 1-methyl·1Η-imidazole-4-carboxylic acid (99 mg), EDC. HC1 (1 96mg), HOBT · H20 (144mg) and dimethylformamide (6mL)

的混合物在室溫進行一晚攪拌。減壓下將溶劑餾去，於殘渣加入飽和碳酸氫鈉水溶液與乙酸乙酯並萃取。將有機層以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨，以無水硫酸鈉乾燥。過濾分離乾燥劑，將濾液在減壓下進行濃縮後，殘渣以管柱層析法（NH匣、己烷/乙酸乙酯=9 : 1〜1 : 1 ) 進行純化。將生成物之135mg溶解於乙酸乙酯，加入4M 201225955 鹽酸/乙酸乙酯並進行5分鐘攪拌後，在減壓下將溶劑餾去。於殘渣加入乙酸乙酯及己烷，將析出的固體過濾取出後得到標題化合物（89mg)。實施例3 1-甲基-N-(丙烷-2-基）-N-〔 3-(三氟甲氧基）苯甲基〕-1H-1，2,4-三唑基-3-胺甲醯【化1 8】The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine and dried over anhydrous sodium sulfate. The desiccant was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc, hexane/ethyl acetate = 9:1 to 1:1). After 135 mg of the product was dissolved in ethyl acetate, 4M 201225955 hydrochloric acid / ethyl acetate was added and stirred for 5 minutes, and then the solvent was evaporated under reduced pressure. Ethyl acetate and hexane were added to the residue. Example 3 1-Methyl-N-(propan-2-yl)-N-[3-(trifluoromethoxy)benzyl]-1H-1,2,4-triazolyl-3-amine Hyperthyroidism

於N-(丙烷-2-基）-Ν·〔3-(三氟甲氧基）苯甲基〕· 1Η-1，2,4-三唑基-3-胺甲醯（ 400mg)的二甲基甲醯胺（ 5mL)溶液中加入氫化鈉（6〇mg)，在室溫進行1〇分鐘攪拌。加入碘化甲基（43〇mg)，在室溫進行2小時攪拌。加入水，以乙酸乙酯萃取後，將溶劑在減壓下餾去。將殘渣以PTLC (矽膠）（氯仿/甲醇=1 8 : 1 )進行純化後得到標題化合物（2 0 0 m g ) ^ 實施例4N-{4-氟- 3-〔4-(三氟甲氧基）苯氧基〕苯甲基 }-卜甲基-N-(丙院-2-基）-1H -咪嗤-4-胺甲醯【化1 9】N-(propan-2-yl)-indole[3-(trifluoromethoxy)benzyl]·1Η-1,2,4-triazolyl-3-aminecarboxamide (400 mg) Sodium hydride (6 mg) was added to a solution of methylformamide (5 mL) and stirred at room temperature for 1 min. Methyl iodide (43 mg) was added and stirred at room temperature for 2 hours. After adding water and extracting with ethyl acetate, the solvent was evaporated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc Phenoxy]benzyl}-bumethyl-N-(propyl-2-yl)-1H-imida-4-amine-methyl hydrazine

將N- ( 4·氟-3-羥基苯甲基）-1-甲基-N-(丙烷-2-基 )-1H-咪唑-4-胺甲醯（i00mg) 、4-三氟甲氧基苯基硼酸 Ό -31 - 201225955 (140mg )、乙酸銅（II) 1水合物（68mg)、三乙胺（ 171mg) 、4A分子舗與氯仿（3mL)之混合物在室溫進行一晚攪伴。加入氯仿及水，分出液體後，將有機層在減壓下進行濃縮。將殘渣以HPLC進行純化後得到標題化合物 (20mg )。實施例5Ν-{3-〔1，1-二氟-2-(吡咯烷-1-基）乙氧基〕_ 4 -氟苯甲基} -1-甲基-N-(丙烷-2-基）-1H -咪唑-4-胺甲醯【化2 0】N-(4.Fluoro-3-hydroxybenzyl)-1-methyl-N-(propan-2-yl)-1H-imidazol-4-aminecarboxamide (i00mg), 4-trifluoromethoxy Mixture of phenylphenylborate -31 - 201225955 (140mg), copper (II) acetate 1 hydrate (68mg), triethylamine (171mg), 4A molecular sieve and chloroform (3mL) at room temperature for one night . After adding chloroform and water, the liquid was separated, and the organic layer was concentrated under reduced pressure. The residue was purified with EtOAcqqqqqq Example 5 Ν-{3-[1,1-Difluoro-2-(pyrrolidin-1-yl)ethoxy]-4-fluorobenzyl}-1-methyl-N-(propane-2- Base)-1H-imidazole-4-amine formazan [化2 0]

(1)將N- ( 4-氟-3-羥基苯甲基）-1-甲基-N-(丙烷-2-基）-1Η-咪唑-4-胺甲醯（150mg) 、4-甲基苯磺酸 2,2- 二氟乙烯基（145mg)、氫氧化鉀（70mg)與乙腈（6mL )的混合物在室溫進行3 0分鐘攪拌》加入水、氯仿，分出液體後，將有機層在減壓下進行濃縮。殘渣以管柱層析法（矽膠匣，氯仿/甲醇=1 : 0〜1 9 : 1 )進行純化，得到 4-甲基苯磺酸 2,2-二氟-2-〔2-氟-5-( { 〔（1-甲基-1H-咪唑-4-基）羰基〕（丙烷-2-基）胺基}甲基）苯氧基〕乙基（260mg)。 (ESI pos. ) m/z : 526 ( 〔 M + H〕+) s -32- 201225955 (2)將4-甲基苯磺酸 2,2-二氟-2-〔 2-氟-5- ( {〔 (1-甲基-1H-咪唑-4-基）羰基〕（丙烷-2-基）胺基}甲基）苯氧基〕乙基（lOOmg )溶解於吡咯烷（3mL)在微波照射下，在150°C進行1小時加熱。將反應液以PTLC ( 氯仿/甲醇=1 8 : 1 )進行純化後得到標題化合物（1 9mg ) 實施例6N-環丁基-N-〔4-氟-3-(三氟甲氧基）苯甲基〕-1-甲基-1H-咪唑-4-胺甲醯鹽酸鹽(1) N-(4-Fluoro-3-hydroxybenzyl)-1-methyl-N-(propan-2-yl)-1Η-imidazol-4-aminecarboxamide (150 mg), 4-methyl A mixture of 2,2-difluorovinyl (145 mg), potassium hydroxide (70 mg) and acetonitrile (6 mL) at room temperature was stirred at room temperature for 30 minutes. Water, chloroform was added, and the liquid was separated and organic The layers were concentrated under reduced pressure. The residue was purified by column chromatography (purine oxime, chloroform/methanol = 1: 0 to 1 : 1 : 1) to give 2-, 4-difluorobenzene. -( { 〔(1-Methyl-1H-imidazol-4-yl)carbonyl)(propan-2-yl)amino}methyl)phenoxy]ethyl (260 mg). (ESI pos. ) m/z : 526 ( [ M + H]+) s -32- 201225955 (2) 4-methylbenzenesulfonic acid 2,2-difluoro-2-[2-fluoro-5- ({[(1-Methyl-1H-imidazol-4-yl)carbonyl)(propan-2-yl)amino}methyl)phenoxy]ethyl (100 mg) dissolved in pyrrolidine (3 mL) in microwave Heating was carried out at 150 ° C for 1 hour under irradiation. The title compound (1 9 mg) was obtained after purification of EtOAc EtOAc (EtOAc (EtOAc) Methyl]-1-methyl-1H-imidazol-4-amine formamidine hydrochloride

於1 -甲基-1 H-咪唑-4-羧酸（256mg )的甲醇（1 OmL ) 溶液中加入二異丙基乙胺（391μΙ>) 、DMT-MM( 655mg) 、及N-〔 4-氟-3-(三氟甲氧基）苯甲基〕環丁烷胺（ 445mg ) ’在室溫進行一晚攪拌。加入飽和碳酸氫鈉水溶液’以氯仿萃取後，將有機層以無水硫酸鎂乾燥。將乾燥劑過濾分離’將濾液在減壓下進行濃縮。將殘渣以HPLC 進行純化，溶解於1 .OM鹽酸後，冷凍乾燥後得到標題化合物（6 8 m g )。實施例1至6所示化合物、與以同樣方法所合成之化合物的結構式與這些儀器數據如表1-1至丨_4所示。表中的實施例欄所記載之數字表示該化合物爲上述實施例1至 6內與所有實施例之同樣方法進行合成者。 -33- 201225955 【表1 一 1】化合物實施例構造 (ESI pos.) m/z NMR 1 2 丫 382 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.95 - 1.93 (m, 10 H), 3.61 - 5.41 (m, 3 H), 7.00 - 7.57 (m, 6 H) 2 1 丫 / 314([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 2.94 - 3.49 (m, 3 H), 3.72 (br. s.. 3 H). 4.67 - 5.43 (m, 2 H). 7.07 - 7.43 (m, 5 H). 7.56 - 7.62 (m. 1 H) 3 1 丫 328([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.11 - 1.28 (m. 3 H), 3.40 - 4.07 (m. 2 H), 3.66 - 3.79 (m, 3 H), 4.68 - 5.44 (m, 2 H), 7.07 - 7.44 (m. 5 H). 7.58 - 7.62 (m, 1 H) 4 1 342([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.76 - 0.97 (m, 3 H), 1.58 - 1.70 (m. 2 H). 3.28 - 3.98 (m, 2 H), 3.71 (br. s., 3 H). 4.67 - 5.45 (m. 2 H), 7.06 - 7.40 (m. 5 H), 7.55 - 7.61 (m. t H) 5 1 Ρ^α°>ρ /〇 380 ([M+Na]+) 1H NMR (600 MHzf CHLOROFORM-d) d ppm 3.30 (br. s.. 3 H). 3.50 - 4.25 (m, 4 H)f 3.71 (br. s.r 3 H), 4.79 - 5.56 (m, 2 H)t 7.04 - 7.64 (m, 6 H) 6 1 356([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.78 - 0.99 (m, 6 H), 1.93 - 2.17 (m, 1 H), 3.17 - 4.07 (m, 2 H), 3.70 (br. s„ 3 H). 4.69 - 5.53 (m, 2 H), 7.04 - 7.63 (m. 5 H) 7 2 οάχτ 丫 / 342([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.08 - 1.23 (m, 6 H), 3.71 (br. s„ 3 H), 4.58 - 5.78 (m. 3 H), 7.01 - 7.58 (m, 6 H) 8 2 / OH 39B([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.55 - 1.86 (m, 8 H), 3.74 (s. 3 H), 3.77 (s, 2 H), 4.34 (s. 2 H), 7.03 - 7.58 (m, 6 H) -34- 201225955 【表1 - 2】化合物實施例構造 (ESI pos.) m/z NMR 9 3 343([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.10 - 1.32 (m, 6 H), 3.84 - 4.04 (m, 3 H), 4.60 - 4.91 (m, 3 H), 7.03 - 7.37 (m, 4H), 7.91 -8.12(m, 1 H) 10 2 ο^οχ 376, 378 ([M+Na]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.11 - 1.26 (m. 6 H) 3.63 - 3.78 (m, 3 H) 4.48 - 5.79 (m. 3 H) 6.95 - 7.59 (m, 5 H) 11 2 416, 418 ([M+Na]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.99 - 1.86 (m, 10 H) 3.70 (br. s., 3 H) 4.33 - 5.32 (mt 3 H) 6.95 - 7.58 (m, 5 H) 12 3 ρότο: 355, 357([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.13 - 1.23 (m, 6 H) 3.88 - 4.04 (m, 3 H) 4.60 - 4.83 (tn, 3 H) 7.00 - 7.08 (m, 1 H) 7.20 - 8.13 (m. 3 H) 13 3 p^CC 395, 397([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.95 - 1.89 (m, 10 H) 3.83 - 4.85 (m. 6H) 6.95 - 8.17 (m, 4 H) 14 2 346([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.17 - 1.24 (m, 6 H), 4.59 - 5.33 (m, 3 H), 7.06 - 7.67 (m, 5 H) 15 2 kJ 01 HCI 416([M+H]+) 1H NMR (600 MHz, METHANOL-d3) d pp巾 1.08 - 1.89 (m. 10 H), 3.94 - 4.94 (m, 6 H), 7.14 - 9.10 (m, 5 H) 16 2 (J^yt 丨 Cl HCI 375([M+H]+) 1H NMR (600 MHz, METHANOU-d3) d ppm 1.26 - 1.36 (m, 6 H), 3.91 - 4.80 (m, 3 H), 4.84 (s, 3 H), 7.17 - 9.07 (m, 5 H)To a solution of 1-methyl-1 H-imidazole-4-carboxylic acid (256 mg) in methanol (1 mL) was added diisopropylethylamine (391 μΙ), DMT-MM (655 mg), and N-[ 4 -Fluoro-3-(trifluoromethoxy)benzyl]cyclobutaneamine (445 mg) 'Agitated overnight at room temperature. After the addition of a saturated aqueous solution of sodium hydrogencarbonate was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate. The desiccant was separated by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc) elute The structural formulas of the compounds shown in Examples 1 to 6, and the compounds synthesized in the same manner are shown in Tables 1-1 to 丨4. The numbers shown in the column of the examples in the table indicate that the compound was synthesized in the same manner as in all of the examples in the above Examples 1 to 6. -33- 201225955 [Table 1 - 1] Compound Example Construction (ESI pos.) m/z NMR 1 2 丫382 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.95 - 1.93 (m, 10 H), 3.61 - 5.41 (m, 3 H), 7.00 - 7.57 (m, 6 H) 2 1 丫/ 314([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d Ppm 2.94 - 3.49 (m, 3 H), 3.72 (br. s.. 3 H). 4.67 - 5.43 (m, 2 H). 7.07 - 7.43 (m, 5 H). 7.56 - 7.62 (m. 1 H 3 1 丫 328([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.11 - 1.28 (m. 3 H), 3.40 - 4.07 (m. 2 H), 3.66 - 3.79 (m , 3 H), 4.68 - 5.44 (m, 2 H), 7.07 - 7.44 (m. 5 H). 7.58 - 7.62 (m, 1 H) 4 1 342([M+H]+) 1H NMR (600 MHz , CHLOROFORM-d) d ppm 0.76 - 0.97 (m, 3 H), 1.58 - 1.70 (m. 2 H). 3.28 - 3.98 (m, 2 H), 3.71 (br. s., 3 H). 4.67 - 5.45 (m. 2 H), 7.06 - 7.40 (m. 5 H), 7.55 - 7.61 (m. t H) 5 1 Ρ^α°>ρ /〇380 ([M+Na]+) 1H NMR ( 600 MHzf CHLOROFORM-d) d ppm 3.30 (br. s.. 3 H). 3.50 - 4.25 (m, 4 H)f 3.71 (br. sr 3 H), 4.79 - 5.56 (m, 2 H)t 7.04 - 7.64 (m, 6 H) 6 1 356([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d pp m 0.78 - 0.99 (m, 6 H), 1.93 - 2.17 (m, 1 H), 3.17 - 4.07 (m, 2 H), 3.70 (br. s„ 3 H). 4.69 - 5.53 (m, 2 H) , 7.04 - 7.63 (m. 5 H) 7 2 οάχτ 丫/ 342([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.08 - 1.23 (m, 6 H), 3.71 (br. s„ 3 H), 4.58 - 5.78 (m. 3 H), 7.01 - 7.58 (m, 6 H) 8 2 / OH 39B([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.55 - 1.86 (m, 8 H), 3.74 (s. 3 H), 3.77 (s, 2 H), 4.34 (s. 2 H), 7.03 - 7.58 (m, 6 H) -34- 201225955 [Table 1 - 2] Compound Example Construction (ESI pos.) m/z NMR 9 3 343 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.10 - 1.32 (m, 6 H), 3.84 - 4.04 (m, 3 H), 4.60 - 4.91 (m, 3 H), 7.03 - 7.37 (m, 4H), 7.91 -8.12(m, 1 H) 10 2 ο^οχ 376, 378 ([M+Na ]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.11 - 1.26 (m. 6 H) 3.63 - 3.78 (m, 3 H) 4.48 - 5.79 (m. 3 H) 6.95 - 7.59 (m, 5 H 11 2 416, 418 ([M+Na]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.99 - 1.86 (m, 10 H) 3.70 (br. s., 3 H) 4.33 - 5.32 (mt 3 H) 6.95 - 7.58 (m, 5 H) 12 3 ρότο: 355, 357 ([M+H ]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.13 - 1.23 (m, 6 H) 3.88 - 4.04 (m, 3 H) 4.60 - 4.83 (tn, 3 H) 7.00 - 7.08 (m, 1 H 7.20 - 8.13 (m. 3 H) 13 3 p^CC 395, 397([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.95 - 1.89 (m, 10 H) 3.83 - 4.85 (m. 6H) 6.95 - 8.17 (m, 4 H) 14 2 346([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.17 - 1.24 (m, 6 H), 4.59 - 5.33 (m, 3 H), 7.06 - 7.67 (m, 5 H) 15 2 kJ 01 HCI 416([M+H]+) 1H NMR (600 MHz, METHANOL-d3) d pp towel 1.08 - 1.89 (m. 10 H), 3.94 - 4.94 (m, 6 H), 7.14 - 9.10 (m, 5 H) 16 2 (J^yt 丨Cl HCI 375([M+H]+) 1H NMR (600 MHz, METHANOU-d3) d ppm 1.26 - 1.36 (m, 6 H), 3.91 - 4.80 (m, 3 H), 4.84 (s, 3 H), 7.17 - 9.07 (m, 5 H)

35- 201225955 【表1 - 3】化合物實施例構造 (ESI pos.) m/z NMR 17 3 Cl 377([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.14-1.30 (m. 6 H), 3.87 - 4.04 (m, 3 H), 4.64 - 4.88 (m, 2 H), 4.71 - 4.80 (m, 1 H), 7.05-8.15 (m. 4 H) 18 3 '~/ Cl 403([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.45 - 1.99 (m, 8 H), 3.86 - 4.06 (m, 3 H). 4.62 - 4.94 (m. 3 H), 7.02 - 8.16 (m. 4 H) 19 2 ρόοα 276 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.11-1.22 (m, 6 H). 3.65 - 3.75 (m, 3 H), 4.55 - 5.74 (m, 3 H), 6.89 - 7.00 (m, 2 H), 7.22 - 7.44 (m, 3 H), 7.50 - 7.56 (m, 1 H) 20 4 Ρ^οοοα 火 452([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.08 - 1.21 (m. 6 H), 3.69 (br. s.. 3 H). 4.51 - 5.70 (m, 3 H), 6.86 - 7.54 (m. 9 H) 21 4 P^rocxr^ 452([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.07 - 1.24 (m, 6 H), 3.70 (br. s., 3 H), 4.52 - 5.75 (m, 3 H). 6.77 - 7.59 (m, 9 H) 22 4 ρόοοοο 368([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.09 - 1.21 (m, 6 H), 3.69 (br. sM 3 H). 4.52 - 5.72 (m. 3 H). 6.85 - 7.55 (m, 10 H) 23 5 425([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.11 - 1.23 (m. β H), 1.77 - 1.91 (m. 4 H), 2.70 - 2.84 (m, 4 H), 3.12 - 3.24 (m, 2 H), 3.69 (br. s„ 3 H), 4.58 - 5.73 (m. 3 H), 6.97 - 7.56 (m, 5 H) 24 3 361([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d 叩m 1.13 - 1.26 (m, 6 H). 3.85 - 4.03 (m. 3 H), 4.61 - 4.85 (m, 3 H), 7.06 - 7.34 (m, 3H), 7.89-8.12 (m, 1 H) s -36- 201225955 【表1 -4】化合物實施例構造 (ESI pos.) m/z NMR 25 2 402([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.59 - 1.84 (m, 4 H), 3.39 - 3.50 (m, 2 H). 3.72 (br. s.. 3 H), 3.91 - 4.01 (m. 2 H). 4.62 - 5.65 (m, 3 H). 7.07 - 7.14 (m. 1 H). 7.15 - 7.40 (m. 3 H), 7.55 - 7.61 (m. 1 H) 26 2 ρΛαχ 2HCI 337, 339 ([M+H]+) 1H NMR (600 MHz. DMSO-d6) d ppm 1.01 - 1.28 (m, 6 H). 3.83 - 3.93 (m. 3 H). 4.54 - 4.96 (m. 3 H). 7.27 - 7.59 (m, 3 H). 8.12 - 8.38 (m. 3 H). 9.07 (br. s.. 1 H) 27 2 ΡΛτσΓ 337, 339 ([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.08 - 1.27 (m, 6 H). 3.72 (br. s.. 3 H). 4.57 - 5.88 (m, 3 H). 7.07 - 7.47 (m. 3 H〉. 7.63 - 7.的（m. 1 H). 8.49 - 8.66 (m. 1 H) 28 2 ρόαχ 355, 357 ([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm t.05 - 1.28 (m. 6 H). 3.60 - 3.78 (m. 3 H), 4.60 - 5.79 (m. 3 H). 7.12 - 7.67 (m. 4H) 29 6 pV〇；t HCI 372([M+H]+) 1H NMR (600 MHz, METHAN0L-d3) d ppm 1.60 - 1.81 (m, 2 H), 2.16 - 2.39 (m. 4 H). 3.99 (br. s.. 3 H). 4.73 - 4.96 (m. 3 H). 7.31 (d. J=6.0 Hz. 3 H). 8.05 (br. s.. 1 H). 9.04 (s. 1 H) 30 2 pVp^ Qhc, F 392 ([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 3.99 (br. s.t 3 H), 4.59 - 5.13 (m, 4 H), 6.93 - 7.81 (m. 10 H), 9.21 (br s., 1 H) 31 2 349. 351 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.57 - 2.28 (m, 6 H), 3.64 - 3.79 (m, 3 H). 4.56 - 5.90 (m, 3 H), 6.18 - 8.30 (m. 5 H) 試驗例1〔甘胺酸之吸收阻礙實驗〕甘胺酸吸收實驗爲依據Neur〇n,8,927-935，1 992所揭示的方法進行。使用表現人類1型甘胺酸運輸體（GlyTl )的神經膠腫之T98G細胞。將T98G細胞播種於96孔盤至2.0 X 1 04個/?L，於碳酸氣恆溫培養器內進行—晚培養。 -37- 201225955 被檢物質溶解於100%DMSO溶液後，溶解於含有150mM 氯化鈉、ImM氯化鈣、5mM氯化鉀、ImM氯化鎂、10mM 葡萄糖及 0.2°/。牛血清白蛋白的 lOmMHEPES緩衝液（ PH7.4 )。除去細胞培養用培養基後，將被檢物質進行1〇分鐘前處置。其後將被檢物質及〔3h〕甘胺酸（最終濃度 2 5 OnM )添加於細胞，在室溫進行1 5分鐘反應。反應終了後，以排氣管吸出細胞外液，除去存在於細胞外之多餘標識甘胺酸後，於0.5M的氫氧化鈉水溶液溶解細胞。存在於細胞內之甘胺酸量藉由將細胞溶解液中之放射活性以液體閃爍細胞計數器進行測定而求得。於ΙΟμΜ的ALX5407 存在下之甘胺酸吸收量作爲非專一性吸收，由ΙΟμΜ的 ALX 5 4 07非存在下之總吸收量減去非專一性吸收量作爲專 —性吸收量。又，由在被檢物質之1〇·9〜1〇_5Μ濃度的抑制曲線算出甘胺酸吸收阻礙活性（IC5Q値）。且 ALX5407 爲 N-〔（ 3R ) -3- (〔 1，1，-聯苯〕-4-氧基）-3-(4 -氟苯基）丙基〕-N -甲基甘胺酸HC1鹽。所有本發明化合物之IC5Q値皆爲ΙμΜ以下。本發明化合物中’化合物1〜7、9〜11、13、15、16、18、20、 21、24〜26、29、31的IC5。値爲〇.1μΜ以下。其中亦以化合物 1、 5〜7、 11、 15、 16、 18、 25、 29 的 IC5〇値爲 0.0 1 μ Μ 以下。試驗例2〔膜透過性實驗〕對於醫藥品開發之膜透過性，由作爲經口投與的醫藥 -38- 201225955 體內吸收率之觀點來看係爲重要要素之1，膜透過性高的化合物作爲醫藥品時可期待對腸管之良好吸收（參考 Pharmaceutical Research ( 2002 ) Vol.19, No.7, 921-925) ο 膜透過性試驗使用PAMPA EvolutionTM(pI〇N公司 )，依據pION公司所推薦的操作手冊進行。即調整評估化合物溶液（將評估化合物的DMSO溶液添加於調整至各 pH (4.0, 5.0，6.2，7.4)的系統溶液（system solution)中並稀釋者），添加於以人工脂質（GIT-0 )形成脂質雙層膜的夾心（sandwich)盤之下段（Donor)。於上段（ Acceptor)添加 acceptor sink buffer，經一定時間後，由 Donor及Acceptor溶液之UV測定所得之化合物的累積透過量算出膜透過係數Pe ( xl(T6Cm/SeC )，評估化合物之膜透過性。該結果得知以實施試驗的本案化合物No.l、4 〜7、9、16、29之所有化合物，以pION公司的操作手冊記載之判定基準判定爲^ high」，表示得到良好膜透過性試驗例3〔 P-gp的基質辨識性試驗〕對中樞神經系產生作用之藥物一般由血中移至腦內在藥效表現上爲重要。作爲於血液腦關門控制藥物移行性的排出（efflux) transporter的代表性物質中存在P-糖蛋白質（P-glycoprotein，P-gp) ，P-gp爲阻礙成爲該基質的藥物之腦移行。因此對於醫藥品開發而言，作爲P-gp的基 -39- 201225955 質無法被辨識者成爲腦移行性的指標。 P-gp的基質辨識性試驗係以依據J Pharmacol. Exp. Ther. ( 1 992 ) Vol. 263，No. 2，840-845 及 J Biol. Chem.( 1992) Vol. 267，No. 34，24248-24252 所記載之方法進行。即，於transwell上進行4天培養的LLC-GA5-COL300 細胞（來自豬腎之培養腎上皮細胞株LLC-PK1的人類 MDR1表現系統），試驗前將孔內以Hank's balanced salt solution ( HBSS )取代後提供於試驗。將評估化合物溶液 (將評估化合物的DMSO溶液以HBSS稀釋，調整至最終濃度1〇μΜ者）添加於，LLC-GA5-COL300細胞的提供體（ Donor )側後，由受體（Acceptor )側經時性地採取一定量HBSS，以LC-MS/MS測定採取樣品中之評估化合物濃度。由對於受體側之化合物的累積透過量，算出 Apical — Basal 及 Basal — Apical 的各膜透過係數（M0·6 cm/sec)，由該比（Efflux Ratio)評估P-gp的基質辨識性。該結果得知實施試驗的本案化合物Νο·9、16、24，對於 N ature Re νi e ws Drug D i s co νer y ( 2 0 1 0 ) ，Vο 1 · 9，2 1 5-23 6所記載之.判定基準皆被判訂爲作爲P-gP的基質無法被辨識，顯示良好腦移行性（Pharmaceutical Research ( 2001) ，Vol. 18，No. 12，1660-1668 参照）。由該結果得知，本案化合物可期待作爲對中樞神經系產生作用之藥物使用時爲有效。35-201225955 [Table 1-3] Compound Example Construction (ESI pos.) m/z NMR 17 3 Cl 377 ([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.14-1.30 ( m. 6 H), 3.87 - 4.04 (m, 3 H), 4.64 - 4.88 (m, 2 H), 4.71 - 4.80 (m, 1 H), 7.05-8.15 (m. 4 H) 18 3 '~/ Cl 403 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.45 - 1.99 (m, 8 H), 3.86 - 4.06 (m, 3 H). 4.62 - 4.94 (m. 3 H ), 7.02 - 8.16 (m. 4 H) 19 2 ρόοα 276 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.11-1.22 (m, 6 H). 3.65 - 3.75 (m , 3 H), 4.55 - 5.74 (m, 3 H), 6.89 - 7.00 (m, 2 H), 7.22 - 7.44 (m, 3 H), 7.50 - 7.56 (m, 1 H) 20 4 Ρ^οοοα fire 452([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.08 - 1.21 (m. 6 H), 3.69 (br. s.. 3 H). 4.51 - 5.70 (m, 3 H ), 6.86 - 7.54 (m. 9 H) 21 4 P^rocxr^ 452([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.07 - 1.24 (m, 6 H), 3.70 ( Br. s., 3 H), 4.52 - 5.75 (m, 3 H). 6.77 - 7.59 (m, 9 H) 22 4 ρόοοοο 368([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.09 - 1.21 (m, 6 H), 3.69 (br. sM 3 H). 4.52 - 5.72 (m. 3 H). 6.85 - 7.55 (m, 10 H) 23 5 425 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.11 - 1.23 (m. β H) , 1.77 - 1.91 (m. 4 H), 2.70 - 2.84 (m, 4 H), 3.12 - 3.24 (m, 2 H), 3.69 (br. s„ 3 H), 4.58 - 5.73 (m. 3 H) , 6.97 - 7.56 (m, 5 H) 24 3 361([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d 叩m 1.13 - 1.26 (m, 6 H). 3.85 - 4.03 (m. 3 H), 4.61 - 4.85 (m, 3 H), 7.06 - 7.34 (m, 3H), 7.89-8.12 (m, 1 H) s -36- 201225955 [Table 1-4] Compound Example Construction (ESI pos .) m/z NMR 25 2 402([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.59 - 1.84 (m, 4 H), 3.39 - 3.50 (m, 2 H). (br. s.. 3 H), 3.91 - 4.01 (m. 2 H). 4.62 - 5.65 (m, 3 H). 7.07 - 7.14 (m. 1 H). 7.15 - 7.40 (m. 3 H), 7.55 - 7.61 (m. 1 H) 26 2 ρΛαχ 2HCI 337, 339 ([M+H]+) 1H NMR (600 MHz. DMSO-d6) d ppm 1.01 - 1.28 (m, 6 H). 3.83 - 3.93 ( m. 3 H). 4.54 - 4.96 (m. 3 H). 7.27 - 7.59 (m, 3 H). 8.12 - 8.38 (m. 3 H). 9.07 (br. s.. 1 H) 27 2 ΡΛτσΓ 337 , 339 ([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.08 - 1.27 (m, 6 H). 3.72 (br. s.. 3 H). 4.57 - 5.88 (m, 3 H). 7.07 - 7.47 (m. 3 H>. 7.63 - 7. (m. 1 H). 8.49 - 8.66 (m. 1 H) 28 2 ρόαχ 355, 357 ([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm t.05 - 1.28 (m. 6 H). 3.60 - 3.78 (m. 3 H), 4.60 - 5.79 (m. 3 H). 7.12 - 7.67 (m. 4H) 29 6 pV〇;t HCI 372([M+H]+) 1H NMR (600 MHz, METHAN0L-d3 d ppm 1.60 - 1.81 (m, 2 H), 2.16 - 2.39 (m. 4 H). 3.99 (br. s.. 3 H). 4.73 - 4.96 (m. 3 H). 7.31 (d. J= 6.0 Hz. 3 H). 8.05 (br. s.. 1 H). 9.04 (s. 1 H) 30 2 pVp^ Qhc, F 392 ([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d ) d ppm 3.99 (br. st 3 H), 4.59 - 5.13 (m, 4 H), 6.93 - 7.81 (m. 10 H), 9.21 (br s., 1 H) 31 2 349. 351 ([M+ H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.57 - 2.28 (m, 6 H), 3.64 - 3.79 (m, 3 H). 4.56 - 5.90 (m, 3 H), 6.18 - 8.30 ( m. 5 H) Test Example 1 [Absorption inhibition test of glycine] The glycine absorption test was carried out in accordance with the method disclosed in Neuron, 8, 927-935, and 992. T98G cells expressing a neuroglioma of human type 1 glycine transporter (GlyTl) were used. T98G cells were seeded in a 96-well plate to 2.0 X 1 04 cells/μL, and cultured in a carbonic acid thermostat. -37- 201225955 After the test substance was dissolved in a 100% DMSO solution, it was dissolved in 150 mM sodium chloride, 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose, and 0.2 °/. Bovine serum albumin in lOmMHEPES buffer (pH 7.4). After the medium for cell culture is removed, the test substance is disposed of 1 minute before. Thereafter, the test substance and [3h]glycine (final concentration 25 OnM) were added to the cells, and the reaction was carried out at room temperature for 15 minutes. After the end of the reaction, the extracellular fluid was aspirated through an exhaust tube to remove excess glycine acid present outside the cells, and the cells were lysed in a 0.5 M aqueous sodium hydroxide solution. The amount of glycine present in the cells is determined by measuring the radioactivity in the cell lysate as a liquid scintillation counter. The amount of glycine absorbed in the presence of ALX5407 in ΙΟμΜ was used as a non-specific absorption, and the total absorption in the absence of ALX 5 4 07 in ΙΟμΜ minus the non-specific absorption was used as the specific absorption. Further, the glycine acid absorption inhibiting activity (IC5Q値) was calculated from the inhibition curve of the concentration of the test substance at a concentration of 1 〇 9 to 1 〇 5 。. And ALX5407 is N-[( 3R ) -3-([ 1,1,-biphenyl]-4-oxy)-3-(4-fluorophenyl)propyl]-N-methylglycine HC1 salt. All IC5Q値 of the compounds of the present invention are below ΙμΜ. In the compound of the present invention, IC5 of 'Compounds 1 to 7, 9 to 11, 13, 15, 16, 18, 20, 21, 24 to 26, 29, 31.値 is 〇.1μΜ or less. Among them, the IC5〇化合物 of the compounds 1, 5 to 7, 11, 15, 16, 18, 25, 29 is 0.0 1 μ Μ or less. Test Example 2 [Film Permeability Test] The membrane permeability of the drug-developed drug is one of the important factors in the in vivo absorption rate of the drug-38-201225955, which is orally administered, and has a high membrane permeability. Good absorption of the intestine can be expected as a pharmaceutical product (refer to Pharmaceutical Research (2002) Vol.19, No. 7, 921-925) ο The membrane permeability test uses PAMPA EvolutionTM (pI〇N), according to the recommendation of pION The operation manual is carried out. That is, the evaluation compound solution was adjusted (the DMSO solution of the evaluation compound was added to a system solution adjusted to each pH (4.0, 5.0, 6.2, 7.4) and diluted), and added to artificial lipid (GIT-0). The lower disc of the sandwich disc (Donor) forming the lipid bilayer membrane. The acceptor sink buffer was added to the upper stage, and after a certain period of time, the membrane permeability coefficient Pe (x1 (T6Cm/SeC) was calculated from the cumulative permeation amount of the compound obtained by UV measurement of the Donor and Acceptor solutions, and the membrane permeability of the compound was evaluated. As a result, it was found that all the compounds of the present compounds No. 1, 4 to 7, 9, 16, and 29 which were tested were judged to be "high" based on the judgment standard described in the operation manual of the pION company, indicating that a good film permeability test was obtained. Example 3 [Principal identification test of P-gp] The drug that acts on the central nervous system is generally important to move from the blood to the brain in terms of pharmacodynamic performance. As a blood-brain-closure control drug migration (efflux) transporter P-glycoprotein (P-gp) is present in a representative substance, and P-gp is a brain migration that hinders the drug to be the matrix. Therefore, for the development of pharmaceuticals, as a base of P-gp-39 - 201225955 The unidentifiable substance becomes an indicator of brain migration. The matrix identification test of P-gp is based on J Pharmacol. Exp. Ther. (1 992 ) Vol. 263, No. 2, 840-845 and J Biol . Ch The method described in em. (1992) Vol. 267, No. 34, 24248-24252, that is, LLC-GA5-COL300 cells cultured on transwell for 4 days (cultured kidney epithelial cell line LLC from pig kidney) PK1 human MDR1 expression system), before the test, the wells were replaced with Hank's balanced salt solution (HBSS) and then provided in the test. The compound solution will be evaluated (the DMSO solution of the evaluation compound is diluted with HBSS and adjusted to a final concentration of 1 μμΜ). After addition to the donor ( Donor ) side of LLC-GA5-COL300 cells, a certain amount of HBSS was taken from the acceptor side over time, and the concentration of the evaluated compound in the sample was taken by LC-MS/MS. The membrane permeability coefficient (M0·6 cm/sec) of Apical-Basal and Basal-Apical was calculated from the cumulative permeation amount of the compound on the receptor side, and the matrix identification of P-gp was evaluated from the ratio (Efflux Ratio). The results of the present invention were found to be the compounds of the present invention Νο·9, 16, 24, as described in Nature Re νi e ws Drug D is co νer y ( 2 0 1 0 ), Vο 1 · 9, 2 1 5-23 6 The criteria are judged as the matrix of P-gP. Is recognized method showed good brain migrating (Pharmaceutical Research (2001), Vol. 18, No. 12,1660-1668 reference). From the results, it is understood that the compound of the present invention can be expected to be effective as a drug which exerts an action on the central nervous system.

S -40- 201225955 產業上可利用性本發明化合物爲具有甘胺酸運輸體（GlyTl )阻礙活性，因次，對於與甘胺酸運輸體關連的疾病，具體爲與精神分裂症、阿茲海默病、認知功能障礙、失智症、焦慮障礙（全般性焦慮障礙、恐慌障礙、強迫性障礙、社會焦慮障礙、創傷後壓力心理障礙、特定恐懼症、急性壓力障礙等）、憂鬱症、藥物依存、痙攣、手震、疼痛、及睡眠障礙等預防或治療有效。 -41 -S -40- 201225955 INDUSTRIAL APPLICABILITY The compound of the present invention has a glycine transporter (GlyTl) inhibitory activity, and, in turn, a disease associated with a glycine transporter, specifically with schizophrenia, Azhai Silent illness, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, medication Prevention or treatment such as dependence, convulsions, hand shocks, pain, and sleep disorders are effective. -41 -

Claims

201225955 VII. Patent application scope: 1 A compound of the formula [ϊ] or a pharmaceutically acceptable salt thereof, which is of the formula [I] [Chemical Formula 1]

(wherein R1 represents a hydrogen atom or (^-6 alkyl group, and R2 represents a) may be selected from a phenyl group substituted with 1 to 5 halogen atoms, a Ci. 6 alkoxy group, a halogen atom, and a C3-6 cycloalkyl group. a group of 1 to 3 substituents substituted with a Ci.6 substituent, or b) a C3-6 cycloalkyl group, Y represents a nitrogen atom or a formula CH, and Ar is not selected from the structure of the following formula [II] ' 【化2】 Rb

Ra represents a Cu alkyl group, a halogenated Cu alkyl group, a Cu alkoxy group, a halogenated C, a 6 alkoxy group which may be substituted by a pyrrolidinyl group, a fluorine atom, a chlorine atom, or may be substituted by a halogenated C!-6 alkoxy group. Phenoxy,. Indicates a halogen atom, S - 42 - 201225955 Rb, Re, Rd, Re, Rg, Rh, and Ri represent the same or different hydrogen or halogen atoms). 2. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 represents a) a group of phenyl groups selected from alkoxy groups and substituted by 1 to 5 halogen atoms. An alkyl group substituted with 1 to 3 substituents, or b) a C3.6 cycloalkyl group, A. " represents a structure selected from the group [II], and Ra represents a halogenated alkyl group which may be substituted by a pyrrolidinyl group. a halogenated CU6 alkoxy group, or a phenoxy group which may be substituted by a halogenated C alkoxy group, Rf is a halogen atom, R°, Rd, and ... are the same or different hydrogen atoms or halogen atoms, Rb, Re, Rh, And Ri is a hydrogen atom. 3. A compound as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is C!-6 alkyl. 4. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein R2 is a Q-6 alkyl group which may be substituted by 1 to 3 Cm alkoxy groups or C3.6 cycloalkyl. 5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein r2 is a branched C3-6 alkyl group or a C3.6 cycloalkyl group. 6. A compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Υ is of formula CH. 7. If you apply for the combination of any of items 1 to 6 of the patent scope

-43- 201225955 A substance or a pharmaceutically acceptable salt thereof, wherein Ar1 is a formula [ΠΙ] [Chemical 3] Rb [丨丨丨] Rd represents a group, Ra is a halogenated Ci. 6 alkoxy group, Re, and ...is the same or a different hydrogen atom or a halogen atom, and Rb, and Re are hydrogen atoms. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient. 9- A preventive or therapeutic agent for diseases in which the diseases are schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, drug dependence, convulsions, hand shocks, pain or sleep disorders It is characterized in that it contains a compound of any one of items 1 to 7 of the patent application or a pharmaceutically acceptable salt thereof as an active ingredient. S -44 - 201225955 IV Designated representative map: (1) The designated representative circle of this case is: None. (2) A brief description of the symbol of the representative figure: None 201225955 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: Formula I

S • 4-